**Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE**

Hiroshi Hashimoto

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52044

### **1. Introduction**

Systemic lupus erythematosus (SLE), which is an inflammatory disease of unknown cause, is a representative autoimmune disease. Although SLE has multisystem organ involvement with a predilection for females, the disease varies from mild to severe and/or from active to inactive. The severity and activity of the disease affect SLE prognosis [1]. Glucocorticosteroids (steroids) have anti-inflammatory and immunosuppressive effects, although the biological effects of steroids are multiple. The anti-inflammatory effect of steroids is powerful and acts rapidly, and the immunosuppressive effect after administration of large doses of steroids is also strong. Therefore, steroids play a major and essential role in the treatment and management of SLE patients, especially those having severe and active SLE. However, the effectiveness and usefulness of steroids are limited because of their severe side effects, unresponsiveness and resistance to steroids. In these situations, additional therapies such as immunosuppressive agents or plasmapheresis, etc. are usually used in conjunction with steroids.

This paper will present clinical data related to steroid therapy from 1,125 patients with SLE who were examined and treated in Juntendo University Hospital between 1955 and 2002. It will show the benefits and risks of treatment with steroids and/or combined therapy with steroids and immunosuppressants.

### **2. Clinical presentation of 1,125 patients with SLE**

### **2.1. Clinical findings**

One thousand one hundred and twenty-five SLE patients fulfilling four or more of the revised ACR (American College of Rheumatology) criteria [2] were examined and treated at

© 2012 Hashimoto, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the Department of Internal Medicine and Rheumatology in Juntendo University School of Medicine between 1955 and 2002. In all patients, the diagnosis and treatment procedures were conducted during a period when the use of steroids and immunosuppressive agents was common. Computerized analysis of clinical manifestations, laboratory and immunological findings, treatments, complications, causes of death and prognosis was conducted.

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 483

800/1125 (71%)

99 ( 9%) 769 (68%) 133 (12%) 124 (11%) 171 (15%) 300/1125 (27%) 160 (53%) 26 ( 9%) 70 (23%) 32 (11%) 12 ( 4%) 105/953 (11%) 25/1125 ( 2%)

while pulmonary manifestations included acute lupus pneumonitis, alveolar hemorrhage, etc. Moderate disease: lupus nephritis without renal failure, pleuritis, pericarditis, meningitis, hemolytic anemia, thrombocytopenic purpura, etc. Mild disease:

PSL ≧60mg/day was used for patients with severe diseases. Pulse therapy was used for patients with severe diseases

Treatments including steroids and immunosuppressive agents are shown in Table 2. Steroids were a mainstay of treatment for SLE. Although there are several kinds of steroids, prednisolone (PSL) is commonly used to treat SLE. The initial dose of steroids was usually determined according to the severity and activity of the disease. The above severe diseases required large doses of steroids usually of 1 mg/kg/day of PSL or more. Sometimes steroid pulse therapy (methylprednisolone 0.5-1g/day, intravenously administration, for 3days) was used followed by large doses of steroids. The above moderate to mild diseases usually required 0.5-1mg/kg/day and less than 0.5mg/kg/day of PSL, respectively. When a satisfactory response was achieved, the daily dose was reduced by 5 to 10% over 2 or 3

Steroids have sometimes little or no effect because of impaired bioavailability due to reduced steroid absorption, increased steroid metabolism, induction of activating protein 1(AP-1) which is mutually antagonistic with steroid receptors for trans-activation effects [8], and insensitive steroid-mediated apoptosis of T cells [9], etc. Furthermore, steroids characteristically have a high risk of serious side effects such as infection, gastric ulcer, diabetes mellitus, osteoporosis, etc. Therefore, the effectiveness and usefulness of steroids were limited because of severe side effects, unresponsiveness and resistance to steroids. In

arthralgia/arthritis, myopathy, skin rash, etc.

PSL ≦ 39mg/day PSL 40-59mg/day PSL ≧ 60mg/day Pulse therapy Immunosuppressants azachioprine 6-mercaptoprine cyclophosphamide

no

Nonsteroidal anti-inflammatory drugs Steroids (initial dose of steroids) (n=1125)

PSL ≦39mg/day was used for patients with mild or moderate diseases. PSL 40-59mg/day was used for patients with moderate or severe diseases.

PSL:prednisolone

weeks until reaching a maintenance dose of 0.2 to 0.3mg/kg/day.

followed by large doses of steroids.

**Table 2.** Treatments of 1125 SLE patients

mizoribin others Plasmapheresis Hemodialysis

azathioprine

The distribution of age at diagnosis and the difference in gender, showing that mean age at diagnosis was 27.1 years old and the male to female ratio was 1:9. In children and adults over the age of 50, the incidence of SLE demonstrated only a slight female predominance, however, for those in their twenties, thirties and forties, close to 90% of patients were women. The frequencies of major clinical manifestations and laboratory findings from observations together with the data from other investigators [3-6] are shown in Table 1.


**Table 1.** Cumulative percentage incidence of clinical and laboratory manifestations in SLE

#### **2.2. Treatment according to disease severity**

Clinical subsets of SLE were divided into three groups according to disease severity that related to prognosis [7]. They were severe, moderate and mild diseases. Severe disease included organ-threatening conditions: lupus nephritis; rapidly progressive glomerulonephritis (RPGN), diffuse proliferative glomerulonephritis (DPGN), nephrotic syndrome, neuropsychiatric lupus (NPLE); acute confusional state or organ brain syndrome, while pulmonary manifestations included acute lupus pneumonitis, alveolar hemorrhage, etc. Moderate disease: lupus nephritis without renal failure, pleuritis, pericarditis, meningitis, hemolytic anemia, thrombocytopenic purpura, etc. Mild disease: arthralgia/arthritis, myopathy, skin rash, etc.


PSL:prednisolone

PSL ≦39mg/day was used for patients with mild or moderate diseases.

PSL 40-59mg/day was used for patients with moderate or severe diseases.

PSL ≧60mg/day was used for patients with severe diseases. Pulse therapy was used for patients with severe diseases followed by large doses of steroids.

**Table 2.** Treatments of 1125 SLE patients

482 Glucocorticoids – New Recognition of Our Familiar Friend

conducted.

the Department of Internal Medicine and Rheumatology in Juntendo University School of Medicine between 1955 and 2002. In all patients, the diagnosis and treatment procedures were conducted during a period when the use of steroids and immunosuppressive agents was common. Computerized analysis of clinical manifestations, laboratory and immunological findings, treatments, complications, causes of death and prognosis was

The distribution of age at diagnosis and the difference in gender, showing that mean age at diagnosis was 27.1 years old and the male to female ratio was 1:9. In children and adults over the age of 50, the incidence of SLE demonstrated only a slight female predominance, however, for those in their twenties, thirties and forties, close to 90% of patients were women. The frequencies of major clinical manifestations and laboratory findings from observations together with the data from other investigators [3-6] are shown in Table 1.

**Table 1.** Cumulative percentage incidence of clinical and laboratory manifestations in SLE

Clinical subsets of SLE were divided into three groups according to disease severity that related to prognosis [7]. They were severe, moderate and mild diseases. Severe disease included organ-threatening conditions: lupus nephritis; rapidly progressive glomerulonephritis (RPGN), diffuse proliferative glomerulonephritis (DPGN), nephrotic syndrome, neuropsychiatric lupus (NPLE); acute confusional state or organ brain syndrome,

**2.2. Treatment according to disease severity** 

Treatments including steroids and immunosuppressive agents are shown in Table 2. Steroids were a mainstay of treatment for SLE. Although there are several kinds of steroids, prednisolone (PSL) is commonly used to treat SLE. The initial dose of steroids was usually determined according to the severity and activity of the disease. The above severe diseases required large doses of steroids usually of 1 mg/kg/day of PSL or more. Sometimes steroid pulse therapy (methylprednisolone 0.5-1g/day, intravenously administration, for 3days) was used followed by large doses of steroids. The above moderate to mild diseases usually required 0.5-1mg/kg/day and less than 0.5mg/kg/day of PSL, respectively. When a satisfactory response was achieved, the daily dose was reduced by 5 to 10% over 2 or 3 weeks until reaching a maintenance dose of 0.2 to 0.3mg/kg/day.

Steroids have sometimes little or no effect because of impaired bioavailability due to reduced steroid absorption, increased steroid metabolism, induction of activating protein 1(AP-1) which is mutually antagonistic with steroid receptors for trans-activation effects [8], and insensitive steroid-mediated apoptosis of T cells [9], etc. Furthermore, steroids characteristically have a high risk of serious side effects such as infection, gastric ulcer, diabetes mellitus, osteoporosis, etc. Therefore, the effectiveness and usefulness of steroids were limited because of severe side effects, unresponsiveness and resistance to steroids. In these situations, immunosuppressive agents such as cyclophosphamide, azathioprine, mizoribine, tacrolimus and/or plasmapheresis or other innovative therapies were usually used in conjunction with steroids. Recently, belimumab (anti-BLyS antibody), the first targeted biological drug, was approved for treatment of SLE by the FDA [10]. Targeted biological and small-molecule therapies in SLE are going to begin to take the place of steroids that have been used as the major drug in SLE for more than 50 years.

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 485

(%) (23) (16) (16) (25) (18) (12)

(%) (16) (84) (45) (37) (17) (95) (74) (62) (41)

The available therapeutic procedures include steroids, immunosuppressive agents, plasmapheresis, anticoagulants and hemodialysis, etc. Steroids were the first choice for treatment of LN. However, doses of steroids were determined according to urinary findings, renal function and renal histopathological findings evaluating the activity and severity of LN. The patients with active and /or severe LN, including persistent or profuse proteinuria, renal dysfunction, DPGN of type IV, rapidly progressive glomerulonephritis (RPGN) or MGN of Type V in conjunction with low serum complement levels and high titers of antidsDNA antibodies, were initially treated with large doses of steroids (PSL 1-1.5mg/kg/day) as induction therapy for remission. Steroid pulse therapy was often administered at first. It led to more rapid recovery which might be result of a rapid nongenomic physicochemical effect. The patients with intermittent proteinuria, abnormal urine sediments, and Type II or III, were initially treated with PSL less than 0.5-1mg/kg/day. After PSL administration for 3- 6 weeks, the dosage of PSL was then reduced by nearly 10% every 2–3 weeks according to the improvement in proteinuria, urinary sediments, abnormal renal function, low serum complement levels and high titers of anti-dsDNA antibodies. If PSL had no or incomplete response, the dosage was increased by 20% or steroid pulse therapy was conducted again. In the patients with DPGN or RPGN, intravenous pulse therapy of cyclophosphamide (IVCY) (500-750mg, monthly for 3 to 6 months), as immunosuppressive agent, was used. Alternative induction therapies included combined therapies with steroids and immunosuppressive agents such as daily oral cyclophosphamide, azathioprine, tacrorimus, mizoribine, and cyclosporine, etc. If an incomplete response after 2 months treatment with

**Table 3.** Lupus nephritis in 1125 cases

VI. Advanced

A. Urinalysis, Renal function No proteinuria Proteinuria Intermittent Persistent

Profuse (>3.5g/day)

II. Mesagial alteration

B. Histopathological findings (WHO classification) I. Minimal change (MC) or Normal

III. Focal segmental glomerulonephritis (FGN) IV. Diffuse proliferative glomerulonephritis (DPGN) V. Membranous glomerulonephritis (MGN)

Microhematuria Urine casts Elevated BUN Elevated S-creatinine

*3.1.2. Treatment of LN* 

#### **2.3. Prognosis and causes of death**

In this paper, the survival rate was 93% at 5years, 89% at 10years and 69% at 20years after diagnosis. One hundred and fifty-one out of 1,125 patients (13%) died. The causes of death were renal failure (30%), cerebrovascular diseases (23%), infection (19%), and others. Infections which led to causes of death included sepsis or bacteremia due to E. coli, methicillin resistant Staphylococcus aureus (MRSA), candidiasis, asprgilosis, Klebsiella, Pseudomonas, etc., and tuberculosis, pneumocyctis carini pneumonia, Cryptococcus meningitis, listeria meningitis, cytomegalovirus infection, etc. In the last 2 or 3 decades it has been noted that the prognosis of SLE has improved [11-13]. Changes in the mortality rate in accordance with the cause of death in SLE patients were also observed, showing a significant reduction in death due to renal failure.

### **3. Steroid therapy in principal organ involvement in SLE**

#### **3.1. Lupus nephritis (LN)**

#### *3.1.1. Clinical analysis of LN*

LN is one of the diseases influencing the prognosis of SLE. The diseases of LN vary from mild to severe and from active to inactive. The clinical pictures of LN and the types of the World Health Organization (WHO) classification according to histopathological findings [14]in this study are shown in Table 3.

Persistent proteinuria of more than 0.2g/day and less than 3.5g/day was observed in approximately 37% of cases and profuse proteinuria of more than 3.5g per day was observed in approximately 17% of cases. Patients without proteinuria accounted for 16%. Abnormal urinary sediments including erythrocytes, leukocytes and casts were observed frequently. An increasing serum creatinine level was observed in 41% of cases. The WHO classification according to histopahological findings of LN by renal biopsy was used in this study, although the classification of LN by the International Nephrology/Renal Pathology Society (ISN/RPS) was proposed in 2003[15]. Diffuse proliferative glomerulonephritis (DPGN) of Type IV, which has a poor prognosis, could be seen in 55 of 216 cases (25%), which underwent renal biopsy. Membranous glomerulonephritis (MGN) of Type V characteristic of nephrotic syndrome, was observed in 18% of cases. Types I and II, which are thought to have better prognosis, were observed in 23% and 16% of cases, respectively. Advanced Type VI, which indicates end stage GN, could be seen in 12% of cases.



#### *3.1.2. Treatment of LN*

484 Glucocorticoids – New Recognition of Our Familiar Friend

**2.3. Prognosis and causes of death** 

significant reduction in death due to renal failure.

**3.1. Lupus nephritis (LN)** 

*3.1.1. Clinical analysis of LN* 

[14]in this study are shown in Table 3.

these situations, immunosuppressive agents such as cyclophosphamide, azathioprine, mizoribine, tacrolimus and/or plasmapheresis or other innovative therapies were usually used in conjunction with steroids. Recently, belimumab (anti-BLyS antibody), the first targeted biological drug, was approved for treatment of SLE by the FDA [10]. Targeted biological and small-molecule therapies in SLE are going to begin to take the place of

In this paper, the survival rate was 93% at 5years, 89% at 10years and 69% at 20years after diagnosis. One hundred and fifty-one out of 1,125 patients (13%) died. The causes of death were renal failure (30%), cerebrovascular diseases (23%), infection (19%), and others. Infections which led to causes of death included sepsis or bacteremia due to E. coli, methicillin resistant Staphylococcus aureus (MRSA), candidiasis, asprgilosis, Klebsiella, Pseudomonas, etc., and tuberculosis, pneumocyctis carini pneumonia, Cryptococcus meningitis, listeria meningitis, cytomegalovirus infection, etc. In the last 2 or 3 decades it has been noted that the prognosis of SLE has improved [11-13]. Changes in the mortality rate in accordance with the cause of death in SLE patients were also observed, showing a

LN is one of the diseases influencing the prognosis of SLE. The diseases of LN vary from mild to severe and from active to inactive. The clinical pictures of LN and the types of the World Health Organization (WHO) classification according to histopathological findings

Persistent proteinuria of more than 0.2g/day and less than 3.5g/day was observed in approximately 37% of cases and profuse proteinuria of more than 3.5g per day was observed in approximately 17% of cases. Patients without proteinuria accounted for 16%. Abnormal urinary sediments including erythrocytes, leukocytes and casts were observed frequently. An increasing serum creatinine level was observed in 41% of cases. The WHO classification according to histopahological findings of LN by renal biopsy was used in this study, although the classification of LN by the International Nephrology/Renal Pathology Society (ISN/RPS) was proposed in 2003[15]. Diffuse proliferative glomerulonephritis (DPGN) of Type IV, which has a poor prognosis, could be seen in 55 of 216 cases (25%), which underwent renal biopsy. Membranous glomerulonephritis (MGN) of Type V characteristic of nephrotic syndrome, was observed in 18% of cases. Types I and II, which are thought to have better prognosis, were observed in 23% and 16% of cases, respectively.

Advanced Type VI, which indicates end stage GN, could be seen in 12% of cases.

steroids that have been used as the major drug in SLE for more than 50 years.

**3. Steroid therapy in principal organ involvement in SLE** 

The available therapeutic procedures include steroids, immunosuppressive agents, plasmapheresis, anticoagulants and hemodialysis, etc. Steroids were the first choice for treatment of LN. However, doses of steroids were determined according to urinary findings, renal function and renal histopathological findings evaluating the activity and severity of LN. The patients with active and /or severe LN, including persistent or profuse proteinuria, renal dysfunction, DPGN of type IV, rapidly progressive glomerulonephritis (RPGN) or MGN of Type V in conjunction with low serum complement levels and high titers of antidsDNA antibodies, were initially treated with large doses of steroids (PSL 1-1.5mg/kg/day) as induction therapy for remission. Steroid pulse therapy was often administered at first. It led to more rapid recovery which might be result of a rapid nongenomic physicochemical effect. The patients with intermittent proteinuria, abnormal urine sediments, and Type II or III, were initially treated with PSL less than 0.5-1mg/kg/day. After PSL administration for 3- 6 weeks, the dosage of PSL was then reduced by nearly 10% every 2–3 weeks according to the improvement in proteinuria, urinary sediments, abnormal renal function, low serum complement levels and high titers of anti-dsDNA antibodies. If PSL had no or incomplete response, the dosage was increased by 20% or steroid pulse therapy was conducted again. In the patients with DPGN or RPGN, intravenous pulse therapy of cyclophosphamide (IVCY) (500-750mg, monthly for 3 to 6 months), as immunosuppressive agent, was used. Alternative induction therapies included combined therapies with steroids and immunosuppressive agents such as daily oral cyclophosphamide, azathioprine, tacrorimus, mizoribine, and cyclosporine, etc. If an incomplete response after 2 months treatment with PSL alone was also observed, immunosuppressant agents were administered in addition to PSL. If the patients had high titers of anti-dsDNA antibodies and/or immune complexes, plasmapheresis was conducted in conjunction with the above steroid and immunosuppressant agent treatment. In patients who achieved remission showing less than 0.5g/day of proteinuria, inactive urine sediment, normal complement levels and /or quiescent extrarenal lupus activity, they continued maintenance treatment with a maintenance dosage of steroids of PSL 5–15mg/day. Thereafter, the PSL dosage was tapered to discontinuance in an extremely gradual manner.

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 487

the disease, but no decrease in the remission rate was observed until later on. Furthermore, in the outcome of 32 patients who were treated over the long-term for over 20 years, the complete remission rate was 27%, the incomplete remission rate was 37.8%, and the worsening rate was 21.6 %. As for the treatments used, those that contributed to remission could not be specified. This fact suggests that the underlying disease types had a greater

The frequencies of various neuropsychiatric manifestations of SLE (NPLE) have been reported to vary from 28 to 59%. In our study, NPLE could be observed in 47.6% of 1,125

**Table 4.** Frequencies of neuropsychiatric manifestations (NPLE) in 1125 lupus patients

aseptic meningitis, headache, and peripheral neuropathy, etc.

The American College of Rheumatology (ACR) proposed new criteria for the classification of neuropsychiatric syndrome of systemic lupus erythematosus (NPSLE) in 1999 [16]. NPLE is divided into psychiatric and neurological manifestations. The frequency of psychiatric manifestations was higher than that of neurological manifestations. The former included acute confusional state or organ brain syndrome, cognitive dysfunction, anxiety disorders and psychosis, etc., while the latter included seizure, cerebrovascular disease, myelopathy,

Although no single pathogenetic process could explain all these manifestations, it was assumed that other potential causes of these manifestations, such as side effects from treatment, complications including infections, etc., had been excluded except for causes due to lupus itself. Many NPLE cases were considered to be caused by lupus itself, excluding obvious causes such as antiphospholipid antibody syndrome (APS), necrotizing angiitis,

influence on the remission rate than the treatment method.

**3.2. Neuropsychiatric manifestations of SLE (NPLE)** 

*3.2.1. Clinical analysis of NPLE* 

cases as shown in Table 4.

and complications.

#### *3.1.3. Outcome and prognosis of LN*

During the past half century, the prognosis of SLE has significantly improved. One of the major factors in this improvement is the significant reduction in renal death. This is assumed to be partially due to early diagnosis and early treatment with the development of diagnostic procedures, as well as the development of treatments including the implementation of hemodialysis [1,11-13]. However, the remission rate of lupus nephritis was not so high.

**Figure 1.** Remission rate of lupus nephritis according the WHO classification type and degree of proteinuria

Figure 1 shows the remission rate after onset according to the WHO classification type and degree of proteinuria. The remission rates of patients with Type IV (DPGN) and profuse peroteiniria or nephrotic syndrome tended to decrease during the course of the disease, while the remission rates of patients with Type II and persistent proteinuria tended to increase. Patients with Type V (MGN) had a low remission rate through out the course of the disease, but no decrease in the remission rate was observed until later on. Furthermore, in the outcome of 32 patients who were treated over the long-term for over 20 years, the complete remission rate was 27%, the incomplete remission rate was 37.8%, and the worsening rate was 21.6 %. As for the treatments used, those that contributed to remission could not be specified. This fact suggests that the underlying disease types had a greater influence on the remission rate than the treatment method.

#### **3.2. Neuropsychiatric manifestations of SLE (NPLE)**

#### *3.2.1. Clinical analysis of NPLE*

486 Glucocorticoids – New Recognition of Our Familiar Friend

to discontinuance in an extremely gradual manner.

*3.1.3. Outcome and prognosis of LN* 

was not so high.

proteinuria

PSL alone was also observed, immunosuppressant agents were administered in addition to PSL. If the patients had high titers of anti-dsDNA antibodies and/or immune complexes, plasmapheresis was conducted in conjunction with the above steroid and immunosuppressant agent treatment. In patients who achieved remission showing less than 0.5g/day of proteinuria, inactive urine sediment, normal complement levels and /or quiescent extrarenal lupus activity, they continued maintenance treatment with a maintenance dosage of steroids of PSL 5–15mg/day. Thereafter, the PSL dosage was tapered

During the past half century, the prognosis of SLE has significantly improved. One of the major factors in this improvement is the significant reduction in renal death. This is assumed to be partially due to early diagnosis and early treatment with the development of diagnostic procedures, as well as the development of treatments including the implementation of hemodialysis [1,11-13]. However, the remission rate of lupus nephritis

**Figure 1.** Remission rate of lupus nephritis according the WHO classification type and degree of

Figure 1 shows the remission rate after onset according to the WHO classification type and degree of proteinuria. The remission rates of patients with Type IV (DPGN) and profuse peroteiniria or nephrotic syndrome tended to decrease during the course of the disease, while the remission rates of patients with Type II and persistent proteinuria tended to increase. Patients with Type V (MGN) had a low remission rate through out the course of The frequencies of various neuropsychiatric manifestations of SLE (NPLE) have been reported to vary from 28 to 59%. In our study, NPLE could be observed in 47.6% of 1,125 cases as shown in Table 4.


**Table 4.** Frequencies of neuropsychiatric manifestations (NPLE) in 1125 lupus patients

The American College of Rheumatology (ACR) proposed new criteria for the classification of neuropsychiatric syndrome of systemic lupus erythematosus (NPSLE) in 1999 [16]. NPLE is divided into psychiatric and neurological manifestations. The frequency of psychiatric manifestations was higher than that of neurological manifestations. The former included acute confusional state or organ brain syndrome, cognitive dysfunction, anxiety disorders and psychosis, etc., while the latter included seizure, cerebrovascular disease, myelopathy, aseptic meningitis, headache, and peripheral neuropathy, etc.

Although no single pathogenetic process could explain all these manifestations, it was assumed that other potential causes of these manifestations, such as side effects from treatment, complications including infections, etc., had been excluded except for causes due to lupus itself. Many NPLE cases were considered to be caused by lupus itself, excluding obvious causes such as antiphospholipid antibody syndrome (APS), necrotizing angiitis, and complications.

NPLE is one of the diseases that influence the prognosis of SLE as well as LN. Especially, patients with acute confusional state or organ brain syndrome (OBS), cognitive dysfunction, recurrent seizure, and cerebrovascular disease, etc., had poor prognosis. Acute OBS exhibits characteristic malfunctions such as consciousness disorders (i.e. delirium), disorientation, memory disorders, and cognitive dysfunction. Acute OBS showed an 85% correlation with SLE activity and exacerbation, which was greater than that of the psychiatric illness group (57%) and the psychosyndrome group (23%) [17].

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 489

and recurrent convulsive seizures were treated with high steroid doses (PSL l–2 mg/kg/day) in conjunction with steroid pulse therapy. However, when improvement could not be seen within 48 hours after treatment, 250 to 500mg of hydrocortone was administered every 12 hours. If improvement could not be seen after treatment of steroids alone, IVCP pulse therapy or oral administration of CP in conjunction with steroids and/or plasmapheresis was given.

When signs of clinical manifestations were stable for more than 6 weeks and acute phase reactants or tests of organ function were improved or stable for 6 weeks, the dose of PSL was reduced by approximately 10 to 20% every two weeks. When the dose of PSL reached

When the patients showed panic or marked agitation and their hallucinations and delusions were threatening, several antipsychotic drugs in conjunction with steroids were also used.

Almost all patients with NPLE improved after immunosuppressive therapies including

1996.7 12 1997.3 4 5 6 7 8 9 10

x 640 (homogeneous) x 40

6300 (599)

6900 (1518)

6700 (503)

7.7 8.3 17.5 12.6 16.7 3.0 0.4 <0.3 **<0.3** <0.3 30.3 48.3 45.7 48.5 1.0 1.4 1.9 1.0

<sup>80</sup> 75 70 <sup>65</sup> 60 55 <sup>50</sup> <sup>45</sup> <sup>40</sup> <sup>35</sup> <sup>30</sup>

+

+

② EEG; θwave

plasmapheresis (anti-lymphocyte antibody )

① EEG;θwave

discharge

(anti-lymphocyte antibody ) ±

+

mPSL 500mg x 3days

PSL (mg/day)

onset admission

**Figure 2.** The clinical course of SLE patient (46 years old, female) with organic brain syndrome (OBS)

5.8 2.1 2800 (672)

2400 (192)

0.64 0.58

PSL: prednisolone, mPSL: methylprednisolone, EEG: electroencephalogram, CSF: cerebrospinal fluid.

about 15mg/day, it was slowly tapered and reduced by 1mg every week.

steroids, immunosuppressive drugs and /or plasmapheresis.

*3.2.3. Outcome and prognosis of NPLE* 

fever

Platelet (x 104/µL) CRP (mg/dL) CH50 (20-50/mL)

unconsciousness, delirium disturbance of articulation mood disorder, depression antinuclear antibody proteinuria (g/day)

White blood cells (lymphocytes)(/µL)

anti DNA antibody (<7.0 IU/mL) CSF IgG index (<0.76)

malar rash eruption

Although acute OBS was correlated with active SLE lesions, correlations with high titers of anti-dsDNA antibodies and low complement levels, which were seen in active LN, were not necessarily observed. Serologically, acute OBS correlated with the serum anti-liposomal P antibody, interferon α and IL-6 in cerebrospinal fluid (CSF) [18-19].

On the other hand, acute neurologic syndrome has been reported to correlate with the antiasialo GM1 antibody, anti-liposomal P antibody, anti-lymphocyte antibody, and antineurocyte antibody, as well as the anti-PCNA antibody and anti-Sm antibody [7,20].

Psychiatric symptoms often required differentiation from steroidal psychiatric symptoms. Differentiation from secondary psychiatric symptoms due to uremia and/or infection was also important. Although quite a number of cases were difficult to determine, the following information might have been helpful:


The evaluation of NPLE should always include an assessment of whether SLE is active or not. In addition, patients with both focal and diffuse syndromes should have various examinations including CSF, electroencephalogram (EEG), and an imaging studies (such as computed tomography (CT) and magnetic resonance imaging (MRI)), cerebral blood flow by angiography or single photon emission computerized tomography (SPECT), etc. The more serious the NPLE, the more aggressive immunosuppressive therapy, including steroids, is needed.

#### *3.2.2. Treatment of NPLE*

If NPLE was active and there was severe major organ involvement, steroid therapy was indicated. In particular, patients with an acute confusional state or organic brain syndrome, and recurrent convulsive seizures were treated with high steroid doses (PSL l–2 mg/kg/day) in conjunction with steroid pulse therapy. However, when improvement could not be seen within 48 hours after treatment, 250 to 500mg of hydrocortone was administered every 12 hours. If improvement could not be seen after treatment of steroids alone, IVCP pulse therapy or oral administration of CP in conjunction with steroids and/or plasmapheresis was given.

When signs of clinical manifestations were stable for more than 6 weeks and acute phase reactants or tests of organ function were improved or stable for 6 weeks, the dose of PSL was reduced by approximately 10 to 20% every two weeks. When the dose of PSL reached about 15mg/day, it was slowly tapered and reduced by 1mg every week.

When the patients showed panic or marked agitation and their hallucinations and delusions were threatening, several antipsychotic drugs in conjunction with steroids were also used.

#### *3.2.3. Outcome and prognosis of NPLE*

488 Glucocorticoids – New Recognition of Our Familiar Friend

(57%) and the psychosyndrome group (23%) [17].

information might have been helpful:

and confusion.

*3.2.2. Treatment of NPLE* 

less than that of lupus-induced psychosis [21].

when over 40mg/day of PSL is administered [22].

antibody, interferon α and IL-6 in cerebrospinal fluid (CSF) [18-19].

NPLE is one of the diseases that influence the prognosis of SLE as well as LN. Especially, patients with acute confusional state or organ brain syndrome (OBS), cognitive dysfunction, recurrent seizure, and cerebrovascular disease, etc., had poor prognosis. Acute OBS exhibits characteristic malfunctions such as consciousness disorders (i.e. delirium), disorientation, memory disorders, and cognitive dysfunction. Acute OBS showed an 85% correlation with SLE activity and exacerbation, which was greater than that of the psychiatric illness group

Although acute OBS was correlated with active SLE lesions, correlations with high titers of anti-dsDNA antibodies and low complement levels, which were seen in active LN, were not necessarily observed. Serologically, acute OBS correlated with the serum anti-liposomal P

On the other hand, acute neurologic syndrome has been reported to correlate with the antiasialo GM1 antibody, anti-liposomal P antibody, anti-lymphocyte antibody, and anti-

Psychiatric symptoms often required differentiation from steroidal psychiatric symptoms. Differentiation from secondary psychiatric symptoms due to uremia and/or infection was also important. Although quite a number of cases were difficult to determine, the following

a. The actual incidence of steroid-induced psychosis is small, probably about 5%, which is

b. The psychiatric side effects of steroids include, most commonly, mild to moderate mood changes such euphoria, sleeplessness, or depression rather than unconsciousness disorders, although there are also perceptual changes, hallucinations, anxiety, insomnia

c. Steroid-induced psychosis appears half a month to one month after administration of steroids. It has been reported that the incidence of steroid-induced psychosis increases

d. Although lupus psychosis may not always be improved by increasing of the dosage of PSL, deterioration of lupus psychosis after increasing the dosage of PSL is rare.

The evaluation of NPLE should always include an assessment of whether SLE is active or not. In addition, patients with both focal and diffuse syndromes should have various examinations including CSF, electroencephalogram (EEG), and an imaging studies (such as computed tomography (CT) and magnetic resonance imaging (MRI)), cerebral blood flow by angiography or single photon emission computerized tomography (SPECT), etc. The more serious the NPLE,

If NPLE was active and there was severe major organ involvement, steroid therapy was indicated. In particular, patients with an acute confusional state or organic brain syndrome,

e. High levels of IgG index and IL-6 in CSF can be seen in lupus psychosis [23].

the more aggressive immunosuppressive therapy, including steroids, is needed.

neurocyte antibody, as well as the anti-PCNA antibody and anti-Sm antibody [7,20].

Almost all patients with NPLE improved after immunosuppressive therapies including steroids, immunosuppressive drugs and /or plasmapheresis.


PSL: prednisolone, mPSL: methylprednisolone, EEG: electroencephalogram, CSF: cerebrospinal fluid.

**Figure 2.** The clinical course of SLE patient (46 years old, female) with organic brain syndrome (OBS)

Figure 2 shows the clinical course of an SLE patient with OBS who was a 46-year old female. She was diagnosed as SLE with malar rash, eruption, leucopenia, thrombocytopenia, proteinuria and positive anti-nuclear antibodies, etc. in March 1997. In April 1997, she had recurrent unconsciousness with delirium, disturbance of articulation with high fever and a worsening malar rash. Although anti-DNA antibodies and low complemetemia could not be seen, she was diagnosed as OBS or acute confusional state and treatment with steroid pulse therapy followed by a PSL dose of 80mg/day. Plasmapheresis was also conducted to remove anti-lymphocyte antibodies. Although mood disorder and depression were observed in August, 1997, her disease improved without increasing doses of steroids or additional treatment with immunosuppressive agents.

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 491

3 patients died of pulmonary hemorrhage despite combined therapy with steroid and

Chronic interstitial pneumonitis in SLE is also rare, showing a low frequency of 3-5%. Six patients with chronic interstitial pneumonitis were observed in this study and they were treated with maintenance therapies including low doses of steroids and/or immunosuppressant agents. In one patient, chronic interstitial pneumonitis deteriorated to acute interstitial pneumonitis during the course of the disease and a large dose of steroids

Alveolar hemorrhage in SLE is relatively rare, and it has been reported to occur in 1.4–1.7%

It is a serious complication and results in poor prognosis. It was observed in 8 out of 1,125

SLE patients with alveolar hemorrhage had hemoptysis and hypoxemia and rapid

All patients with alveolar hemorrhage were treated with steroid pulse therapy following large doses of PSL, but it was also necessary to concomitantly use other immunosuppressive tharapies such as cyclophosphamide including IVCY, and plasmapheresis. Unfortunately, all of the patients with alveolar hemorrhage died, comfirming that the prognosis was very poor.

The most common cardiac abnormality was pericarditis, which occured in 8-25% [27], but it was relatively rare in Japan, with a frequency of 7% (47 out of 1,125cases) in this study. Pericarditis is often one of the first manifestations. Most of the cases with pericarditis improved with administration of PSL 0.5–1 mg/day, but cases with cardiac tamponade, which was rare in this study, needed large doses of PSL over 1mg/day and/or steroid pulse

Myocarditis was rarely observed in 2% in this study. In cases with myocarditis, positive CRP, elevated CK, IgG class anti-dsDNA antibodies, hematuria, etc., in conjunction with tachycardia, cardiac enlargement, congestive heart failure could often be observed. A myocardial biopsy was performed in order to confirm the diagnosis in one patient. The patients with myocarditis associated with congestive heart failure were treated with largedose administration of steroids (PSL l–1.5 mg/kg/day, divided into 3~4 dosages). All of the

patients with myocarditis improved after steroid therapy.

progression of anemia in conjunction with active LN and/or NSLE disease.

immunosuppressant agents and /or plasmapheresis.

of SLE patients in Europe and the United States [26].

was needed

*3.3.3. Alveolar hemorrhage* 

patients (0.7%) in this study.

**3.4. Cardiac manifestations** 

*3.4.1. Pericarditis* 

*3.4.2. Myocarditis* 

therapy.

As for prognosis of lupus patients with NPLE according to the different treatment, patients treated with combined therapy of steroid pulse therapy and other therapies was significantly more favorable than those treated with steroids alone (PSL>40mg/day) and those treated with combined therapy of immunosuppressive agents and steroids.

#### **3.3. Pulmonary manifestations**

#### *3.3.1. Pleuritis*

Pleuritis is by far the most common pulmonary manifestation, occurring at some time in the course in 40 to 50% of lupus patients. However, the frequency of pleuritis in Japanese SLE patiens was lower than that in European countries and the United States. The frequency of pleuritis was 11% in this study. . Clinically, fever, chest pain, cough, dyspnea etc. could be seen in patients with pleuritis. On chest X-rays, slight to moderate pleural effusion caused by pleural inflammation could be observed bilaterally in approximately half of cases.

Pleuritis mostly improved after administration of PSL (20-40mg/day). However, in cases with a large amount of pleural effusion , thoracic drainage was needed.

#### *3.3.2. Interstitial pneumonitis*

Lupus pneumonitis is classified as acute lupus pneumonitis and chronic interstitial pneumonitis/pulmonary fibrosis. Acute lupus pneumonitis was relatively rare with an occurrence of 0.5–11.7% [24-25]. It was observed in 6 of 1,125 patients (0.5%) in this study. As clinical symptoms, fever, chest pain, dry cough, severe dyspnea, and occasional hemoptysis were noted. Bibasilar Velcro rales were noted in all instances. The majority of patients were hypoxic, requiring supplemental oxygen or intubation for assisted ventilation. Acute lupus pneumonitis was diagnosed by several examinations including X-ray, CT scan, KL-6 and/or SP-D as biomarkers, and various kinds of infectious examination to exclude infectious diseases.

All 6 patients with acute lupus pneumonitis were treated with steroid pulse therapy following 1-2mg/kg/day of PSL. Half of the patients drastically improved, but the remaining 3 patients died of pulmonary hemorrhage despite combined therapy with steroid and immunosuppressant agents and /or plasmapheresis.

Chronic interstitial pneumonitis in SLE is also rare, showing a low frequency of 3-5%. Six patients with chronic interstitial pneumonitis were observed in this study and they were treated with maintenance therapies including low doses of steroids and/or immunosuppressant agents. In one patient, chronic interstitial pneumonitis deteriorated to acute interstitial pneumonitis during the course of the disease and a large dose of steroids was needed

### *3.3.3. Alveolar hemorrhage*

490 Glucocorticoids – New Recognition of Our Familiar Friend

treatment with immunosuppressive agents.

**3.3. Pulmonary manifestations** 

*3.3.2. Interstitial pneumonitis* 

infectious diseases.

*3.3.1. Pleuritis* 

Figure 2 shows the clinical course of an SLE patient with OBS who was a 46-year old female. She was diagnosed as SLE with malar rash, eruption, leucopenia, thrombocytopenia, proteinuria and positive anti-nuclear antibodies, etc. in March 1997. In April 1997, she had recurrent unconsciousness with delirium, disturbance of articulation with high fever and a worsening malar rash. Although anti-DNA antibodies and low complemetemia could not be seen, she was diagnosed as OBS or acute confusional state and treatment with steroid pulse therapy followed by a PSL dose of 80mg/day. Plasmapheresis was also conducted to remove anti-lymphocyte antibodies. Although mood disorder and depression were observed in August, 1997, her disease improved without increasing doses of steroids or additional

As for prognosis of lupus patients with NPLE according to the different treatment, patients treated with combined therapy of steroid pulse therapy and other therapies was significantly more favorable than those treated with steroids alone (PSL>40mg/day) and

Pleuritis is by far the most common pulmonary manifestation, occurring at some time in the course in 40 to 50% of lupus patients. However, the frequency of pleuritis in Japanese SLE patiens was lower than that in European countries and the United States. The frequency of pleuritis was 11% in this study. . Clinically, fever, chest pain, cough, dyspnea etc. could be seen in patients with pleuritis. On chest X-rays, slight to moderate pleural effusion caused

Pleuritis mostly improved after administration of PSL (20-40mg/day). However, in cases

Lupus pneumonitis is classified as acute lupus pneumonitis and chronic interstitial pneumonitis/pulmonary fibrosis. Acute lupus pneumonitis was relatively rare with an occurrence of 0.5–11.7% [24-25]. It was observed in 6 of 1,125 patients (0.5%) in this study. As clinical symptoms, fever, chest pain, dry cough, severe dyspnea, and occasional hemoptysis were noted. Bibasilar Velcro rales were noted in all instances. The majority of patients were hypoxic, requiring supplemental oxygen or intubation for assisted ventilation. Acute lupus pneumonitis was diagnosed by several examinations including X-ray, CT scan, KL-6 and/or SP-D as biomarkers, and various kinds of infectious examination to exclude

All 6 patients with acute lupus pneumonitis were treated with steroid pulse therapy following 1-2mg/kg/day of PSL. Half of the patients drastically improved, but the remaining

by pleural inflammation could be observed bilaterally in approximately half of cases.

with a large amount of pleural effusion , thoracic drainage was needed.

those treated with combined therapy of immunosuppressive agents and steroids.

Alveolar hemorrhage in SLE is relatively rare, and it has been reported to occur in 1.4–1.7% of SLE patients in Europe and the United States [26].

It is a serious complication and results in poor prognosis. It was observed in 8 out of 1,125 patients (0.7%) in this study.

SLE patients with alveolar hemorrhage had hemoptysis and hypoxemia and rapid progression of anemia in conjunction with active LN and/or NSLE disease.

All patients with alveolar hemorrhage were treated with steroid pulse therapy following large doses of PSL, but it was also necessary to concomitantly use other immunosuppressive tharapies such as cyclophosphamide including IVCY, and plasmapheresis. Unfortunately, all of the patients with alveolar hemorrhage died, comfirming that the prognosis was very poor.

### **3.4. Cardiac manifestations**

#### *3.4.1. Pericarditis*

The most common cardiac abnormality was pericarditis, which occured in 8-25% [27], but it was relatively rare in Japan, with a frequency of 7% (47 out of 1,125cases) in this study. Pericarditis is often one of the first manifestations. Most of the cases with pericarditis improved with administration of PSL 0.5–1 mg/day, but cases with cardiac tamponade, which was rare in this study, needed large doses of PSL over 1mg/day and/or steroid pulse therapy.

#### *3.4.2. Myocarditis*

Myocarditis was rarely observed in 2% in this study. In cases with myocarditis, positive CRP, elevated CK, IgG class anti-dsDNA antibodies, hematuria, etc., in conjunction with tachycardia, cardiac enlargement, congestive heart failure could often be observed. A myocardial biopsy was performed in order to confirm the diagnosis in one patient. The patients with myocarditis associated with congestive heart failure were treated with largedose administration of steroids (PSL l–1.5 mg/kg/day, divided into 3~4 dosages). All of the patients with myocarditis improved after steroid therapy.

### *3.4.3. Myocardial infarction and coronary artery disease*

Coronary artery disease due to arteriosclerotic changes is more common in SLE patients. Death from myocardial infarction late in the course of the disease is one of the most frequent causes of death after 10 to 30 years of SLE [28]. Eleven lupus patients with myocardial infarction could be seen in this study. The average age at diagnosis of SLE was 37 years old (26–63 years old), and the average age at development of myocardial infarction was 51 years old (41–66 years old) in these patients. There were two death cases, including one case of death from cardiac rupture.

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 493

leukocytopenia, lymphocytopenia, thrombocytopenia, thrombocytopenic purpura (TP), thrombotic thrombocytopenic purpura (TTP), and antiphosphlipid syndrome (APS), etc.

AIHA was observed in 11% of patients in this study. AIHA is rare in Japanese SLE patients in comparison to those in Europe and the United States. Steroids were the mainstay of the treatment for AIHA and a response was achieved in about 75% of patients. PSL was given initially at a dose of 1.0 to1.5mg/kg and continued at that level for at least 4 to 6 weeks. Following a satisfactory response, the dose was reduced gradually by 10% every week. The reticlocyte count was a reliable indicator of both responsiveness to treatment and relapse. In cases of severe fulminant hemolysis, steroid pulse therapy was conducted. Patients with AIHA who failed to respond to steroids were treated with immunosuppressant agents and/or splenectomy. Plasmapheresis, high-dose intravenous gammagloburin therapy (IVIg),

Thrombocytopenia lower than 150,000 was observed in 34% of cases in this study. However, thrombocytopenia lower than 50,000 was relatively rare, and it occured in approximately 10% of cases. Thrombocytopenia in SLE is usually due to antiplatelet autoantibodies (platelet associate-IgG; PA-IgG, platelet binding-IgG; PB-IgG). In some cases, thrombocytopenia was associated with antiphospholipid antibodies. In rare case, so-called Evans syndrome, in which AIHA and TP coexist, was observed. Some cases did not tend to bleed until platelet counts were less than 20,000/ul. Patients with thrombocytopenia less than 20,000 were treated with large doses of steroids. The initial dose of PSL was usually 1- 2mg /kg/day. After an increase in platelet count occurred in response to steroids, the dose was gradually reduced after 4 weeks. If thrombocytopenia did not respond to steroids with bleeding from the major organs such as gastrointestinal tract, kidney, bladder, other mucosal surface, steroid pulse therapy was used. IVIg was useful to achieve a temporary improvement in thrombocytopenia in surgical operations such as splenectomy, which was often conducted in steroid resistant cases. .In steroid resistant cases, immunosuppressive drugs such as azathioprine, cyclophosphamide, and cyclosporine, danazol, and vincristine,

TTP usually consists of a pentad of TP, microangiopathic hemolytic anemia, fever, renal failure, and neurologic manifestations. TTP has been reported in association with various other diseases, including SLE, most of which are characterized by some degree of vasculitis of the small vessels and circulating immune complexes [30]. The main cause of acquired TTP including SLE is assumed to be an autoantibody that is an inhibitor (IgG inhibitor) of von Willebrand factor cleaving protease [31]. It has been clarified that congenital TTP is caused

The diseases, which needed high doses of steroids were AIHA, TP, and TTP.

and danazole were also used for some refractory cases.

*3.6.1. AIHA* 

*3.6.2. TP* 

etc., were also used.

*3.6.3. TTP* 

Several risk factors that cause myocardial infarction due to atherosclerosis in SLE are considered. They are renal involvement, hypertension, hyperlipidemia, long-term administration of steroids, diabetes mellitus, anti-phospholipid syndrome, smoking, etc. In this study, 4 patients had hypertension, hyperlipemia and diabetes mellitus as risk factors. Furthermore, positive antiphospholipid antibodies were observed in 5 cases. Death from myocardial infarction due to inflammation of the coronary arteries has been reported in SLE patients dying early in the course of their disease, but this is a rare event [28].

Regarding the treatment in this study, conservative medical management without large doses of steroids was used in most cases. PTCA and AC bypass procedures were also occasionally conducted.

### **3.5. Intestinal vasculitis**

Acute abdomen caused by intestinal vasculitis is often observed. Occasionally, surgery is needed. According to a report by Zizic, et al. [29], acute abdomen was observed in 15 of 140 cases, and caused death in 53% of cases. Vasculitis was observed in 9 of 11 cases with abdominal surgery, and intestinal perforation was observed in 6 cases. In this study, 4 patients had intestinal vasculitis and 3 died of intestinal perforation. Intestinal bleeding and peritoneal bleeding due to vasculitis were often observed. In cases with mesenteric arteritis, acute abdomen with severe abdominal pain in conjunction with nausea/vomiting, diarrhea, ascites, gastrointestinal bleeding, and fever, etc., were observed. Those symptoms may be masked by steroids or immunosuppressive drugs used for treatment, thus resulting in a delayed diagnosis.

Patients with intestinal vasculitis and/or mesenteric arteritis were treated with large dose steroids including steroid pulse therapy.

When a rapid improvement was not obtained, intermittent IVCY therapy was simultaneously used. In cases associated with bowel infarction or perforation, treatment for infection was also needed.

#### **3.6. Hematologic manifestations**

Hematologic manifestations in SLE include normochromic-normocytic anemia caused by chronic inflammation, autoimmune hemolytic anemia (AIHA), iron-deficiency anemia, leukocytopenia, lymphocytopenia, thrombocytopenia, thrombocytopenic purpura (TP), thrombotic thrombocytopenic purpura (TTP), and antiphosphlipid syndrome (APS), etc. The diseases, which needed high doses of steroids were AIHA, TP, and TTP.

#### *3.6.1. AIHA*

492 Glucocorticoids – New Recognition of Our Familiar Friend

death from cardiac rupture.

occasionally conducted.

delayed diagnosis.

infection was also needed.

steroids including steroid pulse therapy.

**3.6. Hematologic manifestations** 

**3.5. Intestinal vasculitis** 

*3.4.3. Myocardial infarction and coronary artery disease* 

Coronary artery disease due to arteriosclerotic changes is more common in SLE patients. Death from myocardial infarction late in the course of the disease is one of the most frequent causes of death after 10 to 30 years of SLE [28]. Eleven lupus patients with myocardial infarction could be seen in this study. The average age at diagnosis of SLE was 37 years old (26–63 years old), and the average age at development of myocardial infarction was 51 years old (41–66 years old) in these patients. There were two death cases, including one case of

Several risk factors that cause myocardial infarction due to atherosclerosis in SLE are considered. They are renal involvement, hypertension, hyperlipidemia, long-term administration of steroids, diabetes mellitus, anti-phospholipid syndrome, smoking, etc. In this study, 4 patients had hypertension, hyperlipemia and diabetes mellitus as risk factors. Furthermore, positive antiphospholipid antibodies were observed in 5 cases. Death from myocardial infarction due to inflammation of the coronary arteries has been reported in SLE

Regarding the treatment in this study, conservative medical management without large doses of steroids was used in most cases. PTCA and AC bypass procedures were also

Acute abdomen caused by intestinal vasculitis is often observed. Occasionally, surgery is needed. According to a report by Zizic, et al. [29], acute abdomen was observed in 15 of 140 cases, and caused death in 53% of cases. Vasculitis was observed in 9 of 11 cases with abdominal surgery, and intestinal perforation was observed in 6 cases. In this study, 4 patients had intestinal vasculitis and 3 died of intestinal perforation. Intestinal bleeding and peritoneal bleeding due to vasculitis were often observed. In cases with mesenteric arteritis, acute abdomen with severe abdominal pain in conjunction with nausea/vomiting, diarrhea, ascites, gastrointestinal bleeding, and fever, etc., were observed. Those symptoms may be masked by steroids or immunosuppressive drugs used for treatment, thus resulting in a

Patients with intestinal vasculitis and/or mesenteric arteritis were treated with large dose

When a rapid improvement was not obtained, intermittent IVCY therapy was simultaneously used. In cases associated with bowel infarction or perforation, treatment for

Hematologic manifestations in SLE include normochromic-normocytic anemia caused by chronic inflammation, autoimmune hemolytic anemia (AIHA), iron-deficiency anemia,

patients dying early in the course of their disease, but this is a rare event [28].

AIHA was observed in 11% of patients in this study. AIHA is rare in Japanese SLE patients in comparison to those in Europe and the United States. Steroids were the mainstay of the treatment for AIHA and a response was achieved in about 75% of patients. PSL was given initially at a dose of 1.0 to1.5mg/kg and continued at that level for at least 4 to 6 weeks. Following a satisfactory response, the dose was reduced gradually by 10% every week. The reticlocyte count was a reliable indicator of both responsiveness to treatment and relapse. In cases of severe fulminant hemolysis, steroid pulse therapy was conducted. Patients with AIHA who failed to respond to steroids were treated with immunosuppressant agents and/or splenectomy. Plasmapheresis, high-dose intravenous gammagloburin therapy (IVIg), and danazole were also used for some refractory cases.

#### *3.6.2. TP*

Thrombocytopenia lower than 150,000 was observed in 34% of cases in this study. However, thrombocytopenia lower than 50,000 was relatively rare, and it occured in approximately 10% of cases. Thrombocytopenia in SLE is usually due to antiplatelet autoantibodies (platelet associate-IgG; PA-IgG, platelet binding-IgG; PB-IgG). In some cases, thrombocytopenia was associated with antiphospholipid antibodies. In rare case, so-called Evans syndrome, in which AIHA and TP coexist, was observed. Some cases did not tend to bleed until platelet counts were less than 20,000/ul. Patients with thrombocytopenia less than 20,000 were treated with large doses of steroids. The initial dose of PSL was usually 1- 2mg /kg/day. After an increase in platelet count occurred in response to steroids, the dose was gradually reduced after 4 weeks. If thrombocytopenia did not respond to steroids with bleeding from the major organs such as gastrointestinal tract, kidney, bladder, other mucosal surface, steroid pulse therapy was used. IVIg was useful to achieve a temporary improvement in thrombocytopenia in surgical operations such as splenectomy, which was often conducted in steroid resistant cases. .In steroid resistant cases, immunosuppressive drugs such as azathioprine, cyclophosphamide, and cyclosporine, danazol, and vincristine, etc., were also used.

#### *3.6.3. TTP*

TTP usually consists of a pentad of TP, microangiopathic hemolytic anemia, fever, renal failure, and neurologic manifestations. TTP has been reported in association with various other diseases, including SLE, most of which are characterized by some degree of vasculitis of the small vessels and circulating immune complexes [30]. The main cause of acquired TTP including SLE is assumed to be an autoantibody that is an inhibitor (IgG inhibitor) of von Willebrand factor cleaving protease [31]. It has been clarified that congenital TTP is caused by a mutation in the *ADAMTS-13* gene of cleaving protease. TTP must be differentiated from DIC or catastrophic antiphospholipid syndrome, but coexistence of both are often observed.

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 495

pregnancy, the delivery of the fetus was attempted as early as possible in order to start

Because the amount of steroids was increased upon delivery, breast-feeding was prohibited until the dose was reduced to less than 20 mg of PSL, considering the rate of transfer of

Side effects of prolonged treatment with oral steroids are well known. Changes in the physical appearance could usually be seen. They were acne, hirsutism, moon face, buffalo hump, obesity, and abdominal striae, etc. Although reversible with a discontinuation or reduction in dose, hypertension, peptic ulcer, diabetes mellitus, pancreatitis, osteoporosis, psychosis, etc. were also induced. Thinning of the skin, cataracts, glaucoma, osteoporosis,

Infections were major complications in SLE and one of the major causes of death. Susceptibility to infection, particularly bacterial infection, was increased with steroid use. Staples et al. found that the infection rate in hospitalized patients increased from 0.43 to 1.63 per 100 hospital days with an increase in steroid dose from zero to more than 50mg/day [34]. Although infection rarely occurs with a small dose of PSL (2–10 mg/day), the SLE patients treated with PSL of more than 20mg/day have a higher risk of infection due to the higher dose of PSL, especially after 14 days of administration. PSL was also noted to be a major risk factor for the development of opportunistic infection, with the most common organisms including Salmonella, Candida, Strongyloides, and Aspergillus.sp according to a case

It has been noted that systemic administration of steroids could be linked to the higher occurrence of vascular diseases such as coronary artery disease, stroke, peripheral vascular disease than the expected occurrence in SLE. However, it is unclear whether this reflects pro-atherogenic effects of the underlying disease process or adverse metabolic effects associated with steroid use [36]. Recently, the number of patients with complications such as myocardial infarction/angina pectoris, cerebral infarction, diabetes mellitus, hypertension, and aseptic bone necrosis, has tended to increase over a long-term observation period due to

Table 5 shows the frequencies of these complications at the time of occurence in 97 SLE patients who had been observed for over 20 years. The number of patients with myocardial infarction/angina pectoris, diabetes, cerebral infarction increased from the ninth year of the observation period. Hypertension and aseptic osteonecrosis were seen from the onset of SLE. Most of the above complications were thought to be due to treatment including steroids, as well as aging. It was also noted that GC-associated damage accumulated over time to constitute most of the damage at 15 years, although disease –activity related damage

treatment of the mother's clinical manifestations.

steroids (0.1–0.3%/day) to the mother's milk [33].

controlled study of 797 SLE patients [35].

a favorable SLE prognosis.

occurred early [37].

**3.8. Adverse effects and complications due to steroid treatment** 

and osteonecrosis could be observed as irreversible side effects.

*3.7.2.2. Breast-feeding* 

Regarding treatment, plasmapheresis using fresh frozen plasma, and transfusion therapy of normal plasma are used. In addition, large-doses of steroids including steroid pulse therapy, immunosuppressive drugs, IVIg therapy, and anti-platelet drugs, etc. are simultaneously used.

### **3.7. Pregnancy and birth**

When an SLE patient wished to conceive and give birth, a medical determination as to whether pregnancy would be possible was considered. Basically, there were presumed to be almost no problems in pregnancy when the patient was in remission with a maintenance dosage of steroids, and when serious organ failure was not observed. Moreover, even if the patient had active disease, pregnancy was allowed after the disease improved with treatment.

#### *3.7.1. Treatment and management during pregnancy*

It was important for the physician and the gynecologist to be in close communication for the treatment and management during pregnancy. Usually, it was unnecessary to change the maintenance dose of the steroid during pregnancy. When mild deterioration was observed in the early stage of pregnancy, an increased steroid dosage was attempted according to the clinical manifestations. If the clinical manifestations required administration of a large-dose of steroids, considering the risks to the mother and the effect of the steroids on the fetus, an artificial abortion was performed at an early stage. Although the level of serum cortisol in the fetus decreases during the steroid administration, cortisol secretion and response to ACTH are believed to remain normal [32]. If a mother is treated with prednisolone or hydrocortisone, these steroids are assumed to have a minimal effect on the fetus because they are inactivated by 11-β-dehydrogenase in the placenta. However, the use of dexamethasone and betamethasone is avoided because these steroids are difficult for the enzyme to inactivate and were assumed to have an adverse effect on the fetus.

#### *3.7.2. Treatment and management during and after deliverly*

#### *3.7.2.1. Prevention of exacerbation*

The mother was hospitalized prior to the expected delivery date for management of the mother and fetus. If pregnancy remained steady, and SLE activity was not observed, the dose of steroids was increased immediately after delivery to prevent any exacerbation of SLE. The dose of steroids was usually increased to two or three times the pre-delivery dose. The dose was reduced by 10% every 4 to 7 days while confirming no exacerbation, and continually observed until eventually reducing it to the dosage at the time of delivery. If an exacerbation of SLE such as active LN or serositis was observed in the late stage of pregnancy, the delivery of the fetus was attempted as early as possible in order to start treatment of the mother's clinical manifestations.

#### *3.7.2.2. Breast-feeding*

494 Glucocorticoids – New Recognition of Our Familiar Friend

*3.7.1. Treatment and management during pregnancy* 

observed.

used.

treatment.

**3.7. Pregnancy and birth** 

by a mutation in the *ADAMTS-13* gene of cleaving protease. TTP must be differentiated from DIC or catastrophic antiphospholipid syndrome, but coexistence of both are often

Regarding treatment, plasmapheresis using fresh frozen plasma, and transfusion therapy of normal plasma are used. In addition, large-doses of steroids including steroid pulse therapy, immunosuppressive drugs, IVIg therapy, and anti-platelet drugs, etc. are simultaneously

When an SLE patient wished to conceive and give birth, a medical determination as to whether pregnancy would be possible was considered. Basically, there were presumed to be almost no problems in pregnancy when the patient was in remission with a maintenance dosage of steroids, and when serious organ failure was not observed. Moreover, even if the patient had active disease, pregnancy was allowed after the disease improved with

It was important for the physician and the gynecologist to be in close communication for the treatment and management during pregnancy. Usually, it was unnecessary to change the maintenance dose of the steroid during pregnancy. When mild deterioration was observed in the early stage of pregnancy, an increased steroid dosage was attempted according to the clinical manifestations. If the clinical manifestations required administration of a large-dose of steroids, considering the risks to the mother and the effect of the steroids on the fetus, an artificial abortion was performed at an early stage. Although the level of serum cortisol in the fetus decreases during the steroid administration, cortisol secretion and response to ACTH are believed to remain normal [32]. If a mother is treated with prednisolone or hydrocortisone, these steroids are assumed to have a minimal effect on the fetus because they are inactivated by 11-β-dehydrogenase in the placenta. However, the use of dexamethasone and betamethasone is avoided because these steroids are difficult for the

enzyme to inactivate and were assumed to have an adverse effect on the fetus.

The mother was hospitalized prior to the expected delivery date for management of the mother and fetus. If pregnancy remained steady, and SLE activity was not observed, the dose of steroids was increased immediately after delivery to prevent any exacerbation of SLE. The dose of steroids was usually increased to two or three times the pre-delivery dose. The dose was reduced by 10% every 4 to 7 days while confirming no exacerbation, and continually observed until eventually reducing it to the dosage at the time of delivery. If an exacerbation of SLE such as active LN or serositis was observed in the late stage of

*3.7.2. Treatment and management during and after deliverly* 

*3.7.2.1. Prevention of exacerbation* 

Because the amount of steroids was increased upon delivery, breast-feeding was prohibited until the dose was reduced to less than 20 mg of PSL, considering the rate of transfer of steroids (0.1–0.3%/day) to the mother's milk [33].

#### **3.8. Adverse effects and complications due to steroid treatment**

Side effects of prolonged treatment with oral steroids are well known. Changes in the physical appearance could usually be seen. They were acne, hirsutism, moon face, buffalo hump, obesity, and abdominal striae, etc. Although reversible with a discontinuation or reduction in dose, hypertension, peptic ulcer, diabetes mellitus, pancreatitis, osteoporosis, psychosis, etc. were also induced. Thinning of the skin, cataracts, glaucoma, osteoporosis, and osteonecrosis could be observed as irreversible side effects.

Infections were major complications in SLE and one of the major causes of death. Susceptibility to infection, particularly bacterial infection, was increased with steroid use. Staples et al. found that the infection rate in hospitalized patients increased from 0.43 to 1.63 per 100 hospital days with an increase in steroid dose from zero to more than 50mg/day [34]. Although infection rarely occurs with a small dose of PSL (2–10 mg/day), the SLE patients treated with PSL of more than 20mg/day have a higher risk of infection due to the higher dose of PSL, especially after 14 days of administration. PSL was also noted to be a major risk factor for the development of opportunistic infection, with the most common organisms including Salmonella, Candida, Strongyloides, and Aspergillus.sp according to a case controlled study of 797 SLE patients [35].

It has been noted that systemic administration of steroids could be linked to the higher occurrence of vascular diseases such as coronary artery disease, stroke, peripheral vascular disease than the expected occurrence in SLE. However, it is unclear whether this reflects pro-atherogenic effects of the underlying disease process or adverse metabolic effects associated with steroid use [36]. Recently, the number of patients with complications such as myocardial infarction/angina pectoris, cerebral infarction, diabetes mellitus, hypertension, and aseptic bone necrosis, has tended to increase over a long-term observation period due to a favorable SLE prognosis.

Table 5 shows the frequencies of these complications at the time of occurence in 97 SLE patients who had been observed for over 20 years. The number of patients with myocardial infarction/angina pectoris, diabetes, cerebral infarction increased from the ninth year of the observation period. Hypertension and aseptic osteonecrosis were seen from the onset of SLE. Most of the above complications were thought to be due to treatment including steroids, as well as aging. It was also noted that GC-associated damage accumulated over time to constitute most of the damage at 15 years, although disease –activity related damage occurred early [37].


Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 497

In this paper, steroid therapy for SLE based on the clinical analysis of 1,125 cases, especially for principal organ involvement that required large doses of steroids, was evaluated. Although there is no doubt that steroids contribute to a significant improvement in the prognosis in SLE, the effectiveness and usefulness of steroids are limited because of severe

Now, new biological agents that target B cells, T-B cell interaction, co-stimulatory pathways, intracellular molecules, etc. are being developed and are going to begin to revolutionize

[1] Wallace DJ, Dubois EL (1987) Prognostic subsets, natural course, and causes of death in systemic lupus erythematosus, In: Wallace DJ, Dubois EL editors. Dubois' Lupus

[2] Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

[3] Wallace DJ (2007) The clinical presentation of systemic lupus erythematosus. In: Wallece DJ, Hahn BH editors. Dubois' Lupus Erythematosus. 7th ed. Lippincott Williams &

[4] McGehee HA, Shulman LE, Tumulty AP, et al (1954) Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine 33: 291-437 [5] Dubois EL, Tuffanelli DL (1964) Clinical manifestations of systemic lupus

[6] Pistiner M, Wallace DJ, Nessim S, et al (1991) Lupus erythematosus in the 1980s: a

[7] Hashimoto, H, Hirose S, Kano S, et al (1992) Studies on clinical subsets and severity of systemic lupus erythematosus based on a 1987 questionnaire conducted in Japan-Clinical analysis of the outcome and treatments in clinical subsets. Rhumachi 32: 27-

[8] Wilder BL (1997) Glucocorticoids, In: Koopman WJ, editor. Arthritis and Allied

erythematosus. Computer analysis of 520 cases, JAMA 190: 104-111

survey of 570 patients. Semin Arthritis Rheum 21: 55-64

Conditioins. 13th ed. Wiliams & Willkins, Baltimore, pp731

side effects, unresponsiveness and resistance to steroids.

nonspecific therapy to a more specific pathophysiological tharapy in SLE.

*Aiwakai Medical Corporation, Bajikouen Clinic, Rheumatology, Tokyo, Japan* 

Erythematosus, 3rd ed. Lea & Febiger, Philadelphia, pp580

**4. Conclusion** 

**Author details** 

Hiroshi Hashimoto *Professor Emeritus,* 

**5. References** 

(letter)

38

Willkins, Philadelphia, pp638

**Table 5.** Frequencies of complications related to vascular diseases according to the year (s) of the occurrence in 97 SLE patients who had been observed for over 20 years

Steroid use contributes significantly to risk of osteoporosis in women with SLE. Ramsey-Goldman et al. surveyed the frequency of fractures and associated risk factores in702 women with SLE who had been followed for 5951 person-years and found that fractures occurred in 12.3% of patients, an almost fivefold increase compared with a background population [38]. Older age at diagnosis and longer duration of steroid use were important valuables. Sinigaglia, et al. reported that osteoporosis in 22.6% of 84 premenopousal patients with SLE according to bone mineral density (BMD) was observed, and both disease duration and glucocorticoids were associated risks [39]. Steroid–induced osteoporosis leading to fracture, particularly vertebral collapse, was a major problem.

Aseptic osteonecrosis (AON) was observed in approximately 10% of SLE, with the femoral head being a common site. It also appeared in the femoral condyle, caput humeri, proximal end and distal end of the tibia, etc.. It has been suggested that increased doses of steroids (especially in the first year of treatment) and the duration of steroid therapy are correlated with a grater risk of AON in SLE patients [40]. In a prospective survey of SLE patients with administration of high-dose steroids (more than 30 mg/day of PSL for more than one month), AON occurred in 15% (9/62 patients) and the average period from the administration of a large dose of steroids to onset of AON was 640 days [41].

#### **4. Conclusion**

496 Glucocorticoids – New Recognition of Our Familiar Friend

**Table 5.** Frequencies of complications related to vascular diseases according to the year (s) of the

Steroid use contributes significantly to risk of osteoporosis in women with SLE. Ramsey-Goldman et al. surveyed the frequency of fractures and associated risk factores in702 women with SLE who had been followed for 5951 person-years and found that fractures occurred in 12.3% of patients, an almost fivefold increase compared with a background population [38]. Older age at diagnosis and longer duration of steroid use were important valuables. Sinigaglia, et al. reported that osteoporosis in 22.6% of 84 premenopousal patients with SLE according to bone mineral density (BMD) was observed, and both disease duration and glucocorticoids were associated risks [39]. Steroid–induced osteoporosis leading to fracture, particularly vertebral collapse, was a

Aseptic osteonecrosis (AON) was observed in approximately 10% of SLE, with the femoral head being a common site. It also appeared in the femoral condyle, caput humeri, proximal end and distal end of the tibia, etc.. It has been suggested that increased doses of steroids (especially in the first year of treatment) and the duration of steroid therapy are correlated with a grater risk of AON in SLE patients [40]. In a prospective survey of SLE patients with administration of high-dose steroids (more than 30 mg/day of PSL for more than one month), AON occurred in 15% (9/62 patients) and the average period from the administration of a large dose of steroids to onset of AON

occurrence in 97 SLE patients who had been observed for over 20 years

major problem.

was 640 days [41].

