*3.2.2 Kawasaki disease (DK)*

It is a systemic vasculitis, common in male child, with fever, rash, nonexudative bilateral conjunctivitis, oral and pharyngeal mucosal erythema, cervical lymphadenopathy, and it can affect the extremity. They may have fewer common symptoms such as pyuria, meningitis, shock and retropharyngeal or parapharyngeal abscess [10].

The etiology of Kawasaki disease is unknown. The diagnosis of Kawasaki disease is based on the presence of fever for ≥5 days, along with the presence of at least 4 of the 5 main clinical features [10] (**Table 2**).


**Table 2.** *Clinical features in Kawasaki disease [10].*

Patients who have met the diagnostic criteria are considered to have complete Kawasaki disease (also referred to as typical or classic Kawasaki disease). Patients who do not have enough major clinical findings can be diagnosed with incomplete Kawasaki disease [10].

Intravenous immunoglobulin (IVIG) is the basis for treatment. Usually, it is initiated before 10 days of fever and significantly reduces coronary artery aneurysms (CAAs) that decrease from 25% to less than 5%. Around 10–30% of patients are resistant to IVIG treatment [10].

Unfortunately, in some cases, IVIG is discontinued or administered at a reduced dose due to cost. Evidence for therapies beyond IVIG is limited, with no evidencebased recommendations for the management of patients with resistance to initial IVIG treatment.

In the initial treatment, if the patient is in the acute phase treatment, aspirin (30–50 to 80–100 mg/kg/day) and IVIG (2 g/kg) are recommended. The treatment of patients with resistance (persistent or recurrent fever after the end of IVIG after 24 hours) is to initiate IVIG 2 g/kg, associated to corticosteroids and/or infliximab [10, 11].

The use of corticosteroids is controversial due to the cardiovascular risk in prolonged use.

Anti-TNF-alpha is also recommended for patients with coronary artery aneurysms, and in the minority of cases, it can be used in patients without aneurysms. Other therapies possible are anti-interleukin 1, canakinumab and cyclosporine [11].

### **3.3 Small vessel vasculitis (SVV)**

#### *3.3.1 Microscopic polyangiitis*

Microscopic polyangiitis is an ANCA-associated vasculitis with significant morbidity and mortality. Treatment follows the same protocol as granulomatosis with polyangiitis [12].

## *3.3.2 Granulomatosis with polyangiitis (Wegener's)*

It is another necrotizing systemic vasculitis that affects small and medium vessels and is often associated with ANCA. It occurs in patients between 45 and 60 years old from both genders and is rarely observed in Negroids. The main features are the involvement of the upper and lower respiratory tract and the kidneys. Ears, nose and throat may develop with sinusitis and crusted rhinorrhea that are usually severe. Pulmonary nodules and renal involvement with crescent glomerulonephritis can be seen [13, 14].

It is a serious disease, and if left untreated, it almost always progresses to death. With the advent of new therapies, 90% of patients evolve to remission and the survival rate is 80% in 10 years. The first phase, known as the induction phase, aims to put the patient into remission, and it lasts between 3 and 6 months according to the clinical response. The second phase is known as the maintenance phase trying to consolidate the first phase and prevent relapses. It lasts from 12–24 months [13] (**Figure 2**).

In induction, prednisone 1 mg/kg is recommended. For severe forms, methylprednisolone pulse is indicated at doses of 7.5–15 mg/kg/day for 1–3 consecutive days. After 3–4 weeks of treatment, the corticosteroid dose is gradually decreased, but without reaching doses of less than 15 mg/day until 4th month. The combination of two immunosuppressants in the induction phase is essential for severe or refractory patients such as cyclophosphamide or rituximab.

**141**

*Vasculitis and Vasculopathies*

600 mg/m<sup>2</sup>

**Figure 2.**

bolus) [13, 14].

day+30) and then 700 mg/m<sup>2</sup>

recurrent and limited forms.

(20–25 mg/week) [13].

