BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation.

B-cell activating factor (BAFF) levels are increased in rheumatoid arthritis, lupus and primary Sjögren's syndrome (pSS). However, BAFF contribution to pathogenesis is not completely understood. In pSS, immune infiltration of the salivary and lacrimal glands leads to xerostomia and xerophtalmia. Glandular B cell hyperactivation, differentiation into germinal center (GC)-like structures and plasma cell accumulation are histopathological hallmarks that were attributed to increased BAFF. Here, we experimentally tested this hypothesis by overexpressing BAFF in a mouse model of pSS. BAFF overexpression enhanced lymphocytic infiltration and MHCII expression on B cells. Increased BAFF also induced B cell differentiation into GC B cells within the autoimmune target tissue. However, even in these conditions, GC B cells only accounted for <1% of glandular B cells, demonstrating that BAFF is not efficiently promoting ectopic GC formation in pSS and warranting further investigation of therapeutics targeting both BAFF and the related TNF-family member APRIL.

Relation of Autoimmune Cytopenia to Glandular and Systemic Manifestations in Primary Sjögren Syndrome: Analysis of 113 Korean Patients.

OBJECTIVE: To investigate the characteristics of patients with primary Sjögren syndrome (pSS) who have autoimmune cytopenia. METHODS: We analyzed 113 participants from the Korean Initiative of Primary Sjögren Syndrome, a prospective pSS cohort. Autoimmune cytopenia was defined as autoimmune origin neutropenia, anemia, and/or thrombocytopenia without vitamin or iron deficiency, or drug-induced cytopenia. To identify the association between autoimmune cytopenia and the clinical characteristics of pSS, extraglandular manifestations were analyzed according to the European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) definition. Xerophthalmia was assessed with the Ocular Surface Disease Index, Schirmer I test, ocular stain score (OSS), and tear film breakup time. RESULTS: The median total ESSDAI score was 2 (interquartile range 1-6). About a quarter of patients had no systemic activity. Autoimmune cytopenia was observed in 23.9% of patients (n = 27). Moderate biological features were more frequently observed in patients with autoimmune cytopenia than in patients without [10 (37%) and 11 (12.8%), respectively, p = 0.016]. Articular involvement was exhibited in 1 patient with autoimmune cytopenia, but in 23 patients (27.4%) without autoimmune cytopenia (p = 0.013). Higher OSS (p = 0.002) and lower mean Schirmer I test (p = 0.029) were observed in patients with autoimmune cytopenia than in those without. Neutrophils and lymphocytes negatively correlated with OSS (ρ = -0.204, p = 0.041 and ρ = -0.230, p = 0.020, respectively). CONCLUSION: Autoimmune cytopenia is closely associated with severe ocular surface damage in pSS. Therefore, assessment of xerophthalmia by ophthalmologists may be mandatory, particularly in patients with pSS with cytopenia, even if patients do not complain of eye dryness.

Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D/RAE-1 and release of IFN-γ in experimental dry eye.

The Th1-associated chemokines CXCL9, CXCL10, and CXCL11 coordinate migration of CXCR3(+) Th1 cells. The objective of this study was to evaluate the role of the innate immune system in stimulating chemokine expression in an experimental model of dry eye and bridge the gap between innate and adaptive immunity. Desiccating stress (DS) induced very early (6 h) expression and production of Th1-associated chemokines in cornea and conjunctiva of C57BL/6 and RAG1 knockout (KO) mice, demonstrating that chemokine expression does not require innate T cells. We then demonstrated that activating the innate immune system prior to adoptive transfer of T cells to RAG1KO mice increased disease severity. Interestingly, lack of induction of chemokines CXCL9, CXCL10, and CXCL11 in IFN-γKO mice provided evidence that their expression requires IFN-γ for induction. Treatment of RAG1KO mice with anti-NK1.1 prevented the increase of CXCL9, CXCL10, and CXCL11 in response to DS, compared with isotype controls. Additionally, DS increased the expression of NKG2D in the conjunctiva. The expression of the NKG2D ligand, retinoic acid early inducible gene 1, also increased at the ocular surface at both the protein and gene levels. Neutralization of NKG2D at the ocular surface decreased the expression of CXCL9, CXCL10, CXCL11, and IFN-γ. In summary, upregulation of CXCL9, CXCL10, and CXCL11 expression in experimental dry eye is T cell-independent, requiring IFN-γ-producing NKG2D(+) NK cells that are activated in response to DS-induced stress signals. This study provides insight into the events that trigger the initial immune response in dry eye pathology.

