**6. Diagnosis criteria of Sjogren's syndrome**

Over the years (since 2002), pSS recognition has been based on the criteria set by American-European Consensus Group (AECG) in which both Schirmer's test and tear break-up time (BUT) results are assessed. According to former pSS criteria, the examination of salivary secretory function was assessed by measuring minute salivation and evaluation in sialogra‐ phy. From 2012, the American College of Rheumatology (ACR) has proposed new diagnostic criteria that are presented in Table 5 [21–23].


\*Excluding the patients using daily eye drops for glaucoma and who has had corneal surgery or cosmetic eyelid surgery in the last 5 years

#### **Table 5.** Diagnostic criteria of Sjögren's syndrome

It was found that most changes associated with KCS can be demonstrated using the Lissamine green and fluorescein stainings. Both stainings are used for establishing ocular staining score (OSS), determined for each eye separately and used to identify the degree of change in the conjunctiva (Lissamine green) as well as the damage to the cornea (fluorescein) [21]. The slit lamp examination reveals damage to the cornea, but using staining allows for a quantitative and qualitative assessment of these changes. Another test which can be useful in the evaluation of dry eye is a tear osmolality test. However, this test is not included in the criteria for pSS diagnosis [24,25].

The newly proposed criteria also apply to the early stage of diagnosis, when no evidence of the presence of autoantibodies for ribonucleoproteins anti-Ro (SS-A) and anti-La (SS-B) is available. In such a case, the mutual presence of rheumatoid factor (RF) and of antinuclear antibody (ANA, the latter in titer of no less than 1: 320) proves the diagnosis [25].

The important part of establishing pSS diagnosis is confirming the presence of typical changes in histopathology material from minor salivary gland biopsy (MSGB)— mononuclear inflam‐ matory cells form focal infiltrates of more than 50 cells in 4 mm2 of glandular section. The socalled focus score (FS) is based on the assessment of number of such changes in the tested material. The presence of one or more foci is considered as a positive result. Primary Sjogren's syndrome may be accompanied by other than SS-A, SS-B, or RF autoantibodies [26,27]. Most common pSS-specific antibodies, also associated with other autoimmune diseases, are presented in Table 6.


**Table 6.** Autoantibodies in pSS

**6. Diagnosis criteria of Sjogren's syndrome**

criteria that are presented in Table 5 [21–23].

3. Ocular staining score 3 proving keratoconjunctivitis sicca \*

**Sjögren's Syndrome criteria ACR 2012**

156 Advances in Common Eye Infections

Head and neck radiation treatment Active Hepatitis C infection

Graft versus host disease (GVHD) IgG4-related disease (IgG4-RD)

Acquired immunodeficiency syndrome

**Table 5.** Diagnostic criteria of Sjögren's syndrome

Exclusions:

Sarcoidosis Amyloidosis

in the last 5 years

diagnosis [24,25].

Over the years (since 2002), pSS recognition has been based on the criteria set by American-European Consensus Group (AECG) in which both Schirmer's test and tear break-up time (BUT) results are assessed. According to former pSS criteria, the examination of salivary secretory function was assessed by measuring minute salivation and evaluation in sialogra‐ phy. From 2012, the American College of Rheumatology (ACR) has proposed new diagnostic

\*Excluding the patients using daily eye drops for glaucoma and who has had corneal surgery or cosmetic eyelid surgery

It was found that most changes associated with KCS can be demonstrated using the Lissamine green and fluorescein stainings. Both stainings are used for establishing ocular staining score (OSS), determined for each eye separately and used to identify the degree of change in the conjunctiva (Lissamine green) as well as the damage to the cornea (fluorescein) [21]. The slit lamp examination reveals damage to the cornea, but using staining allows for a quantitative and qualitative assessment of these changes. Another test which can be useful in the evaluation of dry eye is a tear osmolality test. However, this test is not included in the criteria for pSS

The newly proposed criteria also apply to the early stage of diagnosis, when no evidence of the presence of autoantibodies for ribonucleoproteins anti-Ro (SS-A) and anti-La (SS-B) is available. In such a case, the mutual presence of rheumatoid factor (RF) and of antinuclear

The important part of establishing pSS diagnosis is confirming the presence of typical changes in histopathology material from minor salivary gland biopsy (MSGB)— mononuclear inflam‐

called focus score (FS) is based on the assessment of number of such changes in the tested

of glandular section. The so-

antibody (ANA, the latter in titer of no less than 1: 320) proves the diagnosis [25].

matory cells form focal infiltrates of more than 50 cells in 4 mm2

1. Positive serum anti-SSA/Ro and/or anti-SSB/La or positive rheumatoid factor and ANA titer 1:320 2. Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score 1 focus/4 mm2

> Several laboratory tests prove helpful in the diagnosis of pSS, although they do not constitute a part of the present diagnostic pSS criteria. In particular, the deviations in the composition of blood cells and proteins occur and the increased erythrocyte sedimentation rate (ESR) with normal or low concentrations of CRP (a similar situation may exist in multiple myeloma) may be present. Laboratory findings in pSS are presented in Table 7.


