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Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein-Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre-clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti-EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA-related autoimmunity.A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age-, sex-, and race-matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre-RA and post-RA diagnosis periods and tested the sera for the presence of 5 anti-EBV antibodies (anti-EBV nuclear antigen 1 IgG isotype, anti-viral capsid antigen [anti-VCA] isotypes IgG and IgA, and anti-early antigen [EA] isotypes IgG and IgA), 7 RA-related autoantibodies (rheumatoid factor measured by nephelometry [RF-Neph] as well as isotype-specific IgA-RF, IgM-RF, and IgG-RF, and anti-cyclic citrullinated peptide [anti-CCP] antibodies, including anti-CCP2, anti-CCP3, and anti-CCP3.1), 22 cytokines/chemokines, 36 individual anti-citrullinated protein antibodies, and IgG-cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti-EBV antibody levels between RA subjects and controls.Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG-EA antibody levels were higher in RA subjects (mean ± SD 0.82 ± 0.72 international standardized ratio [ISR]) compared to controls (mean ± SD 0.49 ± 0.28 ISR). In subjects with RA, elevated serum IgG-EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM-RF levels (P = 0.007), whereas this correlation was not seen in control subjects without RA (P = 0.15). IgG-CMV antibody levels did not differ between groups.Subjects whose serum IgG-EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.

Mitochondria are found in the extracellular space in rheumatoid arthritis (RA). However, whether mitochondria are a source of autoantigens in RA has not been carefully addressed. Thus, we investigated the presence and significance of anti-mitochondrial antibodies (AMA) in patients with RA.AMAs were measured in sera from three cross-sectional RA cohorts (n=95, n=192, and n=117) and healthy individuals (n=38, n=72, n=50) using a flow cytometry-based assay. Further, AMAs were detected using anti-mitofusin-1 (MFN1) IgG ELISA and Western blot. A longitudinal inception cohort, followed for a median of 8 years, was used to study disease progression.AMA levels were elevated in all three RA cohorts as compared to healthy individuals (p0.001, p0.05, and p0.01), with a range of 14-26% positivity. Levels of anti-MFN1 antibodies correlated with AMA levels (r=0.31, p=0.006) and were elevated in RA as compared to healthy individuals (p0.001). Presence of AMA was associated with erosive disease (p0.05) and interstitial lung disease (p0.01). Further, AMA levels could predict erosive disease (OR=4.59, p=0.006) and joint space narrowing (OR=3.08, p=0.02) independent of anti-citrullinated protein antibodies. Finally, anti-MFN1 antibodies identified seronegative patients developing erosive disease (OR=9.33, p=0.02).Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in RA. AMAs stratified patients based on disease phenotype and predicted development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in RA pathogenesis and suggest a possible benefit of therapies targeting mitochondrial-mediated inflammation and clearance in these patients. This article is protected by copyright. All rights reserved.

The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast–derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae . After generating bacterial isolates within the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum from the feces of an individual, we confirmed monoclonal antibody binding and CD4 + T cell activation in individuals with RA compared to control individuals. In addition, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated T H 17 cell expansion, serum RA–relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4 + T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.

Prevotella copri (Pc), a gut commensal, has been reported to be an immune relevant organism in individuals with rheumatoid arthritis (RA). Our goal was to evaluate anti-Pc antibody responses in our participant cohorts and determine when in the natural history of RA such responses develop.Serum levels of IgA and IgG anti-Pc-p27, an immunogenic Pc protein, were analyzed in study participants at-risk for the development of RA, those who transitioned to RA, in those with early RA (one year of disease), and in those with established RA, compared to matched controls. Additionally, levels of anti-Pc-p27 antibodies were evaluated in individuals stratified by RA-related autoantibody status.Overall, participants with RA had significantly higher levels of IgA anti-Pc-p27 antibodies and trends towards higher levels of IgG anti-Pc-p27 antibodies when compared to their matched controls. When stratified by early versus established RA, early RA participants had median values of IgG anti-Pc-p27 antibodies that were overall higher, whereas median values of IgA anti-Pc-p27 were statistically significantly higher in participants with established RA, compared with their matched controls. In the autoantibody specific analyses, the at-risk population with anti-CCP antibodies, but not RF, demonstrated trends towards increased levels of IgG anti-Pc-p27. Additionally, RA participants who were CCP+/RF+ had significantly increased levels of IgA anti-Pc-p27 antibodies and a trend toward levels of IgG anti-Pc-p27 antibodies when compared to their matched controls.These findings support a potential etiologic role for this microorganism in both RA preclinical evolution and the subsequent pathogenesis of synovitis.

The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation and/or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual IgA/IgG family plasmablast-derived monoclonal autoantibodies obtained from peripheral blood of individuals at-risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae. After generating bacterial isolates within Lachnospiraceae/Ruminococcaceae genus Subdoligranulum from the feces of an individual, we confirmed monoclonal antibody binding as well as MHC class II dependent CD4+ T cell activation in RA cases compared to controls. Additionally, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated Th17 cell expansion, serum RA-relevant IgG autoantibodies, and joint swelling reminiscent of early RA with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to the generation of colon isolated lymphoid follicles (ILFs) driving increased fecal and serum IgA by isolate 7, as B and T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate one mucosal mechanism in RA through which an intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.One-sentence summarySubdoligranulum spp. targeted by rheumatoid arthritis (RA)-relevant autoantibodies activate T cells in individuals with RA, and in mice stimulate autoantibodies and joint swelling associated with antibody deposition and complement activation.

Rheumatoid arthritis (RA) is a common condition affecting approximately 1% of the general population. RA is a multisystem disorder that causes progressive articular destruction through synovial inflammation. One of the most common extraarticular manifestations of RA is pulmonary involvement, where all compartments of the pulmonary system can be impacted (e.g., pulmonary vasculature, pleura, parenchyma, and the airways). Although it has been known for decades that a portion of patients with RA develop interstitial lung disease, and recent advancements in understanding the genetic risk and treatment for RA-interstitial lung disease have drawn attention, more recent data have begun to highlight the significance of airway disease in patients with RA. Yet, little is known about the underlying pathogenesis, clinical impact, or optimal treatment strategies for airway disease in RA. This review will focus on airway disease involvement in patients with RA by highlighting areas of clinical inquiry for pulmonologists and rheumatologists and discuss areas for future research. Finally, we discuss a potential screening algorithm for providers when approaching patients with RA with respiratory complaints.

Interstitial lung disease (ILD) is a common manifestation in connective tissue diseases (CTD), such as rheumatoid arthritis (RA), systemic sclerosis (SSc) and inflammatory myositis (IM). ILD is associated with significant morbidity and mortality in nearly all CTD highlighting the critical need for effective treatment strategies in this patient population. In this review, we will summarize the approach to treatment when there is concern for CTD-ILD and highlight recent advancements in therapeutics within various specific CTD-ILDs.