*DOI: http://dx.doi.org/10.5772/intechopen.92778*

Cyclophosphamide is preferred if rapid renal failure occurs at a dose of

*Necrotic vascular purpura (black arrows) of the upper limbs in granulomatosis with polyangiitis-Wegener's [13].*

presence of renal failure and 500 mg fixed dose every 3 weeks—maximum 6

Rituximab is the choice for pregnant women or patients who have failed

4 weeks. Plasmapheresis may be used in severe forms of the disease with severe renal involvement (Cr > 500 μmol/L) or alveolar hemorrhage. Also, corticosteroid

For localized or not very severe cases, methotrexate (20–25 mg per week) is an option. The AGATA study demonstrated efficacy of abatacept (1 mg/kg IV on day+1, day+29 and then once per month) combined with prednisone and an immunosuppressant (azathioprine, methotrexate or mycophenolate mofetil) for

Maintenance lasts between 18 and 24 months after remission has been achieved. Corticosteroids may be combined with azathioprine (2 mg/kg/day) or methotrexate

Eosinophilic granulomatosis polyangiitis (EGPA), also known as Churg-Strauss disease, is characterized by patients with asthma, eosinophilia and necrotizing vasculitis with extravascular eosinophilic granulomas that affect small and large vessels. It is a vasculitis associated with ANCA (neutrophilic cytoplasmic antibodies) and

Treatment with sulfamethoxazole/trimethoprim (400/800 mg) is given to prevent relapse from *Pneumocystis jirovecii* infection. Patients should be vaccinated following the regional schedule and is contraindicated live virus vaccines [13]. *Staphylococcus aureus* was the most identified pathogen in positive cultures, and it is

in total).The dose can be adjusted for age and renal function (500 mg/m<sup>2</sup>

cyclophosphamide or have relapsed. It is used at a dose of 375 mg/m<sup>2</sup>

therapy can be associated with immunosuppressants [13, 14].

important to remember that it also deserves prevention [14].

*3.3.3 Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)*

(maximum 1.2 g/bolus) every 2 weeks for 1 month (day+1, day+15,

every 3 weeks until remission (average of 6–9 cycles

in the

per week for

#### **Figure 2.**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

Kawasaki disease [10].

IVIG treatment.

infliximab [10, 11].

prolonged use.

cyclosporine [11].

**3.3 Small vessel vasculitis (SVV)**

*3.3.2 Granulomatosis with polyangiitis (Wegener's)*

*3.3.1 Microscopic polyangiitis*

nephritis can be seen [13, 14].

with polyangiitis [12].

are resistant to IVIG treatment [10].

Patients who have met the diagnostic criteria are considered to have complete Kawasaki disease (also referred to as typical or classic Kawasaki disease). Patients who do not have enough major clinical findings can be diagnosed with incomplete

Intravenous immunoglobulin (IVIG) is the basis for treatment. Usually, it is initiated before 10 days of fever and significantly reduces coronary artery aneurysms (CAAs) that decrease from 25% to less than 5%. Around 10–30% of patients

Unfortunately, in some cases, IVIG is discontinued or administered at a reduced dose due to cost. Evidence for therapies beyond IVIG is limited, with no evidencebased recommendations for the management of patients with resistance to initial

In the initial treatment, if the patient is in the acute phase treatment, aspirin (30–50 to 80–100 mg/kg/day) and IVIG (2 g/kg) are recommended. The treatment of patients with resistance (persistent or recurrent fever after the end of IVIG after 24 hours) is to initiate IVIG 2 g/kg, associated to corticosteroids and/or

The use of corticosteroids is controversial due to the cardiovascular risk in

Anti-TNF-alpha is also recommended for patients with coronary artery aneurysms, and in the minority of cases, it can be used in patients without aneurysms. Other therapies possible are anti-interleukin 1, canakinumab and

Microscopic polyangiitis is an ANCA-associated vasculitis with significant morbidity and mortality. Treatment follows the same protocol as granulomatosis

It is another necrotizing systemic vasculitis that affects small and medium vessels and is often associated with ANCA. It occurs in patients between 45 and 60 years old from both genders and is rarely observed in Negroids. The main features are the involvement of the upper and lower respiratory tract and the kidneys. Ears, nose and throat may develop with sinusitis and crusted rhinorrhea that are usually severe. Pulmonary nodules and renal involvement with crescent glomerulo-

It is a serious disease, and if left untreated, it almost always progresses to death. With the advent of new therapies, 90% of patients evolve to remission and the survival rate is 80% in 10 years. The first phase, known as the induction phase, aims to put the patient into remission, and it lasts between 3 and 6 months according to the clinical response. The second phase is known as the maintenance phase trying to consolidate the first phase and prevent relapses. It lasts from 12–24 months [13] (**Figure 2**).

