Antibodies to Malondialdehyde-Acetaldehyde Adduct Are Associated with Prevalent and Incident Rheumatoid Arthritis-Associated Interstitial Lung Disease in U.S. Veterans

Nozima Aripova; Geoffrey M Thiele; Michael J Duryee; Carlos D Hunter; Yangyuna Yang; Punyasha Roul; Dana P Ascherman; Scott M Matson; Gary Kunkel; Grant W Cannon; Katherine D Wysham; Gail S Kerr; Paul A Monach; Joshua F Baker; Jill A Poole; Ted R Mikuls; Bryant R England

doi:10.1002/art.42916

Antibodies to Malondialdehyde-Acetaldehyde Adduct Are Associated with Prevalent and Incident Rheumatoid Arthritis-Associated Interstitial Lung Disease in U.S. Veterans

Arthritis Rheumatol. 2024 May 20. doi: 10.1002/art.42916. Online ahead of print.

Authors

Nozima Aripova¹, Geoffrey M Thiele^{1

2}, Michael J Duryee^{1

2}, Carlos D Hunter^{1

2}, Yangyuna Yang^{1

2}, Punyasha Roul^{1

2}, Dana P Ascherman³, Scott M Matson⁴, Gary Kunkel⁵, Grant W Cannon⁵, Katherine D Wysham⁶, Gail S Kerr⁷, Paul A Monach⁸, Joshua F Baker⁹, Jill A Poole¹⁰, Ted R Mikuls^{1

2}, Bryant R England^{1

2}

Affiliations

¹ Division of Rheumatology & Immunology, University of Nebraska Medical Center, Omaha, NE, USA.
² Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
³ Division of Rheumatology, Pittsburgh VA and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Division of Pulmonary, Critical Care and Sleep, University of Kansas, Kansas City, KS, USA.
⁵ Division of Rheumatology, University of Utah and VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
⁶ Division of Rheumatology, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
⁷ Division of Rheumatology, Washington D.C. Veterans Affairs Medical Center, Georgetown and Howard University Hospitals, Washington, DC, USA.
⁸ Boston VA Health Care System, Boston, MA, USA.
⁹ Division of Rheumatology, Corporal Michael J. Crescenz VA and University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰ Division of Allergy & Immunology, University of Nebraska Medical Center, Omaha, NE, USA.

PMID: 38766737
DOI: 10.1002/art.42916

Abstract

Objective: 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 U.S. 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 ELISA. 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 RA participants (88% male, mean age 64 years), there were 114 prevalent and 136 incident RA-ILD cases (average time to diagnosis: 6.6 years). Higher IgM anti-MAA-collagen (per 1 SD: aOR 1.28 [1.02-1.61]), IgA anti-MAA-fibrinogen (aOR 1.48 [1.14-1.92]), and IgA (aOR 1.78 [1.34-2.37]) and IgG (aOR 1.48 [1.14-1.92]) anti-MAA-vimentin antibodies were associated with prevalent RA-ILD. In incident analyses, higher IgA (per 1 SD: aHR 1.40 [1.11-1.76]) and IgM (aHR 1.29 [1.04-1.60]) anti-MAA-albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13 [1.16-3.90]) or IgM (aHR 1.98 [1.08-3.64]) anti-MAA-albumin antibody concentrations in the highest quartile had an approximate 2-fold increased risk of incident RA-ILD. Across all isotypes, anti-MAA-fibrinogen, -collagen, and -vimentin antibodies were not significantly associated with incident RA-ILD.

Conclusions: 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.