**Table 7.** Laboratory findings in pSS

**Figure 2.** Sicca ocular staining score [25]

## **7. Prognosis**

The emergence of pSS carries an increased risk (by 40 times – comparing to the normal population) of lymphoma development. This imposes necessity of regular monitoring and assessment in pSS of factors/markers determining patient's total capacity for developing lymphoma, including the emergence of cryoglobulins, rheumatoid factor (if previously not present) or of monoclonal proteins, chronic enlargement of the salivary glands, or persistent presence of general symptoms, such as weight loss, fever, and lymphadenopathy.

#### **7.1. Eye examinations for the diagnosis of KCS and pSS**

The ophthalmic examination includes first of all a well-known Schirmer's test used to evaluate the extent of decrease in the tear secretion.

In the case of significant intensity of dry eye syndrome, the damage to the cornea can be visualized by applying lissamine green and fluorescein staining [28]. This scoring system has been proposed for the evaluation of KCS in Sjögren's syndrome, but applies in general to the changes in the course of dry eye.

The scoring rules are illustrated in Figure 2, and photographs of eye examination in Figures 3 and 4.

The maximum score for each eye is 12. Scoring more than 3 and higher indicates KCS.

The previous AECG pSS diagnosis criteria consisted, in addition to the Schirmer's test, in other tests confirming the presence of KCS and lacrimation disorder, with Bengal rose staining among the most frequently used. This test allows for the assessment of scaly, dead cells of the corneal epithelium, and conjunctiva as well as mucus particles (filaments) fixed to the corneal

**Figure 3.** Fluorescein staining

**7. Prognosis**

eye

158 Advances in Common Eye Infections

**Figure 2.** Sicca ocular staining score [25]

The emergence of pSS carries an increased risk (by 40 times – comparing to the normal population) of lymphoma development. This imposes necessity of regular monitoring and assessment in pSS of factors/markers determining patient's total capacity for developing lymphoma, including the emergence of cryoglobulins, rheumatoid factor (if previously not present) or of monoclonal proteins, chronic enlargement of the salivary glands, or persistent

For fluoresceine staining the extra points could be added :

+ 1 for patches on confluent staining + 1 for staining in pupilary area + 1 for one or more filaments

The ophthalmic examination includes first of all a well-known Schirmer's test used to evaluate

In the case of significant intensity of dry eye syndrome, the damage to the cornea can be visualized by applying lissamine green and fluorescein staining [28]. This scoring system has been proposed for the evaluation of KCS in Sjögren's syndrome, but applies in general to the

The scoring rules are illustrated in Figure 2, and photographs of eye examination in Figures

The previous AECG pSS diagnosis criteria consisted, in addition to the Schirmer's test, in other tests confirming the presence of KCS and lacrimation disorder, with Bengal rose staining among the most frequently used. This test allows for the assessment of scaly, dead cells of the corneal epithelium, and conjunctiva as well as mucus particles (filaments) fixed to the corneal

The maximum score for each eye is 12. Scoring more than 3 and higher indicates KCS.

presence of general symptoms, such as weight loss, fever, and lymphadenopathy.

**Llissamine green (conjunctiva) Fluoresceine (cornea)** grade dots grade dots

0 0‐90 0 1 10‐32 1 1‐5 2 33‐ 100 2 6‐ 30 3 > 100 3 > 30

**7.1. Eye examinations for the diagnosis of KCS and pSS**

Temporal area Nasal area

the extent of decrease in the tear secretion.

changes in the course of dry eye.

3 and 4.

**Figure 4.** Lissamine green staining

surface, associated with the dry eye syndrome. The results of rose Bengal staining, however, are dose-dependent and cause phototoxicity. The lissamine green dye is less irritating and thus considered better for such use. The quality and quantity of the tear film can be evaluated using tear film break up time (T-BUT)—assessing the time interval between the last complete blink and the first appearance of a dry spot or of disruption of the tear film, observed in the slit lamp. The extension of this test uses fluorescein (F-BUT) staining. The diagnosis of DES is established with BUT result ≤5 seconds. The limitations of this test are eye irritation and increased blink after fluorescein application as well as difficulty in meeting the condition that the patient can blink freely [28].