In this paper, steroid therapy for SLE based on the clinical analysis of 1,125 cases, especially for principal organ involvement that required large doses of steroids, was evaluated. Although there is no doubt that steroids contribute to a significant improvement in the prognosis in SLE, the effectiveness and usefulness of steroids are limited because of severe side effects, unresponsiveness and resistance to steroids.

Now, new biological agents that target B cells, T-B cell interaction, co-stimulatory pathways, intracellular molecules, etc. are being developed and are going to begin to revolutionize nonspecific therapy to a more specific pathophysiological tharapy in SLE.

### **Author details**

Hiroshi Hashimoto *Professor Emeritus, Aiwakai Medical Corporation, Bajikouen Clinic, Rheumatology, Tokyo, Japan* 

#### **5. References**


[9] Seki M, Ushiyama C, Seta N, et al (1998) Apoptosis of lymphocytes induced glucocorticoids and relationship to therapeutic efficacy in patients with systemic lupus erythematosus. Arthritis Rheum 41: 823-830

Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE 499

[24] D'Cruz D, Khamashta MA, Hughes G (2007) Pulmonary manifestations of systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus,

[25] Matthay RA, Schwartz MI, Petty TL, et al (1975) Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine

[26] Baulware DW, hedgpeth MT (1989)Lupus pneumonitis and anti-SSA(Ro) antibodies . J

[27] Bulkley BH, Roberts WC (1975) The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J

[28] Rothfield NF (1996) Cardiac aspects. In; Shur PH, ed. The Clinical Management of

[29] Zizic TM, Classen JN, Stevens MB (1982) Acute abdominal complications of systemic

[30] Shoenfeld Y, Ehrenfelt M(1996) Hematological manifestations. In;Shur PH, ed.The Clinical Management of Systemic lupus Erythematosus, 2nd ed. Lippincott-Raven,

[31] Tsai HM, Lian ECY(1998) Antibodies to von Willebrand factor-cleaving protease in

[32] Blanford AT, Murphy BE (1977) In vitro metabolism of prednisolone, dexamethasone, betamethasone, and cortisol by the human placenta. Am J Obstet Gynecolo 127: 264-

[33] Katz FH, Duncan BR (1975)Letter: entry of prednisone into human milk. N Engl J Med

[34] Staples PJ, Gerding DN, Decker JL, et al (1974) Incidence of infection in systemic lupus

[35] Ritchin C, Dobro J, Senie R, etl. (1989) Opportunistic infections in patients with systemic

[36] Wei L, MacDonald T, Walker B (2004) Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 141:764-770, [37] Gladman DD, Urowitz MB, Rahman P, et al. (2003) Accrual of organ damage over time

[38] Ramsey-Goldman R, Dunn JE, Huang CF, et al (1999) Frequency of fractures in women with systemic lupus erythematosus: comparison with United States population data.

[39] Sinigaglia L, Varenna M, Binelli L, et al (1999) Determinations of bone mass in systemic lupus erythematosus: a cross sectional study on premenopausal women. J Rheumatol

[40] Weiner ES, Abeles (1989) Aseptic necrosis and glucocorticosteroids in systemic lupus

in patients with systemic lupus erythematosus. J Rheumatol 30:1955-1959

lupus erythematosus (abstract). Arthritis Rheum 32(Suppl):S115

erythematosus: reevaluation. J Rheumatol 16: 604-608,

Systemic lupus Erythematosus, 2nd ed. Lippincott-Raven, Philadelphia, pp83

lupus erythematosus and polyarteritis nodosa. Am J Med 73: 525-531

acute thrombotic thrombocytopenic purpura. N Eng J Med 339: 1585-1594

7th ed. Lippincott Williams & Wilkins, Philadelphia, pp678

54:397-409

Rheumatol 16: 479-481

Med 58: 243-264

Philadelphia, pp95

erythematosus. Arthritis Rheum 17: 110

Arthritis Rheum 42: 882-890

26: 1280-1284

267

293:1154


[24] D'Cruz D, Khamashta MA, Hughes G (2007) Pulmonary manifestations of systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus, 7th ed. Lippincott Williams & Wilkins, Philadelphia, pp678

498 Glucocorticoids – New Recognition of Our Familiar Friend

phase 3 trial. Lancet 9767: 721-731

Wilkins, Philadelphia, pp1094

cases. Seishinigaku 28: 661-670(in Japanese)

erythematosus. Am J Med 90: 54-62

psychosis. J Rheumatol 15: 706-710

psychosis. J Nerv Ment Dis 166: 738-742

Nerv Ment Dis 167:229-236

Dis 67:195-205

1319-1323

erythematosus. Arthritis Rheum 41: 823-830

Lippincott Williams & Willkins, Philadelphia, pp1333

systemic lupus erythematosus. Scand J Rheumatol 7: 219-224

erythematosus during the past 3 to 4 decades. J Epidemiol 3:19-27

neuropsychiatric lupus syndromes. Arthritis Rheum 42: 599-608

[9] Seki M, Ushiyama C, Seta N, et al (1998) Apoptosis of lymphocytes induced glucocorticoids and relationship to therapeutic efficacy in patients with systemic lupus

[10] Navarra SV, Guzman RM, Gallacher AE, et al (2011) Efficacy and safety of belimumab in patients with active systemic lupus eryhematosus: a randomized, placebo-controlled,

[11] Gladman DD, Urowitz MB (2007) Prognosis, mortality and morbidity in systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus, 7th ed.

[12] Hashimoto H, Shiokawa Y (1978) Changing pattern of clinical features and prognosis in

[13] Hashimoto H, Sugawara M, Tokano Y, et al. (1993) Follow up study on the changes in the clinical features and prognosis of Japanese patients with systemic lupus

[14] D'Agati VD, Appel GB (2007) Lupus nephritis: pathology and pathogenesis. In: Wallace DJ, Hahn BH, editors, Dubois' Lupus Erythematosus, 7th ed.Lippincott Williams &

[15] Weening JJ, D'Agati VD, Schwartz MM, et al (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 65: 521-530 [16] ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature (1999) The American College of Rheumatology nomenclature and case definitions for

[17] Akazawa S (1986) Psychiatric syndrome in systemic lupus erythematosus-study on 82

[18] Schneebaum AB, Singleton JD,West SG, et al(1991)Association of psychiatric manifestations with antibodies to ribosomal-P proteins in systemic lupus

[19] Hirohata S, Iwamoto S, Sugiyama H, et al(1988) A patient with systemic lupus erythematosus presenting both central nervous system lupus and steroid induced

[20] Bertsias G, Loannidis JPA, Bombardieri S, et al. (2008) EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics. Ann Rhum

[21] Hall RCW, Popkin MK, Kirkpatrick B, et al (1978) Tricyclic exacerbation of steroid

[22] Hall RCW, Popkin MK, Stickney SK, et al (1979) Presentation of steroid psychosis. J

[23] Hirohata S, Kanai Y, Mitsuo A, et al.(2009) Accuracy of cerebrospinal fluid IL-6 testing for diagnosis of lupus psychosis. A multienter retrospective study. Clin Rheumatol 28:

	- [41] Ono K, Tohjima T, Komazawa T(1992) Risk factors of avascular necrosis of the femoral head in patients with systemic lupus erythematosus under high-dose corticosteroid therapy. Clin Orthop 277: 89-97

**Chapter 19** 

© 2012 Alangari, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Triggers of acute asthma exacerbation include allergens like pollens, animal dander, dust mites and mold; viral respiratory tract infections; irritants like smoke and dust; cold air and exercise. When pollens, for instance, are inhaled by an allergic individual, the allergenic protein is taken up by antigen presenting cells (dendritic cells) in the airway. It is then presented to naïve T-helper (Th) cells that develop into Th2 cell phenotype. These cells respond by secreting Th2 cytokines like IL-4 and IL-13 that cause allergen specific B-cells to

**The Use of Glucocorticoids in the Treatment of** 

**1.1. Pathophysiology of asthma and acute asthma exacerbations: Brief overview** 

Asthma is a chronic respiratory disease that is prevalent worldwide. It is considered as a major cause of morbidity and a main contributor to the high health care expenditure especially in developed countries (Subbarao et al, 2009). There are two major pathological features in asthmatics' airways, inflammation and hyperresponsiveness. These features are interrelated but not totally dependent on each other. Airway inflammatory changes include increased airway mucus secretions, airway wall edema, inflammatory cellular infiltrates, epithelial cell damage, smooth muscle hypertrophy, and submucosal fibrosis (Bergeron et al, 2009). The cellular infiltrates are mainly composed of eosinophils, neutrophils, mast cells, lymphocytes, basophils and macrophages. The ratio of these cells may widely vary between patients pointing to asthma heterogeneity (Holgate, 2008). Overall, asthma can be divided into eosinophilic, neutrophilic, and pauci-granulocytic phenotypes. The eosinophilic phenotype is characterized by predominant eosinophilic infiltration of the airways. Patients tend to be allergic, have asthma triggered by exposure to allergens and tend to respond well to glucocorticoids. The neutrophilic phenotype is characterized by predominant neutrophil infiltration of the airways. Patients tend to have severe, more aggressive, poorly controlled asthma, or acute asthma triggered by viral infection. They usually do not respond to glucocorticoids as good as the eosinophilic type. In the pauci-granulocytic phenotype

**Acute Asthma Exacerbations** 

Additional information is available at the end of the chapter

neutrophils and eosinophils are almost absent (Holgate, 2008).

Abdullah A. Alangari

http://dx.doi.org/10.5772/53221

**1. Introduction** 

## **The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations**

Abdullah A. Alangari

500 Glucocorticoids – New Recognition of Our Familiar Friend

therapy. Clin Orthop 277: 89-97

[41] Ono K, Tohjima T, Komazawa T(1992) Risk factors of avascular necrosis of the femoral head in patients with systemic lupus erythematosus under high-dose corticosteroid

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53221

### **1. Introduction**

#### **1.1. Pathophysiology of asthma and acute asthma exacerbations: Brief overview**

Asthma is a chronic respiratory disease that is prevalent worldwide. It is considered as a major cause of morbidity and a main contributor to the high health care expenditure especially in developed countries (Subbarao et al, 2009). There are two major pathological features in asthmatics' airways, inflammation and hyperresponsiveness. These features are interrelated but not totally dependent on each other. Airway inflammatory changes include increased airway mucus secretions, airway wall edema, inflammatory cellular infiltrates, epithelial cell damage, smooth muscle hypertrophy, and submucosal fibrosis (Bergeron et al, 2009). The cellular infiltrates are mainly composed of eosinophils, neutrophils, mast cells, lymphocytes, basophils and macrophages. The ratio of these cells may widely vary between patients pointing to asthma heterogeneity (Holgate, 2008). Overall, asthma can be divided into eosinophilic, neutrophilic, and pauci-granulocytic phenotypes. The eosinophilic phenotype is characterized by predominant eosinophilic infiltration of the airways. Patients tend to be allergic, have asthma triggered by exposure to allergens and tend to respond well to glucocorticoids. The neutrophilic phenotype is characterized by predominant neutrophil infiltration of the airways. Patients tend to have severe, more aggressive, poorly controlled asthma, or acute asthma triggered by viral infection. They usually do not respond to glucocorticoids as good as the eosinophilic type. In the pauci-granulocytic phenotype neutrophils and eosinophils are almost absent (Holgate, 2008).

Triggers of acute asthma exacerbation include allergens like pollens, animal dander, dust mites and mold; viral respiratory tract infections; irritants like smoke and dust; cold air and exercise. When pollens, for instance, are inhaled by an allergic individual, the allergenic protein is taken up by antigen presenting cells (dendritic cells) in the airway. It is then presented to naïve T-helper (Th) cells that develop into Th2 cell phenotype. These cells respond by secreting Th2 cytokines like IL-4 and IL-13 that cause allergen specific B-cells to

switch from IgM producing to IgE producing cells. These cytokines could also contribute to epithelial cell damage, increased mucus secretion and airway hyperresponsiveness. Th2 cells also secrete IL-5 that stimulates eosinophil development, release from the bone marrow and their recruitment to the site of inflammation. IgE antibodies bind to their receptors on the surface of mast cells. Cross linking of adjacent IgE molecules leads to degranulation and release of mediators like histamine and tryptase that are key to features of immediate hypersensitivity reaction. Activation of mast cells and eosinophils will also stimulate the synthesis and release of lipid derived mediators like prostaglandins and cysteinyl leukotrienes that are very potent bronchoconstrictors. Moreover, activation of eosinophils leads to the release of mediators like eosinophil cataionic protein and major basic protein, which can cause airway epithelial cell damage and submucosal fibrosis. New evidence suggests that Th1 cells contribute to chronic changes in the airways including epithelial cells damage and smooth muscle cells activation. Regulatory T cells (Treg) inhibit Th2 cells by secreting IL-10 and tansforming growth factor (TGF). Also, antigen specific Th17 cells were found to play an important role in neutrophilic airway inflammation and the process of airway remodeling (fixed changes to the airway) through the secretion of IL-17A and IL-17F (figure 1). This is a very quick overview, but many other changes take place during this process that are beyond the scope of this chapter.

The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 503

The most common cause of acute asthma exacerbation in both adults and children, but more in children, is viral respiratory tract infections. Viruses may be responsible for up to 80% of wheezing episodes in children and 50-75% of episodes in adults (Jackson et al, 2011b). Many viruses can cause exacerbation of asthma symptoms, the most important and most common is rhinovirus (Khetsuriani et al, 2007). Respiratory syncycial virus and influenza virus also cause significant proportion of exacerbations. The pathology of virally induced asthma exacerbation is more related to the airway epithelial cells which, in response to infection secret chemokines like IL-8 and CCL-5 that can attract inflammatory cells including neutrophils and lymphocytes and augment allergic inflammation (Gern & Busse, 2002). This finding is supported by epidemiological observations that allergen sensitization and respiratory viral infections can synergize to cause asthma exacerbation (Green et al, 2002). Children who are atopic are more likely to have virally induced wheezing and respiratory

Acute asthma exacerbations are defined as "episodes of progressive increase in shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms" (EPR3, 2007; GINA, 2011). Most recently an expert group formed by the NIH agreed to define acute asthma as "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome" (Fuhlbrigge et al, 2012). Acute exacerbation of asthma symptoms is a common complication of the disease. The frequency in which exacerbations happen vary widely depending on the severity of disease (Moore et al, 2007), the degree of control with prophylactic medications (Peters et al, 2007), and exposure to triggers. In a multicenter study from the US (Pollack et al, 2002) the admission rate of all comers to the ER with acute asthma was 23%. On the other hand, a European study showed that only about 7% of all patients with acute asthma exacerbation required hospitalization (Rabe et al, 2000). We have a similar experience in Saudi Arabia where about 8% of all asthmatics with acute exacerbation are hospitalized, but if we look at only the severe group the rate goes up to 40% (unpublished data). These epidemiological data underscores the importance of effective

Patients with acute asthma exacerbation usually present with increasing cough, and dyspnea. On examination patients may have increased respiratory rate, retractions (accessory respiratory muscle use), wheezing, oxygen desaturation on pulse oxymetry and, in more severe cases, inability to speak, silent chest, with reduced respiratory lung volumes, cyanosis and change in mental status. Asthma exacerbations can be classified as mild, moderate, or severe based on the level of severity of the signs and symptoms as illustrated

Different asthma scoring systems have been developed to assess the severity of asthma exacerbations more objectively, which is more useful for research purposes. An example is shown in table 2. (Qureshi et al, 1998). This scoring system is becoming more widely used

distress than non-atopic children (Jackson et al, 2011a).

treatment of asthma exacerbations and their prevention.

in Table 1. (Adams et al, 2011)

because of its high reliability and objectivity.

**1.2. Treatment of acute asthma exacerbation: general overview** 

**Figure 1.** Major immunopahtologic processes that take place in the bronchial airways of patients with asthma. Please see the text for detailed description. FcRI, high-affinity receptor for IgE; IFN, interferon-; TCR, T-cell receptor; TNF, tumour-necrosis factor. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology. Stephen T. Holgate and Riccardo Polosa. Treatment strategies for allergy and asthma. Vol. 8(3):Page 220, Copyright 2008.

The most common cause of acute asthma exacerbation in both adults and children, but more in children, is viral respiratory tract infections. Viruses may be responsible for up to 80% of wheezing episodes in children and 50-75% of episodes in adults (Jackson et al, 2011b). Many viruses can cause exacerbation of asthma symptoms, the most important and most common is rhinovirus (Khetsuriani et al, 2007). Respiratory syncycial virus and influenza virus also cause significant proportion of exacerbations. The pathology of virally induced asthma exacerbation is more related to the airway epithelial cells which, in response to infection secret chemokines like IL-8 and CCL-5 that can attract inflammatory cells including neutrophils and lymphocytes and augment allergic inflammation (Gern & Busse, 2002). This finding is supported by epidemiological observations that allergen sensitization and respiratory viral infections can synergize to cause asthma exacerbation (Green et al, 2002). Children who are atopic are more likely to have virally induced wheezing and respiratory distress than non-atopic children (Jackson et al, 2011a).

#### **1.2. Treatment of acute asthma exacerbation: general overview**

502 Glucocorticoids – New Recognition of Our Familiar Friend

process that are beyond the scope of this chapter.

TH0 cell

Epithelial cell

IL-17 IL-22

Smooth muscle

(Myo)fibroblast

TCR

TH17 cell TH1 cell

APC

MHC class II molecule Allergen

switch from IgM producing to IgE producing cells. These cytokines could also contribute to epithelial cell damage, increased mucus secretion and airway hyperresponsiveness. Th2 cells also secrete IL-5 that stimulates eosinophil development, release from the bone marrow and their recruitment to the site of inflammation. IgE antibodies bind to their receptors on the surface of mast cells. Cross linking of adjacent IgE molecules leads to degranulation and release of mediators like histamine and tryptase that are key to features of immediate hypersensitivity reaction. Activation of mast cells and eosinophils will also stimulate the synthesis and release of lipid derived mediators like prostaglandins and cysteinyl leukotrienes that are very potent bronchoconstrictors. Moreover, activation of eosinophils leads to the release of mediators like eosinophil cataionic protein and major basic protein, which can cause airway epithelial cell damage and submucosal fibrosis. New evidence suggests that Th1 cells contribute to chronic changes in the airways including epithelial cells damage and smooth muscle cells activation. Regulatory T cells (Treg) inhibit Th2 cells by secreting IL-10 and tansforming growth factor (TGF). Also, antigen specific Th17 cells were found to play an important role in neutrophilic airway inflammation and the process of airway remodeling (fixed changes to the airway) through the secretion of IL-17A and IL-17F (figure 1). This is a very quick overview, but many other changes take place during this

**Figure 1.** Major immunopahtologic processes that take place in the bronchial airways of patients with asthma. Please see the text for detailed description. FcRI, high-affinity receptor for IgE; IFN, interferon-; TCR, T-cell receptor; TNF, tumour-necrosis factor. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology. Stephen T. Holgate and Riccardo Polosa.

TReg cell

IL-10 TGF

TH2 cell

IL-13

TNF IFN

IL-9

IL-4

IL-13

Mucus

B cell

IL-5

Mast cell

FcRI

Release of soluble mediators • Histamine • Cysteinyl leukotrienes • Prostaglandins • Cytokines

Eosinophil

IgE

Release of soluble mediators • Basic proteins • Cysteinyl leukotrienes • Cytokines

Treatment strategies for allergy and asthma. Vol. 8(3):Page 220, Copyright 2008.

cell Blood vessel

Acute asthma exacerbations are defined as "episodes of progressive increase in shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms" (EPR3, 2007; GINA, 2011). Most recently an expert group formed by the NIH agreed to define acute asthma as "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome" (Fuhlbrigge et al, 2012). Acute exacerbation of asthma symptoms is a common complication of the disease. The frequency in which exacerbations happen vary widely depending on the severity of disease (Moore et al, 2007), the degree of control with prophylactic medications (Peters et al, 2007), and exposure to triggers. In a multicenter study from the US (Pollack et al, 2002) the admission rate of all comers to the ER with acute asthma was 23%. On the other hand, a European study showed that only about 7% of all patients with acute asthma exacerbation required hospitalization (Rabe et al, 2000). We have a similar experience in Saudi Arabia where about 8% of all asthmatics with acute exacerbation are hospitalized, but if we look at only the severe group the rate goes up to 40% (unpublished data). These epidemiological data underscores the importance of effective treatment of asthma exacerbations and their prevention.

Patients with acute asthma exacerbation usually present with increasing cough, and dyspnea. On examination patients may have increased respiratory rate, retractions (accessory respiratory muscle use), wheezing, oxygen desaturation on pulse oxymetry and, in more severe cases, inability to speak, silent chest, with reduced respiratory lung volumes, cyanosis and change in mental status. Asthma exacerbations can be classified as mild, moderate, or severe based on the level of severity of the signs and symptoms as illustrated in Table 1. (Adams et al, 2011)

Different asthma scoring systems have been developed to assess the severity of asthma exacerbations more objectively, which is more useful for research purposes. An example is shown in table 2. (Qureshi et al, 1998). This scoring system is becoming more widely used because of its high reliability and objectivity.


The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 505

expiration

Widespread

expiratory

decrease Absent/minimal

Audible without stethoscope/silent chest with minimal air entry

Inspiration and expiration without stethoscope

< 30 31-45 46-60 > 60

5/2 5/3 - 5/4 1/1 <1/1

**Score 0 1 2 3** 

**Muscle Use** 0 + ++ +++

**Table 3.** Pulmonary Index Score. \* For patients aged 6 years or older: <20 = 0; 21-35 = 1; 36-50 = 2; >50 = 3

**Signs 0 1 2 3** 

bases

**Table 4.** The Preschool Respiratory Assessment Measure (PRAM). \*If asymmetric findings between

glucocoricoids in the treatment of acute asthma can be found below in section 2.1.

Current guidelines recommend that patients with mild-moderate or moderate exacerbation should receive 3 doses of inhaled or nebulized 2-agonist every 15-20 minutes in the first hour (Camargo et al, 2003). Additional doses may be repeated in the next 2-3 hours every 30-60 minutes. All those patients should be treated with systemic glucocorticoids at a dose of 2mg/kg or a maximum dose of 80 mg early in the course of management as it takes at least 4 hours to start working (Rowe et al, 2004). Doses more than 80 mg will not confer any additional benefit. Systemic glucocorticoids were found to speed resolution of symptoms, decrease the rate of admission and decrease the rate of relapse if administered for 3-5 days after the acute exacerbation. More detailed discussion about the use of systemic

**Wheezing** None End expiration Entire

**retractions** Absent Present

**contraction** Absent Present

**Wheezing\*** Absent Expiration only Inspiratory and

**O2 saturation** 95% 92%-94% <92%

**Air entry\*** Normal Decreased at

right and left lungs, the most severe side is rated.

**Respiratory Rate\*** 

**(breaths/min)** 

**Inspiratory / Expiratory Ratio** 

**Accessory** 

**Suprasternal** 

**Scalene muscle** 

**Table 1.** General classification of asthma severity. \* PEFR: Peak Expiratory Flow Rate

Other frequently used scoring systems in the literature include; the Pulmonary Index Score (Scarfone et al, 1993) (table 3), and to a lesser degree the Preschool Respiratory Assessment Measure (PRAM) (Ducharme et al, 2008)(table 4), and the Pediatrics Asthma Severity Score (PASS) (Gorelick et al, 2004) (table 5).


**Table 2.** Asthma severity score (Qureshi et al). Score interpretation: Mild asthma 5-7, Moderate 8-11, Severe 12-15

In patients with mild asthma exacerbation, inhaled 2-agonists like albuterol (salbutamol) is usually sufficient to resolve symptoms. The dose can be repeated 3 times every 15-20 minutes. Levalbuterol, the (R)-enantiomer of albuterol is the effective form of the drug, but clinical trials did not show any advantage of using it over albuterol in terms of efficacy or side effects (Kelly, 2007). Most patients with mild asthma exacerbation will not require systemic glucocoricoids. However, it is recommended that patients who take them regularly or patients who fail initial treatment with albuterol should be given systemic glucocorticoids.


(PASS) (Gorelick et al, 2004) (table 5).

Respiratory rate (breaths/min)

Oxygen saturation (%)

Auscultation

Dyspnea

Severe 12-15

glucocorticoids.

**Severity Mild Moderate Severe**  PEFR\* 70% 40-69% <40% Speech Sentences Phrases Words Mental Status Anxious Agitated Distressed Accessory muscle use No Sometimes Commonly Oxygen saturation 95% 90-95% <90%

Other frequently used scoring systems in the literature include; the Pulmonary Index Score (Scarfone et al, 1993) (table 3), and to a lesser degree the Preschool Respiratory Assessment Measure (PRAM) (Ducharme et al, 2008)(table 4), and the Pediatrics Asthma Severity Score

**1 point 2 points 3 points** 

> 95 with room air 90 - 95 with room air <90 with room air or

substernal

Speaks in partial sentences or utters short cries

**Table 2.** Asthma severity score (Qureshi et al). Score interpretation: Mild asthma 5-7, Moderate 8-11,

In patients with mild asthma exacerbation, inhaled 2-agonists like albuterol (salbutamol) is usually sufficient to resolve symptoms. The dose can be repeated 3 times every 15-20 minutes. Levalbuterol, the (R)-enantiomer of albuterol is the effective form of the drug, but clinical trials did not show any advantage of using it over albuterol in terms of efficacy or side effects (Kelly, 2007). Most patients with mild asthma exacerbation will not require systemic glucocoricoids. However, it is recommended that patients who take them regularly or patients who fail initial treatment with albuterol should be given systemic

supplemental oxygen

wheezing, diminished breath sounds, or both

Intercostal, substernal, and supraclavicular

Speaks in single words or short phrases or grunts

Expiratory wheezing Inspiratory and expiratory

**Table 1.** General classification of asthma severity. \* PEFR: Peak Expiratory Flow Rate

2-3 years 34 35 - 39 40 4-5 years 30 31 - 35 36 6-12 years 26 27 - 30 31 >12 years 23 24 - 27 28

**Variable Asthma score**

Normal breathing or end-expiratory wheezing

Retractions None or intercostal Intercostal and

Speaks in sentences or coos and babbles



**Table 4.** The Preschool Respiratory Assessment Measure (PRAM). \*If asymmetric findings between right and left lungs, the most severe side is rated.

Current guidelines recommend that patients with mild-moderate or moderate exacerbation should receive 3 doses of inhaled or nebulized 2-agonist every 15-20 minutes in the first hour (Camargo et al, 2003). Additional doses may be repeated in the next 2-3 hours every 30-60 minutes. All those patients should be treated with systemic glucocorticoids at a dose of 2mg/kg or a maximum dose of 80 mg early in the course of management as it takes at least 4 hours to start working (Rowe et al, 2004). Doses more than 80 mg will not confer any additional benefit. Systemic glucocorticoids were found to speed resolution of symptoms, decrease the rate of admission and decrease the rate of relapse if administered for 3-5 days after the acute exacerbation. More detailed discussion about the use of systemic glucocoricoids in the treatment of acute asthma can be found below in section 2.1.


The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 507

with severe asthma exacerbation and therefore are not recommended. Moreover, oral montelukast given to patients post discharge for 5 days was also shown not to be helpful

2-agonists can be delivered via a nebulizer or by metered dose inhaled (MDI) with a holding chamber. An MDI dose of 4-8 puffs depending on age is equivalent to a nebulized dose of 2.5-5 mg of albuterol (Cates et al, 2006). Nebulizer is preferable in cases of severe symptoms when patients are unable to use the MDI effectively or if other nebulized medications are needed to be mixed with albuterol at the same time or if the patient is requiring oxygen supplementation. Oxygen therapy should be given to maintain saturation

Patients who maintain normal oxygen saturation, have no or minimal wheezing on chest auscultation, and have no or mild intercostal retractions can be discharged home after 1 hour of assessment on no additional medications in the emergency room. However, these patients should have a step up in their maintenance medications to prevent relapse. Patients who fail to achieve improvement after 4 hours of treatment should be admitted to the

**1.3. Introduction and evolution of glucocorticoids in the management of asthma:** 

Shortly after the discovery of the structure of adrenal steroid hormones, Hench and his colleagues examined using cortisone to treat arthritis in 1949. The effect was remarkable and that work won the Nobel Prize the next year. It also started a series of trials of corticosteroids in various inflammatory conditions. The first use of corticosteroid to treat acute asthma exacerbation occured in 1956 (Subcommittee on clinical trials in asthma, 1956). Development of corticosteroids that have less mineralocorticoid activity, like prednisone, and later those that have no mineralocorticoid activity, like dexamethasone, made glucocorticoids more attractive therapies to use in asthma. In 1972, Clerk et. al. showed for the first time that inhaled beclomethasone was effective in the management of asthma with less adverse effects than systemic steroids (Clark, 1972). Numerous reports came afterwards describing the efficacy of oral prednisone and prednisolone, intravenous methylprednisolone and inhaled glucocorticoids (IGC) like triamcinolone, budesonide, and fluticasone in the management of asthma. Table 3 shows some common systemic

90% in adults and 95% in pregnant women or children.

hospital for further aggressive therapy.

glucocorticoids and their relative potency.

**Preparation Potency relative** 

**to hydrocortisone** 

**Table 6.** Common types of systemic glucocorticoids and their relative properties

Hydrocortisone 1 1 8-12 Prednisone/Prednisolone 4 0.8 12-36 Methylprednisolone 5 0.5 12-36 Dexamethasone 25 0 36-72

**Relative sodium retention potency**  **Biological half life (h)** 

**Historical background** 

(Schuh et al, 2009).


Patients with severe asthma exacerbation should obviously be treated more aggressively. High dose inhaled (8-12 puffs) or nebulized 2-agonist should be given every 15-20 minutes at least in the first hour, which could be repeated for up to 4 hours then as required. The data are conflicting whether continuous nebulization using 2-agonist is superior to intermittent nebulaization or not (Camargo et al, 2003; Rodrigo & Rodrigo, 2002). Practically, continuous high dose nebulization could be used for the first hour and then intermittent nebulization thereafter as required. Ipratropium bromide has been shown to decrease the rate of hospitalization and shorten the stay in the emergency room in patients with severe or moderate to severe asthma exacerbation in many clinical trials (Qureshi et al, 1998; Rodrigo & Castro-Rodriguez, 2005; Zorc et al, 1999). Therefore, it is recommended to add it to each treatment of 2-agonist at least in the first hour of therapy. Its use in patients after admission to the hospital was not shown to make a difference. Systemic steroids should be used as mentioned in patients with moderate exacerbation. Other treatment modalities may be considered like magnesium sulfate and helium oxygen (heliox) therapy in the more severe and non-responsive patients. Subcutaneous or intravenous 2-agonists (Travers et al, 2002), intravenous aminophylline (Parameswaran et al, 2000), intravenous montelukast (Camargo et al, 2010; Morris et al, 2010), or oral montelukast added to standard therapy in the ER (Todi et al, 2010) were not shown to be helpful in the treatment of patients with severe asthma exacerbation and therefore are not recommended. Moreover, oral montelukast given to patients post discharge for 5 days was also shown not to be helpful (Schuh et al, 2009).

506 Glucocorticoids – New Recognition of Our Familiar Friend

High-pitched expiratory sound heard by auscultation

> Intensity of inspiratory sounds by auscultation

Observed use of accessory muscles, retractions, or inbreathing

Ratio of duration of expiration to inspiration

Respiratory rate above normal for age

Observation of the child's state of alertness

**Table 5.** The Pediatrics Asthma Severity Score (PASS)

**Wheezing** 

**Air entry** 

**Work of breathing** 

**Prolongation of expiration** 

**Tachypnea** 

**Mental status** 

**Clinical Finding Definition 0 1 2** 

Normal or mildly diminished

Normal or mildly prolonged

Patients with severe asthma exacerbation should obviously be treated more aggressively. High dose inhaled (8-12 puffs) or nebulized 2-agonist should be given every 15-20 minutes at least in the first hour, which could be repeated for up to 4 hours then as required. The data are conflicting whether continuous nebulization using 2-agonist is superior to intermittent nebulaization or not (Camargo et al, 2003; Rodrigo & Rodrigo, 2002). Practically, continuous high dose nebulization could be used for the first hour and then intermittent nebulization thereafter as required. Ipratropium bromide has been shown to decrease the rate of hospitalization and shorten the stay in the emergency room in patients with severe or moderate to severe asthma exacerbation in many clinical trials (Qureshi et al, 1998; Rodrigo & Castro-Rodriguez, 2005; Zorc et al, 1999). Therefore, it is recommended to add it to each treatment of 2-agonist at least in the first hour of therapy. Its use in patients after admission to the hospital was not shown to make a difference. Systemic steroids should be used as mentioned in patients with moderate exacerbation. Other treatment modalities may be considered like magnesium sulfate and helium oxygen (heliox) therapy in the more severe and non-responsive patients. Subcutaneous or intravenous 2-agonists (Travers et al, 2002), intravenous aminophylline (Parameswaran et al, 2000), intravenous montelukast (Camargo et al, 2010; Morris et al, 2010), or oral montelukast added to standard therapy in the ER (Todi et al, 2010) were not shown to be helpful in the treatment of patients

None or mild Moderate

Absent Present

Normal Depressed

Moderately diminished

None or mild Moderate Severe

Moderately prolonged

Severe wheezing due to poor air exchange

> Severely diminished

Severely prolonged 2-agonists can be delivered via a nebulizer or by metered dose inhaled (MDI) with a holding chamber. An MDI dose of 4-8 puffs depending on age is equivalent to a nebulized dose of 2.5-5 mg of albuterol (Cates et al, 2006). Nebulizer is preferable in cases of severe symptoms when patients are unable to use the MDI effectively or if other nebulized medications are needed to be mixed with albuterol at the same time or if the patient is requiring oxygen supplementation. Oxygen therapy should be given to maintain saturation 90% in adults and 95% in pregnant women or children.

Patients who maintain normal oxygen saturation, have no or minimal wheezing on chest auscultation, and have no or mild intercostal retractions can be discharged home after 1 hour of assessment on no additional medications in the emergency room. However, these patients should have a step up in their maintenance medications to prevent relapse. Patients who fail to achieve improvement after 4 hours of treatment should be admitted to the hospital for further aggressive therapy.

### **1.3. Introduction and evolution of glucocorticoids in the management of asthma: Historical background**

Shortly after the discovery of the structure of adrenal steroid hormones, Hench and his colleagues examined using cortisone to treat arthritis in 1949. The effect was remarkable and that work won the Nobel Prize the next year. It also started a series of trials of corticosteroids in various inflammatory conditions. The first use of corticosteroid to treat acute asthma exacerbation occured in 1956 (Subcommittee on clinical trials in asthma, 1956). Development of corticosteroids that have less mineralocorticoid activity, like prednisone, and later those that have no mineralocorticoid activity, like dexamethasone, made glucocorticoids more attractive therapies to use in asthma. In 1972, Clerk et. al. showed for the first time that inhaled beclomethasone was effective in the management of asthma with less adverse effects than systemic steroids (Clark, 1972). Numerous reports came afterwards describing the efficacy of oral prednisone and prednisolone, intravenous methylprednisolone and inhaled glucocorticoids (IGC) like triamcinolone, budesonide, and fluticasone in the management of asthma. Table 3 shows some common systemic glucocorticoids and their relative potency.


**Table 6.** Common types of systemic glucocorticoids and their relative properties

#### **1.4. Adverse effects of glucocorticoids**

There are many adverse effects that may result from the use of oral or IGC in the treatment of asthma especially in high doses. I will summarize here the most pertinent ones.

The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 509

**2. Clinical evidence of the effect of glucocorticoids in acute asthma** 

Systemic glucocorticoids given early in the course of treatment of acute asthma exacerbations in the emergency room were overall shown to be effective and are recommended by different asthma guidelines like GINA and EPR3. Littenberg et al. initially showed that they decrease hospital admission rate (Littenberg & Gluck, 1986). Five subsequent studies had, however, conflicting results. Rodrigo & Rodrigo reviewed all these six studies and concluded that there was no improvement in hospital admission rate or lung function (Rodrigo & Rodrigo, 1999). They, however, reported a trend of improvement in lung function only with medium or high doses systemic glucocorticoids. So data in terms of lung function are more encouraging (Fanta et al, 1983; Lin et al, 1999). In terms of effect on exacerbation relapse after discharge from the emergency room, most studies showed less relapse with systemic glucocorticoids (Schneider et al, 1988; Subcommittee on clinical trials in asthma, 1956) although others did not (Rodrigo & Rodrigo, 1994). One important issue with all these studies is the low number of patients recruited. Almost all had subject number less than 100 per study and all were performed in adults. On the other hand, Krishnan et al recently reviewed 9 published studies in the use of systemic glucocorticoids in acute asthma in adults and concluded "systemic corticosteroids provide clinically meaningful benefits in patients presenting with acute asthma" (Krishnan et al, 2009). In children, more limited data showed benefit of systemic steroids used early in the emergency room with decreased rate of admission (Scarfone et al, 1993). A Cochrane database review by Rowe et al showed decrease rate of admission in patients with acute asthma with the use of systemic glucocorticoids in adults and children especially those with severe asthma and those not

There is no significant difference in efficacy of systemic glucocorticoids at doses above 60-80 mg/d or 2 mg/kg/d in regards to pulmonary function, rate of admission, or length of stay in the hospital. For example, Marquette et al compared 1 mg/kg/d to 6 mg/kg/d methylprednisolone in 47 adults hospitalized with severe acute asthma and found no benefit of the high dose over the low dose (Marquette et al, 1995). Manser et al performed a systematic review of randomized controlled studies of patients with acute severe asthma comparing different doses of glucocorticoids with a minimum follow up of 24 hours. They divided the different doses used in the trials included into 3 groups as equivalent dose of methylprednisolone in 24 hours; low dose (≤80 mg), medium dose (>80 mg and ≤360 mg), and high dose (>360 mg). Nine trials were included with a total of 344 adults. They found no

Studies also showed no difference in efficacy between oral or intravenous administration or in their onset on action. Fifty-two adults with severe acute asthma were treated with either IV hydrocortisone or PO prednisolone. There was no difference in their peak flow measurements 24 hours after admission (Harrison et al, 1986). Ratto et al compared four different doses of methylprednisolone; 160 or 320 mg given orally, or 500 or 1000 mg given IV in four divided doses in adults with acute asthma and found no difference in their FEV1,

**2.1. Systemic glucocorticoids** 

currently receiving steroids (Rowe et al, 2001).

difference between the different doses (Manser et al, 2001).


### **2. Clinical evidence of the effect of glucocorticoids in acute asthma**

#### **2.1. Systemic glucocorticoids**

508 Glucocorticoids – New Recognition of Our Familiar Friend

**1.4. Adverse effects of glucocorticoids** 

early morning cortisol level.

2000).

a holding chamber.

psychosis or mood changes.

There are many adverse effects that may result from the use of oral or IGC in the treatment

a. Suppression of the hypothalamic-pituitary-adrenal axis. Soon after the commencement of high dose oral glucocorticoids adrenal suppression may be noticeable. It also occurs with longer use of lower doses. IGC can also be systemically absorbed in their active form through particle deposition in the orophaynx or the lungs (particles deposited in the stomach usually undergo first pass hepatic metabolism where they are deactivated). High doses of IGC, more than 400 mcg of becloemthasone and 200 mcg of fluticasone or budesonide per day, could cause systemic adverse effects especially in children (Gulliver & Eid, 2005). Patients who undergo a stressful situation like major surgery should receive systemic steroid coverage to avoid symptoms of adrenal crises. These symptoms include lethargy, vomiting, change in mental status, and electrolyte disturbances. The hypothalamic-pituitary-adrenal axis can be evaluated by measuring

b. Osteoporosis. A common and serious complication of prolonged oral or high dose IGC therapy. Patients on such treatment, especially women and those with limited physical activity or who are taking medications that increase vitamine D metabolism in the liver, should undergo bone densitometry evaluation because this complication cannot be detected clinically. In one specialized center in the US, 40% of adolescent females

c. Growth suppression. Glucocorticiods have been consistently shown to suppress growth in children. This seems to be independent from the growth suppression caused by the disease itself (Covar et al, 2000). The degree of growth suppression may reach 1 cm especially in the first year after starting IGC treatment. However, children eventually reach their expected height as adults (Agertoft & Pedersen, 2000; Sharek & Bergman,

d. Ophthalmologic adverse effects. Long-term administration of oral glucocorticoids or high doses IGC can lead to the development of posterior capsular cataract (Cumming et al, 1997). Some patients may need lens replacement surgery. Another ophthalmic complication is glaucoma that also may result from prolonged therapy with high dose IGC (Garbe et al, 1997). However, short-term treatment for less than 2 years or the use of moderate doses of IGC was found to be safe (Li et al, 1999; Pelkonen et al, 2008). e. Local adverse effects: Chronic use of IGC can be associated with the development of oral thrush (candidiasis), which could be minimized by washing the mouth with water after the inhalation. It may also be associated with hoarseness of voice and dysphonia due probably to laryngeal edema. These effects can be managed by changing the mode of inhalation (e.g: from dry powder inhaler to MDI) and the use of

f. Other adverse effects: These include immune suppression, metabolic changes like hyperglycemia, acne, hirsutism, skin thinning, delayed wound healing, myopathy,

admitted with severe asthma had osteopenia (Covar et al, 2000).

of asthma especially in high doses. I will summarize here the most pertinent ones.

Systemic glucocorticoids given early in the course of treatment of acute asthma exacerbations in the emergency room were overall shown to be effective and are recommended by different asthma guidelines like GINA and EPR3. Littenberg et al. initially showed that they decrease hospital admission rate (Littenberg & Gluck, 1986). Five subsequent studies had, however, conflicting results. Rodrigo & Rodrigo reviewed all these six studies and concluded that there was no improvement in hospital admission rate or lung function (Rodrigo & Rodrigo, 1999). They, however, reported a trend of improvement in lung function only with medium or high doses systemic glucocorticoids. So data in terms of lung function are more encouraging (Fanta et al, 1983; Lin et al, 1999). In terms of effect on exacerbation relapse after discharge from the emergency room, most studies showed less relapse with systemic glucocorticoids (Schneider et al, 1988; Subcommittee on clinical trials in asthma, 1956) although others did not (Rodrigo & Rodrigo, 1994). One important issue with all these studies is the low number of patients recruited. Almost all had subject number less than 100 per study and all were performed in adults. On the other hand, Krishnan et al recently reviewed 9 published studies in the use of systemic glucocorticoids in acute asthma in adults and concluded "systemic corticosteroids provide clinically meaningful benefits in patients presenting with acute asthma" (Krishnan et al, 2009). In children, more limited data showed benefit of systemic steroids used early in the emergency room with decreased rate of admission (Scarfone et al, 1993). A Cochrane database review by Rowe et al showed decrease rate of admission in patients with acute asthma with the use of systemic glucocorticoids in adults and children especially those with severe asthma and those not currently receiving steroids (Rowe et al, 2001).

There is no significant difference in efficacy of systemic glucocorticoids at doses above 60-80 mg/d or 2 mg/kg/d in regards to pulmonary function, rate of admission, or length of stay in the hospital. For example, Marquette et al compared 1 mg/kg/d to 6 mg/kg/d methylprednisolone in 47 adults hospitalized with severe acute asthma and found no benefit of the high dose over the low dose (Marquette et al, 1995). Manser et al performed a systematic review of randomized controlled studies of patients with acute severe asthma comparing different doses of glucocorticoids with a minimum follow up of 24 hours. They divided the different doses used in the trials included into 3 groups as equivalent dose of methylprednisolone in 24 hours; low dose (≤80 mg), medium dose (>80 mg and ≤360 mg), and high dose (>360 mg). Nine trials were included with a total of 344 adults. They found no difference between the different doses (Manser et al, 2001).

Studies also showed no difference in efficacy between oral or intravenous administration or in their onset on action. Fifty-two adults with severe acute asthma were treated with either IV hydrocortisone or PO prednisolone. There was no difference in their peak flow measurements 24 hours after admission (Harrison et al, 1986). Ratto et al compared four different doses of methylprednisolone; 160 or 320 mg given orally, or 500 or 1000 mg given IV in four divided doses in adults with acute asthma and found no difference in their FEV1,

days of hospitalization (Ratto et al, 1988). In children oral prednisolone was found equivalent to IV methylprednisolone in regards to patients' length of hospital stay (Becker et al, 1999). In addition, oral treatment was cost saving. GINA and the EPR3 guidelines prefer oral administration because it is less invasive except in patients with absorption problems or those who are not able to take orally due to the severity of their respiratory distress or because they are vomiting.

The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 511

glucocorticoids after 1 week resulted in rebound in the level of exhaled NO 2 weeks post discharge despite continuing IGC with no effect on the use of rescue medications or on FEV1 (Khoo & Lim, 2009). GINA guideline state that "IGC are effective as part of therapy for asthma exacerbations….and can be as effective as oral glucocorticoids at preventing relapses"(GINA, 2011), while the EPR3 guidelines state that "high doses of IGC may be considered in the ER, although current evidence is insufficient to permit conclusions about

When IGC were used as add on therapy to systemic glucocorticoids in the ER and continued after discharge for few weeks, Rowe et al found decrease in relapse rate when 1600 mcg/d budesonide for 21 days was added to a course of 50 mg/d prednisone for 7 days as compared to placebo (Rowe et al, 1999). On the other hand, Brenner et al found no difference in the peak expiratory flow rate between high dose flunisolide used for 24 days added to prednisone 40 mg/d for 5 days as compared to placebo (Brenner et al, 2000). A systematic review of ten trials concluded no benefit of adding inhaled to systemic

There are few randomized and blinded studies examining only the short-term effect of IGC in the ER as add on therapy to systemic glucocorticoids plus other standard acute asthma therapy. One study looked at the addition of high dose beclomethasone versus placebo to methylprednisolone in 60 adults and found no difference in FEV1 or symptoms between the two groups (Guttman et al, 1997). One study looked at the addition of budesonide nebulizations to methylprednisolone in a population of 26 children with moderate asthma (Nuhoglu et al, 2005) and found no difference in the primary outcome of pulmonary index score but there was an improvement in the PEFR in the budesonide group compared to placebo. However, the patient number included is very small and PEFR is generally not reliable in young children. The two other randomized and blinded studies that were larger and more rigorous examined the effect of adding 2 mg of budesonide nebulization to prednisone in children with moderate to severe asthma (Sung et al, 1998; Upham et al, 2011). In the study by Sung et al, 44 children with moderate to severe asthma were included. Both groups had no difference in the pulmonary index score. In the Upham et al study, 180 children with moderate to severe asthma were included. There was no difference in the asthma score (adopted form (Qureshi et al, 1998)) at 2 hours after intervention or in the admission rate or time to discharge from the ER between the two groups. Collectively, all these studies, although small in subjects number, indicate that the addition of IGC to systemic steroid is not helpful in patients with moderate to severe acute asthma. We are conducting a larger study that will hopefully shed more light on that question, the results of

**3. A brief overview of the use of glucocorticoids in asthma prophylaxis** 

IGCs are the main stay of asthma management. They were shown to very consistently change many of the pathologic inflammatory features of asthma in the lung airways. They

using IGC rather than oral systemic corticosteroids in the ER"(EPR3, 2007).

glucocorticoids in reducing the relapse rate of acute asthma (Edmonds et al, 2000).

which should be available quite soon.

**3.1. Inhaled glucocorticoids** 

Prescribing oral glucocorticoids for the treatment of acute asthma exacerbations for longer than 5 days was not found to provide any additional benefit (Hasegawa et al, 2000; Jones et al, 2002). In children, a single dose of dexamethasone 0.6 mg/kg (max. 18 mg) was found to be equivalent to prednisolone 2 mg/kg/d in two divided doses for 5 days in terms of symptoms resolution (Altamimi et al, 2006). There is also no benefit from using a dose taper over fixed-dose regimen (Krishnan et al, 2009). Because of poor compliance on oral prednisone after discharge from the emergency, intramuscular injection of methylprednisolone was studied as an alternative but was not found superior, plus there was an evidence of injection-site adverse reaction (see last reference).

#### **2.2. Inhaled glucocorticoids**

IGC were studied in the treatment of acute asthma in 4 contexts: as compared to placebo, as compared to systemic glucocorticoids, as add on therapy to systemic steroids for up to few weeks after discharge from the ER, or as add on therapy to systemic steroids in the ER only.

In the first context, a review that looked at 8 randomized and blinded studies comparing the efficacy of IGC to placebo in acute asthma exacerbation suggested that IGC are superior to placebo especially when given at high doses (> 1mg of budesonide or fluticasone) and to patients with severe exacerbations (Rodrigo, 2006). It is important to note that those studies were quite heterogeneous in terms of the severity of asthma in recruited patients, the dose and frequency of IGC administered, and in the outcome measures that included clinical symptoms, pulmonary function, oxygen saturation, admission rate, or relapse rate. A recent study found that preemptive use of high dose fluticasone (750 mcg BID) at the onset of an upper respiratory tract infection in children with recurrent virus induced wheezing and continuing it for 10 days, reduced the use of rescue oral glucocorticoids (Ducharme et al, 2009).

When IGCs were compared with systemic glucocorticoids in randomized and blinded studies the data were more controversial. Some studies reported superiority of systemic steroids in reducing admission rate (Schuh et al, 2000), some reported equal efficacy in relation to admission rate as well (Lee-Wong et al, 2002; Levy et al, 1996; Scarfone et al, 1995), and some reported clear superiority of IGC (Devidayal et al, 1999; Rodrigo, 2005). A study compared high dose fluticasone in the ER and for 5 days post discharge to systemic glucocorticoids in the same period in patients with mild to moderate asthma found that oral steroids lead to faster improvement in FEV1 at 4 hours in the ER and less relapse rate at 48 hours post discharge (Schuh et al, 2006). One recent study showed that in patients who were given systemic glucocorticoids plus IGC post discharge from the ER, stopping the systemic glucocorticoids after 1 week resulted in rebound in the level of exhaled NO 2 weeks post discharge despite continuing IGC with no effect on the use of rescue medications or on FEV1 (Khoo & Lim, 2009). GINA guideline state that "IGC are effective as part of therapy for asthma exacerbations….and can be as effective as oral glucocorticoids at preventing relapses"(GINA, 2011), while the EPR3 guidelines state that "high doses of IGC may be considered in the ER, although current evidence is insufficient to permit conclusions about using IGC rather than oral systemic corticosteroids in the ER"(EPR3, 2007).

When IGC were used as add on therapy to systemic glucocorticoids in the ER and continued after discharge for few weeks, Rowe et al found decrease in relapse rate when 1600 mcg/d budesonide for 21 days was added to a course of 50 mg/d prednisone for 7 days as compared to placebo (Rowe et al, 1999). On the other hand, Brenner et al found no difference in the peak expiratory flow rate between high dose flunisolide used for 24 days added to prednisone 40 mg/d for 5 days as compared to placebo (Brenner et al, 2000). A systematic review of ten trials concluded no benefit of adding inhaled to systemic glucocorticoids in reducing the relapse rate of acute asthma (Edmonds et al, 2000).

There are few randomized and blinded studies examining only the short-term effect of IGC in the ER as add on therapy to systemic glucocorticoids plus other standard acute asthma therapy. One study looked at the addition of high dose beclomethasone versus placebo to methylprednisolone in 60 adults and found no difference in FEV1 or symptoms between the two groups (Guttman et al, 1997). One study looked at the addition of budesonide nebulizations to methylprednisolone in a population of 26 children with moderate asthma (Nuhoglu et al, 2005) and found no difference in the primary outcome of pulmonary index score but there was an improvement in the PEFR in the budesonide group compared to placebo. However, the patient number included is very small and PEFR is generally not reliable in young children. The two other randomized and blinded studies that were larger and more rigorous examined the effect of adding 2 mg of budesonide nebulization to prednisone in children with moderate to severe asthma (Sung et al, 1998; Upham et al, 2011). In the study by Sung et al, 44 children with moderate to severe asthma were included. Both groups had no difference in the pulmonary index score. In the Upham et al study, 180 children with moderate to severe asthma were included. There was no difference in the asthma score (adopted form (Qureshi et al, 1998)) at 2 hours after intervention or in the admission rate or time to discharge from the ER between the two groups. Collectively, all these studies, although small in subjects number, indicate that the addition of IGC to systemic steroid is not helpful in patients with moderate to severe acute asthma. We are conducting a larger study that will hopefully shed more light on that question, the results of which should be available quite soon.

#### **3. A brief overview of the use of glucocorticoids in asthma prophylaxis**

#### **3.1. Inhaled glucocorticoids**

510 Glucocorticoids – New Recognition of Our Familiar Friend

because they are vomiting.

**2.2. Inhaled glucocorticoids** 

(Ducharme et al, 2009).

days of hospitalization (Ratto et al, 1988). In children oral prednisolone was found equivalent to IV methylprednisolone in regards to patients' length of hospital stay (Becker et al, 1999). In addition, oral treatment was cost saving. GINA and the EPR3 guidelines prefer oral administration because it is less invasive except in patients with absorption problems or those who are not able to take orally due to the severity of their respiratory distress or

Prescribing oral glucocorticoids for the treatment of acute asthma exacerbations for longer than 5 days was not found to provide any additional benefit (Hasegawa et al, 2000; Jones et al, 2002). In children, a single dose of dexamethasone 0.6 mg/kg (max. 18 mg) was found to be equivalent to prednisolone 2 mg/kg/d in two divided doses for 5 days in terms of symptoms resolution (Altamimi et al, 2006). There is also no benefit from using a dose taper over fixed-dose regimen (Krishnan et al, 2009). Because of poor compliance on oral prednisone after discharge from the emergency, intramuscular injection of methylprednisolone was studied as an alternative but was not found superior, plus there

IGC were studied in the treatment of acute asthma in 4 contexts: as compared to placebo, as compared to systemic glucocorticoids, as add on therapy to systemic steroids for up to few weeks after discharge from the ER, or as add on therapy to systemic steroids in the ER only. In the first context, a review that looked at 8 randomized and blinded studies comparing the efficacy of IGC to placebo in acute asthma exacerbation suggested that IGC are superior to placebo especially when given at high doses (> 1mg of budesonide or fluticasone) and to patients with severe exacerbations (Rodrigo, 2006). It is important to note that those studies were quite heterogeneous in terms of the severity of asthma in recruited patients, the dose and frequency of IGC administered, and in the outcome measures that included clinical symptoms, pulmonary function, oxygen saturation, admission rate, or relapse rate. A recent study found that preemptive use of high dose fluticasone (750 mcg BID) at the onset of an upper respiratory tract infection in children with recurrent virus induced wheezing and continuing it for 10 days, reduced the use of rescue oral glucocorticoids

When IGCs were compared with systemic glucocorticoids in randomized and blinded studies the data were more controversial. Some studies reported superiority of systemic steroids in reducing admission rate (Schuh et al, 2000), some reported equal efficacy in relation to admission rate as well (Lee-Wong et al, 2002; Levy et al, 1996; Scarfone et al, 1995), and some reported clear superiority of IGC (Devidayal et al, 1999; Rodrigo, 2005). A study compared high dose fluticasone in the ER and for 5 days post discharge to systemic glucocorticoids in the same period in patients with mild to moderate asthma found that oral steroids lead to faster improvement in FEV1 at 4 hours in the ER and less relapse rate at 48 hours post discharge (Schuh et al, 2006). One recent study showed that in patients who were given systemic glucocorticoids plus IGC post discharge from the ER, stopping the systemic

was an evidence of injection-site adverse reaction (see last reference).

IGCs are the main stay of asthma management. They were shown to very consistently change many of the pathologic inflammatory features of asthma in the lung airways. They

lead to decrease cellular infiltrates including T-lymphocytes, mast cells, eosinophils, and macrophages. Also, epithelial damage, goblet cell hyperplasia, and vascular blood flow significantly decreases with IGC therapy (Fanta, 2009). Consistent with the histological changes, clinical changes are observed. Compliant use of IGC is associated with decreased airway hyperresponsiveness and improved asthma symptomatology (CAMP, 2000; Haahtela et al, 1991). Most patients will also have improved lung function demonstrated by increased FEV1. In addition, the risk of patients' hospitalization from asthma exacerbations is decreased by up to 50% (Donahue et al, 1997). Moreover, the risk of death from asthma is decreased, an effect that is dependent on the patients' compliance on IGC and the duration of their use (Suissa et al, 2000).

The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 513

The main mechanism whereby glucocorticoids deliver their anti-inflammatory action involves genomic action. This mechanism entails binding of glucocorticoids to their cytoplasmic receptors forming complexes that then translocate to the nucleus, where they either homo-dimerize then bind to their glucocorticoid response elements (GRE) in the DNA, or bind to different transcription factors (protein-protein interaction) as monomers (Ito et al, 2006; Lowenberg et al, 2008). Because of this, the genomic action of glucocorticoids takes at least 4 hours to start showing an effect and the duration of action is also prolonged

**Figure 2.** The genomic effect of glucocorticoids is in the form of transactivation or transrepression. In transactivation, the transcription of genes encoding certain anti-inflammatory or regulatory proteins is upregulated, while in transrepression the transcription of certain genes encoding proinflammatory proteins is up regulated. Abbreviations: AP1, activator protein 1; cGCR, cytosolic glucocorticoid receptor; COX-2, cyclooxygenase 2; GRE, glucocorticoid response element; IkB, inhibitor of NFkB; IFNγ interferon IL, interleukin; NF-AT, nuclear factor of activated T cells; NFkB, nuclear factor kB; STAT5, signal transducer and activator of transcription 5; TF, transcription factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Rheumatology. Cindy Stahn and Frank Buttgereit. Vol. 4(10):Page 529, copyright 2008.

**4.1. Genomic action** 

and may exceed 24 hours.

It is important here to note several points. First, the local anti-inflammatory effect of IGC usually plateaus after reaching low to moderate dosages, except probably for the most severe patients. However, the other systemic effects of IGC increase steeply after exceeding the low to moderate dose (Szefler et al, 2005). Therefore, efforts should be made to maintain patients on the lowest possible dose of IGC and, in cases of inappropriate response, long acting beta-agonists (LABA) or leukotriene receptor antagonists (LTRA) or both should be added before doubling the dose of IGC (Fanta, 2009). Second, there is great heterogeneity among asthmatics in their response to IGC. This variability can be attributed to several factors, most importantly are genetic variations between individuals (Lima et al, 2009). Third, multiple studies have shown that IGC therapy over the years do not change the natural history of the disease or prevent decline in lung function. They may have little effect on some features of remodeling but not all of them. Also, IGC, even when used in high risk infants who are very likely to develop asthma, were not able to prevent its development (Murray, 2008).

#### **3.2. Systemic glucocorticoids**

Systemic glucocorticoids are only occasionally used for long-term asthma control. There use is limited to the most severe patients who are difficult to control using other common modalities (EPR3, 2007). This is due to their side effects that can be very serious as stated above. The side effects are dose and duration dependent. Prolonged low dose therapy (<7.5 mg prednisone-equivalent in adults/day) is usually associated with mild adverse effects. Moderate doses (7.5 mg – 30 mg/day) are usually associated with significant adverse effects, and high doses (30 mg – 100 mg) may be associated with serious adverse effects (Stahn & Buttgereit, 2008).

#### **4. Mechanism of action of glucocorticoids in asthma**

Discussion of the mechanism of action of glucocorticoids in asthma is beyond the scope of this chapter and was recently reviewed (Alangari, 2010). Glucocorticoids act either by altering the rate of transcription of certain genes at the DNA level or through non-genomic pathways. Some of these effects could lead to the desirable anti-inflammatory action and some may result in adverse reactions.

#### **4.1. Genomic action**

512 Glucocorticoids – New Recognition of Our Familiar Friend

of their use (Suissa et al, 2000).

(Murray, 2008).

Buttgereit, 2008).

**3.2. Systemic glucocorticoids** 

some may result in adverse reactions.

lead to decrease cellular infiltrates including T-lymphocytes, mast cells, eosinophils, and macrophages. Also, epithelial damage, goblet cell hyperplasia, and vascular blood flow significantly decreases with IGC therapy (Fanta, 2009). Consistent with the histological changes, clinical changes are observed. Compliant use of IGC is associated with decreased airway hyperresponsiveness and improved asthma symptomatology (CAMP, 2000; Haahtela et al, 1991). Most patients will also have improved lung function demonstrated by increased FEV1. In addition, the risk of patients' hospitalization from asthma exacerbations is decreased by up to 50% (Donahue et al, 1997). Moreover, the risk of death from asthma is decreased, an effect that is dependent on the patients' compliance on IGC and the duration

It is important here to note several points. First, the local anti-inflammatory effect of IGC usually plateaus after reaching low to moderate dosages, except probably for the most severe patients. However, the other systemic effects of IGC increase steeply after exceeding the low to moderate dose (Szefler et al, 2005). Therefore, efforts should be made to maintain patients on the lowest possible dose of IGC and, in cases of inappropriate response, long acting beta-agonists (LABA) or leukotriene receptor antagonists (LTRA) or both should be added before doubling the dose of IGC (Fanta, 2009). Second, there is great heterogeneity among asthmatics in their response to IGC. This variability can be attributed to several factors, most importantly are genetic variations between individuals (Lima et al, 2009). Third, multiple studies have shown that IGC therapy over the years do not change the natural history of the disease or prevent decline in lung function. They may have little effect on some features of remodeling but not all of them. Also, IGC, even when used in high risk infants who are very likely to develop asthma, were not able to prevent its development

Systemic glucocorticoids are only occasionally used for long-term asthma control. There use is limited to the most severe patients who are difficult to control using other common modalities (EPR3, 2007). This is due to their side effects that can be very serious as stated above. The side effects are dose and duration dependent. Prolonged low dose therapy (<7.5 mg prednisone-equivalent in adults/day) is usually associated with mild adverse effects. Moderate doses (7.5 mg – 30 mg/day) are usually associated with significant adverse effects, and high doses (30 mg – 100 mg) may be associated with serious adverse effects (Stahn &

Discussion of the mechanism of action of glucocorticoids in asthma is beyond the scope of this chapter and was recently reviewed (Alangari, 2010). Glucocorticoids act either by altering the rate of transcription of certain genes at the DNA level or through non-genomic pathways. Some of these effects could lead to the desirable anti-inflammatory action and

**4. Mechanism of action of glucocorticoids in asthma** 

The main mechanism whereby glucocorticoids deliver their anti-inflammatory action involves genomic action. This mechanism entails binding of glucocorticoids to their cytoplasmic receptors forming complexes that then translocate to the nucleus, where they either homo-dimerize then bind to their glucocorticoid response elements (GRE) in the DNA, or bind to different transcription factors (protein-protein interaction) as monomers (Ito et al, 2006; Lowenberg et al, 2008). Because of this, the genomic action of glucocorticoids takes at least 4 hours to start showing an effect and the duration of action is also prolonged and may exceed 24 hours.

**Figure 2.** The genomic effect of glucocorticoids is in the form of transactivation or transrepression. In transactivation, the transcription of genes encoding certain anti-inflammatory or regulatory proteins is upregulated, while in transrepression the transcription of certain genes encoding proinflammatory proteins is up regulated. Abbreviations: AP1, activator protein 1; cGCR, cytosolic glucocorticoid receptor; COX-2, cyclooxygenase 2; GRE, glucocorticoid response element; IkB, inhibitor of NFkB; IFNγ interferon IL, interleukin; NF-AT, nuclear factor of activated T cells; NFkB, nuclear factor kB; STAT5, signal transducer and activator of transcription 5; TF, transcription factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Rheumatology. Cindy Stahn and Frank Buttgereit. Vol. 4(10):Page 529, copyright 2008.

Binding of glucocorticoid receptors to their GRE activates the transcription of certain genes encoding anti-inflammatory proteins, like IL-10 and IkB, and regulatory proteins. This process is called *transactivation* (figure 2). Some of the glucocorticoids adverse effects like glaucoma and hyperglycemia are mediated through this pathway (Schacke et al, 2002). On the other hand, binding of glucocorticoid receptors to pro-inflammatory transcription factors like nuclear factor kappa B (NFkB) or activator protein 1 (AP-1), or their competition for nuclear coactivators; down regulates the transcription of certain genes encoding proinflammatory proteins like IL-1, IL-2, IL-6, and TNF. This process is called *transrepression* (De Bosscher et al, 2003) (figure 2). Most of the desired genomic actions of glucocorticoids in asthma are mediated through this pathway.

The Use of Glucocorticoids in the Treatment of Acute Asthma Exacerbations 515

asthma and it seems that those medications will stay with us for a long while. Further research is greatly needed to shed more light on the use of IGC in the ER in patients coming with acute asthma exacerbation and on the safety of dispensing oral glucocorticoids for home use in case of asthma exacerbation. Training physicians to follow asthma management guidelines as well as education of patients and their families cannot be over emphasized and

Our improved understanding of the tertiary structure of glucocorticoids and their receptors and their mechanisms of action has led to the discovery and development of selective glucocorticoid receptor modulators (SGRM). Those are new agents that have the transrepression but little or no transactivation properties of glucocorticoids, which means that those compounds could deliver the desired anti-inflammatory action of glucocorticoids while avoiding most of their adverse effects (De Bosscher et al, 2010). Still under investigation, those agents could hold a lot of promise in the future. Moreover, it was recently shown that simultaneous activation of GRα and peroxisome proliferator-activated receptor alpha (PPARα), which are cytosolic receptors with many immunomodulatory functions and multiple natural ligands, can block the GRE mediated transactivating effects of glucocorticoids while potentiating their anti-inflammatory effects in mice (Bougarne et al, 2009). If this holds true in humans, combination therapy of a glucocorticoid and a PPARα

*Department of Pediatrics, College of Medicine, King Saud University, Saudi Arabia* 

I am very grateful to Prof. Dale Umetsu for reviewing this manuscript. This work was supported by a grant form the Program of Strategic Technologies of the National Plan for

Adams JY, Sutter ME, Albertson TE (2011) The Patient with Asthma in the Emergency

Agertoft L, Pedersen S (2000) Effect of long-term treatment with inhaled budesonide on

Alangari AA (2010) Genomic and non-genomic actions of glucocorticoids in asthma. *Ann* 

Altamimi S, Robertson G, Jastaniah W, Davey A, Dehghani N, Chen R, Leung K, Colbourne M (2006) Single-dose oral dexamethasone in the emergency management of children with exacerbations of mild to moderate asthma. *Pediatr Emerg Care* 22(12): 786-793

adult height in children with asthma. *N Engl J Med* 343(15): 1064-1069

Science and Technology and Innovation, Saudi Arabia. Grant number 08-MED520-02.

will save a lot of money.

agonist could be very promising.

