Sjögren Syndrome without Focal Lymphocytic Infiltration of the Salivary Glands.

OBJECTIVE: Primary Sjögren syndrome (SS) is characterized by a focal lymphocytic infiltrate in exocrine glands. We describe patients who lacked this key feature. METHODS: We evaluated patients with sicca in a comprehensive clinic at which medical, dental, and ophthalmological examinations were performed. All subjects underwent a minor salivary gland biopsy with focus score calculation. Extraglandular manifestations were also determined. We categorized subjects as high, intermediate, or low in terms of expression of interferon (IFN)-regulated genes. RESULTS: About 20% (51 of 229, 22%) of those classified as having primary SS had a focus score of zero. Compared to those with anti-Ro positivity and a focus score > 1.0, the patients with focus score of zero (who by classification criteria must be anti-Ro-positive) were statistically less likely to have anti-La (or SSB) and elevated immunoglobulin, as well as less severe corneal staining. The focus score zero patients were less likely to have elevated expression of IFN-regulated genes in peripheral blood mononuclear cells than anti-Ro-positive SS patients with a focal salivary infiltrate. CONCLUSION: There are only a few clinical differences between patients with primary SS with focus score zero and those with both anti-Ro and a focus score > 1.0. The small subset of focus score zero patients tested did not have elevated expression of IFN-regulated genes, but did have systemic disease. Thus, extraglandular manifestations are perhaps more related to the presence of anti-Ro than increased IFN. This may have relevance to pathogenesis of SS.

Reduction in the inflammatory markers CD4, IL-1, IL-6 and TNFα in dogs with keratoconjunctivitis sicca treated topically with mesenchymal stem cells.

Keratoconjunctivitis sicca (KCS) is of predominantly immune-mediated origin. Dogs are an excellent model for understanding this disease, as the origin of KCS in dogs is like that in humans. The objective of this study was to localize and quantify immunological markers, such as CD4 lymphocytes, interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNFα), before and after topical treatment with mesenchymal stem cells (MSCs). Twenty-two dogs positive for KCS were topically treated with 50 µL (1 × 106 MSCs) in the conjunctival sac and were evaluated for 6 months. The levels of the markers CD4, IL-6, IL-1 and TNFα were analyzed in conjunctival biopsy and cytology of the third eyelid gland by immunohistochemistry and immunocytochemistry. The results showed that before treatment, there was marked expression of all the markers (CD4, IL-6, IL-1 and TNFα), and after 6 months, there were significant (p < .05) reductions in the expression levels of all the markers. These results demonstrated that topical MSC treatment promotes a significant decrease in the expression levels of these inflammatory markers and could be used as adjuvant therapy in the treatment of KCS in dogs and humans. In addition, these markers can be excellent tools for diagnosing and analyzing the progression of KCS.

Rheumatoid factor isotype and Ro epitope distribution in primary Sjögren syndrome and rheumatoid arthritis with keratoconjunctivitis sicca.

Primary Sjögren syndrome (pS) is associated with autoantibodies such as rheumatoid factor (RF) and anti-nuclear antibodies such as anti-Ro (SS-A) and/or La (SS-B). Recent developments within autoimmune diagnostics allow quantitation of RF subclasses and anti-Ro epitopes. Will this refinement by autoimmune diagnostics help predicting development of extraglandular manifestations (EGM) in pS patients? A cohort of pS and rheumatoid arthritis (RA) patients with keratoconjunctivitis sicca (n = 35 and 16, resp) was included. Of the pS patients, 54% developed one or more EGM. Antibodies quantitated were IgM-RF, IgA-RF, IgG-RF, anti-Ro52, and anti-Ro60. Upon analysis of RF isotypes, pS patients generally displayed higher IgA-RF concentrations than RA patients (126 versus 49 U/ml, p = 0.015), while the dominant RF isotype in RA patients was IgM-RF (82.5 versus 38 U/ml, p = 0.012). No differences were observed regarding IgG-RF concentrations. In pS without/with EGM, the median RF IgM concentrations were similar, while RF IgA and IgG concentrations tended to be lower in pS patients with EGM > 1. Both Ro epitopes were strongly recognized by almost all pS patients, independent from EGM, while these antibodies were absent in RA patients. Primary Sjögren syndrome and RA patients have distinct serological profiles when analysing RF and Ro-specific antibodies. A longitudinal study of switched RF isotypes in pS patients is worthwhile from an immunological point of view, but its value is limited regarding identification of pS patients prone to developing EGM or RA patients prone to developing secondary sicca symptoms.

