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Objectives Pleuroparenchymal fibroelastosis (PPFE) is characterized by predominantly upper lobe pleural and subjacent parenchymal fibrosis; PPFE features were described in patients with rheumatic autoimmune diseases (RAID). A systematic literature review was performed to investigate the prevalence, prognosis and potential association of PPFE with previous immunosuppression in RAID. Methods EMBASE, Web of Science and PubMed databases were questioned from inception to 1 September 2019. Articles published in English and addressing PPFE in patients with RAID were selected. Results Twenty out of 794 papers were selected with a total of 76 cases of RAID-PPFE patients (20 SSc, 9 RA, 6 IIM6 primary SS, 5 overlap syndromes, 3 ANCA-associated vasculitides, 2 granulomatosis with polyangiitis, 1 microscopic polyangiitis, 1 UCTD, 1 SLE, 1 GCA and 21 patients with non-specified RAID). Dyspnoea was the most frequently reported symptom (37/48 patients, 77%). Patients frequently presented with a restrictive pattern and decline in diffusing lung capacity for carbon monoxide. During the follow-up, 7/12 patients had progression at imaging, 22/39 presented a generic clinical worsening, 19/38 had a functional deterioration and 15/43 remained stable. Conclusion The present systematic literature review confirms that PPFE features are present in RAID. Rheumatologists should be aware of this new radiological pattern that holds a bad prognosis. [ABSTRACT FROM AUTHOR]

Summary: Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects. Adjuvants such as aluminum, mineral oils, and silicone are added to vaccines in order to trigger a stronger immune response. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was introduced in 2011 to address nonspecific symptoms and disorders appearing following vaccinations, which in fact were reported by many papers before the introduction of the syndrome. During the pandemic of COVID-19, a correlation between ASIA, COVID-19, and COVID-19 vaccines has been reported. [ABSTRACT FROM AUTHOR]

Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a chronic gynaecological disorder that affects 2-10% of women of reproductive age. The aetiology of endometriosis is largely under-explored, yet abnormalities in the immune system have been suggested to explain the origin of ectopic endometrial tissues, and an association between endometriosis and autoimmune diseases has been proposed. Evaluation of current evidence investigating the association between endometriosis and autoimmune diseases from population-based studies will facilitate our understanding of the causes and consequences of endometriosis and provide a reference for better healthcare practices population-wide.Objective and Rationale: The aim of this study was to systematically review the literature on population-based studies investigating an association between endometriosis and autoimmune diseases and to conduct a meta-analysis of combinable results to investigate the extent and robustness of evidence.Search Methods: Four electronic databases were searched (MEDLINE, Embase, Web of Science, and CINAHL) from each database inception date until 7 April 2018. Search terms included a combination of database-specific controlled vocabulary terms and free-text terms relating to 'endometriosis' and 'autoimmune diseases'. Study inclusion criteria focused on peer-reviewed published articles that reported an association between endometriosis and autoimmune diseases, excluding case reports/series, review papers, meta-analyses, organizational guidelines, editorial letters, expert opinions, and conference abstracts. Quality assessment of included studies was performed based on GRADE criteria. Key information of eligible studies was abstracted into a standard form. Meta-analysis was performed for autoimmune diseases with combinable study results from at least three studies investigating an association with endometriosis. For cross-sectional studies and case-control studies, raw data from each study were documented to calculate a Mantel-Haenszel odds ratio with 95% CIs. For cohort studies, an inverse variance probability weighted model was used to pool study results to calculate a rate ratio (a hazard ratio or a standardized incidence rate) with 95% CIs.Outcomes: A total of 26 published population-based cross-sectional, case-control, and cohort studies that investigated the association between endometriosis and autoimmune diseases met all eligible criteria and were included in the review. The studies quantified an association between endometriosis and several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatoid arthritis (RA), autoimmune thyroid disorder, coeliac disease (CLD), multiple sclerosis (MS), inflammatory bowel disease (IBD), and Addison's disease. However, the quality of the evidence was generally poor due to the high risk of bias in the majority of the chosen study designs and statistical analyses. Only 5 of the 26 studies could provide high-quality evidence, and among these, 4 supported a statistically significant association between endometriosis and at least 1 autoimmune disease: SLE, SS, RA, CLD, MS, or IBD.Wider Implications: The observed associations between endometriosis and autoimmune diseases suggest that clinicians need to be aware of the potential coexistence of endometriosis and autoimmune diseases when either is diagnosed. Scientists interested in research studies on endometriosis or autoimmune diseases should consider the likelihood of comorbidity when studying these two types of health conditions. Well-designed large prospective cohort studies with confounding control and mediation quantification, as well as genetic and biological studies, are needed to generate further insights into whether endometriosis is a risk factor for, or a consequence of, autoimmune diseases, and whether these two types of disorders share pathophysiological mechanisms even if they arise independently. Such insights may offer opportunities for the development of novel non-hormonal medications such as immuno-modulators or repurposing of existing immunomodulatory therapies for endometriosis. [ABSTRACT FROM AUTHOR]

Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors—such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids—should also be taken into account during risk stratification. [ABSTRACT FROM AUTHOR]

Background Acute myocarditis (AM) is an inflammatory heart disease that may occur as a consequence of autoimmune disorders. Although the correlation between myocarditis and hyperthyroidism has been reported in the literature, the association with hypothyroidism is less frequent. Case summary We describe a characteristic case of lymphocytic acute myocarditis deteriorated into cardiogenic shock due to Hashimoto's thyroiditis treated with vasopressor and inotropic drugs in combination with corticosteroid. On admission, electrocardiography revealed a sinus tachycardia with 1st degree atrioventricular (AV) block, right bundle branch block (RBBB), and left anterior fascicular block. Laboratory tests demonstrated a severe hypothyroidism and high-titre serum of antibodies against thyroglobulin. She presented a favourable clinical course, restoring haemodynamic stability. A resolution of hypothyroidism and a progressive reduction of the value of antibodies against thyroglobulin occurred. On Day 35, the patient was discharged showing on electrocardiogram the occurrence of left posterior fascicular block, disappearance of 1st degree AV block and partial improvement of RBBB along with the normalization of the left ventricular contractility abnormalities on echocardiography. Discussion Autoimmune features, mostly Hashimoto's thyroiditis, are associated in lymphocytic acute myocarditis to a worse prognosis and an increased risk of recurrence. More studies are needed to elucidate the underlying mechanism. [ABSTRACT FROM AUTHOR]