**Author details** 

Abdullah A. Alangari

**Acknowledgement** 

Department. *Clin Rev Allergy Immunol*

*Thorac Med* 5(3): 133-139

**6. References** 

#### **4.2. Non-genomic action**

Non-genomic action of glucocorticoids includes all actions that do not directly alter gene expression and are not blunted by inhibitors of gene transcription (Losel & Wehling, 2003). This mode of action is characterized by its rapid onset (seconds to minutes) and short duration (60-90 min). These actions are dose dependent (Wanner et al, 2004). There are four types of non-genomic action of glucocorticoids (Alangari, 2010). Firstly, acting through the inhibition of the extraneuronal monoamine transporter-mediated uptake of norepinephrine. Asthmatic patients have increased blood flow in their airways (Kumar et al, 1998). IGC were shown to decrease blood flow in the airways within few minutes. This effect will last for 90 minutes only and therefore, cannot be explained by the genomic action (Kumar et al, 2000; Mendes et al, 2003). The proposed mechanism is that IGCs by a topical effect can block the extraneuronal monoamine transporter on the membrane of vascular endothelial cells, preventing their uptake of norepinephrine and thus making it more available in the synaptic cleft (Horvath & Wanner, 2006). Secondly, in high doses, glucocorticoids can induce physiochemical changes in the cell membrane by directly incorporating into the membrane. This can result in immune cell suppression (Buttgereit & Scheffold, 2002). Thirdly, glucocorticoids may interact with membrane bound GRs on mononuclear cells. These receptors are variants of cytosolic GRs and can mediate inhibition of Lck/Fyn kinases down stream form the T-cell receptor leading to immune suppression (Lowenberg et al, 2005; Lowenberg et al, 2007). Lastly, few in vitro studies showed that some protein components associated with GRs complex, which are released upon GR ligation can inactivate cytosolic phospholipase 2 and therefore inhibit the production of arachidonic acid and downstream components like prostaglandins and leukotriens (Croxtall et al, 2000; Croxtall et al, 2002). However this action was not shown to be of clinical significance.

#### **5. Future directions and recommendations**

We have seen through this chapter that glucocorticoids play an extremely important role in the current prophylactic treatment of patients with persistent asthma, in the treatment of acute asthma exacerbations post discharge from the ER and possibly in the acute management in the ER. The introduction of IGC has revolutionized the way we manage asthma and it seems that those medications will stay with us for a long while. Further research is greatly needed to shed more light on the use of IGC in the ER in patients coming with acute asthma exacerbation and on the safety of dispensing oral glucocorticoids for home use in case of asthma exacerbation. Training physicians to follow asthma management guidelines as well as education of patients and their families cannot be over emphasized and will save a lot of money.

Our improved understanding of the tertiary structure of glucocorticoids and their receptors and their mechanisms of action has led to the discovery and development of selective glucocorticoid receptor modulators (SGRM). Those are new agents that have the transrepression but little or no transactivation properties of glucocorticoids, which means that those compounds could deliver the desired anti-inflammatory action of glucocorticoids while avoiding most of their adverse effects (De Bosscher et al, 2010). Still under investigation, those agents could hold a lot of promise in the future. Moreover, it was recently shown that simultaneous activation of GRα and peroxisome proliferator-activated receptor alpha (PPARα), which are cytosolic receptors with many immunomodulatory functions and multiple natural ligands, can block the GRE mediated transactivating effects of glucocorticoids while potentiating their anti-inflammatory effects in mice (Bougarne et al, 2009). If this holds true in humans, combination therapy of a glucocorticoid and a PPARα agonist could be very promising.

### **Author details**

514 Glucocorticoids – New Recognition of Our Familiar Friend

asthma are mediated through this pathway.

However this action was not shown to be of clinical significance.

**5. Future directions and recommendations** 

**4.2. Non-genomic action** 

Binding of glucocorticoid receptors to their GRE activates the transcription of certain genes encoding anti-inflammatory proteins, like IL-10 and IkB, and regulatory proteins. This process is called *transactivation* (figure 2). Some of the glucocorticoids adverse effects like glaucoma and hyperglycemia are mediated through this pathway (Schacke et al, 2002). On the other hand, binding of glucocorticoid receptors to pro-inflammatory transcription factors like nuclear factor kappa B (NFkB) or activator protein 1 (AP-1), or their competition for nuclear coactivators; down regulates the transcription of certain genes encoding proinflammatory proteins like IL-1, IL-2, IL-6, and TNF. This process is called *transrepression* (De Bosscher et al, 2003) (figure 2). Most of the desired genomic actions of glucocorticoids in

Non-genomic action of glucocorticoids includes all actions that do not directly alter gene expression and are not blunted by inhibitors of gene transcription (Losel & Wehling, 2003). This mode of action is characterized by its rapid onset (seconds to minutes) and short duration (60-90 min). These actions are dose dependent (Wanner et al, 2004). There are four types of non-genomic action of glucocorticoids (Alangari, 2010). Firstly, acting through the inhibition of the extraneuronal monoamine transporter-mediated uptake of norepinephrine. Asthmatic patients have increased blood flow in their airways (Kumar et al, 1998). IGC were shown to decrease blood flow in the airways within few minutes. This effect will last for 90 minutes only and therefore, cannot be explained by the genomic action (Kumar et al, 2000; Mendes et al, 2003). The proposed mechanism is that IGCs by a topical effect can block the extraneuronal monoamine transporter on the membrane of vascular endothelial cells, preventing their uptake of norepinephrine and thus making it more available in the synaptic cleft (Horvath & Wanner, 2006). Secondly, in high doses, glucocorticoids can induce physiochemical changes in the cell membrane by directly incorporating into the membrane. This can result in immune cell suppression (Buttgereit & Scheffold, 2002). Thirdly, glucocorticoids may interact with membrane bound GRs on mononuclear cells. These receptors are variants of cytosolic GRs and can mediate inhibition of Lck/Fyn kinases down stream form the T-cell receptor leading to immune suppression (Lowenberg et al, 2005; Lowenberg et al, 2007). Lastly, few in vitro studies showed that some protein components associated with GRs complex, which are released upon GR ligation can inactivate cytosolic phospholipase 2 and therefore inhibit the production of arachidonic acid and downstream components like prostaglandins and leukotriens (Croxtall et al, 2000; Croxtall et al, 2002).

We have seen through this chapter that glucocorticoids play an extremely important role in the current prophylactic treatment of patients with persistent asthma, in the treatment of acute asthma exacerbations post discharge from the ER and possibly in the acute management in the ER. The introduction of IGC has revolutionized the way we manage Abdullah A. Alangari *Department of Pediatrics, College of Medicine, King Saud University, Saudi Arabia* 

### **Acknowledgement**

I am very grateful to Prof. Dale Umetsu for reviewing this manuscript. This work was supported by a grant form the Program of Strategic Technologies of the National Plan for Science and Technology and Innovation, Saudi Arabia. Grant number 08-MED520-02.

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**Chapter 20** 

© 2012 Valera et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Glucocorticoid Resistance in** 

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53105

being the most common disorders.

chronic condition in the American population [4].

work/school, and other daily activities [2].

**1. Introduction** 

**the Upper Respiratory Airways** 

Fabiana C.P. Valera, Edwin Tamashiro and Wilma T. Anselmo-Lima

The nasal mucosa is known to be the first important barrier against inhalants of the respiratory tract. In contrast to initial opinion, this tissue actively interacts with external factors, producing a wide combination of mediators in response to aggressor agents [1]. In this respect, it is easy to understand why the nasal mucosa is predisposed to the development of several chronic inflammatory diseases, with rhinitis and rhinosinusitis

According to the ARIA guideline [2], the prevalence of allergic rhinitis has increased in the last years and has been found to be around 25% in Europe [3]. The prevalence of symptoms related to chronic rhinosinusitis is about 15% in the USA, being the second most prevalent

The most common and studied cause of chronic rhinitis is allergic rhinitis (AR) [2]. AR is a nasal inflammatory disease in which the allergen induces IgE-mediated inflammation. The mediators released by the nasal mucosa will finally lead to intense inflammatory cell recruitment (predominantly eosinophils) [5], epithelial metaplasia (more pronounced in perennial AR) [6], and noticeable stromal edema, especially due to the action of matrix metalloproteinases [7]. This response to allergens will finally induce the classical symptoms of AR, such as sneezing, itching, nasal discharge and nasal obstruction. These symptoms considerably impair the quality of life, affecting sleep quality, concentration during

Chronic rhinosinusitis can be subdivided into two forms: chronic rhinosinusitis without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP). These two entities are almost clinically identical, and it is very difficult to differentiate them based only on nasal symptoms [8]. Both forms present variable degrees of facial pain, decreased sense of smell,

and reproduction in any medium, provided the original work is properly cited.

Zorc JJ, Pusic MV, Ogborn CJ, Lebet R, Duggan AK (1999) Ipratropium bromide added to asthma treatment in the pediatric emergency department. *Pediatrics* 103(4 Pt 1): 748-752

## **Glucocorticoid Resistance in the Upper Respiratory Airways**

Fabiana C.P. Valera, Edwin Tamashiro and Wilma T. Anselmo-Lima

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53105

### **1. Introduction**

522 Glucocorticoids – New Recognition of Our Familiar Friend

*Thoracic Society* 1(3): 235-238

Wanner A, Horvath G, Brieva JL, Kumar SD, Mendes ES (2004) Nongenomic actions of glucocorticosteroids on the airway vasculature in asthma. *Proceedings of the American* 

Zorc JJ, Pusic MV, Ogborn CJ, Lebet R, Duggan AK (1999) Ipratropium bromide added to asthma treatment in the pediatric emergency department. *Pediatrics* 103(4 Pt 1): 748-752

> The nasal mucosa is known to be the first important barrier against inhalants of the respiratory tract. In contrast to initial opinion, this tissue actively interacts with external factors, producing a wide combination of mediators in response to aggressor agents [1]. In this respect, it is easy to understand why the nasal mucosa is predisposed to the development of several chronic inflammatory diseases, with rhinitis and rhinosinusitis being the most common disorders.

> According to the ARIA guideline [2], the prevalence of allergic rhinitis has increased in the last years and has been found to be around 25% in Europe [3]. The prevalence of symptoms related to chronic rhinosinusitis is about 15% in the USA, being the second most prevalent chronic condition in the American population [4].

> The most common and studied cause of chronic rhinitis is allergic rhinitis (AR) [2]. AR is a nasal inflammatory disease in which the allergen induces IgE-mediated inflammation. The mediators released by the nasal mucosa will finally lead to intense inflammatory cell recruitment (predominantly eosinophils) [5], epithelial metaplasia (more pronounced in perennial AR) [6], and noticeable stromal edema, especially due to the action of matrix metalloproteinases [7]. This response to allergens will finally induce the classical symptoms of AR, such as sneezing, itching, nasal discharge and nasal obstruction. These symptoms considerably impair the quality of life, affecting sleep quality, concentration during work/school, and other daily activities [2].

> Chronic rhinosinusitis can be subdivided into two forms: chronic rhinosinusitis without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP). These two entities are almost clinically identical, and it is very difficult to differentiate them based only on nasal symptoms [8]. Both forms present variable degrees of facial pain, decreased sense of smell,

<sup>© 2012</sup> Valera et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

nasal discharge and nasal congestion. Clinically, the differentiation of these two entities is made by the detection of nasal polyps by nasal endoscopy. However, the major differences between CRSsNP and CRSwNP concern histology and molecular biomarkers [9]. CRSsNP is characterized by neutrophil recruitment, light edema, increased remodelling [9] and a Th1 subset profile. In contrast, CRSwNP is characterized by an eosinophil recruitment, intense oedema, loose connective tissue and a Th1/Th2 mixed –subset profile, but with remarkable Th2 polarization [8-10].

Glucocorticoid Resistance in the Upper Respiratory Airways 525

allergen binds to the complex IgE-mediator cell, massive degranulation of allergic molecules (either already existent and newly synthetized) are released in the extracellular compartment. Histamine is the main molecule released and involved in the early phase of symptoms of AR, but other mediators such as leukotriene, bradykinin, prostaglandins, platelet activating factor, and even some proteases (tryptase and chymase) and cytokines (TNF-α, IL-4, IL-5) also have a role in the development of allergic symptoms [14]. These mediators lead to the classical early symptoms of sneezing, itching, rhinorrhea, and nasal congestion that occur within a few minutes after allergen exposure (5-30 minutes). These symptoms are the consequence of direct actions of these mediators on different resident cells [15]. Glands are stimulated by leukotrienes and chymases to produce and release mucous secretions. Endothelial cells of post-capillary venules are affected by histamine, bradykinin, platelet activating factor and leukotrienes, inducing vasodilatation, increased vascular permeability and cell adhesion. Peripheral sensory endings are stimulated by histamine type 1 receptors on nociceptive type C fibers that generate an uncomfortable sensation of pain and pressure, sneezing and itching [16]. As the nasal mucosa is constantly assaulted by physical and chemical agents, the disruption of some areas facilitates the exposure of

After the IgE-mediated inflammatory burst triggered by the allergen, some individuals present total clearance of mediators and have complete resolution of symptoms after some minutes. However, a significant percentage (60-70%) of the allergic population develops the late AR response due to the recruitment of inflammatory cells into the nasal mucosa. The increased vascular permeability added to the expression of adhesion molecules (ICAM-1) and production of chemokines, recruits a variety of inflammatory cells that include

The late phase typically occurs 4-6 hours after the allergen contact and is clinically represented by the nasal obstruction and congestion caused by mucosal edema. Toxic products of eosinophils, such as eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil-derived neurotoxin and eosinophil peroxidase, are evident during the late phase and are proportional to the eosinophil recruitment. These highly charged proteins bind to proteoglycans and hyaluronic acid and cause cell damage and epithelial detachment. Other important inflammatory mediators involved in the late phase are leukotrienes, histamine, and cytokines of the Th2 response (IL-5, IL-6, GM-CSF) [17, 18]. Interestingly, the recruited eosinophils are able to promote an auto-positive feedback to prolong their survival and recruitment into the tissue, which ultimately leads to an independent eosinophilic inflammation (Figure 1). IL-3, IL-5, and GM-CSF are Th2 cytokines that reduce apoptosis and prolong eosinophil cell survival. Besides, IL-5, eotaxin and RANTES produced by eosinophils and other infiltrated cells recruit even more eosinophils to the inflammatory site, explaining the reason why a chronic allergic inflammation can be seen even when the

Lymphocytes are another group of cells that may play an important role in the late phase of AR. Memory T cells, T-cytotoxic and B cells have been demonstrated to be increased in AR

compared to other forms of non-allergic rhinitis and to controls [20].

eosinophils and basophils and, to a lesser extent, neutrophils and other leukocytes.

allergens to allergic mediator cells.

allergen is not present [19].

### **2. Cellular and molecular knowledge in nasal inflammatory diseases**

### **2.1. Allergic Rhinitis**

The development of signs and symptoms that characterize allergic rhinitis (AR) depends on three events: sensitization to an allergen, degranulation of inflammatory mediators after reexposure to the allergen (early phase) and infiltration of inflammatory cells into the tissue (late phase).

The respiratory nasal mucosa is continuously exposed to several particles that are deposited on the mucous blanket that covers the respiratory epithelium. These antigens are processed by antigen-presenting cells (APCs) such as Langerhans cells, that are later presented to a naïve lymphocyte through a major histocompatibility complex (MHC) class II molecule [11]. For reasons not completely elucidated, naïve lymphocytes (Th0) differentiate into Th2 lymphocytes and produce and release a pool of cytokines characteristic of the Th2 response pattern (IL-3, IL-4, IL-5, IL-9, IL-10, IL-13, GM-CSF). Moreover, the differentiated Th2 lymphocytes stimulate the production of specific IgE by plasmocytes through IL-3 and IL-4, and inhibit the differentiation of Th0 lymphocytes into Th1, as well as its messenger molecules. This selective environment polarized to a Th2 response is typically seen in allergic mechanisms, such as AR, asthma and atopic dermatitis, and in helminthic infections. B cells that recognize the processed antigen and receive appropriate contact signals (CD40- CD40) and molecular stimuli (IL-4, IL-6, IL-10, IL-13) start to produce specific IgE. In the presence of continuous antigen stimulation, B-cells switch from the production of a lowaffinity IgE molecule to the production of a high-affinity one [11].

Once high-affinity IgE circulates in the plasma and interstitial fluid, it binds to the Fc receptors. These receptors are present on the surface of mast cells and basophils, and are responsible for activating these cells when exposed to the binomial antibody-pathogen. After mast cells leave the post-capillary venules, they are able to reside in the stroma of the nasal submucosa and intraepithelially, probably by the production of several proteases. Resident mast cells are also able to produce some cytokines related to Th2 polarization (IL-4, IL-5), which in turn can cause an increased cell proliferation and survival time. In allergic mucosa, for instance, mast cells proliferate at a higher rate compared to a non-allergic environment, probably by the effect of Th2 cytokines [12, 13].

In a second phase, after sensitization and priming of resident mast cells with IgE, the respiratory mucosa becomes susceptible to a new exposure. When the specific inspired allergen binds to the complex IgE-mediator cell, massive degranulation of allergic molecules (either already existent and newly synthetized) are released in the extracellular compartment. Histamine is the main molecule released and involved in the early phase of symptoms of AR, but other mediators such as leukotriene, bradykinin, prostaglandins, platelet activating factor, and even some proteases (tryptase and chymase) and cytokines (TNF-α, IL-4, IL-5) also have a role in the development of allergic symptoms [14]. These mediators lead to the classical early symptoms of sneezing, itching, rhinorrhea, and nasal congestion that occur within a few minutes after allergen exposure (5-30 minutes). These symptoms are the consequence of direct actions of these mediators on different resident cells [15]. Glands are stimulated by leukotrienes and chymases to produce and release mucous secretions. Endothelial cells of post-capillary venules are affected by histamine, bradykinin, platelet activating factor and leukotrienes, inducing vasodilatation, increased vascular permeability and cell adhesion. Peripheral sensory endings are stimulated by histamine type 1 receptors on nociceptive type C fibers that generate an uncomfortable sensation of pain and pressure, sneezing and itching [16]. As the nasal mucosa is constantly assaulted by physical and chemical agents, the disruption of some areas facilitates the exposure of allergens to allergic mediator cells.

524 Glucocorticoids – New Recognition of Our Familiar Friend

Th2 polarization [8-10].

**2.1. Allergic Rhinitis** 

(late phase).

nasal discharge and nasal congestion. Clinically, the differentiation of these two entities is made by the detection of nasal polyps by nasal endoscopy. However, the major differences between CRSsNP and CRSwNP concern histology and molecular biomarkers [9]. CRSsNP is characterized by neutrophil recruitment, light edema, increased remodelling [9] and a Th1 subset profile. In contrast, CRSwNP is characterized by an eosinophil recruitment, intense oedema, loose connective tissue and a Th1/Th2 mixed –subset profile, but with remarkable

**2. Cellular and molecular knowledge in nasal inflammatory diseases** 

The development of signs and symptoms that characterize allergic rhinitis (AR) depends on three events: sensitization to an allergen, degranulation of inflammatory mediators after reexposure to the allergen (early phase) and infiltration of inflammatory cells into the tissue

The respiratory nasal mucosa is continuously exposed to several particles that are deposited on the mucous blanket that covers the respiratory epithelium. These antigens are processed by antigen-presenting cells (APCs) such as Langerhans cells, that are later presented to a naïve lymphocyte through a major histocompatibility complex (MHC) class II molecule [11]. For reasons not completely elucidated, naïve lymphocytes (Th0) differentiate into Th2 lymphocytes and produce and release a pool of cytokines characteristic of the Th2 response pattern (IL-3, IL-4, IL-5, IL-9, IL-10, IL-13, GM-CSF). Moreover, the differentiated Th2 lymphocytes stimulate the production of specific IgE by plasmocytes through IL-3 and IL-4, and inhibit the differentiation of Th0 lymphocytes into Th1, as well as its messenger molecules. This selective environment polarized to a Th2 response is typically seen in allergic mechanisms, such as AR, asthma and atopic dermatitis, and in helminthic infections. B cells that recognize the processed antigen and receive appropriate contact signals (CD40- CD40) and molecular stimuli (IL-4, IL-6, IL-10, IL-13) start to produce specific IgE. In the presence of continuous antigen stimulation, B-cells switch from the production of a low-

Once high-affinity IgE circulates in the plasma and interstitial fluid, it binds to the Fc receptors. These receptors are present on the surface of mast cells and basophils, and are responsible for activating these cells when exposed to the binomial antibody-pathogen. After mast cells leave the post-capillary venules, they are able to reside in the stroma of the nasal submucosa and intraepithelially, probably by the production of several proteases. Resident mast cells are also able to produce some cytokines related to Th2 polarization (IL-4, IL-5), which in turn can cause an increased cell proliferation and survival time. In allergic mucosa, for instance, mast cells proliferate at a higher rate compared to a non-allergic

In a second phase, after sensitization and priming of resident mast cells with IgE, the respiratory mucosa becomes susceptible to a new exposure. When the specific inspired

affinity IgE molecule to the production of a high-affinity one [11].

environment, probably by the effect of Th2 cytokines [12, 13].

After the IgE-mediated inflammatory burst triggered by the allergen, some individuals present total clearance of mediators and have complete resolution of symptoms after some minutes. However, a significant percentage (60-70%) of the allergic population develops the late AR response due to the recruitment of inflammatory cells into the nasal mucosa. The increased vascular permeability added to the expression of adhesion molecules (ICAM-1) and production of chemokines, recruits a variety of inflammatory cells that include eosinophils and basophils and, to a lesser extent, neutrophils and other leukocytes.

The late phase typically occurs 4-6 hours after the allergen contact and is clinically represented by the nasal obstruction and congestion caused by mucosal edema. Toxic products of eosinophils, such as eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil-derived neurotoxin and eosinophil peroxidase, are evident during the late phase and are proportional to the eosinophil recruitment. These highly charged proteins bind to proteoglycans and hyaluronic acid and cause cell damage and epithelial detachment. Other important inflammatory mediators involved in the late phase are leukotrienes, histamine, and cytokines of the Th2 response (IL-5, IL-6, GM-CSF) [17, 18]. Interestingly, the recruited eosinophils are able to promote an auto-positive feedback to prolong their survival and recruitment into the tissue, which ultimately leads to an independent eosinophilic inflammation (Figure 1). IL-3, IL-5, and GM-CSF are Th2 cytokines that reduce apoptosis and prolong eosinophil cell survival. Besides, IL-5, eotaxin and RANTES produced by eosinophils and other infiltrated cells recruit even more eosinophils to the inflammatory site, explaining the reason why a chronic allergic inflammation can be seen even when the allergen is not present [19].

Lymphocytes are another group of cells that may play an important role in the late phase of AR. Memory T cells, T-cytotoxic and B cells have been demonstrated to be increased in AR compared to other forms of non-allergic rhinitis and to controls [20].

Glucocorticoid Resistance in the Upper Respiratory Airways 527

In summary, the cellular and molecular mechanisms of AR involve B cell production of IgE and mast cell/basophil priming, activation of resident cells, recruitment of inflammatory cells and, in some circumstances, induction of a persistent inflammatory reaction

Chronic Rhinosinusitis (CRS) is clinically defined as the persistence of signs and symptoms such as nasal obstruction, nasal congestion, rhinorrhea, facial pain, cough, and loss of smell for more than 12 weeks, confirmed by nasal endoscopy or computed tomography. It is related to an inflammatory process of the mucoperiosteal pavement of the sinonasal cavity, whose etiology can be clearly defined in a few subgroups of patients, involving mechanical obstruction, immunodeficiency, cystic fibrosis, and ciliary dyskinesia. However, in the majority of cases, the etiology of CRS cannot be determined. Some investigators have raised different hypotheses for the pathogenesis of CRS such as disruption of the epithelial barrier, allergy, exposure to pollutants, maintenance of mucosal inflammation due to underlying osteitis, persistence of bacterial biofilms, and overreaction to staphylococcal superantigens or fungus. It is interesting to note that individually these theories do not apply to all patients but may explain the pathogenicity in some cases. Despite the unrevealed etiopathogenesis, recent advances have been made in the elucidation of the cellular and molecular events involved in different situations of CRS. Based on molecular phenotyping studies, the classification of CRS into two different clinical subsets has been currently accepted: CRS without nasal polyps (CRS *sine* NP, CRSsNP) and CRS with nasal polyps (CRSwNP) [8, 26]. Clinically, the symptoms of both types are very similar to each other, with slight differences in the severity of nasal congestion, nasal obstruction, rhinorrhea, postnasal drip, change in the sense of smell, cough, and facial pain. In terms of physical examination, they differ by the presence or absence of nasal polyps extruding from the middle meatus of the nasal cavity. This simple difference noted by nasal endoscopy involves profound differences in cellular and molecular aspects that

might be related to the prognosis and treatment of these two subsets of CRS.

Histologically, both forms of CRS are marked by niches of denuded respiratory epithelium with associated metaplasia, basal membrane thickening, and goblet cell hyperplasia. The histology of submucosal stroma demonstrates clear differences between CRSwNP and CRSsNP. In CRSwNP, the submucosal stroma usually is found with robust edema and low cellularity, in contrast to CRSsNP that characteristically involves more pronounced fibrosis

In CRSwNP, eosinophilic infiltration is the hallmark of chronic inflammation. For reasons not fully elucidated, there is an increased expression of pro-inflammatory cytokines (IL-1β) mediated by transcription factors. These cytokines mediate the recruitment of inflammatory cells (eosinophils, lymphocytes, neutrophils, mast cells) through the up-regulation and expression of adhesion molecules (ICAM-1, VCAM-1) and chemokines (IL-8, eotaxin, and RANTES). In CRSwNP, the striking influx of inflammatory cells, especially eosinophils, into the stroma, leads to a positive feedback recruitment similar to allergic rhinitis [27]. In the

maintained by a positive feedback.

and less edema [9].

**2.2. Chronic Rhinosinusitis (CRS)** 

Figure legend: Ag: antigen; APC: antigen presenting cell; TSLP: thymic stromal lymphopoietin; TLR: toll-like receptor; IL: interleukin; TNF: tumor necrosis factor; TF: transcriptor factor; Ig: immunoglobulin; GM-CSF: granulocyte macrophage colony-stimulating factor; LT: leukotriene; PG: prostaglandin; ECP: eosinophil cationic protein; MBP: major basic protein; PAF: platelet activating factor

**Figure 1.** Cellular and molecular events involved in the early and late phase response of AR. Initially, the antigen invades the cell, and either binds to the APC (antigen presenting cell) or activates innate immune response through TSLP or TLR-4. These mechanisms together will activate adaptative immune response, and T cells are triggered to Th2 response, producing cytokines as IL-4, IL-5 and IL-13. These cytokines will induce epithelial cells to produce rhinorrhea and will recruit inflammatory cells (as eosinophils) to nasal mucosa. Eosinophils will produce several cytokines that will lead to nasal obstruction. B cells are activated and produce IgE, which, among the antigen itself, will induce the mast cell to secrete histamine, leukotrienes and prostaglandins, among others, finally leading to the symptoms of sneezing and itching.

Resident cells may also participate in the late phase and development of chronic allergic inflammation. Nasal epithelial cells express an increased number of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8 and GM-CSF in allergic patients [21, 22]. Also, epithelial cells are the main source of thymic stromal lymphopoietin (TSLP) on the nasal mucosa, an important cytokine that drives T cells to produce Th2 cytokines [23] and is increased in AR patients compared to controls [24]. Submucosal glands located in the lamina propria are substantially increased in allergic patients (25%) compared to non-allergic individuals (15%), consistent with the chronic state of increased production of nasal secretions [25]

In summary, the cellular and molecular mechanisms of AR involve B cell production of IgE and mast cell/basophil priming, activation of resident cells, recruitment of inflammatory cells and, in some circumstances, induction of a persistent inflammatory reaction maintained by a positive feedback.

#### **2.2. Chronic Rhinosinusitis (CRS)**

526 Glucocorticoids – New Recognition of Our Familiar Friend

major basic protein; PAF: platelet activating factor

symptoms of sneezing and itching.

secretions [25]

Figure legend: Ag: antigen; APC: antigen presenting cell; TSLP: thymic stromal lymphopoietin; TLR: toll-like receptor; IL: interleukin; TNF: tumor necrosis factor; TF: transcriptor factor; Ig: immunoglobulin; GM-CSF: granulocyte macrophage colony-stimulating factor; LT: leukotriene; PG: prostaglandin; ECP: eosinophil cationic protein; MBP:

**Figure 1.** Cellular and molecular events involved in the early and late phase response of AR. Initially, the antigen invades the cell, and either binds to the APC (antigen presenting cell) or activates innate immune response through TSLP or TLR-4. These mechanisms together will activate adaptative immune response, and T cells are triggered to Th2 response, producing cytokines as IL-4, IL-5 and IL-13. These cytokines will induce epithelial cells to produce rhinorrhea and will recruit inflammatory cells (as eosinophils) to nasal mucosa. Eosinophils will produce several cytokines that will lead to nasal

obstruction. B cells are activated and produce IgE, which, among the antigen itself, will induce the mast

Resident cells may also participate in the late phase and development of chronic allergic inflammation. Nasal epithelial cells express an increased number of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8 and GM-CSF in allergic patients [21, 22]. Also, epithelial cells are the main source of thymic stromal lymphopoietin (TSLP) on the nasal mucosa, an important cytokine that drives T cells to produce Th2 cytokines [23] and is increased in AR patients compared to controls [24]. Submucosal glands located in the lamina propria are substantially increased in allergic patients (25%) compared to non-allergic individuals (15%), consistent with the chronic state of increased production of nasal

cell to secrete histamine, leukotrienes and prostaglandins, among others, finally leading to the

Chronic Rhinosinusitis (CRS) is clinically defined as the persistence of signs and symptoms such as nasal obstruction, nasal congestion, rhinorrhea, facial pain, cough, and loss of smell for more than 12 weeks, confirmed by nasal endoscopy or computed tomography. It is related to an inflammatory process of the mucoperiosteal pavement of the sinonasal cavity, whose etiology can be clearly defined in a few subgroups of patients, involving mechanical obstruction, immunodeficiency, cystic fibrosis, and ciliary dyskinesia. However, in the majority of cases, the etiology of CRS cannot be determined. Some investigators have raised different hypotheses for the pathogenesis of CRS such as disruption of the epithelial barrier, allergy, exposure to pollutants, maintenance of mucosal inflammation due to underlying osteitis, persistence of bacterial biofilms, and overreaction to staphylococcal superantigens or fungus. It is interesting to note that individually these theories do not apply to all patients but may explain the pathogenicity in some cases. Despite the unrevealed etiopathogenesis, recent advances have been made in the elucidation of the cellular and molecular events involved in different situations of CRS. Based on molecular phenotyping studies, the classification of CRS into two different clinical subsets has been currently accepted: CRS without nasal polyps (CRS *sine* NP, CRSsNP) and CRS with nasal polyps (CRSwNP) [8, 26]. Clinically, the symptoms of both types are very similar to each other, with slight differences in the severity of nasal congestion, nasal obstruction, rhinorrhea, postnasal drip, change in the sense of smell, cough, and facial pain. In terms of physical examination, they differ by the presence or absence of nasal polyps extruding from the middle meatus of the nasal cavity. This simple difference noted by nasal endoscopy involves profound differences in cellular and molecular aspects that might be related to the prognosis and treatment of these two subsets of CRS.

Histologically, both forms of CRS are marked by niches of denuded respiratory epithelium with associated metaplasia, basal membrane thickening, and goblet cell hyperplasia. The histology of submucosal stroma demonstrates clear differences between CRSwNP and CRSsNP. In CRSwNP, the submucosal stroma usually is found with robust edema and low cellularity, in contrast to CRSsNP that characteristically involves more pronounced fibrosis and less edema [9].

In CRSwNP, eosinophilic infiltration is the hallmark of chronic inflammation. For reasons not fully elucidated, there is an increased expression of pro-inflammatory cytokines (IL-1β) mediated by transcription factors. These cytokines mediate the recruitment of inflammatory cells (eosinophils, lymphocytes, neutrophils, mast cells) through the up-regulation and expression of adhesion molecules (ICAM-1, VCAM-1) and chemokines (IL-8, eotaxin, and RANTES). In CRSwNP, the striking influx of inflammatory cells, especially eosinophils, into the stroma, leads to a positive feedback recruitment similar to allergic rhinitis [27]. In the Caucasian CRS population, nasal polyps are remarkably characterized by a mixed expression of Th1 (INF-γ, IL-8) and Th2 cytokines, with an imbalance favoring the Th2 response. Th2 cytokines (IL-3, IL-5, GM-CSF) are produced by eosinophils and Th2 cells and increase eosinophil recruitment and survival, creating an autonomous inflammatory cycle even after the removal of the initial trigger. (Figure 2)

Glucocorticoid Resistance in the Upper Respiratory Airways 529

with high expression of T-bet (Th1) and GATA-3 (Th2) demonstrate the deficiency of Treg

In terms of molecular markers, among Caucasians, IL-5 is the most important cytokine found in CRSwNP. IL-5 is related to eosinophil infiltration and activation, and is significantly related to recurrence of nasal polyps after surgical removal [32]. Activated eosinophils also release several inflammatory mediators, such as leukotrienes, and other toxic products (Eosinophil Cationic Protein – ECP, Major Basic Protein – MBP, neurotoxin eosinophil protein). Besides the damage induced by infiltrated inflammatory cells, resident fibroblasts also play a role in the structural modification of the stroma. Stimulated by fibroblast growth factor (FGF) and TGF-β, fibroblasts are recruited, proliferate, and express matrix metalloproteinases (MMP), which degrade extracellular proteins (collagen, laminin, fibronectin, elastin) and favor tissue edema and albumin deposition. Other cells such as eosinophils and neutrophils are also able to produce MMP and may play a role in tissue remodeling [33]. Furthermore, fibroblasts suppress the expression of tissue inhibitors of metalloproteinases (TIMP) which increase the activity of MMP. Taken together, these features explain the main histopathological and molecular findings in CRSwNP, i.e.,

On the other hand, CRSsNP present some different features compared to CRSwNP. Although mixed inflammatory cells are found in CRSsNP, neutrophils are the predominant cells in this subset of CRS and, together with Th1 cells. seem to play the main cellular role in the pathogenesis of the disease. Neutrophil markers of activation such as myeloperoxidase and IL-8 are found in high levels in CRSsNP compared to controls and CRSwNP. Besides, the levels of Th1 cytokines (INF-γ, IL-8) found in CRSsNP are unbalanced with Th2 cytokines, revealing Th1 polarization. In contrast to CRSwNP, FOXP3 and TGF-β are not decreased in CRSsNP, demonstrating that Treg function is not altered in CRSsNP [31]. The up-regulated TGF- β signaling pathways are believed to be an important marker that reflects

In conclusion, in contrast to CRSwNP, the cellular and molecular findings in CRSsNP are characterized by neutrophilic infiltration, tissue fibrosis, and Th1 skewing polarization.

Glucocorticoid (GC) has a broad anti-inflammatory effect, regulating both innate and adaptive immune responses in a wide variety of cells, such as epithelial cells, fibroblasts, eosinophils and T cells [1, 12, 34]. This is the main reason why GC is considered to be the

This wide anti-inflammatory effect of GC is explained by several events induced by it, from the signaling event to post-translational mechanisms. Basically, GC is a lipophilic compound which diffuses though the membrane and binds to its cytoplasmic receptor, called

eosinophilic infiltration, tissue edema, and Th2 skewing polarization.

the fibrosis/albumin deposition remarkably seen in CRSsNP. (Figure 3)

medication of choice to treat chronic rhinitis [2] and rhinosinusitis [8].

**3. Glucocorticoid action on nasal mucosa** 

glucocorticoid receptor (GR) [35].

control in CRSwNP patients [31].

Figure legend: NF-κB: nuclear factor- κB; STAT: signal transducers and activators of tranascription; NFAT: nuclear factor of activated T-cells; AP: activator protein; IL: interleukin; FGF: fibroblast growth factor; TGF: transforming growth factor; Treg: regulatory T cell; GM-CSF: granulocyte-macrophage colony-stimulating factor; ECP: eosinophil cationic protein; LT: leukotriene; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase; RANTES: regulated on activation, normal T cell expressed and secreted; ICAM: intercellular adhesion molecule; VCAM: vascular cell adhesion molecule; Th: T helper cell

**Figure 2.** Cellular and molecular events involved in the pathogenesis of CRSwNP.

Despite the similarities to allergic rhinitis and contrary to some speculations raised in the first studies, the eosinophilic infiltration and activation found in CRSwNP is not dependent on allergic mechanisms mediated by IgE [28, 29]. In the Chinese population, however, CRSwNP has been characterized by a different Th pattern of inflammation. A mixed Th1/Th17 has been found instead of the Th1/Th2 pattern, with a significantly lower GATA-3 (Th2 specific) expression and higher IL-17 levels in the polyp tissue. The Th17 response drives a more neutrophilic infiltration rather than an eosinophilic recruitment [30].

Another important feature of CRSwNP is the impaired regulatory modulation promoted by Treg cells, which balances the T helper cell response. Low levels of Treg cell biomarkers (transforming growth factor-β1 -TGF-β1- and forkhead box protein P3 -FOXP3) together with high expression of T-bet (Th1) and GATA-3 (Th2) demonstrate the deficiency of Treg control in CRSwNP patients [31].

In terms of molecular markers, among Caucasians, IL-5 is the most important cytokine found in CRSwNP. IL-5 is related to eosinophil infiltration and activation, and is significantly related to recurrence of nasal polyps after surgical removal [32]. Activated eosinophils also release several inflammatory mediators, such as leukotrienes, and other toxic products (Eosinophil Cationic Protein – ECP, Major Basic Protein – MBP, neurotoxin eosinophil protein). Besides the damage induced by infiltrated inflammatory cells, resident fibroblasts also play a role in the structural modification of the stroma. Stimulated by fibroblast growth factor (FGF) and TGF-β, fibroblasts are recruited, proliferate, and express matrix metalloproteinases (MMP), which degrade extracellular proteins (collagen, laminin, fibronectin, elastin) and favor tissue edema and albumin deposition. Other cells such as eosinophils and neutrophils are also able to produce MMP and may play a role in tissue remodeling [33]. Furthermore, fibroblasts suppress the expression of tissue inhibitors of metalloproteinases (TIMP) which increase the activity of MMP. Taken together, these features explain the main histopathological and molecular findings in CRSwNP, i.e., eosinophilic infiltration, tissue edema, and Th2 skewing polarization.

On the other hand, CRSsNP present some different features compared to CRSwNP. Although mixed inflammatory cells are found in CRSsNP, neutrophils are the predominant cells in this subset of CRS and, together with Th1 cells. seem to play the main cellular role in the pathogenesis of the disease. Neutrophil markers of activation such as myeloperoxidase and IL-8 are found in high levels in CRSsNP compared to controls and CRSwNP. Besides, the levels of Th1 cytokines (INF-γ, IL-8) found in CRSsNP are unbalanced with Th2 cytokines, revealing Th1 polarization. In contrast to CRSwNP, FOXP3 and TGF-β are not decreased in CRSsNP, demonstrating that Treg function is not altered in CRSsNP [31]. The up-regulated TGF- β signaling pathways are believed to be an important marker that reflects the fibrosis/albumin deposition remarkably seen in CRSsNP. (Figure 3)

In conclusion, in contrast to CRSwNP, the cellular and molecular findings in CRSsNP are characterized by neutrophilic infiltration, tissue fibrosis, and Th1 skewing polarization.

### **3. Glucocorticoid action on nasal mucosa**

528 Glucocorticoids – New Recognition of Our Familiar Friend

even after the removal of the initial trigger. (Figure 2)

VCAM: vascular cell adhesion molecule; Th: T helper cell

Caucasian CRS population, nasal polyps are remarkably characterized by a mixed expression of Th1 (INF-γ, IL-8) and Th2 cytokines, with an imbalance favoring the Th2 response. Th2 cytokines (IL-3, IL-5, GM-CSF) are produced by eosinophils and Th2 cells and increase eosinophil recruitment and survival, creating an autonomous inflammatory cycle

Figure legend: NF-κB: nuclear factor- κB; STAT: signal transducers and activators of tranascription; NFAT: nuclear factor of activated T-cells; AP: activator protein; IL: interleukin; FGF: fibroblast growth factor; TGF: transforming growth factor; Treg: regulatory T cell; GM-CSF: granulocyte-macrophage colony-stimulating factor; ECP: eosinophil cationic protein; LT: leukotriene; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase; RANTES: regulated on activation, normal T cell expressed and secreted; ICAM: intercellular adhesion molecule;

Despite the similarities to allergic rhinitis and contrary to some speculations raised in the first studies, the eosinophilic infiltration and activation found in CRSwNP is not dependent on allergic mechanisms mediated by IgE [28, 29]. In the Chinese population, however, CRSwNP has been characterized by a different Th pattern of inflammation. A mixed Th1/Th17 has been found instead of the Th1/Th2 pattern, with a significantly lower GATA-3 (Th2 specific) expression and higher IL-17 levels in the polyp tissue. The Th17 response

Another important feature of CRSwNP is the impaired regulatory modulation promoted by Treg cells, which balances the T helper cell response. Low levels of Treg cell biomarkers (transforming growth factor-β1 -TGF-β1- and forkhead box protein P3 -FOXP3) together

drives a more neutrophilic infiltration rather than an eosinophilic recruitment [30].

**Figure 2.** Cellular and molecular events involved in the pathogenesis of CRSwNP.

Glucocorticoid (GC) has a broad anti-inflammatory effect, regulating both innate and adaptive immune responses in a wide variety of cells, such as epithelial cells, fibroblasts, eosinophils and T cells [1, 12, 34]. This is the main reason why GC is considered to be the medication of choice to treat chronic rhinitis [2] and rhinosinusitis [8].

This wide anti-inflammatory effect of GC is explained by several events induced by it, from the signaling event to post-translational mechanisms. Basically, GC is a lipophilic compound which diffuses though the membrane and binds to its cytoplasmic receptor, called glucocorticoid receptor (GR) [35].

Glucocorticoid Resistance in the Upper Respiratory Airways 531

Finally, glucocorticoids inhibit the expression of some cytokine receptors, among them IL-2

Due to its holistic action, GC is considered to be the best medication for the treatment of

**Figure 4.** GC mode of action: binding to its cytoplasmic GR, and then translocating into the nucleus. GC: glucocorticoid; GR: glucocorticoid receptor; hsp: heat shock protein; GRE: glucocorticoid response

The GR gene is located in chromosome 5 and is composed of 9 exons. Alternative splicing in the ninth exon (hormone-binding domain) gives raise to several alternative GRs, GRα and

GRα is the predominant GR isoform. It is transcriptionally active and, when ligated to GC, it can translocate into the nucleus, induce expression by binding to GRE, or repress expression

For instance, GRβ is expressed at much lower rates than GRα. It cannot bind to GC, and although it can bind to GRE, nGRE, AP-1 and NF-κB, it does not activate their transcriptional action. Some authors have shown that, when overexpressed, GRβ inhibits the effect of GRα on both transactivation and on AP-1 and NF-κB repression [49-51]. GRβ is thus considered to be the dominant negative of GRα; instead, a recent study has shown that

by either binding to nGRE or by interacting with AP-1 and NF-κB [1, 35, 36].

element; NF-κB: nuclear factor κB; AP-1: activator protein-1

GRβ being the most common [35-39].

chronic inflammatory diseases of the upper respiratory airways.

and IL-4 receptors.

**4. GR splicing** 

Figure legend: Treg: regulatory T cell; IL: interleukin; INF: interferon; TNF: tumor necrosis factor; Th: T helper cell; TGF: transforming growth factor; TIMP: tissue inhibitor of metalloproteinase; MMP: metalloproteinase

**Figure 3.** Cellular and molecular events involved in the pathogenesis of CRSsNP.

GR belongs to a large superfamily of steroid receptors. When inactivated, this receptor stays in the cytosol bound to heat shock proteins (hsp) [36]. When GC binds to GR, phosphorylation occurs to this receptor, which dissociates GR from hsp. The dimer GC-GR is able to translocate into the nucleus and then act as a transcription factor. In this respect, the GC-GR dimer can bind directly to a specific palindromic DNA consensus sequence, called glucocorticoid response elements (GREs), and consequently induces or inhibits (in case of nGREs) the transcription of several genes [35]. Nevertheless, it is recognized that the main anti-inflammatory action of GC at the transcriptional level is mediated by a direct interaction of GC-GR with other transcription factors (TF), inhibiting their action. This inhibition, called "DNA-independent transrepression" affects several pro-inflammatory TF, the most important ones being activator protein-1 (AP-1) and nuclear fator-κB (NF-κB) [1, 35-39] (Figure 4). This connection inhibits gene transcription by direct binding to DNA or by inducing histone deacetylation. Although the non-genomic effect of GC is widely known in the literature [2, 17], there is no report on its effect on chronic upper respiratory diseases, and only few studies have reported controversial results regarding asthma [40, 41].

The final effect of GC on nasal diseases is the inhibition of pro-inflammatory cytokines (IL-1β, TNF-α, GM-CSF, IL-3, IL-5, IL-6), chemokines (IL-8, RANTES, eotaxin) and adhesion molecules (VCAM-1, ICAM-1) [1, 13, 42]. Glucocorticoids also have a favorable effect on tissue remodeling (reducing MMP expression) [43, 44], reduce mucin production [45], increase cell apoptosis [46, 47], and decrease mast cell recruitment and activation [48]. Finally, glucocorticoids inhibit the expression of some cytokine receptors, among them IL-2 and IL-4 receptors.

Due to its holistic action, GC is considered to be the best medication for the treatment of chronic inflammatory diseases of the upper respiratory airways.

**Figure 4.** GC mode of action: binding to its cytoplasmic GR, and then translocating into the nucleus. GC: glucocorticoid; GR: glucocorticoid receptor; hsp: heat shock protein; GRE: glucocorticoid response element; NF-κB: nuclear factor κB; AP-1: activator protein-1

### **4. GR splicing**

530 Glucocorticoids – New Recognition of Our Familiar Friend

Figure legend: Treg: regulatory T cell; IL: interleukin; INF: interferon; TNF: tumor necrosis factor; Th: T helper cell;

GR belongs to a large superfamily of steroid receptors. When inactivated, this receptor stays in the cytosol bound to heat shock proteins (hsp) [36]. When GC binds to GR, phosphorylation occurs to this receptor, which dissociates GR from hsp. The dimer GC-GR is able to translocate into the nucleus and then act as a transcription factor. In this respect, the GC-GR dimer can bind directly to a specific palindromic DNA consensus sequence, called glucocorticoid response elements (GREs), and consequently induces or inhibits (in case of nGREs) the transcription of several genes [35]. Nevertheless, it is recognized that the main anti-inflammatory action of GC at the transcriptional level is mediated by a direct interaction of GC-GR with other transcription factors (TF), inhibiting their action. This inhibition, called "DNA-independent transrepression" affects several pro-inflammatory TF, the most important ones being activator protein-1 (AP-1) and nuclear fator-κB (NF-κB) [1, 35-39] (Figure 4). This connection inhibits gene transcription by direct binding to DNA or by inducing histone deacetylation. Although the non-genomic effect of GC is widely known in the literature [2, 17], there is no report on its effect on chronic upper respiratory diseases,

TGF: transforming growth factor; TIMP: tissue inhibitor of metalloproteinase; MMP: metalloproteinase

and only few studies have reported controversial results regarding asthma [40, 41].

The final effect of GC on nasal diseases is the inhibition of pro-inflammatory cytokines (IL-1β, TNF-α, GM-CSF, IL-3, IL-5, IL-6), chemokines (IL-8, RANTES, eotaxin) and adhesion molecules (VCAM-1, ICAM-1) [1, 13, 42]. Glucocorticoids also have a favorable effect on tissue remodeling (reducing MMP expression) [43, 44], reduce mucin production [45], increase cell apoptosis [46, 47], and decrease mast cell recruitment and activation [48].

**Figure 3.** Cellular and molecular events involved in the pathogenesis of CRSsNP.

The GR gene is located in chromosome 5 and is composed of 9 exons. Alternative splicing in the ninth exon (hormone-binding domain) gives raise to several alternative GRs, GRα and GRβ being the most common [35-39].

GRα is the predominant GR isoform. It is transcriptionally active and, when ligated to GC, it can translocate into the nucleus, induce expression by binding to GRE, or repress expression by either binding to nGRE or by interacting with AP-1 and NF-κB [1, 35, 36].

For instance, GRβ is expressed at much lower rates than GRα. It cannot bind to GC, and although it can bind to GRE, nGRE, AP-1 and NF-κB, it does not activate their transcriptional action. Some authors have shown that, when overexpressed, GRβ inhibits the effect of GRα on both transactivation and on AP-1 and NF-κB repression [49-51]. GRβ is thus considered to be the dominant negative of GRα; instead, a recent study has shown that a glucocorticoid antagonist, named RU-486, has the ability to bind to GRβ, regulating gene expression even in the absence of GRα [52].

Glucocorticoid Resistance in the Upper Respiratory Airways 533

NF-κB is also a heterodimer, mainly consisting of p50 and p65 isoforms. When activated, NF-κB translocates into the nucleus, and p65 directly binds to DNA, inducing gene expression of pro-inflammatory and anti-apoptotic genes [37, 65]. NF-κB is considered pivotal to the regulation of immune and inflammatory genes, and its absence is incompatible with life. It is important to mention that the most important pro-inflammatory cytokines (IL-1β and TNF-α), whose expression is considerably influenced by NF-κB, also

Two studies have reported increased expression of both isoforms (p50 and p65) of NF-κB in patients with CRSwNP when compared to control nasal mucosa [56, 67]. Also, a high expression of p65 was related to a poor clinical outcome in response to medical treatment in CRSwNP patients [56]. This finding suggests that NF-κB may also have a pivotal effect on

Chronic inflammatory nasal diseases are highly prevalent in the population, and therefore nasal TGC has been widely prescribed by physicians. Considering that a high percentage of these patients only partially benefit from TGC, or do not respond to TCG treatment at all, the understanding of possible mechanisms of GC resistance is essential for future

Today, it has been accepted that cellular and molecular mechanisms of resistance do exist in nasal mucosa. Future investigations are still required to recognize affected individuals and how this would influence medical treatment. This will be essential to develop new drugs that would replace or act synergistically with CG, in order to improve the clinical

*Division of Otorhinolaryngology, Departament of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery. Faculty of Medicine of Ribeirao Preto-University of São Paulo, Ribeirao Preto-SP,* 

[1] Stellato, C., Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets. J Allergy Clin Immunol 2007. 120(6): p.

[2] Bousquet J, K.N., Cruz AA, Denburg J, Fokkens WJ, Togias A, et al, Allergic Rhinitis

Fabiana C.P. Valera, Edwin Tamashiro and Wilma T. Anselmo-Lima

and its impact on asthma (ARIA) 2008. Allergy 2008. 63: p. 8-160.

activate NF-κB translocation, inducing perpetuation of the inflammatory process.

GC resistance.

treatments.

outcome.

*Brazil* 

**Author details** 

**7. References** 

1247-63.

**6. Conclusions** 

There is no previous study regarding the influence of GRγ on nasal mucosa.

### **5. Resistance to GC**

Although GC is the medication of choice in chronic upper respiratory diseases in general, the rate of CG therapy failure in CRSwNP is reported to be between 60 and 80% [8]. Although there is no report on GC resistance in chronic rhinitis, resistance is believed to be identical to that occurring in CRSwNP. The main reasons for GC failure are: limited action of topical GC in extensive diseases [53], poor compliance with treatment [54] , and cellular/molecular resistance to GC [36, 55]. Among cellular and molecular mechanisms of GC resistance, the main lines investigated are GRα- GRβ interaction and TF influence.

One of the most studied mechanisms is the GRα-GRβ imbalance. Although GRβ is able to interact directly with GRα within the nucleus, it has a low capacity to bind to GC. This is why GRβ is considered to be an endogenous inhibitor of GRα [36, 56]. GRα-GRβ imbalance has been reported to increase cell resistance in chronic immune-mediated diseases, among those affecting the upper [37, 57] and lower airways [58, 59].

Increased expression of GRβ has been widely reported in the literature on inflammatory respiratory diseases such as CRSwNP and asthma, when compared to control mucosa [36, 55, 60, 61]. This has led to the hypothesis that increased GRβ expression could impair the action of GC. Decreased expression of GRα has also been recently reported in CRswNP with the use of a more reliable quantitative method of analysis [56, 62, 63]. More important than the expression of each individual isoform, GRα-GRβ imbalance might be the most relevant determinant of GC resistance. It is important to mention that some studies have demonstrated that CG therapy in CRSwNP does not change GR isoform expression or the GRα-GRβ relation [56, 63, 64].

Higher expression of TF could also lead to GC resistance, because TF (mainly AP-1 and NFκB) repress the binding of the translocated GC-GR complex to GRE. This mechanism of GC resistance has been reported in several inflammatory diseases, such as inflammatory bowel diseases. Nevertheless, this mechanism has been poorly reported in respiratory diseases.

AP-1 is a dimer predominantly consisting of c-Fos/c-Jun heterodimers. As is the case for most TF, they are located in the cytoplasm and, when activated, translocate into the nucleus and induce the expression of several pro-inflammatory genes which regulate cell inflammation, proliferation, differentiation and apoptosis [65]. Conflicting results have been reported regarding the presence of AP-1 in CRSwNP. c-Fos expression has been studied in two reports because it is more important regarding the transcriptional action. One study [66] has reported an increased presence of c-Fos in patients with CRSwNP than in control mucosa using qualitative PCR, while the other [56] has observed a similar expression in the two groups using quantitative RT-PCR. The latter study also did not observe any influence of c-Fos expression on the outcome of GC treatment.

NF-κB is also a heterodimer, mainly consisting of p50 and p65 isoforms. When activated, NF-κB translocates into the nucleus, and p65 directly binds to DNA, inducing gene expression of pro-inflammatory and anti-apoptotic genes [37, 65]. NF-κB is considered pivotal to the regulation of immune and inflammatory genes, and its absence is incompatible with life. It is important to mention that the most important pro-inflammatory cytokines (IL-1β and TNF-α), whose expression is considerably influenced by NF-κB, also activate NF-κB translocation, inducing perpetuation of the inflammatory process.

Two studies have reported increased expression of both isoforms (p50 and p65) of NF-κB in patients with CRSwNP when compared to control nasal mucosa [56, 67]. Also, a high expression of p65 was related to a poor clinical outcome in response to medical treatment in CRSwNP patients [56]. This finding suggests that NF-κB may also have a pivotal effect on GC resistance.

### **6. Conclusions**

532 Glucocorticoids – New Recognition of Our Familiar Friend

expression even in the absence of GRα [52].

**5. Resistance to GC** 

GRα-GRβ relation [56, 63, 64].

a glucocorticoid antagonist, named RU-486, has the ability to bind to GRβ, regulating gene

Although GC is the medication of choice in chronic upper respiratory diseases in general, the rate of CG therapy failure in CRSwNP is reported to be between 60 and 80% [8]. Although there is no report on GC resistance in chronic rhinitis, resistance is believed to be identical to that occurring in CRSwNP. The main reasons for GC failure are: limited action of topical GC in extensive diseases [53], poor compliance with treatment [54] , and cellular/molecular resistance to GC [36, 55]. Among cellular and molecular mechanisms of GC resistance, the main lines investigated are GRα- GRβ interaction and TF influence.

One of the most studied mechanisms is the GRα-GRβ imbalance. Although GRβ is able to interact directly with GRα within the nucleus, it has a low capacity to bind to GC. This is why GRβ is considered to be an endogenous inhibitor of GRα [36, 56]. GRα-GRβ imbalance has been reported to increase cell resistance in chronic immune-mediated diseases, among

Increased expression of GRβ has been widely reported in the literature on inflammatory respiratory diseases such as CRSwNP and asthma, when compared to control mucosa [36, 55, 60, 61]. This has led to the hypothesis that increased GRβ expression could impair the action of GC. Decreased expression of GRα has also been recently reported in CRswNP with the use of a more reliable quantitative method of analysis [56, 62, 63]. More important than the expression of each individual isoform, GRα-GRβ imbalance might be the most relevant determinant of GC resistance. It is important to mention that some studies have demonstrated that CG therapy in CRSwNP does not change GR isoform expression or the

Higher expression of TF could also lead to GC resistance, because TF (mainly AP-1 and NFκB) repress the binding of the translocated GC-GR complex to GRE. This mechanism of GC resistance has been reported in several inflammatory diseases, such as inflammatory bowel diseases. Nevertheless, this mechanism has been poorly reported in respiratory diseases.

AP-1 is a dimer predominantly consisting of c-Fos/c-Jun heterodimers. As is the case for most TF, they are located in the cytoplasm and, when activated, translocate into the nucleus and induce the expression of several pro-inflammatory genes which regulate cell inflammation, proliferation, differentiation and apoptosis [65]. Conflicting results have been reported regarding the presence of AP-1 in CRSwNP. c-Fos expression has been studied in two reports because it is more important regarding the transcriptional action. One study [66] has reported an increased presence of c-Fos in patients with CRSwNP than in control mucosa using qualitative PCR, while the other [56] has observed a similar expression in the two groups using quantitative RT-PCR. The latter study also did not observe any influence

There is no previous study regarding the influence of GRγ on nasal mucosa.

those affecting the upper [37, 57] and lower airways [58, 59].

of c-Fos expression on the outcome of GC treatment.

Chronic inflammatory nasal diseases are highly prevalent in the population, and therefore nasal TGC has been widely prescribed by physicians. Considering that a high percentage of these patients only partially benefit from TGC, or do not respond to TCG treatment at all, the understanding of possible mechanisms of GC resistance is essential for future treatments.

Today, it has been accepted that cellular and molecular mechanisms of resistance do exist in nasal mucosa. Future investigations are still required to recognize affected individuals and how this would influence medical treatment. This will be essential to develop new drugs that would replace or act synergistically with CG, in order to improve the clinical outcome.

### **Author details**

Fabiana C.P. Valera, Edwin Tamashiro and Wilma T. Anselmo-Lima *Division of Otorhinolaryngology, Departament of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery. Faculty of Medicine of Ribeirao Preto-University of São Paulo, Ribeirao Preto-SP, Brazil* 

### **7. References**


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	- [67] Takeno S, H.K., Ueda T, et al, Nuclear factor-kappa B activation in the nasal polyp epithelium: relationship to local cytokine gene expression. Laryngoscope 2002. 112(1): p. 53-58

**Chapter 21** 

© 2012 Zandi, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**The Role of Corticosteroids in Today's** 

Corticosteroids are group of hormones with similar chemical formulas which are secreted by adrenal cortex. The very slight differences in molecular structure of various corticosteroids give them very different functions. The hormonal steroids are classified according to their biologic effects as glucocorticoids, which mainly affect intermediary metabolism and the immune system, and mineralocorticoids , which have principally a saltretaining activity. Of large number of steroids released into the circulation by adrenal cortex, two are of greater importance – aldosterone, which is a mineralocorticoid, and cortisol,

Mineralocorticoids promote sodium and water retention, and potassium loss by kidney, but

Cortisol, also known as hydrocortisone, is the major glucocorticoid in humans. It is synthesized by the cells of the zona fasciculata and zona reticularis of adrenal cortex; its secretion is regulated by the adrenocorticotropic hormone (ACTH) from anterior pituitary gland. Cortisol has a wide range of physiologic actions such as influencing carbohydrate, protein, and fat metabolism; regulation of blood pressure and cardiovascular function; and

Corticosteroid drugs are the synthetic analogs of cortisol hormone. They bind to specific intracellular receptors upon entering target tissues, and mimic the effects of the naturally occurring hormones; the main differences are the relative glucocorticoid versus mineralocorticoid potency and the long half-life that the synthetic analogs have. The relative potencies and duration of action of representative corticosteroids are presented in

**Oral and Maxillofacial Surgery** 

Additional information is available at the end of the chapter

have no anti-inflammatory or anti-allergic effect.

Mohammad Zandi

**1. Introduction** 

which is a glucocorticoid.

affecting immune system.

Table 1.

http://dx.doi.org/10.5772/48655

**Chapter 21** 

## **The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery**

Mohammad Zandi

538 Glucocorticoids – New Recognition of Our Familiar Friend

53-58

[67] Takeno S, H.K., Ueda T, et al, Nuclear factor-kappa B activation in the nasal polyp epithelium: relationship to local cytokine gene expression. Laryngoscope 2002. 112(1): p.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48655

### **1. Introduction**

Corticosteroids are group of hormones with similar chemical formulas which are secreted by adrenal cortex. The very slight differences in molecular structure of various corticosteroids give them very different functions. The hormonal steroids are classified according to their biologic effects as glucocorticoids, which mainly affect intermediary metabolism and the immune system, and mineralocorticoids , which have principally a saltretaining activity. Of large number of steroids released into the circulation by adrenal cortex, two are of greater importance – aldosterone, which is a mineralocorticoid, and cortisol, which is a glucocorticoid.

Mineralocorticoids promote sodium and water retention, and potassium loss by kidney, but have no anti-inflammatory or anti-allergic effect.

Cortisol, also known as hydrocortisone, is the major glucocorticoid in humans. It is synthesized by the cells of the zona fasciculata and zona reticularis of adrenal cortex; its secretion is regulated by the adrenocorticotropic hormone (ACTH) from anterior pituitary gland. Cortisol has a wide range of physiologic actions such as influencing carbohydrate, protein, and fat metabolism; regulation of blood pressure and cardiovascular function; and affecting immune system.

Corticosteroid drugs are the synthetic analogs of cortisol hormone. They bind to specific intracellular receptors upon entering target tissues, and mimic the effects of the naturally occurring hormones; the main differences are the relative glucocorticoid versus mineralocorticoid potency and the long half-life that the synthetic analogs have. The relative potencies and duration of action of representative corticosteroids are presented in Table 1.

© 2012 Zandi, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery 541

systemic problem. Corticosteroids have their widest application in the management of acute and chronic conditions which have an allergic, immunologic, or inflammatory basis. Therefore, a group of corticosteroids which have predominantly a glucocorticoid activity and little or no mineralocorticoid action such as betamethasone, dexamethasone,

The following are the main therapeutic indications for glucocorticoids in oral and

TMDs are clinical problems involving the temporomandibular joints (TMJs), the masticatory muscles, or both. TMDs affect a significant number of individuals, and are the most common musculoskeletal disorders that cause orofacial pain. [2] Trauma to the joint structures, especially microtrauma, accounts for the majority of patients who develop TMJ problems. However, a small number of joint diseases are caused by nontraumatic etiologic factors including benign and malignant neoplasms (osteoma, chondroma, and synovial sarcoma), congenital or developmental anomalies (condylar agenesis and heperplasia), arthritides (rheumatoid arthritis), and systemic diseases. The most common signs and symptoms of

Treatment of TMDs varies according to their etiologic basis. Conservative managements (splint therapy, thermal application, pharmacotherapy, and physiotherapy), surgical treatments, or a combination of them may be required. A variety of medications have been used to relieve pain, inflammation, muscle spasm and other signs and symptoms associated with TMDs. They include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids,

Various glucocorticoids are used in the treatment of TMDs (Table 2). These drugs have dramatic effects on pain, hypomobility, and inflammation associated with acute TMJ problems. Oral corticosteroids are used mainly for treatment of acute TMJ discomforts or for diagnostic purposes. They should be used in a short term basis (tapering dose lasting 5 to 7 days), and repeated as infrequently as possible. Long term use of corticosteroids for the treatment of TMDs is contraindicated; it can result in a cushing's- like disease process, acute adrenal crisis, hypertension, electrolyte abnormalities, diabetes, and formation of

> **Drug Alternative name Usual dose** Hydrocortisone Hydrocortone 20-240 mg/day Prednisone Deltasone, Orasone 5-60 mg/day Prednisolone Delta-Cortef 5-60 mg/day Dexamethasone Decadron 0.75-9.0 mg/day Betamethasone Celestone 0.6-7.2 mg/day

TMDs are pain, altered mandibular movements, and the elicitation of joint noise.

triamcinolone, and prednisolone are used.

**2.1. Temporomandibular disorders (TMDs)** 

maxillofacial diseases.

analgesics, and muscle relaxants.

osteoporosis including the TMJ. [2]

Adapted and modified from [2]

**Table 2.** Oral corticosteroids used in TMDs

Short: 8-12 hours biologic half-life; Intermediate: 12-36 hours biologic half-life; Long: 36-72 hours biologic half-life. Adapted and modified from [1]

**Table 1.** Relative potencies and equivalent doses of representative corticosteroids

Glucocorticoids are used, either singly or in combination with other drugs, in the treatment of a wide variety of medical disorders. Some therapeutic indications for these drugs are as follows:


Although corticosteroids are widely used for treatment of diseases and conditions affecting oral and maxillofacial region, the scientific literature on this topic is limited and scattered throughout numerous journals and books. By gathering this scattered information, this chapter presents a concise review of various uses of corticosteroid drugs in the treatment of diseases affecting oral and maxillofacial region, and the role they have in reducing postoperative morbidities such as pain, edema and trismus after various maxillofacial surgical procedures. The relation between maternal corticosteroid use and congenital maxillofacial deformities are explained. Also discussed is the perioperative management of patients receiving long-term therapeutic doses of corticosteroids.

### **2. Uses of corticosteroids in the treatment of oral and maxillofacial diseases**

Corticosteroids are widely used in the treatment of diseases, disorders and conditions affecting the oral and maxillofacial area and the adjacent and associated structures. The diseases of the oral and maxillofacial region may be either local or the manifestation of a systemic problem. Corticosteroids have their widest application in the management of acute and chronic conditions which have an allergic, immunologic, or inflammatory basis. Therefore, a group of corticosteroids which have predominantly a glucocorticoid activity and little or no mineralocorticoid action such as betamethasone, dexamethasone, triamcinolone, and prednisolone are used.

The following are the main therapeutic indications for glucocorticoids in oral and maxillofacial diseases.

#### **2.1. Temporomandibular disorders (TMDs)**

540 Glucocorticoids – New Recognition of Our Familiar Friend

**Compound Glucocorticoid** 

Adapted and modified from [1]

follows:

**diseases** 

**potency** 

**Table 1.** Relative potencies and equivalent doses of representative corticosteroids

systemic lupus erythematosus, and vasculitis) Respiratory diseases (sarcoidosis and chronic bronchitis) Gastrointestinal diseases (ulcerative colitis and crohn's disease) Allergic disorders (asthma, hay fever, and allergic rhinitis) Skin conditions (pemphigus, eczema, and dermatitis) Eye diseases (conjunctivitis, uveitis, and optic neuritis)

receiving long-term therapeutic doses of corticosteroids.

Glucocorticoids are used, either singly or in combination with other drugs, in the treatment of a wide variety of medical disorders. Some therapeutic indications for these drugs are as

Musculoskeletal and connective tissue diseases (rheumatoid arthritis, polymyositis,

Oral and maxillofacial diseases (lichen planus, keloid formation, and Bell's palsy)

**2. Uses of corticosteroids in the treatment of oral and maxillofacial** 

Corticosteroids are widely used in the treatment of diseases, disorders and conditions affecting the oral and maxillofacial area and the adjacent and associated structures. The diseases of the oral and maxillofacial region may be either local or the manifestation of a

Although corticosteroids are widely used for treatment of diseases and conditions affecting oral and maxillofacial region, the scientific literature on this topic is limited and scattered throughout numerous journals and books. By gathering this scattered information, this chapter presents a concise review of various uses of corticosteroid drugs in the treatment of diseases affecting oral and maxillofacial region, and the role they have in reducing postoperative morbidities such as pain, edema and trismus after various maxillofacial surgical procedures. The relation between maternal corticosteroid use and congenital maxillofacial deformities are explained. Also discussed is the perioperative management of patients

Cortisol 1 1 short Cortisone 0.8 0.8 short Fludrocortisone 10 125 Intermediate Prednisone 4 0.8 Intermediate Prednisolone 4 0.8 Intermediate Methylprednisolone 5 0.5 Intermediate Triamcinolone 5 0 Intermediate Betamethasone 25 0 Long Dexamethasone 25 0 Long Short: 8-12 hours biologic half-life; Intermediate: 12-36 hours biologic half-life; Long: 36-72 hours biologic half-life.