Serologic Markers Are Associated With Ocular Staining Score in Primary Sjögren Syndrome.

PURPOSE: To investigate the relationship between serologic markers and dry eye severity in subjects with primary Sjögren syndrome (SS). METHODS: This study evaluated 64 patients diagnosed with primary SS according to the 2012 Sjögren's International Collaborative Clinical Alliance (SICCA) classification criteria. Serum anti-Ro/SSA, anti-La/SSB, rheumatoid factor (RF), and antinuclear antibody (ANA) levels, Ocular Surface Disease Index (OSDI), Schirmer I test values, tear film breakup time, and SICCA ocular staining score (OSS) were determined. RESULTS: The conjunctival staining scores were 3.3 ± 1.9, 3.6 ± 2.0, 3.4 ± 1.9, and 3.5 ± 1.9 in the positive anti-Ro (≥25 EU), positive anti-La (≥25 EU), positive RF (≥20 IU/mL), and positive ANA (≥1:320) group, respectively. Subjects with positive anti-Ro, anti-La, RF, or ANA had significantly higher conjunctival staining scores compared with those with negative levels (P < 0.05). The total OSS in the positive ANA group was 5.5 ± 3.0, which was significantly higher than the total OSS (3.4 ± 2.1) in the negative ANA group (P = 0.005). Serum RF and ANA levels had strong correlations with conjunctival staining scores and the total OSS but not with corneal staining scores (r = 0.53, P < 0.001 and r = 0.382, P = 0.002). Other ocular parameters (OSDI, Schirmer I test values, and tear film breakup time) did not differ by the serologic marker level. Interestingly, the OSDI was positively correlated with the corneal staining score and total OSS (r = 0.646, P < 0.001 and r = 0.476, P < 0.001). CONCLUSIONS: Serum RF and ANA levels are associated with conjunctival staining scores and the total OSS according to the SICCA OSS in primary SS.

Increased serum levels of high-mobility group box 1 (HMGB1) in primary Sjögren's syndrome.

OBJECTIVE: To determine serum levels of high-mobility group box 1 (HMGB1) in patients with primary Sjögren's syndrome (pSS) as compared to healthy volunteers and patients with sicca symptoms, and to determine whether serum HMGB1 levels are correlated with disease activity in pSS. METHODS: Serum HMGB1 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 101 patients with pSS, 13 patients with sicca symptoms, and 40 healthy volunteers. Clinical and laboratory variables were also analysed and serum HMGB1 levels were correlated with the Sjögren's Syndrome Disease Activity Index (SSDAI). RESULTS: The serum levels of HMGB1 were significantly increased in pSS patients as compared to patients with sicca symptoms and healthy controls (p = 0.04 and p = 0.01, respectively). In the subgroups of patients with anti-SSA autoantibodies, the serum levels of HMGB1 were significantly higher than those in the subgroup of pSS patients who were anti-SSA negative and in healthy controls and patients with sicca symptoms (p < 0.001, p < 0.001, and p = 0.004, respectively). There was no significant correlation between serum HMGB1 levels (in pSS patients with anti-SSA autoantibodies) and SSDAI score (r = 0.03, p = 0.83). Patients with active disease had higher HMGB1 levels than patients with low disease activity (p = 0.04), but HMGB1 levels did not correlate with the SSDAI. CONCLUSION: Serum HMGB1 levels are increased in pSS patients and more specifically in patients with SSA autoantibodies. There was, however, no correlation of HMGB1 with the SSDAI.

[Extracorporeal treatments for some autoimmune eye diseases].

Fifty-three patients with eye diseases caused by autoimmune disorders received complex treatment involving extracorporeal techniques, such as hemosorption, plasmapheresis, and double cascade plasma filtration in combination with pulse therapy. Clinical, laboratory, morphometric, and biochemical studies show the efficacy of hemosorption in relieving acute manifestations of an inflammatory process and the stabilizing action of these methods on ocular epithelial tissue, immunological activity, and systemic manifestations of the underlying disease.

Anticentromere antibody positive Sjögren's Syndrome: a retrospective descriptive analysis.

