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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. |
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