#### **7.2. Own research**

In our study, 30 patients—22 females (73%), 8 males (27%) in mean age of 52 years (from 22 to 85)—diagnosed with pSS revealed stronger correlation of the Schirmer's test results with FS than with OSS. The correlation coefficient of OSS with ANA, anti–SS-A, RF was higher than that of Schirmer's test with anti–SS-A and RF. OSS correlated negatively with Schirmer's test results (r= −0.54; p=0.007). There were no differences between female and male subjects in the Schirmer's test, a group of male patients presented more pronounced symptoms of ocular dryness in the evaluation of staining scores. Our results suggest that the Schirmer's test reflects the intensity of ocular gland infiltration by inflammatory cells, whereas immunostaining proposed in the new Sjögren's syndrome criteria is more closely associated with the immu‐ noactivity and autoantibodies production. It is obvious that the observed correlation requires further support and analysis of research performed on a more numerous group of patients.

#### *7.2.1. Statistical analysis*

Correlation analyses were performed with the Spearman correlation coefficient (because of the non-normal distribution of variables). The study was approved by the Bioethics Commis‐ sion of the Institute of Rheumatology; the subjects have signed written informed consent statements. The study was supported by National Science Center (Narodowe Centrum Nauki) —grant no. 2012/05/N/NZ5/02838. The correlations are shown in Table 8.


**Table 8.** Correlations in patients group with pSS

The data were presented at the 3rd International Congress on Controversies in Rheumatology and Autoimmunity in 2014 [29]. Toker et al. [30] also studied the presence of anti–SS/A and anti–SS/B antibodies in tears and serum as well as assessed the correlations between subjective and objective clinical score of dry eye (then performed Schirmer's test, TBUT test, and rose Bengal staining). This study demonstrated that serum titer of anti-Ro/SSA and anti-La/SSB correlated positively with DESs and negatively with tear production.

#### **7.3. Treatment of pSS**

**7.2. Own research**

160 Advances in Common Eye Infections

*7.2.1. Statistical analysis*

**Table 8.** Correlations in patients group with pSS

In our study, 30 patients—22 females (73%), 8 males (27%) in mean age of 52 years (from 22 to 85)—diagnosed with pSS revealed stronger correlation of the Schirmer's test results with FS than with OSS. The correlation coefficient of OSS with ANA, anti–SS-A, RF was higher than that of Schirmer's test with anti–SS-A and RF. OSS correlated negatively with Schirmer's test results (r= −0.54; p=0.007). There were no differences between female and male subjects in the Schirmer's test, a group of male patients presented more pronounced symptoms of ocular dryness in the evaluation of staining scores. Our results suggest that the Schirmer's test reflects the intensity of ocular gland infiltration by inflammatory cells, whereas immunostaining proposed in the new Sjögren's syndrome criteria is more closely associated with the immu‐ noactivity and autoantibodies production. It is obvious that the observed correlation requires further support and analysis of research performed on a more numerous group of patients.

Correlation analyses were performed with the Spearman correlation coefficient (because of the non-normal distribution of variables). The study was approved by the Bioethics Commis‐ sion of the Institute of Rheumatology; the subjects have signed written informed consent statements. The study was supported by National Science Center (Narodowe Centrum Nauki)

**Correlations Correlation** 

**OSS mean– SS-A** 0,17 **OSS mean– SS- B** 0,00 **OSS mean – FS** 0,13 **OSS mean – RF** 0,04 **OSS mean – ANA** -0,16 **Schirmer's test mean – SS-A** -0,10 **Schirmer's test mean – SS-B** 0,14 **Schirmer's test mean – FS** 0,07 **Schirmer's test mean – RF** 0,20 **test Schirmera średnia – ppj** -0,01 **SA-A – SS-B** 0,56 **OSS mean – Schirmer's test mean** -0,54 **Ro – FS** 0,04 **Ro – RF** 0,20 **Ro – ppj** 0,25 **La – FS** 0,07 **La – RF** 0,20 **La – ppj** 0,27

**coefficient (Spearman test) N=30** 

—grant no. 2012/05/N/NZ5/02838. The correlations are shown in Table 8.

