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

Abstract

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.