**Mineralocorticoid** 

**potency Duration of action** 

TMDs are clinical problems involving the temporomandibular joints (TMJs), the masticatory muscles, or both. TMDs affect a significant number of individuals, and are the most common musculoskeletal disorders that cause orofacial pain. [2] Trauma to the joint structures, especially microtrauma, accounts for the majority of patients who develop TMJ problems. However, a small number of joint diseases are caused by nontraumatic etiologic factors including benign and malignant neoplasms (osteoma, chondroma, and synovial sarcoma), congenital or developmental anomalies (condylar agenesis and heperplasia), arthritides (rheumatoid arthritis), and systemic diseases. The most common signs and symptoms of TMDs are pain, altered mandibular movements, and the elicitation of joint noise.

Treatment of TMDs varies according to their etiologic basis. Conservative managements (splint therapy, thermal application, pharmacotherapy, and physiotherapy), surgical treatments, or a combination of them may be required. A variety of medications have been used to relieve pain, inflammation, muscle spasm and other signs and symptoms associated with TMDs. They include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, analgesics, and muscle relaxants.

Various glucocorticoids are used in the treatment of TMDs (Table 2). These drugs have dramatic effects on pain, hypomobility, and inflammation associated with acute TMJ problems. Oral corticosteroids are used mainly for treatment of acute TMJ discomforts or for diagnostic purposes. They should be used in a short term basis (tapering dose lasting 5 to 7 days), and repeated as infrequently as possible. Long term use of corticosteroids for the treatment of TMDs is contraindicated; it can result in a cushing's- like disease process, acute adrenal crisis, hypertension, electrolyte abnormalities, diabetes, and formation of osteoporosis including the TMJ. [2]


Adapted and modified from [2]

**Table 2.** Oral corticosteroids used in TMDs

Intracapsular injection of glucocortcoids has been reported to decrease pain in patients with both pain and limited mouth opening secondary to inflammatory disorders of the joint, such as arthritis and capsulitis. [3-5]

The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery 543

glucocorticoid injections for TMJ arthritis observed that this treatment modality was helpful, and there were no radiographically demonstrable side effects of the treatment. [12] In contrast, Haddad IK showed that intra-articular injections of corticosteroids (triamcinolone

Juvenile idiopathic arthritis (JIA) is a chronic rheumatologic disease of children which may involve TMJ region, and cause significant craniofacial growth disturbances. The treatment of TMJ arthritis is controversial. It has been shown that glucocorticoid injection of the TMJ reduces pain and inflammation, and improves the function of TMJ in children with JIA. [14] Other studies also confirmed that corticosteroid injection of the TMJ can be safely performed in children with JIA, and is effective. [15-18] Few studies have evaluated TMJ corticosteroid injection in JIA. In these studies the volume of corticosteroid injected was chosen empirically. Treatment protocols such as injection of 1 cc (40 mg) of triamcinolone acetonide, 1 cc (20 mg) of triamcinolone hexacetonidein, and 0.5 to 1 cc of the diluted (with 1% lidocaine HCL) triamcinolone hexacetonidein into each of the involved TMJs, all have been used in previous studies. [14-16] The peak effect occurs after approximately 6 weeks of treatment, and the expected duration is 6-17 months. The children may receive a second

Side effects of intra-articular steroid injection in children include immediate reactions, such as pain and headache, or delayed side effects, such as joint infection and loss of subcutaneous fat. [16] Because the mandibular endochondral growth zone is located at the head of condyle (at the site of corticosteroid injection), the concern is whether intra-articular corticosteroid injection per se may cause growth retardation. Stoustrup et al., in an animal study demonstrated that intra-articular glucocorticoid injection may result in even more pronounced mandibular growth reduction than that caused by the arthritis alone. [19] Schindler et al. reported a case of severe temporomandibular dysfunction and joint destruction after intra-articular injection of triamcinolone, and El-Hakim et al. showed TMJ resorption with active osteoclastic activity after intra-articular injection of a single dose of

intra-articular corticosteroid injection has been used to improve mouth opening in patients

Corticosteroids are successfully used for the treatment of several ulcerative and vesiculobullous lesions involving the oral cavity and perioral areas including recurrent aphthous stomatitis (RAS), Behcet's syndrome, pemphigus vulgaris, bullous pemphigoid, mucous membrane pemphigoid, erythema multiforme and Stevens-Johnson syndrome

*Recurrent aphthous stomatitis:* These superficial painful ulcers occur commonly in the oral cavity. Minor form of the disease has 1 to 5 ulcers at one episode. The ulcers which are under 1 cm in diameter persist 8 to 14 days, and heal spontaneously without sequelae. The

with anterior disk displacement without reduction (ADDWOR), i.e., closed lock. [22]

acetonide) cause damage to fibrous layer, cartilage, and bone of TMJ. [13]

injection approximately 6 months after the first. [16]

**2.2. Oral ulcerative and vesiculobullous lesions** 

dexamethasone in rats. [20,21]

(Tables 3-5). [23]

A number of mechanisms have been described for the anti-inflammatory actions of glucocorticoids. These drugs inhibit inflammatory mediator release from many cell types involved in inflammation such as macrophages, T-lymphocytes, mast cells, dendritic cells, and neutrophilic leukocytes. Glucocorticoids also reduce prostaglandin production by blocking the phospholipase A2 enzyme.

The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes encoding cytokines, chemokines, inflammatory enzymes, receptors and adhesion molecules. [6] Changes in gene transcription are regulated by proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). These proinflammatory transcription factors switch on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. Glucocorticoids exert their anti-inflammatory effect on responsive cells by binding and activating a cytoplasmic glucocorticoid receptor. The interaction between the activated glucocorticoid receptor and proinflammatory transcription factors may result in deacetylation of histones and repression of inflammatory genes. [7]

In chronic inflammatory disorders of TMJ, macrophages, T-lymphocytes, and other cell types involved in inflammation release many cytokines and chemokines which will induce expression of adhesion molecules, release of variable enzymes from fibroblasts and osteoclasts and result in bone erosion. IL-8, which is a chemokine, is known to cause the infiltration of neutrophils into synovial fluid and promote joint inflammation. It was detected in 80% of the synovial tissue specimens taken from the TMJs with internal derangement. Similarly, IL-11 has been involved in the pathogenesis of osteoarthritis and rheumatoid arthritis. It has been found in synovial fluids of diseased temporomandibular joint and other joints. [8]

Cytokines participate in various inflammatory processes and induce protease synthesis; their effects can be either synergic or inhibitory. In synovial joints, IL-1 *α*, IL-1 *β* and TNF*-α* induce synovitis and promote the production of proteinases resulting in degradation of cartilage, while IL-1ra works to block IL-1α and IL-1 *β* from binding to other cell receptors and has many beneficial effects on inflammatory diseases. [9] In a study by Nordahl et al. it was found that the local production of tumor necrosis factor-*alpha* (TNF-*α*) occured in the TMJ synovium of patients with chronic inflammatory connective tissue disease, and the severity of pain and tenderness of the TMJ was related to the level of TNF-*α.* [10] In a study by Frediksson et al., it was shown that the presence of TNF-*α* in the synovial fluid of TMJ predicted a positive treatment response to intra-articular glucocorticoid injection in patients with chronic TMJ inflammatory disorders. [11]

Long-term complications associated with intra-articular glucocorticoid injection cannot be determined from the limited investigations done to date and thus remained unclear. Wenneberg et al. in a study evaluating the long-term prognosis of intra-articular glucocorticoid injections for TMJ arthritis observed that this treatment modality was helpful, and there were no radiographically demonstrable side effects of the treatment. [12] In contrast, Haddad IK showed that intra-articular injections of corticosteroids (triamcinolone acetonide) cause damage to fibrous layer, cartilage, and bone of TMJ. [13]

542 Glucocorticoids – New Recognition of Our Familiar Friend

blocking the phospholipase A2 enzyme.

as arthritis and capsulitis. [3-5]

joint and other joints. [8]

with chronic TMJ inflammatory disorders. [11]

Intracapsular injection of glucocortcoids has been reported to decrease pain in patients with both pain and limited mouth opening secondary to inflammatory disorders of the joint, such

A number of mechanisms have been described for the anti-inflammatory actions of glucocorticoids. These drugs inhibit inflammatory mediator release from many cell types involved in inflammation such as macrophages, T-lymphocytes, mast cells, dendritic cells, and neutrophilic leukocytes. Glucocorticoids also reduce prostaglandin production by

The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes encoding cytokines, chemokines, inflammatory enzymes, receptors and adhesion molecules. [6] Changes in gene transcription are regulated by proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). These proinflammatory transcription factors switch on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. Glucocorticoids exert their anti-inflammatory effect on responsive cells by binding and activating a cytoplasmic glucocorticoid receptor. The interaction between the activated glucocorticoid receptor and proinflammatory transcription factors may result in deacetylation of histones and repression of inflammatory genes. [7]

In chronic inflammatory disorders of TMJ, macrophages, T-lymphocytes, and other cell types involved in inflammation release many cytokines and chemokines which will induce expression of adhesion molecules, release of variable enzymes from fibroblasts and osteoclasts and result in bone erosion. IL-8, which is a chemokine, is known to cause the infiltration of neutrophils into synovial fluid and promote joint inflammation. It was detected in 80% of the synovial tissue specimens taken from the TMJs with internal derangement. Similarly, IL-11 has been involved in the pathogenesis of osteoarthritis and rheumatoid arthritis. It has been found in synovial fluids of diseased temporomandibular

Cytokines participate in various inflammatory processes and induce protease synthesis; their effects can be either synergic or inhibitory. In synovial joints, IL-1 *α*, IL-1 *β* and TNF*-α* induce synovitis and promote the production of proteinases resulting in degradation of cartilage, while IL-1ra works to block IL-1α and IL-1 *β* from binding to other cell receptors and has many beneficial effects on inflammatory diseases. [9] In a study by Nordahl et al. it was found that the local production of tumor necrosis factor-*alpha* (TNF-*α*) occured in the TMJ synovium of patients with chronic inflammatory connective tissue disease, and the severity of pain and tenderness of the TMJ was related to the level of TNF-*α.* [10] In a study by Frediksson et al., it was shown that the presence of TNF-*α* in the synovial fluid of TMJ predicted a positive treatment response to intra-articular glucocorticoid injection in patients

Long-term complications associated with intra-articular glucocorticoid injection cannot be determined from the limited investigations done to date and thus remained unclear. Wenneberg et al. in a study evaluating the long-term prognosis of intra-articular Juvenile idiopathic arthritis (JIA) is a chronic rheumatologic disease of children which may involve TMJ region, and cause significant craniofacial growth disturbances. The treatment of TMJ arthritis is controversial. It has been shown that glucocorticoid injection of the TMJ reduces pain and inflammation, and improves the function of TMJ in children with JIA. [14] Other studies also confirmed that corticosteroid injection of the TMJ can be safely performed in children with JIA, and is effective. [15-18] Few studies have evaluated TMJ corticosteroid injection in JIA. In these studies the volume of corticosteroid injected was chosen empirically. Treatment protocols such as injection of 1 cc (40 mg) of triamcinolone acetonide, 1 cc (20 mg) of triamcinolone hexacetonidein, and 0.5 to 1 cc of the diluted (with 1% lidocaine HCL) triamcinolone hexacetonidein into each of the involved TMJs, all have been used in previous studies. [14-16] The peak effect occurs after approximately 6 weeks of treatment, and the expected duration is 6-17 months. The children may receive a second injection approximately 6 months after the first. [16]

Side effects of intra-articular steroid injection in children include immediate reactions, such as pain and headache, or delayed side effects, such as joint infection and loss of subcutaneous fat. [16] Because the mandibular endochondral growth zone is located at the head of condyle (at the site of corticosteroid injection), the concern is whether intra-articular corticosteroid injection per se may cause growth retardation. Stoustrup et al., in an animal study demonstrated that intra-articular glucocorticoid injection may result in even more pronounced mandibular growth reduction than that caused by the arthritis alone. [19] Schindler et al. reported a case of severe temporomandibular dysfunction and joint destruction after intra-articular injection of triamcinolone, and El-Hakim et al. showed TMJ resorption with active osteoclastic activity after intra-articular injection of a single dose of dexamethasone in rats. [20,21]

intra-articular corticosteroid injection has been used to improve mouth opening in patients with anterior disk displacement without reduction (ADDWOR), i.e., closed lock. [22]

#### **2.2. Oral ulcerative and vesiculobullous lesions**

Corticosteroids are successfully used for the treatment of several ulcerative and vesiculobullous lesions involving the oral cavity and perioral areas including recurrent aphthous stomatitis (RAS), Behcet's syndrome, pemphigus vulgaris, bullous pemphigoid, mucous membrane pemphigoid, erythema multiforme and Stevens-Johnson syndrome (Tables 3-5). [23]

*Recurrent aphthous stomatitis:* These superficial painful ulcers occur commonly in the oral cavity. Minor form of the disease has 1 to 5 ulcers at one episode. The ulcers which are under 1 cm in diameter persist 8 to 14 days, and heal spontaneously without sequelae. The major aphthous ulcers are larger than 1 cm, and persist for weeks to months. Corticosteroids either alone or in combination with other drugs have been used for treatment of these lesions. [24-28] Topical steroids, such as triamcinolone acetonide and prednisolone (2 times/day), are formulated as oral pastes. Therapeutic benefit can be derived from a mouthwash containing betamethasone. It should be noted that the long-term use of topical steroids may predispose patient to developing oral candidiasis. [28]

The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery 545

major aphthous stomatitis, erosive lichen planus

vaccines, active tuberculosis

healing, mucosal atrophy

Behcet's syndrome, pemphigus vulgaris, pemphigoid

Topical intraoral cream or gel

0.05% cream or gel applied thinly bid

Topical intraoral cream or ointment

0.05% cream or ointment applied thinly bid

Topical intraoral cream

0.05% cream applied thinly bid

**Drug Triamcinolone (10 mg/ml) Dexamethasone (4 mg/ml)** 

Contraindications Hypersensitivity to corticosteroids, systemic fungal infection, live

Unusual side effects Peptic ulceration with perforation, osteoporosis, impaired wound

**Drug Beclomethasone Betamethasone Clobetasol Halobetasol Fluocinonide** 

Topical intraoral cream or gel, soluble tablets as mouth wash

0.1% cream or 0.05% gel applied thinly bid; 0.5 mg 2-4 times daily as mouth wash

Indications Severe recurrent aphthous stomatitis, Behcet's syndrome, pemphigus vulgaris, pemphigoid, erythema multiforme

Contraindications Hypersensitivity to corticosteroids, systemic infection (unless specific

Common side effects Dyspepsia, candidiasis, myopathy, osteoporosis, adrenal suppression, Cushing's syndrome, euphoria, depression Unusual side effects Peptic ulceration with perforation, Cushingoid side effects increasingly likely with doses above 7.5 mg daily

inhibitor given), live vaccines

2. 1-2 mg/kg/day after breakfast until disease controlled 3. 1-2 mg/kg/day, then maintenance of 2.5-15 mg daily

4. 20-40 mg daily for 7-10 days at onset of lesions or until lesions resolve 5. 60 mg daily for 2 days, 50 mg daily for 2 days, 40 mg daily for 2 days, 30 mg daily for 2 days, 20 mg daily for 2 days, 10 mg daily for 2 days

antimicrobial therapy given), peptic disease (unless proton pump

Indications Severe recurrent aphthous stomatitis,

Usual dosage Inject 0.1 cc/cm lesion

Common side effects Candidiasis, hyperglycemia

**Table 3.** Injectable (intralesional) corticosteroids used for treatment of oral lesions

Indications Severe recurrent aphthous stomatitis,

Adapted and modified from [23].

Administration Inhaler spray

Usual dosage 50-100 µg

Adapted and modified from [23].

Adapted and modified from [23].

topically to mucosal lesions

sprayed onto oral lesion

Contraindications Untreated infections Common side effects Oral candidiasis

**Table 4.** Topical corticosteroids used for treatment of oral lesions

**Table 5.** Systemic corticosteroids used for treatment of oral lesions

Unusual side effects Adrenal suppression if doses exceeded

**Drug Prednisone (tablets)**

Usual dosage 1. 30-40 mg daily after breakfast for 4-5 days

Topical and injectable (intralesional) corticosteroids are useful for large and painful lesions. Systemic administration of corticosteroids is reserved for severe cases to prevent lesion formation or to reduce the number of lesions. Systemic corticosteroids should be prescribed in short courses, and only for severe outbreaks or cases that don't respond to topical or injectable corticosteroids. [23]

*Behcet's syndrome:* The treatment of oral lesions of Behcet's syndrome is similar to the treatment of severe or major RAS. [23]

*Pemphigus vulgaris:* Pemphigus vulgaris is a severe, potentially life-threatening vesiculobullous disease that may affect skin and mucous membranes. Oral cavity is involved in nearly 80% of patients. In the past, corticosteroid therapy was the treatment of choice but later, combination therapy involving the use of systemic corticosteroids with immunosuppressive agents was introduced, in an attempt to achieve disease control with lower doses of steroids. [29-31]

The principal treatment of pemphigus vulgaris is systemic administration of corticosteroids at doses of 1 to 2 mg/kg/day. Maintenance of remission may be achieved with topical corticosteroids, allowing reduction of systemic drugs. Isolated lesions can be treated with injectable corticosteroids. [23]

*Bullous and mucous membrane pemphigoid:* The choice of drugs used for the treatment of pemphigoid is based upon the sites of involvement, clinical severity, and disease progression. For more severe disease, or with rapid progression, systemic corticosteroids are the agents of choice for initial treatment, combined with steroid-sparing agents for longterm maintenance. [32] Topical and injectable corticosteroids are useful for treatment of mild or localized oral lesions. [23]

*Erythema multiforme (EM)* and *Stevens-Johnson syndrome (SJS):* It has been shown that corticosteroids have a favorable influence on the outcome of EM and SJS, if administered in high doses, over a short period of time, early in the course of the disease, and with proper tapering of medication. [33-37] However, the dosing and route of administration that provides the most benefit for EMM and SJS patients is in question. Treatment protocols such as early therapy with systemic prednisone (0.5 to 1.0mg/kg/day) or pulse methylprednisolone (1mg/kg/day for 3 days), intravenous pulsed dose methylprednisolone (3 consecutive daily infusions of 20–30mg/kg to a maximum of 500mg given over 2 to 3 hours), and dexamethasone pulse therapy (1.5mg/kg IV over 30 to 60 minutes on 3 consecutive days), all have been shown to be effective. [33-35,37-39]


Adapted and modified from [23].

544 Glucocorticoids – New Recognition of Our Familiar Friend

injectable corticosteroids. [23]

lower doses of steroids. [29-31]

injectable corticosteroids. [23]

or localized oral lesions. [23]

effective. [33-35,37-39]

treatment of severe or major RAS. [23]

major aphthous ulcers are larger than 1 cm, and persist for weeks to months. Corticosteroids either alone or in combination with other drugs have been used for treatment of these lesions. [24-28] Topical steroids, such as triamcinolone acetonide and prednisolone (2 times/day), are formulated as oral pastes. Therapeutic benefit can be derived from a mouthwash containing betamethasone. It should be noted that the long-term use of topical

Topical and injectable (intralesional) corticosteroids are useful for large and painful lesions. Systemic administration of corticosteroids is reserved for severe cases to prevent lesion formation or to reduce the number of lesions. Systemic corticosteroids should be prescribed in short courses, and only for severe outbreaks or cases that don't respond to topical or

*Behcet's syndrome:* The treatment of oral lesions of Behcet's syndrome is similar to the

*Pemphigus vulgaris:* Pemphigus vulgaris is a severe, potentially life-threatening vesiculobullous disease that may affect skin and mucous membranes. Oral cavity is involved in nearly 80% of patients. In the past, corticosteroid therapy was the treatment of choice but later, combination therapy involving the use of systemic corticosteroids with immunosuppressive agents was introduced, in an attempt to achieve disease control with

The principal treatment of pemphigus vulgaris is systemic administration of corticosteroids at doses of 1 to 2 mg/kg/day. Maintenance of remission may be achieved with topical corticosteroids, allowing reduction of systemic drugs. Isolated lesions can be treated with

*Bullous and mucous membrane pemphigoid:* The choice of drugs used for the treatment of pemphigoid is based upon the sites of involvement, clinical severity, and disease progression. For more severe disease, or with rapid progression, systemic corticosteroids are the agents of choice for initial treatment, combined with steroid-sparing agents for longterm maintenance. [32] Topical and injectable corticosteroids are useful for treatment of mild

*Erythema multiforme (EM)* and *Stevens-Johnson syndrome (SJS):* It has been shown that corticosteroids have a favorable influence on the outcome of EM and SJS, if administered in high doses, over a short period of time, early in the course of the disease, and with proper tapering of medication. [33-37] However, the dosing and route of administration that provides the most benefit for EMM and SJS patients is in question. Treatment protocols such as early therapy with systemic prednisone (0.5 to 1.0mg/kg/day) or pulse methylprednisolone (1mg/kg/day for 3 days), intravenous pulsed dose methylprednisolone (3 consecutive daily infusions of 20–30mg/kg to a maximum of 500mg given over 2 to 3 hours), and dexamethasone pulse therapy (1.5mg/kg IV over 30 to 60 minutes on 3 consecutive days), all have been shown to be

steroids may predispose patient to developing oral candidiasis. [28]


Adapted and modified from [23].

**Table 4.** Topical corticosteroids used for treatment of oral lesions


Adapted and modified from [23].

**Table 5.** Systemic corticosteroids used for treatment of oral lesions

#### **2.3. Keloid and hypertrophic scars**

Keloid and hypertrophic scar (HS) represent pathologic overhealing conditions which are caused by excessive production of fibrous tissue following healing of skin injuries. Keloid produces significantly more collagen than HS. Their exact cause is unknown but inflammation, tension, and genetic background are mentioned as contributing factors. Keloid and HS have different clinical features. Keloids extend beyond the confines of the original wound, develop months after injury, and rarely regress. HS is a raised scar that remains confined to the area of the injury, usually form within weeks, and may regress without intervention.

The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery 547

resemblance of central giant cell granuloma to sarcoid. Because corticosteroids have been effective in the treatment of sarcoid, it was thought that they may have a similar therapeutic effect on central giant cell granuloma. In addition, corticosteroids may act by suppressing

Bell's palsy is an idiopathic inflammation of the facial nerve (the seventh of twelve paired cranial nerves) which occurs almost always on one side only. It is characterized by facial muscle weakness, hyperacusis, decreased tearing, and loss of taste on the anterior two thirds of the tongue. Because Bell's palsy results from inflammation and edema of the facial nerve, corticosteroids constitute the standard medicine in the treatment of this condition. [46-48] For adults, prednisolone at doses of 1 mg/kg/day for 7 to 10 days, taken in divided doses in

**2.6. Management of post-operative morbidities associated with maxillofacial** 

Facial pain, edema, ecchymosis and limitation of mouth opening are the expected sequelae of oral and maxillofacial surgeries. These post-operative complications affect the ability of patient to interrelate and to return to the daily life and activities, and deteriorate the quality

Many modalities are used to abate sequelae in the oral and maxillofacial surgery including

Corticosteroids are commonly used to control post-operative morbidities and to provide comfort for patients. However, there are no definite protocols relative to molecules, doses, schedules, and routes of administration. [51] The most commonly administered types of corticosteroids are betamethasone, dexamethasone, and methylprednisolone, administered intravenously, orally or by injection into the masseter muscle. The morbidity-management

To decrease post-rhinoplasty edema, the administration of corticosteroids has been advocated for many years. In a study by Gurlek et al., it was shown that high dose methylprednisolone was effective in preventing and reducing both the periorbital ecchymosis and edema in open rhinoplasty. [52] In the same line, Kargi et al., and Kara and Gokalan showed that the perioperative use of corticosteroids reduced edema and ecchymosis associated with rhinoplasty surgery. [53,54] In contrast, Hoffmann et al. did not observe any increase either in the edema or the ecchymosis after rhinoplasty surgery. [55]

Regarding orthognathic surgery, several investigations demonstrated that perioperative corticosteroid administration significantly reduced post-operative inflammation and edema. [56-59] In contrast, Munro et al. did not observe any significant decrease in postoperative edema even with the highest doses and the longest durations of corticosteroid treatment. (56)

use of ice pack, pressure dressing, surgical drain, and drugs.

protocol also varies depending upon the type of surgery being performed.

any angiogenic component of the lesion. [45]

the morning and evening, is suggested.

**2.5. Bell's palsy** 

**surgeries** 

of life of patient. [49,50]

Various treatment modalities have been used for prevention and treatment of keloid and HSs such as pressure therapy, silicone gel sheeting, topical flavonoids, corticosteroid therapy, radiotherapy, and surgery.

Topical and intralesional glucocorticoids are frequently used to treat existing keloid and HS or, prophylactically, to prevent their formation or recurrence after surgical removal. Topical administration of steroids doesn't appear to be as efficacious as intralesional injection of the drug. Intralesional steroid injection, either on its own or in combination with other treatment modalities is the most common treatment used for keloid and HSs. Glucocorticoids have a multiplicity of effects on scars including suppressive effects on the inflammatory process in the wound, diminishing collagen and glycosaminoglycan synthesis, inhibition of fibroblast growth, and enhancing collagen and fibroblast degeneration. [40,41] Triamcinolone acetonide is the most commonly used steroid for the treatment of HS and keloid. It is used in a concentration of 10-20 mg/ml, though it can be given at a dose of 40 mg/ml for a tough bulky lesion; the concentration depends upon the size and site of the lesion and age of the individual. [42] Side effects of steroid injection include hypopigmentation, dermal atrophy, telangiectasia, and cushingoid effects from systemic absorption. [41] Cushing's syndrome secondary to injection of triamcinolone acetonide for the treatment of keloids have been reported by several investigators. [43,44]

#### **2.4. Central giant cell granuloma**

Central giant cell granuloma of the jaws is a benign tumor which occurs most often in children and young adults. This tumor is made up of loose fibrous connective tissue stroma with many interspersed proliferating fibroblasts, aggregations of multinucleated giant cells, and foci of hemorrhage.

Various surgical and nonsurgical treatments have been advocated for this lesion. One of the nonsurgical treatments proposed is intralesional corticosteroid injections. Intralesional injection of triamcinolone acetonide has been shown to induce partial and in some cases complete resolution of central giant cell granuloma. However, there is no reasonably strong consensus in the literature regarding optimal dosage and duration of treatment that provides the most benefit. The mechanism of action of corticosteroids in the treatment of central giant cell granuloma is unknown. A rationale for its use has been the histologic resemblance of central giant cell granuloma to sarcoid. Because corticosteroids have been effective in the treatment of sarcoid, it was thought that they may have a similar therapeutic effect on central giant cell granuloma. In addition, corticosteroids may act by suppressing any angiogenic component of the lesion. [45]

#### **2.5. Bell's palsy**

546 Glucocorticoids – New Recognition of Our Familiar Friend

Keloid and hypertrophic scar (HS) represent pathologic overhealing conditions which are caused by excessive production of fibrous tissue following healing of skin injuries. Keloid produces significantly more collagen than HS. Their exact cause is unknown but inflammation, tension, and genetic background are mentioned as contributing factors. Keloid and HS have different clinical features. Keloids extend beyond the confines of the original wound, develop months after injury, and rarely regress. HS is a raised scar that remains confined to the area of the injury, usually form within weeks, and may regress

Various treatment modalities have been used for prevention and treatment of keloid and HSs such as pressure therapy, silicone gel sheeting, topical flavonoids, corticosteroid

Topical and intralesional glucocorticoids are frequently used to treat existing keloid and HS or, prophylactically, to prevent their formation or recurrence after surgical removal. Topical administration of steroids doesn't appear to be as efficacious as intralesional injection of the drug. Intralesional steroid injection, either on its own or in combination with other treatment modalities is the most common treatment used for keloid and HSs. Glucocorticoids have a multiplicity of effects on scars including suppressive effects on the inflammatory process in the wound, diminishing collagen and glycosaminoglycan synthesis, inhibition of fibroblast growth, and enhancing collagen and fibroblast degeneration. [40,41] Triamcinolone acetonide is the most commonly used steroid for the treatment of HS and keloid. It is used in a concentration of 10-20 mg/ml, though it can be given at a dose of 40 mg/ml for a tough bulky lesion; the concentration depends upon the size and site of the lesion and age of the individual. [42] Side effects of steroid injection include hypopigmentation, dermal atrophy, telangiectasia, and cushingoid effects from systemic absorption. [41] Cushing's syndrome secondary to injection of triamcinolone acetonide for the treatment of keloids have been reported by several investigators. [43,44]

Central giant cell granuloma of the jaws is a benign tumor which occurs most often in children and young adults. This tumor is made up of loose fibrous connective tissue stroma with many interspersed proliferating fibroblasts, aggregations of multinucleated giant cells,

Various surgical and nonsurgical treatments have been advocated for this lesion. One of the nonsurgical treatments proposed is intralesional corticosteroid injections. Intralesional injection of triamcinolone acetonide has been shown to induce partial and in some cases complete resolution of central giant cell granuloma. However, there is no reasonably strong consensus in the literature regarding optimal dosage and duration of treatment that provides the most benefit. The mechanism of action of corticosteroids in the treatment of central giant cell granuloma is unknown. A rationale for its use has been the histologic

**2.3. Keloid and hypertrophic scars** 

therapy, radiotherapy, and surgery.

**2.4. Central giant cell granuloma** 

and foci of hemorrhage.

without intervention.

Bell's palsy is an idiopathic inflammation of the facial nerve (the seventh of twelve paired cranial nerves) which occurs almost always on one side only. It is characterized by facial muscle weakness, hyperacusis, decreased tearing, and loss of taste on the anterior two thirds of the tongue. Because Bell's palsy results from inflammation and edema of the facial nerve, corticosteroids constitute the standard medicine in the treatment of this condition. [46-48] For adults, prednisolone at doses of 1 mg/kg/day for 7 to 10 days, taken in divided doses in the morning and evening, is suggested.

### **2.6. Management of post-operative morbidities associated with maxillofacial surgeries**

Facial pain, edema, ecchymosis and limitation of mouth opening are the expected sequelae of oral and maxillofacial surgeries. These post-operative complications affect the ability of patient to interrelate and to return to the daily life and activities, and deteriorate the quality of life of patient. [49,50]

Many modalities are used to abate sequelae in the oral and maxillofacial surgery including use of ice pack, pressure dressing, surgical drain, and drugs.

Corticosteroids are commonly used to control post-operative morbidities and to provide comfort for patients. However, there are no definite protocols relative to molecules, doses, schedules, and routes of administration. [51] The most commonly administered types of corticosteroids are betamethasone, dexamethasone, and methylprednisolone, administered intravenously, orally or by injection into the masseter muscle. The morbidity-management protocol also varies depending upon the type of surgery being performed.

To decrease post-rhinoplasty edema, the administration of corticosteroids has been advocated for many years. In a study by Gurlek et al., it was shown that high dose methylprednisolone was effective in preventing and reducing both the periorbital ecchymosis and edema in open rhinoplasty. [52] In the same line, Kargi et al., and Kara and Gokalan showed that the perioperative use of corticosteroids reduced edema and ecchymosis associated with rhinoplasty surgery. [53,54] In contrast, Hoffmann et al. did not observe any increase either in the edema or the ecchymosis after rhinoplasty surgery. [55]

Regarding orthognathic surgery, several investigations demonstrated that perioperative corticosteroid administration significantly reduced post-operative inflammation and edema. [56-59] In contrast, Munro et al. did not observe any significant decrease in postoperative edema even with the highest doses and the longest durations of corticosteroid treatment. (56)

The effects of corticosteroids on post-operative edema after oral surgery have been widely investigated in the literature. Many prior studies demonstrated a significant decrease in post-operative edema after administration of corticosteroids. [60-63] In a study by Zandi, it was shown that steroids not only reduced the facial swelling, but also the severity of pain after surgery. [60] Similarly, several studies reported that corticosteroids significantly decreased post-operative edema and pain, indicating a strong correlation between edema and pain decreases. [62-64]

The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery 549

Although corticosteroids have great potential in the treatment of various diseases and conditions affecting oral and maxillofacial region, they also carry the risk of many side effects. Therefore, benefits from corticosteroids should always be weighed against their potential risks. Side effects of corticosteroids vary depending on the type and dose of the medication, rout of administration, and length of treatment. Significant adverse effects are most likely to occur in patients using oral corticosteroids for a long period of time. These may include weight gain, impaired growth, adrenal insufficiency, electrolyte abnormalities, increased susceptibility to infection, myopathy, osteoporosis, osteonecrosis, cataract, glaucoma, psychological problems, fractures, hypertension, insomnia, moon face, diabetes,

Topical glucocorticoids may cause adverse effects such as skin atrophy, hypopigmentation, subcutaneous fat wasting, telangectasia, contact dermatitis, oral thrush, and cushingoid effects from systemic absorption. [28,41] Application of topical corticosteroids on eyelids has been reported to cause glaucoma. Adrenal suppression, growth retardation in children, and cushing's syndrome are rare adverse effects of long

Intralesional glucocorticoids may cause sterile abscess, skin atrophy, hypopigmentation,

Although the frequency of side effects of inhaled corticosteroids is lower than systemic corticosteroids, high doses of inhaled corticosteroids have the potential to produce various local and systemic side effects. Systemic side effects associated with inhaled corticosteroids include osteoporosis, retarded growth in children, cataracts, glaucoma, and skin thinning. Inhaled corticosteroids may cause local side effects including oropharyngeal candidiasis,

**5. Perioperative management of patients with adrenal insufficiency** 

Insufficient adrenocortical function is a rare disorder resulting from endogenous deficiency (primary) or from the administration of exogenous corticosteroids (secondary). Adrenal suppression should be suspected in those patients receiving the equivalent of 20 mg of prednisone daily for one week or the equivalent of 7.5 mg of prednisone daily for one month within the past year. [2] In adrenal suppression the body is not able to appropriately manage the challenge of stresses such as medical illness, surgery, and trauma. This may precipitate an adrenal crisis, signaled by the onset of fever, restlessness, flank and

Any patient suspected of having adrenal insufficiency should be evaluated with an ACTH (cortrosyn) stimulation test or be given supplemental corticosteroids empirically perioperatively. Cortrosyn stimulation test measures how well the adrenal glands respond

dysphonia, reflex cough, bronchospasm, and pharyngitis. [67]

abdominal pain, vomiting, lethargy, hypotension, or coma.

to a synthetic ACTH administered to the patient.

**4. Corticosteroids side effects** 

and peptic ulcer. [1,66]

term topical corticosteroid use.

panniculitis, and skin necrosis.

Even though the effects of corticosteroids on post-operative morbidities after various oral and maxillofacial surgeries have been widely investigated in the literature, methodological differences, variation in agents, doses, and routes of administration of the drugs have compromised the scientific conclusions.

### **2.7. Other uses of corticosteroids in oral and maxillofacial surgery**

In addition to the aforementioned indications, corticosteroids are successfully used in the management of acute trigeminal nerve injuries, traumatic facial nerve paralysis, chronic facial pain, and allergic diseases involving maxillofacial area.

### **3. Corticosteroids contraindications**

In prescribing corticosteroids, physicians must be aware that some patients are poor candidates for systemic, locally injected, or topical corticosteroid therapy.

Systemic corticosteroids must be used with the greatest of caution in patients with uncontrolled hypertension, diabetes, active peptic ulcer, heart diseases, infections, psychiatric disorders, osteoporosis, cataract, glaucoma, tuberculosis, mycobacterial diseases, herpes simplex infection, pregnancy, varicella zoster infection, immune deficiency, underactive thyroid, and mental disorders.

Injectable corticosteroid use is contraindicated in patients with hypersensitivity to corticosteroids, infections, and active tuberculosis.

Use of topical corticosteroids is absolutely contraindicated in the treatment of primary bacterial infections such as impetigo, furuncles, carbuncles, erysipelas, cellulitis, lymphangitis, and erythrasma. Topical corticosteroids are also contraindicated in patients with a history of hypersensitivity to any of the components of the preparation. Currently, little is known about the safety of topical corticosteroids in pregnancy. Although it has been reported that there is an association between very potent topical corticosteroids and congenital abnormalities including low birth weight and orofacial clefts, use of these drugs in pregnancy is not recommended unless the potential benefit justifies the potential risks to fetus. [65]

Ophthalmic use of topical corticosteroids is contraindicated in most viral, bacterial, and fungal diseases of ocular structures.

### **4. Corticosteroids side effects**

548 Glucocorticoids – New Recognition of Our Familiar Friend

and pain decreases. [62-64]

compromised the scientific conclusions.

**3. Corticosteroids contraindications** 

underactive thyroid, and mental disorders.

fungal diseases of ocular structures.

fetus. [65]

corticosteroids, infections, and active tuberculosis.

The effects of corticosteroids on post-operative edema after oral surgery have been widely investigated in the literature. Many prior studies demonstrated a significant decrease in post-operative edema after administration of corticosteroids. [60-63] In a study by Zandi, it was shown that steroids not only reduced the facial swelling, but also the severity of pain after surgery. [60] Similarly, several studies reported that corticosteroids significantly decreased post-operative edema and pain, indicating a strong correlation between edema

Even though the effects of corticosteroids on post-operative morbidities after various oral and maxillofacial surgeries have been widely investigated in the literature, methodological differences, variation in agents, doses, and routes of administration of the drugs have

In addition to the aforementioned indications, corticosteroids are successfully used in the management of acute trigeminal nerve injuries, traumatic facial nerve paralysis, chronic

In prescribing corticosteroids, physicians must be aware that some patients are poor

Systemic corticosteroids must be used with the greatest of caution in patients with uncontrolled hypertension, diabetes, active peptic ulcer, heart diseases, infections, psychiatric disorders, osteoporosis, cataract, glaucoma, tuberculosis, mycobacterial diseases, herpes simplex infection, pregnancy, varicella zoster infection, immune deficiency,

Injectable corticosteroid use is contraindicated in patients with hypersensitivity to

Use of topical corticosteroids is absolutely contraindicated in the treatment of primary bacterial infections such as impetigo, furuncles, carbuncles, erysipelas, cellulitis, lymphangitis, and erythrasma. Topical corticosteroids are also contraindicated in patients with a history of hypersensitivity to any of the components of the preparation. Currently, little is known about the safety of topical corticosteroids in pregnancy. Although it has been reported that there is an association between very potent topical corticosteroids and congenital abnormalities including low birth weight and orofacial clefts, use of these drugs in pregnancy is not recommended unless the potential benefit justifies the potential risks to

Ophthalmic use of topical corticosteroids is contraindicated in most viral, bacterial, and

**2.7. Other uses of corticosteroids in oral and maxillofacial surgery** 

candidates for systemic, locally injected, or topical corticosteroid therapy.

facial pain, and allergic diseases involving maxillofacial area.

Although corticosteroids have great potential in the treatment of various diseases and conditions affecting oral and maxillofacial region, they also carry the risk of many side effects. Therefore, benefits from corticosteroids should always be weighed against their potential risks. Side effects of corticosteroids vary depending on the type and dose of the medication, rout of administration, and length of treatment. Significant adverse effects are most likely to occur in patients using oral corticosteroids for a long period of time. These may include weight gain, impaired growth, adrenal insufficiency, electrolyte abnormalities, increased susceptibility to infection, myopathy, osteoporosis, osteonecrosis, cataract, glaucoma, psychological problems, fractures, hypertension, insomnia, moon face, diabetes, and peptic ulcer. [1,66]

Topical glucocorticoids may cause adverse effects such as skin atrophy, hypopigmentation, subcutaneous fat wasting, telangectasia, contact dermatitis, oral thrush, and cushingoid effects from systemic absorption. [28,41] Application of topical corticosteroids on eyelids has been reported to cause glaucoma. Adrenal suppression, growth retardation in children, and cushing's syndrome are rare adverse effects of long term topical corticosteroid use.

Intralesional glucocorticoids may cause sterile abscess, skin atrophy, hypopigmentation, panniculitis, and skin necrosis.

Although the frequency of side effects of inhaled corticosteroids is lower than systemic corticosteroids, high doses of inhaled corticosteroids have the potential to produce various local and systemic side effects. Systemic side effects associated with inhaled corticosteroids

include osteoporosis, retarded growth in children, cataracts, glaucoma, and skin thinning. Inhaled corticosteroids may cause local side effects including oropharyngeal candidiasis, dysphonia, reflex cough, bronchospasm, and pharyngitis. [67]

### **5. Perioperative management of patients with adrenal insufficiency**

Insufficient adrenocortical function is a rare disorder resulting from endogenous deficiency (primary) or from the administration of exogenous corticosteroids (secondary). Adrenal suppression should be suspected in those patients receiving the equivalent of 20 mg of prednisone daily for one week or the equivalent of 7.5 mg of prednisone daily for one month within the past year. [2] In adrenal suppression the body is not able to appropriately manage the challenge of stresses such as medical illness, surgery, and trauma. This may precipitate an adrenal crisis, signaled by the onset of fever, restlessness, flank and abdominal pain, vomiting, lethargy, hypotension, or coma.

Any patient suspected of having adrenal insufficiency should be evaluated with an ACTH (cortrosyn) stimulation test or be given supplemental corticosteroids empirically perioperatively. Cortrosyn stimulation test measures how well the adrenal glands respond to a synthetic ACTH administered to the patient.

The currently recommended corticosteroid coverage for various surgical procedures is based on the magnitude of stress and the known glucocorticoid production rate associated with it, and includes the following: [2,68]

The Role of Corticosteroids in Today's Oral and Maxillofacial Surgery 551

minimize expected post-operative morbidities such as pain and edema after oral and maxillofacial surgeries. Because of anti-inflammatory and anti-allergic actions of glucocorticoids, they have their widest application in the management of acute and chronic conditions which have allergic, immunologic, or inflammatory basis. However, corticosteroids carry the risk of potential side effects which are sometimes severe and life threatening. Therefore, benefits from corticosteroids should always be weighed against their

Prescribing the minimal dose and the least potent type of corticosteroids necessary to produce a given therapeutic effect, simultaneous use of non-steroidal agents to reduce the dose of corticosteroids, and prescribing corticosteroids for a short period of time or

The author wishes to express his deep appreciation to Dr. Mojgan Ahmadian for her

[1] Brunton LL, Lazo JS, Parker KL (2005) Goodman & Gilman's The pharmacological basis

[2] Fonseca RJ, Marciani RD, Turvey TA (2009) Oral and maxillofacial surgery. Second

[3] Kopp S, Akerman S, Nilner M (1991) Short-term effects of intra-articular sodium hyaluronate, glucocorticoid, and saline injections on rheumatoid arthritis of the

[4] Alstergren P, Appelgren A, Appelgren B, Kopp S, Lundeberg T, Theodorsson E (1996) The effect on joint fluid concentration of neuropeptide Y by intra-articular injection of

[7] Adcock IM, Ito K, Barnes PJ (2004) Glucocorticoids: effects on gene transcription. Proc

glucocorticoid in temporomandibular joint arthritis. Acta Odontol Scand. 54: 1-7. [5] Fredriksson L, Alstergren P, Kopp S (2005) Serotonergic mechanisms influence the response to glucocorticoid treatment in TMJ arthritis. Mediators Inflamm. 2005:194–201. [6] Barnes PJ (1998) Anti-inflammatory actions of glucocorticoids: molecular mechanisms.

sporadically are some strategies to minimize corticosteroids adverse effects.

potential risks in each patient.

*Department of Oral and Maxillofacial Surgery,* 

*Researcher, Dental Research Center,* 

*Hamedan University of Medical Sciences, Hamedan, Iran* 

*Hamedan University of medical sciences, Hamedan, Iran* 

extensive assistance in the preparation of this chapter.

of therapeutics. Eleventh edition. New York: McGraw-Hill.

temporomandibular joint. J Craniomandib Disord. 5: 231-238*.* 

**Author details** 

Mohammad Zandi

**Acknowledgement** 

edition. Saunders.

Clin Sci. 94: 557–572.

Am Thorac Soc. 1: 247-254.

**8. References** 


In the case of postoperative complications such as fever and pain, it is recommended that the corticosteroid administration be continued consistent with the post-operative stress response. [68]

### **6. Maternal corticosteroid use and the risk of orofacial clefts in infants**

Orofacial clefts are the most common congenital deformity affecting maxillofacial area. The etiology of facial clefting is complex and has been extensively investigated. There are both major and minor genetic influences involved, with variable interactions from environmental factors. [69] Several environmental factors such as maternal drug intake, trauma, smoking, and exposure to x-rays during the pregnancy period have been suggested to increase the chance of cleft development in infants. [70]

Pregnant women often use topical, inhaled, or systemic corticosteroid drugs for a variety of inflammatory and allergic conditions. Several investigations have reported that the use of corticosteroids during early pregnancy is associated with a 3- to 6-fold increased risk of orofacial clefts. [71-75] Although systemic corticosteroids are associated with a higher risk of orofacial clefts than topical corticosteroids, the latter is not without risk. It has been shown that application of hydrocortisone cream on eczematous skin is associated with significant increase in the level of plasma cortisol. [76] In a study by Edwards et al., a significant association between topical corticosteroids and orofacial cleft was observed. [77] Epidemiologic data have shown that low-to-moderate doses of inhaled corticosteroids taken during the first trimester of pregnancy are safe but raise concerns about high doses. [78]

The mechanism of cleft palate production by corticosteroids is uncertain; it is a complicated interference in a complex developmental program involving many genetic and biochemical processes. Glucocorticoids may cause cleft palate deformity by delaying palatal shelf elevation. [79] Corticosteroids can reduce the collagen content of connective tissue by inhibiting collagen synthesis, which could disrupt cell-cell interaction and tissue-tissue interactions. [71]

### **7. Conclusion**

Glucocorticoids are used, either singly or in combination with other drugs, for the treatment of various diseases affecting oral and maxillofacial area. They are also frequently used to minimize expected post-operative morbidities such as pain and edema after oral and maxillofacial surgeries. Because of anti-inflammatory and anti-allergic actions of glucocorticoids, they have their widest application in the management of acute and chronic conditions which have allergic, immunologic, or inflammatory basis. However, corticosteroids carry the risk of potential side effects which are sometimes severe and life threatening. Therefore, benefits from corticosteroids should always be weighed against their potential risks in each patient.

Prescribing the minimal dose and the least potent type of corticosteroids necessary to produce a given therapeutic effect, simultaneous use of non-steroidal agents to reduce the dose of corticosteroids, and prescribing corticosteroids for a short period of time or sporadically are some strategies to minimize corticosteroids adverse effects.

### **Author details**

550 Glucocorticoids – New Recognition of Our Familiar Friend

with it, and includes the following: [2,68]

chance of cleft development in infants. [70]

response. [68]

**7. Conclusion** 

hydrocortisone equivalent for 1 to 2 days.

The currently recommended corticosteroid coverage for various surgical procedures is based on the magnitude of stress and the known glucocorticoid production rate associated

Minor surgical stress such as tooth extraction, biopsy, periodontal surgery, genioplasty,

Moderate surgical stress such as panfacial fractures, two jaw surgery, etc: 50-75 mg of

Major surgical stress such as extensive head and neck resection and reconstruction, etc:

In the case of postoperative complications such as fever and pain, it is recommended that the corticosteroid administration be continued consistent with the post-operative stress

**6. Maternal corticosteroid use and the risk of orofacial clefts in infants** 

Orofacial clefts are the most common congenital deformity affecting maxillofacial area. The etiology of facial clefting is complex and has been extensively investigated. There are both major and minor genetic influences involved, with variable interactions from environmental factors. [69] Several environmental factors such as maternal drug intake, trauma, smoking, and exposure to x-rays during the pregnancy period have been suggested to increase the

Pregnant women often use topical, inhaled, or systemic corticosteroid drugs for a variety of inflammatory and allergic conditions. Several investigations have reported that the use of corticosteroids during early pregnancy is associated with a 3- to 6-fold increased risk of orofacial clefts. [71-75] Although systemic corticosteroids are associated with a higher risk of orofacial clefts than topical corticosteroids, the latter is not without risk. It has been shown that application of hydrocortisone cream on eczematous skin is associated with significant increase in the level of plasma cortisol. [76] In a study by Edwards et al., a significant association between topical corticosteroids and orofacial cleft was observed. [77] Epidemiologic data have shown that low-to-moderate doses of inhaled corticosteroids taken during the first trimester of pregnancy are safe but raise concerns about high doses. [78]

The mechanism of cleft palate production by corticosteroids is uncertain; it is a complicated interference in a complex developmental program involving many genetic and biochemical processes. Glucocorticoids may cause cleft palate deformity by delaying palatal shelf elevation. [79] Corticosteroids can reduce the collagen content of connective tissue by inhibiting collagen

Glucocorticoids are used, either singly or in combination with other drugs, for the treatment of various diseases affecting oral and maxillofacial area. They are also frequently used to

synthesis, which could disrupt cell-cell interaction and tissue-tissue interactions. [71]

etc: 25 mg of hydrocortisone equivalent, the day of surgery

100-150 mg of hydrocortisone equivalent for 2 to 3 days.

Mohammad Zandi *Department of Oral and Maxillofacial Surgery, Hamedan University of Medical Sciences, Hamedan, Iran Researcher, Dental Research Center, Hamedan University of medical sciences, Hamedan, Iran* 

### **Acknowledgement**

The author wishes to express his deep appreciation to Dr. Mojgan Ahmadian for her extensive assistance in the preparation of this chapter.

### **8. References**


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[39] Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M (2008) Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR

[40] Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG (2011) Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies.

[41] Donkor P (2007) Head and neck keloid: treatment by core excision and delayed

[42] Gupta S, Sharma VK (2011) Standard guidelines of care: Keloids and hypertrophic scars.

[43] Langston JR, Kolodny SC (1976) Cushing's syndrome associated with the intradermal

[44] Ritota PC, Lo AK (1996) Cushing's syndrome in postburn children following

[45] Ferretti C, Muthray E (2011) Management of central giant cell granuloma of mandible using intralesional corticosteroids: case report and review of literature. J Oral Maxillofac

[46] Sheikh SB, Jacobus C (2012) Are steroids effective for treating Bell's palsy? Ann Emerg

[47] Sherbino J (2010) Evidence-based emergency medicine: clinical synopsis. Do antiviral medications improve recovery in patients with Bell's palsy? Ann Emerg Med. 55: 475-

[48] Gilden D (2009) Treatment of Bell's palsy--the pendulum has swung back to steroids

[49] McGrath C, Comfort MB, Lo EC, Luo Y (2003) Changes in life quality following third

[50] Colorado-Bonnin M, Valmaseda-Castellón E, Berini-Aytés L, Gay-Escoda C (2006) Quality of life following lower third molar removal. Int J Oral Maxillofac Surg. 35: 343-

[51] Sortino F, Cicciù M (2011) Strategies used to inhibit postoperative swelling following

[52] Gürlek A, Fariz A, Aydoğan H, Ersöz-Oztürk A, Evans GR (2009) Effects of high dose corticosteroids in open rhinoplasty. J Plast Reconstr Aesthet Surg. 62: 650-655.

molar surgery--the immediate postoperative period. Br Dent J. 194: 265-8.

removal of impacted lower third molar. Dent Res J (Isfahan). 8: 162-171.

intralesional injection of steroid. J Oral Maxillofac Surg. 65: 1292-1296.

	- [69] Zandi M, Miresmaeili A (2007) Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly. Int J Oral Maxillofac Surg. 36: 200-206.

**Chapter 22** 

© 2012 Amin and Osman, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Assessment of Glucocorticoids ‒** 

Amr Amin and Zeinab Nawito

http://dx.doi.org/10.5772/52889

**1. Introduction** 

effects [3, 4].

Additional information is available at the end of the chapter

**Induced Preclinical Atherosclerosis** 

In 1948, the US rheumatologist Philip Hench and his associates at the Mayo Clinic first administered hydrocortisone to a patient with rheumatoid arthritis and discovered its clinical benefits [1]. Two years later, Hench, together with biochemists Edward Kendall and Tadeus Reichstein, shared the Nobel Prize in Medicine. Today, glucocorticoids are among the most frequently prescribed class of anti-inflammatory medications [2]. They are part of the standard treatment for a wide range of disorders which feature inflammation and/or immune activation, such as asthma, chronic obstructive pulmonary disease, hypersensitivity reactions, autoimmune diseases, and in organ transplantation. However, even early on, the euphoria generated by the discovery of corticosteroids was rapidly tempered by the realization that clinicians were, in a sense, engaging in a Faustian pact between its impressive anti-inflammatory benefits and its potentially devastating Cushingoid side

From a cardiovascular standpoint, the propensity of glucocorticoids to produce hyperglycemia, hypertension, dyslipidemia, and central obesity has long produced concern regarding possible adverse cardiovascular events [5]. Glucocorticoids administration increases blood pressure in a dose dependent fashion. The mechanisms of glucocorticoidsmediated hypertension are incompletely understood but appear to be principally related to increased peripheral vascular resistance rather than to mineralocorticoid receptor mediated effects of increased sodium retention and plasma volume expansion [6]. Dyslipidemia in the context of long term glucocorticoids use is characterized by increased total cholesterol, low density lipoprotein cholesterol, and triglycerides. Corticosteroid treatment increases the risk of glucose intolerance in patients without known diabetes and is associated with deterioration of glycaemic control in diabetic patients [7]. Glucocorticoids treatment therefore contributes to the exacerbation of a cluster of cardiovascular risk factors that are

and reproduction in any medium, provided the original work is properly cited.


## **Assessment of Glucocorticoids ‒ Induced Preclinical Atherosclerosis**

Amr Amin and Zeinab Nawito

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52889

#### **1. Introduction**

556 Glucocorticoids – New Recognition of Our Familiar Friend

Am J Obstet Gynecol. 197: 585.e1-7.

corticoids. Cleft Palate Craniofac J. 40: 624-628.

pregnancy. Am J Med Genet. 120: 459-463.

pregnancy. Am J Med Genet A. 120: 459-463.

dermatitis. Br J Dermatol. 124: 358-360.

Allergy Clin Immunol. 124: 1229-1234.

cleft palate. Curr Top Dev Biol. 19: 217-239.

67: 968-970.

385-392.

iran: a 15-year study. Cleft Palate Craniofac J. 48: 483-489.

[69] Zandi M, Miresmaeili A (2007) Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly. Int J Oral Maxillofac Surg. 36: 200-206. [70] Zandi M, Heidari A (2011) An epidemiologic study of orofacial clefts in hamedan city,

[71] Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ; National Birth Defects Prevention Study (2007) Maternal corticosteroid use and orofacial clefts.

[72] Pradat P, Robert-Gnansia E, Di Tanna GL, Rosano A, Lisi A, Mastroiacovo P (2003) First trimester exposure to corticosteroids and oral clefts. Birth Defects Res Clin Mol Teratol.

[73] Kallen B (2003) Maternal drug use and infant cleft lip/palate with special reference to

[74] Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, Friesen MH, Jacobson S, Kasapinovic S, Chang D, Diav-Citrin O, Chitayat D, Nulman I, Einarson TR, Koren G (2000) Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 62:

[75] Edwards MJ, Agho K, Attia J, Diaz P, Hayes T, Illingworth A, Roddick LG (2003) Casecontrol study of cleft lip or palate after maternal use of topical corticosteroids during

[76] Turpeinen M (1991) Absorption of hydrocortisone from the skin reservoir in atopic

[77] Edwards MJ, Agho K, Attia J, Diaz P, Hayes T, Illingworth A, Roddick LG (2003) Casecontrol study of cleft lip or palate after maternal use of topical corticosteroids during

[78] Blais L, Beauchesne MF, Lemière C, Elftouh N (2009) High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations. J

[79] Goldman AS (1984) Biochemical mechanism of glucocorticoid-and phenytoin-induced

In 1948, the US rheumatologist Philip Hench and his associates at the Mayo Clinic first administered hydrocortisone to a patient with rheumatoid arthritis and discovered its clinical benefits [1]. Two years later, Hench, together with biochemists Edward Kendall and Tadeus Reichstein, shared the Nobel Prize in Medicine. Today, glucocorticoids are among the most frequently prescribed class of anti-inflammatory medications [2]. They are part of the standard treatment for a wide range of disorders which feature inflammation and/or immune activation, such as asthma, chronic obstructive pulmonary disease, hypersensitivity reactions, autoimmune diseases, and in organ transplantation. However, even early on, the euphoria generated by the discovery of corticosteroids was rapidly tempered by the realization that clinicians were, in a sense, engaging in a Faustian pact between its impressive anti-inflammatory benefits and its potentially devastating Cushingoid side effects [3, 4].

From a cardiovascular standpoint, the propensity of glucocorticoids to produce hyperglycemia, hypertension, dyslipidemia, and central obesity has long produced concern regarding possible adverse cardiovascular events [5]. Glucocorticoids administration increases blood pressure in a dose dependent fashion. The mechanisms of glucocorticoidsmediated hypertension are incompletely understood but appear to be principally related to increased peripheral vascular resistance rather than to mineralocorticoid receptor mediated effects of increased sodium retention and plasma volume expansion [6]. Dyslipidemia in the context of long term glucocorticoids use is characterized by increased total cholesterol, low density lipoprotein cholesterol, and triglycerides. Corticosteroid treatment increases the risk of glucose intolerance in patients without known diabetes and is associated with deterioration of glycaemic control in diabetic patients [7]. Glucocorticoids treatment therefore contributes to the exacerbation of a cluster of cardiovascular risk factors that are

© 2012 Amin and Osman, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

central to the metabolic syndrome. However, as inflammation plays a central role in the pathogenesis of atherosclerosis [8], it is also possible that glucocorticoids may exert some anti-atherosclerotic effects.

Assessment of Glucocorticoids Induced Preclinical Atherosclerosis 559

increasing age. They suggested that coronary calcification might be an alarm signal of potential ischemic heart disease. Currently, it is generally recognized that the incidence of Coronary artery disease (CAD) was greater in patients with coronary calcification and

The presence of preclinical atherosclerosis increases global cardiovascular risk; therefore, it can be considered an emerging determinant in assessing such a risk. Single or multiple risk factors increase cardiovascular risk in an exponential manner, meanwhile the presence of one or more risk factors for atherosclerosis is associated with the development of cardiovascular disease. *A specific issue is defined as risk factor when it is possible, on the basis of a strong statistical association, to relate it to the incidence of new cases of disease and if it is clinically* 

Atherosclerosis is defined as a progressive structural remodeling of a vessel wall towards definitive plaque formation and possible related complications. According to new data, the disease begins as an endothelium functional disorder [dysfunction] inducing loss of vascular homeostasis and related functional reserve that initially can become clinically evident only in conditions in which there is a need to increase tissue metabolic requirements (as for instance effort Angina, transient Ischemic Attack, intermittent Claudication) while, after more time, they can become symptomatic at rest because even basal perfusion [blood flow] is impaired (acute coronary syndrome, stroke, critical leg ischemia, and even

Coronary atherosclerosis is the leading cause of death in industrialized western countries. In up to 50% of its victims the first manifestation of CAD is sudden death or acute myocardial infarction. The cost of lost human value and approximate dollars spent (\$90 billion annually) due to coronary artery disease in the western society is of great concern and is the reason for increased efforts for its prevention and its consequences as well. The detection of CAD in its asymptomatic stage is highly desirable because it is an increasingly treatable disease, but till now it has been hindered by the lack of sensitive and specific tests [13].

In evaluating atherosclerosis the following demographic and clinical data are needed; sex, age, cigarette smoking, alcohol consumption, physical activity and life style, socioeconomic status, previous diseases, family history, BMI, WHR [waist to hip ratio] and blood pressure

Chronic subclinical inflammation is thought to be part of the metabolic syndrome [MetSyn]. The latter is characterized by a clustering of atherosclerotic CVD risk factors. The WHO definition of MetSyn [14] requires the presence of insulin resistance plus 2 other of central

atherosclerosis than in those without calcification [16].

cardiovascular death) [12].

**4. Methodology of assessment** 

assessments in the standard way.

**4.1. Clinical background and limitations** 

**3. Value of assessment of preclinical atherosclerosis** 

*demonstrated that new disease cases can be reduced by correcting the same risk factor.* 

There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome. The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest odds ratios were observed in the group with the highest average daily dose, although the dose– response relation was not continuous. Current use was associated with an increased risk of heart failure, which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease [9].

RA population has an increased cardio-vascular mortality and premature death rate, but why does these patients have a higher incidence of atherosclerosis? There are several factors which are known risks in the development of atherosclerosis. Steroids may play a role in the increased mortality from vascular disease. Some reports have suggested that prolonged treatment with steroids accelerates the development of atherosclerosis. Steroids have atherogenic properties that are known to enhance the development of atherosclerosis and they induce vascular injury. In addition, they produce a state of hypercoagulability. In Moreland and O'Dell study, they found an increased atherosclerotic burden in the patients who were on long-term steroids. This suggests that steroid treatment may be a contributor to the higher rate of atherosclerosis seen in them [10]. Del Rincón et al. studied the carotid and lower-limb arteries in a sample of RA patients, and found that the extent of cumulative glucocorticoids dose was significantly associated with arterial incompressibility. This association displayed a gradient in which the proportion of incompressible arteries increased with higher glucocorticoids exposure. This pattern was independent of age at RA onset, sex, disease duration, CV risk factors, and manifestations of RA [11].

#### **2. Historical background**

Calcification of the arterial atheroma occurs in the coronary tree as it does in the remainder of the arterial tree. Such calcified coronary arteries are occasionally noted on routine chest radiographs but are difficult to distinguish from normal mediastinal structures and are confused with calcification in the chest wall, lungs, or other intracardiac structures [12]. Calcification of the coronary arteries is a common autopsy finding and is generally present in 80 to 90% of post-mortem studies. Despite this common pathologic finding, description of coronary calcification was rare until the work of Lenk [13] in 1927, who noted calcification of the left coronary artery on a posteroanterior chest radiograph in a 61-year-old male with left ventricular aneurysm. In 1964 Beadenkopf et al. [14] reported their findings in 904 consecutive autopsies; their results indicated that as the number of coronary arteries with calcification increased, coronary artery wall thickness increased. Tampas and Soule [15] in 1965 using radiographs in 1097 patients over the age of 40 found an incidence of 15% coronary calcification with a male to female ratio of 3 to 2 that was associated with increasing age. They suggested that coronary calcification might be an alarm signal of potential ischemic heart disease. Currently, it is generally recognized that the incidence of Coronary artery disease (CAD) was greater in patients with coronary calcification and atherosclerosis than in those without calcification [16].

### **3. Value of assessment of preclinical atherosclerosis**

558 Glucocorticoids – New Recognition of Our Familiar Friend

anti-atherosclerotic effects.

**2. Historical background** 

central to the metabolic syndrome. However, as inflammation plays a central role in the pathogenesis of atherosclerosis [8], it is also possible that glucocorticoids may exert some

There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome. The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest odds ratios were observed in the group with the highest average daily dose, although the dose– response relation was not continuous. Current use was associated with an increased risk of heart failure, which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease [9].

RA population has an increased cardio-vascular mortality and premature death rate, but why does these patients have a higher incidence of atherosclerosis? There are several factors which are known risks in the development of atherosclerosis. Steroids may play a role in the increased mortality from vascular disease. Some reports have suggested that prolonged treatment with steroids accelerates the development of atherosclerosis. Steroids have atherogenic properties that are known to enhance the development of atherosclerosis and they induce vascular injury. In addition, they produce a state of hypercoagulability. In Moreland and O'Dell study, they found an increased atherosclerotic burden in the patients who were on long-term steroids. This suggests that steroid treatment may be a contributor to the higher rate of atherosclerosis seen in them [10]. Del Rincón et al. studied the carotid and lower-limb arteries in a sample of RA patients, and found that the extent of cumulative glucocorticoids dose was significantly associated with arterial incompressibility. This association displayed a gradient in which the proportion of incompressible arteries increased with higher glucocorticoids exposure. This pattern was independent of age at RA

Calcification of the arterial atheroma occurs in the coronary tree as it does in the remainder of the arterial tree. Such calcified coronary arteries are occasionally noted on routine chest radiographs but are difficult to distinguish from normal mediastinal structures and are confused with calcification in the chest wall, lungs, or other intracardiac structures [12]. Calcification of the coronary arteries is a common autopsy finding and is generally present in 80 to 90% of post-mortem studies. Despite this common pathologic finding, description of coronary calcification was rare until the work of Lenk [13] in 1927, who noted calcification of the left coronary artery on a posteroanterior chest radiograph in a 61-year-old male with left ventricular aneurysm. In 1964 Beadenkopf et al. [14] reported their findings in 904 consecutive autopsies; their results indicated that as the number of coronary arteries with calcification increased, coronary artery wall thickness increased. Tampas and Soule [15] in 1965 using radiographs in 1097 patients over the age of 40 found an incidence of 15% coronary calcification with a male to female ratio of 3 to 2 that was associated with

onset, sex, disease duration, CV risk factors, and manifestations of RA [11].

The presence of preclinical atherosclerosis increases global cardiovascular risk; therefore, it can be considered an emerging determinant in assessing such a risk. Single or multiple risk factors increase cardiovascular risk in an exponential manner, meanwhile the presence of one or more risk factors for atherosclerosis is associated with the development of cardiovascular disease. *A specific issue is defined as risk factor when it is possible, on the basis of a strong statistical association, to relate it to the incidence of new cases of disease and if it is clinically demonstrated that new disease cases can be reduced by correcting the same risk factor.* 

Atherosclerosis is defined as a progressive structural remodeling of a vessel wall towards definitive plaque formation and possible related complications. According to new data, the disease begins as an endothelium functional disorder [dysfunction] inducing loss of vascular homeostasis and related functional reserve that initially can become clinically evident only in conditions in which there is a need to increase tissue metabolic requirements (as for instance effort Angina, transient Ischemic Attack, intermittent Claudication) while, after more time, they can become symptomatic at rest because even basal perfusion [blood flow] is impaired (acute coronary syndrome, stroke, critical leg ischemia, and even cardiovascular death) [12].

Coronary atherosclerosis is the leading cause of death in industrialized western countries. In up to 50% of its victims the first manifestation of CAD is sudden death or acute myocardial infarction. The cost of lost human value and approximate dollars spent (\$90 billion annually) due to coronary artery disease in the western society is of great concern and is the reason for increased efforts for its prevention and its consequences as well. The detection of CAD in its asymptomatic stage is highly desirable because it is an increasingly treatable disease, but till now it has been hindered by the lack of sensitive and specific tests [13].

### **4. Methodology of assessment**

#### **4.1. Clinical background and limitations**

In evaluating atherosclerosis the following demographic and clinical data are needed; sex, age, cigarette smoking, alcohol consumption, physical activity and life style, socioeconomic status, previous diseases, family history, BMI, WHR [waist to hip ratio] and blood pressure assessments in the standard way.

Chronic subclinical inflammation is thought to be part of the metabolic syndrome [MetSyn]. The latter is characterized by a clustering of atherosclerotic CVD risk factors. The WHO definition of MetSyn [14] requires the presence of insulin resistance plus 2 other of central obesity, hypertension, or dyslipidemia. Insulin resistance is thought to be the most prominent pathophysiological process underlying MetSyn. Recent studies of coronary artery calcification (CAC) in asymptomatic samples have shown an association of MetSyn and insulin resistance with the burden of coronary atherosclerosis [13]. Lakka et al. [15] found a 2 to 4-fold increased risk of cardiovascular death with MetSyn in a sample of 1209 Finnish men free from diabetes and CVD at baseline. MetSyn predicted atherosclerosis progression and CVD events in 888 subjects in the Bruneck study, whereas most individual components of the syndrome were not significantly associated with CVD out-comes [16] supporting the concept that MetSyn provides information that is "more than the sum of its parts."[17].

