Primary Sjögren's syndrome and occupational risk factors: A case–control study

ObjectivesA case–control study was carried out to investigate the relation between primary Sjögren's syndrome (pSS) and occupational exposure.MethodsOne hundred seventy five cases of pSS followed up into the internal medicine departments of three French university hospitals from 2010 to 2013 were included. For each case, two age and gender matched controls were selected during the same period in the same departments. Occupational exposure was assessed retrospectively by industrial hygienists and occupational practitioners. Exposure to occupational factors such as organic solvents or silica was investigated using semiquantitative estimates of exposure. An exposure score was calculated for each subject based on probability, intensity, daily frequency, and duration of exposure for each period of employment. The final cumulative exposure score was obtained, taking into account all periods of employment.ResultsSignificant associations with pSS were observed for dichloromethane (OR 9.28, 95%CI 2.60–33.03), perchlorethylene (OR 2.64, 95%CI 1.20–5.77) chlorinated solvents (OR 2.95, 95%CI 1.77–4.93), benzene (OR 3.30, 95%CI 1.07–10.26), toluene (OR 4.18 95%CI 1.41–12.43), white spirit (OR 3.60, 95%CI 1.39–9.33), aromatic solvents (OR 3.03, 95%CI 1.41–6.50) and any types of solvents (OR 2.76, 95%CI 1.70–4.47). Risk of pSS was significantly associated with a high cumulative exposure score of occupational exposure to toluene (OR 4.69, 95%CI 1.42–15.45), white spirit (OR 3.30, 95%CI 1.07–10.26), aromatic solvents (OR 2.50, 95%CI 1.06–5.91) and any types of solvents (OR 2.25, 95%CI 1.20–4.22).ConclusionThis work suggests the influence of occupational risk factors in the occurrence of pSS.     

Variant form of STAT4 is associated with primary Sjögren's syndrome

Single nucleotide polymorphisms in the STAT4 gene have recently been shown to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Primary Sj?gren's syndrome (pSS) is a related autoimmune disease thought to have a pathogenesis similar to these diseases. To test the hypothesis that the variant haplotype of STAT4 seen in RA and SLE is also associated with pSS, we genotyped rs7574865, the most strongly disease-associated SNP in the variant STAT4 haplotype, in 124 Caucasian pSS subjects and compared them to 1143 Caucasian controls. The disease-associated T allele was more common in chromosomes of the pSS patients (29.6%) than in controls (22.3%), leading to a P-value for association of 0.01. These results implicate polymorphisms in the STAT4 gene in the pathogenesis of pSS.     

A short review of the pathogenesis of Sjögren's syndrome

Sj?gren's syndrome can present in a heterogeneous manner with symptoms varying from systemic features such as unexplained fever, weight loss and neurological manifestations to the more typical symptoms of dry mucus membranes. There is discussion of the wide differential diagnosis, followed by a brief overview of the diagnosis, extraglandular manifestations and pathogenesis of primary Sj?gren's syndrome.     

Sjögren's syndrome and the epithelial target: A comprehensive review

The most difficult component in our understanding of human autoimmunity remains a rigorous dissection of etiological events. Indeed, the vast literature on autoimmune diseases focuses on the inflammatory response, with the hope of developing drugs that reduce inflammation. However, there is increasing recognition that understanding the immunobiology of target tissues will also have direct relevance to disease natural history, including breach of tolerance. Sjögren's syndrome is essentially an epitheliitis and there are major changes to normal architectural salivary organization. We propose that loss of homeostasis is the initial event that precipitates inflammation and that such inflammatory response includes not only the adaptive response, but also an intense innate immune/bystander response. To understand these events this review focuses on the architecture, phenotype, function and epithelial cell organization. We further submit that there are several critical issues that must be defined to fully understand epithelial cell immunobiology in Sjögren's syndrome, including defining epithelial cell polarity, cell–cell and cell to extracellular matrix interactions and a variety of chemical and mechanical signals. We also argue that disruption of tight junctions induces disorganization of the apical pole of salivary acinar cells in Sjögren's syndrome. In addition, there will be a critical role of inflammatory cytokines in the apico-basal relocation of tight junction proteins. Further, the altered disorganization and relocation of proteins that participate in secretory granule formation are also dysregulated in Sjögren's syndrome and will contribute to abnormalities of mucins within the extracellular matrix. Our ability to understand Sjögren's syndrome and develop viable therapeutic options will depend on defining these events of epithelial cell biology.     

