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Sjögren's syndrome (SS) is a chronic autoimmune disease with broad clinical spectrum, extending from benign exocrinopathy to severe systemic disease and lymphoma development. The glandular and extraglandular dysfunction of SS is associated with lymphocytic infiltrates that invade the epithelial structures of affected organs. The in-depth study of autoimmune lesions in the minor salivary glands (MSG), which are the major target-organ of SS responses, revealed that the lymphocytic infiltrates vary in severity and composition among SS-patients, are full-blown at diagnosis and remain unchanged thereafter. Although the pathogenetic pathways underlying SS have not yet elucidated, it is well-established that glandular epithelial cells are central regulators of local autoimmune responses. Moreover, chronic inflammation affects epithelial function and phenotype, which strengthens or weakens their immunoregulatory/secretory function, leading to deterioration of autoimmune phenomena. Herein, the current findings regarding the autoimmune lesions, the role of epithelial cells and their interaction with infiltrating lymphocytic cells are discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Autoimmune diseases constitute a diverse group of disorders characterized by cellular and humoral responses against self. The humoral autoimmune responses are directed against various cellular and extracellular components. These responses are highly specific for each autoimmune disease and result in the production of autoantibodies that characterize certain disease entities, representing a valuable tool for the diagnosis of autoimmune diseases. Furthermore, certain autoantibodies are helpful in the prognosis of disease development, progression and severity, as well as in the classification of patients with distinct disease subtypes. Today, the value of autoantibodies in the follow-up of patients is limited, but preliminary data suggest that they may be useful in predicting response to treatment.

Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example anti-tumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients., Competing Interests: Compliance with Ethical Standards Required Author Forms Disclosure forms provided by the authors are available with the online version of this article.

Background: Primary Sjogren's syndrome (pSS) is characterized by the presence of autoantibodies targeting mainly the Ro/La ribonucleoprotein complex. It is now appreciated that the production of autoantibodies is an antigen-driven immune response., Design: In this review, candidate mechanisms for autoantigen presentation and perpetuation of the autoimmune response within the autoimmune tissue lesion of pSS are discussed., Results: Several studies have shown that the epithelial cell in labial salivary glands of patients with Sjogren's syndrome is activated, bearing characteristics of an antigen-presenting cell, as suggested by inappropriate expression of class II HLA and co-stimulatory molecules. Other studies have confirmed that in salivary glands, there is an increased autoantigen presentation via apoptotic blebs and bodies, exosomes and heat shock protein-mediated cross-priming. There is also an increased expression of interferon (IFN)-induced genes, such as the autoantigen Ro52, which provide negative feedback regulation in inflammation. Ro60 and La autoantigens also appear to play a major role in the local autoimmune response in Sjogren's syndrome. In this regard, La and Ro60 the messenger RNA (mRNA) expression is upregulated in the affected salivary glands with different isoforms of La autoantigen mRNA to be expressed in patients with pSS. At the protein level, La/SSB in pSS salivary glands is found to be post-translationally modified., Conclusions:  Autoantigen alterations in a microenvironment of local inflammation with increased in situ apoptosis, Toll-like receptor (TLR) signalling and antigen presentation may drive the autoimmune response and local autoantibody production in pSS., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

Sjögren's syndrome is a chronic inflammatory process that primarily involves the exocrine glands. Its clinical manifestations range from autoimmune exocrinopathy to extraglandular (systemic) involvement affecting the lungs, kidneys, blood vessels, and muscles; it can occur alone (primary Sjögren's syndrome) or in association with other autoimmune diseases (secondary Sjögren's syndrome). In recent years, clinical and laboratory observations have highlighted the central role of the epithelial cell and it has been suggested that the etiological name of the disease should be 'autoimmune epithelitis'. The extraglandular manifestations of the disease are divided in two groups: (1) lung, kidney (interstitial nephritis), and liver involvement as a result of lymphocytic invasion in epithelial tissues; and (2) skin vasculitis, peripheral neuropathy, and glomerulonephritis, with low C4 levels, which is the result of immune complex disease, are associated with increased morbidity and high risk for lymphoma. The diagnosis of the disease is based on the classification criteria, raised by the American-European Study Group and which have been built on the European preliminary classification criteria, developed in 1992. The association of Sjögren's syndrome with lymphoma is well documented as in approximately 5% of patients the benign autoimmune process is transformed into a lymphoid malignancy. The salivary extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue type are the most common lymphoma in Sjögren's syndrome. These tumors are antigen-stimulated B-cell lymphomas and are characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. Among the clinical and serological parameters that have been associated with lymphoma development in patients with Sjögren's syndrome, the presence of palpable purpura, low C4 and mixed monoclonal cryoglobulinemia constitute the main predictive markers; patients displaying these risk factors should be monitored closely. The purpose of this review is to discuss the clinical picture, the diagnostic procedure, and the malignant lymphoproliferation in the disease.