Assessment of Glucocorticoids Induced Preclinical Atherosclerosis 561

evaluation of flow disturbance that helps to quantify stenosis severity. It measures the IMT and size and number of atheromatous plaques. According to the European Society of Cardiology; 2007-Guidelines on the Management of arterial Hypertension, normal IMT is the distance between the media-adventitia and the intima-media interfaces and is

While all conditions in which it is greater than 1.5 mm can be considered an ACP.

Increased IMT (or ACP) is related to the presence, number, intensity and duration of atherosclerosis risk factors as well as endothelial dysfunction [24, 25]. Also, IMT is a potent and independent predictor of future cerebro- and cardiovascular events, as proven by

Normally, ankle systolic arterial pressure (posterior or anterior tibial artery) is just a little higher than brachial pressure measurements so that their ratio always is always > 1.0. This parameter is called the Ankle-Brachial pressure Index (ABI) and can reflect altered pressure values. It is reduced < 0.90 if atherosclerosis induced arterial system impairment is present; hence the patient is considered to have an asymptomatic peripheral artery disease. It is a simple, non-expensive procedure and can also be practiced by general practitioners [17]. Several population trials evidenced an important correlation between decreased ABI,

carotid or coronary atherosclerosis and future cardiac or cerebrovascular events (27).

A new, non-invasive technique was introduced to evaluate brachial artery flow-mediated dilatation (FMD). The evaluation through a sonographic assessment of brachial artery in basal condition and after 5 minutes of occlusion using pneumonic cuff (250 mm Hg) determined a reactive hyperemia and therefore, FMD. A low FMD is a marker of multifocal atherosclerosis and severity of the disease where the progressive reduction of FMD is associated with more extensive coronary tree involvement and future cardiovascular events

*4.3.4. Targeted Ultrasound Detection of Vascular Cell Adhesion Molecule-1 (VCAM-1)* 

VCAM-1 is expressed by activated endothelial cells and participates in leukocyte rolling and adhesion primarily by interacting with its counterligand VLA-4 (*α4 β1*) on monocytes and lymphocytes. VCAM-1 expression on the vessel endothelial surface or the underlying vasa vasorum plays an important role in atherosclerotic plaque development by monocyte and Tlymphocyte recruitment. It is an ideal target for molecular imaging because there is little constitutive expression and its upregulation occurs at the earliest stages of atherogenesis. It

interpreted as follows:

 under 0,9 mm of the entire vascular wall; normal between 0.9 and 1.5 mm is an increased IMT,

several studies (Finnish, American Rotterdam groups) [17].

*4.3.2. Ankle Brachial Pressure Index (ABI)* 

*4.3.3. Endothelial function evaluation* 

[28, 29].

#### **4.2. Laboratory methods**

In more than 15 large prospective studies, C-reactive protein (CRP) has emerged as an independent predictor of an incident cardiovascular event in initially healthy subjects and outcome after acute coronary syndrome [18]. More importantly, its high levels have been demonstrated to be an even stronger predictor of cardiovascular events than LDL cholesterol levels. CRP represents only one of several new inammatory biomarkers to be associated, independent of lipid prole, with future cardiovascular events. Among these, serum amyloid A (SAA), soluble vascular cell adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule 1 (ICAM-1), lipoprotein associated phospholipase A2 (Lp-PLA2), homocysteine and monocyte chemoattractant protein-1 (MCP-1) are the best characterized. Interestingly, from the most recent epidemiological trials, evidence has consistently emerged that these biomarkers are independent from cholesterol levels, but also unrelated to each other. For instance, in healthy middle-aged men, CRP levels were found to correlate only marginally to Lp-PLA2 and MCP-1. The direct evidence that inammatory biomarkers contribute to atherogenesis would be validated from the utilization of novel specic inhibitors for each of the soluble molecules which should prevent atherogenesis and coronary artery disease [18].

#### **4.3. Sonographic modalities**

Atherosclerosis is a chronic inflammatory disorder that often progresses silently for decades before becoming clinically evident. In this section we will preview sonographic noninvasive imaging of the vascular changes that occur in the atherosclerosis disease process including assessment of its inflammatory component. Because inflammation participates in plaque initiation and progression, a method capable of imaging the extent of vascular inflammation could potentially provide powerful predictive information on both early disease presence and future risk for disease progression.

#### *4.3.1. Intima-Media Thickness (IMT) or Asymptomatic Carotid Plaque (ACP)*

Echocolordoppler scanning evaluation of the carotid wall is a non invasive, low cost, and highly reproducible procedure even if, like most parts of the echographic analysis, it is strongly operator dependent. The Doppler mode permits the visualization of vessels and an evaluation of flow disturbance that helps to quantify stenosis severity. It measures the IMT and size and number of atheromatous plaques. According to the European Society of Cardiology; 2007-Guidelines on the Management of arterial Hypertension, normal IMT is the distance between the media-adventitia and the intima-media interfaces and is interpreted as follows:


560 Glucocorticoids – New Recognition of Our Familiar Friend

**4.2. Laboratory methods** 

coronary artery disease [18].

**4.3. Sonographic modalities** 

and future risk for disease progression.

obesity, hypertension, or dyslipidemia. Insulin resistance is thought to be the most prominent pathophysiological process underlying MetSyn. Recent studies of coronary artery calcification (CAC) in asymptomatic samples have shown an association of MetSyn and insulin resistance with the burden of coronary atherosclerosis [13]. Lakka et al. [15] found a 2 to 4-fold increased risk of cardiovascular death with MetSyn in a sample of 1209 Finnish men free from diabetes and CVD at baseline. MetSyn predicted atherosclerosis progression and CVD events in 888 subjects in the Bruneck study, whereas most individual components of the syndrome were not significantly associated with CVD out-comes [16] supporting the concept

In more than 15 large prospective studies, C-reactive protein (CRP) has emerged as an independent predictor of an incident cardiovascular event in initially healthy subjects and outcome after acute coronary syndrome [18]. More importantly, its high levels have been demonstrated to be an even stronger predictor of cardiovascular events than LDL cholesterol levels. CRP represents only one of several new inammatory biomarkers to be associated, independent of lipid prole, with future cardiovascular events. Among these, serum amyloid A (SAA), soluble vascular cell adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule 1 (ICAM-1), lipoprotein associated phospholipase A2 (Lp-PLA2), homocysteine and monocyte chemoattractant protein-1 (MCP-1) are the best characterized. Interestingly, from the most recent epidemiological trials, evidence has consistently emerged that these biomarkers are independent from cholesterol levels, but also unrelated to each other. For instance, in healthy middle-aged men, CRP levels were found to correlate only marginally to Lp-PLA2 and MCP-1. The direct evidence that inammatory biomarkers contribute to atherogenesis would be validated from the utilization of novel specic inhibitors for each of the soluble molecules which should prevent atherogenesis and

Atherosclerosis is a chronic inflammatory disorder that often progresses silently for decades before becoming clinically evident. In this section we will preview sonographic noninvasive imaging of the vascular changes that occur in the atherosclerosis disease process including assessment of its inflammatory component. Because inflammation participates in plaque initiation and progression, a method capable of imaging the extent of vascular inflammation could potentially provide powerful predictive information on both early disease presence

Echocolordoppler scanning evaluation of the carotid wall is a non invasive, low cost, and highly reproducible procedure even if, like most parts of the echographic analysis, it is strongly operator dependent. The Doppler mode permits the visualization of vessels and an

*4.3.1. Intima-Media Thickness (IMT) or Asymptomatic Carotid Plaque (ACP)* 

that MetSyn provides information that is "more than the sum of its parts."[17].

While all conditions in which it is greater than 1.5 mm can be considered an ACP.

Increased IMT (or ACP) is related to the presence, number, intensity and duration of atherosclerosis risk factors as well as endothelial dysfunction [24, 25]. Also, IMT is a potent and independent predictor of future cerebro- and cardiovascular events, as proven by several studies (Finnish, American Rotterdam groups) [17].

#### *4.3.2. Ankle Brachial Pressure Index (ABI)*

Normally, ankle systolic arterial pressure (posterior or anterior tibial artery) is just a little higher than brachial pressure measurements so that their ratio always is always > 1.0. This parameter is called the Ankle-Brachial pressure Index (ABI) and can reflect altered pressure values. It is reduced < 0.90 if atherosclerosis induced arterial system impairment is present; hence the patient is considered to have an asymptomatic peripheral artery disease. It is a simple, non-expensive procedure and can also be practiced by general practitioners [17]. Several population trials evidenced an important correlation between decreased ABI, carotid or coronary atherosclerosis and future cardiac or cerebrovascular events (27).

#### *4.3.3. Endothelial function evaluation*

A new, non-invasive technique was introduced to evaluate brachial artery flow-mediated dilatation (FMD). The evaluation through a sonographic assessment of brachial artery in basal condition and after 5 minutes of occlusion using pneumonic cuff (250 mm Hg) determined a reactive hyperemia and therefore, FMD. A low FMD is a marker of multifocal atherosclerosis and severity of the disease where the progressive reduction of FMD is associated with more extensive coronary tree involvement and future cardiovascular events [28, 29].

#### *4.3.4. Targeted Ultrasound Detection of Vascular Cell Adhesion Molecule-1 (VCAM-1)*

VCAM-1 is expressed by activated endothelial cells and participates in leukocyte rolling and adhesion primarily by interacting with its counterligand VLA-4 (*α4 β1*) on monocytes and lymphocytes. VCAM-1 expression on the vessel endothelial surface or the underlying vasa vasorum plays an important role in atherosclerotic plaque development by monocyte and Tlymphocyte recruitment. It is an ideal target for molecular imaging because there is little constitutive expression and its upregulation occurs at the earliest stages of atherogenesis. It

was hypothesized that molecular imaging with *targeted contrast enhanced ultrasound* **[CEU]**  could be used to evaluate the degree of vascular inflammation in atherosclerosis. CEU have multiple practical considerations; low cost, short duration [10 Minutes], good sensitivity and balance between spatial resolution and sensitivity for targeted contrast agent detection. It can potentially be useful in the early diagnosis of atherosclerosis and in monitoring the efficacy of therapeutic interventions.

Assessment of Glucocorticoids Induced Preclinical Atherosclerosis 563

coronary atherosclerotic disease non-invasively and quantification with the use of calciumvolume score. Although the ACC/AHA [American College of Cardiology (ACC) and the American Heart Association (AHA)] guidelines affirm the strong negative predictive value of a normal EBCT they are not supportive for its widespread use in asymptomatic patients [18].

Imaging techniques are needed that allow earlier and more rened diagnosis, guide targeted treatment in individual patients and monitor response to that treatment. MRI is well-suited to these tasks as it can provide anatomical, structural, and functional data of the arterial wall. Its capabilities are further enhanced by the use of a range of increasingly sophisticated contrast agents that target specic molecules, cells, and biological processes. Currently, it is considered to identify biologically relevant targets involved in the pathogenesis of

For assessment of lesions that encroach on the vessel lumen inducing ischemia as in angina; angiography provides excellent resolution for the affected vascular territory with possible therapeutic intervention. However, atherosclerosis commonly develops within the walls of arteries without impinging on the vessel lumen; even established disease can be concealed from lumenographic methods. Unfortunately, even these non-stenotic lesions can rupture or

Distinct from alternative imaging modalities, MRI can provide data on a large range of vascular parameters that includes measures of vascular physiology (compliance, pulse wave velocity, and ow-mediated vasodilatation), cellular imaging, molecular imaging [adhesion molecule expression (VCAM-1), brin and platelets targeting] and functional anatomical

Amin et al. [34] stated that Tc-99m sestamibi lower extremity muscle scan is a technique that can be effectively used to diagnose preclinical atherosclerosis in rheumatoid arthritis disease by measuring the so called perfusion reserve [PR]. They reported that it has a place as a screening tool considering the fact; whenever the diagnosis, the better it is the result, however, it could be used for detecting preclinical atherosclerosis even in apparently

Prior to the administration of Tc-99m sestamibi for measurement of PR in lower limbs, each subject moved her right foot to produce maximal dorsal and plantar exion 30–40 times in the sitting position (exercising side). 185 mBq of Tc-99m sestamibi was injected through

erode precipitating intra-arterial thrombosis and acute ischemic events.

data such as wall sheer stresses and density of neovascularization [33].

*4.5.1. Tc-99m sestamibi lower extremity muscle scan* 

*4.4.3. Magnetic Resonance Imaging [MRI]* 

atherosclerosis along its different stages [33].

**4.5. Radionuclide evaluation** 

healthy subjects.

*4.5.2. Technique* 

### **4.4. Radiological modalities**

#### *4.4.1. Fluoroscopy*

The detection of coronary calcification on chest films is not easy and the accuracy is only 42% compared with fluoroscopy, which itself is not sensitive. Fluoroscopy has frequently been used to detect calcification in the coronary arteries [31]. Data from the Duke registry of 800 patients by Margolis et al. [32] showed that patients with fluoroscopic evidence of calcium in the coronary arterial tree had a remarkably high prevalence of significant disease (94%). Only 6% of patients with coronary calcification had normal coronary angiograms. Among those without demonstrable calcification, 87% survived for more than 5 years compared to 58% with coronary calcification. Hence the latter implies a greater risk of future cardiac events. Fluoroscopy is widely available but it has several disadvantages [18]:


#### *4.4.2. Computed tomography (CT)*

*Conventional CT* is extremely sensitive in detecting vascular calcification. CT showed 50% more calcified vessels than did fluoroscopy. Its limitations are slow scan times resulting in motion artifacts, breathing misregistration, and inability to quantify amount of plaque. *Helical CT* has considerably faster scan times than conventional CT and overlapping sections improves calcium detection. *Double-helix CT scanners* appear to be more sensitive and now termed *electron beam (EBCT)* to distinguish them from conventional CT scanners.

Only *EBCT* can quantitate the amount or volume of calcium. The absence of calcific deposits on an EBCT scan implies the absence of significant angiographic coronary narrowing; however, it does not imply the absence of atherosclerosis, including unstable plaque. One of the most appealing features of EBCT is the potential to detect progression or regression of coronary atherosclerotic disease non-invasively and quantification with the use of calciumvolume score. Although the ACC/AHA [American College of Cardiology (ACC) and the American Heart Association (AHA)] guidelines affirm the strong negative predictive value of a normal EBCT they are not supportive for its widespread use in asymptomatic patients [18].

#### *4.4.3. Magnetic Resonance Imaging [MRI]*

562 Glucocorticoids – New Recognition of Our Familiar Friend

efficacy of therapeutic interventions.

**4.4. Radiological modalities** 

calcifications is low.

anatomic structures.

*4.4.2. Computed tomography (CT)* 

operator as well as the number of views studied.

documentation is not commonly obtained.

*4.4.1. Fluoroscopy* 

was hypothesized that molecular imaging with *targeted contrast enhanced ultrasound* **[CEU]**  could be used to evaluate the degree of vascular inflammation in atherosclerosis. CEU have multiple practical considerations; low cost, short duration [10 Minutes], good sensitivity and balance between spatial resolution and sensitivity for targeted contrast agent detection. It can potentially be useful in the early diagnosis of atherosclerosis and in monitoring the

The detection of coronary calcification on chest films is not easy and the accuracy is only 42% compared with fluoroscopy, which itself is not sensitive. Fluoroscopy has frequently been used to detect calcification in the coronary arteries [31]. Data from the Duke registry of 800 patients by Margolis et al. [32] showed that patients with fluoroscopic evidence of calcium in the coronary arterial tree had a remarkably high prevalence of significant disease (94%). Only 6% of patients with coronary calcification had normal coronary angiograms. Among those without demonstrable calcification, 87% survived for more than 5 years compared to 58% with coronary calcification. Hence the latter implies a greater risk of future

cardiac events. Fluoroscopy is widely available but it has several disadvantages [18]:

1. Although it can detect moderate to large calcifications; its ability to identify small

2. Fluoroscopic detection of calcification is dependent on the skill and experience of the

3. Other important factors include variability of the equipment, patient's body habitus, and calcifications in other structures such as valves and vertebrae and overlying

4. Finally with fluoroscopy, quantification of calcium is not possible and film

*Conventional CT* is extremely sensitive in detecting vascular calcification. CT showed 50% more calcified vessels than did fluoroscopy. Its limitations are slow scan times resulting in motion artifacts, breathing misregistration, and inability to quantify amount of plaque. *Helical CT* has considerably faster scan times than conventional CT and overlapping sections improves calcium detection. *Double-helix CT scanners* appear to be more sensitive and now

Only *EBCT* can quantitate the amount or volume of calcium. The absence of calcific deposits on an EBCT scan implies the absence of significant angiographic coronary narrowing; however, it does not imply the absence of atherosclerosis, including unstable plaque. One of the most appealing features of EBCT is the potential to detect progression or regression of

termed *electron beam (EBCT)* to distinguish them from conventional CT scanners.

Imaging techniques are needed that allow earlier and more rened diagnosis, guide targeted treatment in individual patients and monitor response to that treatment. MRI is well-suited to these tasks as it can provide anatomical, structural, and functional data of the arterial wall. Its capabilities are further enhanced by the use of a range of increasingly sophisticated contrast agents that target specic molecules, cells, and biological processes. Currently, it is considered to identify biologically relevant targets involved in the pathogenesis of atherosclerosis along its different stages [33].

For assessment of lesions that encroach on the vessel lumen inducing ischemia as in angina; angiography provides excellent resolution for the affected vascular territory with possible therapeutic intervention. However, atherosclerosis commonly develops within the walls of arteries without impinging on the vessel lumen; even established disease can be concealed from lumenographic methods. Unfortunately, even these non-stenotic lesions can rupture or erode precipitating intra-arterial thrombosis and acute ischemic events.

Distinct from alternative imaging modalities, MRI can provide data on a large range of vascular parameters that includes measures of vascular physiology (compliance, pulse wave velocity, and ow-mediated vasodilatation), cellular imaging, molecular imaging [adhesion molecule expression (VCAM-1), brin and platelets targeting] and functional anatomical data such as wall sheer stresses and density of neovascularization [33].

#### **4.5. Radionuclide evaluation**

#### *4.5.1. Tc-99m sestamibi lower extremity muscle scan*

Amin et al. [34] stated that Tc-99m sestamibi lower extremity muscle scan is a technique that can be effectively used to diagnose preclinical atherosclerosis in rheumatoid arthritis disease by measuring the so called perfusion reserve [PR]. They reported that it has a place as a screening tool considering the fact; whenever the diagnosis, the better it is the result, however, it could be used for detecting preclinical atherosclerosis even in apparently healthy subjects.

#### *4.5.2. Technique*

Prior to the administration of Tc-99m sestamibi for measurement of PR in lower limbs, each subject moved her right foot to produce maximal dorsal and plantar exion 30–40 times in the sitting position (exercising side). 185 mBq of Tc-99m sestamibi was injected through intravenous line at least 10 sec before exercise termination. Posterior images of each calf were obtained 10 min post-injection. The processing phase was carried out by drawing symmetrical and equal regions of interest (ROI) over both exercising and resting calves. The total counts (Cts) in each (ROI) were obtained through a closed program inherent to the computer system [figure 1]. The percentage of increase of Cts in the exercising right calf was calculated, and the percentile increase obtained was considered as the perfusion reserve using the following formula [normal PR is approx. 50%]:

Assessment of Glucocorticoids Induced Preclinical Atherosclerosis 565

wall motion during radionuclide imaging. Hence, we used Dipyridamole stress in conjunction with Tc-99m sestamibi Gated-SPECT as a screening tool for SCED [Figure 2 and

**Figure 2.** A 35-year-old male with stress induced reduced flow in LAD [anterior wall] and RCA vascular territories [inferior wall] with Complete recovery in the rest phase Coronary angiography was

**Figure 3.** A 33-year-old negative Case for SCED [Stress; Upper row and Rest; Lower row-Short axis

Symptomatic lower extremity arterial occlusive disease in young adults is presumably rare provided that atherosclerosis is a natural consequence of ageing process. Several factors contribute to the "neglect" of premature lower extremity atherosclerosis (*PLEA*) among young population in clinical practice; including low public health awareness of this pathology, absence of large-scale epidemiologic studies, and overall low index of suspicion for vascular etiology of effort-induced lower extremity symptoms. A number of small clinical studies published in the last decade have strongly suggested that PLEA is the major

Levy report in 2002 identified 3 major clinical presentations of PLEA; the majority of patients had typical symptoms of effort-induced claudication, frequently misdiagnosed and attributed to arthritides, muscle spasms, and trauma. Approximately 20-25% present with "blue toe syndrome" caused by atheromatous embolization, most frequently originating

normal; [Stress; Upper row and Rest; Lower row- Short axis slices]

3].

slices]

**5. Special consideration** 

**5.1. Premature lower limb atherosclerosis** 

cause for peripheral arterial disease (PAD) in young patients [35].

**Figure 1.** Tc-99m sestamibi muscle scans of an RA patient (PR 29.4%) [Left panel] and a control subject (PR 85%) [Right panel]

#### *4.5.3. Myocardial sestaMIBI Gated-SPECT*

Also, in our center a study was designed to evaluate usefulness of Dipyridamole pharmacological stress test in conjunction with Tc-99m sestamibi Gated-SPECT to screen the prevalence of subclinical coronary vascular dysfunction [SCED] in asymptomatic Egyptian Behçet's disease patients and to identify those at higher risk for the presence of such abnormalities as a predictor for preclinical atherosclerosis [*data are not published yet*]. Dipyridamole is an indirect coronary vasodilator that works by increasing intravascular adenosine through inhibition of phosphodiesterase that prohibits reuptake of endogenously produced adenosine into endothelial and red blood cells leading to arteriolar vasodilatation. This increases coronary arterial flow to approximately three times resting values in healthy endothelial state, however it is attenuated in diseased coronary arteries that cannot further dilate in response to adenosine. So, Dipyridamole infusion produces relative flow heterogeneity throughout coronary arteries, resulting in relatively more coronary blood flow in healthy arteries compared with the diseased-arteries inducing ischemia via a "*coronary steal phenomenon*" with subsequent perfusion defects ± abnormal left ventricular wall motion during radionuclide imaging. Hence, we used Dipyridamole stress in conjunction with Tc-99m sestamibi Gated-SPECT as a screening tool for SCED [Figure 2 and 3].

**Figure 2.** A 35-year-old male with stress induced reduced flow in LAD [anterior wall] and RCA vascular territories [inferior wall] with Complete recovery in the rest phase Coronary angiography was normal; [Stress; Upper row and Rest; Lower row- Short axis slices]

**Figure 3.** A 33-year-old negative Case for SCED [Stress; Upper row and Rest; Lower row-Short axis slices]

### **5. Special consideration**

564 Glucocorticoids – New Recognition of Our Familiar Friend

(PR 85%) [Right panel]

*4.5.3. Myocardial sestaMIBI Gated-SPECT* 

using the following formula [normal PR is approx. 50%]:

intravenous line at least 10 sec before exercise termination. Posterior images of each calf were obtained 10 min post-injection. The processing phase was carried out by drawing symmetrical and equal regions of interest (ROI) over both exercising and resting calves. The total counts (Cts) in each (ROI) were obtained through a closed program inherent to the computer system [figure 1]. The percentage of increase of Cts in the exercising right calf was calculated, and the percentile increase obtained was considered as the perfusion reserve

**Figure 1.** Tc-99m sestamibi muscle scans of an RA patient (PR 29.4%) [Left panel] and a control subject

Also, in our center a study was designed to evaluate usefulness of Dipyridamole pharmacological stress test in conjunction with Tc-99m sestamibi Gated-SPECT to screen the prevalence of subclinical coronary vascular dysfunction [SCED] in asymptomatic Egyptian Behçet's disease patients and to identify those at higher risk for the presence of such abnormalities as a predictor for preclinical atherosclerosis [*data are not published yet*]. Dipyridamole is an indirect coronary vasodilator that works by increasing intravascular adenosine through inhibition of phosphodiesterase that prohibits reuptake of endogenously produced adenosine into endothelial and red blood cells leading to arteriolar vasodilatation. This increases coronary arterial flow to approximately three times resting values in healthy endothelial state, however it is attenuated in diseased coronary arteries that cannot further dilate in response to adenosine. So, Dipyridamole infusion produces relative flow heterogeneity throughout coronary arteries, resulting in relatively more coronary blood flow in healthy arteries compared with the diseased-arteries inducing ischemia via a "*coronary steal phenomenon*" with subsequent perfusion defects ± abnormal left ventricular

#### **5.1. Premature lower limb atherosclerosis**

Symptomatic lower extremity arterial occlusive disease in young adults is presumably rare provided that atherosclerosis is a natural consequence of ageing process. Several factors contribute to the "neglect" of premature lower extremity atherosclerosis (*PLEA*) among young population in clinical practice; including low public health awareness of this pathology, absence of large-scale epidemiologic studies, and overall low index of suspicion for vascular etiology of effort-induced lower extremity symptoms. A number of small clinical studies published in the last decade have strongly suggested that PLEA is the major cause for peripheral arterial disease (PAD) in young patients [35].

Levy report in 2002 identified 3 major clinical presentations of PLEA; the majority of patients had typical symptoms of effort-induced claudication, frequently misdiagnosed and attributed to arthritides, muscle spasms, and trauma. Approximately 20-25% present with "blue toe syndrome" caused by atheromatous embolization, most frequently originating from a segmental aortoiliac atherosclerotic lesion. The rest of patients presents with rapidly progressive symptoms of limb-threatening ischemia secondary to atherothrombosis. Also, they observed that many younger patients with isolated aortoiliac atherosclerotic disease had prolonged lower back pain on ambulation involving the spinal muscles who have been treated for several years for chronic low back pain by orthopedic surgeons, or neurosurgeons and some of them even had "unsuccessful" laminectomies before the diagnosis of PAD. In PLEA patients, clinical atherosclerotic disease was present in more than one anatomic location in approximately 60% including the coronary tree. Noninvasive studies are a mainstay of the PLEA diagnosis including ABI measurement and standardized lower extremity treadmill testing that has been developed to assess hyperemic blood flow response to exercise with repeat ABIs compared to the resting ABI with pulse-wave recordings. Also, Tc-99m sestamibi lower extremity muscle scan is suggested as a diagnostic test in PLEA patients [35].

Assessment of Glucocorticoids Induced Preclinical Atherosclerosis 567

[3] Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing's syndrome. Am J

[4] Plotz CM, Knowlton AI, Ragan C. Natural course of Cushing's syndrome as compared with the course of rheumatoid arthritis treated by hormones. Ann Rheum Dis

[5] Sholter DE, Armstrong PW. Adverse effects of corticosteroids on the cardiovascular

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[9] Rheumatoid arthritis and macrovascular diseasJ. K. Alkaabi, M. Ho1

[10] Moreland LW, O'Dell JR. Glucocorticoids and Rheumatoid Arthritis Back to the Future?

[11] Del Rincón I, O'Leary DH, Haas RW, Escalante A. Effect of glucocorticoids on the

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[13] Lenk R: Rontgendiagnose der Koronarsklerose in vivo. Fortschr ad Geb D

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[18] Fuseini M, Goodwin WJ, Ferris EJ, Mehta JL. Does electron beam computer tomography provide added value in the diagnosis of coronary artery disease? Curr

[19] Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications, II: diagnosis and classification of diabetes mellitus provisional report

[20] Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged

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### **6. Summary and conclusions**

In summary, improved understanding of atherogenesis allowed the identication of a large number of molecules and processes. This will provide functional insights to aid diagnosis and to guide treatment with the introduction of new molecular imaging approaches that hold much promise for translation to the clinical practice. In fact, inflammatory biomarkers and imaging will combine structural and functional information to provide a comprehensive evaluation of vascular status at an early stage; hoping to be reversible.

### **Author details**

Amr Amin *Nuclear Medicine, Cairo University, Egypt* 

Zeinab Nawito *Rheumatology & Rehabilitation, Cairo University, Egypt* 

### **Acknowledgement**

To our parents and families for their patience, time and support they give all through our life time.

#### **7. References**


test in PLEA patients [35].

**Author details** 

Amr Amin

life time.

**7. References** 

Zeinab Nawito

**Acknowledgement** 

1949;24:181–97.

**6. Summary and conclusions** 

*Nuclear Medicine, Cairo University, Egypt* 

*Rheumatology & Rehabilitation, Cairo University, Egypt* 

glucocorticoids. Pharmacol Ther 2002;96:23–43.

from a segmental aortoiliac atherosclerotic lesion. The rest of patients presents with rapidly progressive symptoms of limb-threatening ischemia secondary to atherothrombosis. Also, they observed that many younger patients with isolated aortoiliac atherosclerotic disease had prolonged lower back pain on ambulation involving the spinal muscles who have been treated for several years for chronic low back pain by orthopedic surgeons, or neurosurgeons and some of them even had "unsuccessful" laminectomies before the diagnosis of PAD. In PLEA patients, clinical atherosclerotic disease was present in more than one anatomic location in approximately 60% including the coronary tree. Noninvasive studies are a mainstay of the PLEA diagnosis including ABI measurement and standardized lower extremity treadmill testing that has been developed to assess hyperemic blood flow response to exercise with repeat ABIs compared to the resting ABI with pulse-wave recordings. Also, Tc-99m sestamibi lower extremity muscle scan is suggested as a diagnostic

In summary, improved understanding of atherogenesis allowed the identication of a large number of molecules and processes. This will provide functional insights to aid diagnosis and to guide treatment with the introduction of new molecular imaging approaches that hold much promise for translation to the clinical practice. In fact, inflammatory biomarkers and imaging will combine structural and functional information to provide a comprehensive evaluation of vascular status at an early stage; hoping to be reversible.

To our parents and families for their patience, time and support they give all through our

[1] Hench PS, Kendall EC, Slocumb CH, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone, compound 8E) and of pituitary adrenocorticotrophic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin

[2] Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of


[21] Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, et al. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study. Diabetes Care. 2003;26:1251–1257.

**Chapter 23** 

© 2012 Bassam and Mayank, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Steroids in Asthma: Friend or Foe** 

imposing a huge cost on the healthcare facilities in all countries.

Asthma is a common chronic inflammatory disease of the respiratory tract characterized by episodic exacerbations with a heterogeneous population distribution. The prevalence of asthma has increased substantially over the past 5 decades throughout the globe, yet the reasons for this increase remain unknown. The disease represents a substantial burden, not only in terms of morbidity, mortality and reduced quality of life of patients, but also

Approximately 300 million people worldwide currently have asthma, and its prevalence increases by 50% every decade, seeing a rise to 400 million by year 2025 (Braman, 2006; Masoli et al., 2004) The increasing number of hospital admissions for asthma, which are most pronounced in young children, reflect an increase in severe asthma, poor disease management, and poverty. Worldwide, approximately 180,000 deaths annually are attributable to asthma. Most asthma deaths occur in those >45 years old and are largely preventable, frequently being related to inadequate long-term medical care or delays in

The financial burden on patients with asthma in different western countries ranges from \$300 to \$1,300 per patient per year, disproportionately affecting those with the most severe disease. It is the most common chronic disorder in children and adolescents, with more than

Asthma is a cause of concern due to under diagnosis, under investigated, under control and non-adherence to treatment (Barreto, 2006, National Institutes of Health, Bethesda, 2006, Woolcock, 1989, Bassam, 2012). A recent report from WHO suggests that 50% of patients from developed world with chronic diseases do not take their medications as recommended. In developing countries, the situation may be even worse when considering together all the

and reproduction in any medium, provided the original work is properly cited.

3 million asthma attacks occurring in more than 5% of all children each year.

Mahboub Bassam and Vats Mayank

http://dx.doi.org/10.5772/50536

**1. Introduction** 

**2. Burden of asthma** 

obtaining medical help during the attack.

Additional information is available at the end of the chapter


## **Steroids in Asthma: Friend or Foe**

Mahboub Bassam and Vats Mayank

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/50536

**1. Introduction** 

568 Glucocorticoids – New Recognition of Our Familiar Friend

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[21] Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, et al. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data

[22] Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts?

[23] Ferri N, Paoletti R, Corsini A. Biomarkers for atherosclerosis: pathophysiological role

[24] Novo S, Pernice C, Barbagallo C M, Tantillo R, Caruso R, Longo B. Influence of risk factors and aging on asymptomatic carotid lesions. In: Advances in Vascular Pathology 1997, A. N. Nicolaides and S. Novo (Eds.), Elsevier Science, Excerpta Medica,

[25] Corrado E, Bonura F., Tantillo R, Muratori I, Rizzo M, Vitale G, Mansueto S, Novo S. Markers of infection and inflammation influence the outcome of patients with baseline

[26] Corrado E, Muratori I, Tantillo R, Contorno F, Coppola G, Strano A, Novo S. Relationship between endothelial dysfunction, intima media thickness and

[28] Corrado E, Rizzo M, Coppola G, Muratori I, Carella M, Novo S. Endothelial dysfunction and carotid lesions are strong predictors of clinical events in patients with early stages of atherosclerosis: a 24-month follow-up study. Coron Artery Dis. 2008;

[29] Landmesser U, Hornig B, Drexler H Endothelium Function: A Critical Determinant in

[30] Kaufmann BA, Sanders JM, Davis C, Xie A, Aldred P, Sarembock IJ, Lindner JR. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound

[31] Souza AS, Bream PR, Elliot LP: Chest film detection of coronary artery calcification: the

[32] Margolis JR, Chen JTT, Kong Y, et al.: The diagnostic and prognostic significance of

[33] Choudhury RP. Atherosclerosis and thrombosis: identification of targets for magnetic

[34] Amin AM, Nawito ZO, Atfy RA, El-Hadidi KT. Tc-99m sestamibi lower extremity muscle scan, is it a useful screening tool for assessment of preclinical atherosclerosis in rheumatoid arthritis patients? Rheumatol Int. 2012

[35] Levy PJ. . Premature lower extremity atherosclerosis: clinical aspects. Am J Med Sci.

detection of vascular cell adhesion molecule-1. Circulation. 2007; 116:276-84.

resonance imaging. Top Magn Reson Imaging. 2007 Oct;18(5):319-27.

asymptomatic carotid lesions in a 5 years follow-up. Stroke 2006; 37: 482-6.

cardiovascular risk factors in asymptomatic subjects. Int Angiol. 2005; 24:52-8. [27] Diehm C, Lange S, Darius H, Pittrow D, von Stritzky B, Tepohl G, Haberl RL, Allenberg JR, Dasch B, Trampisch HJ. Association of low ankle brachial index with high mortality

and pharmacological modulation. Curr Opin Lipidol. 2006; 17:495-501.

from the Bruneck study. Diabetes Care. 2003;26:1251–1257.

Asthma is a common chronic inflammatory disease of the respiratory tract characterized by episodic exacerbations with a heterogeneous population distribution. The prevalence of asthma has increased substantially over the past 5 decades throughout the globe, yet the reasons for this increase remain unknown. The disease represents a substantial burden, not only in terms of morbidity, mortality and reduced quality of life of patients, but also imposing a huge cost on the healthcare facilities in all countries.

### **2. Burden of asthma**

Approximately 300 million people worldwide currently have asthma, and its prevalence increases by 50% every decade, seeing a rise to 400 million by year 2025 (Braman, 2006; Masoli et al., 2004) The increasing number of hospital admissions for asthma, which are most pronounced in young children, reflect an increase in severe asthma, poor disease management, and poverty. Worldwide, approximately 180,000 deaths annually are attributable to asthma. Most asthma deaths occur in those >45 years old and are largely preventable, frequently being related to inadequate long-term medical care or delays in obtaining medical help during the attack.

The financial burden on patients with asthma in different western countries ranges from \$300 to \$1,300 per patient per year, disproportionately affecting those with the most severe disease. It is the most common chronic disorder in children and adolescents, with more than 3 million asthma attacks occurring in more than 5% of all children each year.

Asthma is a cause of concern due to under diagnosis, under investigated, under control and non-adherence to treatment (Barreto, 2006, National Institutes of Health, Bethesda, 2006, Woolcock, 1989, Bassam, 2012). A recent report from WHO suggests that 50% of patients from developed world with chronic diseases do not take their medications as recommended. In developing countries, the situation may be even worse when considering together all the

© 2012 Bassam and Mayank, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

issues related with poor access to health care, lack of appropriate diagnosis, and limited access to medicines. Poor adherence seriously threatens any effort to tackle such chronic illness (WHO, 2003, Horne, 2003).

Steroids in Asthma: Friend or Foe 571

IL-4 and IL-12 activate the Jak-Stat signaling cascade discussed elsewhere in this Perspective series. In this signaling pathway, binding of a cytokine to its receptor leads to the activation of members of the JAK family of receptor associated kinases. These kinases subsequently activate, via tyrosine phosphorylation, preexistent cytoplasmic factors termed Stats (signal transducer and activator of transcription). Tyrosine phosphorylation allows the Stat proteins to dimerize and translocate to the nucleus, where they mediate changes in gene expression by binding specific DNA elements. Although both IL-4 and IL-12 follow this basic signaling framework, the two cytokines differ in the specific Jak and Stat components that they activate (Wurster, A.L. et al 2000). IL-4 stimulates Jak1 and Jak3 to activate Stat6. In contrast, interaction of IL-12 with its receptor leads to the activation of Jak2 and Tyk2 and the subsequent phosphorylation of Stat4. Activation of Stat6 and Stat4 are thus critical events in

**Mechanism of Action of steroids:** Glucocorticoids (GC's) are potent anti-inflammatory agents and are useful in the treatment of both allergic and idiosyncratic asthma. Although the mechanisms of corticosteroid action in asthma are poorly understood, several possible sites of action have been proposed which help reverse the pathologic process of bronchial asthma.

Glucocorticoid receptors (GRs) are specific cytoplasmic transcription factors that mediate the biological actions of corticosteroids (Beato M et al *1995*). On ligand binding, GR translocates into the nucleus and binds to DNA at glucocorticoid response elements (GREs) in the promoter region of corticosteroid-responsive genes that induce transcription (Barnes PJ & Adcock IM 1998). GR activation may also influence antiinflammatory events by nongenomic pathways, forming inhibitory interactions within the nucleus with proinflammatory DNA-binding transcription factors, such as activator protein (AP)-1 or nuclear factor (NF)–\_B, or by recruitment of co-repressors, and thereby repressing the actions of these important inflammatory proteins (Karin M. 1998, Ito K et al. 2000). GR

nuclear translocation is, therefore, essential and necessary for corticosteroid action.

It has been well investigated that the novel mechanism of GC action is by blocking cytokine signaling via the JAK-STAT signaling pathway. Dexamethasone inhibited IL-2-induced DNA binding, tyrosine phosphorylation, and nuclear translocation of Stat5 in primary T cells. Inhibition of Stat5 correlated with inhibition of expression of IL-2-inducible genes and T cell proliferation. The mechanism of inhibition involved suppression of IL-2 receptor and Jak3 expression. Signaling by IL-4, IL-7, and IL-15, which use IL-2 receptor components, also was inhibited, indicating a block in T cell responses similar to that seen in immunodeficient

IL-2 signaling also was blocked in patients after treatment with GC's, suggesting that inhibition of cytokine signaling contributes to the clinical efficacy of GC's. Hence inhibition of both cytokine production and Jak- stat signaling contribute to their therapeutic potency

Corticosteroids enhance the beta-adrenergic response to relieve the muscle spasm. They also act by reversing the mucosal edema, decreasing vascular permeability by vasoconstriction,

the signaling cascades of IL-4 and IL-12, respectively.

patients lacking the IL-2 receptor gamma chain or Jak3.

(Bianchi, 2000).

**Steroids V/S No Steroids in asthma:** If ever there was a magic potion that should resolve the symptoms of an affliction, it is the use of glucocorticoids in asthma. Since their first clinical application, there has been uniform agreement that the anti-inflammatory activities of the corticosteroids make them ideal agents to stabilize asthma during all stages of asthma symptomatology ranging from chronic persistent phase to acute severe life threatening exacerbations.

**Pathophysiology of asthma:** Asthmatic inflammatory process results from inappropriate immune responses to common environmental antigens in a genetically susceptible individual (Wills-Karp 1999). These inappropriate immune responses are orchestrated by a subset of CD4+ T helper cells termed T helper 2 (Th2) cells.

Cytokines play a pivotal role in the development of asthma by regulating the expansion of Th2 cells and by mediating many of the Th2 effector functions that underlie the pathogenic events of an asthmatic response. Much effort has recently been placed in elucidating the pathways used by cytokines to mediate their actions. These studies have revealed that cytokine-mediated signals are primarily transduced by the Janus Kinase- Signal Transducer and Activator of Transcription (JAK-STAT) signaling cascade (Darnell, 1997). Recent advances have shown the important roles of JAK-STAT signaling pathway in the pathogenesis of asthma.

### **3. JAK-STAT signaling in Th1 and Th2 differentiation:**

The two major subsets of CD4+ T helper cells, Th1 and Th2, secrete mutually distinct profiles of cytokines and thereby coordinate different classes of immune response. The cytokines IL-12 and IL-4 direct the differentiation of Th1 and Th2 cells, respectively, from naive T helper cells. Th1 cells secrete IL-2, IFN-γ, and TNF-β, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13.

Th1 cells are critically involved in the generation of delayed-type hypersensitivity responses, whereas Th2 cells can direct B cells to mount strong humoral responses. Polarization of immune response toward a Th2 phenotype and when directed against an otherwise innocuous environmental antigen result in the pathogenesis of allergic diseases like asthma.

The Th2 cytokines (IL-4, IL-5, and IL-13) control all the major components that characterize an inflammatory asthmatic response, including IgE isotype switching, mucus production, and the recruitment and activation of eosinophils and have been corroborated by studies in humans. The population of Th2 cells is notably expanded in the airways of asthmatic subjects, and presence of these cells correlates with airway hyper responsiveness (AHR) and airway eosinophilia (Rengarajan et al., 2000, Murphy et al., 2000).

IL-4 and IL-12 activate the Jak-Stat signaling cascade discussed elsewhere in this Perspective series. In this signaling pathway, binding of a cytokine to its receptor leads to the activation of members of the JAK family of receptor associated kinases. These kinases subsequently activate, via tyrosine phosphorylation, preexistent cytoplasmic factors termed Stats (signal transducer and activator of transcription). Tyrosine phosphorylation allows the Stat proteins to dimerize and translocate to the nucleus, where they mediate changes in gene expression by binding specific DNA elements. Although both IL-4 and IL-12 follow this basic signaling framework, the two cytokines differ in the specific Jak and Stat components that they activate (Wurster, A.L. et al 2000). IL-4 stimulates Jak1 and Jak3 to activate Stat6. In contrast, interaction of IL-12 with its receptor leads to the activation of Jak2 and Tyk2 and the subsequent phosphorylation of Stat4. Activation of Stat6 and Stat4 are thus critical events in the signaling cascades of IL-4 and IL-12, respectively.

570 Glucocorticoids – New Recognition of Our Familiar Friend

subset of CD4+ T helper cells termed T helper 2 (Th2) cells.

**3. JAK-STAT signaling in Th1 and Th2 differentiation:** 

airway eosinophilia (Rengarajan et al., 2000, Murphy et al., 2000).

illness (WHO, 2003, Horne, 2003).

exacerbations.

pathogenesis of asthma.

4, IL-5, IL-6, IL-10, and IL-13.

like asthma.

issues related with poor access to health care, lack of appropriate diagnosis, and limited access to medicines. Poor adherence seriously threatens any effort to tackle such chronic

**Steroids V/S No Steroids in asthma:** If ever there was a magic potion that should resolve the symptoms of an affliction, it is the use of glucocorticoids in asthma. Since their first clinical application, there has been uniform agreement that the anti-inflammatory activities of the corticosteroids make them ideal agents to stabilize asthma during all stages of asthma symptomatology ranging from chronic persistent phase to acute severe life threatening

**Pathophysiology of asthma:** Asthmatic inflammatory process results from inappropriate immune responses to common environmental antigens in a genetically susceptible individual (Wills-Karp 1999). These inappropriate immune responses are orchestrated by a

Cytokines play a pivotal role in the development of asthma by regulating the expansion of Th2 cells and by mediating many of the Th2 effector functions that underlie the pathogenic events of an asthmatic response. Much effort has recently been placed in elucidating the pathways used by cytokines to mediate their actions. These studies have revealed that cytokine-mediated signals are primarily transduced by the Janus Kinase- Signal Transducer and Activator of Transcription (JAK-STAT) signaling cascade (Darnell, 1997). Recent advances have shown the important roles of JAK-STAT signaling pathway in the

The two major subsets of CD4+ T helper cells, Th1 and Th2, secrete mutually distinct profiles of cytokines and thereby coordinate different classes of immune response. The cytokines IL-12 and IL-4 direct the differentiation of Th1 and Th2 cells, respectively, from naive T helper cells. Th1 cells secrete IL-2, IFN-γ, and TNF-β, whereas Th2 cells produce IL-

Th1 cells are critically involved in the generation of delayed-type hypersensitivity responses, whereas Th2 cells can direct B cells to mount strong humoral responses. Polarization of immune response toward a Th2 phenotype and when directed against an otherwise innocuous environmental antigen result in the pathogenesis of allergic diseases

The Th2 cytokines (IL-4, IL-5, and IL-13) control all the major components that characterize an inflammatory asthmatic response, including IgE isotype switching, mucus production, and the recruitment and activation of eosinophils and have been corroborated by studies in humans. The population of Th2 cells is notably expanded in the airways of asthmatic subjects, and presence of these cells correlates with airway hyper responsiveness (AHR) and **Mechanism of Action of steroids:** Glucocorticoids (GC's) are potent anti-inflammatory agents and are useful in the treatment of both allergic and idiosyncratic asthma. Although the mechanisms of corticosteroid action in asthma are poorly understood, several possible sites of action have been proposed which help reverse the pathologic process of bronchial asthma.

Glucocorticoid receptors (GRs) are specific cytoplasmic transcription factors that mediate the biological actions of corticosteroids (Beato M et al *1995*). On ligand binding, GR translocates into the nucleus and binds to DNA at glucocorticoid response elements (GREs) in the promoter region of corticosteroid-responsive genes that induce transcription (Barnes PJ & Adcock IM 1998). GR activation may also influence antiinflammatory events by nongenomic pathways, forming inhibitory interactions within the nucleus with proinflammatory DNA-binding transcription factors, such as activator protein (AP)-1 or nuclear factor (NF)–\_B, or by recruitment of co-repressors, and thereby repressing the actions of these important inflammatory proteins (Karin M. 1998, Ito K et al. 2000). GR nuclear translocation is, therefore, essential and necessary for corticosteroid action.

It has been well investigated that the novel mechanism of GC action is by blocking cytokine signaling via the JAK-STAT signaling pathway. Dexamethasone inhibited IL-2-induced DNA binding, tyrosine phosphorylation, and nuclear translocation of Stat5 in primary T cells. Inhibition of Stat5 correlated with inhibition of expression of IL-2-inducible genes and T cell proliferation. The mechanism of inhibition involved suppression of IL-2 receptor and Jak3 expression. Signaling by IL-4, IL-7, and IL-15, which use IL-2 receptor components, also was inhibited, indicating a block in T cell responses similar to that seen in immunodeficient patients lacking the IL-2 receptor gamma chain or Jak3.

IL-2 signaling also was blocked in patients after treatment with GC's, suggesting that inhibition of cytokine signaling contributes to the clinical efficacy of GC's. Hence inhibition of both cytokine production and Jak- stat signaling contribute to their therapeutic potency (Bianchi, 2000).

Corticosteroids enhance the beta-adrenergic response to relieve the muscle spasm. They also act by reversing the mucosal edema, decreasing vascular permeability by vasoconstriction,

and inhibiting the release of Leukotrienes (LT) LT-C4 and LT-D4. Corticosteroids reduce the mucus secretion by inhibiting the release of secretagogue from macrophages. Corticosteroids inhibit the late phase reaction by inhibiting the inflammatory response and interfering with chemotaxis due to the inhibition of LT-B4 release. The eosinopenic effect of corticosteroids may help to prevent the cytotoxic effect of the major basic protein and other inflammatory mediators released from eosinophils. Corticosteroids have no effect on the immediate hypersensitivity reaction and have no direct role in bronchial reactivity. By blocking the late reaction, they prevent the increased airway reactivity observed with late bronchial reactions, all of which aid in the resolution of bronchospasm in asthmatic patients (**Figure 1**)

Steroids in Asthma: Friend or Foe 573

High Daily dose

(µgm)

to avoid worsening of symptoms (if underdosing done) or side effects (if overdosing done). **Table 2** summarizes the equivalent doses of various types of intravenous or oral steroids.

Dipropionate 200-500 500-1000 1000-2000 Budesonide 200-400 400-800 800-1600 Ciclesonide 80-160 10-320 320-1280 Flunisolide 500-1000 1000-2000 >2000 Fluticasone Propionate 100-250 250-500 500-1000 Mometasone Furoate 200 400 800 Triamcinolone acetonide 400-1000 1000-2000 >2000

Glucocorticoid Approximate Equivalent dose (mg) Half-life(Biologic) hours Short-Acting

Intermediate-Acting

Long-Acting

**Steroids in Children:** ICS are the first-line therapy for persistent asthma in children. Major safety concerns of long-term ICS therapy in children include suppression of adrenal function and impaired growth and bone development. Dosage, type of inhaler device used, patient technique, and characteristics of the individual drug influence systemic effects of ICS's. Systemic side effects can occur when continuous high-dose treatment is required for severe asthma or when prescribed dosage is excessive and compliance is unusually good.

It is very important to know that uncontrolled or severe asthma adversely affects growth and final adult height in children & no long-term controlled studies have reported any statistically or clinically significant adverse effects on growth of 100-200 µg/ day of ICS's however it may be seen with all ICS's when a high dose is administered for prolonged periods (dose dependent effect). Different age groups seem to differ in their susceptibility to the growth-retarding effects of ICS's, children aged 4 to 10 are more susceptible than

(µgm)

Medicum Daily dose

(http://www.globalrph.com/corticocalc.htm)

Drug Low Daily dose

Beclomethasone

(µgm)

**Table 1.** Estimated Equipotent daily doses of all formulations of ICS in adults

Cortisone 25 8-12 Hydrocortisone 20 8-12

Methylprednisolone 4 18-36 Prednisolone/ Prednisone 5 18-36 Triamcinolone 4 18-36

Betamethasone 0.6 - 0.75 36-54 Dexamethasone 0.75 36-54

**Table 2.** Estimated Equipotent daily doses of all formulations of glucocorticoids in adults

**Figure 1.** Mechanism of Action of Corticosteroids in asthma

**Mode of Delivery:** All levels of persistent asthma require daily anti-inflammatory treatment (with additional doses of oral or intravenous steroid based on the severity of symptoms). Inhaled corticosteroids (ICS's) are the safest and most effective anti-inflammatory treatment for patients with persistent asthma of all severity having a significant positive impact on outcomes. Although steroids may be given orally or systemically, and numerous nonsteroidal medications are available for treating persistent asthma, ICS's are the treatment of choice considering their risk-benefit and cost-effectiveness ratio. Even when ICS's are given daily over prolong period of time, they have less toxicity than oral or systemic steroids administered only occasionally. A wide range of ICS's are available & the choice depends upon the availability, cost, physician and patient's preference, however it is important to use the equipotent doses of various ICS's while switching over the ICS's for control of asthma **(Table-1)**

In cases of acute severe asthma or patients requiring maintenance therapy with steroids for chronic persistent asthma intravenous or oral routes are to be preferred, it's important to know the equipotent doses of various type of steroid while starting or switching from one form to another or from one steroids to another in order to get the equivalent response and to avoid worsening of symptoms (if underdosing done) or side effects (if overdosing done). **Table 2** summarizes the equivalent doses of various types of intravenous or oral steroids. (http://www.globalrph.com/corticocalc.htm)


**Table 1.** Estimated Equipotent daily doses of all formulations of ICS in adults

572 Glucocorticoids – New Recognition of Our Familiar Friend

**Figure 1.** Mechanism of Action of Corticosteroids in asthma

(**Figure 1**)

**(Table-1)**

and inhibiting the release of Leukotrienes (LT) LT-C4 and LT-D4. Corticosteroids reduce the mucus secretion by inhibiting the release of secretagogue from macrophages. Corticosteroids inhibit the late phase reaction by inhibiting the inflammatory response and interfering with chemotaxis due to the inhibition of LT-B4 release. The eosinopenic effect of corticosteroids may help to prevent the cytotoxic effect of the major basic protein and other inflammatory mediators released from eosinophils. Corticosteroids have no effect on the immediate hypersensitivity reaction and have no direct role in bronchial reactivity. By blocking the late reaction, they prevent the increased airway reactivity observed with late bronchial reactions, all of which aid in the resolution of bronchospasm in asthmatic patients

**Mode of Delivery:** All levels of persistent asthma require daily anti-inflammatory treatment (with additional doses of oral or intravenous steroid based on the severity of symptoms). Inhaled corticosteroids (ICS's) are the safest and most effective anti-inflammatory treatment for patients with persistent asthma of all severity having a significant positive impact on outcomes. Although steroids may be given orally or systemically, and numerous nonsteroidal medications are available for treating persistent asthma, ICS's are the treatment of choice considering their risk-benefit and cost-effectiveness ratio. Even when ICS's are given daily over prolong period of time, they have less toxicity than oral or systemic steroids administered only occasionally. A wide range of ICS's are available & the choice depends upon the availability, cost, physician and patient's preference, however it is important to use the equipotent doses of various ICS's while switching over the ICS's for control of asthma

In cases of acute severe asthma or patients requiring maintenance therapy with steroids for chronic persistent asthma intravenous or oral routes are to be preferred, it's important to know the equipotent doses of various type of steroid while starting or switching from one form to another or from one steroids to another in order to get the equivalent response and


**Table 2.** Estimated Equipotent daily doses of all formulations of glucocorticoids in adults

**Steroids in Children:** ICS are the first-line therapy for persistent asthma in children. Major safety concerns of long-term ICS therapy in children include suppression of adrenal function and impaired growth and bone development. Dosage, type of inhaler device used, patient technique, and characteristics of the individual drug influence systemic effects of ICS's. Systemic side effects can occur when continuous high-dose treatment is required for severe asthma or when prescribed dosage is excessive and compliance is unusually good.

It is very important to know that uncontrolled or severe asthma adversely affects growth and final adult height in children & no long-term controlled studies have reported any statistically or clinically significant adverse effects on growth of 100-200 µg/ day of ICS's however it may be seen with all ICS's when a high dose is administered for prolonged periods (dose dependent effect). Different age groups seem to differ in their susceptibility to the growth-retarding effects of ICS's, children aged 4 to 10 are more susceptible than

adolescents, however Children with asthma treated with ICS's attain normal adult height (predicted from family members) but at a later age( Pedersen, 2001, Agertoft & Pedersen, 2000,. Sharek, & Bergman 2000). No studies have reported any statistically significant increase in risk of fracture in children taking ICS's.

Steroids in Asthma: Friend or Foe 575

The issue of noncompliance is complicated by different patterns of noncompliance and a variety of measurements of noncompliance. Cochrane GM 1996 identified several patterns of noncompliance, including taking only half of the medications at the prescribed times, taking the medication regularly for a period and stopping, and skipping prescribed doses. Compliance with preventive therapy such as ICSs whose effect is seen over a period of weeks may be less than compliance with drugs that relieve asthma symptoms more rapidly. Patient adherence to medication is influenced by a number of factors relating to how the individual judges the necessity of their treatment relative to their concerns. These factors can

Discomfort of drug administration (eg, bad taste, dry throat, hoarseness, fungal

Poor perception of the impact of the disease (symptoms, experience, expectations &

Non-volitional non-adherence: from failure to take medication properly (e.g. ICS±

3. Contextual issues: Past experiences, Cultural issues/ Social beliefs/ Poor pt /View of

It is important to keep the medication regimen as simple as possible, prioritize recommendations, educate the patient regarding disease management, and individualized

2**.) Inhalation technique.** The effectiveness of inhaler therapy depends not only on compliance, but also on the inhaler technique. Various types of inhaler devices are available including trubohaler, discus etc however they can be broadly categorized based on the form of drugs used as dry powder inhalers (DPI) and Metered Dose inhalers (MDI). Although both types of inhalers are equally effective but While prescribing ICS to patient due consideration should be given to the age of the patient, comorbid conditions, coordination between the hands & mouth & the educational level of patient, otherwise the inhaled ICS

Belief that medication is not really needed ( esp. Controller medicine (ICS)

Fear of adverse effects or dependence/ negative orientation to medicines

Volitional non-adherence: voluntarily not taking medication

be categorized as follows:

infections)

Steroid phobia

LABA)

2. Behavioral factors

 Dosing schedule too frequent cost / non-availability of medicine

Need to use proper inhaler technique

Belief that medication would not work

the dosing and schedule of ICS as per patient's requirment.

interpretation of illness )

Forgetting to take medication

others/ Practical difficulties

Complexity or inconvenience of treatment regimen

 Physician's Inertia / Attitude/ lack of communication Proper education about the disease not given by physician

1. Treatment factors:

Oral or systemic steroids increases the risk of fracture in children with a 32 % increase in 4 courses ever, however ICS's are safe in this regard. Controlled longitudinal studies of 2-5 yrs duration and several cross sectional studies found no adverse effect of ICS on bone mineral density (Agertoft & Pedersen , 1998, Hopp et al., 1995).

**Suppression of Hypothalamic-pituitary-adrenal (HPA) axis:** Though differences exist between the various ICS's and inhaler devices, treatment with ICS's doses of less than 200 µg budesonide or equivalent daily is normally not associated with any significant suppression of the HPA axis in children. At higher doses, small changes in HPA axis function can be detected with sensitive methods. The clinical relevance of these findings is not known, since there have not been reports of adrenal crisis in clinical trials of ICS's in children. However, adrenal crisis has been reported in children treated with excessively high doses of ICS's (Roux et al., 2003).

Recent studies confirm that benefits of ICS, properly prescribed and used, clearly outweigh not only their potential adverse effects but also the risks associated with poorly controlled asthma.

Benefits of oral corticosteroids for asthma include reduction in mucus production, chest tightness, coughing, and wheezing. Other non-asthma related conditions, such as sinus conditions and psoriasis, may also improve due to the anti-inflammatory properties of oral steroids.

**Side effects of steroids:** Side effects of short-term oral steroids include fluid retention, stomach upset, excessive hunger, and blurred vision. Difficulty concentrating, insomnia, and mood changes can also occur as a result of taking oral corticosteroids. The systemic side-effects of long-term treatment with high doses of ICS's may include cataracts, osteoporosis, easy bruising, and hair loss, Weight gain, an increase in facial hair in women, and muscle weakness. Long term use of oral corticosteroids may also increase the risk of diabetes, high blood pressure, and certain infections. Systemic effects of inhaled glucocorticosteroids are not a problem in adults at doses of ≤ 400 mg budesonide or equivalent daily.

**Factors affecting response of ICS's:** Three most important factors that appear to have significant impact on the effectiveness of inhaled corticosteroid (ICS) treatment are:

1.) **Patient compliance with inhaled anti-asthma therapy:** The term "Compliance" is defined as the extent to which a patient's behavior matches the prescriber's advice but recently it has mostly been superseded by the term adherence, a similar concept but having fewer negative connotations from physician/patient relationship point of view (Haynes, 1979). Adherence is defined as the extent to which the patient's behavior matches agreed recommendations from the prescriber.

The issue of noncompliance is complicated by different patterns of noncompliance and a variety of measurements of noncompliance. Cochrane GM 1996 identified several patterns of noncompliance, including taking only half of the medications at the prescribed times, taking the medication regularly for a period and stopping, and skipping prescribed doses. Compliance with preventive therapy such as ICSs whose effect is seen over a period of weeks may be less than compliance with drugs that relieve asthma symptoms more rapidly. Patient adherence to medication is influenced by a number of factors relating to how the individual judges the necessity of their treatment relative to their concerns. These factors can be categorized as follows:

1. Treatment factors:

574 Glucocorticoids – New Recognition of Our Familiar Friend

increase in risk of fracture in children taking ICS's.

density (Agertoft & Pedersen , 1998, Hopp et al., 1995).

high doses of ICS's (Roux et al., 2003).

recommendations from the prescriber.

steroids.

equivalent daily.

adolescents, however Children with asthma treated with ICS's attain normal adult height (predicted from family members) but at a later age( Pedersen, 2001, Agertoft & Pedersen, 2000,. Sharek, & Bergman 2000). No studies have reported any statistically significant

Oral or systemic steroids increases the risk of fracture in children with a 32 % increase in 4 courses ever, however ICS's are safe in this regard. Controlled longitudinal studies of 2-5 yrs duration and several cross sectional studies found no adverse effect of ICS on bone mineral

**Suppression of Hypothalamic-pituitary-adrenal (HPA) axis:** Though differences exist between the various ICS's and inhaler devices, treatment with ICS's doses of less than 200 µg budesonide or equivalent daily is normally not associated with any significant suppression of the HPA axis in children. At higher doses, small changes in HPA axis function can be detected with sensitive methods. The clinical relevance of these findings is not known, since there have not been reports of adrenal crisis in clinical trials of ICS's in children. However, adrenal crisis has been reported in children treated with excessively

Recent studies confirm that benefits of ICS, properly prescribed and used, clearly outweigh not only their potential adverse effects but also the risks associated with poorly controlled asthma. Benefits of oral corticosteroids for asthma include reduction in mucus production, chest tightness, coughing, and wheezing. Other non-asthma related conditions, such as sinus conditions and psoriasis, may also improve due to the anti-inflammatory properties of oral

**Side effects of steroids:** Side effects of short-term oral steroids include fluid retention, stomach upset, excessive hunger, and blurred vision. Difficulty concentrating, insomnia, and mood changes can also occur as a result of taking oral corticosteroids. The systemic side-effects of long-term treatment with high doses of ICS's may include cataracts, osteoporosis, easy bruising, and hair loss, Weight gain, an increase in facial hair in women, and muscle weakness. Long term use of oral corticosteroids may also increase the risk of diabetes, high blood pressure, and certain infections. Systemic effects of inhaled glucocorticosteroids are not a problem in adults at doses of ≤ 400 mg budesonide or

**Factors affecting response of ICS's:** Three most important factors that appear to have

1.) **Patient compliance with inhaled anti-asthma therapy:** The term "Compliance" is defined as the extent to which a patient's behavior matches the prescriber's advice but recently it has mostly been superseded by the term adherence, a similar concept but having fewer negative connotations from physician/patient relationship point of view (Haynes, 1979). Adherence is defined as the extent to which the patient's behavior matches agreed

significant impact on the effectiveness of inhaled corticosteroid (ICS) treatment are:

	- Belief that medication is not really needed ( esp. Controller medicine (ICS)
	- Belief that medication would not work
	- Poor perception of the impact of the disease (symptoms, experience, expectations & interpretation of illness )
	- Fear of adverse effects or dependence/ negative orientation to medicines
	- Steroid phobia
	- Forgetting to take medication
	- Volitional non-adherence: voluntarily not taking medication
	- Non-volitional non-adherence: from failure to take medication properly (e.g. ICS± LABA)

It is important to keep the medication regimen as simple as possible, prioritize recommendations, educate the patient regarding disease management, and individualized the dosing and schedule of ICS as per patient's requirment.

2**.) Inhalation technique.** The effectiveness of inhaler therapy depends not only on compliance, but also on the inhaler technique. Various types of inhaler devices are available including trubohaler, discus etc however they can be broadly categorized based on the form of drugs used as dry powder inhalers (DPI) and Metered Dose inhalers (MDI). Although both types of inhalers are equally effective but While prescribing ICS to patient due consideration should be given to the age of the patient, comorbid conditions, coordination between the hands & mouth & the educational level of patient, otherwise the inhaled ICS will get deposited in the oropharynx & produce local side effects(such as change in voice, Oropharyngeal candidiasis). Use of Spacer with MDI can largely reduce the deposition of the ICS in throat & hence avoid local side effects of the steroids.

Steroids in Asthma: Friend or Foe 577

Lack of portability

form

Expensive

treatment

Lengthy treatment time Device cleaning required Contamination possible

Pressurized gas source required

Not all medication available in solution

Does not aerosolize suspensions well

Expensive when compressor added

Does not nebulize suspensions well Possible drug degradation airway

Coordination of breathing and device

irritation with some drugs

High pharyngeal deposition Upper limit to unit dose content Remaining doses difficult to determine

Not all medications available

Inhalation can be more complex for

Can reduce dose available if not used

More expensive/Less portable Integral actuator devices may alter aerosol properties compared to native actuator

Requires moderate to high inspiratory

Can result in high pharyngeal

Not all medications available

actuation needed

Potential for abuse

some patients

properly

flow

deposition

Device preparation required Performance variability

Need for electric power source Contamination possible Not all medication available Device preparation required before

Type Advantages Disadvantages

Patient coordination not required Effective with tidal breathing

Can deliver combination therapies

Patient coordination not required

Faster delivery than jet nebulizer No drug loss during exhalation (breath actuated devices)

Dose modification possible

High dose possible

oxygen

if compatible

High dose possible

Small dead volume small and portable

Portable and compact Treatment time is short No drug preparation required No contamination of contents Dose-dose reproducibility high Some can be used with breath

actuated mouthpiece

Breath-actuated

Reduces need for coordination Reduces pharyngeal deposition

Less coordination required No Propellant required Small and portable Short treatment time Dose counters

CFC-Cloro-fluor-Carbon, HFA- hydro-fluoro-alkane, MDI- Metered dose inhaler, DPI- Dry Powder inhaler

**Table 4.** Advantages and Disadvantages of Aerosol-Generating Device or System

Dose modification possible Can be used with supplemental

Small-volume jet nebulizer (Respiratory solution, Respules, nebules)

Ultrasonic nebulizer

Pressurized MDI

(CFC/ HFA as propellant) accuhaler, Evohalers

Holding chamber, reverse flow spacer, or spacer (Zerostat, Zerostat-v **spacer**)

DPI

(Turbohaler, Diskus, Rotahaler, Handihaler, aerolizer)

3.) **Impact of inhalation technique and device on drug deposition in the lungs:** For ICSs, the efficacy depends on the topical activity of the drug that reaches the target area, whereas the adverse events depend both on oral deposition and systemic activity. Systemic activity of the drug depends on the amount of the drug absorbed either through the GI tract or through the lungs, as well as on the first-pass metabolism for drug absorbed through the GI tract.

The amount of drug delivered to the lungs depends on the inhalation technique,(Dolovich, 1981, Jackson & Lipworth , 1995) as well as on the type of inhaler used and the fine particle size (respirable particle diameter between 1- 4 µm) of the drug. **Table -3** shows the Estimates of the Lung to Systemic Bioavailability Ratios for different types of ICS's.


BDP-beclomethasone dipropionate. CFC-chlorofluorocarbon. MDI-metered-dose inhaler, DPI- dry powder inhaler.

**Table 3.** Estimates of the Lung to Systemic Bioavailability Ratios for Inhaled Corticosteroids

Recent Recommendations about the delivery device for ICS from American College of Chest Physicians/American College of Asthma, Allergy, and Immunology states that:



Product % Dose Deposited in

the Lungs

tract.