Common and specific associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies in systemic lupus erythematosus.

Little information exists about the association of anti-SSA/Ro60 and anti-Ro52/TRIM21 with systemic lupus erytematosus (SLE) features. In this work, we analysed the associations of both anti-Ro reactivities with clinical and immunological manifestations in 141 SLE patients. Photosensitivity and xerophtalmia/xerostomia were found to be positively associated with both anti-SSA/Ro60 (P = 0.024 and P = 0.019, resp.) and anti-Ro52/TRIM21 (P = 0.026 and P = 0.022, resp.). In contrast, a negative association was detected regarding anti-phospholipid antibodies, anti-SSA/Ro60 having a stronger effect (P = 0.014) than anti-Ro52/TRIM21. Anti-SSA/Ro60 showed a specific positive association with hypocomplementemia (P = 0.041), mainly with low C4 levels (P = 0.008), whereas anti-Ro52/TRIM21 was found to be positively associated with Raynaud's phenomenon (P = 0.026) and cytopenia (P = 0.048) and negatively associated with anti-dsDNA (P = 0.013). Lymphocytes are involved in the relationship between anti-Ro52/TRIM21 and cytopenia since positive patients showed lower cell levels than negative patients (P = 0.036). In conclusion, anti-SSA/Ro60 and anti-Ro52/TRIM21 showed both common and specific associations in SLE. These data thus increase evidence of the different associations of the two anti-Ro specificities even in a particular disease.

Chemokine receptors CCR6 and CXCR3 are necessary for CD4(+) T cell mediated ocular surface disease in experimental dry eye disease.

CD4(+) T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4(+) T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4(+) T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4(+) T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease.

Surfactant protein D contributes to ocular defense against Pseudomonas aeruginosa in a murine model of dry eye disease.

Dry eye disease can cause ocular surface inflammation that disrupts the corneal epithelial barrier. While dry eye patients are known to have an increased risk of corneal infection, it is not known whether there is a direct causal relationship between these two conditions. Here, we tested the hypothesis that experimentally-induced dry eye (EDE) increases susceptibility to corneal infection using a mouse model. In doing so, we also examined the role of surfactant protein D (SP-D), which we have previously shown is involved in corneal defense against infection. Scopolamine injections and fan-driven air were used to cause EDE in C57BL/6 or Black Swiss mice (wild-type and SP-D gene-knockout). Controls received PBS injections and were housed normally. After 5 or 10 days, otherwise uninjured corneas were inoculated with 10(9) cfu of Pseudomonas aeruginosa strain PAO1. Anesthesia was maintained for 3 h post-inoculation. Viable bacteria were quantified in ocular surface washes and corneal homogenates 6 h post-inoculation. SP-D was measured by Western immunoblot, and corneal pathology assessed from 6 h to 4 days. EDE mice showed reduced tear volumes after 5 and 10 days (each by ∼75%, p<0.001) and showed fluorescein staining (i.e. epithelial disruption). Surprisingly, there was no significant difference in corneal pathology between EDE mice and controls (∼10-14% incidence). Before bacterial inoculation, EDE mice showed elevated SP-D in ocular washes. After inoculation, fewer bacteria were recovered from ocular washes of EDE mice (<2% of controls, p = 0.0004). Furthermore, SP-D knockout mice showed a significant increase in P. aeruginosa corneal colonization under EDE conditions. Taken together, these data suggest that SP-D contributes to corneal defense against P. aeruginosa colonization and infection in EDE despite the loss of barrier function to fluorescein.

