Activation-induced cell death of peripheral blood T lymphocytes in patients with primary Sjögren’s syndrome

Activation-induced cell death (AICD) in T lymphocytes is important for the maintenance of peripheral tolerance. We studied AICD of peripheral blood T cells from patients with primary Sjögren’s syndrome (SS). AICD was induced in mitogen-activated T cellsin vitro using mAb to CD3 or Fas (CD95). Cell death and proliferation, Fas and Fas ligand (FasL) expression, and soluble Fas and soluble FasL production were measured. Surface phenotypes and cytokine production of AICD-surviving cells and effects of cytokines on AICD were examined. Anti-CD3 mAb induced cell death is SS and normal T cells in the presence of exogenous interleukin (IL)-2. In the absence of IL-2 anti-CD3 mAb induced cell proliferation in SS and normal T cells. There was no significant difference in Fas/FasL expression and sFas/sFasL production between SS patients and normals. AICD-surviving cells consisted of more CD4⁺ T cells and less CD8⁺ T cells in SS compared to normals. AICD-surviving cells produced abundant interferon-γ and little IL-4. There was no significant difference in the effects of cytokines on AICD between SS patients and normals. These findings suggest that IL-2 is a critical factor for AICD. AICD works almost normally in SS T cells when sufficient IL-2 is present prior to T cell receptor re-stimulation.     

Activation-induced cell death of peripheral blood T lymphocytes in patients with primary Sjögren’s syndrome

Abstract

Activation-induced cell death (AICD) in T lymphocytes is important for the maintenance of peripheral tolerance. We studied AICD of peripheral blood T cells from patients with primary Sjögren’s syndrome (SS). AICD was induced in mitogen-activated T cells in vitro using mAb to CD3 or Fas (CD95). Cell death and proliferation, Fas and Fas ligand (FasL) expression, and soluble Fas and soluble FasL production were measured. Surface phenotypes and cytokine production of AICD-surviving cells and effects of cytokines on AICD were examined. Anti-CD3 mAb induced cell death is SS and normal T cells in the presence of exogenous interleukin (IL)-2. In the absence of IL-2 anti-CD3 mAb induced cell proliferation in SS and normal T cells. There was no significant difference in Fas/FasL expression and sFas/sFasL production between SS patients and normals. AICD-surviving cells consisted of more CD4⁺ T cells and less CD8⁺ T cells in SS compared to normals. AICD-surviving cells produced abundant interferon-γ and little IL-4. There was no significant difference in the effects of cytokines on AICD between SS patients and normals. These findings suggest that IL-2 is a critical factor for AICD. AICD works almost normally in SS T cells when sufficient IL-2 is present prior to T cell receptor re-stimulation.     

Altered expression of circular RNA in primary Sjögren’s syndrome

Clinical Rheumatology - This study evaluated expression of circRNA in primary Sjögren’s syndrome (pSS) patients so as to find novel biomarkers for pSS screening and discussed possible...     

Anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren’s syndrome

Sjögren’s syndrome (SS) is an autoimmune disease that affects exocrine glands including salivary and lacrimal glands. Recently, autoantibodies against muscarinic acetylcholine receptor M3 (M3R) have been detected in serum from 9 to 100 % of patients with SS in addition to anti-SS-A and anti-SS-B antibodies. These observations suggest the possibility that anti-M3R antibodies could serve as a new diagnostic test in patients with SS. Some anti-M3R antibodies are directly responsible for salivary underproduction in patients with SS. Thus, strategies designed to eliminate such pathogenic antibodies could help cure SS sufferers. In this review, we summarize the current state of knowledge of anti-M3R autoantibodies in patients with SS and the correlation between B cell epitopes and the function of anti-M3R antibodies.     

Higher risk of Parkinson disease in patients with primary Sjögren’s syndrome

Clinical Rheumatology - This study assessed the risk of Parkinson disease (PD) in patients with primary Sjögren’s syndrome (pSS) using a nationwide, population-based cohort during a...     

Manometric assessment of esophageal motility in patients with primary Sjögren’s syndrome

Objective The aim of this study was to assess the esophageal motility by manometry in patients with primary Sjögrens syndrome.Methods Esophageal manometry was carried out in 40 patients with primary Sjögrens syndrome (SS), 15 with rheumatoid arthritis (RA), 15 with RA and secondary SS, and 21 healthy volunteers.Results We found that the mean lower esophageal sphincter (LES) pressures measured by station pull-through and rapid pull-through techniques were significantly higher in primary SS patients than with healthy controls and RA patients with or without SS (P<0.05). Our study did not show any major differences when comparing the three patient groups (P>0.05). However, peristaltic contraction velocity was lower and peristaltic contraction duration significantly higher at the middle and lower thirds of the esophagus in primary SS patients than in healthy controls (P<0.05).Conclusion The results of our study support the view that various esophageal motility disorders can be found in patients with primary SS which could be related to an increase in LES pressure. We also found no correlation of the esophageal abnormalities with other factors studied, suggesting that the cause of dysphagia is multifactorial in nature.     