BDP via CFC

BDP (non-CFC

the ICS in throat & hence avoid local side effects of the steroids.

will get deposited in the oropharynx & produce local side effects(such as change in voice, Oropharyngeal candidiasis). Use of Spacer with MDI can largely reduce the deposition of

3.) **Impact of inhalation technique and device on drug deposition in the lungs:** For ICSs, the efficacy depends on the topical activity of the drug that reaches the target area, whereas the adverse events depend both on oral deposition and systemic activity. Systemic activity of the drug depends on the amount of the drug absorbed either through the GI tract or through the lungs, as well as on the first-pass metabolism for drug absorbed through the GI

The amount of drug delivered to the lungs depends on the inhalation technique,(Dolovich, 1981, Jackson & Lipworth , 1995) as well as on the type of inhaler used and the fine particle size (respirable particle diameter between 1- 4 µm) of the drug. **Table -3** shows the

% Dose Reaching the

Lung/Systemic Bioavailability Ratio

Circulation after Absorption from the Gastrointestinal Tract

Systemic

Estimates of the Lung to Systemic Bioavailability Ratios for different types of ICS's.

propellant 5.5 14.7 0.27

propellant) 56.1 5.5 0.92 Budesonide via MDI 15 7.7 0.66 Budesonide via DPI 30 5.3 0.85

BDP-beclomethasone dipropionate. CFC-chlorofluorocarbon. MDI-metered-dose inhaler, DPI- dry powder inhaler.

Recent Recommendations about the delivery device for ICS from American College of Chest

1. For the treatment of asthma in the outpatient setting, both the MDI with a spacer/holding chamber and the DPI are appropriate devices for the delivery of ICS's. 2. For outpatient asthma therapy, the selection of an appropriate aerosol delivery device for ICS's includes the patient's ability to use the device correctly, the preferences of the patient for the device, the availability of the drug/device combination, the compatibility between the drug and delivery device, the lack of time or skills to properly instruct the patient in the use of the device or monitor the appropriate use, the cost of therapy, and the potential for reimbursement( Dolovich, 2005). **Table -4** summarizes the advantages

**Table 3.** Estimates of the Lung to Systemic Bioavailability Ratios for Inhaled Corticosteroids

Physicians/American College of Asthma, Allergy, and Immunology states that:

& disadvantages of all the devices available for the delivery of ICS's

CFC-Cloro-fluor-Carbon, HFA- hydro-fluoro-alkane, MDI- Metered dose inhaler, DPI- Dry Powder inhaler

**Table 4.** Advantages and Disadvantages of Aerosol-Generating Device or System

In short, effective asthma treatment requires a combination of pharmacology and psychology. Effective prescribing needs to take account of patients' beliefs, expectations, and adherence behavior.

Steroids in Asthma: Friend or Foe 579

**Component 2: Identify and Reduce Exposure to Risk Factors:** To improve control of asthma and reduce medication needs, despite physical activity is a common cause of asthma symptoms however patients should not avoid exercise. Common strategies for avoiding allergens and pollutants include the followings; Stay away from tobacco smoke, patients and parents should not smoke, avoid drugs, foods, and additives if they are known to cause symptoms, reduce or, preferably, avoid exposure to occupational

**Component 3: Assess, Treat, and Monitor Asthma:** Each patient is assigned to one of five treatment "steps" based on the frequency and severity of symptoms, PFT values and the exacerbations. At each treatment step, asthma education, environmental control & vaccination are important component of asthma control. Rescue medication should be provided for quick relief of symptoms as needed. As the severity of disease increases, from Steps 2- 5, patients should be given one or more regular controller medications (*ICS* ) in order to keep asthma under control & to avoid the morbidity & mortality related with asthma and to prevent the long term consequences of the disease. Regular use of ICS has *demonstrated* high efficiency in reducing asthma symptoms, reducing frequency & severity of exacerbations, reducing mortality, improving quality of life, improving lung function, decreasing airway hyper-responsiveness & controlling airway

**Component 4: Managing asthma exacerbations:** Exacerbations of asthma are characterized by episodes of progressive increase in shortness of breath, cough, wheezing or chest tightness, or some combination of these symptoms. Mamgement of asthma exacerbation requires close objective monitoring (both clinical and using PEF), repetitive administration of rapid-acting inhaled bronchodilators, early introduction of systemic glucocorticosteroids and oxygen supplementation. It is very important to use systemic steroids early in case of exacerbation in order to control the underlying inflammation earliest possible. GINA guidelines have simplified the recognition of severity of acute exacerbation of asthma and management in acute care setting base on the severity of symptoms & response to treatment

**Stepwise approach for asthma Management:** GINA guidelines have simplified the management of asthma at all stages in stepwise manner starting from rescue medicines to

Although glucocorticoids are highly effective in the control of chronic inflammation or immune dysregulation occurring in asthma pts however a small proportion of patients displays persistent immune activation and airway inflammation and fail to respond despite high doses of oral corticosteroids imposing a big challenge for the physicians. (Barnes, 1995,

1995, Sze¯er, 1997). This group of patients has been classified as "steroid-resistant"

sensitizers.

inflammation.

(For details: www.ginasthma.org)

regular controller medicine. (**Figure 3**)

**4. Glucocorticoid resistance** 

**Goal of Asthma Management:** According to Global Initiative for Asthma (**GINA 2010**) Guidelines issued by the National Heart Lung & Blood institute, the goals for successful management of asthma are to:


Therefore, for successful management of asthma and optimum control of asthma , patients should always be assessed to know their status of asthma control , Following classification of asthma by level of control is more relevant and **useful** (Figure 2).


Adopted from Global Initiative for Asthma (GINA 2010) Guidelines

\* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.

† By denition, an exacerbation in any week makes that an uncontrolled asthma week.

‡ Lung function testing is not reliable for children 5 years and younger.

**Figure 2.** Classification of asthma by level of control

To reach this goal, four interrelated components of therapy are required:

**Component 1: Develop patient/doctor partnership:** In order to help in the effective management of asthma so that the asthmatic patient can learn how to: avoid risk factors, take medications correctly, understand the difference between "controller" and "reliever" medications, monitor their status using symptoms and, if relevant Peak expiratory Flow (PEF) recognize signs that asthma is worsening and take action, seek medical help as appropriate.

**Component 2: Identify and Reduce Exposure to Risk Factors:** To improve control of asthma and reduce medication needs, despite physical activity is a common cause of asthma symptoms however patients should not avoid exercise. Common strategies for avoiding allergens and pollutants include the followings; Stay away from tobacco smoke, patients and parents should not smoke, avoid drugs, foods, and additives if they are known to cause symptoms, reduce or, preferably, avoid exposure to occupational sensitizers.

**Component 3: Assess, Treat, and Monitor Asthma:** Each patient is assigned to one of five treatment "steps" based on the frequency and severity of symptoms, PFT values and the exacerbations. At each treatment step, asthma education, environmental control & vaccination are important component of asthma control. Rescue medication should be provided for quick relief of symptoms as needed. As the severity of disease increases, from Steps 2- 5, patients should be given one or more regular controller medications (*ICS* ) in order to keep asthma under control & to avoid the morbidity & mortality related with asthma and to prevent the long term consequences of the disease. Regular use of ICS has *demonstrated* high efficiency in reducing asthma symptoms, reducing frequency & severity of exacerbations, reducing mortality, improving quality of life, improving lung function, decreasing airway hyper-responsiveness & controlling airway inflammation.

**Component 4: Managing asthma exacerbations:** Exacerbations of asthma are characterized by episodes of progressive increase in shortness of breath, cough, wheezing or chest tightness, or some combination of these symptoms. Mamgement of asthma exacerbation requires close objective monitoring (both clinical and using PEF), repetitive administration of rapid-acting inhaled bronchodilators, early introduction of systemic glucocorticosteroids and oxygen supplementation. It is very important to use systemic steroids early in case of exacerbation in order to control the underlying inflammation earliest possible. GINA guidelines have simplified the recognition of severity of acute exacerbation of asthma and management in acute care setting base on the severity of symptoms & response to treatment (For details: www.ginasthma.org)

**Stepwise approach for asthma Management:** GINA guidelines have simplified the management of asthma at all stages in stepwise manner starting from rescue medicines to regular controller medicine. (**Figure 3**)

#### **4. Glucocorticoid resistance**

578 Glucocorticoids – New Recognition of Our Familiar Friend

 Achieve and maintain control of symptoms Maintain normal activity level including exercise

Avoid side effects from asthma medications

Adopted from Global Initiative for Asthma (GINA 2010) Guidelines

‡ Lung function testing is not reliable for children 5 years and younger.

**Figure 2.** Classification of asthma by level of control

appropriate.

\* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.

To reach this goal, four interrelated components of therapy are required:

**Component 1: Develop patient/doctor partnership:** In order to help in the effective management of asthma so that the asthmatic patient can learn how to: avoid risk factors, take medications correctly, understand the difference between "controller" and "reliever" medications, monitor their status using symptoms and, if relevant Peak expiratory Flow (PEF) recognize signs that asthma is worsening and take action, seek medical help as

† By denition, an exacerbation in any week makes that an uncontrolled asthma week.

Maintain pulmonary functions as close to normal as possible

of asthma by level of control is more relevant and **useful** (Figure 2).

and adherence behavior.

management of asthma are to:

Prevent asthma exacerbations

Avoid asthma mortality

In short, effective asthma treatment requires a combination of pharmacology and psychology. Effective prescribing needs to take account of patients' beliefs, expectations,

**Goal of Asthma Management:** According to Global Initiative for Asthma (**GINA 2010**) Guidelines issued by the National Heart Lung & Blood institute, the goals for successful

Therefore, for successful management of asthma and optimum control of asthma , patients should always be assessed to know their status of asthma control , Following classification

> Although glucocorticoids are highly effective in the control of chronic inflammation or immune dysregulation occurring in asthma pts however a small proportion of patients displays persistent immune activation and airway inflammation and fail to respond despite high doses of oral corticosteroids imposing a big challenge for the physicians. (Barnes, 1995, 1995, Sze¯er, 1997). This group of patients has been classified as "steroid-resistant"


Steroids in Asthma: Friend or Foe 581

after high doses of prednisone, it is critical to confirm that they are taking the oral prednisone by checking their morning serum cortisol after a course of therapy under strict supervision.

**Features Type 1 steroid resistances Type 2 steroid resistances** 

genetic), Allergy, Microbes Genetic

It is imperative to exclude confounding factors when trying to make the diagnosis of steroid-resistant asthma in a patient. These factors include non-adherence with asthma medication, inadequate inhalation technique, incorrect diagnosis, unrecognized concomitant diagnoses, and ongoing exposure to environmental allergens, abnormal corticosteroid pharmacokinetics, and psychosocial disturbances. Low dose methotrexate, cyclosporine, Intravenous immunoglobulin, leukotriene antagonists, such as zafirlukast and montelukast and Nedocromil sodium has been used in steroid resistant patients with varying success

Glucocorticoid resistance in asthma was first described in six patients with asthma who did not respond clinically to high doses of systemic glucocorticoids and in whom there was also a reduced eosinopenic response (Schwartz et al .,1968). Larger groups of patients with chronic asthma who were glucocorticoid resistant were subsequently identified (Carmichael et al ., 1981). These patients were not Addisonian and did not suffer from the abnormalities in sex hormones described in familial glucocorticoid resistance (see below). Plasma cortisol and adrenal suppression in response to exogenous cortisol is normal (Lane et al., 1996). Complete glucocorticoid resistance in asthma is very rare, but reduced responsiveness is more common, so that oral glucocorticoids are needed to control asthma adequately

**Mechanisms of glucocorticoid resistance:** There may be several mechanisms for resistance to the effects of glucocorticoids. Although a family history of asthma is more common in patients with GCR than GCS asthma, little is known about its inheritance. It is possible that a certain proportion of the population has glucocorticoid resistance which only becomes manifest when they develop a severe immunological or immune disease that requires glucocorticoid therapy. Resistance to the inflammatory and immune effects of

Such individuals need alternative approaches to control their pulmonary inflammation.

AM cortisol levels Suppressed No Cushingoid side effects Yes No

binding affinity Reduced Normal GCR numbers Normal or High Low Reversibility of GCR defect Yes No

Cause Cytokine induced(May be

**Table 5.** Summarizes difference in both Types of steroid resistance

**5. Clinical features of glucocorticoid-resistant asthma** 

GCR ligand and DNA

rates and with associated side effects.

(steroid-dependent asthma).

Adopted from Global Initiative for Asthma (GINA 2010) Guidelines

**Figure 3.** Stepwise approach for asthma Management

**Steroid resistant asthma:** American Thoracic Society (ATS) defined Steroid resistant patients as characterized by a pre-bronchodilator Force expiratory volume in 1 sec (FEV1) of less than 70% predicted with a maintained bronchodilator response. Steroid resistance is defined by administering a course of oral prednisone e.g. 40 mg/d (divided doses) for 7 days or preferably 2 wk, and observing the effect on morning pre-bronchodilator FEV1 (Lee, 1996). If the FEV1 fails to increase by 15% (and 200 ml), the patient is considered steroid resistant (Sally et al., 2000). These patients show the typical diurnal variability in peak expiratory flow and bronchodilatation with inhaled B-2 agonists. This type of trial can also assess the possibility of poor adherence to the maintenance regimen.

Patients with steroid resistance can be grouped into two broad categories,

**Type 1 steroid resistance:** is either immune-mediated or acquired as the result of environmental triggers or lifestyle. Clinically, such patients will develop steroid side effects, including adrenal gland suppression, osteoporosis, and cushingoid features from pharmacologic doses of systemic steroids. This is because there is only one (glucocorticoid resistant) GR gene and these patients have steroid resistance only at the level of their immune/inflammatory cells (i.e., T cells). The rest of the tissues in their body remain sensitive to the deleterious effects of systemic steroids.

**Type 2 steroid resistances:** is rare but involves a generalized primary cortisol resistance that affects all tissues and is likely associated with a mutation in the GR gene or genes that modulate GR function. This form is not associated with the development of steroid's side effects or suppression of morning cortisol levels (**Table 5**). It is analogous to genetically inherited familial cortisol resistance. When patients present with a history of no side effects after high doses of prednisone, it is critical to confirm that they are taking the oral prednisone by checking their morning serum cortisol after a course of therapy under strict supervision. Such individuals need alternative approaches to control their pulmonary inflammation.


**Table 5.** Summarizes difference in both Types of steroid resistance

580 Glucocorticoids – New Recognition of Our Familiar Friend

Adopted from Global Initiative for Asthma (GINA 2010) Guidelines **Figure 3.** Stepwise approach for asthma Management

assess the possibility of poor adherence to the maintenance regimen.

sensitive to the deleterious effects of systemic steroids.

Patients with steroid resistance can be grouped into two broad categories,

**Steroid resistant asthma:** American Thoracic Society (ATS) defined Steroid resistant patients as characterized by a pre-bronchodilator Force expiratory volume in 1 sec (FEV1) of less than 70% predicted with a maintained bronchodilator response. Steroid resistance is defined by administering a course of oral prednisone e.g. 40 mg/d (divided doses) for 7 days or preferably 2 wk, and observing the effect on morning pre-bronchodilator FEV1 (Lee, 1996). If the FEV1 fails to increase by 15% (and 200 ml), the patient is considered steroid resistant (Sally et al., 2000). These patients show the typical diurnal variability in peak expiratory flow and bronchodilatation with inhaled B-2 agonists. This type of trial can also

**Type 1 steroid resistance:** is either immune-mediated or acquired as the result of environmental triggers or lifestyle. Clinically, such patients will develop steroid side effects, including adrenal gland suppression, osteoporosis, and cushingoid features from pharmacologic doses of systemic steroids. This is because there is only one (glucocorticoid resistant) GR gene and these patients have steroid resistance only at the level of their immune/inflammatory cells (i.e., T cells). The rest of the tissues in their body remain

**Type 2 steroid resistances:** is rare but involves a generalized primary cortisol resistance that affects all tissues and is likely associated with a mutation in the GR gene or genes that modulate GR function. This form is not associated with the development of steroid's side effects or suppression of morning cortisol levels (**Table 5**). It is analogous to genetically inherited familial cortisol resistance. When patients present with a history of no side effects It is imperative to exclude confounding factors when trying to make the diagnosis of steroid-resistant asthma in a patient. These factors include non-adherence with asthma medication, inadequate inhalation technique, incorrect diagnosis, unrecognized concomitant diagnoses, and ongoing exposure to environmental allergens, abnormal corticosteroid pharmacokinetics, and psychosocial disturbances. Low dose methotrexate, cyclosporine, Intravenous immunoglobulin, leukotriene antagonists, such as zafirlukast and montelukast and Nedocromil sodium has been used in steroid resistant patients with varying success rates and with associated side effects.

#### **5. Clinical features of glucocorticoid-resistant asthma**

Glucocorticoid resistance in asthma was first described in six patients with asthma who did not respond clinically to high doses of systemic glucocorticoids and in whom there was also a reduced eosinopenic response (Schwartz et al .,1968). Larger groups of patients with chronic asthma who were glucocorticoid resistant were subsequently identified (Carmichael et al ., 1981). These patients were not Addisonian and did not suffer from the abnormalities in sex hormones described in familial glucocorticoid resistance (see below). Plasma cortisol and adrenal suppression in response to exogenous cortisol is normal (Lane et al., 1996). Complete glucocorticoid resistance in asthma is very rare, but reduced responsiveness is more common, so that oral glucocorticoids are needed to control asthma adequately (steroid-dependent asthma).

**Mechanisms of glucocorticoid resistance:** There may be several mechanisms for resistance to the effects of glucocorticoids. Although a family history of asthma is more common in patients with GCR than GCS asthma, little is known about its inheritance. It is possible that a certain proportion of the population has glucocorticoid resistance which only becomes manifest when they develop a severe immunological or immune disease that requires glucocorticoid therapy. Resistance to the inflammatory and immune effects of glucocorticoids should be distinguished from the rare familial glucocorticoid resistance, where there is an abnormality of glucocorticoid binding to GR.

Steroids in Asthma: Friend or Foe 583

Infection is a common trigger for pulmonary disease. An analysis of the T-cell repertoire in patients whose asthma was poorly controlled (FEV1 <75% predicted despite use of high-dose corticosteroids) revealed that their T cells were activated by a microbial superantigen. To determine whether microbial super antigens could alter corticosteroid sensitivity, the capacity of corticosteroids to inhibit the activation of T cells from normal subjects with super antigens as compared with the mitogen, phytohemagglutinin, was studied. While corticosteroids caused a 99% inhibition of phytohemagglutinin-induced PBMC proliferation, there was only 19% inhibition of super antigen-induced T-cell proliferation. The mechanism by which super antigens induce corticosteroid resistance of human T cells is via activation of the Mitogen-Activated protein Kinase Kinase/Extracellular signal-Regulated Kinase (MEKK-ERK ) pathway (Li et al., 2004, Goleva et al., 2004). Viruses can also alter response in corticosteroids. In particular, rhinovirus has been reported to reduce GR nuclear

The nature of the inflammatory infiltrate will also determine whether the particular pulmonary disease being treated is likely to resolve with corticosteroid therapy. Pulmonary diseases associated with infiltration of neutrophils are likely to be Steroid resistant. To determine the potential mechanism of corticosteroid resistance in neutrophils, Strickland et al.,2001 examined relative amounts of GRα and GRβ in freshly isolated neutrophils and observed increased GRβ, but not GRα, protein and mRNA expression in neutrophils at baseline and after IL-8 exposure (Strickland et al. 2001). High constitutive expression of GRβ by neutrophils may provide a mechanism by which these cells escape corticosteroid-

Other factors contributing to steroid resistance include smoking, stress, obesity, ethnicity, and vitamin D deficiency. In smokers, oxidative stress results in reduced levels of histone deacetylase-2 (Barnes, Adcock, 2009). Stress may induce steroid resistance via multiple mechanisms, including the chronic elevation of the stress hormone, cortisol, which downregulates expression of the GR (Haczku , Panettieri, 2010). The association of steroid resistance with obesity may be related to the systemic inflammation found in this condition, leading to chronic elevation of TNF and mitogen-activated protein kinase (MAPK) activation that causes GR dysfunction (Sutherland et al., 2008) Black patients with asthma have also been found to have reduced steroid responsiveness compared with white asthmatics (Federico, 2005), although the reason for this is not known, but it could be due to

Several recent studies on asthmatics have now shown that low vitamin D levels are associated with increased corticosteroid requirements, and there is a potential role for

vitamin D in the enhancement of corticosteroid response (Sutherland et al., 2010)

translocation and thereby reduce corticosteroid response.

**6.4. Other factors contributing to steroid resistance** 

a combination of genetic and environmental factors.

**6.2. Infection** 

**6.3. Neutrophilia** 

induced cell death.

Glucocorticoid resistance may be *primary* (inherited or acquired of unknown cause) or *secondary due to* reduced glucocorticoid responsiveness (glucocorticoids themselves, cytokines, b-adrenergic agonists).

**Primary glucocorticoid resistance:** There are several possible mechanisms for a reduced anti-inflammatory response to glucocorticoids.


Secondary glucocorticoid resistance: various probable mechanisms include:


### **6. Factors contributing to corticosteroid resistance**

A variety of factors known to contribute to immune activation and pulmonary disease have been found to alter corticosteroid responsiveness (**Table 6**).


**Table 6.** Factors Contributing to Corticosteroid Insensitivity

#### **6.1. Allergen exposure**

Allergen exposure in vivo reduces GR binding affinity in PBMCs from atopic asthmatics. In vitro treatment with cat allergen of peripheral blood mononuclear cell (PBMC) from catallergic asthmatics was also observed to reduce GR binding affinity and T-cell proliferation induced by allergens compared with control antigens. The induction of these GR binding abnormalities was found to be IL-2 and IL-4 dependent.

#### **6.2. Infection**

582 Glucocorticoids – New Recognition of Our Familiar Friend

anti-inflammatory response to glucocorticoids.

e. Interaction between GR and transcription factors.

**6. Factors contributing to corticosteroid resistance** 

been found to alter corticosteroid responsiveness (**Table 6**).

Clinical allergy and allergen exposure

Secondary glucocorticoid resistance: various probable mechanisms include:

cytokines, b-adrenergic agonists).

a. Pharmacokinetic abnormalities. b. Antibodies to lipocortin-1. c. Cellular abnormalities. d. Abnormality in GR function.

a. Down-regulation of GR. b. Effects of cytokines. c. Effect of B2 agonists.

> Infection Smoking Obesity Stress Ethnicity

**6.1. Allergen exposure** 

Low vitamin D level

**Table 6.** Factors Contributing to Corticosteroid Insensitivity

abnormalities was found to be IL-2 and IL-4 dependent.

where there is an abnormality of glucocorticoid binding to GR.

glucocorticoids should be distinguished from the rare familial glucocorticoid resistance,

Glucocorticoid resistance may be *primary* (inherited or acquired of unknown cause) or *secondary due to* reduced glucocorticoid responsiveness (glucocorticoids themselves,

**Primary glucocorticoid resistance:** There are several possible mechanisms for a reduced

A variety of factors known to contribute to immune activation and pulmonary disease have

Allergen exposure in vivo reduces GR binding affinity in PBMCs from atopic asthmatics. In vitro treatment with cat allergen of peripheral blood mononuclear cell (PBMC) from catallergic asthmatics was also observed to reduce GR binding affinity and T-cell proliferation induced by allergens compared with control antigens. The induction of these GR binding Infection is a common trigger for pulmonary disease. An analysis of the T-cell repertoire in patients whose asthma was poorly controlled (FEV1 <75% predicted despite use of high-dose corticosteroids) revealed that their T cells were activated by a microbial superantigen. To determine whether microbial super antigens could alter corticosteroid sensitivity, the capacity of corticosteroids to inhibit the activation of T cells from normal subjects with super antigens as compared with the mitogen, phytohemagglutinin, was studied. While corticosteroids caused a 99% inhibition of phytohemagglutinin-induced PBMC proliferation, there was only 19% inhibition of super antigen-induced T-cell proliferation. The mechanism by which super antigens induce corticosteroid resistance of human T cells is via activation of the Mitogen-Activated protein Kinase Kinase/Extracellular signal-Regulated Kinase (MEKK-ERK ) pathway (Li et al., 2004, Goleva et al., 2004). Viruses can also alter response in corticosteroids. In particular, rhinovirus has been reported to reduce GR nuclear translocation and thereby reduce corticosteroid response.

#### **6.3. Neutrophilia**

The nature of the inflammatory infiltrate will also determine whether the particular pulmonary disease being treated is likely to resolve with corticosteroid therapy. Pulmonary diseases associated with infiltration of neutrophils are likely to be Steroid resistant. To determine the potential mechanism of corticosteroid resistance in neutrophils, Strickland et al.,2001 examined relative amounts of GRα and GRβ in freshly isolated neutrophils and observed increased GRβ, but not GRα, protein and mRNA expression in neutrophils at baseline and after IL-8 exposure (Strickland et al. 2001). High constitutive expression of GRβ by neutrophils may provide a mechanism by which these cells escape corticosteroidinduced cell death.

#### **6.4. Other factors contributing to steroid resistance**

Other factors contributing to steroid resistance include smoking, stress, obesity, ethnicity, and vitamin D deficiency. In smokers, oxidative stress results in reduced levels of histone deacetylase-2 (Barnes, Adcock, 2009). Stress may induce steroid resistance via multiple mechanisms, including the chronic elevation of the stress hormone, cortisol, which downregulates expression of the GR (Haczku , Panettieri, 2010). The association of steroid resistance with obesity may be related to the systemic inflammation found in this condition, leading to chronic elevation of TNF and mitogen-activated protein kinase (MAPK) activation that causes GR dysfunction (Sutherland et al., 2008) Black patients with asthma have also been found to have reduced steroid responsiveness compared with white asthmatics (Federico, 2005), although the reason for this is not known, but it could be due to a combination of genetic and environmental factors.

Several recent studies on asthmatics have now shown that low vitamin D levels are associated with increased corticosteroid requirements, and there is a potential role for vitamin D in the enhancement of corticosteroid response (Sutherland et al., 2010)

### **7. Management of corticosteroid resistance**

The management of steroid resistant (SR) asthma poses a significant challenge to the clinician. Identification of the SR patient early in the course of illness is important to prevent tissue remodeling and irreversible changes in lung pathology. Definitions of clinical response to steroid therapy will be dictated by the pulmonary disease being treated and time frame for improvement of clinical disease before unacceptable steroid side effects occur. In the case of asthma, clinical studies have suggested that favorable response to inhaled steroids is associated with high levels of exhaled nitric oxide, high bronchodilator response, and a low FEV1/FVC ratio prior to treatment (Barnes,2008)

Steroids in Asthma: Friend or Foe 585

**Figure 4.** Flow diagram to manage steroid resistant asthma

nidocromil sodium( Marin, 1996) and theophylline.

dosing regimen (morning & afternoon) is suggested.

to lower vitamin D levels.

**Step 6.** Search for factors affecting lifestyle and steroid responsiveness. Patients with Vitamin D deficiency have increased steroid requirements. Other cofactors, including obesity, smoking, no or little exposure to sunlight and pigmented skin are well known

**Step 7.** Combination therapy can be used to maximize clinical response. Inhaled longacting β2-agonists (LABA) have been found to enhance Glucocorticoid receptor (GR) nuclear translocation and reduced corticosteroid requirements. Consider addition of other steroid-sparing drugs such as leukotriene modifiers, anticholinergic drugs,

**Step 8.** In very difficult case, studies to identify systemic steroid pharmacokinetics and receptors to assess the basis for corticosteroid resistance to determine whether there is incomplete corticosteroid absorption, failure to convert corticosteroids to an active form, or rapid elimination of steroids (frequently as a result of interactions with other medications). Patients with poor absorption of prednisone usually respond well to oral liquid steroid preparations. In patients with rapid corticosteroid elimination, a split

A systematic, stepwise approach is important for a successful outcome (Leung and Bloom, 2003). **Table 7** lists factors to be considered in the evaluation of patients with a history of steroid resistance.


**Table 7.** Considerations in Treating Steroid Resistance


**Figure 4.** Flow diagram to manage steroid resistant asthma

steroid resistance.

Correct diagnosis

Drug adherence Drug delivery

reflex

**7. Management of corticosteroid resistance** 

response, and a low FEV1/FVC ratio prior to treatment (Barnes,2008)

Drug interactions causing enhanced metabolism of steroids

Alternative anti-inflammatory therapies

**Table 7.** Considerations in Treating Steroid Resistance

failure, COPD & broncholitis etc.(**Figure 4**)

take corrective measures for them.

adverse effects.

steroids.

The management of steroid resistant (SR) asthma poses a significant challenge to the clinician. Identification of the SR patient early in the course of illness is important to prevent tissue remodeling and irreversible changes in lung pathology. Definitions of clinical response to steroid therapy will be dictated by the pulmonary disease being treated and time frame for improvement of clinical disease before unacceptable steroid side effects occur. In the case of asthma, clinical studies have suggested that favorable response to inhaled steroids is associated with high levels of exhaled nitric oxide, high bronchodilator

A systematic, stepwise approach is important for a successful outcome (Leung and Bloom, 2003). **Table 7** lists factors to be considered in the evaluation of patients with a history of

Comorbid conditions- rhinosinusitis, congestive heart failure, COPD, Gastro Esophageal

**Step 1.** Complete Evaluation including history, physical examination, pulmonary function testing, and appropriate laboratory tests to confirm the diagnosis and rule out concomitant medical disorders such as vocal cord dysfunction, Gastroesophageal reflux/aspiration, chronic rhinosinusitis, allergic bronchopulmonary aspergillosis, heart

**Step 2.** Try to find out psychological & social factors including adherence to therapy and

**Step 3.** Observe the inhalational technique of patient, reeducate, reinforce about the proper technique especially in patients requiring high doses of ICS for severe persistent asthma. Spacer devices should be used to maximize ICS dose delivery and reduce

**Step 4.** Strict environmental control at home, in school, and at work including finding the source of allergens & eliminating the same because persistent allergen exposure will

**Step 5.** Search for concomitant bacterial/ mycobacterial/ fungal infection of the tracheobronchial tree especially in patients taking high doses of ICS or chronic oral steroids. Chronic colonization with *Mycoplasma pneumoniae* or *Chlamydia pneumoniae,* can trigger airway inflammation in chronic asthmatics and thus poor responsiveness to

increase the symptoms of asthma & reduces steroid responsiveness.


**Step 9.** Consider Steroid sparing anti-inflammatory therapies that would enhance corticosteroid action including cyclosporine (Alexander et al., 1992), IV Immunoglobulin (Mazer , 1991), methotrexate (Mullarkey et al. 1998, Erzurum et al., 1991), mycophenolate mofetil, azathioprine, Macrolides, trolendamycin and gold, depending on the severity of asthma and the potential of significant side effects. Omalizumab (recombinant anti IgE antibody) is useful in patients with primarily allergic asthma & with severe persistent allergic rhinitis.

Steroids in Asthma: Friend or Foe 587

subjects on maintenance ICS without deterioration in asthma control. They are most effective when combined with ICS, and this combination therapy is the preferred treatment when a medium dose of ICS alone fails to achieve control of asthma (Gibson, 2005). The addition of a LABA to a daily regimen of ICS improves symptom scores, decreases nocturnal symptoms, improves lung function, decreases the use of relief medication, reduces the number of exacerbations and achieves clinical control of asthma in more patients, more rapidly, and at a lower dose of ICS, than ICS given alone(Greening,1994,

Certain case reports have documented tiotropium as a useful steroid sparing agent however future clinical trials are warranted that explore the use of tiotropium as a potential 'steroid-

**Methotrexate:** Methotrexate may have a small steroid sparing effect in adults with asthma who are dependent on oral corticosteroids. However, the overall reduction in daily steroid use is probably not large enough to reduce steroid-induced adverse effects. This small potential to reduce the impact of steroid side-effects is probably insufficient to offset the

**Azathioprine :** Currently there is a clear lack of evidence to support the use of azathioprine in the treatment of chronic asthma as a steroid sparing-agent. Large, long-term studies with pre-defined steroid reducing protocols are required before recommendations for clinical

**Cyclosporine:** The improvement in asthma with cyclosporin are small and of questionable clinical significance. Given the side effects of cyclosporin, the evidence available does not recommend routine use of this drug in the treatment of oral corticosteroid dependent

**Chloroquine :** There is insufficient evidence to support the use of chloroquine as an oral steroid-sparing agent in chronic asthma. Further trials should optimise oral steroid dosage

**Troleandomycin :** There is insufficient evidence to support the use of troleandomycin in the

**Gold:** Gold has limited clinically significanct benefits as steroid sparing agent & given the side effects of gold and necessity for monitoring the use of gold as a steroid sparing agent in

Inhaled Corticosteroids are the most effective first line of therapeutic intervention to control the primary immunologic mechanism of the disease and to avoid the devastating

sparing agent' in severe refractory asthma (Kapoor, 2009).

**9. Immunomodulator therapy as steroid sparing** 

before addition of the steroid-sparing agent (Dewey, 2003)

treatment of steroid dependent asthma.( Evans ,2001)

asthma cannot be recommended.(Evans , 2001)

adverse effects of methotrexate (Davies, 1998)

practice can be made (Dean, 2004)

asthma (Evans, 2001)

**10. Conclusion** 

Pauwel, 1997).

Further Studies are needed to determine whether cytokine antagonism—TNF-α, IL-2, IL-4, or IL-13—could restore steroid responsiveness because such cytokines have been found to induce steroid resistance. Vitamin D has recently been demonstrated to induce IL-10 producing regulatory T cells (Xystrakis et al., 2006) and enhance steroid action, and may therefore be steroid sparing( Zhang et al., 2010)

### **8. Novel steroids**

Steroids, either systemic or inhaled, are exquisitely active and effective in asthma, but their mechanism of action is broad, and concern for toxicity—even with topical steroids—has limited their wider use. A variety of approaches are being pursued to maximize local activity within the airways and at the same time to minimize systemic absorption and toxicity. One approach is development of on-site-activated steroids such as ciclesonide, which is a nonhalogenated ICS prodrug that requires endogenous cleavage by esterases for activity. Soft steroids are also being developed; these have improved local, topical selectivity and have much less steroid effect outside the target area. They may be inactivated by esterases or other enzymes (for example a lactone–glucocorticosteroid conjugate).

**Dissociated glucocorticoids:** The recognition that most of the anti-inflammatory effects of glucocorticoids are mediated by repression of transcription factors (transrepression), whereas the endocrine and metabolic effects of steroids are likely to be mediated via glucocorticoid response element binding (transactivation) has led to a search for novel corticosteroids that selectively transrepress, thus reducing the potential risk of systemic side effects. These dissociated steroids which favor monomeric glucocorticoid receptor complexes (i.e., they produce transrepression) and avoid dimerization or transactivation, which is undesirable in asthma would make the treatment of asthma more effective without the current fear of steroid's side effects. Agents from each of these categories are undergoing clinical trials.

**Steroid sparing :** The combination of long acting beta agonist (LABA) with inhaled corticosteroid (ICS) is used frequently in asthma and a benefit from adding LABA to ICS has been described. One review compared reduced dose (mean 60% reduction in inhaled steroid) ICS/LABA combination to either a fixed moderate/high dose ICS or a reduced/tapering ICS dose. In adults with asthma, who use moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. LABA permit a reduction of 37% (253 mcg BDP) in subjects on minimum maintenance ICS and up to 60% (300 mcg FP) in subjects on maintenance ICS without deterioration in asthma control. They are most effective when combined with ICS, and this combination therapy is the preferred treatment when a medium dose of ICS alone fails to achieve control of asthma (Gibson, 2005). The addition of a LABA to a daily regimen of ICS improves symptom scores, decreases nocturnal symptoms, improves lung function, decreases the use of relief medication, reduces the number of exacerbations and achieves clinical control of asthma in more patients, more rapidly, and at a lower dose of ICS, than ICS given alone(Greening,1994, Pauwel, 1997).

Certain case reports have documented tiotropium as a useful steroid sparing agent however future clinical trials are warranted that explore the use of tiotropium as a potential 'steroidsparing agent' in severe refractory asthma (Kapoor, 2009).

### **9. Immunomodulator therapy as steroid sparing**

**Methotrexate:** Methotrexate may have a small steroid sparing effect in adults with asthma who are dependent on oral corticosteroids. However, the overall reduction in daily steroid use is probably not large enough to reduce steroid-induced adverse effects. This small potential to reduce the impact of steroid side-effects is probably insufficient to offset the adverse effects of methotrexate (Davies, 1998)

**Azathioprine :** Currently there is a clear lack of evidence to support the use of azathioprine in the treatment of chronic asthma as a steroid sparing-agent. Large, long-term studies with pre-defined steroid reducing protocols are required before recommendations for clinical practice can be made (Dean, 2004)

**Cyclosporine:** The improvement in asthma with cyclosporin are small and of questionable clinical significance. Given the side effects of cyclosporin, the evidence available does not recommend routine use of this drug in the treatment of oral corticosteroid dependent asthma (Evans, 2001)

**Chloroquine :** There is insufficient evidence to support the use of chloroquine as an oral steroid-sparing agent in chronic asthma. Further trials should optimise oral steroid dosage before addition of the steroid-sparing agent (Dewey, 2003)

**Troleandomycin :** There is insufficient evidence to support the use of troleandomycin in the treatment of steroid dependent asthma.( Evans ,2001)

**Gold:** Gold has limited clinically significanct benefits as steroid sparing agent & given the side effects of gold and necessity for monitoring the use of gold as a steroid sparing agent in asthma cannot be recommended.(Evans , 2001)

#### **10. Conclusion**

586 Glucocorticoids – New Recognition of Our Familiar Friend

therefore be steroid sparing( Zhang et al., 2010)

**8. Novel steroids** 

clinical trials.

allergic asthma & with severe persistent allergic rhinitis.

**Step 9.** Consider Steroid sparing anti-inflammatory therapies that would enhance corticosteroid action including cyclosporine (Alexander et al., 1992), IV Immunoglobulin (Mazer , 1991), methotrexate (Mullarkey et al. 1998, Erzurum et al., 1991), mycophenolate mofetil, azathioprine, Macrolides, trolendamycin and gold, depending on the severity of asthma and the potential of significant side effects. Omalizumab (recombinant anti IgE antibody) is useful in patients with primarily

Further Studies are needed to determine whether cytokine antagonism—TNF-α, IL-2, IL-4, or IL-13—could restore steroid responsiveness because such cytokines have been found to induce steroid resistance. Vitamin D has recently been demonstrated to induce IL-10 producing regulatory T cells (Xystrakis et al., 2006) and enhance steroid action, and may

Steroids, either systemic or inhaled, are exquisitely active and effective in asthma, but their mechanism of action is broad, and concern for toxicity—even with topical steroids—has limited their wider use. A variety of approaches are being pursued to maximize local activity within the airways and at the same time to minimize systemic absorption and toxicity. One approach is development of on-site-activated steroids such as ciclesonide, which is a nonhalogenated ICS prodrug that requires endogenous cleavage by esterases for activity. Soft steroids are also being developed; these have improved local, topical selectivity and have much less steroid effect outside the target area. They may be inactivated by

**Dissociated glucocorticoids:** The recognition that most of the anti-inflammatory effects of glucocorticoids are mediated by repression of transcription factors (transrepression), whereas the endocrine and metabolic effects of steroids are likely to be mediated via glucocorticoid response element binding (transactivation) has led to a search for novel corticosteroids that selectively transrepress, thus reducing the potential risk of systemic side effects. These dissociated steroids which favor monomeric glucocorticoid receptor complexes (i.e., they produce transrepression) and avoid dimerization or transactivation, which is undesirable in asthma would make the treatment of asthma more effective without the current fear of steroid's side effects. Agents from each of these categories are undergoing

**Steroid sparing :** The combination of long acting beta agonist (LABA) with inhaled corticosteroid (ICS) is used frequently in asthma and a benefit from adding LABA to ICS has been described. One review compared reduced dose (mean 60% reduction in inhaled steroid) ICS/LABA combination to either a fixed moderate/high dose ICS or a reduced/tapering ICS dose. In adults with asthma, who use moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. LABA permit a reduction of 37% (253 mcg BDP) in subjects on minimum maintenance ICS and up to 60% (300 mcg FP) in

esterases or other enzymes (for example a lactone–glucocorticosteroid conjugate).

Inhaled Corticosteroids are the most effective first line of therapeutic intervention to control the primary immunologic mechanism of the disease and to avoid the devastating consequences of this disease with resultant cost- effectiveness and risk benefits analysis leading to best control of asthma. As far as steroids are concerned, there is over fear of its side effects in the patients as well as physicians which has to be removed. It should be make clear that steroids are friends of asthma pts if optimally used but if overused it may turned out to be foe, hence emphasis should be given on the optimized and appropriate use of steroids based on the asthma severity, Hence physicians should try to use the both edges of this **"double edged sword"** for the benefit of patients.

Steroids in Asthma: Friend or Foe 589

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Davies HRH R, Olson LLG, Gibson PG. (1998). Methotrexate as a steroid sparing agent for asthma in adults. *Cochrane Database of Systematic Reviews*, Issue 3. Art. No.: CD000391 Dean TP, Dewey A, Bara A, Lasserson TJ, Walters EH. (2004)Azathioprine as an oral corticosteroid sparing agent for asthma. *Cochrane Database of Systematic Reviews*, Issue 1.

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In addition to pharmacological intervention, emphasis should always be given on the patient's education about asthma including its pathogenesis, medications, inhalation technique and strict environmental control on every visit of the patient. Definitively the safety issues of the use of

Steroids in asthma has to be taken in to consideration in order to address the instructions of Hippocrates, **"first do no harm"** in relation to the steroids, however steroids continue to be the most potent and the most effective controller medication for asthma, and their use in the appropriate clinical setting remains invaluable for the control & management of asthma in clinical practice.

### **Author details**

Mahboub Bassam and Vats Mayank *Department of Pulmonology and Allergy & Sleep Medicine , Rashid Hospital, Dubai* 

### **11. References**


safety issues of the use of

clinical practice.

**Author details** 

**11. References** 

Mahboub Bassam and Vats Mayank

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In addition to pharmacological intervention, emphasis should always be given on the patient's education about asthma including its pathogenesis, medications, inhalation technique and strict environmental control on every visit of the patient. Definitively the

Steroids in asthma has to be taken in to consideration in order to address the instructions of Hippocrates, **"first do no harm"** in relation to the steroids, however steroids continue to be the most potent and the most effective controller medication for asthma, and their use in the appropriate clinical setting remains invaluable for the control & management of asthma in

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**New Formula of Glucocorticoids in Clinical Treatment** 

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**Chapter 24** 

© 2012 Senyigit and Ozer, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Corticosteroids for Skin Delivery:** 

Taner Senyigit and Ozgen Ozer

http://dx.doi.org/10.5772/53909

**1. Introduction** 

delivery [8].

Additional information is available at the end of the chapter

potent products especially preferred for shorter regimes.

**Challenges and New Formulation Opportunities** 

Currently, corticosteroids are the most widely used class of anti-inflammatory drugs. The introduction of topical hydrocortisone in the early 1950s provided great advantages over previously available therapies and initiated a new era for dermatological therapy. Their clinical effectiveness in the treatment of dermatological disorders is related to their vasoconstrictive, anti-inflammatory, immunosuppressive and anti-proliferative effects. Despite their benefit in the therapy of inflammatory diseases, topical corticosteroids (TC) are associated number of side effects that limit their use. Most TC are absorbed in quantities that can produce both systemic and topical side effects [1-2]. Table 1 shows the currently used TC in various dermatological disorders according to the British classification system [3]. In general, mild and moderate TC are used for long-term treatments while the potent and very

Over the years, research has focused on strategies to optimize the potency of steroids while minimizing adverse effects due to drug absorption across the skin. In other words, research focus no longer been on the synthesis of more potent derivatives but on safer one. Several attempts have been made to increase the safety of TC treatment, including new application schedules, special vehicles and new synthesized agents [4]. However, "ideal" TC have not yet been synthesized. They should be able to permeate the stratum corneum (SC) and reach adequate concentrations in the epidermis without reaching high systemic concentrations.

One of the approaches to reduce the adverse effects of TC is to enhance their permeability so as to reduce the topically applied dose [5]. Several approaches have been attempted, such as iontophoresis, electroporation or the application of eutectic mixtures [6,7]. However, the use of chemical penetration enhancers is the most widely used approach to increase skin

and reproduction in any medium, provided the original work is properly cited.

## **Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities**

Taner Senyigit and Ozgen Ozer

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53909

### **1. Introduction**

Currently, corticosteroids are the most widely used class of anti-inflammatory drugs. The introduction of topical hydrocortisone in the early 1950s provided great advantages over previously available therapies and initiated a new era for dermatological therapy. Their clinical effectiveness in the treatment of dermatological disorders is related to their vasoconstrictive, anti-inflammatory, immunosuppressive and anti-proliferative effects. Despite their benefit in the therapy of inflammatory diseases, topical corticosteroids (TC) are associated number of side effects that limit their use. Most TC are absorbed in quantities that can produce both systemic and topical side effects [1-2]. Table 1 shows the currently used TC in various dermatological disorders according to the British classification system [3]. In general, mild and moderate TC are used for long-term treatments while the potent and very potent products especially preferred for shorter regimes.

Over the years, research has focused on strategies to optimize the potency of steroids while minimizing adverse effects due to drug absorption across the skin. In other words, research focus no longer been on the synthesis of more potent derivatives but on safer one. Several attempts have been made to increase the safety of TC treatment, including new application schedules, special vehicles and new synthesized agents [4]. However, "ideal" TC have not yet been synthesized. They should be able to permeate the stratum corneum (SC) and reach adequate concentrations in the epidermis without reaching high systemic concentrations.

One of the approaches to reduce the adverse effects of TC is to enhance their permeability so as to reduce the topically applied dose [5]. Several approaches have been attempted, such as iontophoresis, electroporation or the application of eutectic mixtures [6,7]. However, the use of chemical penetration enhancers is the most widely used approach to increase skin delivery [8].

© 2012 Senyigit and Ozer, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities 597

thickness of the skin is highly variable (average thickness of 1.5 mm), depending of several factors as the anatomic location, age and sex. The functions of the skin have been classified as protective, homeostatic, or sensorial. To maintain its characteristics, this organ is in a

Anatomically, the skin consists on 3 basic layers: epidermis, dermis and subcutaneous tissues. Depending on the region considered, the epidermis is made of 4-5 sublayers that, from bottom to top, are: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum (present only in palm and soles) and SC or horny layer. In addition to these structures, there are also several associated appendages: hair follicles, sweat glands,

The most important skin function is permeability barrier function. The outermost layer of the epidermis, the SC, with its peculiar structure, plays an important role in permeability barrier function [15]. Due to its barrier properties, the skin membrane is equally capable at limiting the molecular transport from and into the body. Overcoming this barrier function

TC are successfully used in the treatment of several common cutaneous diseases but their major limitation is still their side effect potential. The most common side-effects occur locally in the areas of skin treated with the steroid. Probably the most well known is thinning of the skin (atrophy), which sometimes results in permanent stretch marks (striae). Fine blood vessels may swell and become prominent under the skin surface (telangiectasia), again a permanent change. In addition, there may be a temporary loss of pigment in the areas of skin treated; this may be more noticeable in dark-skinned people. Sometimes the skin may become allergic to the steroid, making the eczema appear to get worse. The skin

The occurrence and severity of the side effects are depend on the duration of use, dosage, dosing regime and spesific drug used, along with individual patient variability. However, the highest risk factor seems to be prolonged use [16-18]. The concentration of corticosteroid in systemic circulation and risk of sytemic side effects are increased by prolonged therapy with TC. Systemic side-effects of TC, such as pituitary–adrenal axis suppression, should be taken into account when treating children. Children have a higher ratio of total body surface area to body weight (about 2.5- to 3-fold that of adults) and adrenal suppression may cause

The principle systemic side effects associated with TC are bodyweight gain, Cushing's syndrome, electrolyte imbalance, hypertension, diabetes mellitus, pseudoprimary aldosteronisim, growth retardation, osteoporosis peptic ulser and gastritis. In addition, TC are mostly capable of causing local side effects. One particularly important local side effect is epidermal thinning or atrophy [19]. This effect is characterized with the reduction in cell size and number of cell layers in epidermis. Other local side effects related to TC treatment

continual renewing process [13].

apocrine glands, and nails [14].

growth retardation.

will be the purpose of skin drug delivery.

**3. Clinical limitations and side effects of TC** 

may also bruise more easily and become more susceptible to infection.

**Table 1.** The currently used TC in various dermatological disorders [3]

TC are formulated in a variety of conventional vehicles, including ointments, creams, lotions and gels. In addition to conventional formulations several innovative systems such as nanoparticles, liposomes, microemulsions, foams and patches have been evaluated for different dermatological conditions. Colloidal drug carrier systems, such as liposomes and nanoparticles, could target TC to the viable epidermis, where the inflammatory reactions take place. In particular, liposomal preparations showed a strong affinity for the SC. Patents filed on topical nanoparticulate formulations also claimed the importance of colloidal drug carrier systems for this type of applications [9-12].

This chapter will review major innovations and advances in TC formulations based on the published articles and patent applications. The main factors influencing the effectiveness and bioavailability of TC will be also briefly discussed before emphasizing formulation alternatives.

### **2. Skin structure**

The skin, in Latin called cutis, is considered the largest organ of the body, accounting more than 10% of the body mass and having an average surface of approximately 2 m2. The thickness of the skin is highly variable (average thickness of 1.5 mm), depending of several factors as the anatomic location, age and sex. The functions of the skin have been classified as protective, homeostatic, or sensorial. To maintain its characteristics, this organ is in a continual renewing process [13].

Anatomically, the skin consists on 3 basic layers: epidermis, dermis and subcutaneous tissues. Depending on the region considered, the epidermis is made of 4-5 sublayers that, from bottom to top, are: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum (present only in palm and soles) and SC or horny layer. In addition to these structures, there are also several associated appendages: hair follicles, sweat glands, apocrine glands, and nails [14].

The most important skin function is permeability barrier function. The outermost layer of the epidermis, the SC, with its peculiar structure, plays an important role in permeability barrier function [15]. Due to its barrier properties, the skin membrane is equally capable at limiting the molecular transport from and into the body. Overcoming this barrier function will be the purpose of skin drug delivery.

### **3. Clinical limitations and side effects of TC**

596 Glucocorticoids – New Recognition of Our Familiar Friend

**Mild**

**Moderate**

**Potent**

**POTENCY DOSE % (w/w) TC** 

**Very potent** 0.1 Halcinonide

TC are formulated in a variety of conventional vehicles, including ointments, creams, lotions and gels. In addition to conventional formulations several innovative systems such as nanoparticles, liposomes, microemulsions, foams and patches have been evaluated for different dermatological conditions. Colloidal drug carrier systems, such as liposomes and nanoparticles, could target TC to the viable epidermis, where the inflammatory reactions take place. In particular, liposomal preparations showed a strong affinity for the SC. Patents filed on topical nanoparticulate formulations also claimed the importance of colloidal drug

This chapter will review major innovations and advances in TC formulations based on the published articles and patent applications. The main factors influencing the effectiveness and bioavailability of TC will be also briefly discussed before emphasizing formulation

The skin, in Latin called cutis, is considered the largest organ of the body, accounting more than 10% of the body mass and having an average surface of approximately 2 m2. The

**Table 1.** The currently used TC in various dermatological disorders [3]

carrier systems for this type of applications [9-12].

alternatives.

**2. Skin structure** 

 Hydrocortisone 1 Hydrocortisone acetate 0.25 Methylprednisolone 0.05 Alclometasone

0.01-0.1 Dexamethasone 0.0025 Fluocinolone acetonide 0.75 Fluocortyn butyl ester 0.5 Prednisolone

0.05 Clobetasone butyrate 0.02 Triamcinolone acetonide 0.005 Fluocinolone acetonide

0.05 Betamethasone

0.05 Halometasone

0.1 Diflucortolone valerate

0.05 Clobetasol propionate

0.1 Betamethasone valerate 0.025 Fluocinolone acetonide 0.1 Hydrocortisone butyrate

dipropionate

dipropionate

monohydrate

TC are successfully used in the treatment of several common cutaneous diseases but their major limitation is still their side effect potential. The most common side-effects occur locally in the areas of skin treated with the steroid. Probably the most well known is thinning of the skin (atrophy), which sometimes results in permanent stretch marks (striae). Fine blood vessels may swell and become prominent under the skin surface (telangiectasia), again a permanent change. In addition, there may be a temporary loss of pigment in the areas of skin treated; this may be more noticeable in dark-skinned people. Sometimes the skin may become allergic to the steroid, making the eczema appear to get worse. The skin may also bruise more easily and become more susceptible to infection.

The occurrence and severity of the side effects are depend on the duration of use, dosage, dosing regime and spesific drug used, along with individual patient variability. However, the highest risk factor seems to be prolonged use [16-18]. The concentration of corticosteroid in systemic circulation and risk of sytemic side effects are increased by prolonged therapy with TC. Systemic side-effects of TC, such as pituitary–adrenal axis suppression, should be taken into account when treating children. Children have a higher ratio of total body surface area to body weight (about 2.5- to 3-fold that of adults) and adrenal suppression may cause growth retardation.

The principle systemic side effects associated with TC are bodyweight gain, Cushing's syndrome, electrolyte imbalance, hypertension, diabetes mellitus, pseudoprimary aldosteronisim, growth retardation, osteoporosis peptic ulser and gastritis. In addition, TC are mostly capable of causing local side effects. One particularly important local side effect is epidermal thinning or atrophy [19]. This effect is characterized with the reduction in cell size and number of cell layers in epidermis. Other local side effects related to TC treatment

are steroid acne, rosacea, perioral dermatitis, corticoid acne, allergic contact dermatitis, hypopigmentation, glaucoma, cataracts, worsening of cutaneous infections and hypertrichosis [2]. Table 2 represents the possible local and systemic side effects of TC which are organized in subsections for tissue-organ level.

Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities 599

TC are formulated in a variety of conventional vehicles, including ointments, creams, lotions and gels. As mentioned previously, the character of the vehicle system defines the potency

Ointments are semi-solid preparations intended for application to skin or mucous membranes. There are four types of ointment bases; hydrocarbon bases, absorption bases, emulsion bases and water-soluble bases. The potential of the absorption is affected by choice of the bases. Hence, appropriate selection of the base is important for the efficacy of the

Ointment formulations are generally more effective than creams containing the same drug and they are especially preferred for infiltrated, lichenified lesions. In a comparative study, the absorption of clobetasol propionate from ointment and cream formulations was evaluated and it was reported that a greater amount of clobetasol propionate was absorbed from the ointment [24]. Ointments including well-known and new synthesized TC were formulated and they were still first-option for treatment of dermatological diseases. However, the greasy nature and hardness of the removal from the skin due to their lack of

Mobile dispersions intended for topical application are generally described as lotions and semi-solid systems as creams. Although, creams are usually emulsions of the oil-in-water type (aqueous creams) or water-in-oil type (oily creams), lotions are mostly oil-in-water emulsions [25]. Regarding to the phase of disease, lotions and creams are generally recommended in acute and subacute dermatoses. Good compliance is obtained by prescribing creams and lotions which are easily applied by patients rather than ointments in case of large extensional dermatoses. Sequeira et al. [26] filed a patent application which provided a corticosteroid lotion formulation exhibiting high vasoconstrictor and excellent anti-inflammatory activities in steroid responsive dermatoses. The addition of propylene glycol to a hydro-alcoholic lotion base exhibited and significantly higher vasoconstrictor

Gels are semi-solid systems with dispersions of small or large molecules in an aqueose vehicle with a gelling agent. The gel formulations are suitable for topical delivery of drugs for treatment of diseases due to lack of irritating components. Pharmaceutical gel formulations for topical drug delivery include drug and gelling agent [27]. Gels based on carbopol, cellulose derivatives and chitosan are commonly used in the pharmaceutical and

Recently, new hydrogel formulation intended for cosmetic use was introduced as a novel formulation of steroids for the treatment of atopic dermatitis. The formulation was prepared with carbopol-based polymer that contained 0.05% (w/w) of micronized desonide which is a well-known synthetic corticosteroid. This formulation was easily applied for atopic dermatitis patients aged 3 months. A wide variety of studies have been performed to validate the safety and efficacy of this product and these studies supported very favourable

of topical preparations and its selection is crucial for product performance.

dermal therapy [23].

water-washability is their disadvantages.

cosmetic industries [28, 29].

safety, tolerability and efficacy profile [30, 31].

activity than the corresponding lotion without propylene glycol.


**Table 2.** The possible local and systemic side effects of TC

#### **4. Classification of TC**

TC are classified in two different ways by American and British National Formulary classification systems [20-21]. The American classification system includes seven potency groups while the British National Formulary contains four groups. In the former system, the potency of a product is defined by the corticosteroid, its concentration and the nature of the vehicle. On the other hand, The British classification system is irrespective of the topical vehicle used. According to the American classification sytem, it is important to note that the greater in potency for TC result in the greater therapeutic efficacy and side effects. Therefore, low-potency formulations should be used for long term treatments by physicians while the more potent products should be chosen for short periods and sites such as palms and soles, where low potency TC are ineffective [1,2].

### **5. Formulations of TC**

It is well known that, besides the active molecule, the potency of each topical formulation can be influenced by vehicle characteristics. Vehicles should allow adequate release of the active compound, spread easily and be aesthetically pleasant [21]. Some important rules should be considered when choosing a vehicle; the solubility, release rate and stability of the therapeutic agent in the vehicle, the ability of the vehicle to hydrate the SC, the physical and chemical interactions of the vehicle with the skin and active molecule and also the phase, localization and extent of disease [22].

TC are formulated in a variety of conventional vehicles, including ointments, creams, lotions and gels. As mentioned previously, the character of the vehicle system defines the potency of topical preparations and its selection is crucial for product performance.

598 Glucocorticoids – New Recognition of Our Familiar Friend

are organized in subsections for tissue-organ level.

**TISSUE - ORGAN SIDE EFFECTS Cardiovascular system** Hypertension

**Eye** Glaucoma, cataract

**Gastrointestinal** Peptic ulser, gastritis

**Table 2.** The possible local and systemic side effects of TC

and soles, where low potency TC are ineffective [1,2].

**4. Classification of TC** 

**5. Formulations of TC** 

localization and extent of disease [22].

**Skeleton and muscle** Growth retardation, osteoporosis

are steroid acne, rosacea, perioral dermatitis, corticoid acne, allergic contact dermatitis, hypopigmentation, glaucoma, cataracts, worsening of cutaneous infections and hypertrichosis [2]. Table 2 represents the possible local and systemic side effects of TC which

**Endocrin system** Adrenal insufficiency, Cushing's syndrome, diabetes

**Immune system** Increased risk of infection, re-activation of latent viruses

**Central nervous system** Behavioural changes, loss of memory/cognition

**Skin** Atrophy, striae, allergic contact dermatitis, delayed

hypopigmentation

TC are classified in two different ways by American and British National Formulary classification systems [20-21]. The American classification system includes seven potency groups while the British National Formulary contains four groups. In the former system, the potency of a product is defined by the corticosteroid, its concentration and the nature of the vehicle. On the other hand, The British classification system is irrespective of the topical vehicle used. According to the American classification sytem, it is important to note that the greater in potency for TC result in the greater therapeutic efficacy and side effects. Therefore, low-potency formulations should be used for long term treatments by physicians while the more potent products should be chosen for short periods and sites such as palms

It is well known that, besides the active molecule, the potency of each topical formulation can be influenced by vehicle characteristics. Vehicles should allow adequate release of the active compound, spread easily and be aesthetically pleasant [21]. Some important rules should be considered when choosing a vehicle; the solubility, release rate and stability of the therapeutic agent in the vehicle, the ability of the vehicle to hydrate the SC, the physical and chemical interactions of the vehicle with the skin and active molecule and also the phase,

mellitus, bodyweight gain, pseudoprimary aldosteronism

wound healing, steroid acne, perioral dermatitis, rosacea,

erythema, teleangiectasia, hypertrichosis,

Ointments are semi-solid preparations intended for application to skin or mucous membranes. There are four types of ointment bases; hydrocarbon bases, absorption bases, emulsion bases and water-soluble bases. The potential of the absorption is affected by choice of the bases. Hence, appropriate selection of the base is important for the efficacy of the dermal therapy [23].

Ointment formulations are generally more effective than creams containing the same drug and they are especially preferred for infiltrated, lichenified lesions. In a comparative study, the absorption of clobetasol propionate from ointment and cream formulations was evaluated and it was reported that a greater amount of clobetasol propionate was absorbed from the ointment [24]. Ointments including well-known and new synthesized TC were formulated and they were still first-option for treatment of dermatological diseases. However, the greasy nature and hardness of the removal from the skin due to their lack of water-washability is their disadvantages.

Mobile dispersions intended for topical application are generally described as lotions and semi-solid systems as creams. Although, creams are usually emulsions of the oil-in-water type (aqueous creams) or water-in-oil type (oily creams), lotions are mostly oil-in-water emulsions [25]. Regarding to the phase of disease, lotions and creams are generally recommended in acute and subacute dermatoses. Good compliance is obtained by prescribing creams and lotions which are easily applied by patients rather than ointments in case of large extensional dermatoses. Sequeira et al. [26] filed a patent application which provided a corticosteroid lotion formulation exhibiting high vasoconstrictor and excellent anti-inflammatory activities in steroid responsive dermatoses. The addition of propylene glycol to a hydro-alcoholic lotion base exhibited and significantly higher vasoconstrictor activity than the corresponding lotion without propylene glycol.

Gels are semi-solid systems with dispersions of small or large molecules in an aqueose vehicle with a gelling agent. The gel formulations are suitable for topical delivery of drugs for treatment of diseases due to lack of irritating components. Pharmaceutical gel formulations for topical drug delivery include drug and gelling agent [27]. Gels based on carbopol, cellulose derivatives and chitosan are commonly used in the pharmaceutical and cosmetic industries [28, 29].

Recently, new hydrogel formulation intended for cosmetic use was introduced as a novel formulation of steroids for the treatment of atopic dermatitis. The formulation was prepared with carbopol-based polymer that contained 0.05% (w/w) of micronized desonide which is a well-known synthetic corticosteroid. This formulation was easily applied for atopic dermatitis patients aged 3 months. A wide variety of studies have been performed to validate the safety and efficacy of this product and these studies supported very favourable safety, tolerability and efficacy profile [30, 31].

Senyigit et al. [32] investigated the effect of vehicles (chitosan and sodium-deoxycholate gel) on the skin accumulation and permeation of two topical corticosteroids: clobetasol propionate and mometasone furoate. Commercial cream formulations containing the same amount of drug were also used for comparison. It was reported that sodiumdeoxycholate gel formulation dramatically improved the amount of drug in the skin although chitosan gel produced the same skin accumulation as commercial creams for both active agents. In addition, all of these gel formulations did not induce the permeation.

Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities 601

The activity of a TC formulation can be enhanced by adding a chemical penetration enhancer which may result in an increase of drug delivery into skin. Chemical penetration enhancers have been reviewed by several researchers and the authors underline the difficulty to select rationally a penetration enhancer for a specific permeant [34-36]. Recent studies showed that terpenes appear to be promising penetration enhancers for pharmaceutical formulations with favourable properties such as low cutaneous irritancy

Recently, it has been a great interest in developing new drug carriers for TC that may contribute to reduction of side effects. Therefore, in addition to previously mentioned conventional formulations several innovative systems such as nanoparticles, liposomes,

Liposomes, microemulsions, solid lipid and polymeric nanoparticles have been proposed to increase percutaneous absorption of therapeutic agents while mitigating the damage to the skin barrier function [38,39]. Besides, the drug targeting to the skin or even to its substructures could be realized by micro- and nanoparticulate systems [40,41]. These drug carrier systems could target glucocorticoids to the viable epidermis, where the inflammatory reactions take place [9]. In particular, liposomal preparations showed strong affinity for the

The loading of therapeutic agents into nanoparticles and administration to the skin using a simple vehicle offer many advantages over other traditional topical formulations, including enhanced formulation aesthetics, protection of unstable active agents against degredation, targeting of active agents to the skin layers and prolonged active agent release [43]. As a consequence of their proposed advantages in dermal/transdermal formulations two most common types of particles have been produced: Lipid nanoparticles and polymeric nanoparticles. The uses of lipid and polymeric nanoparticles for pharmaceutical formulations applied to skin have been reviewed by several authors [40, 44-46]. Most of the data reported on TC was obtained using lipid nanoparticles of differing lipid compositions. The inclusion of prednicarbate into solid lipid nanoparticles (SLN) of various composition appeared to increase the penetration of the drug into human skin by 30% as compared to cream, permeation of reconstructed epidermis increased even 3-fold [47]. In a subsequent report SLN were shown to induce prednicarbate targeting in the epidermal layer in excised human skin and reconstructed epidermis [9]. Epidermal targeting was evidenced also for prednisolone, the diester prednicarbate and the monoester betamethasone 17-valerate included in solid lipid nanoparticles [48]. The authors hypothesized specific interactions of the drug-carrier complex and the skin surface, possible by the lipid nature and nanosize of the carrier. On the other hand, using the appropriate lipid combination, the skin retention of betamethasone 17 valerate was increased when SLN was used as a vehicle compared to a conventional formulations [49], both using intact skin as well as barrier impaired [50].

Clobetasol propionate was included in SLN as well [51]. SLN containing cream registered significant improvement in therapeutic response (1.9 fold inflammation, 1.2 fold itching) in terms of percent reduction in degree of inflammation and itching against marketed cream.

and possess good toxicological profile [32, 37].

SC [42].

microemulsions, foams and patches have been developed for TC.

For conventional formulations it can be stated that the effectiveness of the active agent is directly related to the composition of the formulation. In general, the potency of the corticosteroids in the formulations could be listed in order such as; ointments> gels> creams> lotions. This generalization was supported with a patent filed by McCadden [33]. The brief summary about conventional TC formulations including pharmaceutical characteristics, clinical usage, benefits and disadvantages were given in Table 3.


The activity of a TC formulation can be enhanced by adding a chemical penetration enhancer which may result in an increase of drug delivery into skin. Chemical penetration enhancers have been reviewed by several researchers and the authors underline the difficulty to select rationally a penetration enhancer for a specific permeant [34-36]. Recent studies showed that terpenes appear to be promising penetration enhancers for pharmaceutical formulations with favourable properties such as low cutaneous irritancy and possess good toxicological profile [32, 37].

600 Glucocorticoids – New Recognition of Our Familiar Friend

permeation.

**Formulation type** 

Senyigit et al. [32] investigated the effect of vehicles (chitosan and sodium-deoxycholate gel) on the skin accumulation and permeation of two topical corticosteroids: clobetasol propionate and mometasone furoate. Commercial cream formulations containing the same amount of drug were also used for comparison. It was reported that sodiumdeoxycholate gel formulation dramatically improved the amount of drug in the skin although chitosan gel produced the same skin accumulation as commercial creams for both active agents. In addition, all of these gel formulations did not induce the

For conventional formulations it can be stated that the effectiveness of the active agent is directly related to the composition of the formulation. In general, the potency of the corticosteroids in the formulations could be listed in order such as; ointments> gels> creams> lotions. This generalization was supported with a patent filed by McCadden [33]. The brief summary about conventional TC formulations including pharmaceutical

> **Clinical usage**

Infiltrated, lichenified lesions

Acute and subacute dermatoses

Acute and subacute dermatoses

Suitable for all types of skin diseases **Benefits Disadvantages** 

Greasy nature and hardness of the removal from the skin due to their lack of waterwashability

Difficulty of spreadability and soiling linen and clothing during treatment for oily creams

Not suitable for use on dry skin


Occlusive property on the skin for inducing skin hydration at the skin-ointment interface

Easy application and good patient compliance

Easy application and good patient compliance

Easy application, easy to attach to the skin, good patient compliance and lack of irritating components

characteristics, clinical usage, benefits and disadvantages were given in Table 3.