Anticuerpo anticitrulina y manifestaciones extra articulares en artritis reumatoidea / Anticitrulin antibody and the extra-articular manifestations in rheumatoid arthritis

Los pacientes con artritis reumatidea (AR) pueden desarrollar manifestaciones extra articulares (MExA), relacionadas a su morbi-mortalidad. Los anticuerpos anti-péptidos citrulinados cíclicos (ACCP) son específicos para la AR y estan relacionados con el daño articular; y podrían tener rol patogénico en las MExA. Nuestro objetivo fue determinar la relación entre los anticuerpos ACCP y MExA en pacientes con AR. Se incluyeron 74 pacientes con diagnóstico de AR (ACR 1987) mayores de 18 años, de más de 6 meses de evolución, con MExA, y un control apareado por sexo y edad sin MExA por cada paciente. Las variables demográficas, clínicas y de laboratorio se compararon con test t, chi cuadrado o Mann-Whitney. Se realizó análisis multivariado; p ≤ 0.05. Los pacientes con MExA presentaron mayor título de anticuerpo ACCP (116 vs. 34, p < 0.01) y de factor reumatoideo (FR) (108 vs. 34.5, p < 0.01). En el análisis multivariado hubo asociación entre la presencia de MExA y tabaquismo activo (p = 0.02, OR: 3.78, IC 95%: 1.17-12.2), FR positivo (p = 0.04, OR: 3.23, IC95%: 1.04-11.8) y anticuerpo ACCP positivo (p = 0.04, OR: 3.23, IC 95%: 1.04-10). Presentaron mayor título de anticuerpo ACCP que los controles los pacientes con xerostomía (109 vs. 34, p = 0.04), xeroftalmia (150 vs. 34, p < 0.01), nódulos sub-cutáneos (NSC) (141 vs. 34, p < 0.01) y fibrosis pulmonar (158 vs. 34, p = 0.04). En conclusión, el anticuerpo ACCP positivo, el FR positivo y el tabaquismo activo fueron factores de riesgo independientes para el desarrollo de MExA.

A large proportion of rheumatoid arthritis (RA) patients develop extra-articular manifestations (EAM), which are associated with morbidity and early mortality. Anti cyclic citrullinated peptide (ACCP) antibody has proven to be highly specific for the diagnosis of RA, associated with severe joint damage and may have some role in the pathogenesis of EAM. The aim of this study was to determine the relationship between ACCP antibody and the presence of EAM in RA patients. Seventy four RA patients (ACR 1987) with EAM, > 18 years, more than 6 months duration were included, and an EAM free control, matched by sex and age, for each patient. Demographic, clinical and laboratory variables were compared using t-test, chi-square or Mann-Whitney test. Multivariate analysis was performed: p ≤ 0.05. Patients with EAM presented a greater value of ACCP antibody (116 vs. 34, p < 0.01) and rheumatoid factor (108 vs. 34.5, p < 0.01). Independent association with current smoking habit (p = 0.02, OR = 3.78, 95%: 1.17-12.2), RF positive (p = 0.04, OR 3.23, CI 95%: 1.04 to 11.8) and ACCP antibody positive (p = 0.04, OR 3.23, 95% CI: 1.04-10) was found. The patients with xerostomia (109 vs. 34, p = 0.04), xerophthalmia (150 vs. 34, p < 0.01), subcutaneous nodules (141 vs. 34, p < 0.01) and pulmonary fibrosis (158 vs. 34, p = 0.04) had a higher degree of the ACCP antibody, than controls. In conclusion, ACCP antibody positive, RF positive and smoking were independent risk factors for the development of MEXA.