Heat-shock or stress proteins (HSPs) are intracellular molecules that are expressed under cellular stress and have housekeeping and cytoprotective functions. Many of them act also as molecular chaperones, assisting the correct folding, stabilization, and translocation of proteins. In pathological situations, such as necrotic cell death, they can be released into the extracellular environment complexed with intact or fragmented cellular proteins. Evidence is now accumulating to indicate that, under certain circumstances, these complexes can contribute to induction of autoimmunity by receptor-mediated activation of the innate immune response (signaling the "danger") and by participation in the presentation of autoantigens for the adaptive immune response (acting as natural adjuvants). In addition, the conservation of HSPs through prokaryotes and eukaryotes, together with the increased production of host and microbial HSPs at the site of infection, has led to the proposition that these proteins may provide a link between infection and autoimmunity. This review outlines the mechanisms for the potential involvement of chaperones in the induction of autoimmune disease.

A common laboratory finding in systemic autoimmune diseases is the presence of autoantibodies against intracellular autoantigens. Although their pathogenesis is not fully understood, autoantibodies are important tools for establishing diagnosis, classification, and prognosis of autoimmune diseases. Autoantibodies mainly target multicomponent complexes containing both protein antigens and (ribo)-nucleic acid(s), such as the spliceosome or Ro/La RNPs. In this review, we address the main characteristics and the clinical value of the main autoantibody types with respect to their disease association, and we describe the corresponding autoantigens, their biologic function, and their B-cell antigenic determinants (epitopes). The structural characteristics and clinical associations of these epitopes, and their utility as tools to investigate the autoimmune response, are discussed in detail. New insights into the pathogenetic role of epitopes in systemic autoimmunity are also examined. In this regard, using the defined structures of the B-cell antigenic epitopes, complementary epitopes can be designed according to the "molecular recognition" theory. These complementary epitopes can be used as probes to study pathogenetic and immunoregulatory aspects of the anti-idiotypic response. The origin of humoral autoimmunity and the spreading of the epitopes in systemic lupus erythematosus are also discussed. Finally, the ability of post-translational modifications to induce autoreactive immune attack via the generation of neo-epitopes is summarized.

An increased prevalence of hematologic malignancies is often described in patients with Sjögren's syndrome (SS). Viruses have been proposed as possible etiologic or triggering agents of systemic autoimmune diseases (SADs), with hepatitis C virus (HCV) being one of the viruses most frequently associated with autoimmune features and with systemic autoimmune diseases such as mixed cryoglobulinemia or SS. Moreover, the association between HCV infection and hematologic malignancies, mainly non-Hodgkin's lymphoma (NHL), is supported by several studies. For these reasons, the recognized association of specific systemic autoimmune diseases (mainly SS and mixed cryoglobulinemia) with HCV infection, added to the possible evolution of any one of these entities into a B-cell NHL, suggests the possibility of a close relationship among SS, HCV and B-cell lymphoproliferative disorders, especially in patients with type II mixed cryoglobulinemia.

Among other systemic autoimmune diseases, primary Sjögren syndrome (pSS) bears the highest risk for lymphoma development. In pSS, chronic antigenic stimulation gradually drives the evolution from polyclonal B-cell expansion to oligoclonal/monoclonal B-cell predominance to malignant B-cell transformation. Thus, most pSS-related lymphomas are B-cell non-Hodgkin lymphomas (NHLs), with mucosa-associated lymphoid tissue (MALT) lymphomas predominating, followed by diffuse large B-cell lymphomas (DLBCLs) and nodal marginal zone lymphomas (NMZLs). Since lymphomagenesis is one of the most serious complications of pSS, affecting patients' survival, a plethora of possible predisposing factors has been studied over the years, ranging from classical clinical, serological, hematological, and histological, to the more recently proposed genetic and molecular, allowing clinicians to timely detect and to closely follow-up the subgroup of pSS patients with increased risk for lymphoma development. Overall predisposing factors for pSS-related lymphomagenesis reflect the status of B-cell hyperactivity. Different clinical features have been described for each of the distinct pSS-related B-cell NHL subtypes. While generally pSS patients developing B-cell NHLs display a fairly good prognosis, outcomes in terms of treatment response and survival rates seem to differ depending on the lymphoma subtype, with MALT lymphomas being characterized by a rather indolent course and DLBCLs gravely affecting patients' survival. [ABSTRACT FROM AUTHOR]