Acquired generalized lipodystrophy (AGL) is an extremely rare disease that is characterized by loss of body fat affecting nearly all parts of the body. It is often associated with autoimmune diseases or panniculitis, whereas in other patients the underlying etiology is unclear. We report a 52-year-old male individual who was diagnosed with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) that spontaneously went into remission. Years later he developed new subcutaneous nodules most concerning for relapse SPTCL or lupus panniculitis, followed by onset of hemophagocytic lymphohistiocytosis (HLH) that was treated with allogeneic stem cell transplantation. Notably, around the same time, he also developed generalized subcutaneous fat loss of both upper and lower extremities, chest, abdomen, and face that persisted after treatment of the HLH. Whole exome sequencing was performed to search for pathogenic variants that are associated with SPTCL, including those in hepatitis A virus cellular receptor 2 (HAVCR2), but did not detect any potential disease-causing variant. Our report brings to the attention a novel subtype of panniculitis-variety of AGL. Whether generalized loss of subcutaneous fat in this patient is due to lymphoma-associated panniculitis or due to development of adipose tissue-directed autoantibodies as a paraneoplastic "autoimmune" manifestation of SPTCL remains unclear. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) develops when there are insufficient insulinproducing beta cells to maintain glucose homeostasis. The prevailing view has been that T1D is caused by immune-mediated destruction of the pancreatic beta cells. However, several recent papers have challenged the long-standing paradigm describing T1D as a tissue-specific autoimmune disease. These authors have highlighted the gaps in our knowledge and understanding of the aetiology of T1D in humans. Here we review the evidence and argue the case for the autoimmune basis of human T1D. In particular, recent analysis of human islet-infiltrating T cells brings important new evidence to this question. Further data in support of the autoimmune basis of T1D from many fields, including genetics, experimental therapies and immunology, is discussed. Finally, we highlight some of the persistent questions relating to the pathogenesis of human type 1 diabetes that remain to be answered. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite an estimated prevalence of 10% in women, the etiology of endometriosis remains poorly understood. Over recent decades, endometriosis has been associated with risk of several chronic diseases, such as cancer, autoimmune diseases, asthma/atopic diseases and cardiovascular diseases. A deeper understanding of these associations is needed as they may provide new leads into the causes or consequences of endometriosis. This review summarizes the available epidemiological findings on the associations between endometriosis and other chronic diseases and discusses hypotheses for underlying mechanisms, potential sources of bias and methodological complexities. METHODS: We performed a comprehensive search of the PubMed/Medline and ISIWeb of Knowledge databases for all studies reporting on the associations between endometriosis and other diseases published in English through to May 2014, using numerous search terms. We additionally examined the reference lists of all identified papers to capture any additional articles that were not identified through computer searches. RESULTS: We identified 21 studies on the associations between endometriosis and ovarian cancer, 14 for breast cancer, 8 for endometrial cancer, 4 for cervical cancer, 12 for cutaneous melanoma and 3 for non-Hodgkin's lymphoma, as well as 9 on the links between endometriosis and autoimmune diseases, 6 on the links with asthma and atopic diseases, and 4 on the links with cardiovascular diseases. Endometriosis patients were reported to be at higher risk of ovarian and breast cancers, cutaneous melanoma, asthma, and some autoimmune, cardiovascular and atopic diseases, and at decreased risk of cervical cancer. CONCLUSIONS: Increasing evidence suggests that endometriosis patients are at higher risk of several chronic diseases. Although the underlying mechanisms are not yet understood, the available data to date suggest that endometriosis is not harmless with respects to women's longterm health. If these relationships are confirmed, these findings mayhave important implications in screening practices and in the management and care of endometriosis patients. [ABSTRACT FROM AUTHOR]

Different studies over the last decade have linked the B cell-attracting chemokine CXC ligand 13 ( CXCL13) to the autoimmune disease systemic lupus erythematosus ( SLE). A pathogenetic role of this chemokine for disease manifestation in SLE was described initially in mouse models for SLE. Mechanisms of CXCL13 actions were also identified in SLE patients. Moreover, various clinical studies have identified CXCL13 serum levels as a useful biomarker in patients with SLE of different ethnicities for disease activity. In addition, CXCL13 seems to be a promising marker for the diagnosis of lupus nephritis, one of the most severe complications of SLE. However, its exact place within the mechanisms that lead to SLE remains to be defined. Further research is needed to resolve more details of the pathomechanism and the signalling pathway of CXCL13 in SLE. Blocking CXCL13 or the signal pathways of CXCL13 is seen as a promising therapeutic approach for SLE and will be addressed in the near future. This review summarizes all papers that linked CXCL13 to SLE and highlights its importance in the pathogenesis and diagnosis of SLE [ABSTRACT FROM AUTHOR]

This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis ( MG). Nowadays the term 'myasthenia gravis' includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase ( MuSK), low-density lipoprotein receptor-related protein 4 ( LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte- macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective. [ABSTRACT FROM AUTHOR]

In a recent workshop organized by the JDRF focused on the 'Identification and Utilization of Robust Biomarkers in Type1 Diabetes', leaders in the field of type 1 diabetes ( T1D)/autoimmunity and assay technology came together from academia, government and industry to assess the current state of the field, evaluate available resources/technologies and identify gaps that need to be filled for moving the field of T1D research forward. The highlights of this workshop are discussed in this paper, as well as the proposal for a larger, planned consortium effort, incorporating a JDRF Biomarker Core, to foster collaboration and accelerate progress in this critically needed area of T1D research. [ABSTRACT FROM AUTHOR]

Since first defined in 1998, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and its later, broader iteration, paediatric acute-onset neuropsychiatric syndrome (PANS), have garnered significant attention and controversy. The role of streptococcal infection in children with explosive onset obsessive-compulsive disorder and new onset tics, the natural history of this entity, and the role of symptomatic and disease-modifying therapies, including antibiotics, immunotherapy, and psychoactive drugs, are all issues that have yet to be definitively addressed. While definitive proof of the autoimmune hypothesis of PANDAS is lacking, given the heightened attention to this entity and apparent rise in use of this diagnostic category, addressing questions around diagnosis, treatment, and etiology is imperative. In this paper, we review current working definitions of PANDAS/PANS, discuss published evidence for interventions related to this entity, and propose a clinical approach to children presenting with acute symptoms satisfying criteria for PANDAS/PANS. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is the most common autoimmune inflammatory polyarthritis. Significant advances in the understanding of its pathogenesis have led in the past two decades to major advancement in its therapy. We used data from articles in Cochrane Database of Systematic Reviews on ‘rheumatoid arthritis’, meta-analyses and randomized controlled trials on adult RA (age >19 years) published in English within the past 5 years and identified in PubMed, and other key papers on management of RA. Appropriate, early and aggressive therapy is required for confirmed active cases of RA. The choice of disease-modifying drugs and different combinations, especially the newer biologic agents in regards of their early and long-term usage remains debated because of high costs and long-term safety concerns. Development of newer biologic agents working on different pathways of inflammation is underway in different stages. It remains to be determined how and when each of these agents will fit in the overall management of RA. Furthermore, post-marketing surveillance of the safety and response sustainability of these drugs is warranted. [ABSTRACT FROM PUBLISHER]