INTRODUCTION: A subgroup of patients with primary Sjögren's Syndrome (SS) and positive anticentromere antibodies (ACA) were recognized as having features intermediate between SS and systemic sclerosis (SSc). Our goal was to describe this group clinically and serologically and define its tendency to evolve to full blown SSc. METHODS: Among 535 patients with primary SS we identified 20 ACA positive (ACA+/SS). We compared them to 61 randomly selected ACA negative SS patients (ACA-/SS), 31 ACA positive SSc patients with sicca manifestations [SSc/(+) sicca] and 20 ACA positive SSc patients without sicca manifestations [SSc/(-) sicca]. RESULTS: Prevalence of ACA among SS patients was 3.7%. Cases and controls did not differ in sex ratio and age at disease onset. ACA+/SS patients had a lower prevalence of dry eyes, hypergammaglobulinaemia, anti-Ro and anti-La antibodies and a higher prevalence of Raynaud's phenomenon and dysphagia compared to ACA-/SS patients. They also had lower prevalence of telangiectasias, puffy fingers, sclerodactyly, Raynaud's phenomenon, digital ulcers and gastroesophageal reflux in comparison to both of the SSc subgroups and a lower prevalence of dyspnoea and lung fibrosis compared to the SSc/(+) sicca subgroup. Two patients originally having ACA+/SS evolved to full blown SSc. Four deaths occurred, all among SSc patients. Kaplan Meier analysis showed a significant difference between cases and controls in time from disease onset to development of gastroesophageal reflux, telangiectasias, digital ulcers, arthritis, puffy fingers, xerostomia, hypergammaglobulinaemia and dysphagia. CONCLUSIONS: ACA+/SS has a clinical phenotype intermediate between ACA-/SS and SSc and shows little tendency to evolve to SSc.

Study of autoantibodies in patients with keratoconjunctivitis sicca infected by the human T cell lymphotropic virus type 1.

Human T cell lymphotropic virus type 1 (HTLV-1) is endemic in many regions of the world, including Brazil, and has been associated to several immunological manifestations such as arthritis, uveitis, dermatitis and Sjögren's syndrome. This study was intended to evaluate the frequency of autoantibodies in patients infected with HTLV-1 and manifesting keratoconjunctivitis sicca (KCS). HTLV-1 patients with KCS, enrolled in a reference ambulatory of the city of Salvador, were tested for autoantibodies such as antinuclear antibodies, rheumatoid factor, anti-SSA/Ro and anti-SSB/La. Two comparison groups were also included: (a) HTLV-1 patients without KCS and (b) seronegative patients with KCS. Correlation of proviral load (PVL) in HTLV-1 patients with presence or absence of KCS was also assessed. No autoantibodies were detected in HTLV-1 patients with KCS. The PVL of HTLV-1 patients was higher in patients with KCS without other clinical manifestations customarily associated to HTLV-1. In conclusion, in this study, no changes were observed in humoral immunity concerning production of certain autoantibodies in HTLV-1-infected patients with KCS, which suggests that other mechanisms may be involved in the pathogenesis of this manifestation. Additionally, PVL may be a marker of KCS development in these patients.

Differences in clinical findings between Caucasians and African Americans with biopsy-proven sarcoidosis.

OBJECTIVE: To study the prevalence of ocular manifestations in African American and Caucasian patients with biopsy-proven sarcoidosis at the initial ophthalmic examination and to determine the relationship between angiotensin-converting enzyme (ACE) levels, chest x-ray findings, and ocular signs of sarcoidosis. DESIGN: Retrospective, cross-sectional, observational study. PARTICIPANTS: Eighty-one consecutive patients with biopsy-proven sarcoidosis seen at the Doheny Eye Institute from January 1989 through April 2005. METHODS: Medical records were reviewed to obtain demographic data, biopsy site, initial ocular findings, pulmonary symptoms, and results of serum ACE levels and chest x-rays. Associations between ACE level/chest x-ray stages and ocular manifestations related to sarcoidosis were obtained from these data. MAIN OUTCOME MEASURES: Ocular manifestations related to sarcoidosis. RESULTS: Of the 81 patients, 35 were Caucasian; 29 were African American; and the remaining 17 were Hispanic, Asian Indian, and other races. Female patients were older than males (P = 0.05). Sixty-five (80%) of the 81 patients had ocular manifestations related to sarcoidosis. Thirty-three patients (40.7%) had uveitis, 12 (14.8%) had adnexal granulomas, and 25 (30.8%) had keratoconjunctivitis sicca. Of the 33 patients with uveitis, 22 presented with nongranulomatous inflammation. There was no significant association between ocular manifestations related to sarcoidosis and serum ACE levels (P = 0.43) or chest x-ray stage (P>0.99). Of the 29 African American patients, 26 (89.7%) had ocular manifestations related to sarcoidosis, compared with 24 (68.6%) of the 35 Caucasians (P = 0.12). The African American patients were younger (mean age, 44.4 years) than the Caucasian patients (mean age, 52.0) (P = 0.003) and had higher mean ACE levels (P = 0.003). A significantly high proportion of African American males presented with uveitis (P = 0.005), and a significantly high proportion of African American females presented with adnexal granulomas (P = 0.05). CONCLUSIONS: The present study reveals that patients with sarcoidosis can present initially with clinical features of nongranulomatous uveitis. Relative to Caucasians, African American patients with sarcoidosis tend to be younger when they first present to the ophthalmologist and to present with uveitis and/or adnexal granuloma. Serum ACE levels and chest x-ray stages may not help predict the occurrence of ocular changes in sarcoidosis.