There is strong evidence that COVID-19 pathophysiology is mainly driven by a spatiotemporal immune deregulation. Both its phenotypic heterogeneity, spanning from asymptomatic to severe disease/death, and its associated mortality, are dictated by and linked to maladaptive innate and adaptive immune responses against SARS-CoV-2, the etiologic factor of the disease. Deregulated interferon and cytokine responses, with the contribution of immune and cellular stress-response mediators (like cellular senescence or uncontrolled inflammatory cell death), result in innate and adaptive immune system malfunction, endothelial activation and inflammation (endothelitis), as well as immunothrombosis (with enhanced platelet activation, NET production/release and complement hyper-activation). All these factors play key roles in the development of severe COVID-19. Interestingly, another consequence of this immune deregulation, is the production of autoantibodies and the subsequent development of autoimmune phenomena observed in some COVID-19 patients with severe disease. These new aspects of the disease that are now emerging (like autoimmunity and cellular senescence), could offer us new opportunities in the field of disease prevention and treatment. Simultaneously, lessons already learned from the immunobiology of COVID-19 could offer new insights, not only for this disease, but also for a variety of chronic inflammatory responses observed in autoimmune and (auto)inflammatory diseases. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj5 knockout mouse model for Sjögren's syndrome and to elucidate possible mechanisms for the morbid phenotype development. At the same time, we describe for the first time the sexual dimorphism of the murine submandibular salivary gland at the proteome level. Methods: We performed Liquid Chromatography/Mass Spectrometry in salivary gland tissues from both sexes of ERdj5 knockout and 129SV wildtype mice. The resulting list of proteins was evaluated with bioinformatic analysis and selected proteins were validated by western blot and immunohistochemistry and further analyzed at the transcription level by qRT-PCR. Results: We identified 88 deregulated proteins in females, and 55 in males in wildtype vs knockout comparisons. In both sexes, Kallikrein 1b22 was highly upregulated (fold change>25, ANOVA p<0.0001), while all other proteases of this family were either downregulated or not significantly affected by the genotype. Bioinformatic analysis revealed a possible connection with the downregulated NGF that was further validated by independent methods. Concurrently, we identified 416 proteins that were significantly different in the salivary gland proteome of wildtype female vs male mice and highlighted pathways that could be driving the strong female bias of the pathology. Conclusion: Our research provides a list of novel targets and supports the involvement of an NGF-mediating proteolytic deregulation pathway as a focus point towards the better understanding of the underlying mechanism of Sjögren's syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Sjögren's syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients' morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements. Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients' management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren's syndrome covering several research fields including clinical, translational, and basic research has been reviewed. Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis. [ABSTRACT FROM AUTHOR]

Objectives: Development of non-Hodgkin's lymphoma (NHL) is the major adverse outcome of Sjögren's syndrome (SS) affecting both morbidity and mortality. Preliminary evidence suggested that, although not deregulated compared with sicca controls, miR200b-5p levels are decreased in the minor salivary glands (MSGs) of SS patients with NHL. The aim of the current study was to evaluate the MSG expression of miR200b-5p in SS-associated NHLs and its potential predictive value for the identification of patients with SS susceptible to develop NHL.Methods: miR200b-5p expression was investigated in MSG tissues of patients with SS who were at: (A) low risk and did not develop NHL during follow-up (n=27; median follow-up time on biopsy performance, range: 8.9 years, 1.33-14 years), (B) high-risk and diagnosed with NHL during follow-up (prelymphoma; n=17; median follow-up to until lymphoma diagnosis, range: 3.67 years, 0.42-8.5 years) and (C) had NHL (n=35), as well as non-SS sialadenitis controls (sarcoidosis and hepatitis C virus (HCV) infection, four each). The differential miR200b-5p expression, correlations with disease features and its discriminative/predictive value, was evaluated by appropriate statistical approaches.Results: The MSG levels of miR200b-5p were significantly downregulated in patients with SS who will develop or have NHL and strongly discriminated (p<0.0001) them from those without lymphoma or non-SS sialadenitis. Furthermore, they were reduced long before clinical onset of lymphoma, did not significantly change on transition to lymphoma and, importantly, were proved strong independent predictors of patients who will develop NHL (p<0.0001).Conclusions: These findings support that miR200b-5p levels in MSGs represent a novel predictive and possibly pathogenetic mechanism-related factor for the development of SS-associated NHL, since its expression is impaired years before lymphoma clinical onset. [ABSTRACT FROM AUTHOR]