Type 1 diabetes (T1D) is often considered the prototype organ-specific autoimmune disease in clinical immunology circles. The key disease features − precise destruction of a single endocrine cell type occurring on a distinct genetic and autoimmune background − have been unravelled in recent years to such an extent that there is a growing expectation that the disease should be curable. T1D is something of an orphan disease, currently managed by endocrinologists yet dependent upon the wit of immunologists, both basic and clinical, to find the best approaches to prevention and cure. Type 1 diabetes thus represents one of the most active arenas for translational research, as novel immune-based interventions find their way to the clinic. The first serious attempt at immune-based treatment for T1D was in 1984, the first at prevention in 1993; current and planned trials will take us into the next decade before reporting their results. This paper represents the first attempt at a comprehensive review of this quarter century of endeavour, documenting all the strategies that have emerged into clinical studies. Importantly, the intense clinical activity has established robust infrastructures for future T1D trials and frameworks for their design. The evident success of the monoclonal anti-CD3 antibody trials in established T1D demonstrate that modulation of islet autoimmunity in humans after the onset of overt disease can be achieved, and give some reason to be cautiously optimistic for the ability of these and other agents, alone and in combination, to provide an effective immunotherapy for the disease. [ABSTRACT FROM AUTHOR]

Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-β towards Treg and IL-6 and TGF-β towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORγt for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-γ and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis. [ABSTRACT FROM AUTHOR]

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. We find raised levels of anti-DSG2 autoantibodies in sera from individuals following severe COVID-19. Staining of post-mortem cardiac tissue from individuals that died from COVID-19 with an anti-DSG2 antibody revealed disruption of the intercalated disc between cardiomyocytes that was consistent with separation of the DSG2 protein homodimer. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. [ABSTRACT FROM AUTHOR]

Patients of some rheumatic autoimmune diseases like systemic lupus erythematosus have in their sera autoantibodies to vimentin, the main protein of intermediate sized filaments of the cytoskeleton of connective tissue cells. Immunoprecipitation and Western blotting techniques have been used to detect the interaction between human anti-vimentin autoantibodies and the two peptides that resulted from the cleavage of vimentin by N-chlorosuccinimide. Both methods and also immunoabsorption of sera with the isolated peptides suggest that the interaction of vimentin and immunoglobulins is mainly carried out through a peptide of 30kD mol. wt located close to the amino-terminal part of the vimentin molecule. The same results were obtained when a serum from a rabbit immunized with human vimentin was used. [ABSTRACT FROM AUTHOR]

The article presents information on IgM-IgG cryoglobulinaemia with IgM paraprotein component. Four patients with mixed IgM-IgG cryoglobulinaemia are described. Clinically they all had some features of an autoimmune disease, while two of them had a lympho-epithelial tumor in the parotid gland. The term paraprotein is used in this article for electrophoretically homogeneous immunogiobulins, which belong to only one light chain type. It implies no further assumptions about their nature and origin. It is the intention of this paper to report in detail the clinical and biochemical findings in four patients with IgM-IgG cryoglobulins, the IgM part of which had the characteristics of a paraprotein with anti-IgG activity.

Objectives Satoyoshi syndrome is a rare multisystem disease of presumed autoimmune aetiology. We carried out a systematic review to evaluate the available evidence to support that autoimmune hypothesis. Methods We searched for Satoyoshi syndrome cases in PubMed, the Web of Science and Scopus up to January 2022, using keywords 'Satoyoshi syndrome' or 'Komuragaeri disease'. Data on symptoms, associated autoimmune diseases, presence of autoantibodies and response to treatment were collected. Results A total of 77 patients from 57 articles published between 1967 and 2021 were included; 59 patients were women. The mean age at diagnosis was 21.2 years. All cases had painful muscular spasms and alopecia. Frequent manifestations included: diarrhoea, malabsorption, growth retardation, amenorrhoea and bone deformity. Satoyoshi syndrome was associated with other autoimmune diseases: myasthenia gravis, autoimmune thyroiditis, idiopathic thrombocytopenic purpura, atopic dermatitis, bronchial and lupus erythematosus. Autoantibody determinations were performed in 39 patients, of which 27 had positive results. The most frequently detected autoantibodies were ANAs. Other less frequently found autoantibodies were: anti-acetylcholine receptor antibodies, anti-DNA antibodies, antithyroid antibodies, anti-glutamic acid decarboxylase (anti-GAD) and anti-gliadin antibodies. Pharmacological treatment was reported in 50 patients. Most of them improved with CS, immunosuppressants and immunoglobulins, or a combination of these medications. Conclusion Satoyoshi syndrome is associated with other autoimmune diseases and a variety of autoantibodies. Improvement after CS or other immunosuppressant treatment was observed in 90% of cases. These data support an autoimmune aetiology for Satoyoshi syndrome. More studies including systematic determination of autoantibodies in all patients with Satoyoshi syndrome will help us advance in our understanding of this disease. [ABSTRACT FROM AUTHOR]

Immune-related adverse events (irAEs) clinically resemble autoimmune diseases, indicating autoantibodies could be potential biomarkers for the prediction of irAEs. This study aimed to assess the predictive value of peripheral blood antinuclear antibody (ANA) status for irAEs, considering the time and severity of irAEs, as well as treatment outcome in liver cancer patients administered anti-PD-1 therapy. Ninety-three patients with advanced primary liver cancer administered anti-PD-1 treatment were analyzed retrospectively. They were divided into the ANA positive (ANA+, titer ≥ 1:100) and negative (ANA-, titer < 1:100) groups. Development of irAEs, progression-free survival (PFS), and overall survival (OS) were assessed. Compared with ANA- patients, ANA+ cases were more prone to develop irAEs (43.3% vs. 19.2%, P = 0.031). With the increase of ANA titers, the frequency of irAEs increased. The time interval between anti-PD-1 therapy and the onset of irAEs was significantly shorter in ANA+ patients compared with the ANA- group (median, 1.7 months vs. 5.0 months, P = 0.022). Moreover, the time between anti-PD-1 therapy and irAE occurrence decreased with increasing ANA titer. In addition, PFS and OS were decreased in ANA+ patients compared with the ANA− group (median PFS, 2.8 months vs. 4.2 months, P = 0.043; median OS, 21.1 months vs. not reached, P = 0.041). IrAEs occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. ANA titer could help predict irAE development and treatment outcome in these patients. Immune-related adverse events (irAEs) occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

The authors comment on a study by Pepper et al that investigated the use of glucocorticoid (GC)-free maintenance for anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). They claim that findings from the study require cautious interpretation because a longer duration of GC in a proportion of more severe patients might have swayed the results favorably. They assert that it is important to consider newer treatment strategies for AAV especially those on reduced exposure to GC.

