Autoantibodies to Malondialdehyde–Acetaldehyde Are Detected Prior to Rheumatoid Arthritis Diagnosis and After Other Disease Specific Autoantibodies

Objective: To examine serum autoantibodies to malondialdehyde–acetaldehyde (MAA) prior to rheumatoid arthritis (RA) diagnosis. Methods: Concentrations of anti-MAA antibody isotypes, anti–cyclic citrullinated peptide 2 (anti–CCP-2), and IgM rheumatoid factor (IgM-RF) were evaluated before and after RA diagnosis in samples from cases (n = 214) and controls (n = 210). The timing of elevations in autoantibody concentrations relative to RA diagnosis was explored using separate mixed models for each antibody and/or isotype. Associations between prediagnosis autoantibody concentrations in RA patients were examined using mixed effects linear regression models. Results: Concentrations of IgG (log₂ difference 0.34) and IgA (log₂ difference 0.43) anti-MAA antibodies in RA patients diverged from controls at 3.0 years and 2.3 years prior to diagnosis, respectively (P < 0.05 for both). There was no evidence of case–control divergence for IgM anti-MAA antibody concentration. Anti–CCP-2 and IgM-RF concentrations diverged between RA patients and controls beginning at 17.6 years and 7.2 years prior to RA diagnosis, respectively. All 3 anti-MAA antibody isotypes (IgA, IgM, and IgG) were significantly associated with anti–CCP-2 antibody and RF concentrations prior to diagnosis (β = 0.22–0.27 for IgM-RF; β = 0.44–0.93 for anti–CCP-2) (P < 0.001). Conclusion: IgG and IgA anti-MAA autoantibodies are elevated prior to RA diagnosis but appear later in the preclinical course than anti–CCP-2 or RF. These findings suggest that MAA formation and anti-MAA immune responses could play a role in the transition from subclinical autoimmunity to clinically apparent arthritis.