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Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease characterised by xerostomia and xerophthalmia. In at least one-third of patients, the disease may be complicated by extraglandular involvement. Due to the lack of evidence-based recommendations, current therapeutic options for pSS are mainly empirical, often reflecting their use in other autoimmune diseases. Nevertheless, recent advances in the understanding of pathogenic pathways in pSS encourage the belief that blocking them may be of value in the treatment of the disease. Despite failing to demonstrate efficacy in clinical trials, because of the well-established role of B-lymphocytes in the pathogenesis of pSS, rituximab has been the most frequently used to date, but with much less success than in the treatment of patients with rheumatoid arthritis, vasculitis and lupus. However, in the last few years a number of other biologics have been developed and are under investigation. The aim of this article is to review the use of biologic therapies in pSS.

APS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (β2GPI) via its N-terminal domain I (DI). We previously showed that bacterially-expressed recombinant DI inhibits biological actions of IgG derived from serum of patients with APS (APS-IgG). DI is too small (7 kDa) to be a viable therapeutic agent. Addition of polyethylene glycol (PEGylation) to small molecules enhances the serum half-life, reduces proteolytic targeting and can decrease immunogenicity. It is a common method of tailoring pharmacokinetic parameters and has been used in the production of many therapies in the clinic. However, PEGylation of molecules may reduce their biological activity, and the size of the PEG group can alter the balance between activity and half-life extension. Here we achieve production of site-specific PEGylation of recombinant DI (PEG-DI) and describe the activities in vitro and in vivo of three variants with different size PEG groups. All variants were able to inhibit APS-IgG from: binding to whole β2GPI in ELISA, altering the clotting properties of human plasma and promoting thrombosis and tissue factor expression in mice. These findings provide an important step on the path to developing DI into a first-in-class therapeutic in APS.

Antiphospholipid antibodies (aPL) cause vascular thrombosis (VT) and/or pregnancy morbidity (PM). Differential mechanisms however, underlying the pathogenesis of these different manifestations of antiphospholipid syndrome (APS) are not fully understood. Therefore, we compared the effects of aPL from patients with thrombotic or obstetric APS on monocytes to identify different molecular pathways involved in the pathogenesis of APS subtypes. VT or PM IgG induced similar numbers of differentially expressed (DE) genes in monocytes. However, gene ontology (GO) analysis of DE genes revealed disease-specific genome signatures. Compared to PM, VT-IgG showed specific up regulation of genes associated with cell response to stress, regulation of MAPK signalling pathway and cell communication. In contrast, PM-IgG regulated genes involved in cell adhesion, extracellular matrix and embryonic and skeletal development. A novel gene expression analysis based on differential variability (DV) was also applied. This analysis identified similar GO categories compared to DE analysis but also uncovered novel pathways modulated solely by PM or VT-IgG. Gene expression analysis distinguished a differential effect of VT or PM-IgG upon monocytes supporting the hypothesis that they trigger distinctive physiological mechanisms. This finding contributes to our understanding of the pathology of APS and may lead to the development of different targeted therapies for VT or PM APS.

International audience; OBJECTIVES:To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS).METHODS:The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays.RESULTS:By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p

Lupus nephritis (LN) affects up to 50% of patients with Systemic Lupus Erythematosus (SLE) and is associated with a worse prognosis. LN usually develops within the first 5 years of the onset of the disease. We report three patients with very delayed LN (DLN) diagnosed after 15 or more years after SLE diagnosis. The three patients were non-Caucasian women with adolescent or adult-onset SLE. Each had antinuclear, anti-dsDNA and anti-Ro antibodies. Hydroxychloroquine was prescribed for each. Their disease courses were characterised by sporadic non-renal flares controlled by steroids and, in two cases, by one cycle of rituximab. Unexpectedly, they developed proteinuria, haematuria and lowering of estimated glomerular filtration rate with clinical signs of renal disease. LN was confirmed by renal biopsy. Reviewing them, each showed serological signs of increasing disease activity (rising levels of anti-dsDNA antibodies and fall in C3) that predated clinical or laboratory signs of LN by 1-3 years. Reviewing the literature, we found a lack of knowledge about DLN starting more than 15 years after SLE diagnosis. With the increasing life expectancy of patients with SLE it is likely that more cases of very DLN will emerge. info:eu-repo/semantics/publishedVersion

Immunological abnormalities seen in relatives of patients with autoimmune disorders can be useful in understanding the pathogenesis of the disease since, unlike in patients, they cannot result from the disease process or drug treatment. In this article we present a brief overview of our studies of the basic immunological status of close relatives of SLE patients. We looked at blood levels of IgG, IgM and antibodies to double-stranded DNA, as well as at NK cell numbers and cytotoxic activity and the levels of NKT, B and T cells. As many as 60% of relatives showed one or more abnormalities in these assays. Most notably there were increased levels of IgG in male and female relatives and a reduction of IgM in females. IgG correlated inversely with NKT cell numbers adding strength to the concept that the presence of IgG autoantibodies in patients is due to impaired regulation by NKT cells. IgM, on the other hand, correlated inversely with NK cells which may thus have a role in bringing about the reduced IgM seen in some patients. Immunological abnormalities were found to be more often associated with parents and offspring of patients than with their siblings, pointing to the involvement of environmental or epigenetic influences in lupus pathogenesis.

OBJECTIVE: To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of

Objective. IgG aPL against domain I of β2-glycoprotein I (β2GPI) [anti-DI (aDI)] is associated with the pathogenesis of APS, an autoimmune disease defined by thrombosis and pregnancy morbidity. To date, however, no study has demonstrated direct pathogenicity of IgG aDI in vivo. In this proof-of-concept study, we designed a novel system to affinity purify polyclonal aDI aPL in order to assess its prothrombotic ability in a well-characterized mouse microcirculation model for APS. Methods. Two polyclonal IgG fractions were isolated from serum of a patient with APS, both with high aPL activity but differing in aDI activity (aDI-rich and aDI-poor). These IgG fractions were tested for their pathogenic ability in an in vivo mouse model of thrombosis. Male CD1 mice were injected intraperitoneally with either aDI-rich or aDI-poor IgG; as a control, IgG isolated from healthy serum was used. A pinch injury was applied to the right femoral vein and thrombus dynamics and tissue factor activity in isolated tissue were evaluated. Results. Both aDI-rich and aDI-poor IgG retained aCL and anti-β2GPI activity, while only aDI-rich IgG displayed high aDI activity, as defined by our in-house cut-offs for positivity in each assay. aDI-rich IgG induced significantly larger thrombi in vivo compared with aDI-poor IgG (P < 0.0001). Similarly, aDI-rich IgG significantly enhanced the procoagulant activity of carotid artery endothelium and peritoneal macrophages isolated from experimental animals (P < 0.01). Conclusion. These data directly demonstrate that the ability to cause thrombosis in vivo is concentrated in the aDI fraction of aPL.

The presence of auto-antibodies in infectious diseases continues to puzzle and provoke. It is hoped that sequencing studies in particular will yield further clues as to the role and mechanism of production of autoantibodies in infectious diseases. This, in turn, may also provide further insights into the role of auto-antibodies in auto-immune diseases. From a practical clinical viewpoint, the search for improved auto-antibody tests and new diagnostic markers with improved sensitivity and specificity must continue in the tropics. Until this is achieved, the results of auto-antibody tests in persons living in the tropics, persons from the tropics or patients with tropical infections, must be interpreted with caution.