Graves disease and Hashimoto disease form part of the spectrum of autoimmune thyroid disease (AITD), to which genetic and environmental factors are recognized contributors. Epigenetics provides a potential link between environmental influences, gene expression, and thyroid autoimmunity. DNA methylation (DNAm) is the best studied epigenetic process, and global hypomethylation of leukocyte DNA is reported in several autoimmune disorders. This review summarizes the current understanding of DNAm in AITD. Targeted DNAm studies of blood samples from AITD patients have reported differential DNAm in the promoter regions of several genes implicated in AITD, including TNF, IFNG, IL2RA, IL6, ICAM1, and PTPN22. In many cases, however, the findings await replication and are unsupported by functional studies to support causal roles in AITD pathogenesis. Furthermore, thyroid hormones affect DNAm, and in many studies confounding by reverse causation has not been considered. Recent studies have shown that DNAm patterns in candidate genes including ITGA6, PRKAA2, and DAPK1 differ between AITD patients from regions with different iodine status, providing a potential mechanism for associations between iodine and AITD. Research focus in the field is moving from candidate gene studies to an epigenome-wide approach. Genome-wide methylation studies of AITD patients have demonstrated multiple differentially methylated positions, including some in immunoregulatory genes such as NOTCH1, HLA-DRB1, TNF, and ICAM1. Large, epigenome-wide studies are required to elucidate the pathophysiological role of DNAm in AITD, with the potential to provide novel diagnostic and prognostic biomarkers as well as therapeutic targets. [ABSTRACT FROM AUTHOR]

Mitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses, and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system toward immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference. [ABSTRACT FROM AUTHOR]

Objectives In women with systemic autoimmune rheumatic diseases (SARDs), female sexual dysfunction (SD) remains underestimated. We aimed to explore the prevalence and correlates of SD in females with SARDs. Methods We performed a systematic review and meta-analysis of studies assessing the prevalence of SD and the pooled Female Sexual Function Index (FSFI) scores in this setting (PROSPERO: CRD42021287346). We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases and grey literature until February 2022. We evaluated the quality of the selected records using the Hoy Risk of Bias tool. A random-effects meta-analysis of proportions with the double arcsine transformation was conducted. Subgroup and sensitivity analyses, as well as meta-regression of important correlates, were conducted. Results We included 68 studies with 5457 females diagnosed with a SARD (mean age: 43.7 [12.9] years). The overall SD prevalence was 63% (95% CI: 56, 69%, I 2 = 94%) and the overall FSFI total score was 19.7 points (95% CI: 18.4, 21, I 2 = 97%). Including only sexually active females, the SD prevalence was estimated as 60% (95% CI: 53, 67%, I 2 = 88%), whereas the FSFI total score was 22 points (95% CI: 20.8, 23.1, I 2 = 93%). Across the different SARDs, women with Sjögren's syndrome and systemic sclerosis reported the highest levels of SD (74%, 95% CI: 58, 87%, I 2 = 84% and 69%, 95% CI: 54, 83%, I 2 = 94%, respectively). Conclusion Sexual function in females with SARDs seems to be severely impaired, irrespective of the type of SARD. Screening and treatment of SD in females with SARDs should become an integral part of healthcare clinical practice. [ABSTRACT FROM AUTHOR]

Summary: Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients. [ABSTRACT FROM AUTHOR]

Objectives An increased risk of adverse maternal and foetal pregnancy complications (including pre-eclampsia, intrauterine growth restriction, and small for gestational age) is well described in women with autoimmune rheumatic disease (ARD) compared with the general population (GenPop). It is less clear, however, whether this risk of adverse pregnancy outcome (APO) also exists in women with 'preclinical ARD' (pre-ARD) before they are diagnosed with an ARD many years post-partum. Therefore, we have undertaken a systematic review of the available evidence on APO in patients who subsequently were diagnosed with a rheumatic disease to identify whether there is an increased risk in pre-ARD. Methods The present study was reported in accordance with the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard. A systematic literature review was performed using the online PubMed database. Pre-SLE and pre-RA patients were defined as those who, over the subsequent years, developed SLE or RA according to international classification criteria. Results A total of 176 articles were screened, and 27 original articles were selected for final analysis. Pre-RA was the most studied group, with 15 studies and a total of >1600 pregnancies, and pre-SLE was the second-most studied pre-ARD in pregnancy, with 14 studies and a total of >1000 pregnancies. We found that patients who subsequently developed SLE had an increased burden of poor pregnancy outcomes compared with pregnant women from the GenPop, but fewer APOs compared with pregnancies of women with SLE. In contrast, a similar rate of APOs was found when pre-RA pregnancies were compared with GenPop pregnancies. Conclusion Our findings of an increased risk of APO in certain pre-ARDs highlights the relevance of taking an obstetric history during the first rheumatology appointment and the need for novel screening strategies for the prediction of APOs. Further research is required to elucidate the immune basis of APOs in preclinical and clinical ARD. [ABSTRACT FROM AUTHOR]

