Background/Purpose: Previous work has demonstrated that malondialdehyde-acetalehyde (MAA) adducts, resulting from oxidative stress, are formed in synovial and lung tissues of patients with rheumatoid arthritis (RA).  Moreover, MAA co-localizes in these tissues with citrulline and generates robust anti-MAA antibody responses, suggesting a pathogenic role for MAA-adducted antigens in RA (Thiele GM et al. 2015, England BR et al. 2019).  In this study, we sought to examine whether anti-MAA antibody responses were detectable in pre-clinical RA.

Methods: Using the Department of Defense Serum Repository, we identified 214 RA cases and 210 matched controls. We tested a mean of 3 serial serum samples from pre-RA diagnosis, and 1 post-RA diagnosis sample, for anti-MAA immunoglobulin (Ig) isotypes A, IgG, and IgM, anti-CCP antibody (CCP2 and CCP3.1), and RF (IgM). The relative timing and trajectories of autoantibody isotypes were evaluated. Case-control samples were compared for each time point using Wilcoxon rank-sum tests.

Results: RA cases and controls were similar in age, sex, race, and smoking status (p >0.05).  The timespan of oldest to newest sample was similar in RA cases (mean 12.8±5.6 years) and control (12.3±5.4 years) (p=0.4). Anti-MAA, CCP2, CCP3.1, and RF-IgM concentrations by sample in cases and controls are shown in the Table. CCP2, CCP3.1 and RF were significantly elevated in cases vs. controls in the earliest pre-RA diagnosis samples while anti-MAA (IgA, IgM) became significantly elevated in the midterm and closest samples pre-RA diagnosis.

Conclusion: IgA and IgG autoantibodies to MAA are increased pre-RA diagnosis, supporting a potential pathogenic role of immune responses targeting MAA in RA.  In contrast to RF and anti-CCP, anti-MAA antibodies appear to be increased later in the pre-clinical period closer to the time of disease onset with higher IgA and IgG anti-MAA appearing, on average, at least 2-3 years prior to RA diagnosis. This suggests that anti-MAA responses may play a role in disease amplification and/or the transition to clinically-apparent RA, potentially after other autoantibodies (e.g. CCP and RF) have become elevated.

Table

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibodies-to-malondialdehyde-acetaldehyde-preceding-the-diagnosis-of-rheumatoid-arthritis/