**1.** Systemic treatment of Sjogren's syndrome

The therapy of autoimmune diseases, such as pSS, is based on the elimination of inflammation and inhibition of stimulation of the immune system. Initially, immunosuppressant drugs, such as corticosteroids, methotrexate, cyclosporine A, and azathioprine are applied. For years, the effectiveness and relevance of applying antimalaria drugs for the treatment of pSS have been debated [31–33]. A number of studies confirm beneficial effects of this drug on the symptoms of dryness and the reduction of BAFF in patients with pSS without significant internal organ involvement [32–34]. In severe cases with life threatening organ involvement, the use of cyclophosphamide, infusions of immunoglobulins, and plasmapheresis are considered necessary.

In the case of renal tubular acidosis, sodium and/or potassium are administered. Considering the role of B cells in pSS, monoclonal anti-CD20 (rituximab RTX) antibodies seem to be a favorable option for therapy. RTX has already shown efficacy in the treatment of rheumatoid arthritis, SLE, and vasculitis [35–37]. The full effectiveness of other biologic drugs causing the depletion of B cells—such as Belimumab (BLyS/BAFF inhibitor) and epratuzumab (humanized anti-CD22 monoclonal antibody)—has not yet been confirmed in pSS treatment [38]. The purpose of the therapy could also be the inhibition of interferon alpha and gamma (IFN-α and IFN-γ) involved in the stimulation of B cells, but this course of therapy requires further study.

Currently, the use of mesenchymal stem cell (MSC) transplantation as a method of treat‐ ment of various autoimmune diseases, including Sjogren's syndrome, is also being contem‐ plated [39].

**2.** Topical treatment—the fight against dryness

Apart from the systemic treatment, no less important for pSS patients is local treatment and alleviation of dryness symptoms. Firstly, in the case of dry eye, the influence of exacerbating factors, such as dryness, dust, long hours of working with computer, and smoking, should be limited. It is recommended to use artificial tears during the day and lubricant ointment at night. Agents used as preservatives in medical drops, even those in moisturizers- among them: benzalkonium chloride (BAK) and disodium (EDTA) pose another problem [40]. The use of over-the-counter (OTC) drops with a higher dose of preservatives increases the symptoms of dryness [41].

The wide array of medications is being used in topical treatment: eye lubricants and moistur‐ izers, such as drops, gels, ointments containing tear substitutes, oils and petrolatum, acrylic acid, hyaluronic acid, glycerin, erythritol, levocarnitine, hydroxymethylcellose, carboxyme‐ thylcelulose, or glycol. The preparations without preservatives that replace tears include, e.g., Refresh (Allergan), TheraTears, Soothe (Bausch + Lomb), and System (Alcon) [41].

Ocular lubricants and moisturizers are designed to supplement the shortage of tears, osmo‐ larity, and to improve tear film stability and act protectively. A patient with severe DES both in the course of PSS and from other causes, however, should consult the use of these substances with an ophthalmologist. Increasing the amount of tears can be achieved by permanent occluding of nasolacrimal channel and by the use of biological tear substitutes, namely a drop of the patient's own serum. The inflammatory process in the course KCS also requires antiinflammatory therapy with cyclosporine drops and topical glucocorticoids. Research is being conducted on the use of pimecrolimus and tacrolimus as immunomodulatory drugs in drops. Also drugs stimulating tear secretion with cholinergic agonists are being used and two of them, namely pilocarpine and cevimeline, are used widely. Currently, studies are being carried out on other stimulants, among others diquafosol (P2Y2 receptor agonist) and rebamipide [42,43].

Tetracyclines (minocycline, tetracycline) might also be considered as important drugs for pSS therapy, showing both antibacterial and immunomodulating effect. They have greater than just antimicrobial effect on inflammation by inhibiting the proinflammatory cytokines as TNF or interleukin-1 (IL-1) and also inhibiting angiogenesis. They have been applied to treat eye infections, ocular and skin manifestations of acne rosacea and are used in the case of meibo‐ mian gland dysfunction [44]. In the case of complications of bacterial infection in the course of KCS, typical antibiotics covering the activities of most common pathogens are being used. These include aminoglycosides (e.g., Tobramycin), macrolides, fluoroquinolones, sodium sulfacetamide, or trimethoprim/polymyxin. While wearing contact lenses is as a possible cause of dry eye, in the treatment of DES contact lenses made of special materials such as silicone rubber and highly oxygen permeable materials may protect the eye from drying [45,46].

The surgical treatment, including placement of punctual plugs (collagen or silicone) and cauterization of the puncta, is used in cases of severe corneal injuries and at a risk of a loss of vision. The transplantation of minor salivary glands is an interesting and promising method, but so far with limited use as a therapeutic option [47]. The salivary glands are transplanted as a complex graft to the posterior lamella of the eyelids to increase an ocular surface lubrication and reduce a discomfort in dry eyes.