B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. Indeed, similarly to T cells, there is significant heterogeneity in cytokine-driven responses by B cells, ranging from the production of pro-inflammatory effector cytokines such as IL-6, through to the release of immunosuppressive cytokines such as IL-10. In this review, focusing on human B cells, we summarize the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases. B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. In this review, focusing on human B cells, we summarise the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objective To establish the demographic characteristics, laboratory findings and clinical outcomes in patients with autoimmune disease (AD) compared with a propensity-matched cohort of patients without AD admitted with COVID-19 to hospitals in the UK. Methods This is a multicentre observational study across 26 NHS Trusts. Data were collected both retrospectively and prospectively using a predesigned standardized case record form. Adult patients (≥18 years) admitted between 1 April 2020 and 31 July 2020 were included. Results Overall, 6288 patients were included to the study. Of these, 394 patients had AD prior to admission with COVID-19. Of 394 patients, 80 patients with SLE, RA or aPL syndrome were classified as severe rheumatologic AD. A higher proportion of those with AD had anaemia [240 (60.91%) vs 206 (52.28%), P  = 0.015], elevated LDH [150 (38.08%) vs 43 (10.92%), P  < 0.001] and raised creatinine [122 (30.96%) vs 86 (21.83%), P  = 0.01], respectively. A significantly higher proportion of patients with severe rheumatologic AD had elevated CRP [77 (96.25%) vs 70 (87.5%), P  = 0.044] and LDH [20 (25%) vs 6 (7.5%), P  = 0.021]. Patients with severe rheumatologic AD had significantly higher mortality [32/80 (40%)] compared with propensity matched cohort of patients without AD [20/80 (25%), P  = 0.043]. However, there was no difference in 180-day mortality between propensity-matched cohorts of patients with or without AD in general (P  = 0.47). Conclusions Patients with severe rheumatologic AD had significantly higher mortality. Anaemia, renal impairment and elevated LDH were more frequent in patients with any AD while elevated CRP and LDH were more frequent in patients with severe rheumatologic AD both of which have been shown to associate with increased mortality in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Objectives To systematically review the psychometric properties of outcome measurement instruments used in ANCA-associated vasculitis (AAV). Methods Medline, EMBASE, Cochrane, Scopus and Web of Science were searched from inception to 14 July 2020 for validation studies of instruments used in AAV. Following the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) and OMERACT frameworks, different psychometric properties (validity, reliability, responsiveness and feasibility) were summarized. Risk of bias was assessed according to the COSMIN checklist. Results From 2505 articles identified, 32 met the predefined selection criteria, providing information on 22 instruments assessing disease activity (n  = 7), damage (n  = 2), activity and damage (n  = 1), health-related quality of life (HRQoL; n  = 9) and function (n  = 3). Most of the instruments were tested in AAV as a group or in granulomatosis with polyangiitis only. The BVAS, any version, the Vasculitis Damage Index (VDI) and the AAV-Patient-Reported Outcome (AAV-PRO) have been more extensively validated than the other instruments. BVAS for Wegener Granulomatosis (BVAS/WG) has been shown to be valid for measuring disease activity [correlation with Physician global assessment (r = 0.90)], reliability (inter-observer intraclass correlation coefficient = 0.97), responsiveness and feasibility. For damage, VDI was shown to be moderately valid (correlations with BVAS version 3 at 6 months r = 0.14, BVAS/WG at 1 year r = 0.40 and 5 years r = 0.20), and feasible. For HRQoL, AAV-PRO demonstrated validity (correlations of the six AAV-PRO domains with EQ-5D-5L: −0.78 to −0.55; discrimination between active disease and remission, P  < 0.0001 for all comparisons). The overall performance of instruments assessing function was low-to-moderate. Conclusion Among the 22 outcome measurement instruments used for AAV, BVAS (any version), VDI and AAV-PRO had the strongest psychometric properties. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis of gender bias in frequency of unconventional T cells. Unconventional T cells exist as minor subsets of T cells in peripheral blood. Despite their low number, they play a crucial role in various immune‐mediated diseases such as inflammation, autoimmunity, allergy, and cancer. Gender‐based frequency of these cells altogether on large number of healthy individuals are unestablished creating hurdles to manifest association with various immune‐mediated pathologic conditions. In this study, we used a multicolor flow cytometric panel to identify iNKT cells, γδ T cells, and MAIT cells altogether in the peripheral blood samples of 93 healthy adult males and 109 healthy adult females from the Caucasian population. The results revealed iNKT cell median value (% T cells) in females was higher: 0.114% ranging from 0.011 to 3.84%, than males: 0.076% (p value 0.0292), ranging from 0.007 to 0.816% and found to be negatively correlated with age in females (p value 0.0047). However, γδ T cell median value in males was higher: 2.52% ranging from 0.31 to 16.09%, than females: 1.79% (p value 0.0155), ranging from 0.078 to 12.49% and each gender was negatively correlated with age (male p value 0.0003 and female p value 0.0007). MAIT cell median values were 3.04% ranging from 0.11 to 10.75% in males and 2.67% ranging from 0.2 to 18.36% in females. MAIT cells did not show any statistically significant difference between genders and found to be negatively correlated with age (p value < 0.0001). Our results could be used for further gender‐wise investigations of various pathologic conditions such as cancer and their prognosis, autoimmune diseases, allergies, and their pathogenicity. [ABSTRACT FROM AUTHOR]

Autoimmune rheumatic diseases (ARDs) involve multiple organs including the heart and vasculature. Despite novel treatments, patients with ARDs still experience a reduced life expectancy, partly caused by the higher prevalence of cardiovascular disease (CVD). This includes CV inflammation, rhythm disturbances, perfusion abnormalities (ischaemia/infarction), dysregulation of vasoreactivity, myocardial fibrosis, coagulation abnormalities, pulmonary hypertension, valvular disease, and side-effects of immunomodulatory therapy. Currently, the evaluation of CV involvement in patients with ARDs is based on the assessment of cardiac symptoms, coupled with electrocardiography, blood testing, and echocardiography. However, CVD may not become overt until late in the course of the disease, thus potentially limiting the therapeutic window for intervention. More recently, cardiovascular magnetic resonance (CMR) has allowed for the early identification of pathophysiologic structural/functional alterations that take place before the onset of clinically overt CVD. CMR allows for detailed evaluation of biventricular function together with tissue characterization of vessels/myocardium in the same examination, yielding a reliable assessment of disease activity that might not be mirrored by blood biomarkers and other imaging modalities. Therefore, CMR provides diagnostic information that enables timely clinical decision-making and facilitates the tailoring of treatment to individual patients. Here we review the role of CMR in the early and accurate diagnosis of CVD in patients with ARDs compared with other non-invasive imaging modalities. Furthermore, we present a consensus-based decision algorithm for when a CMR study could be considered in patients with ARDs, together with a standardized study protocol. Lastly, we discuss the clinical implications of findings from a CMR examination. [ABSTRACT FROM AUTHOR]

Background Ankylosing spondylitis (AS) is a chronic inflammatory disease of primarily the joints of the spine. In the literature, AS is known to have cardiac manifestations. Most frequently, this is aortic regurgitation. However, in rare cases also mitral valve (MV) disease is observed in AS patients. The extent and mechanism of this involvement are still unclear. We aim to describe a histologically validated case report to add understanding on this topic. Case summary We show the case of a 51-year-old male who suffered since his youth from back pain and uveitis, which was later diagnosed as AS. After a first presentation with combined heart valve disease, the patient recovered on cardiac medical therapy and biologic treatment for AS. Four years later, cardiac complaints worsened mainly due to severe MV stenosis. Surgical treatment was performed with histopathologic analysis of the excised MV validating involvement of AS. Discussion Histopathologic analysis showed chronic fibro inflammatory thickening of the MV leaflets and subvalvular apparatus. These pathological features could fit with the inflammatory nature of AS. Since this is a rare case, the recognition of fibro inflammatory thickening leading to commissural fusion and stenosis may contribute to better understanding of heart valve disease in AS to create a base for better cardiac management in this specific patient group. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell transplantation (MSCT) regulates immune cells, and is a promising therapeutic approach for treating autoimmune diseases. Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population from the cranial neural crest with high self‐renewal, multipotent differentiation, and superior immunomodulatory properties. However, the mechanisms by which SHED can treat autoimmune diseases remain unclear. Sjögren's syndrome (SS) is an autoimmune disease histologically characterized by high lymphocytic infiltration in the salivary and lacrimal glands that results in dryness symptoms. This study explores the potential of systemic transplantation of SHED to ameliorate SS‐induced dryness symptoms in mice. Overall, SHED could rescue the balance of regulatory T cell (Treg)/T helper cell 17 (Th17) in the recipient SS mice. Mechanistically, SHED promoted Treg conversion and inhibited Th17 function via paracrine effects, which were related to the secretion of soluble programmed cell death ligand 1 (sPD‐L1). Moreover, it directly induced Th17 apoptosis via cell‐cell contact, leading to the up‐regulation of Treg and down‐regulation of Th17 cells. In summary, SHED‐mediated rescue of Treg/Th17 balance via the sPD‐L1/PD‐1 pathway ameliorates the gland inflammation and dryness symptoms in SS mice. These findings suggest that SHED are a promising stem cell source for the treatment of autoimmune diseases in the clinical setting. [ABSTRACT FROM AUTHOR]