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus. [ABSTRACT FROM AUTHOR]

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN path-ways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ-induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS), a chronic autoimmune disorder, particularly compromises the function of exocrine glands. The involvement of these glands is characterized by focal, mononuclear cell infiltrates that surround the ducts and replace the secretory units. The pathogenetic mechanisms of this autoimmune exocrinopathy have not been fully elucidated. Immunologically-activated or apoptotic glandular epithelial cells that expose autoantigens in genetically predisposed individuals might drive autoimmune-mediated tissue injury. Alterations in several immune mediators, such as upregulation of type I interferon-regulated genes, abnormal expression of B-cell-activating factor and activation of the interleukin-23-type 17 T-helper cell pathway, have been reported. Extension of the pathological process that affects the exocrine glands into periepithelial and extraepithelial tissue can cause a considerable percentage of patients to exhibit systemic findings that involve the lungs, liver or kidneys. These manifestations develop as a result of lymphocytic invasion or an immune-complex-mediated process, or both, and present as skin vasculitis coupled with peripheral neuropathy or glomerulonephritis (or both). Patients with systemic extraepithelial manifestations display low serum levels of the complement component C4 and mixed type II cryoglobulins, and show an increased risk of developing non-Hodgkin lymphoma, thereby reflecting an overall worse prognosis with higher mortality rates than those without extraepithelial manifestations. [ABSTRACT FROM AUTHOR]

Interactions among the immune, nervous and endocrine systems, which are mediated by hormones, neuropeptides, neurotransmitters, cytokines and their receptors, appear to play an important role in modulating host susceptibility and resistance to inflammatory disease. The neuroendocrine system has two main components: the central and the peripheral. The central compartment is located in the locus ceruleus, the brainstem centers of the autonomic system and the paraventricular nucleus; the peripheral mainly consists of the sympathetic/adrenomedullary system, the hypothalamic-pituitary-adrenal axis (HPA), the hypothalamic-pituitary-gonadal (HPG) axis, and the neuroendocrine tissue located in several organs throughout the body. Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways or alter the function of different cell types in target organs. Recent studies highlighted alterations of the neuroendocrine system in systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and Sjögren’s syndrome (SS). SS, a prototype autoimmune disorder, has a wide clinical spectrum, extending from organ involvement (autoimmune exocrinopathy) to systemic disease and B cell lymphoma. In SS, several functions of the neuroendocrine system are impaired. First, the HPA axis appears to be disturbed, since significantly lower basal ACTH and cortisol levels were found in patients with SS and were associated with a blunted pituitary and adrenal response to ovine corticotropin-releasing factor compared to normal controls. Second, HPG axis is also involved, since lack of estrogens is associated with human disease and the development of autoimmune exocrinopathy in several experimental models. Finally, exocrine glands are enriched with neuroendocrine-related molecules, adjacent to local autoimmune lesions. Certain clinical manifestations of the disease, including the sicca manifestations, easy fatigue, fibromyalgia and psychological disturbances can be very well explained by mechanisms directly related to disturbances of the neuroendocrine axis. On the other hand, the molecular and biochemical effects of the inflammatory molecules or cell-to-cell interaction, observed during the local or systemic autoimmune injury with cells and mediators of the neuroendocrine system, are largely unexplored. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sjögren's syndrome is a chronic inflammatory disease, primarily involving the exocrine glands. Its association with lymphoma is well documented. The salivary extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue type are the most common type of lymphoma in Sjögren's syndrome and constitute the major complication of the disease. These tumors are antigen-stimulated B-cell lymphomas and are characterized by localized stage, indolent clinical course and recurrence in other extranodal sites. This article reviews the literature and discusses the clinical, histopathological and therapeutic aspects of these tumors in Sjögren's syndrome. In addition, the predictive markers of lymphoma development and the mortality rate in Sjögren's syndrome are also highlighted. [ABSTRACT FROM AUTHOR]