In induction, prednisone 1 mg/kg is recommended. For severe forms, methylprednisolone pulse is indicated at doses of 7.5–15 mg/kg/day for 1–3 consecutive days. After 3–4 weeks of treatment, the corticosteroid dose is gradually decreased, but without reaching doses of less than 15 mg/day until 4th month. The combination of two immunosuppressants in the induction phase is essential for severe or

refractory patients such as cyclophosphamide or rituximab.

**140**

*Necrotic vascular purpura (black arrows) of the upper limbs in granulomatosis with polyangiitis-Wegener's [13].*

Cyclophosphamide is preferred if rapid renal failure occurs at a dose of 600 mg/m<sup>2</sup> (maximum 1.2 g/bolus) every 2 weeks for 1 month (day+1, day+15, day+30) and then 700 mg/m<sup>2</sup> every 3 weeks until remission (average of 6–9 cycles in total).The dose can be adjusted for age and renal function (500 mg/m<sup>2</sup> in the presence of renal failure and 500 mg fixed dose every 3 weeks—maximum 6 bolus) [13, 14].

Rituximab is the choice for pregnant women or patients who have failed cyclophosphamide or have relapsed. It is used at a dose of 375 mg/m<sup>2</sup> per week for 4 weeks. Plasmapheresis may be used in severe forms of the disease with severe renal involvement (Cr > 500 μmol/L) or alveolar hemorrhage. Also, corticosteroid therapy can be associated with immunosuppressants [13, 14].

For localized or not very severe cases, methotrexate (20–25 mg per week) is an option. The AGATA study demonstrated efficacy of abatacept (1 mg/kg IV on day+1, day+29 and then once per month) combined with prednisone and an immunosuppressant (azathioprine, methotrexate or mycophenolate mofetil) for recurrent and limited forms.

Maintenance lasts between 18 and 24 months after remission has been achieved. Corticosteroids may be combined with azathioprine (2 mg/kg/day) or methotrexate (20–25 mg/week) [13].

Treatment with sulfamethoxazole/trimethoprim (400/800 mg) is given to prevent relapse from *Pneumocystis jirovecii* infection. Patients should be vaccinated following the regional schedule and is contraindicated live virus vaccines [13]. *Staphylococcus aureus* was the most identified pathogen in positive cultures, and it is important to remember that it also deserves prevention [14].

#### *3.3.3 Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)*

Eosinophilic granulomatosis polyangiitis (EGPA), also known as Churg-Strauss disease, is characterized by patients with asthma, eosinophilia and necrotizing vasculitis with extravascular eosinophilic granulomas that affect small and large vessels. It is a vasculitis associated with ANCA (neutrophilic cytoplasmic antibodies) and

the rarest vasculitis within the group of ANCA-associated vasculitis, and that is why there are no highly recommended treatments based on the literature [15].

Corticosteroids are usually used to induce remission of the disease as well as immunosuppressants, for example cyclophosphamide in more severe cases. Longterm maintenance of immunosuppressants is used to prevent disease recurrence, but their long-term efficacy is discussed. Azathioprine has been recommended as maintenance therapy. The efficacy of mepolizumab, an anti-IL5 monoclonal antibody, has been recommended for these patients alone or in combination with corticotherapy. Others monoclonal anti-IL5, reslizumab and benralizumab drugs are still being studied. Studies suggest that rituximab may be effective in EGPA. Other drugs such as IFN-α appear to be effective in remission induction and maintenance; however, the safety profile restricts their use. Drugs such as anti-IgE (omalizumab) are used to control asthma, but their effects are unknown in the treatment of vasculitis. High doses of immunoglobulin have also been used to induce disease remission with good results. Intravenous immunoglobulin may be effective in treating residual peripheral neuropathy [15].

#### **3.4 Immune complex SVV**

#### *3.4.1 Cryoglobulinemic vasculitis*

Cryoglobulins are cold precipitated immunoglobulins that can cause vasculitis and vasculopathy. Type I cryoglobulins are responsible for 10–15% of symptomatic vasculitis cases and are related to malignant hematological disorders such as myeloma, B-cell lymphoma or undetermined monoclonal gammopathy (MGUS). Mixed cryoglobulins correspond to 80–85% of cases and are associated with infectious diseases, especially chronic hepatitis C, B-cell malignancies and autoimmune diseases such as Sjögren's syndrome and lupus. Vasculitis is most associated with mixed cryoglobulins. Women are affected more than men 2:1 [12].