Newly identified PD-1hiCXCR5–CD4+ T-cells, termed as peripheral helper T-cells (Tph), have been found elevated and playing a pathogenic role in some autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatic arthritis (RA). However, the potential role of Tph-cells in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains unclear. Here, we explored the potential clinical significance of circulating Tph-cells in the pathogenesis of AAV. Comparing 32 active AAV patients and 18 age- and sex-matched healthy controls (HCs), we found that the frequency of circulating Tph-cells was significantly expanded in active AAV patients. Besides, programmed death 1 (PD-1) expression on the surface of Tph-cells was significantly up-regulated in active AAV patients. Importantly, the frequency of circulating Tph-cells was greatly decreased in AAV patients after receiving treatment. Tph-cells frequency was positively correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil lymphocyte ratio (NLR), and cellular crescent in active AAV patients, but negatively correlated with fibrosus crescent. Tph-cells frequency was also positively correlated with naïve B-cells, serum concentration of MPO-ANCAs, serum tumor necrosis factor-α (TNF-α), IL-4, IL-21, and IL-12. However, serum IL-10 exhibited a negative correlation with circulating Tph-cells in active AAV patients. These results demonstrate that circulating Tph-cells are greatly expanded in active AAV patients and are positively associated with serum MPO-ANCAs and disease activity, thus contributing to the pathogenesis of AAV. The role of newly identified peripheral helper T cells (Tph) in ANCA-associated vasculitis (AAV) remains largely unknown, although they have been found elevated and playing pathogenic role in some autoimmune disease including SLE and RA. In this study, Liu et al found that Tph cells were greatly expanded in active AAV patients and decreased after treatment with methylprednisolone and cyclophosphamide, and they were positively correlated with vasculitis activity index, serum concentration of MPO-ANCA, IL-4 and IL-21. These results indicate that Tph cells may play a pathogenic role in AAV through promoting plasma cell activation possibly by secreting IL-4 and IL-21. [ABSTRACT FROM AUTHOR]

Objectives To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. Methods Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4–CD8–TCRαβ+ T lymphocytes (DNT), CD25+CD3+, HLA–DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. Results A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n  = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαβ+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαβ+B220+ lymphocytes. Conclusions Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS. [ABSTRACT FROM AUTHOR]

Members of the Fc receptor‐like (FCRL) family modulate B and T cell responses, yet their functional roles remain enigmatic. Nevertheless, FCRL3 promoter polymorphism that alters gene expression has been associated with autoimmune disease risk, indicating physiologic importance. Providing essential functional context, human FCRL3, FCRL4, and FCRL5 have recently been identified as secretory IgA (SIgA), dimeric IgA, and IgG receptors, respectively, revealing novel ways lymphocytes can interact with antibodies. FCRL3 and FCRL4 are able to distinguish the mucosal and systemic origin of IgA‐containing immune complexes, respectively, with clear implications in guiding mucosal responses. SIgA can signal mucosal breach through FCRL3, driving the functional plasticity of regulatory T cells toward inflammatory to help control invading pathogens. Conversely, recognition of dimeric IgA by FCRL4 on memory B cells located in mucosa‐associated lymphoid tissues could promote tolerance to commensals. Memory B cells that accumulate under conditions of chronic antigen presence frequently express FCRL4 and FCRL5, and antibody ligands could provide functional feedback to the cells. FCRL5 apparently recognizes the age of the IgG molecule, using deamidation as a molecular clock, conceivably playing regulatory roles in chronic antibody responses. A framework of FCRL3, FCRL4, and FCRL5 operating as sensors of antibodies in immune complexes is proposed. Sensing the spatial origin and age of immune complexes can shape lymphocyte functional attributes and inform their participation in mucosal immune responses. The potential contributions of FCRL3 and SIgA to the pathogenesis of autoimmune diseases are discussed. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease of the joints and is caused by both genetic and environmental factors. In the past six years, genome-wide association studies (GWASs) have identified many risk variants associated with RA. However, not all associations reported from GWASs are reproduced when tested in follow-up studies. To establish a reliable set of RA risk variants, we systematically classified common variants identified in GWASs by the degree of reproducibility among independent studies. We collected comprehensive genetic associations from 90 papers of GWASs and meta-analysis. The genetic variants were assessed according to the statistical significance and reproducibility between or within nine geographical populations. As a result, 82 and 19 single nucleotide polymorphisms (SNPs) were confirmed as intra- and inter-population-reproduced variants, respectively. Interestingly, majority of the intra-population-reproduced variants from European and East Asian populations were not common in two populations, but their nearby genes appeared to be the components of common pathways. Furthermore, a tool to predict the individual's genetic risk of RA was developed to facilitate personalized medicine and preventive health care. For further clinical researches, the list of reliable genetic variants of RA and the genetic risk prediction tool are provided by open access database RAvariome. [ABSTRACT FROM AUTHOR]

Introduction Coeliac disease is a common but often under diagnosed condition with important complications. It is due to immune-mediated gluten intolerance and may present in a number of ways. It has become more frequently diagnosed due to the recognition of the atypical presentations. In recent years, more sensitive and specific serological markers have been developed but the gold standard of diagnosis remains duodenal biopsy. Compliance with a strict, lifelong gluten-free diet is the cornerstone of management, improving symptoms and reducing complications of the disease. Sources of data For this review, we focused on papers published on coeliac disease in recent years. Particular emphasis was given to clinical papers examining new methods for the diagnosis of coeliac disease or newer therapies for managing complications. The main source was PubMed and the major gastroenterology journals. Areas of agreement Coeliac disease is more common than once thought with a prevalence of around 1%. Diagnosis should always be confirmed with a duodenal biopsy. Management of coeliac disease with a gluten-free diet remains the cornerstone of treatment. Areas of controversy Some complications of coeliac disease, especially neurological, are not widely accepted despite growing support from the literature. Management of enteropathy-associated lymphoma has been difficult, and the optimal therapy is not known. Growing points Current understanding is such that coeliac disease is the most widely understood autoimmune condition. ‘Atypical’ presentations are becoming the most common presenting features of coeliac disease. Areas timely for developing research Alternatives to the gluten-free diet are about to go into clinical studies. Similarly, better serological screening tests may obviate the need for duodenal biopsy. This review will try to summarize the current understanding of coeliac disease with regard to diagnosis, management, complications and future perspectives. [ABSTRACT FROM AUTHOR]