Blood concentrations of cyclosporin a during long-term treatment with cyclosporin a ophthalmic emulsions in patients with moderate to severe dry eye disease.

To quantify blood cyclosporin A (CsA) concentrations during treatment with CsA topical ophthalmic emulsions, blood was collected from 128 patients enrolled in a Phase 3, multicenter, double-masked, randomized, parallel-group study of CsA eyedrops for treatment of moderate to severe dry eye disease. Patients received 0.05% CsA, 0.1% CsA, or vehicle b.i.d. for 6 months; vehicle-treated patients then crossed over to 0.1% CsA b.i.d. for 6 months. CsA concentrations were measured using a validated LC/MS-MS assay (quantitation limit = 0.1 ng/mL). No patient receiving 0.05% CsA had any quantifiable CsA in the blood (n = 96 samples). All but 7 of 128 (5.5%) trough blood samples from the 0.1% CsA group were below the quantitation limit for CsA; none exceeded 0.3 ng/mL. CsA was also below the limit of quantitation in 205 of 208 (98.6%) of serial postdose blood samples collected from 26 patients during 1 dosing interval between months 9 and 12. The highest C(max) measured, 0.105 ng/mL at 3 hours postdose, occurred in a 0.1% CsA-treated patient. These results indicate that long-term use of topical CsA ophthalmic emulsions at doses that are clinically efficacious for treating dry eye will not cause any system-wide effects.

Treatment of keratoconjunctivitis sicca with topical androgen.

OBJECTIVE: Androgens have been reported to influence lipid production of sebaceous glands and even many ocular tissues. The effect of topical androgen therapy on a 54-year-old patient with keratoconjunctivitis sicca (KCS) and decreased lipid phase of the tear film is reported. METHODS: For assessment of the lipid phase of the tear film, break up time (BUT) and lipid layer thickness (LLT) were monitored during 6 months before treatment as well as 3 months while using a daily topical androgen therapy. RESULTS: During the topical androgen therapy the pathological lipid phase of the tear film was completely restored indicated by the normalisation of the values of BUT and LLT. CONCLUSION: These findings are consistent with animal experiments indicating that topical administered androgen can restore the decreased lipid phase of the tear film. This may open up new therapeutic strategies for KCS.

Clinical course of primary Sjögren's syndrome: salivary, oral, and serologic aspects.

OBJECTIVE: To assess changes in symptoms and signs, salivary function, serologic activity, and disease progression in primary Sjogren's syndrome (SS). METHODS: Treatment records on 80 patients seen in clinic and diagnosed with primary SS by defined criteria were reviewed. Forty-nine patients were evaluated at least twice a minimum of 5 years (mean 7 years) apart. Salivary flow rates from each of the major salivary glands and laboratory values were obtained. A structured interview with questions pertaining to signs and symptoms of primary SS was given and a physical examination was performed. An additional 26 patients completed a followup questionnaire by mail and their current medical records were obtained for review. For this group, the followup period was a mean of 10 years after their initial evaluation. Five patients were deceased. RESULTS: The patients seen twice showed relative stability in their salivary measurements and in their serologic values. The subjective sicca symptoms of oral and ocular dryness among the 75 surviving patients remained prominent. Very few individuals developed another connective tissue disease, therefore evolving into secondary SS. Among the 80 patients, 6 cases of B cell lymphoma were recognized during the followup period. CONCLUSION: Although it is not a benign condition, primary SS is a very slowly progressing disease without rapid deterioration in salivary function, systemic markers of disease activity, or dramatic changes in symptoms, with the exception of a high incidence of lymphoma.