In symptomatic patients with cryoglobulinemia type I, it is indicated to treat the hematologic basis diseases. Lymphomas require a combination of chemotherapy and myeloma treatment with drugs such as bortezomib, thalidomide, lenalidomide and other alkylating agents. Bone marrow transplantation can be performed in patients with cryoglobulinemia-associated myeloma. MGUS can be treated with the same myeloma drugs; however, rituximab has been the drug of choice. Plasmapheresis may be used for patients with severe renal involvement or extensive lower limb necrosis. Avoiding exposure to cold is essential [12].

Mixed cryoglobulins, usually hepatitis C-associated cryoglobulinemic vasculitis, are well-treated as suppression of hepatitis C replication occurs. Studies reported between 2011 and 2013 associated with pegylated interferon (PegIFN) and ribavirin for 12 months achieved a 50–60% control response to hepatitis C. The introduction of antiviral agents dramatically changed cryoglobulinemia-associated vasculitis. They promote shorter treatment without the need for interferon and with responses greater than 95% associated with few adverse effects. The drugs used are sofosbuvir, simeprevir, ledipasvir and daclatasvir, that can be associated with ribavirin. In some cases of more severe vasculitis, low doses of rituximab and other immunosuppressants may be used in selected cases. Rituximab targets B-cell populations that produce cryoglobulins and treats severe vasculitis [12] (**Figure 3**).

#### *3.4.2 Urticaria vasculitis*

The term urticaria vasculitis is used for plaques of urticaria that present leukocytoclasia on histopathological examination. It is a clinical pathological diagnosis,

**143**

*Vasculitis and Vasculopathies*

*DOI: http://dx.doi.org/10.5772/intechopen.92778*

characterized by a skin inflammation of the dermis capillaries and postcapillary venules, with a range of clinical signs from hives picture to a well-established vasculitis. Like any vasculitis, it can affect the skin and other organs, including skeletal, pulmonary, renal, gastrointestinal, cardiac and ophthalmic systems. The disease is

*Clinical manifestations of cryoglobulinemic vasculitis; (a) severe skin ulcer; (b) nerve biopsy specimen showing vasculitis with a perivascular inflammatory infiltrate; (c) distribution of the peripheral neurological involvement indicating length dependency; (d) renal biopsy showing membranoproliferative* 

*glomerulonephritis; (e) magnetic resonance imaging of the brain showing vasculitis [12].*

Related etiological factors are infections, medications, autoimmune reactions, malignancies or idiopathic reasons. It can be classified as normocomplementemic or NUV that presents normal levels of complement, usually not with systemic involvement, and hypocomplementemic or HUV that has low complement levels and may

The treatment of vasculitis urticaria is a challenge, and there are no guidelines for the management of this disease. There are reports in the literature of the use of hydroxychloroquine and colchicine, which are as effective as systemic corticoste-

Immunosuppressive drugs are used such as azathioprine, mycophenolate mofetil

or cyclophosphamide. Rituximab with the usual doses also seems to have a good response. To manage the symptoms, sedative and nonsedating antihistamines may be used if urticaria is prominent. However, it is not usually effective. Nonsteroidal anti-inflammatory drugs are very useful in these cases such as naproxen, indo-

Another alternative therapy is to combine corticosteroids up to 1 mg/kg and another immunosuppressant (methotrexate, mycophenolate mofetil, azathioprine, cyclosporine and very rarely cyclophosphamide). Recent reports include rituximab,

anakinra, canakinumab and omalizumab as therapeutic arsenal [17].

spectral, ranging from mild to severe [16, 17].

have systemic involvement [17].

methacin and ibuprofen [13, 16].

roids [16, 18].

**Figure 3.**

**Figure 3.**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

peripheral neuropathy [15].

