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Abstract
Objective
In rheumatoid arthritis (RA), anti–citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly used to aid in the diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPAs and RF alone. In addition, anti–carbamylated protein (anti‐CarP) antibodies have diagnostic and prognostic value, since their presence is associated with joint damage in RA patients and also associated with the future development of RA in patients with arthralgia. Therefore, the aim of the present study was to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA.
Methods
A literature search resulted in identification of 12 relevant studies, consisting of RA patients, pre‐RA individuals, disease controls, healthy first‐degree relatives of RA patients, and healthy control subjects, in which data on RF, ACPAs, and anti‐CarP antibody status were available. Using these data, random effects meta‐analyses were carried out for several antibody combinations.
Results
The individual antibodies were highly prevalent in patients with RA (34–80%) compared to the control groups, but were also present in non‐RA controls (0–23%). For the classification of most subjects correctly as having RA or as a non‐RA control, the combination of ACPAs and/or RF often performed well (specificity 65–100%, sensitivity 59–88%). However, triple positivity for ACPAs, RF, and anti‐CarP antibodies resulted in a higher specificity for RA (98–100%), accompanied by a lower sensitivity (11–39%).
Conclusion
As the rheumatology field is moving toward very early identification of RA and possible screening for individuals at maximum risk of RA in populations with a low pretest probability, an autoantibody profile of triple positivity for ACPAs, RF, and anti‐CarP provides interesting information that might help identify individuals at risk of developing RA.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 29, 2018 12:13 PM
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The B cell survival cytokine BAFF has been linked with the pathogenesis of systemic lupus erythematosus (SLE). BAFF binds distinct BAFF-family surface receptors, including the BAFF-R and transmembrane activator and CAML interactor (TACI). Although originally characterized as a negative regulator of B cell activation, TACI signals are critical for class-switched autoantibody (autoAb) production in BAFF transgenic mice. Consistent with this finding, a subset of transitional splenic B cells upregulate surface TACI expression and contribute to BAFF-driven autoAb. In the current study, we interrogated the B cell signals required for transitional B cell TACI expression and Ab production. Surprisingly, despite established roles for dual BCR and TLR signals in autoAb production in SLE, signals downstream of these receptors exerted distinct impacts on transitional B cell TACI expression and autoAb titers. Whereas loss of BCR signals prevented transitional B cell TACI expression and resulted in loss of serum autoAb across all Ig isotypes, lack of TLR signals exerted a more limited impact restricted to autoAb class-switch recombination without altering transitional B cell TACI expression. Finally, in parallel with the protective effect of TACI deletion, loss of BAFF-R signaling also protected against BAFF-driven autoimmunity. Together, these findings highlight how multiple signaling pathways integrate to promote class-switched autoAb production by transitional B cells, events that likely impact the pathogenesis of SLE and other BAFF-dependent autoimmune diseases.
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Gilbert C FAURE
November 29, 2018 1:29 AM
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Objective to appraise the role of epitope spreading in established human systemic lupus erythematosus (SLE). Methods IgG‐autoantibody reactivity to 398 distinct recombinant proteins was measured in 69 SLE patients over 6 years and compared to 45 controls. Changes in mean fluorescence intensity (MFI), number of autoantibodies to distinct antigens, and reactivity to distinct clones of selected established antigenic targets U1‐RNP, Sm, and ribosomal P representing epitope fine mapping were assessed. Linear mixed modelling adjusted for age and sex with Bonferroni correction was applied. Results The total number of autoantibodies, mean MFI, and number of autoantibodies in epitope fine mapping were higher in SLE compared to controls (p<0.0001). The total number of antibodies to distinct autoantigens remained stable, while the mean MFI decreased over time in SLE (p<0.021). SLE patients showed variable recognition of epitopes in fine mapping over time. In particular, SLE patients recognized more clones of the U1‐RNP complex at the time of new organ involvement (+0.65, p =0.007). Patients with lupus nephritis had a higher mean MFI (p=0.047). Time‐averaged MFI of 22 individual autoantibodies were higher in SLE after Bonferroni correction including dsDNA (p<0.0001). DsDNA and histone cluster 2 H3c MFIs were associated to the SLAM (p<0.0001). Conclusion Longitudinal surveillance of the IgG‐autoantibody repertoire in established SLE reveals evidence for sustained breadth of autoantibody repertoire without significant expansion. Associations of disease activity are confirmed for dsDNA and histone H3 autoantibodies. This article is protected by copyright. All rights reserved.