[Anticitrulin antibody and the extra-articular manifestations in rheumatoid arthritis]. / Anticuerpo anticitrulina y manifestaciones extra articulares en artritis reumatoidea.

A large proportion of rheumatoid arthritis (RA) patients develop extra-articular manifestations (EAM), which are associated with morbidity and early mortality. Anti cyclic citrullinated peptide (ACCP) antibody has proven to be highly specific for the diagnosis of RA, associated with severe joint damage and may have some role in the pathogenesis of EAM. The aim of this study was to determine the relationship between ACCP antibody and the presence of EAM in RA patients. Seventy four RA patients (ACR 1987) with EAM, > 18 years, more than 6 months duration were included, and an EAM free control, matched by sex and age, for each patient. Demographic, clinical and laboratory variables were compared using t-test, chi-square or Mann-Whitney test. Multivariate analysis was performed: p = 0.05. Patients with EAM presented a greater value of ACCP antibody (116 vs. 34, p < 0.01) and rheumatoid factor (108 vs. 34.5, p < 0.01). Independent association with current smoking habit (p = 0.02, OR = 3.78, 95%: 1.17-12.2), RF positive (p = 0.04, OR 3.23, CI 95%: 1.04 to 11.8) and ACCP antibody positive (p = 0.04, OR 3.23, 95% CI: 1.04-10) was found. The patients with xerostomia (109 vs. 34, p = 0.04), xerophthalmia (150 vs. 34, p < 0.01), subcutaneous nodules (141 vs. 34, p < 0.01) and pulmonary fibrosis (158 vs. 34, p = 0.04) had a higher degree of the ACCP antibody, than controls. In conclusion, ACCP antibody positive, RF positive and smoking were independent risk factors for the development of MEXA.

Novel autoantibodies in Sjogren's syndrome.

Sjogren's syndrome (SS) is defined by autoantibodies to Ro and La. The current studies identified additional autoantibodies in SS to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These autoantibodies were present in two animal models for SS and occurred earlier in the course of the disease than antibodies to Ro or La. Patients with SS also produced antibodies to SP-1, CA6 and PSP. These antibodies were found in 45% of patients meeting the criteria for SS who lacked antibodies to Ro or La. Furthermore, in patients with idiopathic xerostomia and xerophthalmia for less than 2 years, 76% had antibodies to SP-1 and/or CA6 while only 31% had antibodies to Ro or La. Antibodies to SP-1, CA6 and PSP may be useful markers for identifying patients with SS at early stages of the disease or those that lack antibodies to either Ro or La.

Cytokines in tear fluid of patients with ocular graft-versus-host disease after allogeneic stem cell transplantation.

PURPOSE: To investigate the profile of cytokines in tear fluid of patients after allogeneic stem cell transplantation (allo-SCT) and determine their relation to the presence and manifestations of ocular graft-versus-host disease (GvHD). METHODS: In this cross sectional study tear fluid was collected in 34 consecutive adult patients that previously underwent allo-SCT (16 with ocular GvHD and 18 without) and 16 age- and gender-matched healthy controls using the Schirmer test under local anesthesia. Tear fluid was analyzed by multiplex immunoassay for the presence of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ. Levels of measured cytokines were correlated with the findings in slit lamp examination and the Ocular Surface Disease Index (OSDI). RESULTS: The levels of IL-6 and IFN-γ in tear fluid in ocular GvHD patients were significantly elevated in comparison to patients without ocular GvHD and healthy controls (p<0.005 for each) The levels of IFN-γ correlated with the Schirmer score (r=-0.48, p<0.0001) and tear break up time (TBUT; r=-0.38, p=0.03). Tear IL-6 levels correlated with complaints of dry eyes (r=0.39, p=0.02), tear production (r=-0.59, p<0.0001), fluorescent staining of the cornea (r=0.42, p=0.01), and with the OSDI score (r=0.40, p=0.005). CONCLUSIONS: IL-6 and IFN-γ were elevated in tear fluid of patients with ocular GvHD and correlated with different symptoms of dry eye disease, suggesting that IFN-γ is elevated during the early stages and IL-6 is involved in later stages of ocular GVHD and exhibits moreover an association with its severity.