Incidence of ocular complications in rheumatoid arthritis and the relation of keratoconjunctivitis sicca with its systemic activity.

To investigate the incidence of ocular complications in patients with rheumatoid arthritis under modern modalities of treatment and find the relationship between its systemic activity and ocular complications, routine ophthalmological examinations were done as a prospective study in 111 consecutive patients including 89 inpatients and 22 outpatients with rheumatoid arthritis seen from April to May 1995, in a hospital with a special clinic for rheumatology. Keratoconjunctivitis sicca (secondary Sjögren's syndrome) was found in 19 patients (17.1%), scleritis in one patient (0.9%), central retinal vein occlusion in 2 patients (1.8%), and idiopathic retinal hemorrhage in 3 patients (2.7%). Patients with keratoconjunctivitis sicca had significantly higher titers of rheumatoid factor (Mann-Whitney's U-test, p = 0.0048), higher levels of IgM (p = 0.0484), and lower levels of HDL-cholesterol (p = 0.0191), compared to patients without it. The incidence of ocular complications was comparable to the previous studies and keratoconjunctivitis sicca should be considered in patients with high titers of rheumatoid factor.

[Keratoconjunctivitis sicca in patients with lipoprotein (a) elevation]. / Keratoconjunctivitis sicca bei Patienten mit Lipoprotein-(a)-Erhöhung.

BACKGROUND: Elevated Lp(a) levels are known as risk factor for premature coronary artery disease and apoplexy. To our knowledge ophthalmologic alterations have not been described in combination with elevated Lp(a) levels. We examined whether patients with LP (a) elevation had an increased incidence of keratoconjunctivitis sicca. PATIENTS AND METHODS: 27 patients, 16 women and 11 men were examined. The Lp(a) value was in all patients definitively pathological. The following examinations were performed: history, slitlamp examination, Schirmer-test, impressioncytology, fluorescein staining of the cornea, applanation tonometry and examination of the ocular fundus. RESULTS: The results show a pathologic Schirmer-test in 70.3% of the eyes, in 81.5% a pathologic impressioncytology, and in 48.1% a pathologic fluorescein staining. The Schirmer-test is not sufficiently sensitive and specific in diagnosing the dry eye, whereas impression cytology is highly sensitive and specific. CONCLUSIONS: We could show, that in more than 80% of the examined patients at least one sign of keratoconjunctivitis sicca was found; however we did not find a correlation between the height of the Lp(a) level and the degree of pathologic impression cytology. Further examinations are needed to investigate the causal connection between keratoconjunctivitis sicca and Lp(a) elevation.

Sjogren's syndrome and keratoconjunctivitis sicca.

Keratoconjunctivitis sicca patients diagnosed on the basis of a history, dry-eye symptoms, and definite clinical signs of keratoconjunctivitis sicca, with the associated symptoms of dry mouth and/or arthritis, had measurements of tear osmolarity, Schirmer tear test without anesthetic, stimulated parotid salivary flow, and serum analysis for the presence of autoantibodies associated with Sjogren's Syndrome. In contrast to previous studies, a lower incidence of SS-A or SS-B (1-3%), ANA (41-47%), DNA (11-16%), and RF (9-12%) serum antibodies was detected. Salivary-stimulated parotid flow was abnormally decreased in 59% of the patients. Sjogren's syndrome, as indicated by the presence of serum antibodies, appears to have a lower incidence in keratoconjunctivitis sicca than considered previously.

Beneficial effect of topical fibronectin in patients with keratoconjunctivitis sicca of Sjögren's syndrome.

Fibronectin, a high molecular weight plasma protein, was applied locally to 12 patients with keratoconjunctivitis sicca of Sjögren's syndrome refractory to conventional treatment. All patients had ophthalmologically proved keratoconjunctivitis sicca of unknown etiology and were suffering from severe eye symptoms. Fibronectin was purified from autologous plasma and administered to the patients as tear drops 3 times a day. All patients responded to the therapy with fewer subjective symptoms and decreased fluorescein staining. All but 3 responded to the therapy as judged by rose bengal test. No adverse effects were encountered. We conclude that local application of fibronectin may benefit patients with keratoconjunctivitis sicca of Sjögren's syndrome.