HLA and Sjögren's syndrome susceptibility. A meta-analysis of worldwide studies

The aim of this work was to identify common HLA Class II alleles contributing to primary Sj?gren's syndrome (pSS) susceptibility worldwide and to analyze their biological implications through a binding prediction approach of peptides from major pSS auto-antigens. Case-control studies on HLA-DQ and HLA-DR in pSS were searched in various literature databases through April 2011 by a systematic review. The effect summary odds ratios and 95% confidence intervals were obtained by means of the random effect model. A total of 1166 cases and 6470 controls from 23 studies were analyzed. At the allelic level, DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were found to be risk factors for disease. Conversely, the DQA1*02:01, DQA1*03:01 and DQB1*05:01 alleles were protective factors. The current study stresses the significant size effect HLA exhibits in the development of pSS. Analysis of susceptibility and protective alleles revealed physicochemical differences in critical amino acids located within the antigen-binding groove of DRβ, DQα and DQβ chains, allowing us to infer a mechanistic approach to understand the role of HLA in pSS and other autoimmune diseases.     

Crohn's disease associated with Sweet's syndrome and Sjögren's syndrome treated with infliximab

The association of Crohn''s disease (CD) and Sweet''s syndrome is rare and the presence of Sjögren''s syndrome in Crohn''s disease is even rarer, with only three reports found in the literature. We describe two cases of Crohn''s disease associated with Sweet''s syndrome, one of which is the first case of CD and Sweet''s concomitantly associated with Sjögren''s syndrome. Both cases responded rapidly to Infliximab therapy with complete resolution of the skin lesions.     

Primary biliary cirrhosis and Sjögren's syndrome: autoimmune epithelitis

Primary biliary cirrhosis (PBC) has been often coined a model autoimmune disease based on the homogeneity amongst patients, the frequency and similarity of antimitochondrial antibodies, including the highly directed immune response to pyruvate dehydrogenase (PDC-E2). A significant number of patients with PBC suffer from sicca and amongst these, there are patients who also have classic Sj?gren's syndrome. Indeed, both PBC and Sj?gren's syndrome are characterized by inflammation of target epithelial elements. Both diseases can be considered on the basis of a number of other related clinical aspects, including proposed unique apoptotic features of the target tissue, the role of secretory IgA, and the frequency with which both diseases overlap with each other. Indeed, PBC may be considered a Sj?gren's syndrome of the liver, whereas Sj?gren's syndrome can be equally discussed as PBC of the salivary glands. Dissection of the genetic predispositions for both diseases and especially the molecular basis of effector mechanisms, will become critical elements in developing new therapies.     

Diagnostic value of labial minor salivary gland biopsy for Sjögren's syndrome: A systematic review

ObjectivesTo assess the diagnostic value of minor salivary gland biopsy (MSGB) for primary Sjögren's syndrome (pSS).MethodsSystematic review of studies retrieved from PUBMED and EMBASE using the terms ‘salivary glands’ AND ‘Sjögren's syndrome’ AND ‘biopsy’, conducted in patients with suspected pSS, and defining positive biopsies as a focus score (FS) ≥ 1. Sensitivity and specificity of MSGB were abstracted from the articles or calculated when possible.ResultsOf 238 publications identified initially, 9 were included in the study. MSGB sensitivity ranged from 63.5% to 93.7% and specificity from 61.2% to 100%. Specificity was > 89% in six studies. An attempt to separate patients with and without pSS without using MSGB findings or via clinical re-evaluation was made in only two studies, in 73 and 120 patients, respectively, with sicca syndrome in the first study and suspected pSS in the other. The reference standard for diagnosing pSS was a set of criteria that did not include MSGB in the first and patient re-evaluation by three experienced rheumatologists who were aware of MSGB findings in the other. In these studies, sensitivity was 63.9% and 85.7% and specificity was 91.9% and 89.7%, respectively.ConclusionsFew published studies have evaluated the diagnostic usefulness of MSGB in pSS. Only two studies used a methodology that precluded circular reasoning. Our study indicates a lack of information about the diagnostic value of MSGB. Specificity and positive predictive values (PPV) are high and sensitivity is variable.     