Abstract: The CD40–CD40L costimulatory pathway is involved in the evolution of many autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren''s syndrome (SS). Increased levels of sCD40L in the serum have been associated with disease activity in SLE. The aim of this study was to investigate the role of sCD40L in the development of lupus nephritis and examine its possible association with cryoglobulinemia in Sjögren''s syndrome. We used a 2-site sandwich ELISA to measure the levels of sCD40L in sera, from 64 patients with SLE, RA and SS and 17 healthy blood donors. Biological specimens from the affected tissues such as urine from patients with lupus nephritis and saliva from patients with SS were also tested. In this regard, paired sera and first morning urine samples from 6 SLE patients (3 with active lupus nephritis and 3 with inactive lupus nephritis) were tested with the sCD40L ELISA protocol as well as paired sera and salivary samples from 5 patients with SS and cryoglobulinemia, 5 patients with SS and anti-Ro or anti-La autoantibodies and 5 age-matched healthy control donors. We also examined possible correlations of sCD40L levels with several laboratory and clinical parameters in SS and SLE. We found that sera from SLE and SS patients had significantly higher levels of sCD40L compared to sera from healthy control donors. No sCD40L was detected, in urine samples of patients with either active or inactive nephritis and in salivary samples from SS patients or normal subjects. Soluble CD40L is elevated in sera of SS and SLE patients but further investigation is needed to determine its possible role in SLE nephritis and Sjögren''s syndrome. [Copyright &y& Elsevier]

The prevalence of autoantibodies during pregnancy was studied. Sera from 568 women (203 pregnant and 365 non-pregnant) were tested for autoantibodies to double-stranded DNA, car diolipin and extractable cellular antigens. Nineteen out of 203 pregnant women (9.4%) had at least one autoantibody against double-stranded DNA or cardiolipin, mainly of the IgM class. The non-pregnant control group had significantly higher incidence of autoantibodies (17.8%; X2 = 7.39, P < 0.01). Sixty-six out of 568 women had had spontaneous abortions in their past medical history, but there was no correlation between them and the presence of anticardiolipin antibodies. Two of the non-pregnant women had anti-Ro(SSA) antibodies. These findings suggest that (a) the prevalence of autoantibodies decreases during pregnancy; and (b) the presence of anticardiolipin antibodies in healthy pregnant women does not cor relate with any pregnancy-related complications. However, our results indicated that auto immunity is a rather common disorder in healthy women. [ABSTRACT FROM PUBLISHER]

Recent data suggest the association of the autoimmune gene variant PTPN22W* with dampened type I Interferon (IFN) responses, seen in a subset of primary Sjogren's Syndrome (pSS) patients. We sought to explore the potential contribution of PTPN22W* in this setting. PTPN22W* was identified in DNA samples derived from 352 pSS patients and 482 healthy controls (HC). Type I IFN score was determined in available peripheral blood cDNA of 164 pSS patients by Real-Time PCR. Increased prevalence of the PTPN22W* variant was detected in pSS patients compared to HC [9.7% vs 5.0%, p-value: 0.02]. Of interest, only the low but not the high type I IFN pSS subgroup displayed higher PTPN22W* rates compared to HC (12.2% vs 5.0%, p-value: 0.03). PTPN22W* risk variant increases susceptibility for pSS, particularly the low type I IFN subset implying the presence of distinct genetic backgrounds among low and high type I IFN autoimmune subgroups. [ABSTRACT FROM AUTHOR]

Abstract: Background/purpose: Primary Sjögren’s syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS. Methods: Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed. Results: Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status. Conclusions: In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested. [Copyright &y& Elsevier]

Abstract: In sIBM, an inflammatory process mediated by cytotoxic T cells and cytokines in conjunction with a degenerative process, deposits of beta amyloid and misfolded proteins appear to be the main culprits in disease pathogenesis. IL-1β may play a key role because it is upregulated in sIBM myofibers, co-localizes with Amyloid Precursor Protein (APP) and promotes the production of APP and amyloid deposits. We performed a small, pilot study to examine whether anakinra, an IL1 receptor antagonist could benefit sIBM patients. Four patients with biopsy-proven sIBM received anakinra for a mean period of 7.7months. No improvement in muscle strength or stabilization was noted in any of the patients based on grip strength and MRC measurements. The treatment failure may be due to insufficiency of anakinra to suppress the intramuscular IL1, the short study period, or the irrelevance of IL1 in the disease process. [Copyright &y& Elsevier]