Effect of the H2 receptor antagonist nizatidine on xerostomia in patients with primary Sjögren’s syndrome

Abstract

In Sjögren’s syndrome (SS), oral dryness (xerostomia) is frequently the most bothersome symptom. An H2 histamine receptor antagonist is often administered to SS patients to treat associated superficial gastritis. The aim of the present study was to assess the ability of nizatidine, an H2 receptor antagonist, to also relieve xerostomia in patients with primary SS. Twenty-seven patients with primary SS were randomly assigned to receive nizatidine (n = 14, 300 mg a day) or another H2 blocker, famotidine (n = 13, 40 mg a day; control), were followed for eight weeks, and were asked for both subjective and objective assessments of oral dryness using a visual analog scale (VAS; 1–100 mm) and the Saxon’s test, respectively. Patients receiving oral nizatidine, but not famotidine, obtained significant objective relief from their xerostomia (Saxon’s test; baseline, 0.57 g/2 min; after eight weeks, 0.90 g/2 min, P < 0.05). VAS scores indicated that nizatidine also provides mild improvement (20% improvement over baseline) of xerostomia-related clinical conditions, including mouth dryness and difficulty in chewing, tasting and swallowing food. Both drugs were generally well tolerated, without adverse effects. The present preliminary study suggests that nizatidine may represent a new option for the treatment of xerostomia in SS.     

Effect of the H2 receptor antagonist nizatidine on xerostomia in patients with primary Sjögren’s syndrome

In Sjögren’s syndrome (SS), oral dryness (xerostomia) is frequently the most bothersome symptom. An H2 histamine receptor antagonist is often administered to SS patients to treat associated superficial gastritis. The aim of the present study was to assess the ability of nizatidine, an H2 receptor antagonist, to also relieve xerostomia in patients with primary SS. Twenty-seven patients with primary SS were randomly assigned to receive nizatidine (n = 14, 300 mg a day) or another H2 blocker, famotidine (n = 13, 40 mg a day; control), were followed for eight weeks, and were asked for both subjective and objective assessments of oral dryness using a visual analog scale (VAS; 1–100 mm) and the Saxon’s test, respectively. Patients receiving oral nizatidine, but not famotidine, obtained significant objective relief from their xerostomia (Saxon’s test; baseline, 0.57 g/2 min; after eight weeks, 0.90 g/2 min, P < 0.05). VAS scores indicated that nizatidine also provides mild improvement (20% improvement over baseline) of xerostomia-related clinical conditions, including mouth dryness and difficulty in chewing, tasting and swallowing food. Both drugs were generally well tolerated, without adverse effects. The present preliminary study suggests that nizatidine may represent a new option for the treatment of xerostomia in SS.     

The composition and function profile of the gut microbiota of patients with primary Sjögren’s syndrome

Clinical Rheumatology - This healthy volunteer control-based study was conducted to explore alterations of compositions and function of gut microbiota in Chinese pSS patients. The high-throughput...     

Insights from the ganglionic acetylcholine receptor autoantibodies in patients with Sjögren’s syndrome

Objective: It is not known whether autonomic neuropathy is a feature of Sjögren’s syndrome (SS) or whether it is related to circulating antiganglionic acetylcholine receptor (gAChR) antibodies. The goal of the present study was to investigate the autonomic dysfunction in patients with SS and the associations between autonomic dysfunction, anti-gAChR antibodies, and clinical features of SS.

Methods: (1) The first observational study tested for the presence of gAChR antibodies in the serum samples from 39 patients with SS (absent information regarding autonomic symptoms) and healthy volunteers. (2) In the second study, serological and clinical data from 10 Japanese patients diagnosed with SS were reviewed. These patients showed autonomic dysfunction, and luciferase immunoprecipitation systems (LIPS) test was conducted to detect anti-α3 and anti-β4 gAChR antibodies. (3) In the final analysis, we combined the data of seropositive SS patients with autonomic symptom from the first study with all of the patients from the second study, and analyzed the clinical features.

Results: (1) The LIPS assay revealed that anti-gAChRα3 and anti-gAChRβ4 antibodies were detected in the sera from patients with SS (23.1%, 9/39). Five of nine SS patients had autonomic symptoms. (2) Anti-α3 and anti-β4 gAChR antibodies were also detected in 80.0% (8/10) of patients with SS with autonomic symptoms. Six of the ten patients were diagnosed as having SS after neurological symptoms developed. These seropositive patients had predominant and severe autonomic symptoms and were diagnosed with autonomic neuropathy. (3) Thirteen of fifteen SS patients with autonomic symptoms (86.7%) were seropositive for anti-gAChR antibodies, and we confirmed sicca complex, orthostatic hypotension, upper and lower gastrointestinal (GI) symptoms, and bladder dysfunction at high rates.