**3.4 Immune complex SVV**

*3.4.1 Cryoglobulinemic vasculitis*

the rarest vasculitis within the group of ANCA-associated vasculitis, and that is why

Corticosteroids are usually used to induce remission of the disease as well as immunosuppressants, for example cyclophosphamide in more severe cases. Longterm maintenance of immunosuppressants is used to prevent disease recurrence, but their long-term efficacy is discussed. Azathioprine has been recommended as maintenance therapy. The efficacy of mepolizumab, an anti-IL5 monoclonal antibody, has been recommended for these patients alone or in combination with corticotherapy. Others monoclonal anti-IL5, reslizumab and benralizumab drugs are still being studied. Studies suggest that rituximab may be effective in EGPA. Other drugs such as IFN-α appear to be effective in remission induction and maintenance; however, the safety profile restricts their use. Drugs such as anti-IgE (omalizumab) are used to control asthma, but their effects are unknown in the treatment of vasculitis. High doses of immunoglobulin have also been used to induce disease remission with good results. Intravenous immunoglobulin may be effective in treating residual

Cryoglobulins are cold precipitated immunoglobulins that can cause vasculitis and vasculopathy. Type I cryoglobulins are responsible for 10–15% of symptomatic vasculitis cases and are related to malignant hematological disorders such as myeloma, B-cell lymphoma or undetermined monoclonal gammopathy (MGUS). Mixed cryoglobulins correspond to 80–85% of cases and are associated with infectious diseases, especially chronic hepatitis C, B-cell malignancies and autoimmune diseases such as Sjögren's syndrome and lupus. Vasculitis is most associated with

In symptomatic patients with cryoglobulinemia type I, it is indicated to treat the hematologic basis diseases. Lymphomas require a combination of chemotherapy and myeloma treatment with drugs such as bortezomib, thalidomide, lenalidomide and other alkylating agents. Bone marrow transplantation can be performed in patients with cryoglobulinemia-associated myeloma. MGUS can be treated with the same myeloma drugs; however, rituximab has been the drug of choice. Plasmapheresis may be used for patients with severe renal involvement or extensive

Mixed cryoglobulins, usually hepatitis C-associated cryoglobulinemic vasculitis, are well-treated as suppression of hepatitis C replication occurs. Studies reported between 2011 and 2013 associated with pegylated interferon (PegIFN) and ribavirin for 12 months achieved a 50–60% control response to hepatitis C. The introduction of antiviral agents dramatically changed cryoglobulinemia-associated vasculitis. They promote shorter treatment without the need for interferon and with responses greater than 95% associated with few adverse effects. The drugs used are sofosbuvir, simeprevir, ledipasvir and daclatasvir, that can be associated with ribavirin. In some cases of more severe vasculitis, low doses of rituximab and other immunosuppressants may be used in selected cases. Rituximab targets B-cell populations that

The term urticaria vasculitis is used for plaques of urticaria that present leukocytoclasia on histopathological examination. It is a clinical pathological diagnosis,

mixed cryoglobulins. Women are affected more than men 2:1 [12].

lower limb necrosis. Avoiding exposure to cold is essential [12].

produce cryoglobulins and treats severe vasculitis [12] (**Figure 3**).

there are no highly recommended treatments based on the literature [15].

**142**

*3.4.2 Urticaria vasculitis*

*Clinical manifestations of cryoglobulinemic vasculitis; (a) severe skin ulcer; (b) nerve biopsy specimen showing vasculitis with a perivascular inflammatory infiltrate; (c) distribution of the peripheral neurological involvement indicating length dependency; (d) renal biopsy showing membranoproliferative glomerulonephritis; (e) magnetic resonance imaging of the brain showing vasculitis [12].*

characterized by a skin inflammation of the dermis capillaries and postcapillary venules, with a range of clinical signs from hives picture to a well-established vasculitis. Like any vasculitis, it can affect the skin and other organs, including skeletal, pulmonary, renal, gastrointestinal, cardiac and ophthalmic systems. The disease is spectral, ranging from mild to severe [16, 17].

Related etiological factors are infections, medications, autoimmune reactions, malignancies or idiopathic reasons. It can be classified as normocomplementemic or NUV that presents normal levels of complement, usually not with systemic involvement, and hypocomplementemic or HUV that has low complement levels and may have systemic involvement [17].

The treatment of vasculitis urticaria is a challenge, and there are no guidelines for the management of this disease. There are reports in the literature of the use of hydroxychloroquine and colchicine, which are as effective as systemic corticosteroids [16, 18].