Discrimination between Sjögren's and non-Sjögren's sicca syndrome by sialoscintigraphy and antibodies against alpha-fodrin and Ro/La autoantigens.

Both Sjögren's syndrome (SS) and non-Sjögren's syndrome (NSS) can present with the sicca symptoms of dry eyes and a dry mouth but they are distinct pathological entities that require diagnostic discrimination. This study included 82 sicca syndrome patients and examined the ability of sialoscintigraphy and antibodies against the autoantigens alpha-fodrin, Ro and La to discriminate between SS and NSS. A total of 30.8% of SS patients compared with 58.8% of NSS patients were alpha-fodrin positive. The prevalence of Ro positivity was 69.4% for SS patients compared with 0% for NSS patients. The prevalence of La positivity was 52.4% for SS compared with 0% for NSS patients. Sialoscintigraphy showed that more NSS patients had grade III salivary gland impairment compared with SS patients (64.7% versus 19.4%). These data suggest that using sialoscintigraphy in combination with measuring the levels of serum alpha-fodrin, Ro and La might be useful for SS and NSS discrimination.

Treatment of sicca symptoms with hydroxychloroquine in patients with Sjogren's syndrome.

OBJECTIVE: There is no established disease-modifying treatment of xerostomia and xerophthalmia in SS. This retrospective study was performed in order to evaluate the efficacy of HCQ for glandular function, i.e. saliva and tear production. METHODS: Fourteen patients with primary SS (pSS) were included (Group A). All patients were anti-Ro and/or -La antibody positive except one. Patients were treated with HCQ for a period of up to 6 months. Glandular function was determined by Saxon's and Schirmer's tests for the dominant eye at baseline and at the end of the treatment. We included a control group of 21 patients with objective sicca symptoms and positive alpha-fodrin antibodies (Group B). RESULTS: In patients with pSS (Group A), a significant increase in saliva production after HCQ treatment (P = 0.022) was observed. A subanalysis revealed that particularly the alpha-fodrin-positive patients responded to HCQ (P = 0.017 alpha-fodrin positive vs P = 0.4 alpha-fodrin negative). Interestingly, patients with sicca symptoms and alpha-fodrin antibodies (Group B) showed a significant increase in tear production (P = 0.001). In addition, there was a positive correlation between the alpha-fodrin IgA antibody concentration and the Schirmer's test at baseline (r = 0.66; P = 0.001) and after treatment (r = 0.6; P = 0.004) in this group. CONCLUSIONS: HCQ treatment led to a beneficial effect on xerostomia in patients with pSS who lack severe organ manifestations. The response was greater in alpha-fodrin-positive patients.

Ocular surface and intraocular inflammation are related in SS-I and rheumatoid arthritis patients.

The purpose of this study is to evaluate the intraocular inflammation at a sub clinical level, in patients suffering from Sjogren's syndrome (SS-I) and Rheumatoid Arthritis (RA), to relate it with the ocular surface status and to verify the diagnostic performance of the method. Twenty-eight patients suffering from SS-I, 31 patients suffering from RA and 31 normal subjects matched in age and gender were included in the study. A Kowa 500F laser cell flare meter was utilized to quantify the aqueous cells and flare in vivo, ocular surface inflammation was graded by conjunctival cytology and dosage of serum albumin in tears, eye dryness was scored with Tear Function Index. All data resulted significantly different in both SS-I and RA patients vs. control group and also different comparing SS-I vs. RA patients group, except for the Flare values. A blood-aqueous barrier breakdown occurs either in SS-I and RA patients; the degree of the damage is related with ocular surface inflammation and dryness. We recommend the aqueous flare be analysed in those rheumatic patients where an ocular surface inflammation has been documented.