Via Krishan Maggon
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Gilbert C FAURE
November 26, 2018 8:14 AM
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Altogether there are more than 80 autoimmune conditions known to science, but the reason for the rise in incidence is not known.
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Gilbert C FAURE
November 25, 2018 1:22 PM
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It is often stated that type 1 diabetes results from a complex interplay between varying degrees of genetic susceptibility and environmental factors. While agreeing with this principal, our desire is that this Perspectives article will highlight another ...
Biomarkers for pulmonary manifestations in systemic lupus erythematosus (SLE) are missing. Plasma samples of nine SLE patients with known pulmonary involvement ...
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 24, 2018 2:08 PM
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Autoimmunity and hematological malignancies are often concomitant in patients. A causal bidirectional relationship exists between them. Loss of immunological tolerance with inappropriate activation of the immune system, likely due to environmental and genetic factors, can represent a breeding...
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Gilbert C FAURE
November 23, 2018 2:34 AM
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Detection of antinuclear antibodies (ANAs) is of paramount importance for diagnosis and assessment of autoimmune diseases (ADs), but may vary depending on the method used. Therefore, we aimed to compare three different line immunoassays (LIAs) for ANAs testing in order to simultaneously evaluate their concordance with the results obtained by a well known and widely used ELISA. Sera from women with established systemic lupus erythematosus (SLE, n=62) and Sjogren’s syndrome (SS, n=28) were examined. Patients with SLE had an average age of 48.7 years (IQR 36.8–57.0) with a disease duration of 14.8 years (IQR 9.0–18.0). Patients with SS had an average age of 62.1 years (IQR 55.5–71.0) with a duration of disease of 13.1 years (IQR 8.3–17).
Table 1 shows the results from the two-by-two comparison for the four techniques. Different levels of agreement were observed among the assays. In general, they were deficient. The analysis showed only one ‘strong’ level of agreement between ELISA and IMTEC-ANA-LIA Maxx for anti-Ro measurement. Out of 39 comparisons, 14 did …
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Gilbert C FAURE
November 20, 2018 4:38 AM
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anti-C1q antibodies in SLE
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Gilbert C FAURE
November 19, 2018 1:48 PM
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Autoimmune diseases and kidney transplantation can result in immune-mediated kidney pathology. In this Review, the authors discuss the roles of effector and regulatory B cells and the efficacy of B cell-targeting therapies in these settings.
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Scooped by
Gilbert C FAURE
November 19, 2018 4:41 AM
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Sjögren’s syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining...
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Scooped by
Gilbert C FAURE
November 19, 2018 3:46 AM
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Antiphospholipid syndrome is an autoimmune disease associated with a variety of symptoms, including thrombosis and obstetrical complications. This Primer provides an update on the epidemiology, pathogenesis, diagnosis and therapeutic aspects and offers an outlook on future research topics.
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The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS. The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo. The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.
Via Krishan Maggon
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and etiology characterized by chronic inflammation and autoantibody production. The purpose of this study was to ascertain copy number variation (CNV) in SLE using a case-control design in an admixed...