Immunosuppressive drugs are used such as azathioprine, mycophenolate mofetil or cyclophosphamide. Rituximab with the usual doses also seems to have a good response. To manage the symptoms, sedative and nonsedating antihistamines may be used if urticaria is prominent. However, it is not usually effective. Nonsteroidal anti-inflammatory drugs are very useful in these cases such as naproxen, indomethacin and ibuprofen [13, 16].

Another alternative therapy is to combine corticosteroids up to 1 mg/kg and another immunosuppressant (methotrexate, mycophenolate mofetil, azathioprine, cyclosporine and very rarely cyclophosphamide). Recent reports include rituximab, anakinra, canakinumab and omalizumab as therapeutic arsenal [17].

#### *3.4.3 Immunoglobulin A vasculitis (Henoch-Schönlein purpura)*

It is the most common small vessel vasculitis of childhood, with a predominance of IgA deposits. Typically, it involves the skin, intestines and glomeruli and may be associated with arthralgia and/or arthritis. In most patients, only supportive treatment is required and analgesia [19, 20]. The disease regresses spontaneously most often within 4 weeks, but in some cases, it may last for more than 6 weeks [19]. In these cases, the therapeutic options may be dapsone (on average 1–2 mg/kg) or colchicine, but there are still no randomized controlled trials with the optimal dose and duration of treatment [18, 21]. Some patients require treatment with systemic corticosteroids, such as nephritis, orchitis, cerebral vasculitis, pulmonary hemorrhage and severe gastrointestinal involvement [19].

Other therapies used are the addition of cytotoxic immunosuppressants, intravenous immunoglobulins and plasmapheresis [20]. In case of severe rectal pain or abdominal pain, the use of systemic corticosteroids is recommended [19, 20].

The recommended doses for prednisolone are 1–2 mg/kg/day for 1–2 weeks followed by weaning. In severe cases, it is possible also to use methylprednisolone pulses 10–30 mg/kg maximum 1 g/day for 3 consecutive days. Corticosteroid prophylaxis to decrease the chance of developing nephritis is not indicated. There is evidence showing that the use of angiotensin-converting enzyme inhibitors (ACE inhibitors) may have beneficial effects in patients with proteinuria. In patients with proteinuria longer than 3 months, regardless of whether they are receiving prednisone or another immunosuppressive drug, the use of ACE inhibitors or angiotensin receptor blockers is recommended to prevent and/or limit secondary glomerular injury. The first choice for mild nephritis treatment is prednisolone. If proteinuria persists, azathioprine, mycophenolate mofetil, cyclosporine or other corticosteroidsparing treatment can be started. Also, IV methylprednisolone pulses can be considered.

In the treatment for moderate nephritis, the first line is oral, or IV prednisolone, or IV methylprednisolone. Azathioprine, mycophenolate mofetil IV or cyclosporine may be used according to renal histopathological findings [19].

The treatment for severe nephritis however is high doses of corticosteroids and IV cyclosporine to induce remission, and low doses of corticosteroids associated with azathioprine or mycophenolate mofetil as maintenance treatment [19].

#### **3.5 Variable vessel vasculitis**

#### *3.5.1 Behçet's syndrome*

Behçet's syndrome has been known since ancient times and was described by Hippocrates, but it was reported as a separate disease by Huluci Behçet in 1937. It is currently classified as a vasculitis belonging to the subgroup of variable vessel vasculitis. It was initially reported in countries bordering the silk route, but nowadays, it is found all over the world. The most common manifestation is oral apotheosis and is seen in over 90% of cases [22].

It is characterized by progressing multiple attacks and remissions. The duration of remission may vary from one attack to another and from one system to another. The attack, in most cases, is followed by a complete recovery called Restitutio ad Integrum of the tissue. A good example is oral aphthosis, and it is exceptional to see a scar. In case of oral aphthosis, it is uncommon to have a scar. In other organs such as the eyes, central nervous system and vascular system, we usually observe sequelae, which may even progress to death. In these cases, aggressive treatment is mandatory [22].

**145**

authors [18].

*Vasculitis and Vasculopathies*

and IL-6 blockers [8].

**3.6 Single-organ vasculitis**

*3.6.1 Cutaneous leukocytoclastic angiitis*

lower limbs and can cause arthralgia [24, 25].

agulants [23].

