Antibodies to Malondialdehyde‐Acetaldehyde Adduct Are Associated With Prevalent and Incident Rheumatoid Arthritis–Associated Interstitial Lung Disease in US Veterans

Objective The objective of this study is to determine the associations of protein‐specific anti–malondialdehyde‐acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis–interstitial lung disease (RA‐ILD). Methods Within a multicenter, prospective cohort of US veterans with RA, RA‐ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA‐albumin, MAA‐collagen, MAA‐fibrinogen, and MAA‐vimentin (IgA, IgM, and IgG) were measured by a standardized enzyme‐linked immunosorbent assay. Associations of anti‐MAA antibodies with prevalent and incident RA‐ILD were assessed using multivariable regression models adjusting for established RA‐ILD risk factors. Results Among 2,739 participants with RA (88% male, mean age of 64 years), there were 114 with prevalent and 136 with incident RA‐ILD (average time to diagnosis: 6.6 years). Higher IgM anti–MAA‐collagen (per 1 SD: adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.02–1.61), IgA anti–MAA‐fibrinogen (aOR 1.48, 95% CI 1.14–1.92), and IgA (aOR 1.78, 95% CI 1.34–2.37) and IgG (aOR 1.48, 95% CI 1.14–1.92) anti–MAA‐vimentin antibodies were associated with prevalent RA‐ILD. In incident analyses, higher IgA (per one SD: adjusted hazards ratio [aHR] 1.40, 95% CI 1.11–1.76) and IgM (aHR 1.29, 95% CI 1.04–1.60) anti–MAA‐albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13, 95% CI 1.16–3.90) or IgM (aHR 1.98, 95% CI 1.08–3.64) anti–MAA‐albumin antibody concentrations in the highest quartile had an approximately two‐fold increased risk of incident RA‐ILD. Across all isotypes, anti–MAA‐fibrinogen, anti–MAA‐collagen, and anti–MAA‐vimentin antibodies were not significantly associated with incident RA‐ILD. Conclusion Protein‐specific anti‐MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA‐ILD. IgA and IgM anti–MAA‐albumin antibodies were associated with a higher risk of incident RA‐ILD. These findings suggest that MAA modifications and resultant immune responses may contribute to RA‐ILD pathogenesis.