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 28, 2018 1:19 PM
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Diabetogenic T cells infiltrate the pancreatic islets by transmigrating across the microcapillaries residing close to, or within, the pancreatic islets. Deficiency in IFNgamma signaling prevents efficient migration of T cells into the pancreatic islets, but the IFNgamma-regulated molecules that mediate this are uncertain. Homing of autoreactive T cells into target tissues may require antigen specificity through presentation of cognate antigen by MHC expressed on the vascular endothelium. We investigated the hypothesis that IFNgamma promotes the migration of islet antigen-specific CD4+ T cells by upregulating MHC class II on islet endothelial cells (IEC), thereby providing an antigen-specific signal for islet infiltration. Upon IFNgamma stimulation, MHC class II, which is not constitutively expressed on IEC, was induced. IFNgamma-dependent upregulation of MHC class II was detected in IEC isolated from prediabetic NOD mice at the earliest stages of insulitis, before other markers of inflammation were present. Using a CD4+ T cell-mediated adoptive transfer model of autoimmune diabetes we observed that even though diabetes does not develop in recipient mice lacking IFNgamma receptors, mice with MHC class II-deficient IEC were not protected from disease. Thus, IFNgamma-regulated molecules, but not MHC class II or antigen presentation by IECs is required for the early migration of antigen-specific CD4+ T cells into the pancreatic islets.
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Scooped by
Gilbert C FAURE
November 26, 2018 1:01 PM
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Connect Immune Research, a collaboration between JDRF, MS Society and Versus Arthritis, issues report revealing rise in autoimmune conditions
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Gilbert C FAURE
November 25, 2018 1:42 PM
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A recent study in the Annals of Internal Medicine investigated the frequency of antiphospholipid antibodies in first-time heart attack patients.
A new interesting article has been published in Arthritis Rheumatol. 2018 Nov 8. doi: 10.1002/art.40772.[Epub ahead of print] and titled: Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid …...
Via Krishan Maggon
Abstract
Introduction: Multiple pathways are involved in the pathogenesis of systemic lupus erythematosus (SLE). The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway mediates the intracellular signals of more than 60 cytokines, growth factors and hormones from the type I/II cytokine receptors. Dysregulation of the cytokines is a hallmark of SLE; inhibition of downstream signaling mediated by the JAKs is an attractive therapeutic option.
Areas covered: This article reviews the preliminary data concerning the efficacy of the JAK inhibitors (Jakinibs) in SLE. JAK inhibition has shown promise in murine lupus dermatitis and nephritis. Ex-vivo studies of human SLE have demonstrated the effect of JAK1/2 inhibition on the activation of the STAT proteins and autoantibody production from B cells. A phase II trial reported modest efficacy of baricitinib in improving synovitis in SLE patients.
Expert opinions: Inhibition of the JAK-STAT pathway is an attractive therapeutic option. The convenience of oral administration and lower production cost of the Jakinibs could replace the biological agents in the treatment hierarchy of autoimmune inflammatory diseases. Additional clinical data are needed; results of ongoing studies of the newer Jakinibs in cutaneous and non-life-threatening lupus are eagerly awaited.
Keywords: JAK, Jakinib, lupus, targeted, therapeutic, systemic lupus, SLE, autoimmune disease
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 24, 2018 3:53 AM
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Curr Opin Rheumatol. 2019 Jan;31(1):3-8. doi: 10.1097/BOR.0000000000000557.
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Gilbert C FAURE
November 22, 2018 4:52 AM
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Autoimmune myocarditis often leads to dilated cardiomyopathy. Although T cell reactivity to cardiac self-antigen is common in the disease, it is unknown which antigen presenting cell (APC) triggers autoimmunity. Experimental autoimmune myocarditis (EAM) was induced by immunizing mice with α-myosin loaded bone marrow APCs cultured in GM-CSF. APCs found in such cultures include conventional type 2 CD11b+ cDCs (GM-cDC2s) and monocyte-derived cells (GM-MCs). However, only α-myosin loaded GM-cDC2s could induce EAM. We also studied antigen presenting capacity of endogenous type 1 CD24+ cDCs (cDC1s), cDC2s and MCs for α-myosin-specific TCR-transgenic TCR-M CD4+ T cells. After EAM induction, all cardiac APCs significantly increased and cDCs migrated to the heart-draining mediastinal lymph node. Primarily cDC2s presented α-myosin to TCR-M cells and induced Th1/Th17 differentiation. Loss of IRF4 in Irf4fl/fl.Cd11cCre mice reduced MHCII expression on GM-cDC2s in vitro and cDC2 migration in vivo. However, partly defective cDC2 functions in Irf4fl/fl.Cd11cCre mice did not suppress EAM. MCs were the largest APC subset in the inflamed heart and produced pro-inflammatory cytokines. Targeting APC populations could be exploited in the design of new therapies for cardiac autoimmunity.