*DOI: http://dx.doi.org/10.5772/intechopen.92778*

drugs are used such as apremilast [23].

Treatment will vary depending on systemic involvement. Mucocutaneous manifestations do not require aggressive treatment, only topical treatment. Arthritis goes on with outbreaks and remissions, which can last from weeks to months, but usually respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). Usually, the remission in these cases is long and the patient may discontinue the medication.

There is usually no progression to destruction and deformities [22, 23].

Treatment of the gastrointestinal tract depends on the severity. For other manifestations, aggressive treatments are often required, starting with cytotoxic/ immunomodulatory drugs associated with corticotherapy. Eventually, biological

When the patient suffers from eye involvement, infliximab or adalimumab anti-TNF drugs may be considered as first- or second-line therapies, or in the exacerbation of pre-existing disease. The European League first recommends corticosteroid-associated azathioprine therapy in all patients with subsequent involvement and the addition of cyclosporine or infliximab, or switching to interferon alfa with or without corticosteroids in patients with severe involvement as more than two drop lines in visual acuity on a 10/10 scale and/or retinal disease (retinal vasculitis or macular involvement) [23]. Other biological drugs are being studied such as IL-1

Intravitreal use of fluocinolone acetonide also has been suggested in refractory

A retrospective multicenter study demonstrated a decrease in relapse in immunosuppressant versus untreated patients. Behçet-associated Budd-Chiari syndrome has a high mortality rate, and monthly cyclophosphamide pulses associated with corticosteroid therapy are the treatment of choice. Anti-TNF-alpha was used in 5 patients with refractory disease. Two of these patients already had terminal liver disease during infliximab administration and died due to liver failure. Two patients were successfully treated with infliximab and the fifth patient was stable with

Cutaneous leukocytoclastic angiitis is an inflammation of small vessels, characterized by an inflammatory infiltrate associated with leukocytoclasia by neutrophil fragmentation and fibrinoid necrosis in small vessel postcapillary venules. It is the most common histological type of cutaneous vasculitis and usually is idiopathic, although antibiotics are also linked [24]. It is often clinically manifested by a palpable purpura, which is found anywhere on the body, but usually affects more

Several symptomatic treatments may be proposed to patients: analgesics, nonsteroidal anti-inflammatory drugs and antihistamines. For chronic or persistent vasculitis, dapsone and/or colchicine may be effective. The use of colchicine in the treatment is beneficial through its effect on reducing neutrophil chemotaxis, blocking leukocyte adhesion and stabilizing lysosomal membranes. Colchicine at a dose of 0.6–1.8 mg/day induces resolution within 1–2 weeks, according to several

cases. In these cases, the increased intraocular pressure and infections should be monitored. With the higher cause of morbidity and mortality, it is vascular involvement. It can affect arteries and veins of any caliber, and with various presentations such as thrombosis, occlusions and aneurysms. Immunosuppressive therapy is one of choices in these cases and there is no consensus regarding antico-

etanercept but had dural sinus thrombosis during follow-up [23].

#### *Vasculitis and Vasculopathies DOI: http://dx.doi.org/10.5772/intechopen.92778*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

*3.4.3 Immunoglobulin A vasculitis (Henoch-Schönlein purpura)*

rhage and severe gastrointestinal involvement [19].

It is the most common small vessel vasculitis of childhood, with a predominance of IgA deposits. Typically, it involves the skin, intestines and glomeruli and may be associated with arthralgia and/or arthritis. In most patients, only supportive treatment is required and analgesia [19, 20]. The disease regresses spontaneously most often within 4 weeks, but in some cases, it may last for more than 6 weeks [19]. In these cases, the therapeutic options may be dapsone (on average 1–2 mg/kg) or colchicine, but there are still no randomized controlled trials with the optimal dose and duration of treatment [18, 21]. Some patients require treatment with systemic corticosteroids, such as nephritis, orchitis, cerebral vasculitis, pulmonary hemor-