Anti-citrullinated protein/peptide antibodies (ACPA) are a hallmark of rheumatoid arthritis (RA) and can be measured using different citrullinated substrates. In this paper we describe a new viral citrullinated peptide - VCP2 - derived from the Epstein-Barr virus-encoded protein EBNA-2 and analyse its potential as substrate for ACPA detection. Analysing sera from 100 RA patients and 306 controls, anti-VCP2 immunoglobulin (Ig)G were found in 66% of RA sera, IgM in 46% and IgA in 39%, compared with less than 3% of control sera. Anti-VCP2 IgG was associated with erosive arthritis, the presence of rheumatoid factor and anti-VCP1 and anti-cyclic citrullinated peptide (CCP) antibodies. Anti-VCP2 antibodies were detected in 1% and anti-VCP1 antibodies in 4% of CCP-negative RA sera; conversely, 3% of the VCP-negative sera were CCP-positive. Taken together, these data suggest that VCP2 could offer a valuable tool for ACPA detection. Inhibition assays showed that two non-overlapping epitopes - a citrulline-glycine stretch shared between VCP1 and VCP2 and the N-terminal portion of the VCP2 sequence - were targeted by anti-VCP2 antibodies. Moreover, in some RA sera that tested positive in CCP and VCP2 assays, preincubation with VCP2 inhibited binding to CCP, whereas in other sera the binding was unaffected. Thus, the reactivity with more than one ACPA substrate might be due in some RA patients to antibody populations with different specificities, and in others to cross-reactive antibody populations. Finally, affinity-purified anti-VCP2 antibodies immunoprecipitated deiminated Epstein-Barr virus nuclear antigen (EBNA-2) from an EBNA-2-transfected cell line, suggesting that viral sequences may be involved in the generation of the ACPA response. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4+ T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8+ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes. [ABSTRACT FROM AUTHOR]

High-dose intravenous immunoglobulin (IVIg) preparations are used currently for the treatment of autoimmune or inflammatory diseases. Despite numerous studies demonstrating efficacy, the precise mode of action of IVIg remains unclear. Paradoxically, IgG can exert both pro- and anti-inflammatory activities, depending on its concentration. The proinflammatory activity of low-dose IVIg requires complement activation or binding of the Fc fragment of IgG to IgG-specific receptors (FcγR) on innate immune effector cells. In contrast, when administered in high concentrations, IVIg has anti-inflammatory properties. How this anti-inflammatory effect is mediated has not yet been elucidated fully, and several mutually non-exclusive mechanisms have been proposed. This paper represents the proceedings of a session entitled ‘IVIg – Understanding properties and mechanisms’ at the 6th International Immunoglobulin Symposium that was held in Interlaken on 26–28 March 2009. The presentations addressed how IgG may affect the cellular compartment, evidence for IVIg-mediated scavenging of complement fragments, the role of the dimeric fraction of IVIg, the anti-inflammatory properties of the minor fraction of sialylated IgG molecules, and the genetic organization and variation in FcγRs. These findings demonstrate the considerable progress that has been made in understanding the mechanisms of action of IVIgs, and may influence future perspectives in the field of Ig therapy. [ABSTRACT FROM AUTHOR]

With the rapid development of next-generation sequencing technology, many laboratories have produced a large amount of single-cell transcriptome data of blood and tissue samples from patients with autoimmune diseases, which enables in-depth studies of the relationship between gene transcription and autoimmune diseases. However, there is still a lack of a database that integrates the large amount of autoimmune disease transcriptome sequencing data and conducts effective analysis. In this study, we developed a user-friendly web database tool, Interactive Analysis and Atlas for Autoimmune disease (IAAA), which integrates bulk RNA-seq data of 929 samples of 10 autoimmune diseases and single-cell RNA-seq data of 783 203 cells in 96 samples of 6 autoimmune diseases. IAAA also provides customizable analysis modules, including gene expression, difference, correlation, similar gene detection and cell–cell interaction, and can display results in three formats (plot, table and pdf) through custom parameters. IAAA provides valuable data resources for researchers studying autoimmune diseases and helps users deeply explore the potential value of the current transcriptome data. IAAA is available. Database URL : http://galaxy.ustc.edu.cn/IAAA [ABSTRACT FROM AUTHOR]

The 78‐kDa glucose‐regulated protein (GRP78) has extracellular, anti‐inflammatory properties that can aid resolving inflammation. It has been established previously that GRP78 induced myeloid CD11c+ cell differentiation into distinct tolerogenic cells. This tolerance induction makes GRP78 a potential therapeutic agent for transplanted allogeneic grafts and autoimmune diseases, such as type 1 diabetes. In this research, it is revealed that rmGRP78‐treated NOD mice bone marrow‐derived CD11c+ cells (GRP78‐DCs) highly expressed B7‐H4 but down‐regulated CD86 and CD40, and retained a tolerogenic signature even after stimulation by LPS. In the assessment of in vivo therapeutic efficacy after the adoptive transfer of GRP78‐DCs into NOD mice, fluorescent imaging analyses revealed that the transfer specifically homed in inflamed pancreases, promoting β‐cell survival and alleviating insulitis in NOD mice. The adoptive transfer of GRP78‐DCs also helped reduce Th1, Th17, and CTL, suppressing inflammatory cytokine production in vivo. The findings suggest that adoptive GRP78‐DC transfer is critical to resolving inflammation in NOD mice and may have relevance in a clinical setting. [ABSTRACT FROM AUTHOR]

SS is a chronic, autoimmune condition characterized by lymphocytic infiltration of the exocrine glands and B-cell dysfunction. Current treatment strategies are largely empirical and offer only symptomatic relief for patients. There are no proven treatments that alter disease progression or treat the systemic manifestations of disease. B-cell depletion is used in patients with systemic disease but its overall clinical efficacy has not been demonstrated in two large randomized controlled trials. Studies are now focussing on alternative strategies to target B-cells, including co-stimulation targets, with promising data. It is increasingly clear that clinical trials in SS will require patient stratification and relevant and sensitive outcome measures to identify successful treatment modalities. [ABSTRACT FROM AUTHOR]