Immunization with vaccines and Sjögren's syndrome

Sjögren's syndrome (SjS) is a systemic autoimmune disease with complex pathogenesis and still unknown etiology. Infections are listed among the main environmental factors triggering the disease in genetically predisposed individuals. Among other environmental factors, the role of immunization with vaccines in the etiopathogenesis of SjS has not yet been elucidated. Although immunization with vaccines is safe for the majority of subjects, in rare cases it can trigger or exacerbate autoimmune and rheumatic inflammatory conditions. In this paper we investigate the possible links between immunization with vaccines and the pathogenesis of SjS. The current scientific evidence about safety and efficacy of vaccines in the course of SjS are also reviewed.     

Non-Hodgkin's lymphoma & primary biliary cirrhosis with Sjögren's syndrome

Sj?gren's syndrome (SS) is an autoimmune disease characterized by a lymphocytic infiltration of the salivary and lacrimal glands leading to a progressive destruction of these glands due to the production of autoantibodies. This disorder is either isolated (primary SS) or associated with other systemic diseases (secondary SS). The occurrence of B-cell non-Hodgkin's lymphoma (NHL) represents the major complication in the evolution of SS patients. The risk of developing NHL, which is equivalent for both primary and secondary SS, was estimated to be 44 times greater than that observed in a comparable normal population. NHLs in SS patients occur preferentially in the salivary glands and in other mucosa-associated lymphoid tissues (MALT). However, it can also occur in the lymph nodes or bone marrow. We documented a case of low-grade B-cell lymphoma of MALT in the right eyelid and primary biliary cirrhosis (PBC) of a patient with SS. To the best of our knowledge, this is the first case reported in Korea.     

Val247Leu β2-glycoprotein-I allelic variant is associated with antiphospholipid syndrome: systematic review and meta-analysis

Introduction

Previous studies have suggested that the possession of the Val/Val genotype of the Val247Leu polymorphism of the β₂-glycoproteinI (β₂-GPI) gene may be associated with antiphospholipid syndrome (APS), and, among patients with APS, with the production of anti-β₂-GPI antibodies or the development of thrombosis. Given the controversial results reported, the aim of this work is to combine previous findings by means of a systematic review and a meta-analysis.

Methods

We retrieved studies analyzing the genotype of the above-mentioned polymorphism among patients with APS by means of electronic database search. A meta-analysis was conducted in a random effects model and calculations of odds ratio (OR) and confidence intervals (CI) were done. Sensitivity analysis and tests for heterogeneity of the results were performed.

Results

Eight previous studies analyzed the association of APS, anti-β₂-GPI antibodies and/or thrombosis with the Val247Leu polymorphism. After meta-analysis, patients with APS had a significantly higher prevalence of the Val/Val genotype of this genetic variant when compared with controls (OR = 2.04; 95% CI: 1.12, 3.73; P = 0.02). Among patients with APS, those with anti-β₂-GPI antibodies had a higher prevalence of this genotype (OR = 1.73; 95% CI: 1.04, 2.87; P = 0.03). No significant results were found for the presence of arterial or venous thrombosis.

Conclusions

Val/Val genotype of β₂-GPI gene is associated with a significant excess risk to suffer from APS and, among patients with APS, to have anti-β₂-GPI antibodies. No definite conclusions can be made regarding the association of this polymorphism with thrombosis among APS patients.     

Outcome measures for primary Sjögren's syndrome: A comprehensive review

Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sjögren's syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, great efforts have been made to develop valid tools for the assessment of these both facets. Disease specific questionnaires such as Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptom Inventory (SSI) have been proposed for evaluation of patients' symptoms, whereas different composite indexes have been suggested for the assessment of systemic disease activity. After that, an international project supported by EULAR, emerged to develop consensus disease activity indexes: the EULAR Sjögren's Syndrome Patients Reported Index (ESSPRI), and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. Both EULAR indexes have been developed in an international collaboration to be consensual. Both indices have now been validated in a large independent international cohort. They both have been shown to be feasible, valid and reliable instruments. Also, we have found that these two scores did not correlate, suggesting that these two indexes assess two different disease components that poorly overlap, but were complementary. The sensitivity to change of both scores has been assessed, they are both able to detect change, however, ESSDAI score, like other systemic score, is more sensitive to change than ESSPRI and other patient scores. Current work is ongoing to define disease activity levels and clinically important changes for defining significant clinical improvement with the systemic score ESSDAI, and ESSPRI. We hope that this increased knowledge on the way to assess patients with primary SS, along with the emergence of new targeted therapy, will put a great input in the improvement of conduction of clinical trials in pSS.     