Conclusion: The present results suggest the possibility of anti-gAChR antibodies aiding the diagnostics of SS with autonomic dysfunction.     

Sjögren’s syndrome in patients with ankylosing spondylitis

There are few reports about the coexistence of Sjögren’s syndrome (SS) and ankylosing spondylitis (AS). To evaluate the frequency of SS in patients with AS. We studied 70 patients with AS presenting to the university outpatient clinic between January 2002 and November 2003. All the patients were asked about sicca symptoms by using sicca questionnaire. Rheumatoid factor, anti-nuclear antibody, anti-Ro, and anti-La antibodies were examined for each of the patients. Salivary flowmetry for the existence of xerostomia, Schirmer’s test, and break-up time for the existence of xerophtalmia were performed in all patients with AS. Minor salivary gland biopsy was performed on the patients with at least three positive responses to the sicca questionnaire and positive xerostomia/ xerophtalmia tests. Biopsies were regarded as pathological when they showed focal grade III and grade IV sialoadenitis according to Chisholm grading criteria. Among 70 AS cases, 56 (80%) were men, 14 (20%) were women, and the mean age was 42 years old. Minor salivary gland biopsy was performed on the 16 patients. Of 16 minor salivary gland biopsies, 7 were assessed as pathological—5 of them showed grade III, and 2 of them showed grade IV sialoadenitis. Of these seven patients, one was anti-Ro-positive, and two were anti-La-positive. There was no patient with normal salivary gland biopsy and anti-Ro and/or anti-La positivity. In our study group, 7 (10%) of 70 AS patients had concomitant SS. Therefore, it seems likely that AS may have pathogenetic association with SS.     

The prevalence and the clinical relevance of anti-Ro52 in Korean patients with primary Sjögren’s syndrome

So far, there was no report on the prevalence and clinical relevance of anti-Ro52 in primary Sjögren’s syndrome (pSS) patients in Korea. In this study, we investigated the prevalence and the clinical relevance of anti-Ro52 in Korean patients with pSS. We retrospectively reviewed the medical records of 96 patients with pSS. On the first visit clinical manifestations, laboratory features and autoantibodies were assessed. We divided subjects into 4 groups according to the presence of anti-Ro60 or anti-Ro52 and investigated the association between those autoantibodies and clinical manifestations. Anti-Ro52 (66.7%) was the most frequently detected autoantibody, followed by anti-Ro60 (52.1%) and anti-La (49.0%). Patients with anti-Ro52 had higher frequency of liver and muscle involvements than those without, while anti-Ro60 exhibited negative association with liver involvement. Anti-Ro52 showed significant relative risk for liver involvement (OR = 5.987, P = 0.038, 95% CI = 1.109–32.326), while anti-Ro60 showed inverse relative risk for liver involvement (OR = 0.122, P = 0.003, 95% CI = 0.031–0.479). Anti-Ro52 also showed significant OR for muscle involvement (OR = 9.533, P = 0.044, 95% CI = 1.059–85.793). In conclusion, anti-Ro52 was the most frequently detected autoantibody except ANA in patients with pSS in Korea. Anti-Ro52 was significantly associated with liver and muscle involvements, while anti-Ro60 was inversely associated with liver involvement in Korean patients with pSS.     

Decreased expression of thymic stromal lymphopoietin in salivary glands of patients with primary Sjögren’s syndrome is associated with increased disease activity

Objectives: Thymic Stromal Lymphopoietin (TSLP) is a potent immunomodulatory cytokine involved in Th2- and Th17-mediated immune responses in different autoimmune diseases. TSLP expression in relation to disease activity was studied in salivary glands of primary Sjögren’s syndrome (pSS) patients as compared to non-SS sicca (nSS) controls.

Methods: Tissue sections of minor salivary glands from pSS and nSS patients were stained with monoclonal antibodies against human TSLP, CD3, CD19 and cytokeratin high molecular weight (CK HMW) or stained for Alcian blue to detect mucus production. The number of TSLP-expressing cells was quantified and expression was correlated to local and systemic disease parameters.

Results: The number of TSLP-expressing cells was significantly lower in pSS patients than in nSS controls and correlated with a range of disease markers. In pSS patients, TSLP was expressed outside of lymphocytic infiltrates at sections that also encompassed high numbers of intact acinar cells. This difference was independent of tissue destruction.