Validity of screening tests for Sjögren's syndrome in ambulatory patients with chronic diseases.

OBJECTIVE: To determine the validity of screening tests for Sjogren's syndrome (SS) in ambulatory patients with chronic diseases. METHODS: Three hundred randomly selected patients from the rheumatology and internal medicine clinics of a tertiary care center were assessed for SS according to the American-European Consensus Group criteria. During the screening phase, an interview, the European questionnaire for sicca symptoms, Schirmer-I test, and the wafer test were carried out in all patients. Patients with positive screening had confirmatory tests including fluorescein staining test, nonstimulated whole salivary flow, and autoantibody testing. Confirmatory tests were also done in 13 patients with negative screening. During the last phase, lip biopsy was proposed to patients who met preestablished criteria. RESULTS: Women made up 79% of the study population. Mean age of subjects was 42.8+/-15.7 years. Two hundred twenty patients (73%) had positive screening. The distribution of positive test results was: xerophthalmia 118 (39%), xerostomia 103 (34%), Schirmer-I test 101 (34%), and wafer test 187 (62%) patients. Forty (13%) patients met criteria for SS. All screening tests were useful for identifying patients with SS; however, the model composed of at least one positive response to the European questionnaire (EQ1), Schirmer-I test, and wafer test showed the best performance. CONCLUSION: Use of the European questionnaire, Schirmer-I test, and wafer test in parallel was useful for identifying patients with SS among ambulatory patients with chronic diseases.

Anti-Ro/SSA antibodies in rheumatoid arthritis: clinical and immunologic associations.

OBJECTIVE: To assess the prevalence of anti-Ro/SSA in RA and to analyse clinical and serological features of anti-Ro/SSA positive patients with RA. METHODS: 195 consecutive patients affected by RA were studied by counterimmunoelectrophoresis and ELISA for the detection of anti-Ro/SSA antibodies. Anti-Ro were found in 12 patients, with a prevalence of 6%. These 12 patients were pooled with other 15 patients known to have anti-Ro/SSA antibodies and RA, in order to evaluate their clinical and laboratory features. RESULTS: Anti-Ro positive patients showed a common pattern of joint involvement at onset and a comparable progression of disease compared to anti-Ro negative subjects. In addition, extra-articular manifestations (such as xerophthalmia, xerostomia, scleritis, oral ulcers and amyloidosis) and peculiar autoantibody profile (hypergammaglobulinemia, anti-dsDNA and AMA) were found significantly associated to anti-Ro/SSA positivity. Even though DMARDs withdrawals were more frequently detected in anti-Ro/SSA patients, especially when using gold salts, no statistical difference between the two groups was detected. In addition, anti-TNFalpha treatment did not cause further progression of autoimmunity neither on laboratory nor on clinical ground. CONCLUSION: Anti-Ro/SSA can be detected in about 6% of patients affected by RA. These patients presented a peculiar clinical picture characterised by extra-articular manifestations some of which are known to be anti-Ro/SSA correlated, while others are more disease-specific (amyloidosis, episcleritis). Anti-Ro/SSA are significantly associated with other autoantibodies not specific for RA such as anti-dsDNA and AMA. Treatment with anti-TNF drugs did not cause further progression of autoimmunity neither on laboratory nor on clinical ground.

Corneal melt as the initial presentation of primary Sjögren's syndrome.

Corneal melting is a rare complication of S ogren's syndrome (SS). Previously reported cases of corneal ulceration occurred in patients with established SS, usually secondary to RA. We describe the first case of corneal ulceration with stromal melting as the initial presentation of primary SS. A 79-year-old man without prior sicca symptoms developed a large sterile corneal ulcer that required extensive treatment over several months with ocular lubricants, systemic immunosuppressives, and surgical repair. Evaluation for an underlying connective tissue disease revealed positive antinuclear antibodies (1:640 speckled) and anti-SSA antibody. A lip biopsy established the diagnosis of SS. Ulceration later occurred in the contralateral eye. Two years after the last corneal ulcer and no longer taking prednisone, the patient's ocular disease remained quiescent taking azathioprine 175 mg and hydroxychloroquine 400 mg daily. This case highlights the potential for primary SS to present with serious ocular complications despite lack of a priori sicca symptoms, as well as the importance of immunosuppressive therapy in the treatment of this complication.