**Pharmaceutical characteristics** 

preparations containing different types of ointment bases

(aqueous creams) or water-in-oil (oily creams) type of emulsion

water emulsions

formulated with a gelling agent

**Table 3.** The summary about conventional TC formulations

**Ointment** Semi-solid

**Cream** Oil-in-water

**Lotion** Generally oil-in-

**Gel** Dispersions

Recently, it has been a great interest in developing new drug carriers for TC that may contribute to reduction of side effects. Therefore, in addition to previously mentioned conventional formulations several innovative systems such as nanoparticles, liposomes, microemulsions, foams and patches have been developed for TC.

Liposomes, microemulsions, solid lipid and polymeric nanoparticles have been proposed to increase percutaneous absorption of therapeutic agents while mitigating the damage to the skin barrier function [38,39]. Besides, the drug targeting to the skin or even to its substructures could be realized by micro- and nanoparticulate systems [40,41]. These drug carrier systems could target glucocorticoids to the viable epidermis, where the inflammatory reactions take place [9]. In particular, liposomal preparations showed strong affinity for the SC [42].

The loading of therapeutic agents into nanoparticles and administration to the skin using a simple vehicle offer many advantages over other traditional topical formulations, including enhanced formulation aesthetics, protection of unstable active agents against degredation, targeting of active agents to the skin layers and prolonged active agent release [43]. As a consequence of their proposed advantages in dermal/transdermal formulations two most common types of particles have been produced: Lipid nanoparticles and polymeric nanoparticles. The uses of lipid and polymeric nanoparticles for pharmaceutical formulations applied to skin have been reviewed by several authors [40, 44-46]. Most of the data reported on TC was obtained using lipid nanoparticles of differing lipid compositions.

The inclusion of prednicarbate into solid lipid nanoparticles (SLN) of various composition appeared to increase the penetration of the drug into human skin by 30% as compared to cream, permeation of reconstructed epidermis increased even 3-fold [47]. In a subsequent report SLN were shown to induce prednicarbate targeting in the epidermal layer in excised human skin and reconstructed epidermis [9]. Epidermal targeting was evidenced also for prednisolone, the diester prednicarbate and the monoester betamethasone 17-valerate included in solid lipid nanoparticles [48]. The authors hypothesized specific interactions of the drug-carrier complex and the skin surface, possible by the lipid nature and nanosize of the carrier. On the other hand, using the appropriate lipid combination, the skin retention of betamethasone 17 valerate was increased when SLN was used as a vehicle compared to a conventional formulations [49], both using intact skin as well as barrier impaired [50].

Clobetasol propionate was included in SLN as well [51]. SLN containing cream registered significant improvement in therapeutic response (1.9 fold inflammation, 1.2 fold itching) in terms of percent reduction in degree of inflammation and itching against marketed cream.

de Vringer disclosed a stable aqueous suspension of SLNs, comprising at least one lipid and preferably also at least one emulsifier for topical application to the body. According to this invention steroidal anti-inflammatory compound such as hydrocortisone, hydrocortisone-17α-butyrate, budesonide or TA, anti-proliferatives, anti-psoriatics, anti-eczema agents and dithranol could be succesfully incorporated into the suspension of SLNs. It was stated that a combination of two or more topically effective medicaments could also be used [52]. Senyigit et al. [53] prepared lecithin/chitosan nanoparticles containing clobetasol propionate and found a preferential retention in the epidermis while no permeation across the skin was observed. In vivo studies including transepidermal water loss measurements, antiinflammatory effect and histological evaluation of the formulations on wistar albino rats were also performed and the results were promising (Data not published).

Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities 603

Niosomes, non-ionic surfactant vesicules, are widely studied as an alternative to liposomes for topical and transdermal drug delivery. Niosomes alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids and high cost. In addition, they have the potential for controlled and targeted drug delivery to the skin [63- 65]. Deformable liposomes (Transfersomes®) are the first generation of elastic vesicles introduced by Cevc [66]. They consist of phospholipids and an edge activator. An edge activator is often a single chain surfactant that destabilizes lipid bilayers of the vesicles and

Cevc et al. [69] investigated the regio-specificity potential of transfersomes which included different corticosteroids (hydrocortisone, dexamethasone and TA). They demonstrated that transfersomes ameliorate the targetability of all tested corticosteroids into the viable skin. They also suggested that the introduction of transfersomal corticosteroids creates new

In another study performed by Fesq et al. [70], the efficacy of transfersomes was compared with commercially available cream and ointment formulations of TA in humans. According to the results of this study, 10-fold lower dose of TA in transfersome was found bioequivalent to conventional formulations as measured by erythema suppression. Ultrasonic measurements also revealed significantly reduced atrophogenic potential of

Ethosome is another novel lipid carrier showing enhanced skin delivery and recently developed by Touitou. The ethosomal system is composed of phospholipid, ethanol and water. The use of high ethanol content was decribed for ethosomes although liposomal

Microemulsions are thermodynamically stable, transparent, isotropic, low-viscosity colloidal dispersions consisting of microdomains of oil and/or water stabilized by an interfacial film of alternating surfactant and cosurfactant molecules [73]. Microemulsions are effective formulations for the dermal and transdermal delivery of particularly lipophilic compounds like TC because of their solubilizing properties and also their components may

Wiedersberg et al. [76] studied the dermato-pharmacokinetic properties of betamethasone valerate from two different formulations either in the reference vehicle consisting of medium chain triglycerides or in the microemulsion. The results showed that

In another study, the penetration behaviour of hydrocortisone from the microemulsion system and a commercialy available cream formulation containing the same amount of hydrocortisone (0.5%) was investigated. *Ex vivo* penetration studies on human breast skin were carried out and the drug contents in the different skin layers were measured. With regard to the cream, the results showed that, a higher percentage of hydrocortisone was found in the epidermis and dermis. This result pointed out the skin targeting effect achieved

microemulsion significantly increased the extent of drug delivery into the SC.

increases deformability of the bilayers [67-68].

opportunities for the well controlled topical medication.

transfersomes in comparison to commercial formulations.

formulations containing up to 10% ethanol [71, 72].

act as penetration enhancers [74, 75].

by microemulsion formulation [77, 78].

Liposomes are lipid vesicles prepared with phospholipids which have been shown to facilitate transport of drugs into and across skin [54]. Recently, many reports have been published on percutaneous enhancing property of liposomes for both hydrophilic and lipophilic compounds [55]. Liposomes do not only enhance the drug penetration into the skin by showing slow release, but also decrease the clearence of drug by minimizing its absorption into the systemic circulation [56]. Hence, the liposomes can improve the therapeutic effectiveness of TC while reducing systemic side effects. However, many stability problems are reported for liposomes.

Mezei et al. [57, 58] applied triamcinolone acetonide (TA) in liposomes and compared it with TA in Dermabase®. In this study, four- to five fold higher TA concentrations in the epidermis and dermis, with lower systemic drug levels were observed when the drug was delivered from liposomal lotion in comparison with conventional formulations of the same drug concentration.

Lasch and Wohlrab [59, 60] studied the skin distribution of cortisol and hydrocortison after application in a cream and liposomes. As a result, improved concentration-time profile was observed in skin layers by liposomes for both drugs.

Korting et al. [61] compared the efficacy of betamethasone dipropionate encapsulated in liposomes and cream. The liposomes were prepared with egg lecithine and incorporated in a polyacrylate gel. The in vivo studies were carried out in patients with atopic eczema and psoriasis vulgaris. It was concluded that, betamethasone encapsulated in liposomes improved the antiinflammatory action, but not the antiproliferative effect.

Fresta et al. [62] prepared skin-lipid liposome formulations of different corticosteroids (hydrocortisone, betamethasone valerate and TA). They indicated that skin lipid liposomes showed a 6 and 1.3 fold higher blanching effect than control formulations of ointment and the phospholipid-based liposomes, respectively. Skin-lipid liposomes also produced a reduction in drug levels in the blood and urine. Consequently, this liposome formulation was proposed for improving the pharmacological effectiveness and reducing the systemic absorption of TC.

In order to overcome the stability problem of liposomes, new attempts have been maden and new drug carrier systems have been developed by adding some functional chemicals into the liposome structure. These systems are niosomes, transfersomes and ethosomes.

Niosomes, non-ionic surfactant vesicules, are widely studied as an alternative to liposomes for topical and transdermal drug delivery. Niosomes alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids and high cost. In addition, they have the potential for controlled and targeted drug delivery to the skin [63- 65]. Deformable liposomes (Transfersomes®) are the first generation of elastic vesicles introduced by Cevc [66]. They consist of phospholipids and an edge activator. An edge activator is often a single chain surfactant that destabilizes lipid bilayers of the vesicles and increases deformability of the bilayers [67-68].

602 Glucocorticoids – New Recognition of Our Familiar Friend

stability problems are reported for liposomes.

observed in skin layers by liposomes for both drugs.

drug concentration.

absorption of TC.

de Vringer disclosed a stable aqueous suspension of SLNs, comprising at least one lipid and preferably also at least one emulsifier for topical application to the body. According to this invention steroidal anti-inflammatory compound such as hydrocortisone, hydrocortisone-17α-butyrate, budesonide or TA, anti-proliferatives, anti-psoriatics, anti-eczema agents and dithranol could be succesfully incorporated into the suspension of SLNs. It was stated that a combination of two or more topically effective medicaments could also be used [52]. Senyigit et al. [53] prepared lecithin/chitosan nanoparticles containing clobetasol propionate and found a preferential retention in the epidermis while no permeation across the skin was observed. In vivo studies including transepidermal water loss measurements, antiinflammatory effect and histological evaluation of the formulations on wistar albino rats

Liposomes are lipid vesicles prepared with phospholipids which have been shown to facilitate transport of drugs into and across skin [54]. Recently, many reports have been published on percutaneous enhancing property of liposomes for both hydrophilic and lipophilic compounds [55]. Liposomes do not only enhance the drug penetration into the skin by showing slow release, but also decrease the clearence of drug by minimizing its absorption into the systemic circulation [56]. Hence, the liposomes can improve the therapeutic effectiveness of TC while reducing systemic side effects. However, many

Mezei et al. [57, 58] applied triamcinolone acetonide (TA) in liposomes and compared it with TA in Dermabase®. In this study, four- to five fold higher TA concentrations in the epidermis and dermis, with lower systemic drug levels were observed when the drug was delivered from liposomal lotion in comparison with conventional formulations of the same

Lasch and Wohlrab [59, 60] studied the skin distribution of cortisol and hydrocortison after application in a cream and liposomes. As a result, improved concentration-time profile was

Korting et al. [61] compared the efficacy of betamethasone dipropionate encapsulated in liposomes and cream. The liposomes were prepared with egg lecithine and incorporated in a polyacrylate gel. The in vivo studies were carried out in patients with atopic eczema and psoriasis vulgaris. It was concluded that, betamethasone encapsulated in liposomes

Fresta et al. [62] prepared skin-lipid liposome formulations of different corticosteroids (hydrocortisone, betamethasone valerate and TA). They indicated that skin lipid liposomes showed a 6 and 1.3 fold higher blanching effect than control formulations of ointment and the phospholipid-based liposomes, respectively. Skin-lipid liposomes also produced a reduction in drug levels in the blood and urine. Consequently, this liposome formulation was proposed for improving the pharmacological effectiveness and reducing the systemic

In order to overcome the stability problem of liposomes, new attempts have been maden and new drug carrier systems have been developed by adding some functional chemicals into the liposome structure. These systems are niosomes, transfersomes and ethosomes.

improved the antiinflammatory action, but not the antiproliferative effect.

were also performed and the results were promising (Data not published).

Cevc et al. [69] investigated the regio-specificity potential of transfersomes which included different corticosteroids (hydrocortisone, dexamethasone and TA). They demonstrated that transfersomes ameliorate the targetability of all tested corticosteroids into the viable skin. They also suggested that the introduction of transfersomal corticosteroids creates new opportunities for the well controlled topical medication.

In another study performed by Fesq et al. [70], the efficacy of transfersomes was compared with commercially available cream and ointment formulations of TA in humans. According to the results of this study, 10-fold lower dose of TA in transfersome was found bioequivalent to conventional formulations as measured by erythema suppression. Ultrasonic measurements also revealed significantly reduced atrophogenic potential of transfersomes in comparison to commercial formulations.

Ethosome is another novel lipid carrier showing enhanced skin delivery and recently developed by Touitou. The ethosomal system is composed of phospholipid, ethanol and water. The use of high ethanol content was decribed for ethosomes although liposomal formulations containing up to 10% ethanol [71, 72].

Microemulsions are thermodynamically stable, transparent, isotropic, low-viscosity colloidal dispersions consisting of microdomains of oil and/or water stabilized by an interfacial film of alternating surfactant and cosurfactant molecules [73]. Microemulsions are effective formulations for the dermal and transdermal delivery of particularly lipophilic compounds like TC because of their solubilizing properties and also their components may act as penetration enhancers [74, 75].

Wiedersberg et al. [76] studied the dermato-pharmacokinetic properties of betamethasone valerate from two different formulations either in the reference vehicle consisting of medium chain triglycerides or in the microemulsion. The results showed that microemulsion significantly increased the extent of drug delivery into the SC.

In another study, the penetration behaviour of hydrocortisone from the microemulsion system and a commercialy available cream formulation containing the same amount of hydrocortisone (0.5%) was investigated. *Ex vivo* penetration studies on human breast skin were carried out and the drug contents in the different skin layers were measured. With regard to the cream, the results showed that, a higher percentage of hydrocortisone was found in the epidermis and dermis. This result pointed out the skin targeting effect achieved by microemulsion formulation [77, 78].


Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities 605

Ease of manufacturing and high loading capacity.

Effective formulations for the dermal and transdermal delivery of particularly lipophilic compounds.

Provides the administration of effective and known drug amount to the skin and the occlusive effect

More convenient topical drug delivery with easy application and spreadability characteristics in comparision to other topical dosage forms

**Benefits Disadvantages** 


Skin irritation


**Formulation type** 

**Pharmaceutical characteristics** 

stable, transparent, isotropic, low-viscosity colloidal dispersions consisting of microdomains of oil and/or water stabilized by an interfacial film of alternating surfactant and cosurfactant molecules

> intended for skin application

agents, solvents, cosolvents, surfactants and propellants in a sealed canister under pressure

Patches are other innovative drug delivery systems intended for skin application in view of achieving local or systemic effect. The patch provides the administration of effective and

The occlusive effect of Actiderm® (hydrocolloid dermatological patch) has been studied on the percutaneous penetration of several drugs including corticosteroids. It was found to be effective in controlling and sustaining the localized delivery of the steroid into the skin and

Ladenheim et al. [82] investigated the effect of occlusion on *in vitro* TA penetration using hydrocolloid containing patches by measuring transepidermal water loss. They found that the diffusion rate of TA was increased 3-4 fold when applied occluded patch in comparison with unoccluded. Same research group was also evaluated the occlusive properties of a range of hydrocolloid patches containing TA on the drug penetration *in vivo* using visual assessment and the graded multiple-measuremet procedure. They concluded that these patch formulations showed great potential for localized prolonged delivery of drugs to the

skin, which would be desirable for the topical use of other corticosteroids [83].

**Microemulsions** Thermodynamically

**Patches** Drug delivery systems

**Foams** Incorporate active

**Table 4.** The summary about innovative TC formulations

enhancing the healing of dermatological disorders [80, 81].

known drug amount to the skin [79].


**Table 4.** The summary about innovative TC formulations

604 Glucocorticoids – New Recognition of Our Familiar Friend

**Nanoparticles** Solid lipid

**Liposomes** Lipid vesicles prepared

**Niosomes** Non-ionic surfactant

**Transfersomes** Consist of

**Ethosomes** Composed of

**Pharmaceutical characteristics** 

nanoparticles include solid or the mixture of solid and fluid lipids

Polymeric nanoparticles contain non-biodegradable and biodegradable polymers

with phospholipids

vesicules

phospholipids and an edge activator

phospholipid, ethanol and water.

**Benefits Disadvantages** 

Mechanism of interaction between nanoparticles skin structures and in vivo toxicity issues are need to be clarified

> Stability problems

Less effective drug delivery in comparison to liposomes


The mechanism of action is not clear

Enhanced formulation aesthetics, protection of unstable active agents against degredation, targeting of active agents to the skin layers and prolonged active agent release

Percutaneous absorption enhancing property, slow release and decrease the clearence of drug by minimizing its absorption into the systemic circulation

Alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids and high cost.

Controlled and targeted drug delivery to the skin.

Improved therapeutic risk-benefit ratio,due to better targeting and longer drug presence in the skin

Improved dermal/transdermal delivery of lipophilic or hydrophilic molecules

**Formulation type** 

> Patches are other innovative drug delivery systems intended for skin application in view of achieving local or systemic effect. The patch provides the administration of effective and known drug amount to the skin [79].

> The occlusive effect of Actiderm® (hydrocolloid dermatological patch) has been studied on the percutaneous penetration of several drugs including corticosteroids. It was found to be effective in controlling and sustaining the localized delivery of the steroid into the skin and enhancing the healing of dermatological disorders [80, 81].

> Ladenheim et al. [82] investigated the effect of occlusion on *in vitro* TA penetration using hydrocolloid containing patches by measuring transepidermal water loss. They found that the diffusion rate of TA was increased 3-4 fold when applied occluded patch in comparison with unoccluded. Same research group was also evaluated the occlusive properties of a range of hydrocolloid patches containing TA on the drug penetration *in vivo* using visual assessment and the graded multiple-measuremet procedure. They concluded that these patch formulations showed great potential for localized prolonged delivery of drugs to the skin, which would be desirable for the topical use of other corticosteroids [83].

More recently, novel foam formulations of TC have been developed and proposed as alternative therapy to conventional formulations. They offer more convenient topical drug delivery with easy application and spreadability characteristics in comparision to other topical dosage forms [84, 85].

Corticosteroids for Skin Delivery: Challenges and New Formulation Opportunities 607

[1] Wiedersberg S, Leopold CS, Guy RH (2008) Bioavailability and Bioequivalence of

[2] Brazzini B, Pimpinelli N. (2002) New and Established Topical Corticosteroids in

[3] British National Formulary (2004) London: British Medical Association and the Royal

[4] Schackert C, Korting HC, Schafer-Korting M (2000) Qualitative and Quantitative Assessment of the Benefit-Risk Ratio of Medium Potency Topical Corticosteroids In Vitro and In Vivo Characterisation of Drugs with an Increased Benefit-Risk Ratio.

[5] Fang JY, Fang CL, Sung KC, Chen HY. (1999) Effect of Low Frequency Ultrasound on the In Vitro Percutaneous Absorption of Clobetasol 17-Propionate. Int. j. pharm. 191:33-

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**7. References** 

42.

A novel foam formulation with enhanced BMV bioavailability has been shown to be superior in efficacy when compared with a lotion in the treatment of disease, without an concomitant increase in toxicity [86]. Another study has been performed comparing the ability of a foam formulation to release the active ingredient (betamethasone benzoate) with ointment, gel, and cream formulations. It was found that the release of betamethasone benzoate from the foam formulation better than the release from the cream [87].

The thermolabile and low-residue foam formulations of corticosteroids (betamethasone valerate and clobetasol propionate) are available in USA market. These foam formulations are associated with better patient compliance and improvements in quality of life [88, 89]. Table 4 summarizes the new drug carrier formulations of TC.

### **6. Conclusion**

Current therapy of dermatological disorders with conventional dosage forms including TC is insufficient due to the low absorption rate and the risk of side effects. Therefore, it is necessary to synthesize the new topical corticosteroid molecules with adequate antiinflammatory activity and minimal side effects. Fluticasone propionate, mometasone furoate and prednicarbate are very promising molecules showed lower side effects and better tolerability as a member of new generation TC. Also, improved dermal absorption of established TC may be obtained by new designed vehicle system as an alternative to conventional formulation. Recently, lipid and polymeric based carriers such as liposomes, niosomes, transfersomes, ethosomes, microemulsions and nanoparticles have been studied intensively and the potential of these carrier systems have also been described. Another alternative approach for TC treatment is a combined therapy which is more effective than in case of drug alone. The combined use of TC and synthetic vitamin D analogues such as calcipotriol would be promising for the treatment of inflammatory skin diseases. I

In conclusion, due to the difficulty of synthesizing new steroid molecules, developing the novel alternative drug carrier systems which improve the risk-benefit ratio of TC would be more beneficial in topical corticosteroid treatment. Besides, more in vivo study is required to validate the ability of new formulations in enhancing topical delivery of corticosteroids.

### **Author details**

Taner Senyigit and Ozgen Ozer *Ege University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Bornova, Izmir, Turkey* 

#### **7. References**

606 Glucocorticoids – New Recognition of Our Familiar Friend

topical dosage forms [84, 85].

**6. Conclusion** 

diseases. I

corticosteroids.

*Turkey* 

**Author details** 

Taner Senyigit and Ozgen Ozer

More recently, novel foam formulations of TC have been developed and proposed as alternative therapy to conventional formulations. They offer more convenient topical drug delivery with easy application and spreadability characteristics in comparision to other

A novel foam formulation with enhanced BMV bioavailability has been shown to be superior in efficacy when compared with a lotion in the treatment of disease, without an concomitant increase in toxicity [86]. Another study has been performed comparing the ability of a foam formulation to release the active ingredient (betamethasone benzoate) with ointment, gel, and cream formulations. It was found that the release of betamethasone

The thermolabile and low-residue foam formulations of corticosteroids (betamethasone valerate and clobetasol propionate) are available in USA market. These foam formulations are associated with better patient compliance and improvements in quality of life [88, 89].

Current therapy of dermatological disorders with conventional dosage forms including TC is insufficient due to the low absorption rate and the risk of side effects. Therefore, it is necessary to synthesize the new topical corticosteroid molecules with adequate antiinflammatory activity and minimal side effects. Fluticasone propionate, mometasone furoate and prednicarbate are very promising molecules showed lower side effects and better tolerability as a member of new generation TC. Also, improved dermal absorption of established TC may be obtained by new designed vehicle system as an alternative to conventional formulation. Recently, lipid and polymeric based carriers such as liposomes, niosomes, transfersomes, ethosomes, microemulsions and nanoparticles have been studied intensively and the potential of these carrier systems have also been described. Another alternative approach for TC treatment is a combined therapy which is more effective than in case of drug alone. The combined use of TC and synthetic vitamin D analogues such as calcipotriol would be promising for the treatment of inflammatory skin

In conclusion, due to the difficulty of synthesizing new steroid molecules, developing the novel alternative drug carrier systems which improve the risk-benefit ratio of TC would be more beneficial in topical corticosteroid treatment. Besides, more in vivo study is required to validate the ability of new formulations in enhancing topical delivery of

*Ege University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Bornova, Izmir,* 

benzoate from the foam formulation better than the release from the cream [87].

Table 4 summarizes the new drug carrier formulations of TC.


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**Chapter 25** 

© 2012 Chowdhury and Borah, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

**Soft Glucocorticoids: Eye-Targeted Chemical** 

**Delivery Systems (CDSs) and Retrometabolic** 

Steroids play a vital role in human physiology and medicine. Glucocorticoids have dominated the class of anti-inflammatory agents quite successfully over other drugs since their introduction to dermatology more than fifty years ago. Later they have been developed both as topical and systemic anti-inflammatory agents. From studies it has been found that glucocorticoids normally release their anti-inflammatory effects mainly through the modulation of the cytosolic glucocorticoid receptor (GR) at the genomic level [1, 2]. The activated glucocorticoid-GR complex formed *via* binding of glucocorticoid with the GR in the cytoplasm, migrates to the nucleus, where it upregulates the expression of antiinflammatory proteins and repress the expression of pro-inflammatory proteins. In some recent work, it has been reported that the activated glucocorticoid-GR complex has also been found to initiate nongenomic effects like inhibition of vasodilation, vascular permeability and migration of leukocytes [1, 3]. Glucocorticoids also mediate antiinflammatory activity through membrane-bound GR-mediated nongenomic effects and also through direct non specific interaction with cellular membranes [3, 4]. Since GR is involved in a plethora of signalling pathways, more than 5000 genes are expressed or suppressed following glucocorticoid exposure [4, 5]. Therefore long term use or high dosages of glucocorticoids could result in adverse drug reactions (ADRs) like increased Intraocular Pressure (IOP) [6, 7] in ocular therapeutics. Glucocorticoids- induced ocular hypertension is of great concern in ophthalmic therapeutics as it can lead to secondary iatrogenic open-angle glaucoma. Glaucoma is a group of eye diseases characterized by progressive optic nerve cupping with visual field loss leading to bilateral blindness. It has been reported that glaucoma is estimated to affect more than 50 million people worldwide as defined by the

**Drug Design: A Review** 

Pritish Chowdhury and Juri Moni Borah

http://dx.doi.org/10.5772/48380

World Health Organization (WHO) [8].

**1. Introduction** 

Additional information is available at the end of the chapter

[89] Franz TJ, Parsell DA, Halualani RM, Hannigan JF, Kalbach JP, Harkonen WS. (1999) Betamethasone Valerate Foam 0.12%: A Novel Vehicle with Enhanced Delivery and Efficacy. Int. j. dermatol. 38(8):628–632.

## **Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review**

Pritish Chowdhury and Juri Moni Borah

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48380

### **1. Introduction**

612 Glucocorticoids – New Recognition of Our Familiar Friend

Efficacy. Int. j. dermatol. 38(8):628–632.

[88] Stein L. (2005) Clinical Studies of a New Vehicle Formulation for Topical Corticosteroids in the Treatment of Psoriasis. J. am. acad. dermatol. 53(S1):39-49. [89] Franz TJ, Parsell DA, Halualani RM, Hannigan JF, Kalbach JP, Harkonen WS. (1999) Betamethasone Valerate Foam 0.12%: A Novel Vehicle with Enhanced Delivery and

> Steroids play a vital role in human physiology and medicine. Glucocorticoids have dominated the class of anti-inflammatory agents quite successfully over other drugs since their introduction to dermatology more than fifty years ago. Later they have been developed both as topical and systemic anti-inflammatory agents. From studies it has been found that glucocorticoids normally release their anti-inflammatory effects mainly through the modulation of the cytosolic glucocorticoid receptor (GR) at the genomic level [1, 2]. The activated glucocorticoid-GR complex formed *via* binding of glucocorticoid with the GR in the cytoplasm, migrates to the nucleus, where it upregulates the expression of antiinflammatory proteins and repress the expression of pro-inflammatory proteins. In some recent work, it has been reported that the activated glucocorticoid-GR complex has also been found to initiate nongenomic effects like inhibition of vasodilation, vascular permeability and migration of leukocytes [1, 3]. Glucocorticoids also mediate antiinflammatory activity through membrane-bound GR-mediated nongenomic effects and also through direct non specific interaction with cellular membranes [3, 4]. Since GR is involved in a plethora of signalling pathways, more than 5000 genes are expressed or suppressed following glucocorticoid exposure [4, 5]. Therefore long term use or high dosages of glucocorticoids could result in adverse drug reactions (ADRs) like increased Intraocular Pressure (IOP) [6, 7] in ocular therapeutics. Glucocorticoids- induced ocular hypertension is of great concern in ophthalmic therapeutics as it can lead to secondary iatrogenic open-angle glaucoma. Glaucoma is a group of eye diseases characterized by progressive optic nerve cupping with visual field loss leading to bilateral blindness. It has been reported that glaucoma is estimated to affect more than 50 million people worldwide as defined by the World Health Organization (WHO) [8].

© 2012 Chowdhury and Borah, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

However, the use of corticosteroids has become more and more restricted and unacceptable because most of these agents are found to be associated with severe side effects, including percutaneous absorption and cutaneous atrophy [9]. Also allergic contact dermatitis is an unexpected adverse effect in most of these corticosteroids. On the other hand because of their high efficacy, their use is inevitable to give them the status of life saving drugs. The severe side effects associated with these glucocorticoids, has led to the pharmaceutical industry to make a productive effort towards the introduction of new generation of topical corticosteroids with specific substituents in their parent molecules to make them safer in comparison to the old generation glucocorticoids [10].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 615

O

Arachidonic Acid (**C**)

OH

eye, resulting in the development of symptoms of ocular inflammation such as redness, pain, swelling and itching [19]. Ocular inflammation is a serious problem, negligence of

Clinical studies suggest that topical glucocorticoids are effective in the management of anterior segment inflammation. They impart a number of potent anti-inflammatory effects [21]. They are found to suppress cellular infiltration, capillary dilution, proliferation of fibroblasts, collagen deposition leading to scar formation; they also stabilize intracellular and extracellular membranes. Glucocorticoids increase the synthesis of lipocortins which block *phospholipase A2* and also inhibit Histamine (**A**) synthesis in mast cells. A critical step in the inflammatory cascade is the inhibition of *phospholipase A2* that inhibits the transformation of Phospholipids (**B**) to Arachidonic acid (**C**). Glucocorticoids are also found to increase the enzyme histaminase and modulate transcription factors present in mast cell nuclei [21, 22]. The formation of cataract is also one of the severe adverse drug reactions (ADRs) associated

which may lead to temporary or permanent blindness [20].

with glucocorticoids when used for ocular problems.

O P

H2C CH CH2

O

Phospholipids (**B**)

It has been reported by Manabe *et al* [23] that the mechanism of steroid-induced cataract formation is chemically based and possibly not related to the downstream effects of glucocorticoid receptor (GR) activation. At present the most accepted hypothesis of this mechanism is likely to involve non-enzymatic formation of Schiff base intermediates between the steroid C-20 ketone group and nucleophilic groups such as -amino groups of lysine residues of proteins (**Figure 1**). Schiff base formation is followed by a Heyns rearrangement [23] involving the nearby C-21 hydroxyl group of the glucocorticoid molecule furnishing stable amine-linked adducts. This covalent binding results in the

C O

CH2

O

O C

H2C

O

O

N

N

<sup>H</sup> NH2 Histamine (**A**)

The effectiveness of hydrocortisone was first demonstrated by Sulzberger and Witten during 1950 [11] and soon after the new and more effective fluorinated hydrocortisones were introduced in the market during 1960 [12]. Further R&D works on these glucocorticoids led to introduction of super potent corticosteroids in the 1970s and 1980s. Cornell and Stoughton [13] had proposed a potency rating of these topically applied glucocorticoids in 1984, based primarily on the vasoconstrictor assay or skin-blanching of corticosteroid preparations. Again based upon the consensus of the United States Pharmacopoeia (USP) Dermatology Advisory Panel, a classification of the potency ranking for these glucocorticoids had been done as low, medium, high and very high [14]. New generation of glucocorticoids do not cause much cutaneous atrophy or systemic absorption in human body. Molecular configuration of these new corticosteroids tends to display a rapidly declining concentration gradient in the skin. Many of these new generation glucocorticoids are developed through the concept of prodrugs – a tool for improving physiochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. Thus prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic or chemical transformation *in vivo* to release the active parent drug, which could then exert the desired pharmacological effect. These new generation glucocorticoids primarily act in the top layers of the skin where the most important mediators of the inflammatory reactions are [10, 14] found.

As for these new generation glucocorticoids, the action in the deeper layer is considerably diminished making them having less systemic side effects [14]. European and North American based clinical studies have shown that the new generation corticosteroids with their improved risk- benefit ratio are as effective as products currently available in the market [15]. These new generation glucocorticoids are highly effective in treating plethora of disease including psoriasis, allergies, asthma, rheumatoid arthritis and lupus [2-8, 14,15].

Again the application of anti-inflammatory agents in ophthalmic therapeutic is a challenging task because of severe complications arising out of the currently used antiinflammatory agents. The eye is vulnerable to damage from low level of intraocular inflammation. The blood-aqueous and blood-retinal barriers generally limit penetration of protein and cells from peripheral circulation, while regulatory molecules and cells in the eye actively suppress immunological responses [16]. The fact that ocular inflammatory conditions and surgical trauma induce changes in the blood- aqueous and blood-retinal barriers [16-18], due to which immune cells and mediators of inflammation could enter the eye, resulting in the development of symptoms of ocular inflammation such as redness, pain, swelling and itching [19]. Ocular inflammation is a serious problem, negligence of which may lead to temporary or permanent blindness [20].

614 Glucocorticoids – New Recognition of Our Familiar Friend

comparison to the old generation glucocorticoids [10].

inflammatory reactions are [10, 14] found.

However, the use of corticosteroids has become more and more restricted and unacceptable because most of these agents are found to be associated with severe side effects, including percutaneous absorption and cutaneous atrophy [9]. Also allergic contact dermatitis is an unexpected adverse effect in most of these corticosteroids. On the other hand because of their high efficacy, their use is inevitable to give them the status of life saving drugs. The severe side effects associated with these glucocorticoids, has led to the pharmaceutical industry to make a productive effort towards the introduction of new generation of topical corticosteroids with specific substituents in their parent molecules to make them safer in

The effectiveness of hydrocortisone was first demonstrated by Sulzberger and Witten during 1950 [11] and soon after the new and more effective fluorinated hydrocortisones were introduced in the market during 1960 [12]. Further R&D works on these glucocorticoids led to introduction of super potent corticosteroids in the 1970s and 1980s. Cornell and Stoughton [13] had proposed a potency rating of these topically applied glucocorticoids in 1984, based primarily on the vasoconstrictor assay or skin-blanching of corticosteroid preparations. Again based upon the consensus of the United States Pharmacopoeia (USP) Dermatology Advisory Panel, a classification of the potency ranking for these glucocorticoids had been done as low, medium, high and very high [14]. New generation of glucocorticoids do not cause much cutaneous atrophy or systemic absorption in human body. Molecular configuration of these new corticosteroids tends to display a rapidly declining concentration gradient in the skin. Many of these new generation glucocorticoids are developed through the concept of prodrugs – a tool for improving physiochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. Thus prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic or chemical transformation *in vivo* to release the active parent drug, which could then exert the desired pharmacological effect. These new generation glucocorticoids primarily act in the top layers of the skin where the most important mediators of the

As for these new generation glucocorticoids, the action in the deeper layer is considerably diminished making them having less systemic side effects [14]. European and North American based clinical studies have shown that the new generation corticosteroids with their improved risk- benefit ratio are as effective as products currently available in the market [15]. These new generation glucocorticoids are highly effective in treating plethora of disease including psoriasis, allergies, asthma, rheumatoid arthritis and lupus [2-8, 14,15].

Again the application of anti-inflammatory agents in ophthalmic therapeutic is a challenging task because of severe complications arising out of the currently used antiinflammatory agents. The eye is vulnerable to damage from low level of intraocular inflammation. The blood-aqueous and blood-retinal barriers generally limit penetration of protein and cells from peripheral circulation, while regulatory molecules and cells in the eye actively suppress immunological responses [16]. The fact that ocular inflammatory conditions and surgical trauma induce changes in the blood- aqueous and blood-retinal barriers [16-18], due to which immune cells and mediators of inflammation could enter the Clinical studies suggest that topical glucocorticoids are effective in the management of anterior segment inflammation. They impart a number of potent anti-inflammatory effects [21]. They are found to suppress cellular infiltration, capillary dilution, proliferation of fibroblasts, collagen deposition leading to scar formation; they also stabilize intracellular and extracellular membranes. Glucocorticoids increase the synthesis of lipocortins which block *phospholipase A2* and also inhibit Histamine (**A**) synthesis in mast cells. A critical step in the inflammatory cascade is the inhibition of *phospholipase A2* that inhibits the transformation of Phospholipids (**B**) to Arachidonic acid (**C**). Glucocorticoids are also found to increase the enzyme histaminase and modulate transcription factors present in mast cell nuclei [21, 22]. The formation of cataract is also one of the severe adverse drug reactions (ADRs) associated with glucocorticoids when used for ocular problems.

It has been reported by Manabe *et al* [23] that the mechanism of steroid-induced cataract formation is chemically based and possibly not related to the downstream effects of glucocorticoid receptor (GR) activation. At present the most accepted hypothesis of this mechanism is likely to involve non-enzymatic formation of Schiff base intermediates between the steroid C-20 ketone group and nucleophilic groups such as -amino groups of lysine residues of proteins (**Figure 1**). Schiff base formation is followed by a Heyns rearrangement [23] involving the nearby C-21 hydroxyl group of the glucocorticoid molecule furnishing stable amine-linked adducts. This covalent binding results in the destabilization of the protein structure allowing further oxidation leading to steroid-induced cataract formation [23].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 617

OH

OH

framework. Glucocorticoid soft drugs such as Loteprednol Etabonate, and Etiprednol Dicloacetate and -blockers such as Betaxoxime, and Adaprolol are some of the new chemical entities developed as soft drugs for ocular applications. Besides, many of these soft drugs have already reached the clinical development phase in various ophthalmic areas and one of them Loteprednol Etabonate has already been marketed [ 24]. Herein we review the important aspects of the development of new generation glucocorticoids through prodrug approach with special reference to the development of the first and second generation glucocorticoid soft drugs by the application chemical delivery systems (CDSs) and retrometabolic drug design approaches towards ophthalmic therapeutics. A few examples of soft ocular –blockers have also been cited to know more about the retrometabolic drug design approach in depth as have been put forwarded by Bodor and his co-workers (24).

As discussed earlier several numbers of new entities of glucocorticoids have been developed during the last two decades. Many of them are already in market for their high efficacy and less systemic side effects. These new generation corticosteroids were developed with modifications made in the basic glucocorticoid molecules, *viz*., Betamethasone **1** or Dexamethasone **2** extensively used during early stage of glucocorticoids therapy. The main object of synthesizing these modified glucocorticoids was to get better skin penetration,

OH

O

Even then in some cases it was observed that the changes that increased potency, also led sometimes to more systemic side effects. As per clinical investigations by various workers, these new generation glucocorticoids have been found to act *via* hepatic or extra hepatic biotransformation. These results in lesser systemic side effects and hence are much safer drugs to be used specially by adults and non- erythrodermic patients. However, while systemic side effects are of concern, cutaneous side effects are generally common involving problems such as striae formation, atrophy, purpura, peri-oral dermatitis, steroid rosacea, hypertrichosis and steroid acne [2,6]. Most of the side effects associated even with these new generation glucocorticoids are basically related to the duration and potency of the application, the manner of application, the presence of penetration-enhancing substances and the state of skin barrier. Besides these, the anatomic site and the age of the patient could also adversely influence the side effect profile [2, 6]. In both drug discovery and

F

Dexamethasone (**2**)

HO

H

O

H

OH

**2. New generation glucocorticoids: Prodrugs** 

F

HO

H

Betamethasone (**1**)

O

slower enzyme degradation, and greater affinity for cytosol receptors [5].

O

H

**Figure 1.** Mechanism of steroid-induced cataract formation due to the synthesis of the stable steroidamine adduct between the C-20 carbonyl group of glucocorticoids and nucleophilic group such as amino groups of lysine residues of proteins via formation Schiff Base

R&D work in understanding the mechanism of action of steroids, both for their antiinflammatory effects and adverse drug reactions (ADRs) has lead to the development new generation glucocorticoids mainly through prodrug design approach to find use in treating plethora of diseases as mentioned earlier. All these new generation glucocorticoids are not designed for ophthalmic therapeutics. Hence a real breakthrough in the field of ophthalmic therapeutic could be achieved only by specifically designing new drug entities to incorporate the eye targeting possibility into their chemical structure [24,25]. Chemical Delivery Systems (CDSs) and Retrometabolic drug design principles have led to development of a new but unique class of glucocorticoids which are safe and effective in treating a wide variety of ocular inflammatory conditions including giant papillary conjunctivitis, seasonal allergic conjunctivitis, and uveities as well as in the treatment of ocular inflammation and pain following cataract surgery. This new and unique class of glucocorticoids are now known as soft glucocorticoids which are associated with highly minimized ADRs to justify terming them as `soft drugs' [24, 26].

It is pertinent to note that, this important drug design based on Chemical Delivery Systems (CDSs) and Soft drug (SD) approaches integrate the specific pharmacological, metabolic, and targeting requirements for ophthalmic therapeutics. .A number of glucocorticoid soft drugs and soft -blockers have been developed this way for clinical trials. Their potential is already documented by the results obtained with several soft drugs designed within this framework. Glucocorticoid soft drugs such as Loteprednol Etabonate, and Etiprednol Dicloacetate and -blockers such as Betaxoxime, and Adaprolol are some of the new chemical entities developed as soft drugs for ocular applications. Besides, many of these soft drugs have already reached the clinical development phase in various ophthalmic areas and one of them Loteprednol Etabonate has already been marketed [ 24]. Herein we review the important aspects of the development of new generation glucocorticoids through prodrug approach with special reference to the development of the first and second generation glucocorticoid soft drugs by the application chemical delivery systems (CDSs) and retrometabolic drug design approaches towards ophthalmic therapeutics. A few examples of soft ocular –blockers have also been cited to know more about the retrometabolic drug design approach in depth as have been put forwarded by Bodor and his co-workers (24).

#### **2. New generation glucocorticoids: Prodrugs**

616 Glucocorticoids – New Recognition of Our Familiar Friend

HO

Stable glucocorticoid-amine

HO

H N

amino groups of lysine residues of proteins via formation Schiff Base

minimized ADRs to justify terming them as `soft drugs' [24, 26].

OH

O

Glucocorticoid

cataract formation [23].

NH2 <sup>+</sup> Protein

Protein

adduct

destabilization of the protein structure allowing further oxidation leading to steroid-induced

OH OH

Heyns Rearrangement

**Figure 1.** Mechanism of steroid-induced cataract formation due to the synthesis of the stable steroidamine adduct between the C-20 carbonyl group of glucocorticoids and nucleophilic group such as -

R&D work in understanding the mechanism of action of steroids, both for their antiinflammatory effects and adverse drug reactions (ADRs) has lead to the development new generation glucocorticoids mainly through prodrug design approach to find use in treating plethora of diseases as mentioned earlier. All these new generation glucocorticoids are not designed for ophthalmic therapeutics. Hence a real breakthrough in the field of ophthalmic therapeutic could be achieved only by specifically designing new drug entities to incorporate the eye targeting possibility into their chemical structure [24,25]. Chemical Delivery Systems (CDSs) and Retrometabolic drug design principles have led to development of a new but unique class of glucocorticoids which are safe and effective in treating a wide variety of ocular inflammatory conditions including giant papillary conjunctivitis, seasonal allergic conjunctivitis, and uveities as well as in the treatment of ocular inflammation and pain following cataract surgery. This new and unique class of glucocorticoids are now known as soft glucocorticoids which are associated with highly

It is pertinent to note that, this important drug design based on Chemical Delivery Systems (CDSs) and Soft drug (SD) approaches integrate the specific pharmacological, metabolic, and targeting requirements for ophthalmic therapeutics. .A number of glucocorticoid soft drugs and soft -blockers have been developed this way for clinical trials. Their potential is already documented by the results obtained with several soft drugs designed within this

Protein

Protein

HO

HO

OH OH

<sup>H</sup> OH <sup>N</sup>


Schiff Base

OH

OH N

O

As discussed earlier several numbers of new entities of glucocorticoids have been developed during the last two decades. Many of them are already in market for their high efficacy and less systemic side effects. These new generation corticosteroids were developed with modifications made in the basic glucocorticoid molecules, *viz*., Betamethasone **1** or Dexamethasone **2** extensively used during early stage of glucocorticoids therapy. The main object of synthesizing these modified glucocorticoids was to get better skin penetration, slower enzyme degradation, and greater affinity for cytosol receptors [5].

Even then in some cases it was observed that the changes that increased potency, also led sometimes to more systemic side effects. As per clinical investigations by various workers, these new generation glucocorticoids have been found to act *via* hepatic or extra hepatic biotransformation. These results in lesser systemic side effects and hence are much safer drugs to be used specially by adults and non- erythrodermic patients. However, while systemic side effects are of concern, cutaneous side effects are generally common involving problems such as striae formation, atrophy, purpura, peri-oral dermatitis, steroid rosacea, hypertrichosis and steroid acne [2,6]. Most of the side effects associated even with these new generation glucocorticoids are basically related to the duration and potency of the application, the manner of application, the presence of penetration-enhancing substances and the state of skin barrier. Besides these, the anatomic site and the age of the patient could also adversely influence the side effect profile [2, 6]. In both drug discovery and

development, prodrug design approach helped to maximize the amount of an active drug to reach its target through changing the physicochemical, pharmacokinetics or biopharmaceutical properties of the drug. Therefore the term prodrug refers to a pharmacologically inactive compound which is converted to an active drug by metabolic biotransformation which may occur prior, during or after absorption or at specific target sites within the body because of their specific molecular configurations [28-30]. The labile `prodrug' corticosteroids such as 17-Prednicarbate, Alclometasone, Methylprednisolone aceponate, Fluticasone Propionate and Fluocortin butylester are some of these new generation glucocorticoids which are developed through prodrug approach [2,6]. Based on the molecular configuration of these new generation glucocorticoids, they are classified into several categories [**Table1**] [2, 6].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 619

Ciclesonide (**8**)

17-Prednicarbate (**9**)

Mometasone furoate (**10)**

Fluticasone propionate (**11)**

HO

**8**

HO

**9**

Cl O O

HO

**11**

O

O

H Cl <sup>O</sup> <sup>H</sup>

> O **10**

> > <sup>S</sup> <sup>O</sup> <sup>F</sup>

**Table 1.** Classification of new generation glucocorticoids on the basis of their molecular configurations

Chemical stability is another criteria for classification of these new generation corticosteroids. Based on this, most of these newer drugs can be regarded as prodrugs because immediately after application to the system, they undergo metabolization and acyl-exchanges to form the active molecule to fight the ailment in the system. As mentioned earlier, all these glucocorticoids have been developed through prodrugs design approach in order to maximize the amount of an active drug reaching its target through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of drugs. Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic or chemical transformation *in vivo* to release the active parent drug, which can then exert the desired pharmacological effect [28-30]. Most of the new generation corticosteroids have been found belonging to the class of molecules

H H F

F

H H H O O

O

O

O

O O

O

O

O

O

O

O O

H

O CH3

O

CH3

O

O

C-17 –Prednicarbonates

Carbothiates


several categories [**Table1**] [2, 6].

C-21-Carboxylesters

Asymmetric acetonides <sup>O</sup>

O

O

O

O

**3**

H H H

F

HO

**4**

HO

**5**

HO

**6**

HO H

<sup>O</sup> **<sup>7</sup>**

development, prodrug design approach helped to maximize the amount of an active drug to reach its target through changing the physicochemical, pharmacokinetics or biopharmaceutical properties of the drug. Therefore the term prodrug refers to a pharmacologically inactive compound which is converted to an active drug by metabolic biotransformation which may occur prior, during or after absorption or at specific target sites within the body because of their specific molecular configurations [28-30]. The labile `prodrug' corticosteroids such as 17-Prednicarbate, Alclometasone, Methylprednisolone aceponate, Fluticasone Propionate and Fluocortin butylester are some of these new generation glucocorticoids which are developed through prodrug approach [2,6]. Based on the molecular configuration of these new generation glucocorticoids, they are classified into

**Molecular Configurations Structures Names** 

O

H HO H H H

> <sup>O</sup> <sup>O</sup> O

> > O

O

H H H Cl

H

Cl

O

O O

OH

O OH OH

H

OH

H H H O

\*

H

CH3

CH3

O

Budesonide (**3)**

Fluocortin butylester (**4)**

Methylprednisolone aceponate (**5)**

Alclometasone dipropionate( **6)**

Beclomethasone (**7**)

OH

**Table 1.** Classification of new generation glucocorticoids on the basis of their molecular configurations

Chemical stability is another criteria for classification of these new generation corticosteroids. Based on this, most of these newer drugs can be regarded as prodrugs because immediately after application to the system, they undergo metabolization and acyl-exchanges to form the active molecule to fight the ailment in the system. As mentioned earlier, all these glucocorticoids have been developed through prodrugs design approach in order to maximize the amount of an active drug reaching its target through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of drugs. Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic or chemical transformation *in vivo* to release the active parent drug, which can then exert the desired pharmacological effect [28-30]. Most of the new generation corticosteroids have been found belonging to the class of molecules having high potency. By introducing various substituents at different positions, changes or modifications were made on the parent hydrocortisone molecules, such as Betamethasone (**1)** and Dexamethasone (2**)** in order to get better skin penetration, slower enzymatic degradation and greater affinity for the cytosol receptor for these molecules to reduce or eliminate their systemic side effects [6]. The systemic side effects of these new corticosteroids are reduced due to rapid biotransformation while applying them for treatment of atopic dermatitis. However it is pertinent to note that there are still risks of having potential hypothalamus and pituitary axis (HPA) suppression with some of these new generation glucocorticoids while treating young children and erythrodermic patients. Clinical safety has been demonstrated in most of these newer corticosteroids with restricted duration of treatment up to six weeks [2, 6]. Even then skin atropy and some telangiectasia have been observed in some patients. A large number of reports of contact allergic reactions associated with these new generation glucocorticoids were still of great concern. To explain the increased allergenicity, data from clinical studies and literature were reviewed to define precisely some of the more important groups of cross-reacting molecules [31]. **Table2** represents the various allergy groups of these newer glucocorticoids based on their molecular structures and configurations. Clinical studies have revealed that Tixocortol pivalate (**19**) has been identified as a good screening agent for the Group A [32]. Budesonide (**3**) is infact a 1:1 mixture of two diasteriomers (R- and S- isomer). The R-isomer has been found to be a marker for the Group B while the S-isomer for the Group D. Glucocorticoid members of Group C cause minimized contact sensitivity and do not cross react with other groups. As shown in **Table2**, Group D has been divided in two sub-groups D1 and D2 based on recent studies [2, 33] with respect to their mode of substitutions.

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 621

HO

H H H

Hydrocortisone-17-butyrate (**14**)

O

S

O HO

O

OH

O

O O

O

OH

To the Group D1, belong not only the old generation glucocorticoid molecules like Betamethasone dipropionate (**15**), Betamethasone-17α-valerate (**16**) and Clobetasol 17α propionate (**17**) but also new generation corticosteroids such as Mometasone furoate (**10**) and Fluticasone propionate (**11**). These glucocorticoids are found to possess very less systemic side effects and so can be used safely even in case of patients who are allergic to other corticosteroids. To the Group D2 belong Hydrocortisone-17α- valerate (**18**) and Hydrocortisone - 17α-butyrate (**14** ) as well as the labile new generation glucocorticoids like 17-Prednicarbate (**9**) and Methylprednisolone Aceponate (**5**). They are sometimes found to cause allergic reactions.

HO

Hydrocortisone (**12)**

O

H H H

HO

H F H

Betamethasone Dipropionate (**15**)

O

HO

O

O

HO

H H H

Hydrocortisone-17-Valerate (**18**)

O

O

O

OH

OH

O

O

O

O

HO

H F H

Triamcinolone (**13**)

O

O

HO

O

OH OH

O

H

F H

Betamethasone-17-Valerate (**16**)

O

HO

O

O

H

Tixocortol pivalate (**19**)

HO

H

H

Cl

O

O

H

F H

Clobetasol-17-Propionate (**17**)

O

OH

O


**Table 2.** Allergy Groups of new generation corticosteroids based on their molecular structures and configurations

To the Group D1, belong not only the old generation glucocorticoid molecules like Betamethasone dipropionate (**15**), Betamethasone-17α-valerate (**16**) and Clobetasol 17α propionate (**17**) but also new generation corticosteroids such as Mometasone furoate (**10**) and Fluticasone propionate (**11**). These glucocorticoids are found to possess very less systemic side effects and so can be used safely even in case of patients who are allergic to other corticosteroids. To the Group D2 belong Hydrocortisone-17α- valerate (**18**) and Hydrocortisone - 17α-butyrate (**14** ) as well as the labile new generation glucocorticoids like 17-Prednicarbate (**9**) and Methylprednisolone Aceponate (**5**). They are sometimes found to cause allergic reactions.

620 Glucocorticoids – New Recognition of Our Familiar Friend

recent studies [2, 33] with respect to their mode of substitutions.

D Hydrocortisone-17αbutyrate(14) type

> Betamethasone Dipropionate(15)

Betamethasone17α-Valerate (16) Clobetasol 17α -Propionate (17) Mometasone Furoate (10) Fluticasone Propionate (11)

> Hydrocortisone-17αbutyrate(14)

Hydrocortisone 17α-Valerate (18) 17-Prednicarbate (9) Methylprednisolone Aceponate (5)

D1

D2

configurations

**Group Molecular configuration Characteristics of substituent**

B Triamcinolone (13 ) type C-16,C-17-*cis*-ketal or –diol structure

Fluocortin Butylester (4) chain at C-21.

A Hydrocortisone (12) type No substitution in D ring, except a short chain ester on C-17 or C-

<sup>C</sup>Betamethasone (1) type C-16 methyl substitution, no side chain on C-17; possible side

**Table 2.** Allergy Groups of new generation corticosteroids based on their molecular structures and

21 or a thioester on C-21

Long chain ester at C-17 and/or C-21 with or without C-16 methyl substitution.

Long chain ester at C-17 and/or C-21 with C-16 methyl substitution; halogen substituent in ring B

Long chain ester at C-17; possibly a side chain at C-21; no methyl substitution at C-16 and no halogen substituent in ring B.

having high potency. By introducing various substituents at different positions, changes or modifications were made on the parent hydrocortisone molecules, such as Betamethasone (**1)** and Dexamethasone (2**)** in order to get better skin penetration, slower enzymatic degradation and greater affinity for the cytosol receptor for these molecules to reduce or eliminate their systemic side effects [6]. The systemic side effects of these new corticosteroids are reduced due to rapid biotransformation while applying them for treatment of atopic dermatitis. However it is pertinent to note that there are still risks of having potential hypothalamus and pituitary axis (HPA) suppression with some of these new generation glucocorticoids while treating young children and erythrodermic patients. Clinical safety has been demonstrated in most of these newer corticosteroids with restricted duration of treatment up to six weeks [2, 6]. Even then skin atropy and some telangiectasia have been observed in some patients. A large number of reports of contact allergic reactions associated with these new generation glucocorticoids were still of great concern. To explain the increased allergenicity, data from clinical studies and literature were reviewed to define precisely some of the more important groups of cross-reacting molecules [31]. **Table2** represents the various allergy groups of these newer glucocorticoids based on their molecular structures and configurations. Clinical studies have revealed that Tixocortol pivalate (**19**) has been identified as a good screening agent for the Group A [32]. Budesonide (**3**) is infact a 1:1 mixture of two diasteriomers (R- and S- isomer). The R-isomer has been found to be a marker for the Group B while the S-isomer for the Group D. Glucocorticoid members of Group C cause minimized contact sensitivity and do not cross react with other groups. As shown in **Table2**, Group D has been divided in two sub-groups D1 and D2 based on

Hydrocortisone-17-Valerate (**18**)

Tixocortol pivalate (**19**)

S-isomer of Budesonide (**3**) is the marker for this Group D2, but they can cross react with the Group A. **Table 3** illustrates the safety profile, potency , side effects and allergy groups of some of the new generation glucocorticoids along with their manufactures.

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 623

> Contact hypersensitivity is very rare

> Contact hypersensitivity is very rare

> Contact hypersensitivity is rare

D1

D1

D1

*-Blockers* 

High potency

High potency

High Potency

Fluticasone propionate (11)

Beclomethasone(7)

Cyclesonide (8)

*and Soft Glucocorticoids* 

Cutivate, Glaxo Wellcome

Schwitz Biotech, Havione Farmaciencies, Portugal

Brand Name: Alvesco, Taj Pharmaceuticals Ltd. India

A fluorinated topical glucocorticoid. Readily metabolized in the liver resulting in a locally potent sterid drug with a low HPA inhibitory potency

A chlorinated topical corticosteroid. Readily metabolized in the liver resulting in a locally potent steroid with a low HPA inhibitory potency

A triamcinolone type Glucocorticoid with low HPA inhibitory potency

Continuous efforts are still being still sought after by pharmaceutical companies worldwide to develop and market more and more safer glucocorticoids as anti-inflammatory agents, because clinical investigations on some already marketed newer glucocorticoids have revealed that many of them are still prone to cause allergic reactions and other systemic side effects specially on prolonged use. However, glucocorticoids are still regarded as life saving drugs dominating over the other anti-inflammatory agents for the treatment of a number of

Soft corticosteroids or Soft glucocorticoids can be termed as a unique class of new generation glucocorticoids that are designed specifically for ophthalmic therapeutics [24- 27]. The new generation glucocorticoids developed by prodrug approach as described earlier have brought revolution in treating a plethora of disease including psoriasis, allergies, asthma, rheumatoid arthritis and lupus because of their minimized systemic side effects. However, these new generation glucocorticoids are still not useful for ophthalmic applications due to their association with adverse drug reactions (ADRs) including elevation of intraocular pressure (IOP) and steroid-induced cataract formation [23] in ophthalmic applications. For the therapeutic treatment of most of ocular problems, topical

**Table 3.** Some of the marketed new generation glucocorticoids and their allergy groups:

diseases including psoriasis, allergies, acute asthma, rheumatoid arthritis and lupus.

*Eye–targeted Chemical Delivery Systems (CDSs) and retrometabolic drug design: Soft* 



Budesonide(3) Astra, Entcort

Schering-Plough, Elocom

Schering Corp.- Essex, Varlane

Schering-Plough, Aclovate, Glaxo- welcome

Hoechst-Roussel,Dermatop Emollient

Schering Corp. Essex, Advantan

Mometasone Furoate (10)

Fluocortin butylester(4)

Alclometasone dipropionate(6)

17-Prednicarbate( 9)

Methylprednisolone aceponate(5)

S-isomer of Budesonide (**3**) is the marker for this Group D2, but they can cross react with the Group A. **Table 3** illustrates the safety profile, potency , side effects and allergy groups of

**Product Manufacturer Safety profile Potency Side effect Allergygroup** 

High potency

High potency

Medium potency

High potency

High potency

High potency May be problem with contact sensitivity

Very rare contact hypersensitivity

> Rare contact hypersensitivity

Occasional Contact hypersensitivity

Contact hypersensitivity is observed. Also can cross-react with the Group A

Contact hypersensitivity is not rare

B

D1

C

D2

D2

D2

A Stable asymmetric acetonide undergoing rapid biotransformation in liver with less systemic side effects

A stable chlorinated topical glucocorticoid with low penetration with high biliary excretion, and also low resorption in the circulation with fast biotransformation in the liver resulting in rare local systemic side effect.

Biotransformation into the non- active fluocortolone-21 acid in skin.

A labile prodrug metabolizing to inactive compound

A labile prodrug glucocorticoid, converting to prednisolone in the skin

A labile prodrug. Get transformed into methyl prednisolone in the skin and into nonactive derivatives in the liver

some of the new generation glucocorticoids along with their manufactures.


Continuous efforts are still being still sought after by pharmaceutical companies worldwide to develop and market more and more safer glucocorticoids as anti-inflammatory agents, because clinical investigations on some already marketed newer glucocorticoids have revealed that many of them are still prone to cause allergic reactions and other systemic side effects specially on prolonged use. However, glucocorticoids are still regarded as life saving drugs dominating over the other anti-inflammatory agents for the treatment of a number of diseases including psoriasis, allergies, acute asthma, rheumatoid arthritis and lupus.

#### *Eye–targeted Chemical Delivery Systems (CDSs) and retrometabolic drug design: Soft -Blockers and Soft Glucocorticoids*

Soft corticosteroids or Soft glucocorticoids can be termed as a unique class of new generation glucocorticoids that are designed specifically for ophthalmic therapeutics [24- 27]. The new generation glucocorticoids developed by prodrug approach as described earlier have brought revolution in treating a plethora of disease including psoriasis, allergies, asthma, rheumatoid arthritis and lupus because of their minimized systemic side effects. However, these new generation glucocorticoids are still not useful for ophthalmic applications due to their association with adverse drug reactions (ADRs) including elevation of intraocular pressure (IOP) and steroid-induced cataract formation [23] in ophthalmic applications. For the therapeutic treatment of most of ocular problems, topical administration undoubtedly seems preferred mode, because for systemically administered drugs, only a very small fraction of the total dose will reach the eye from the general circulatory system. Even distribution for this fraction to the inside of the eye is further hindered by the blood-retinal barrier (BRB), which is almost as effective as blood-brain barrier (BBB) in restricting the passage of xenobiotics from the blood stream [34]. Therefore despite its apparent accessibility, the eye, in fact, is well protected against the absorption of foreign materials, including drug molecules, by the eyelids, by flow of tears, and also by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other side as mentioned above [24]. Because of this a significant portion of the applied drug is absorbed through nasolacrimal duct and the mucosal membranes of the nasal, oropharyngeal, and gastrointestinal tract to pass to the system. It has been found that no more than 2% of medication introduced topically to the eye is adsorbed [35-37]. Again clinical studies by various workers reveal that the main biological barrier for penetration to the eye is represented by the cornea. The relatively lipophilic corneal epithelium tissue having low porosity and high tortuosity due to tight annular junctions, is the primary barrier for hydrophilic drugs, where as the middle stromal layer consisting mainly of water interspersed with collagen fibrils( major thickness of cornea), is the main barrier for the lipophilic drugs [38-41]. All these facts result not only in a low net eye drug delivery, but also in substantial systemic availability of ophthalmic drugs after

Travoprost (**23**)

Prostaglandin F2 (**24**)

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 625

design approaches have been tried to eliminate the problems of low ocular delivery and potential for substantial systemic side effects [6, 43]. It has been found that prodrug approach here had some limitations. Prodrugs are pharmacologically not active (or may be weakly active) compounds that results from transient chemical modifications of biologically active species, so that they are metabolically transformed into effective drugs following administration [28-30, 44-47]. Compared with the original structures, prodrug structures incorporate chemical modifications to get improvement in some deficient physiological properties, such as membrane permeability or water solubility or to overcome some other problems like rapid elimination, bad taste, a formulation difficulty etc. After administration, the prodrug because of its improved characteristics, is more systemically or locally available than the parent drug. However the prodrug must undergo chemical or biochemical conversion to the active form before exerting its biological effect. Some of the marketed ophthalmic prodrugs include Dipivefrine (**21**)-the dipivalate ester prodrug of epinephrine (**20**), latanoprost (**22**) and travoprost (**23**) -isopropyl ester prodrugs that are prostaglandin

Because of the adverse drug reactions (ADRs) associated even with the new generation glucocorticoids in ocular treatment, the real breakthrough in the area of ophthalmic therapeutics could be achieved only by specifically designing new drugs with their ophthalmic applications in mind, so that the possibility of eye targeting with reduced systemic side effects is already incorporated in their chemical structures. In an effort to minimize ADRs and other complicacies associated with glucocorticoids, Bodor and his colleagues for the first time have developed the concept of retrometabolic drug design for ophthalmic therapeutics to introduce a new and unique class of glucocorticoids now known as soft corticosteroids or soft glucocorticoids that helped in developing glucocorticoid soft drugs for ophthalmic use [24, 48-50]. Soft -blockers are also falling in this soft drug category. The concept of soft drugs has been originated from the pioneer work of Prof. N Bodor and his co-workers at the Center for Drug Discovery, University of Florida, Health Science Center, Gainesville, FL 32610-0497, USA [24, 48-50]. The possibility of developing these soft drugs has been extensively studied along the lines of retro- metabolic drug design for two important classes of ophthalmic drugs, - blockers and glucocorticoids [24]. The underlying principle of retrometabolic drug design involves synthesizing analogs of lead molecules or reference molecules, starting from one of the known inactive metabolites of that lead compound. The inactive metabolite is then converted to an isosteric or isoelectronic analog with structural modifications designed for a rapid and predictable metabolism back to the original inactive metabolite after exerting the desired therapeutic effect at the site (**Figure 2**) [24, 26]. These analogs or soft drugs were predicted to have therapeutic potential similar to that of the lead compound, but because of the structural modifications provided by the design, any active drug remaining after attainment of the therapeutic effect would be metabolically deactivated, thus reducing adverse drug reactions (ADRs) [24, 26, 48-51]. According to Prof Bodor, in developing soft drugs the goal is not to avoid metabolism but rather to control and direct it. Inclusion of a metabolically sensitive moiety into the parent drug molecule can make possible the design and prediction of the major metabolic pathway

F2α (**24**) analogs [24].

*Retrometabolic Drug Design:* 

topical administration giving systemic side effects [42]. Moreover as mentioned earlier, existing ophthalmic drugs are actually not developed for ocular applications, they were intended for other therapeutic areas which were later converted to ocular applications following their high efficacy. This further has decreased the likelihood of achieving eyespecific delivery along with reduced systemic side effects. In view of this, various drug design approaches have been tried to eliminate the problems of low ocular delivery and potential for substantial systemic side effects [6, 43]. It has been found that prodrug approach here had some limitations. Prodrugs are pharmacologically not active (or may be weakly active) compounds that results from transient chemical modifications of biologically active species, so that they are metabolically transformed into effective drugs following administration [28-30, 44-47]. Compared with the original structures, prodrug structures incorporate chemical modifications to get improvement in some deficient physiological properties, such as membrane permeability or water solubility or to overcome some other problems like rapid elimination, bad taste, a formulation difficulty etc. After administration, the prodrug because of its improved characteristics, is more systemically or locally available than the parent drug. However the prodrug must undergo chemical or biochemical conversion to the active form before exerting its biological effect. Some of the marketed ophthalmic prodrugs include Dipivefrine (**21**)-the dipivalate ester prodrug of epinephrine (**20**), latanoprost (**22**) and travoprost (**23**) -isopropyl ester prodrugs that are prostaglandin F2α (**24**) analogs [24].