Sjögren's syndrome: A forty-year scientific journey

My long scientific journey studying as a disease model Sjogren's syndrome (SS) gave me the opportunity to uncover the mysteries of systemic autoimmune diseases. After an extensive training, under the supervision of the major autoimmune disease investigators, I was able to convey and expand the acquired knowledge through inspiring my students and collaborators. Our research enriches the understanding of the wide clinical spectrum of the syndrome and the clinical, laboratory and molecular events predicting or being responsible for lymphomagenesis. Our molecular and cellular studies indicated that the target of autoimmunity in SS, the activated glandular epithelial cells, play significant role in the initiation and perpetuation of the autoimmune process. Furthermore, discovery of the epitopes on autoantigens where the autoimmune humoral reactivity is directed against, provided us tools to develop specific and sensitive diagnostic assays, to unmask similarities of the epitope sequence with infectious agents and gave us the potential to use them as therapeutic modalities.     

Beta-adrenergic drugs and risk of Parkinson’s disease: A systematic review and meta-analysis

BackgroundParkinson’s Disease (PD) is a neurodegenerative disorder manifested by rest tremor, rigidity, bradykinesia, and postural instability. Recent pharmaco-epidemiological studies evaluating beta-adrenergic drug use and risk of PD have reported conflicting findings.ObjectivesThis systematic review and meta-analyses evaluate the association between beta-adrenergic (agonists and antagonists) drugs’ use and PD.MethodsAn electronic literature search of eight databases was performed from inception to July 2021 to identify pharmaco-epidemiological studies (case-control and cohort) reporting the risk of PD in beta-adrenergic users compared to non-users. We used the generic inverse variance method and RevMan (5.3.5) to estimate pooled adjusted risk ratios (aRRs) of PD using a random-effects model.ResultsOf 3168 records, 15 studies (10 case-control; five cohort) with 6508,877 participants, including 87,011 PD cases, were included. In the pooled analysis (n = 10) including any beta-antagonist users, compared with non-users, the aRR for PD was 1.19 (CI: 1.05,1.35); for any beta-agonist users (n = 8) aRR for PD was 0.87 (CI: 0.78,0.97). Propranolol users had a significantly increased risk of PD (aRR:1.91; CI:1.20,3.06), whereas salbutamol use was associated with reduced risk of PD (aRR:0.95; CI:0.92,0.99). Significant heterogeneity (I² >87%) was observed, but the majority (n = 13) of the studies were of high quality, based on the JBI tool.ConclusionsBeta-antagonist use was associated with a modestly increased risk of PD, whereas beta-agonist use was associated with a modest decreased risk of PD. Future epidemiological studies should address the issues of protopathic bias and indirect association using appropriate epidemiological methods.     

Primary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue-type in the thymus of a patient with Sjögren's syndrome and rheumatoid arthritis

Primary thymic marginal zone B-cell lymphoma (MZBL) of mucosa-associated lymphoid tissue (MALT)-type is a very rare disease with distinct clinicopathologic features. I herein report a rare case of primary thymic MZBL of MALT-type arising in the thymus in a patient with Sjogren''s syndrome and rheumatoid arthritis. A mediastinal mass was detected by computerized tomography in a 43-yr-old Korean woman with a history of Sjögren''s syndrome and rheumatoid arthritis and the thymus was resected through median sternotomy. The solid and nodular tumor (7x6x3 cm) was confined in the thymus. Histologically, the lymphoid infiltrate comprised monotonous centrocyte-like cells with monocytoid cells, small lymphocytes, and plasma cells. Prominent lymphoepithelial lesions were formed by centrocyte-like cells infiltrating the Hassall''s corpuscles. Immunohistochemically, the tumor cells were positive for CD20, CD79a, and bcl-2 and negative for CD3, CD5, CD10, CD23, and bcl-6. IgA and kappa light chain restriction were also found in plasma cells in the tumor. Sjögren''s syndrome and rheumatoid arthritis are known to be associated with MALT lymphoma and were considered to play an important role in the development of malignant lymphoma in this patient.