Other therapies used are the addition of cytotoxic immunosuppressants, intravenous immunoglobulins and plasmapheresis [20]. In case of severe rectal pain or abdominal pain, the use of systemic corticosteroids is recommended [19, 20]. The recommended doses for prednisolone are 1–2 mg/kg/day for 1–2 weeks followed by weaning. In severe cases, it is possible also to use methylprednisolone pulses 10–30 mg/kg maximum 1 g/day for 3 consecutive days. Corticosteroid prophylaxis to decrease the chance of developing nephritis is not indicated. There is evidence showing that the use of angiotensin-converting enzyme inhibitors (ACE inhibitors) may have beneficial effects in patients with proteinuria. In patients with proteinuria longer than 3 months, regardless of whether they are receiving prednisone or another immunosuppressive drug, the use of ACE inhibitors or angiotensin receptor blockers is recommended to prevent and/or limit secondary glomerular injury. The first choice for mild nephritis treatment is prednisolone. If proteinuria persists, azathioprine, mycophenolate mofetil, cyclosporine or other corticosteroidsparing treatment can be started. Also, IV methylprednisolone pulses can be

In the treatment for moderate nephritis, the first line is oral, or IV prednisolone, or IV methylprednisolone. Azathioprine, mycophenolate mofetil IV or cyclosporine

The treatment for severe nephritis however is high doses of corticosteroids and IV cyclosporine to induce remission, and low doses of corticosteroids associated with azathioprine or mycophenolate mofetil as maintenance treatment [19].

Behçet's syndrome has been known since ancient times and was described by Hippocrates, but it was reported as a separate disease by Huluci Behçet in 1937. It is currently classified as a vasculitis belonging to the subgroup of variable vessel vasculitis. It was initially reported in countries bordering the silk route, but nowadays, it is found all over the world. The most common manifestation is oral apotheosis

It is characterized by progressing multiple attacks and remissions. The duration of remission may vary from one attack to another and from one system to another. The attack, in most cases, is followed by a complete recovery called Restitutio ad Integrum of the tissue. A good example is oral aphthosis, and it is exceptional to see a scar. In case of oral aphthosis, it is uncommon to have a scar. In other organs such as the eyes, central nervous system and vascular system, we usually observe sequelae, which may even progress to death. In these cases, aggressive treatment is

may be used according to renal histopathological findings [19].

**144**

mandatory [22].

considered.

**3.5 Variable vessel vasculitis**

and is seen in over 90% of cases [22].

*3.5.1 Behçet's syndrome*

Treatment will vary depending on systemic involvement. Mucocutaneous manifestations do not require aggressive treatment, only topical treatment. Arthritis goes on with outbreaks and remissions, which can last from weeks to months, but usually respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). Usually, the remission in these cases is long and the patient may discontinue the medication. There is usually no progression to destruction and deformities [22, 23].

Treatment of the gastrointestinal tract depends on the severity. For other manifestations, aggressive treatments are often required, starting with cytotoxic/ immunomodulatory drugs associated with corticotherapy. Eventually, biological drugs are used such as apremilast [23].

When the patient suffers from eye involvement, infliximab or adalimumab anti-TNF drugs may be considered as first- or second-line therapies, or in the exacerbation of pre-existing disease. The European League first recommends corticosteroid-associated azathioprine therapy in all patients with subsequent involvement and the addition of cyclosporine or infliximab, or switching to interferon alfa with or without corticosteroids in patients with severe involvement as more than two drop lines in visual acuity on a 10/10 scale and/or retinal disease (retinal vasculitis or macular involvement) [23]. Other biological drugs are being studied such as IL-1 and IL-6 blockers [8].

Intravitreal use of fluocinolone acetonide also has been suggested in refractory cases. In these cases, the increased intraocular pressure and infections should be monitored. With the higher cause of morbidity and mortality, it is vascular involvement. It can affect arteries and veins of any caliber, and with various presentations such as thrombosis, occlusions and aneurysms. Immunosuppressive therapy is one of choices in these cases and there is no consensus regarding anticoagulants [23].

A retrospective multicenter study demonstrated a decrease in relapse in immunosuppressant versus untreated patients. Behçet-associated Budd-Chiari syndrome has a high mortality rate, and monthly cyclophosphamide pulses associated with corticosteroid therapy are the treatment of choice. Anti-TNF-alpha was used in 5 patients with refractory disease. Two of these patients already had terminal liver disease during infliximab administration and died due to liver failure. Two patients were successfully treated with infliximab and the fifth patient was stable with etanercept but had dural sinus thrombosis during follow-up [23].

### **3.6 Single-organ vasculitis**