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Scooped by
Gilbert C FAURE
November 20, 2018 4:35 AM
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Although anti-C1q autoantibodies have been described more than four decades ago a constant stream of papers describing clinical associations or functional consequences highlights that anti-C1q antibodies are still hot and happening. By far the larges
Mycobacterium avium subspecies paratuberculosis (MAP) is the known infectious cause of Johne’s disease, an enteric inflammatory disease mostly studied in ruminant animals. MAP has also been implicated in the very similar Crohn’s disease of humans as well as sarcoidosis. Recently, MAP has been associated with juvenile sarcoidosis (Blau syndrome), autoimmune diabetes, autoimmune thyroiditis, and multiple sclerosis. While it is intuitive to implicate MAP in granulomatous diseases where the microbe participates in the granuloma, it is more difficult to assign a role for MAP in diseases where autoantibodies are a primary feature. MAP may trigger autoimmune antibodies via its heat shock proteins. Mycobacterial heat shock protein 65 (HSP65) is an immunodominant protein that shares sequential and conformational elements with several human host proteins. This molecular mimicry is the proposed etiopathology by which MAP stimulates autoantibodies associated with autoimmune (type 1) diabetes, autoimmune (Hashimoto’s) thyroiditis, and multiple sclerosis. This paper proposes that MAP is a source of mycobacterial HSP65 and acts as a trigger of autoimmune disease.
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
November 19, 2018 4:41 AM
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Objectives To determine the expressions of Toll‐like receptors (TLRs) 7–9 and type I interferon (IFN) signal in labial salivary glands (LSGs) and cultured salivary gland epithelial cells (SGECs) from primary Sjögren's syndrome (pSS) patients. Methods We performed an immunohistochemistry analysis of LSGs from 11 patients with pSS as defined by American‐European Consensus Group classification criteria and five healthy subjects. The pSS patients’ SGECs were analyzed by immunofluorescence and western blotting. IFN‐α expression was examined by immunosorbent assay and flow cytometry. Results Mononuclear cells (MNCs) from pSS patients’ LSGs showed TLR7‐dominant expression. B cells, plasma cells, and plasmacytoid dendritic cells (pDCs) co‐expressed with TLR7. MyD88, TRAF6, and IRF7 co‐expressed with the pDC marker CD303 in LSGs. Ducts from pSS patients dominantly expressed TLR7, and TLR7 in the ducts co‐expressed with MyD88, TRAF6 and IRF7. Type I IFNs including IFN‐α and IFN‐β were detected in MNCs and ducts in pSS patients’ LSGs. Increased TRAF6 expression and the nuclear translocation of IRF7 in SGECs were detected by immunofluorescence following loxoribine (a TLR7 ligand) stimulation despite IFN‐β pretreatment. Western blotting showed increased TRAF6 expression in SGECs following IFN‐β and loxoribine stimulation. Although no increase in IFN‐α was detected in supernatant from stimulated SGECs, the IFN‐α in supernatant from stimulated peripheral blood pDCs from pSS patients was significantly increased. Conclusion Our findings suggest that TLR7 is dominantly expressed in both MNCs and ducts with downstream signals for type I IFNs, indicating that TLR7‐dominant innate immunity is related to the development of sialadenitis in pSS. This article is protected by copyright. All rights reserved.
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