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Prediction of Erosive Disease Development by Antimitochondrial Antibodies in Rheumatoid Arthritis
Richard E Moore1, Ting Wang1, Bhargavi Duvvuri1
1Division of Rheumatology, University of Washington, Seattle.
Objective:
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 undertook this study to investigate the presence and significance of antimitochondrial antibodies (AMAs) in patients with RA.
Methods:
AMAs were measured in serum samples from 3 cross-sectional cohorts of RA patients (n = 95, n = 192, and n = 117) and healthy individuals (n = 38, n = 72, and n = 50) using a flow cytometry-based assay. Further, AMAs were detected using an anti-mitofusin-1 (anti-MFN-1) IgG enzyme-linked immunosorbent assay and Western blot analysis. A longitudinal inception cohort, followed up for a median of 8 years, was used to study disease progression.
Results:
AMA levels were elevated in RA patients from all 3 cohorts as compared to healthy individuals (P < 0.001, P < 0.05, and P < 0.01), with a range of 14-26% positivity. Levels of anti-MFN-1 antibodies correlated with AMA levels (r = 0.31, P = 0.006) and were elevated in RA patients as compared to healthy individuals (P < 0.001). The presence of AMAs was associated with erosive disease (P < 0.05) and interstitial lung disease (P < 0.01). Further, AMA levels were found to predict erosive disease (odds ratio [OR] 4.59, P = 0.006) and joint space narrowing (OR 3.08, P = 0.02) independent of anti-citrullinated protein antibodies. Finally, anti-MFN-1 antibodies identified seronegative patients developing erosive disease (OR 9.33; P = 0.02).
Conclusion:
Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in the setting of RA. AMAs were used to stratify patients based on disease phenotype and to predict development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in the pathogenesis of RA and suggest a possible benefit of therapies targeting mitochondrial-mediated inflammation and clearance in these patients.
Insights
Antimitochondrial antibodies (AMAs) are elevated in rheumatoid arthritis (RA) patients and can predict erosive disease progression, even in seronegative cases. These findings highlight mitochondria's role in RA pathogenesis and potential therapeutic targets.
Area of Science:
- Immunology
- Rheumatology
- Cell Biology
Background:
- Mitochondria are present in extracellular spaces in rheumatoid arthritis (RA).
- The role of mitochondria as autoantigens in RA remains under-investigated.
- This study addresses the presence and significance of antimitochondrial antibodies (AMAs) in RA patients.
Purpose of the Study:
- To investigate the presence and significance of antimitochondrial antibodies (AMAs) in patients with rheumatoid arthritis (RA).
- To determine if AMAs can serve as biomarkers for disease phenotype and progression in RA.
- To explore the potential role of mitochondria in RA pathogenesis.
Main Methods:
- Serum samples from RA patients and healthy individuals across three cohorts were analyzed for AMAs using flow cytometry.
- Anti-mitofusin-1 (anti-MFN-1) IgG antibodies were detected via ELISA and Western blot.
- A longitudinal cohort was used to assess the association between AMAs and disease progression over time.
Main Results:
- Elevated AMA levels were observed in RA patients compared to healthy controls across all cohorts.
- Anti-MFN-1 antibody levels correlated with AMA levels and were higher in RA patients.
- AMA presence was associated with erosive disease and interstitial lung disease, and predicted erosive disease and joint space narrowing independently of anti-citrullinated protein antibodies.
- Anti-MFN-1 antibodies identified seronegative patients who later developed erosive disease.
Conclusions:
- Novel autoantibodies targeting mitochondria (AMAs) are present in RA patients.
- AMAs can stratify RA patients by disease phenotype and predict erosive disease development, including in seronegative individuals.
- Mitochondria play a crucial role in RA pathogenesis, suggesting potential therapeutic strategies targeting mitochondrial-mediated inflammation.
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