Clinical data on vaccinated patients with coronavirus disease 2019 (COVID-19) who have systemic autoimmune and autoinflammatory rheumatic diseases (SAARD) are limited. This observational study aimed to report the clinical features and outcomes of COVID-19 among cases with SAARD that were unvaccinated or were 2- and 3-dose vaccinated against SARS-CoV-2 and were consecutively recorded by the treating physician. Unvaccinated and 2- and 3-dose vaccinated patients were compared in terms of COVID-19 symptomatology, hospitalizations, oxygen supplementation requirements, and death rates. From the beginning of the pandemic to February 15, 2022, 134 vaccine-naïve COVID-19 cases were recorded among our study cohort. From March 1, 2021 to February 15, 2022, 89 2-dose vaccinated and 105 3-dose vaccinated patients who were infected with SARS-CoV-2 ≥14 days after the second dose were included. The hospitalization rate was higher in the unvaccinated (n = 36, 26.9%) than in the 2-dose (n = 13, 14.6%, p = 0.03) or 3-dose (n = 5, 4.8%, p < 0.001) vaccinated patients. Severe/critical COVID-19 cases requiring oxygen supplementation were the least among 3-dose vaccinated (n = 4, 3.8%) compared to both 2-dose vaccinated (n = 12, 13.5%, p = 0.018) and unvaccinated (n = 25, 18.7%, p < 0.001) patients. ICU admission and death rates were similar among unvaccinated (n = 5, 3.7% and n = 3, 2.2%, respectively) and 2-dose vaccinated patients (n = 4, 4.5%; and n = 2, 2.2%, respectively), while no 3-dose vaccinated patients died or required ICU admission. Logistic regression analysis revealed a significant inverse association between 3-dose vaccination and severe/critical COVID-19 (OR = 0.078, 95% CI: 0.022–0.273, p < 0.001). In conclusion, these findings argue in favor of booster vaccination against SARS-CoV-2 in patients with SAARD. • Clinical data on vaccinated patients with COVID-19 who have rheumatic diseases are limited. • Breakthrough COVID-19 is less severe in 3-dose vaccinated patients with rheumatic diseases. • Booster vaccination is important for patients with rheumatic diseases. [ABSTRACT FROM AUTHOR]

Objectives Fibromyalgia (FM) is one of the most common chronic pain syndromes. Various pathogenetic mechanisms have been implicated but none is proven. Our scope was to determine if Intraepidermal Nerve Fiber Density (IENFD) is reduced in the skin of FM patients, as observed in patients with painful small fiber sensory neuropathy (SFSN). Design, setting and participants We prospectively studied 46 FM patients (5 men and 41 women), aged 29 to 76 (mean: 52.5) years, diagnosed according to the ACR 2010 criteria, and 34 controls (18 women and 16 men) aged 19 to 84 (mean: 31.7) years. IENFD was measured using published guidelines and immune markers were sought immunocytochemically. In 30 FM patients, pain intensity was assessed with the Neuropathic Pain Symptom Inventory (NPSI), a scale validated for neuropathic pain. Results 15 of 46 (32.6%) FM patients had reduced IENFD [range: 0.6–12.5 fibers/mm (mean: 4.83 SD: 2.5)], compared to healthy controls [2.8–11.5 fibers/mm (mean: 7.35, SD: 1.85)] (p < 0.0001). No significant correlation was noticed between NPSI scores and IENFD. No difference in the Langerhans cells, the major Antigen Presenting Cells (APCs) in the epidermis, or in IL-6 staining, was noted between FM and controls. IENFD was equally reduced in a subset of FM patients who also had another autoimmune disease. Conclusion This is one of the largest series of FM patients demonstrating a significant reduction of IENFD in their skin biopsies. The findings indicate that in a subset of FM patients, the pain syndrome is, at least partially, of neuropathic origin. Skin biopsy may prove a useful tool and a potential biomarker in future studies of FM patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate the prevalence of serum antibodies against hepatitis C virus and other infectious agents in a large cohort of well-characterized patients with autoimmune diseases (AID). Methods: We utilized 1322 sera from patients with 18 different AID and 236 sera from healthy controls from the same countries and with similar age and sex distribution. All sera were tested for the presence of serum anti-hepatitis C virus (HCV) antibodies as well as antibodies directed at other infectious agents and autoantibodies. Results: Anti-HCV antibody was detected in 115/1322 (8.7%) of patients with AID and 0.4% of matched healthy controls (P <0.0001). The prevalence of anti-HCV antibody was significantly higher in 7/18 different AID (i.e. cryoglobulinemia, mixed cryoglobulinemia pemphigus vulgaris, vasculitis, secondary anti-phospholipid syndrome, Hashimoto''s thyroiditis, and inflammatory bowel disease) compared to controls. Patients with AID and serum anti-HCV positivity had an increased prevalence of antibodies against hepatitis B virus, Toxoplasma gondii and Cytomegalovirus as opposed to a lower frequency of serum autoantibodies. Conclusions: The enhanced prevalence of anti-HCV serum antibodies in AID may suggest a role for HCV in tolerance to breakdown, similarly to its established role in mixed cryoglobulinemia. This immune mediated effect does not rule out the role of other infectious agents. [Copyright &y& Elsevier]