Frequent blinking is also important for the prophylaxis and complementary action treatment for symptoms of dry eye; avoiding situations that increase the evaporation of the tear film (e.g. wind, air conditioning, and smoking) is recommended as well. The patients with pSS and symptoms of dry eye should be controlled both by a rheumatologist and an ophthalmologist. Routine check of a dry eye should take place at least once every 3 months. However ophthal‐ mologic monitoring frequency will depend on the severity of DESs and the presence of dry eye complications, such as infections. In the latter case, the control should be performed every few days until the infection is cured. The aim of the topical therapy is to eliminate symptoms of dryness and to directly protect mucous membranes. The systemic treatment is directed at achieving a remission—the inhibition of the disease progress, changes in internal organs, and inflammation and infiltration of exocrine glands.

## **8. Summary**

acid, hyaluronic acid, glycerin, erythritol, levocarnitine, hydroxymethylcellose, carboxyme‐ thylcelulose, or glycol. The preparations without preservatives that replace tears include, e.g.,

Ocular lubricants and moisturizers are designed to supplement the shortage of tears, osmo‐ larity, and to improve tear film stability and act protectively. A patient with severe DES both in the course of PSS and from other causes, however, should consult the use of these substances with an ophthalmologist. Increasing the amount of tears can be achieved by permanent occluding of nasolacrimal channel and by the use of biological tear substitutes, namely a drop of the patient's own serum. The inflammatory process in the course KCS also requires antiinflammatory therapy with cyclosporine drops and topical glucocorticoids. Research is being conducted on the use of pimecrolimus and tacrolimus as immunomodulatory drugs in drops. Also drugs stimulating tear secretion with cholinergic agonists are being used and two of them, namely pilocarpine and cevimeline, are used widely. Currently, studies are being carried out on other stimulants, among others diquafosol (P2Y2 receptor agonist) and rebamipide [42,43]. Tetracyclines (minocycline, tetracycline) might also be considered as important drugs for pSS therapy, showing both antibacterial and immunomodulating effect. They have greater than just antimicrobial effect on inflammation by inhibiting the proinflammatory cytokines as TNF or interleukin-1 (IL-1) and also inhibiting angiogenesis. They have been applied to treat eye infections, ocular and skin manifestations of acne rosacea and are used in the case of meibo‐ mian gland dysfunction [44]. In the case of complications of bacterial infection in the course of KCS, typical antibiotics covering the activities of most common pathogens are being used. These include aminoglycosides (e.g., Tobramycin), macrolides, fluoroquinolones, sodium sulfacetamide, or trimethoprim/polymyxin. While wearing contact lenses is as a possible cause of dry eye, in the treatment of DES contact lenses made of special materials such as silicone rubber and highly oxygen permeable materials may protect the eye from drying [45,46].

The surgical treatment, including placement of punctual plugs (collagen or silicone) and cauterization of the puncta, is used in cases of severe corneal injuries and at a risk of a loss of vision. The transplantation of minor salivary glands is an interesting and promising method, but so far with limited use as a therapeutic option [47]. The salivary glands are transplanted as a complex graft to the posterior lamella of the eyelids to increase an ocular surface lubrication

Frequent blinking is also important for the prophylaxis and complementary action treatment for symptoms of dry eye; avoiding situations that increase the evaporation of the tear film (e.g. wind, air conditioning, and smoking) is recommended as well. The patients with pSS and symptoms of dry eye should be controlled both by a rheumatologist and an ophthalmologist. Routine check of a dry eye should take place at least once every 3 months. However ophthal‐ mologic monitoring frequency will depend on the severity of DESs and the presence of dry eye complications, such as infections. In the latter case, the control should be performed every few days until the infection is cured. The aim of the topical therapy is to eliminate symptoms of dryness and to directly protect mucous membranes. The systemic treatment is directed at achieving a remission—the inhibition of the disease progress, changes in internal organs, and

and reduce a discomfort in dry eyes.

162 Advances in Common Eye Infections

inflammation and infiltration of exocrine glands.

Refresh (Allergan), TheraTears, Soothe (Bausch + Lomb), and System (Alcon) [41].

The Sjögren's syndrome is one of the most common rheumatic diseases with predominant symptoms of dryness, particularly of the eye. Therefore, the knowledge on dry eye disease or KCS symptoms is essential not only for ophthalmologic but also for rheumatologic practice. The above section certainly does not exhaust the problem of Sjögren's syndrome, its intricate and still uncertain pathogenesis and a differentiated clinical picture. The author's intention was primarily to draw attention to the problem of DESs and associated complications, including infections.