#### *Retrometabolic Drug Design:*

624 Glucocorticoids – New Recognition of Our Familiar Friend

N

OH

Travoprost (**23**)

HO

O

O

O

Dipivefrine (**21**)

OH

OH HO <sup>H</sup>

Epinephrine (**20**)

HO

F3C

administration undoubtedly seems preferred mode, because for systemically administered drugs, only a very small fraction of the total dose will reach the eye from the general circulatory system. Even distribution for this fraction to the inside of the eye is further hindered by the blood-retinal barrier (BRB), which is almost as effective as blood-brain barrier (BBB) in restricting the passage of xenobiotics from the blood stream [34]. Therefore despite its apparent accessibility, the eye, in fact, is well protected against the absorption of foreign materials, including drug molecules, by the eyelids, by flow of tears, and also by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other side as mentioned above [24]. Because of this a significant portion of the applied drug is absorbed through nasolacrimal duct and the mucosal membranes of the nasal, oropharyngeal, and gastrointestinal tract to pass to the system. It has been found that no more than 2% of medication introduced topically to the eye is adsorbed [35-37]. Again clinical studies by various workers reveal that the main biological barrier for penetration to the eye is represented by the cornea. The relatively lipophilic corneal epithelium tissue having low porosity and high tortuosity due to tight annular junctions, is the primary barrier for hydrophilic drugs, where as the middle stromal layer consisting mainly of water interspersed with collagen fibrils( major thickness of cornea), is the main barrier for the lipophilic drugs [38-41]. All these facts result not only in a low net eye drug delivery, but also in substantial systemic availability of ophthalmic drugs after

N

O

O

topical administration giving systemic side effects [42]. Moreover as mentioned earlier, existing ophthalmic drugs are actually not developed for ocular applications, they were intended for other therapeutic areas which were later converted to ocular applications following their high efficacy. This further has decreased the likelihood of achieving eyespecific delivery along with reduced systemic side effects. In view of this, various drug

Ho

HO

HO

O

O

OH

O

OH Latanoprost (**22**)

OH OH

Prostaglandin F2 (**24**)

OH O H Because of the adverse drug reactions (ADRs) associated even with the new generation glucocorticoids in ocular treatment, the real breakthrough in the area of ophthalmic therapeutics could be achieved only by specifically designing new drugs with their ophthalmic applications in mind, so that the possibility of eye targeting with reduced systemic side effects is already incorporated in their chemical structures. In an effort to minimize ADRs and other complicacies associated with glucocorticoids, Bodor and his colleagues for the first time have developed the concept of retrometabolic drug design for ophthalmic therapeutics to introduce a new and unique class of glucocorticoids now known as soft corticosteroids or soft glucocorticoids that helped in developing glucocorticoid soft drugs for ophthalmic use [24, 48-50]. Soft -blockers are also falling in this soft drug category. The concept of soft drugs has been originated from the pioneer work of Prof. N Bodor and his co-workers at the Center for Drug Discovery, University of Florida, Health Science Center, Gainesville, FL 32610-0497, USA [24, 48-50]. The possibility of developing these soft drugs has been extensively studied along the lines of retro- metabolic drug design for two important classes of ophthalmic drugs, - blockers and glucocorticoids [24]. The underlying principle of retrometabolic drug design involves synthesizing analogs of lead molecules or reference molecules, starting from one of the known inactive metabolites of that lead compound. The inactive metabolite is then converted to an isosteric or isoelectronic analog with structural modifications designed for a rapid and predictable metabolism back to the original inactive metabolite after exerting the desired therapeutic effect at the site (**Figure 2**) [24, 26]. These analogs or soft drugs were predicted to have therapeutic potential similar to that of the lead compound, but because of the structural modifications provided by the design, any active drug remaining after attainment of the therapeutic effect would be metabolically deactivated, thus reducing adverse drug reactions (ADRs) [24, 26, 48-51]. According to Prof Bodor, in developing soft drugs the goal is not to avoid metabolism but rather to control and direct it. Inclusion of a metabolically sensitive moiety into the parent drug molecule can make possible the design and prediction of the major metabolic pathway preventing the formation of undesired toxic, active, or high-energy intermediates. It is desired that, If possible, inactivation should take place as the result of a single, low- energy and high- capacity step that gives the inactive species subject to rapid elimination. Most critical metabolic pathways in a biological system are mediated by *oxygenases*, a consequence of the fact that the normal reaction of an organism to a foreign material is to burn it up as food [52]. However *oxygenases* exhibit not only interspecies, but also inter individual and are subject to inhibition and induction (24) and because the rates of hepatic *mono-oxygenases* reactions are at least two orders of magnitude lower than the slowest of the other enzymatic reactions [53,54], it is usually desirable to avoid oxidative pathways as well as these slow, easily saturable *oxidase*s. In view of this, the design of soft drugs must be based on moieties activated by hydrolytic enzymes. Rapid metabolism could be more reliably performed by these ubiquitously distributed *esterases*. Bodor et al (26) suggested that it is desirable not to rely exclusively on metabolism by organs such as kidney or liver to have an additional advantage because blood flow and enzyme activities in these organs can be fatally damaged in critically ill patients. However, the increase in the therapeutic index can only be achieved if the drug is stable enough to reach its receptor site to deliver the desired effect, and any free drug remaining thereafter should be metabolized to minimize ADRs [24].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 627

> R=H, Oxime dvt R=Me, Methoxime dvt

> > N N OR

> > > H N

(s) Alcohol S-(-) Isomer (active)

OH

O N H N

> N OR

R=H, Oxime dvt R=Me, Methoxime dvt

**32**

<sup>O</sup> <sup>O</sup> <sup>H</sup>

Ar O

N S N

ketone reductase

Oximation

 Enzymatic Reduction (Stereospecific) in eye

systemic enzyme

tissues

29a R=H, Oxime dvt. 29b, R=Me, Methoxime dvt.

<sup>O</sup> <sup>H</sup> N

N OR

CH2

O

<sup>O</sup> <sup>H</sup> N

OH

Alprenolol (**25**) <sup>O</sup> <sup>O</sup> <sup>H</sup>

Betaxolol (**26**)

Ar <sup>O</sup>

Ar <sup>O</sup>

N S N

Timolol (**27**)

Z(syn)

O

E (anti)

*Soft-*  H N

activation of their oximes and alkyl oximes.

<sup>N</sup> OR

Oxime (R=H) or Methoxime (R=CH3)

of **28** or **29**

*-Blockers:* 

**31**

(inactive)

H N

O N OH

H N

N RO

CH2

N

Oxdn.

Oxdn.

Oxdn.

O

Oxime hydrolase

systemic enzyme

Ar <sup>O</sup>

<sup>O</sup> <sup>H</sup> N

Betaxolone (**29**)

N S N

Timolone (**30**)

O

CH2 Alprenolone (**28**)

<sup>O</sup> <sup>O</sup> <sup>H</sup>

O N H N

O

H N

O

**Figure 3.** Site- and Stereospecific delivery of -adrenergic antagonists to the eye through sequential

As because soft drug design is a general concept, topically applied soft drugs that show local activity with reduced systemic side effects could become potential therapeutics for any ocular diseases [24]. During the last three decades, Bodor and his colleagues have applied retrometabolic drug design to a variety of therapeutic agents such as - blockers, antimicrobials, analgesics, and acetyl *cholinesterase* (ACE) inhibitors and were successful in developing retrometabolically designed compounds with market potential. As for example, in addition to the oxime or methoxime -blocker analogs, the development of soft blockers could represent another possible route toward improved and safer antiglaucoma agents [54-62]. Several oxime and methoxime analogs of known -Adrenergic blockers such as Alprenolol (**25**), Betaxolol (**26**)l, Timolol (**27**) etc. were synthesized from their respective ketone derivatives, *viz*., Alprenolone (**28**), Betaxolone (**29**), Timolone (**30**) and studied clinically [54-62]. They are potential drugs which have been developed applying general retrometabolic drug design principle and can be recognized as site-specific enzymatic

ketone (inactive) N

Oximation

O

Oximation

OH

**Figure 2.** Retrometabolic drug design approach: Synthesis of new lead molecules (Soft drugs) based on an inactive metabolite of an original lead molecule

#### Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 627

**Figure 3.** Site- and Stereospecific delivery of -adrenergic antagonists to the eye through sequential activation of their oximes and alkyl oximes.

#### *Soft- -Blockers:*

626 Glucocorticoids – New Recognition of Our Familiar Friend

preventing the formation of undesired toxic, active, or high-energy intermediates. It is desired that, If possible, inactivation should take place as the result of a single, low- energy and high- capacity step that gives the inactive species subject to rapid elimination. Most critical metabolic pathways in a biological system are mediated by *oxygenases*, a consequence of the fact that the normal reaction of an organism to a foreign material is to burn it up as food [52]. However *oxygenases* exhibit not only interspecies, but also inter individual and are subject to inhibition and induction (24) and because the rates of hepatic *mono-oxygenases* reactions are at least two orders of magnitude lower than the slowest of the other enzymatic reactions [53,54], it is usually desirable to avoid oxidative pathways as well as these slow, easily saturable *oxidase*s. In view of this, the design of soft drugs must be based on moieties activated by hydrolytic enzymes. Rapid metabolism could be more reliably performed by these ubiquitously distributed *esterases*. Bodor et al (26) suggested that it is desirable not to rely exclusively on metabolism by organs such as kidney or liver to have an additional advantage because blood flow and enzyme activities in these organs can be fatally damaged in critically ill patients. However, the increase in the therapeutic index can only be achieved if the drug is stable enough to reach its receptor site to deliver the desired effect, and any

free drug remaining thereafter should be metabolized to minimize ADRs [24].

**Highly Minimized Adverse Drug Reactions** 

**Figure 2.** Retrometabolic drug design approach: Synthesis of new lead molecules (Soft drugs) based on

**Metabolism** 

**Active Metabolites** 

**Original Lead Molecule** 

**Adverse Drug Reaction**

an inactive metabolite of an original lead molecule

**Retrometabolic** 

**Metabolism** 

**Drug Design Metabolism** 

**Inactive Metabolites** 

**New Lead Molecules or Soft Drugs** 

> As because soft drug design is a general concept, topically applied soft drugs that show local activity with reduced systemic side effects could become potential therapeutics for any ocular diseases [24]. During the last three decades, Bodor and his colleagues have applied retrometabolic drug design to a variety of therapeutic agents such as - blockers, antimicrobials, analgesics, and acetyl *cholinesterase* (ACE) inhibitors and were successful in developing retrometabolically designed compounds with market potential. As for example, in addition to the oxime or methoxime -blocker analogs, the development of soft blockers could represent another possible route toward improved and safer antiglaucoma agents [54-62]. Several oxime and methoxime analogs of known -Adrenergic blockers such as Alprenolol (**25**), Betaxolol (**26**)l, Timolol (**27**) etc. were synthesized from their respective ketone derivatives, *viz*., Alprenolone (**28**), Betaxolone (**29**), Timolone (**30**) and studied clinically [54-62]. They are potential drugs which have been developed applying general retrometabolic drug design principle and can be recognized as site-specific enzymatic

chemical delivery systems (CDSs) [54-62]. In these compounds, a -amino oxime or alkyloxime function replaces the corresponding -amino alcohol pharmacore part of the original molecules (**Figure 3**). These oxime or alkyloxime derivatives (**31**) are found to exist in Z (syn) or E (anti) configuration. They are hydrolyzed within the eye by enzymes located in the iris-cillary body and subsequently again by reductive enzymes present there producing only the active S- (-) stereoisomeric alcohol (**32**) of the corresponding -blockers [54]. For aryl -amino alcohol-type -adrenergic agonists and antagonists, most of the activity has been known to be

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 629

Again as Prof. Bodor and his team suggest [24,26], soft drugs (SDs) represent a different, conceptually opposite targeting concept; whereas eye-targeting CDSs, represented here by the above discussed oxime analogs, are inactive compounds designed to achieve the targeted effects *via* a multi-step activation process by enzymes found at their intended site of action. However soft drugs represented by -blockers or glucocorticoids are active compounds designed to achieve the targeted effects *via* a single-step inactivation process involving enzymes found ubiquitously in the systemic circulation. Because in this class, inactive metabolite based soft drugs can be achieved introducing the hydrolytically sensitive functionality at a flexible pharmacophore region, there is considerable freedom for structural modifications. As a result, transport and metabolism properties are easier to control. From the various soft -blockers developed along these lines by Bodor and Buchwald [24], Adaprolol (**33**), an adamantane ethyl ester was selected as a potential candidate for a new topical antiglaucoma agent [24 ]. The metabolism of the well-known blocker Metoprolol (**34**) has been compared with that of the soft -blocker Adaprolol which has been designed starting from one of Metoprolol`s inactive acid metabolite (**35**), *viz*., phenyl acetic acid (**Figure 4**). Its other metabolites include -hydroxymetoprolol (**36)** and O-Dimethylmetoprolol (**37**) both of which are active. Another inactive metabolite includes the acid derivative **38.** Adaprolol was chosen because of the fact that if membrane transport (lipophilicity) and relative stability are important for pharmacological activity as they are needed to achieve right corneal permeability, then the ester goup should be relatively lipophilic and should provide ester stability [66-70]. In clinical trials Adaprolol (**33**) indeed produced prolonged and significant IOP-reduction while hydrolyzed relatively fast [67, 68]. Therefore, it was possible to separate local activity from undesired systemic cardiovascular or pulmonary activity, a characteristic highly desirable in development of antiglaucoma therapy [24]. Adaprolol (**33**) could be now a potent antiglaucoma soft -blocker to replace the traditional -blocker Metoprolol (**34**). Further clinical studies confirmed that Adaprolol is not only effective in reducing intraocular pressure (IOP) but also has a safer cardiovascular profile than Timolol (**27**) because unlike Timolol, Adaprolol did not reduce

Along the line of soft -blockers, development of soft anti-inflammatory glucocorticoids represents a promising and successful ophthalmic drug design area initiated by Bodor and his colleagues [24,26]. Inflammation in the eye could result from surgery, injury, infection, conjunctivitis, or uvitis-conditions that can cause severe discomfort even leading to loss of vision. As mentioned earlier, topical glucocorticoids represent an important class of molecules to treat ocular inflammations and allergies as they are the most effective antiinflammatory compounds offering the broadest range of treatment. However a number of contradictions limit their usefulness severely [12]. In addition to the general systemic side effects or adverse drug reactions (ADRs) associated with these glucocorticoids, they also cause several ocular complications such as IOP-elevation resulting steroid- induced glaucoma, induction of cataract formation and other secondary complications [12, 71]. In this context design of soft anti-inflammatory glucocorticoids has been one of the most active

the systolic blood pressure [24].

*Glucocorticoid Soft Drugs: Ophthalmic Therapeutics* 

**Figure 4.** Inactive Metabolite-based Soft Drug Design: Comparison of the structure and metabolism of the soft -blocker Adaprolol (23) with that of the traditional -blocker Metoprolol(24).

present with the S- (-) stereoisomer [63-65], possibly because this isomer allows better interaction of all three important functionalities (aromatic, amino and -hydroxyl moieties) with the -adrenoceptor. In fact these oxime and alkyloxime derivatives have been found to exhibit significant intraocular pressure (IOP) lowering activity, but even their intravenous administration did not produce the active -blocker metabolically; as a result they are void of any cardiovascular activity, which has been found to be a major drawback of classical antiglaucoma agents [26].

According to Bodor and his team [24], the oxime-type CDS approach clearly demonstrates the site- specific or site-enhanced drug delivery through sequential, multi-step enzymatic and/or chemical transformations through a targetor moiety that is converted into a biologically active function by enzymatic reactions which take place primarily at the site of action as a result of differential distribution of some enzymes found in the eye [24].

Again as Prof. Bodor and his team suggest [24,26], soft drugs (SDs) represent a different, conceptually opposite targeting concept; whereas eye-targeting CDSs, represented here by the above discussed oxime analogs, are inactive compounds designed to achieve the targeted effects *via* a multi-step activation process by enzymes found at their intended site of action. However soft drugs represented by -blockers or glucocorticoids are active compounds designed to achieve the targeted effects *via* a single-step inactivation process involving enzymes found ubiquitously in the systemic circulation. Because in this class, inactive metabolite based soft drugs can be achieved introducing the hydrolytically sensitive functionality at a flexible pharmacophore region, there is considerable freedom for structural modifications. As a result, transport and metabolism properties are easier to control. From the various soft -blockers developed along these lines by Bodor and Buchwald [24], Adaprolol (**33**), an adamantane ethyl ester was selected as a potential candidate for a new topical antiglaucoma agent [24 ]. The metabolism of the well-known blocker Metoprolol (**34**) has been compared with that of the soft -blocker Adaprolol which has been designed starting from one of Metoprolol`s inactive acid metabolite (**35**), *viz*., phenyl acetic acid (**Figure 4**). Its other metabolites include -hydroxymetoprolol (**36)** and O-Dimethylmetoprolol (**37**) both of which are active. Another inactive metabolite includes the acid derivative **38.** Adaprolol was chosen because of the fact that if membrane transport (lipophilicity) and relative stability are important for pharmacological activity as they are needed to achieve right corneal permeability, then the ester goup should be relatively lipophilic and should provide ester stability [66-70]. In clinical trials Adaprolol (**33**) indeed produced prolonged and significant IOP-reduction while hydrolyzed relatively fast [67, 68]. Therefore, it was possible to separate local activity from undesired systemic cardiovascular or pulmonary activity, a characteristic highly desirable in development of antiglaucoma therapy [24]. Adaprolol (**33**) could be now a potent antiglaucoma soft -blocker to replace the traditional -blocker Metoprolol (**34**). Further clinical studies confirmed that Adaprolol is not only effective in reducing intraocular pressure (IOP) but also has a safer cardiovascular profile than Timolol (**27**) because unlike Timolol, Adaprolol did not reduce the systolic blood pressure [24].

#### *Glucocorticoid Soft Drugs: Ophthalmic Therapeutics*

628 Glucocorticoids – New Recognition of Our Familiar Friend

activity has been known to be

O

O

(**34**)

Metabolism

O N H

OH H

O

O

H N OH

(**37**)

O

O

HO


antiglaucoma agents [26].

chemical delivery systems (CDSs) [54-62]. In these compounds, a -amino oxime or alkyloxime function replaces the corresponding -amino alcohol pharmacore part of the original molecules (**Figure 3**). These oxime or alkyloxime derivatives (**31**) are found to exist in Z (syn) or E (anti) configuration. They are hydrolyzed within the eye by enzymes located in the iris-cillary body and subsequently again by reductive enzymes present there producing only the active S- (-) stereoisomeric alcohol (**32**) of the corresponding -blockers [54]. For aryl -amino alcohol-type -adrenergic agonists and antagonists, most of the

Metoprolol (inactive) (**38**)

Metabolism

Metabolism

H N OH

Adaprolol (**33**) Inactive Metabolite

**Figure 4.** Inactive Metabolite-based Soft Drug Design: Comparison of the structure and metabolism of

present with the S- (-) stereoisomer [63-65], possibly because this isomer allows better interaction of all three important functionalities (aromatic, amino and -hydroxyl moieties) with the -adrenoceptor. In fact these oxime and alkyloxime derivatives have been found to exhibit significant intraocular pressure (IOP) lowering activity, but even their intravenous administration did not produce the active -blocker metabolically; as a result they are void of any cardiovascular activity, which has been found to be a major drawback of classical

According to Bodor and his team [24], the oxime-type CDS approach clearly demonstrates the site- specific or site-enhanced drug delivery through sequential, multi-step enzymatic and/or chemical transformations through a targetor moiety that is converted into a biologically active function by enzymatic reactions which take place primarily at the site of

action as a result of differential distribution of some enzymes found in the eye [24].

the soft -blocker Adaprolol (23) with that of the traditional -blocker Metoprolol(24).

Metabolism

HO

HO O

O

O

O-demethylmetoprolol (**36**)

Metoprolol, Acid Metabolite 2

O

O O OH

Metoprolol, Acid Metabolite 1

H N OH

Metabolism

OH

H N OH

(**35**)

Along the line of soft -blockers, development of soft anti-inflammatory glucocorticoids represents a promising and successful ophthalmic drug design area initiated by Bodor and his colleagues [24,26]. Inflammation in the eye could result from surgery, injury, infection, conjunctivitis, or uvitis-conditions that can cause severe discomfort even leading to loss of vision. As mentioned earlier, topical glucocorticoids represent an important class of molecules to treat ocular inflammations and allergies as they are the most effective antiinflammatory compounds offering the broadest range of treatment. However a number of contradictions limit their usefulness severely [12]. In addition to the general systemic side effects or adverse drug reactions (ADRs) associated with these glucocorticoids, they also cause several ocular complications such as IOP-elevation resulting steroid- induced glaucoma, induction of cataract formation and other secondary complications [12, 71]. In this context design of soft anti-inflammatory glucocorticoids has been one of the most active

and productive fields of soft drug design. Ophthalmic use of glucocorticoids usually causes increased intraocular pressure (IOP) as a result of increased resistance to aqueous humour outflow. The design of soft anti-inflammatory glucocorticoids has been one of the most important and most successful areas of Soft Drug design. Although the soft nature of such drugs are mainly associated with fast hydrolytic degradation, in fact it is not necessarily be so as Bodor and his co-workers suggested [24].Too much rapid hydrolysis may in fact result in weak activity. The desired increase of therapeutic index can be obtained only if the drug is sufficiently stable to reach the receptor sites at the target organ to produce the desired effect, but the free, non-protein-bound drug undergoes facile hydrolysis to avoid undesired systemic side effects. Therefore to develop a soft drug and hence separating successfully the desired local activity from systemic toxicity, an adequate balance between intrinsic activity, solubility/lipophilicity, tissue distribution, protein binding and rate of metabolic deactivation have to be achieved. In the case of slow, sustained release to the general circulatory system from delivery site, even a relatively slow hydrolysis could result in a very low, almost steady-state systemic concentration [24]. Based on these concepts of eyetargeting chemical delivery systems (CDSs) and retrometabolic drug design approaches, Bodor and his group was successful in developing glucocorticoid soft drugs for ophthalmic therapeutics having potential market value.

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 631

HO

HOOC

H

H H

OH

O

that the best substituent for maximal therapeutic activity included a haloester at 17 position and a carbonate or ether moiety at 17 position. Incorporation of 17 carbonates or ether was preferred over 17 esters to increase stability and to prevent potential formation of mixed anhydrides by reaction of a 17 ester with a 17 acid functionality and subsequent potential for lens protein binding leading to steroid- induced cataract formation.

HO OH

O

CHO

O

O O

R21: alkyl, Alkoxyalkyl, COOalkyl etc.

1,2 : Double bond (present or absent)

X9

HO

X6

R17: Alkyl, Haloalkyl etc.

R16: H, CH3etc. X6, X9: H, F etc. O R17

R16

R21

C-21 Aldehyde C-21 Acid ( Cortisolic Acid)

H

H H

**Figure 5.** Oxidative metabolism of hydrocortisone by local esterases into C-21 Aldehyde and C-21 Acid

Therefore in addition to the C-20 ketone functionality of prednisolone being replaced to eliminate the possibility of Schiff base intermediates, other chemical features associated with cataracterogenesis were also eliminated by the proposed design. The carbonates were expected to be less reactive than the corresponding esters due to the lower electrophilicity of

O

1,2

**Loteprednol Etabonate**(**41**) **1st Generation Soft Glucocorticoid Analogs** (**42**)

**Figure 6.** Design of 1st Generation Cortienic acid-based Glucocorticoid Soft Drugs (**42**) with their

[o] [o]

HO

19

1

<sup>3</sup> <sup>4</sup> <sup>5</sup>

(Cortisolic Acid)

Hydrocortisone

the carbonyl carbon [24].

HO

HO

O O


Cortienic Acid(**39**)

O

OH OH

O

O

Cl

O

Glucocorticoid Soft Drug representative Loteprednol Etabonate (LE)(**41**)

O

O

H

(**12**)

13 <sup>14</sup> 15

17 18

21

H

> 6 7

O

2

OH

OH

16

20

O

O

#### *First Generation Cortienic Acid (39)-based Glucocorticoid Soft Drugs: Loteprednol Etabonate (41) and its Analogs (42):*

#### *Synthesis of Dug molecules and Structure-Activity Studies:*

As already mentioned**,** Bodor and his colleagues [24, 26] have applied retrometabolic drug design approach to a variety of therapeutic agents such as - blockers, antimicrobials, analgesics, and acetyl cholinesterase (ACE) inhibitors and were successful in developing retrometabolically designed molecules reaching towards market application. They had designed a number of analogs starting with 1-cortienic acid (**40**), the primary metabolite of prednisolone that lacks corticosteroid activity [25]. Hydrocortisone can undergo a variety of oxidative and reductive metabolic conversions [72] by local *esterases* within the system. Thus oxidation of its dihydroxyacetone side chain leads to the formation of cortienic acid *via* 21 dehydrocortisol (21-aldehyde) and cortisolic acid (21-acid) [**Figure 5**]. Cortienic acid (**39**) is an ideal lead molecule for the inactive metabolite soft drug (SD) approaches because it is lack of corticosteroid activity and therefore is major metabolite excreted in human urine. To get the new lead compounds, the pharmacophore moieties of the 17-hydroxyl and 17 carboxy substituents of the lead compound had to be restored by suitable isosteric/isoelectronic substitution containing esters or other types of functions that could restore the anti-inflammatory potency of the original corticosteroid while at the same time incorporating hydrolytic features to ensure metabolism. Other structural considerations included the presence or absence of double bond at C-1 position, presence of 6 or 9 fluorine, and 16 & 16 –methyl group (**Figure 6**). More than hundred possible drug molecules were synthesized and tested in pre-clinical anti-inflammatory models [5]. Structure-activity studies by Bodor and his group [24] of these molecules have confirmed

that the best substituent for maximal therapeutic activity included a haloester at 17 position and a carbonate or ether moiety at 17 position. Incorporation of 17 carbonates or ether was preferred over 17 esters to increase stability and to prevent potential formation of mixed anhydrides by reaction of a 17 ester with a 17 acid functionality and subsequent potential for lens protein binding leading to steroid- induced cataract formation.

**Figure 5.** Oxidative metabolism of hydrocortisone by local esterases into C-21 Aldehyde and C-21 Acid (Cortisolic Acid)

Therefore in addition to the C-20 ketone functionality of prednisolone being replaced to eliminate the possibility of Schiff base intermediates, other chemical features associated with cataracterogenesis were also eliminated by the proposed design. The carbonates were expected to be less reactive than the corresponding esters due to the lower electrophilicity of the carbonyl carbon [24].

630 Glucocorticoids – New Recognition of Our Familiar Friend

therapeutics having potential market value.

*Synthesis of Dug molecules and Structure-Activity Studies:* 

*and its Analogs (42):* 

and productive fields of soft drug design. Ophthalmic use of glucocorticoids usually causes increased intraocular pressure (IOP) as a result of increased resistance to aqueous humour outflow. The design of soft anti-inflammatory glucocorticoids has been one of the most important and most successful areas of Soft Drug design. Although the soft nature of such drugs are mainly associated with fast hydrolytic degradation, in fact it is not necessarily be so as Bodor and his co-workers suggested [24].Too much rapid hydrolysis may in fact result in weak activity. The desired increase of therapeutic index can be obtained only if the drug is sufficiently stable to reach the receptor sites at the target organ to produce the desired effect, but the free, non-protein-bound drug undergoes facile hydrolysis to avoid undesired systemic side effects. Therefore to develop a soft drug and hence separating successfully the desired local activity from systemic toxicity, an adequate balance between intrinsic activity, solubility/lipophilicity, tissue distribution, protein binding and rate of metabolic deactivation have to be achieved. In the case of slow, sustained release to the general circulatory system from delivery site, even a relatively slow hydrolysis could result in a very low, almost steady-state systemic concentration [24]. Based on these concepts of eyetargeting chemical delivery systems (CDSs) and retrometabolic drug design approaches, Bodor and his group was successful in developing glucocorticoid soft drugs for ophthalmic

*First Generation Cortienic Acid (39)-based Glucocorticoid Soft Drugs: Loteprednol Etabonate (41)* 

As already mentioned**,** Bodor and his colleagues [24, 26] have applied retrometabolic drug design approach to a variety of therapeutic agents such as - blockers, antimicrobials, analgesics, and acetyl cholinesterase (ACE) inhibitors and were successful in developing retrometabolically designed molecules reaching towards market application. They had designed a number of analogs starting with 1-cortienic acid (**40**), the primary metabolite of prednisolone that lacks corticosteroid activity [25]. Hydrocortisone can undergo a variety of oxidative and reductive metabolic conversions [72] by local *esterases* within the system. Thus oxidation of its dihydroxyacetone side chain leads to the formation of cortienic acid *via* 21 dehydrocortisol (21-aldehyde) and cortisolic acid (21-acid) [**Figure 5**]. Cortienic acid (**39**) is an ideal lead molecule for the inactive metabolite soft drug (SD) approaches because it is lack of corticosteroid activity and therefore is major metabolite excreted in human urine. To get the new lead compounds, the pharmacophore moieties of the 17-hydroxyl and 17 carboxy substituents of the lead compound had to be restored by suitable isosteric/isoelectronic substitution containing esters or other types of functions that could restore the anti-inflammatory potency of the original corticosteroid while at the same time incorporating hydrolytic features to ensure metabolism. Other structural considerations included the presence or absence of double bond at C-1 position, presence of 6 or 9 fluorine, and 16 & 16 –methyl group (**Figure 6**). More than hundred possible drug molecules were synthesized and tested in pre-clinical anti-inflammatory models [5]. Structure-activity studies by Bodor and his group [24] of these molecules have confirmed

**Loteprednol Etabonate**(**41**) **1st Generation Soft Glucocorticoid Analogs** (**42**)

**Figure 6.** Design of 1st Generation Cortienic acid-based Glucocorticoid Soft Drugs (**42**) with their Glucocorticoid Soft Drug representative Loteprednol Etabonate (LE)(**41**)

Loteprednol Etabonate (LE) namely chloromethyl- 17-[(ethoxycarbonyl) oxy]-11-hydroxy-3-oxoandrosta-1, 4-diene-17 -carboxylate (**41**), was the most promising drug candidate among the various cortienic acid-based derivatives synthesized by Bodor and his group (**Figure 6**)]. In Loteprednol Elaborate (**41**), a metabolically labile ester function occupies 17 - position, while a stable carbonate group occupies 17-position. The ester is hydrolyzed to an inactive carboxylic acid, Δ1-cortienic acid etabonate (**43**), and then into Δ1-cortienic acid (**40**) in biological systems after exerting the desired therapeutic effect, thereby minimizing the likelihood of toxicity [**Figure 7**]. As a result of the predictable conversion of Loteprednol Etabonate into an inactive metabolite in the eye following topical administration, this glucocorticoid has a low propensity for undesirable toxicity while possessing increased antiinflammatory activity. In fact Loteprednol Etabonate (**41**) has been found to be 1.5 times more potent than the parent anti-inflammatory agent dexamethasone [24].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 633

easiness of metabolic deactivation (Softness)[24]. In traditional glucocorticoids such as Hydrocortisone 17-butyrate (**14**), Betamethasone 17-valerate (**16**) and Clobetasol 17 propionate (**17**), efficacy and toxicity are closely correlated ( r2 =0.996) applying the relationship between the anti- inflammatory and thymus involution activities [24] determined in the cotton pellet granuloma test (**Figure 8**). In these glucocorticoids, the reported results [24] have shown that TI have been found to be almost similar regardless of their intrinsic activities; however glucocorticoid soft drug Loteprednol Etabonate (41) owing to its softness and improved toxicity profile, provides a significant improvement(24) (**Table** 

HO O


(inactive)

**Figure 7.** Metabolism of Loteprednol Etabonate (41) to 1-Cortienic acid etabonate (4**3**) and then to 1-

Loteprednol Etabonate (LE) is predictably metabolized by local *esterases* into its inactive metabolite Δ1-cortienic acid (**40**) which has been confirmed through animal studies [20]. Clinical studies by Druzgala *et al* [78] have confirmed that the highest concentration of LE was found in cornea, followed by the iris/ciliary body and aqueous humour. The cornea also showed the highest ratio of metabolite to Loteprednol Etabonate (**41**), indicating that the cornea was the prime site of metabolism, while aqueous humour concentrations of LE were nearly 100-fold lower. This finding suggested that Loteprednol Etabonate may exert a decreased IOP effect as compared to other glucocorticoids [78]. Further a comparison of the IOP-elevating activity of Loteprednol Etabonate with that of Dexamethasone (**2**) in rabbits confirmed a lack of IOP effect with LE [79, 80]. LE was found to have a terminal half- life (t1/2) of 2.8 hrs in dogs following intravenous administration [81]. Further when absorbed systemically, LE was found to be metabolized to 1-cortienic acid etabonate (**43**) and then to 1-cortienic acid (**40**) (**Figure 7**) and have been found to be eliminated rapidly through the bile and urine [26, 81, 82]. So far numerous preclinical tests were carried out on Loteprednol Etabonate (**41**) including more recent ones by Comstock and DeCory [20, 83]. Most of these clinical studies have confirmed that Loteprednol Etabonate achieves the required balance between the solubility/lipophilicity, ocular tissue distribution, receptor binding, and subsequent rate of metabolic deactivation as have been outlined by Bodor when he

Since the design of this glucocorticoid soft drug LE by Bodor and his group, various ophthalmic suspension formulation of LE *viz*., a 0.2% suspension, a 0.5% suspension and a combination suspension of LE 0.5% plus tobramycin 0.3%, have been developed and clinically tested in various ocular inflammatory conditions and postoperative ocular inflammation.

O OH

O


O

O

conceptualized for the first time the retrometabolic drug design.

**4**).

Loteprednol Etabonate (LE) (**41**)

Cortienic acid(**40**).

#### *Loteprednol Etabonate (41) and its Clinical Investigations in Ophthalmic Therapeutics:*

Clinical study confirmed that Loteprednol Etabonate and some of the other soft glucocorticoids synthesized, provided a significant improvement of the therapeutic index, determined as the ratio between the anti-inflammatory activity and the thymus evolution activity [24]. In addition, binding studies using rat lung cytosolic corticosteroid receptors exhibited that the receptor binding affinity of LE and some of its analogs even exceeded that of the most potent glucocorticoids known[24]. Loteprednol Etabonate (**41**) is the one of the first-generation cortienic acid-based glucocorticoid soft drugs to get approved by Food and Drug Administration (FDA), USA for use in all inflammatory and allergy-related ophthalmic disorders, including inflammation after cataract surgery, uveitis, allergic conjunctivitis, and giant papillary conjunctivitis (GPC) [73-76]. Clinical tests on LE (**41**) by various groups of workers suggest it to be a potent glucocorticoid soft drug for ocular therapeutics. LE has also been selected for development as a potent glucocorticoid soft drug based on various considerations including the therapeutic index, availability, synthesis, and `softness' (the rate and easiness of metabolic deactivation). LE is now the active ingredient of a number of ophthalmic preparations available in the market (*Lotemax, Alrex, Zylet etc*.) [73, 74, 76].

Loteprednol Etabonate (**41**) has been found to be highly lipophilic which is 10 times greater than that of Dexamethasone (**2**), a characteristic that could increase its efficacy by enhancing penetration through biological membranes [24,26]. Competitive binding studies with rat lung type II GRs confirmed that binding affinity of LE was more than 4 times that of Dexamerhasone [77]. A vasoconstriction test in humans used to assess the bioavailability exhibited that LE could produce a blanching response similar to that of Betamethasone 17 valerate (**16)** to confirm its good penetration properties and strong potency [11]. Bodor and his group, have reported the therapeutic index of LE having more than 20-fold better than that of other glucocorticoids including Hydrocortisone 17-butyrate (**14**), Betamethasone 17-valerate (**16**) and Clobetasol 17-propionate (**17**) based on their cotton pellet glaucoma test and thymolysis potency [9]. LE (**41**) has been rightly selected on the basis of considerations including Therapeutic Index (TI) which is the ratio between the median toxic dose (TD50) and the median effective dose (ED50), availability, synthesis and the rate and easiness of metabolic deactivation (Softness)[24]. In traditional glucocorticoids such as Hydrocortisone 17-butyrate (**14**), Betamethasone 17-valerate (**16**) and Clobetasol 17 propionate (**17**), efficacy and toxicity are closely correlated ( r2 =0.996) applying the relationship between the anti- inflammatory and thymus involution activities [24] determined in the cotton pellet granuloma test (**Figure 8**). In these glucocorticoids, the reported results [24] have shown that TI have been found to be almost similar regardless of their intrinsic activities; however glucocorticoid soft drug Loteprednol Etabonate (41) owing to its softness and improved toxicity profile, provides a significant improvement(24) (**Table 4**).

632 Glucocorticoids – New Recognition of Our Familiar Friend

[73, 74, 76].

Loteprednol Etabonate (LE) namely chloromethyl- 17-[(ethoxycarbonyl) oxy]-11-hydroxy-3-oxoandrosta-1, 4-diene-17 -carboxylate (**41**), was the most promising drug candidate among the various cortienic acid-based derivatives synthesized by Bodor and his group (**Figure 6**)]. In Loteprednol Elaborate (**41**), a metabolically labile ester function occupies 17 - position, while a stable carbonate group occupies 17-position. The ester is hydrolyzed to an inactive carboxylic acid, Δ1-cortienic acid etabonate (**43**), and then into Δ1-cortienic acid (**40**) in biological systems after exerting the desired therapeutic effect, thereby minimizing the likelihood of toxicity [**Figure 7**]. As a result of the predictable conversion of Loteprednol Etabonate into an inactive metabolite in the eye following topical administration, this glucocorticoid has a low propensity for undesirable toxicity while possessing increased antiinflammatory activity. In fact Loteprednol Etabonate (**41**) has been found to be 1.5 times

more potent than the parent anti-inflammatory agent dexamethasone [24].

*Loteprednol Etabonate (41) and its Clinical Investigations in Ophthalmic Therapeutics:* 

Clinical study confirmed that Loteprednol Etabonate and some of the other soft glucocorticoids synthesized, provided a significant improvement of the therapeutic index, determined as the ratio between the anti-inflammatory activity and the thymus evolution activity [24]. In addition, binding studies using rat lung cytosolic corticosteroid receptors exhibited that the receptor binding affinity of LE and some of its analogs even exceeded that of the most potent glucocorticoids known[24]. Loteprednol Etabonate (**41**) is the one of the first-generation cortienic acid-based glucocorticoid soft drugs to get approved by Food and Drug Administration (FDA), USA for use in all inflammatory and allergy-related ophthalmic disorders, including inflammation after cataract surgery, uveitis, allergic conjunctivitis, and giant papillary conjunctivitis (GPC) [73-76]. Clinical tests on LE (**41**) by various groups of workers suggest it to be a potent glucocorticoid soft drug for ocular therapeutics. LE has also been selected for development as a potent glucocorticoid soft drug based on various considerations including the therapeutic index, availability, synthesis, and `softness' (the rate and easiness of metabolic deactivation). LE is now the active ingredient of a number of ophthalmic preparations available in the market (*Lotemax, Alrex, Zylet etc*.)

Loteprednol Etabonate (**41**) has been found to be highly lipophilic which is 10 times greater than that of Dexamethasone (**2**), a characteristic that could increase its efficacy by enhancing penetration through biological membranes [24,26]. Competitive binding studies with rat lung type II GRs confirmed that binding affinity of LE was more than 4 times that of Dexamerhasone [77]. A vasoconstriction test in humans used to assess the bioavailability exhibited that LE could produce a blanching response similar to that of Betamethasone 17 valerate (**16)** to confirm its good penetration properties and strong potency [11]. Bodor and his group, have reported the therapeutic index of LE having more than 20-fold better than that of other glucocorticoids including Hydrocortisone 17-butyrate (**14**), Betamethasone 17-valerate (**16**) and Clobetasol 17-propionate (**17**) based on their cotton pellet glaucoma test and thymolysis potency [9]. LE (**41**) has been rightly selected on the basis of considerations including Therapeutic Index (TI) which is the ratio between the median toxic dose (TD50) and the median effective dose (ED50), availability, synthesis and the rate and

**Figure 7.** Metabolism of Loteprednol Etabonate (41) to 1-Cortienic acid etabonate (4**3**) and then to 1- Cortienic acid(**40**).

Loteprednol Etabonate (LE) is predictably metabolized by local *esterases* into its inactive metabolite Δ1-cortienic acid (**40**) which has been confirmed through animal studies [20]. Clinical studies by Druzgala *et al* [78] have confirmed that the highest concentration of LE was found in cornea, followed by the iris/ciliary body and aqueous humour. The cornea also showed the highest ratio of metabolite to Loteprednol Etabonate (**41**), indicating that the cornea was the prime site of metabolism, while aqueous humour concentrations of LE were nearly 100-fold lower. This finding suggested that Loteprednol Etabonate may exert a decreased IOP effect as compared to other glucocorticoids [78]. Further a comparison of the IOP-elevating activity of Loteprednol Etabonate with that of Dexamethasone (**2**) in rabbits confirmed a lack of IOP effect with LE [79, 80]. LE was found to have a terminal half- life (t1/2) of 2.8 hrs in dogs following intravenous administration [81]. Further when absorbed systemically, LE was found to be metabolized to 1-cortienic acid etabonate (**43**) and then to 1-cortienic acid (**40**) (**Figure 7**) and have been found to be eliminated rapidly through the bile and urine [26, 81, 82]. So far numerous preclinical tests were carried out on Loteprednol Etabonate (**41**) including more recent ones by Comstock and DeCory [20, 83]. Most of these clinical studies have confirmed that Loteprednol Etabonate achieves the required balance between the solubility/lipophilicity, ocular tissue distribution, receptor binding, and subsequent rate of metabolic deactivation as have been outlined by Bodor when he conceptualized for the first time the retrometabolic drug design.

Since the design of this glucocorticoid soft drug LE by Bodor and his group, various ophthalmic suspension formulation of LE *viz*., a 0.2% suspension, a 0.5% suspension and a combination suspension of LE 0.5% plus tobramycin 0.3%, have been developed and clinically tested in various ocular inflammatory conditions and postoperative ocular inflammation.

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 635

perennial conjunctivitis patients who used LE 0.2% on a daily basis for extended periods of time. The results showed the absence of significant ADRs as there were no reports of posterior subcapsular opacification with quite insignificant IOP in most of the patients. In fact there was no observation of IOP elevation greater than 4mm Hg over base line at any

Besides, safety and efficacy of LE ophthalmic ointment 0.5% in the treatment of inflammation and pain following cataract surgery was studied in two randomized, multicentre, double-masked, parallel group, vehicle-controlled studies [20]. A very fewer LE ointment-treated patients needed rescue medication and most of them did not showed any ocular adverse event. Clinical trials on gel formulation of LE in treatment of ocular inflammation and pain after cataract surgery have been taken up more recently [20]. It is because of the high lipophilic nature of LE, gel formulation could provide improved product homogeneity over a suspension formulation to enhance its more consistent clinical

LE has been designed by Bodor and his group with a C-20 ester rather than a C-20 ketone and so LE is unable to form covalent adduct with lens protein, the main reason behind steroid-induced cataract formation as discussed earlier. Global market research indicates that an estimated more than 20 million LE units have been distributed globally. Clinical studies suggest the rapid metabolism of LE into inactive metabolites in conjunction with the lack of C-20 carbonyl functionality have resulted in LE – to become a unique glucocorticoid soft drug with significantly less, if any, potential for promoting steroid-induced cataract formation.[20]. LE has now been proved as a safe and effective treatment for contact lensassociated GPC, seasonal allergic conjunctivitis, postoperative inflammation or uveitis. Retrospective study established that even long time (>1 year) use of LE caused no reported

*Synthesis of the Side Chain of Loteprednol Etabonate (41) directly from 20-Oxopregnane (44) to* 

Based on promising results from animal studies, further clinical trials on Loteprednol Etabonate (**41**) are also going on for a safer treatment of gastrointestinal inflammation and other diseases such as asthma, rhinitis, and dermatological problems [76,82,84-86]. Success story of this retrometabolically designed glucocorticoid soft drug Loteprednol Etabonate has drawn attention to pharmaceutical industries as well as people working in steroid field worldwide. The authors of this chapter [87], recently, have reported a facile synthesis of the side chain of this potent ocular glucocorticoid soft drug, starting directly from 20 oxopregnanes, *viz*., 3β-acetoxy-pregn-5(6),16(17)-diene-20-one (16- dehydropregnenolone acetate i.e. 16-DPA) (**44**)- a potent steroid drug intermediate, utilizing their recently developed metal mediated halogenation technique as a key reaction [88,89 ] to furnish the final product –an analog (**45**) of Loteprednol Etabonate (**41**) with the requisite side chain

The present methodology paves a useful and productive way to construct the side chain of this important glucocorticoid soft drug directly from 20-oxopregnanes *via* its C-21

period of time.

response.

adverse effects. .

[**Scheme 1**].

*furnish an Analog (45) of LE:* 

**Figure 8.** Literature reported [24] graph showing the relationship between the Efficacy [log 1/ED50 (μg/pellet)] and Toxicity [log 1/TD50 (μg/pellet) of Hydrocortisone-17 α-Butyrate (14: 0.1%), Betamethasone-17 α-Valerate (16: 0.12%), Clobetasone-17 α-Propionate (17: 0.1%) and Loteprednol Etabonate (41: 0.1%). Relative TI being computed with Betamethasone-17 α-Valerate (16) as reference.


**Table 4.** Literature reported Therapeutic Index (TI) and Relative Therapeutic Index (Rel. TI) of some glucocorticoids and Loteprednol Etabonate (**41**). Relative Therapeutic Index was computed with Betamethasone-17 -Valerate (BMV)(**16**) as the reference.

Ocular diseases against which LE formulations were clinically tested included Giant Papillary Conjunctivitis, Prophylaxis of Seasonal Allergic Conjunctivitis, Seasonal Allergic Conjunctivitis, Anterior Uveitis, Blepharokerato Conjunctivitis, and Keratoconjunctivitis sicca etc. All these studies confirmed the clinical anti-inflammatory potency of LE and lack of significant IOP after its use [20]. Again two identical placebo-controlled trials examined the safety and efficacy of LE in treating post operative inflammation following cataract surgery with intraocular lens implantation [92]. Ilyas *et al* [93] have studied the long term safety of LE 0.2% by conducting a retrospective review of more than 350 seasonal and perennial conjunctivitis patients who used LE 0.2% on a daily basis for extended periods of time. The results showed the absence of significant ADRs as there were no reports of posterior subcapsular opacification with quite insignificant IOP in most of the patients. In fact there was no observation of IOP elevation greater than 4mm Hg over base line at any period of time.

634 Glucocorticoids – New Recognition of Our Familiar Friend

**Figure 8.** Literature reported [24] graph showing the relationship between the Efficacy [log 1/ED50 (μg/pellet)] and Toxicity [log 1/TD50 (μg/pellet) of Hydrocortisone-17 α-Butyrate (14: 0.1%), Betamethasone-17 α-Valerate (16: 0.12%), Clobetasone-17 α-Propionate (17: 0.1%) and Loteprednol Etabonate (41: 0.1%). Relative TI being computed with Betamethasone-17 α-Valerate (16) as reference.

Loteprednol Etabonate (41) 56.2 22.5 Clobetasone-17-Propionate (17) 3.8 1.5 Hydrocortisone-17 -Butyrate (14) 3.1 1.3

(BMV: 16) 2.5 1.0

**Table 4.** Literature reported Therapeutic Index (TI) and Relative Therapeutic Index (Rel. TI) of some glucocorticoids and Loteprednol Etabonate (**41**). Relative Therapeutic Index was computed with

Ocular diseases against which LE formulations were clinically tested included Giant Papillary Conjunctivitis, Prophylaxis of Seasonal Allergic Conjunctivitis, Seasonal Allergic Conjunctivitis, Anterior Uveitis, Blepharokerato Conjunctivitis, and Keratoconjunctivitis sicca etc. All these studies confirmed the clinical anti-inflammatory potency of LE and lack of significant IOP after its use [20]. Again two identical placebo-controlled trials examined the safety and efficacy of LE in treating post operative inflammation following cataract surgery with intraocular lens implantation [92]. Ilyas *et al* [93] have studied the long term safety of LE 0.2% by conducting a retrospective review of more than 350 seasonal and

TD50/ED50

Relative Therapeutic Index (Rel TI) TI/TIBMV

Glucocorticoids Therapeutic Index (TI)

Betamethasone-17 -Valerate

Betamethasone-17 -Valerate (BMV)(**16**) as the reference.

Besides, safety and efficacy of LE ophthalmic ointment 0.5% in the treatment of inflammation and pain following cataract surgery was studied in two randomized, multicentre, double-masked, parallel group, vehicle-controlled studies [20]. A very fewer LE ointment-treated patients needed rescue medication and most of them did not showed any ocular adverse event. Clinical trials on gel formulation of LE in treatment of ocular inflammation and pain after cataract surgery have been taken up more recently [20]. It is because of the high lipophilic nature of LE, gel formulation could provide improved product homogeneity over a suspension formulation to enhance its more consistent clinical response.

LE has been designed by Bodor and his group with a C-20 ester rather than a C-20 ketone and so LE is unable to form covalent adduct with lens protein, the main reason behind steroid-induced cataract formation as discussed earlier. Global market research indicates that an estimated more than 20 million LE units have been distributed globally. Clinical studies suggest the rapid metabolism of LE into inactive metabolites in conjunction with the lack of C-20 carbonyl functionality have resulted in LE – to become a unique glucocorticoid soft drug with significantly less, if any, potential for promoting steroid-induced cataract formation.[20]. LE has now been proved as a safe and effective treatment for contact lensassociated GPC, seasonal allergic conjunctivitis, postoperative inflammation or uveitis. Retrospective study established that even long time (>1 year) use of LE caused no reported adverse effects. .

#### *Synthesis of the Side Chain of Loteprednol Etabonate (41) directly from 20-Oxopregnane (44) to furnish an Analog (45) of LE:*

Based on promising results from animal studies, further clinical trials on Loteprednol Etabonate (**41**) are also going on for a safer treatment of gastrointestinal inflammation and other diseases such as asthma, rhinitis, and dermatological problems [76,82,84-86]. Success story of this retrometabolically designed glucocorticoid soft drug Loteprednol Etabonate has drawn attention to pharmaceutical industries as well as people working in steroid field worldwide. The authors of this chapter [87], recently, have reported a facile synthesis of the side chain of this potent ocular glucocorticoid soft drug, starting directly from 20 oxopregnanes, *viz*., 3β-acetoxy-pregn-5(6),16(17)-diene-20-one (16- dehydropregnenolone acetate i.e. 16-DPA) (**44**)- a potent steroid drug intermediate, utilizing their recently developed metal mediated halogenation technique as a key reaction [88,89 ] to furnish the final product –an analog (**45**) of Loteprednol Etabonate (**41**) with the requisite side chain [**Scheme 1**].

The present methodology paves a useful and productive way to construct the side chain of this important glucocorticoid soft drug directly from 20-oxopregnanes *via* its C-21 functionalization in much simpler and easier way with their newly developed metal mediated halogenation technique, which avoids application of harsh and tedious reaction conditions associated with this conversion [90, 91].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 637

halogen substituent at the 17 position. Nevertheless, the pharmacophore portions of these second- generation cortienic acid-based soft glucocorticoids, having the halogen atoms at 17 position, can be positioned so as to provide excellent overlap with those of the traditional glucocorticoids [24, 95]. It has been conceived the idea that dichlorinated substituents seem required for activity and sufficiently soft nature. Molecular configuration suggests that with dicholrinated substituents, one of the chlorine atom would necessarily point in the direction needed for pharmacophore overlap, whereas with monochlorinated substituents, steric hindrance might force the lone chlorine atom to point away from this desired direction. Secondly experimentally it has been found that as compared with the unsubstituted ester, dichloro substituents could cause ~20 fold increase in the second-order rate constant kcat/KM of enzymatic hydrolysis in acetate esters, on the other hand monochloro

Z

X9

X6

X6,X9: H,F,Cl,CH3.

R16: H,CH3, OH, =CH2, etc.

1,2 : Double bond (present or absent)

O X

O

O

R21

R16

R21: C1-C4 Alkyl, C1-C4 Alkoxy, C1-C4 Alkylthio;

Cl

Cl

O

 1,2

X: O,S Z: C=O,

**Etiprednol Dicloacetate**(**46**) **2nd Generation Soft Glucorticoid Analogs**(**47**)

**Figure 9.** Design of 2nd Generation Cortienic Acid-based Soft Glucocorticoids Soft Drugs (**47**) and their

substituent did not cause any change [96]. Unlike first generation soft glucocorticoids, in the second generation of this soft steroid series, hydrolysis primarily cleaves the 17- ester group and not the 17-ester group. The corresponding metabolites are also not active. From large no of compounds synthesized in this series, Etiprednol Dicloacetate (ED) (**46**) had been

In animal and in human clinical trials, in accordance with its soft nature, Etiprednol Dicloacetate (**46**) was found to have low systemic toxicity [94, 97-99]. Etiprednol Dicloacetate had also shown better receptor binding capacity than Loteprednol Etabonate and was found to be more effective than Budesonide (**3**) in various asthma models [24]. Further No Observable Adverse Effect Level (NOAEL) of ED after oral administration for 28 days was

HO

 Cortienic Acid (**39**) 1-Cortienic Acid (**40)**

O

O O

O

O

Glucocorticoid Soft Drug representative Etiprednol Dicloacetate (ED)(**46)** 

Cl Cl

selected for development as a potent ocular glucocorticoid soft drug [24].

*Etiprednol Dicloacetate (46) and its Clinical Investigations in Ophthalmic Therapeutics:* 

OH OH

O

HO

O

**Scheme 1.** Reagents and conditions: (i) H2,Pd-C, 95% (ii) MnO2-TMSCl/AcCl-AcOH, 81% (iii) 3% KOH, MeOH-H2O, 75% (iv) LiAlH4,THF, 88% (v) CAN, AcOH, 75% (vi) *m*-CPBA, CHCl3, 62% (vii) H2SO4,acetone-H2O, 48% (viii) Jones reagent, 57% (ix) OsO4 – H2O2, rt., 50% (x) NaIO4 , Ethyl chloroformate, 70% xi) Chloromethyl iodide, 75% .

*Second –generation Cortienic Acid (39)-based Glucocorticoid soft drugs: Etiprednol dicloacetate (46) and its Analogs (47):* 

#### *Synthesis of Drug molecules and Structure-Activity Studies:*

Based on their retrometabolic drug design approach, Nicholas Bodor [94] have more recently introduced another new class of soft glucocorticoids with 17-dicloroester substituent. These are now known as the second generation soft glucocorticoids (**Figure 9**). This is said to be a unique design as no known glucocorticoid has been found to contain a halogen substituent at the 17 position. Nevertheless, the pharmacophore portions of these second- generation cortienic acid-based soft glucocorticoids, having the halogen atoms at 17 position, can be positioned so as to provide excellent overlap with those of the traditional glucocorticoids [24, 95]. It has been conceived the idea that dichlorinated substituents seem required for activity and sufficiently soft nature. Molecular configuration suggests that with dicholrinated substituents, one of the chlorine atom would necessarily point in the direction needed for pharmacophore overlap, whereas with monochlorinated substituents, steric hindrance might force the lone chlorine atom to point away from this desired direction. Secondly experimentally it has been found that as compared with the unsubstituted ester, dichloro substituents could cause ~20 fold increase in the second-order rate constant kcat/KM of enzymatic hydrolysis in acetate esters, on the other hand monochloro

636 Glucocorticoids – New Recognition of Our Familiar Friend

O

20 21

AcO

AcO

**44**

<sup>4</sup> <sup>5</sup> <sup>6</sup>

19

11 12 13 14 15 16 17 18

7 8 9 10

1 2 3

AcO <sup>H</sup>

*and its Analogs (47):* 

AcO <sup>H</sup>

H

vii

H3O<sup>+</sup>

OAc

OH

OH

viii

chloroformate, 70% xi) Chloromethyl iodide, 75% .

AcO <sup>H</sup>

*Synthesis of Drug molecules and Structure-Activity Studies:* 

conditions associated with this conversion [90, 91].

AcO

H OAc

OAc

H O

O

vi

H

AcO <sup>H</sup>

OAc

OH O

x.xi

**Scheme 1.** Reagents and conditions: (i) H2,Pd-C, 95% (ii) MnO2-TMSCl/AcCl-AcOH, 81% (iii) 3% KOH,

*Second –generation Cortienic Acid (39)-based Glucocorticoid soft drugs: Etiprednol dicloacetate (46)* 

Based on their retrometabolic drug design approach, Nicholas Bodor [94] have more recently introduced another new class of soft glucocorticoids with 17-dicloroester substituent. These are now known as the second generation soft glucocorticoids (**Figure 9**). This is said to be a unique design as no known glucocorticoid has been found to contain a

MeOH-H2O, 75% (iv) LiAlH4,THF, 88% (v) CAN, AcOH, 75% (vi) *m*-CPBA, CHCl3, 62% (vii) H2SO4,acetone-H2O, 48% (viii) Jones reagent, 57% (ix) OsO4 – H2O2, rt., 50% (x) NaIO4 , Ethyl

ix

AcO H

**45**

functionalization in much simpler and easier way with their newly developed metal mediated halogenation technique, which avoids application of harsh and tedious reaction

O

H

<sup>i</sup> ii iii

AcO

H OAc

H

v

O

Cl

Cl

HO

HO <sup>H</sup>

O <sup>O</sup> Cl <sup>O</sup>

O O

H

iv

H OMe

O

H OH

**Etiprednol Dicloacetate**(**46**) **2nd Generation Soft Glucorticoid Analogs**(**47**)

**Figure 9.** Design of 2nd Generation Cortienic Acid-based Soft Glucocorticoids Soft Drugs (**47**) and their Glucocorticoid Soft Drug representative Etiprednol Dicloacetate (ED)(**46)** 

substituent did not cause any change [96]. Unlike first generation soft glucocorticoids, in the second generation of this soft steroid series, hydrolysis primarily cleaves the 17- ester group and not the 17-ester group. The corresponding metabolites are also not active. From large no of compounds synthesized in this series, Etiprednol Dicloacetate (ED) (**46**) had been selected for development as a potent ocular glucocorticoid soft drug [24].

#### *Etiprednol Dicloacetate (46) and its Clinical Investigations in Ophthalmic Therapeutics:*

In animal and in human clinical trials, in accordance with its soft nature, Etiprednol Dicloacetate (**46**) was found to have low systemic toxicity [94, 97-99]. Etiprednol Dicloacetate had also shown better receptor binding capacity than Loteprednol Etabonate and was found to be more effective than Budesonide (**3**) in various asthma models [24]. Further No Observable Adverse Effect Level (NOAEL) of ED after oral administration for 28 days was found to be 2mg/kg in rats and dogs, and about 40 times higher than that of Budesonide [97].

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 639

systemic side effects. At the initial stage, several new generation glucocorticoids were developed using prodrug design approach involving changes or modifications made in glucocorticoid molecules introducing specific substituents at various specific positions of the basic glucocorticoid skeletons to obtain better skin penetration, slower enzyme degradation and greater affinity for the cytosol receptor. The term prodrug refers to a pharmacologically inactive molecule that is converted to an active drug by metabolic biotransformations that may occur prior, during or after adsorption or at specific target sites within the body. This approach has given several potent new generation glucocorticoids such as Budesonide (**3**), 17-Prednicarbate (**9**), Fluticasone propionate (**11**), Methyl prednisolone aceponate (**5**), Beclomethasone (**7**) etc towards successful treatment of plethora of diseases including psoriasis, allergies, asthma, rheumatoid arthritis and lupus, with significantly minimized systemic side effects. However, all these old and new generation glucocorticoids are effective in reducing anterior segment inflammation only and not suitable for ophthalmic therapeutics as they are found to be associated with Adverse Drug Reactions (ADRs) including elevation of Intraocular Pressure (IOP) and steroid-induced cataract formation in case of ophthalmic therapeutics as they were not designed for ocular treatment. Successful eye-specific therapeutic agents can only be achieved by suitable drug-design approaches which thoroughly can integrate the specific pharmacological, metabolic, and targeting requirements of ophthalmic drugs. Chemical Delivery Systems (CDSs) and Retrometabolic Soft Drug Design approaches initiated by Prof.Nicholas Bodor and his group at the Center for Drug Discovery, University of Florida, Health Science Center, USA, are found to be quite successful with a major break through for this purpose providing flexible and generally applicable solutions. Their potential is indeed well illustrated by the results obtained with a number of soft -blockers and glucocorticoid soft drugs designed within this framework towards ophthalmic therapeutics. Soft -blockers, *viz*., Betaxoxime (**29a**), Adaprolol (**33**) and Glucocorticoid Soft drugs *viz*.,, Loteprednol Etabonate (**41**) and Etiprednol Dicloacetate (**46**) are some of the soft drugs developed by this retrometabolic drug design approach which have already reached the clinical development phase in various ophthalmic areas and one of them Loteprednol Etabonate (LE) is already being in the market as a promising glucocorticoid soft drug in ophthalmic therapeutics. Not only that, based on clinical results from animal studies, LE now also finds place in safer treatment of gastrointestinal inflammations and other diseases such as asthma, rhinitis and dermatological problems. Moreover dissociation of transactivating and transrepressing activity found in the second generation glucocorticoid soft drug, viz., Etiprednol Dicloacetate (ED) could open up a novel and promising mechanistic pathways towards the development of more and more

potent glucocorticoid soft drugs in future.

Pritish Chowdhury and Juri Moni Borah

*Natural Products Chemistry Division CSIR- North East Institute of Science & Technology, Jorhat,* 

**Author details** 

*India* 

The comparison of the transrepressing and transactivating activity of Etiprednol Dicolacetate (**46**) and Budesonide(**3**) were done by measuring their inhibition in interleukin(IL)-1 production of a simulated human monocyte cell line and by evaluating glucocorticoid-induced increase in the activity of tyrosine-amino-transferase ( TAT) of a rat hepatoma cell line respectively [99] and the measured activities were expressed relative to Dexamethasone (**2**) From the results it was found that ED (**46**) possesses less transactivating activity with a preserved transrepressing acivity, and hence ED is to be called as a dissociated glucocorticoid. Dissociation of transactivating ( carbohydrate metabolism altering) and transrepressing ( anti-inflammatory) activity found in Etiprednol Dicloacetate(ED) is a fruitful advantage in subsequent help in separating the most beneficial anti-inflammatory activity from the undesired side effects or adverse drug reactions (ADRs).A comparison of transrepression ( anti-inflammatory effect) and transactivation (carbohydrate metabolism altering) effects of dexamethasone (**2**), used as 100% reference, Budesonide (**3**) and Etiprenol Dicloacette (**46**) determined on an average of two experiments for concentrations of 10 -7 (98) is depicted in **Figure 10** [24]. Hence this productive effort in developing dissociated glucocorticoids can be termed as one of the novel and sought after mechanistic approaches towards the development of newer glucocorticoid soft drugs [24, 100,101].

**Figure 10.** Literature reported [24] tentative comparison of transrepression (anti-inflammatory effect) and transactivation (carbohydrate metabolism altering) effects of dexamethasone (**2**)(used as 100% reference), Budesonide (**3**) and Etiprednol Dicloacetate (**46)**

#### **3. Conclusion**

Since the introduction of glucocorticoids in drug industry more than a half century ago, new series of glucocorticoids have been introduced for site specificity as well as for minimizing systemic side effects. At the initial stage, several new generation glucocorticoids were developed using prodrug design approach involving changes or modifications made in glucocorticoid molecules introducing specific substituents at various specific positions of the basic glucocorticoid skeletons to obtain better skin penetration, slower enzyme degradation and greater affinity for the cytosol receptor. The term prodrug refers to a pharmacologically inactive molecule that is converted to an active drug by metabolic biotransformations that may occur prior, during or after adsorption or at specific target sites within the body. This approach has given several potent new generation glucocorticoids such as Budesonide (**3**), 17-Prednicarbate (**9**), Fluticasone propionate (**11**), Methyl prednisolone aceponate (**5**), Beclomethasone (**7**) etc towards successful treatment of plethora of diseases including psoriasis, allergies, asthma, rheumatoid arthritis and lupus, with significantly minimized systemic side effects. However, all these old and new generation glucocorticoids are effective in reducing anterior segment inflammation only and not suitable for ophthalmic therapeutics as they are found to be associated with Adverse Drug Reactions (ADRs) including elevation of Intraocular Pressure (IOP) and steroid-induced cataract formation in case of ophthalmic therapeutics as they were not designed for ocular treatment. Successful eye-specific therapeutic agents can only be achieved by suitable drug-design approaches which thoroughly can integrate the specific pharmacological, metabolic, and targeting requirements of ophthalmic drugs. Chemical Delivery Systems (CDSs) and Retrometabolic Soft Drug Design approaches initiated by Prof.Nicholas Bodor and his group at the Center for Drug Discovery, University of Florida, Health Science Center, USA, are found to be quite successful with a major break through for this purpose providing flexible and generally applicable solutions. Their potential is indeed well illustrated by the results obtained with a number of soft -blockers and glucocorticoid soft drugs designed within this framework towards ophthalmic therapeutics. Soft -blockers, *viz*., Betaxoxime (**29a**), Adaprolol (**33**) and Glucocorticoid Soft drugs *viz*.,, Loteprednol Etabonate (**41**) and Etiprednol Dicloacetate (**46**) are some of the soft drugs developed by this retrometabolic drug design approach which have already reached the clinical development phase in various ophthalmic areas and one of them Loteprednol Etabonate (LE) is already being in the market as a promising glucocorticoid soft drug in ophthalmic therapeutics. Not only that, based on clinical results from animal studies, LE now also finds place in safer treatment of gastrointestinal inflammations and other diseases such as asthma, rhinitis and dermatological problems. Moreover dissociation of transactivating and transrepressing activity found in the second generation glucocorticoid soft drug, viz., Etiprednol Dicloacetate (ED) could open up a novel and promising mechanistic pathways towards the development of more and more potent glucocorticoid soft drugs in future.

#### **Author details**

638 Glucocorticoids – New Recognition of Our Familiar Friend

[97].

100,101].

**3. Conclusion** 

found to be 2mg/kg in rats and dogs, and about 40 times higher than that of Budesonide

The comparison of the transrepressing and transactivating activity of Etiprednol Dicolacetate (**46**) and Budesonide(**3**) were done by measuring their inhibition in interleukin(IL)-1 production of a simulated human monocyte cell line and by evaluating glucocorticoid-induced increase in the activity of tyrosine-amino-transferase ( TAT) of a rat hepatoma cell line respectively [99] and the measured activities were expressed relative to Dexamethasone (**2**) From the results it was found that ED (**46**) possesses less transactivating activity with a preserved transrepressing acivity, and hence ED is to be called as a dissociated glucocorticoid. Dissociation of transactivating ( carbohydrate metabolism altering) and transrepressing ( anti-inflammatory) activity found in Etiprednol Dicloacetate(ED) is a fruitful advantage in subsequent help in separating the most beneficial anti-inflammatory activity from the undesired side effects or adverse drug reactions (ADRs).A comparison of transrepression ( anti-inflammatory effect) and transactivation (carbohydrate metabolism altering) effects of dexamethasone (**2**), used as 100% reference, Budesonide (**3**) and Etiprenol Dicloacette (**46**) determined on an average of two experiments for concentrations of 10 -7 (98) is depicted in **Figure 10** [24]. Hence this productive effort in developing dissociated glucocorticoids can be termed as one of the novel and sought after mechanistic approaches towards the development of newer glucocorticoid soft drugs [24,

**Figure 10.** Literature reported [24] tentative comparison of transrepression (anti-inflammatory effect) and transactivation (carbohydrate metabolism altering) effects of dexamethasone (**2**)(used as 100%

Since the introduction of glucocorticoids in drug industry more than a half century ago, new series of glucocorticoids have been introduced for site specificity as well as for minimizing

reference), Budesonide (**3**) and Etiprednol Dicloacetate (**46)**

Pritish Chowdhury and Juri Moni Borah *Natural Products Chemistry Division CSIR- North East Institute of Science & Technology, Jorhat, India* 

### **Acknowledgement**

We sincerely thank Prof Nicholas Bodor, Executive Director, Center for Drug Discovery, University of Florida, USA for his helpful suggestions. Department of Biotechnology (DBT), New Delhi, India is thankfully acknowledged for financial support. Thanks are also due to Ms Ashma Begum, PhD scholar, for her help in preparing the manuscript.

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review 641

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## *Edited by Xiaoxiao Qian*

As one class of the most important steroid hormones, glucocorticoids have long been recognised and their therapeutic benefits have been widely used in clinical treatment, especially in anti-inflammation cases. Glucocorticoids regulate various processes in the body including the mobilization of energy stores, immune functions, gene expression, and maintenance of the homeostasis as well as the stress response, this is not surprising that the concept of "glucocorticoids" is mentioned in almost all medical text books that focus on specific organs or systems such as the cardiovascular system, the immune system, and the neuroendocrine system. The book of Glucocorticoids - New Recognition of Our Familiar Friend aims to introduce the latest findings relating to glucocorticoids, either freshly from the laboratory or from clinical case studies, and to open up a new angle of looking at the issue of balancing the therapeutic benefits and side effects brought up by glucocorticoids.

Glucocorticoids - New Recognition of Our Familiar Friend

Glucocorticoids

New Recognition of Our Familiar Friend

*Edited by Xiaoxiao Qian*

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