Conclusions: Reduced TSLP expression in pSS patients is associated with increased local and systemic inflammatory markers. Loss of TSLP expression may contribute to Th1/Th17-associated immunopathology in pSS, in line with previous studies demonstrating that TSLP promotes a protective Th2 milieu at mucosal sites.     

Targeting primary Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Hallmarks of the disease are a loss of salivary and lacrimal gland function as well as lymphocytic infiltration, elevated proinflammatory cytokines, and circulating autoantibodies. Patients often experience significant fatigue and a decrease in their quality of life. Approximately 30–50% of pSS patients develop extra-glandular manifestations including malignant lymphoma. Although therapeutic approaches for pSS target both dryness and systemic manifestations, effective treatments are limited. However, new therapies targeting specific immune pathways associated with pSS are being developed. This review describes current and future targeted therapies against pSS.     

Efficacy prediction of cevimeline in patients with Sjögren’s syndrome

The objective of this study was to examine the clinical and immunological factors influencing the efficacy of cevimeline hydrochloride hydrate (cevimeline) for the treatment of xerostomia in patients with Sjögren’s syndrome (SS). Thirty primary SS patients who were medicated with cevimeline were enrolled in this study. Whole stimulated sialometry (WSS) was compared between pre- and posttreatment points (4 weeks after oral cevimeline administration) and the increment rate of WSS was calculated. Multiple regression was employed to examine the relative contributions of the clinical and immunological factors, including age, pretreatment WSS, duration of disease, sialography, minor salivary gland biopsy, anti-Ro/SS-A antibodies, anti-La/SS-B antibodies, and antibodies to muscarinic type 3 receptors to the posttreatment WSS. Patients with normal sialography findings, negative minor salivary gland biopsy, and absence of anti-La/SS-B antibodies had significantly higher increment rates of WSS compared with those with positive findings (p?=?0.042, 0.002, and 0.018, respectively). Results of the multiple regression analysis showed that sialography (coefficient = ?0.867, p?=?0.004) and minor salivary gland biopsy (coefficient = ?0.869, p?=?0.003) had significant associations with the posttreatment WSS. Our preliminary results demonstrated the relationship between the effect of cevimeline on saliva secretion and the degree of salivary gland destruction evaluated by sialography and histopathological findings in the labial minor salivary glands. These diagnostic approaches could provide useful prognostic information on the efficacy of cevimeline in SS patients.     

Polymyalgia rheumatica in primary Sjögren’s syndrome

The aim of the study was to describe the clinical and laboratory aspects of primary Sjögren’s syndrome (pSS) associated with polymyalgia rheumatica (PMR). The retrospective study compares the clinical and laboratory aspects of patients with pSS associated with PMR on a relatively large cohort of patients (n=16) and pSS patients without PMR (n=531). The prevalence of PMR among pSS patients was 3%, while in the average population, the prevalence of PMR is only 0.75%. PMR developed 8.7 years after the diagnosis of pSS in the older female pSS population (over 50 years of age), and in those with only glandular features. Interestingly the pSS/PMR patients had hypo gammaglobuline levels, while in the pSS patient group hypergammaglobulinaemia presented. Furthermore, positive ANA serology was more frequent among pSS/PMR patients. Since the clinical management of pSS/PMR is different from pSS, a better understanding of this clinical entity is essential.     

Decreased levels of soluble receptor for advanced glycation end products in patients with primary Sjögren’s syndrome

The purpose of this study was to evaluate the levels of sRAGE in primary Sjögren’s syndrome (SS), and to assess whether there is an association between sRAGE levels and disease characteristics. Thirteen patients were randomly selected from three subgroups: primary SS, (n = 6), secondary Sjögren’s, (n = 4), and ANA(+) but lacking criteria for further disease classification (n = 3). Levels of serum sRAGE were measured in triplicate using an enzyme-linked immunosorbent assay kit. Mean sRAGE levels were significantly lower in the primary Sjögren’s group. Logistic regression analysis indicated that plasma sRAGE level was a significant predictor of diagnostic status. Analyses using routine serological tests for diagnosing autoimmune disorders failed to reach statistical significance. This preliminary study supports the hypothesis that the RAGE system might participate in the disease pathway of primary SS, and that sRAGE may be a potential biomarker to aid in the diagnosis of primary SS.     

Pre-sarcopenia is associated with health-related quality of life in patients with primary Sjögren’s syndrome

Clinical Rheumatology - Primary Sjögren’s syndrome leads to pain and fatigue that may cause impaired muscle function and muscle mass. This study aimed to determine the presence of...     

Effectiveness and safety of abatacept for the treatment of patients with primary Sjögren’s syndrome

Clinical Rheumatology - Sjögren’s syndrome is an autoimmune disease characterized by inflammation of the exocrine glands. The disease can be primary or secondary (if it is associated...