Objectives Many patients with interstitial lung disease (ILD) have autoimmune manifestations but do not meet criteria for a systemic rheumatic disease. A subset meets criteria for interstitial pneumonia with autoimmune features (IPAF) and have ILD requiring therapy. We conducted a multicentre observational study to examine the use of rituximab (RTX) in IPAF. Methods Patients from Mass General Brigham (MGB) and University of Chicago Medicine (UCM) were included if they were ≥18 years old, met the 2015 classification criteria for IPAF and were treated with RTX. Clinical improvement was defined as improvement in four out of four domains at 1 year after RTX initiation: documented clinician global assessment; oxygen requirement; need for respiratory-related hospitalization; and survival. Results At MGB, 36 IPAF patients (mean age 61 years, 44% female) were treated with RTX. At 1 year, 18 (50%) were clinically improved, 12 (33%) were stable, and 6 (17%) died from progressive respiratory failure. At UCM, 14 IPAF patients (mean age 53 years, 71% female) were treated with RTX. At 1 year, eight (57%) were improved, two (14%) were stable, three (21%) died from progressive respiratory failure, and one (7%) was lost to follow-up. Two patients experienced minor infusion reactions, and two patients discontinued therapy owing to adverse events (infections). Conclusion In patients with IPAF treated with RTX at two medical centres, the majority (40 [80%]) demonstrated improvement/stability at 1 year. These findings call for prospective studies, including randomized clinical trials, to determine the risks, benefits and cost effectiveness of RTX in IPAF. [ABSTRACT FROM AUTHOR]

Objective The primary objective of this study was to investigate adverse effects of ambient particulate matter of various sizes on the incidence of the prevalent autoimmune rheumatic diseases (AIRDs): RA, AS and SLE. Methods We investigated 230 034 participants in three metropolitan cities of South Korea from the National Health Insurance Service–National Sample Cohort (NHIS-NSC). Starting from January 2010, subjects were followed up until the first event of prevalent AIRDs, death, or December 2013. The 2008–2009 respective averages of particulate matter2.5 (<2.5 μm) and particulate mattercoarse (2.5 μm to 10 μm) were linked with participants' administrative district codes. Adjusted hazard ratios (aHRs) and 95% CIs were estimated using Cox regression analysis in one- and two-pollutant models. Results Adjusted for age, sex, region, and household income, in the two-pollutant model, RA incidence was positively associated with the 10 μg/m³ increment of particulate matter2.5 (aHR = 1.74, 95% CI: 1.06, 2.86), but not with particulate mattercoarse (aHR = 1.27, 95% CI: 0.87, 1.85). In the one-pollutant model, the elevated incidence rate of RA was slightly attenuated (particulate matter2.5 aHR = 1.61, 95% CI: 0.99, 2.61; particulate mattercoarse aHR = 1.13, 95% CI: 0.80, 1.61), with marginal statistical significance for particulate matter2.5. The RA incidence was also higher in the 4th quartile group of particulate matter2.5 compared with the first quartile group (aHR = 1.83, 95% CI: 1.07, 3.11). Adverse effects from particulate matter were not found for AS or SLE in either the one- or two-pollutant models. Conclusion The important components of particulate matter10 associated with RA incidence were the fine fractions (particulate matter2.5); no positive association was found between particulate matter and AS or SLE. [ABSTRACT FROM AUTHOR]

Objective To assess the association of severe pulmonary arterial hypertension (PAH) with particulate matter <2.5 μm (p.m.2.5) and clinical data in patients with systemic autoimmune rheumatic diseases (SARDs). Methods We used the 2003–2017 nationwide data in Taiwan to identify patients with SARDs, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis/polymyositis and primary Sjögren's syndrome. We identified 479 cases with severe PAH and selected controls matched (1:4) for age, sex, and index year. We used conditional logistic regression analysis to determine factors associated with risks for severe PAH shown as odds ratios (ORs) with 95% confidence intervals (CIs). Results We found that severe PAH was highly associated with interstitial lung disease (OR, 8.57; 95% CI: 5.52, 13.32), congestive heart failure (OR, 7.62; 95% CI: 5.02, 11.55), valvular heart disease (OR, 3.34; 95% CI: 2.03, 5.50) and slightly associated with thyroid diseases (OR, 1.88; 95% CI: 1.18, 3.00), but not the level of exposure to p.m.2.5. Increased risk for PAH was found in patients receiving corticosteroid (prednisolone equivalent dosage, mg/day, OR, 1.03; 95% CI: 1.01, 1.05), biologics (OR, 2.18; 95% CI: 1.15, 4.12) as well as immunosuppressants, including ciclosporin (OR, 2.17; 95% CI: 1.31, 3.59), azathioprine (OR, 1.96; 95% CI: 1.48, 2.61), cyclophosphamide (OR, 2.01; 95% CI: 1.30, 3.11) and mycophenolate mofetil/mycophenolic acid (OR, 2.42; 95% CI: 1.37, 4.27), and those with the highest level of insured amount (reference, lowest level; OR, 0.53; 95% CI: 0.34, 0.83). Conclusion The population-based study identified risks for severe PAH in patients with SARDs, and these findings provide evidence for PAH risk stratification in patients with SARDs. [ABSTRACT FROM AUTHOR]

Objective Patients with autoimmune diseases were advised to shield to avoid coronavirus disease 2019 (COVID-19), but information on their prognosis is lacking. We characterized 30-day outcomes and mortality after hospitalization with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza. Methods A multinational network cohort study was conducted using electronic health records data from Columbia University Irving Medical Center [USA, Optum (USA), Department of Veterans Affairs (USA), Information System for Research in Primary Care-Hospitalization Linked Data (Spain) and claims data from IQVIA Open Claims (USA) and Health Insurance and Review Assessment (South Korea). All patients with prevalent autoimmune diseases, diagnosed and/or hospitalized between January and June 2020 with COVID-19, and similar patients hospitalized with influenza in 2017–18 were included. Outcomes were death and complications within 30 days of hospitalization. Results We studied 133 589 patients diagnosed and 48 418 hospitalized with COVID-19 with prevalent autoimmune diseases. Most patients were female, aged ≥50 years with previous comorbidities. The prevalence of hypertension (45.5–93.2%), chronic kidney disease (14.0–52.7%) and heart disease (29.0–83.8%) was higher in hospitalized vs diagnosed patients with COVID-19. Compared with 70 660 hospitalized with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2–4.3% vs 6.32–24.6%). Conclusion Compared with influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality. [ABSTRACT FROM AUTHOR]

Much is said about precision medicine, but its real significance and potential are far from certain. Several studies in each of the autoimmune diseases have provided important insights into molecular pathways, but the use of molecular studies, particularly those looking into transcriptome pathways, has seldom approached the possibility of using the data for disease stratification and then for prediction, or for diagnosis. Only the type I IFN signature has been considered for therapeutic purposes, particularly in the case of SLE. This review provides an update on precision medicine, on what can be translated into clinical practice and on what single-cell molecular studies contribute to our knowledge of autoimmune diseases, focusing on a few examples. The main message is that we should try to move from precision medicine of established diseases to preventive medicine in order to predict the development of disease. [ABSTRACT FROM AUTHOR]