Weak association between subjective symptoms or and objective testing for dry eyes and dry mouth: results from a population based study.

OBJECTIVES: To determine associations between symptoms of dry eyes and dry mouth and objective evidence of lacrimal and salivary gland dysfunction in a population based sample. To determine associations between these elements and the presence of autoantibodies. METHODS: A cross sectional population based survey. Subjects were interviewed and examined (Schirmer-1 test and unstimulated salivary flow) for the presence of dry eyes and mouth. Antibodies (anti-Ro [SS-A], anti-La [SS-B], rheumatoid factor, antinuclear antibody) were measured. RESULTS: 341 subjects were examined. Twenty four per cent had dry eye symptoms, 29% dry mouth symptoms, and 14% both. There was only a weak association between the presence of oral or ocular symptoms and their respective test results. Associations were strongest between dry mouth symptoms and positive test results, and in subjects under 55 years of age. There was no association between the presence of autoantibodies and either symptoms or signs of dry eyes or dry mouth. CONCLUSION: Only weak associations were found between self reported symptoms of dry eyes and dry mouth and objective measures said to define Sjögrens syndrome in the general population. The clinical significance of these symptoms in the community needs reappraisal.

Effect of topical cyclosporin A on conjunctival T cells in patients with secondary Sjögren's syndrome.

The effect of topical cyclosporin A on conjunctival T cells was studied in nine patients with secondary Sjögren's disease. Patients had conjunctival biopsies performed before and after a 6-week course of topical cyclosporin. Epithelium and substantia propria in the Sjögren's patients before treatment showed significantly more CD4+ cells than specimens taken from nine age- and sex-matched controls. Following treatment with topical cyclosporin, there was a significant reduction in the number of CD4+ cells in both the conjunctival epithelium and substantia propria. Despite the fact that the treatment resulted in immunopathological improvement, the clinical benefit was not as favorable. Our results suggest that topical cyclosporin may have a local immunosuppressive effect on the conjunctiva in patients with Sjögren's disease.

Abnormal T-cell subset proportions in vitamin-A-deficient children.

Although vitamin A deficiency in children seems to increase susceptibility to infection and community trials have shown that vitamin A supplementation can reduce childhood mortality from infectious diseases, the underlying biological mechanisms are largely unknown. We conducted a randomised, double-masked, placebo-controlled clinical trial among children in West Java, Indonesia, to determine whether vitamin A deficiency is associated with abnormalities in T-cell subsets and whether vitamin A supplementation affects T-cell subsets. We studied 55 children aged 3-6 years--30 with xerophthalmia and 25 without. Acutely malnourished children (< 80% of reference weight-for-height) were excluded. CD4/CD8 ratios and the proportions of circulating CD4 naive, CD4 memory, CD8, CD45RA, and CD8, CD45RO T-cell subsets were measured. Children with xerophthalmia had lower CD4/CD8 ratios (p < 0.08), lower proportions of CD4 naive T cells (p < 0.03), and higher proportions of CD8, CD45RO T cells (p < 0.04) than those without xerophthalmia. 26 children were given vitamin A supplementation (60 mg retinol equivalent) and 29 received placebo. 5 weeks later the vitamin A group had higher CD4/CD8 ratios (p < 0.001), higher proportions of CD4 naive T cells (p < 0.01), and lower proportions of CD8, CD45RO T cells (p < 0.05) than the placebo group. Vitamin-A-deficient children have underlying immune abnormalities in T-cell subsets and these abnormalities are reversible with vitamin A supplementation.