Abstract: The four major autoantigens (IA-2, IA-2β, GAD65 and insulin) of type 1 diabetes are all associated with dense core or synaptic vesicles. This raised the possibility that other secretory vesicle-associated proteins might be targets of the autoimmune response in type 1 diabetes. To test this hypothesis 56 proteins, two-thirds of which are associated with secretory vesicles, were prepared by in vitro transcription/translation and screened for autoantibodies by liquid phase radioimmunoprecipitation. Two secretory vesicle-associated proteins, VAMP2 and NPY, were identified as new minor autoantigens with 21% and 9%, respectively, of 200 type 1 diabetes sera reacting positively. These findings add support to the hypothesis that secretory vesicle-associated proteins are particularly important, but not the exclusive, targets of the autoimmune response in type 1 diabetes. Selective screening of the human proteome offers a useful approach for identifying new autoantigens in autoimmune diseases. [Copyright &y& Elsevier]

The impact of SARS-CoV-2 infection in patients with autoimmune/auto-inflammatory rheumatic diseases (AARD) under immunomodulatory treatment has been a focus of interest during the COVID-19 pandemic. In this observational study, demographic data, disease related features and comorbidities, COVID-19 manifestations and outcome as well as antibody responses to SARS-CoV-2 were recorded among 77 consecutive patients with underlying AARD infected by SARS-CoV-2. Analysis of data was performed using univariate and multivariate models. Most patients (68.8%) had a mild COVID-19 course. The predominant clinical manifestations were fatigue (58.4%), low grade fever (45.4%) and upper respiratory tract symptoms (68.8%). About a quarter of patients required hospitalization (23.3%) and the mortality rate was 1.3%. Regarding COVID-19 severity, prior treatment with corticosteroids, mycophenolate mofetil or rituximab was more common in patients who developed a more serious disease course (60.0 vs 29.9%, p = 0.003, 40.0 vs 7.5%, p = 0.003, 10.0 vs 0.0%, p = 0.009, respectively). When disease related features and comorbidities were considered in multivariate models, older age and lung disease in the context of the AARD were found to be independent predictive factors for hospitalization (OR [95%]: 1.09 [1.03–1.15] and 6.43 [1.11–37.19]). Among COVID-19 related features, patients with shortness of breath and high-grade fever were more likely to get hospitalized (OR [95%]: 7.06 [1.36–36.57], 12.04 [2.96–48.86]), while anosmia was independently associated with lower hospitalization risk (OR [95%]: 0.09 [0.01–0.99]). Though the majority of AARD patients displayed a mild COVID-19 course, certain underlying disease features and COVID-19 related manifestations should prompt alertness for the physician to identify patients with AARD at high risk for severe COVID-19 and need for hospitalization. • Most of rheumatic disease patients infected by SARS-CoV-2 experienced a mild disease and did not require hospitalization. • Nonspecific symptomatology like fatigue, low grade fever and musculoskeletal complaints was predominant among COVID-19 features. • Previous treatment with corticosteroids, mycophenolate mofetil or rituximab was more common in severe COVID-19 patients. • Older age and lung disease in the context of the underlying disease were independent predictive factors of hospitalization. [ABSTRACT FROM AUTHOR]