Background/Purpose: Anti-malondialdehyde-acetaldehyde adduct (MAA) antibodies target immunogenic products of oxidative stress, are detected in higher concentration in paired synovial fluid vs serum in RA, and are associated with higher RA disease activity. Moreover, MAA-modified proteins, citrullinated antigens, and immune cells colocalize in RA synovial tissues – suggesting a role in RA pathogenesis. Airway inflammation, a proposed mechanism of disease initiation and a common extra-articular manifestation in RA, is stimulated by MAA in mice. Whether MAA-modification and resulting anti-MAA immune responses occur within the lungs of individuals with RA is unknown.

Methods: Paired serum and sputum samples were collected from subjects with established anti-CCP positive RA (n = 27) and healthy controls (HC; n = 29). CCP2 (IgG), CCP3.1 (IgG/IgA), RF (IgA, IgM, IgG), and anti-MAA (IgA, IgM, IgG) antibodies were measured by ELISA and total Ig by nephelometry. We used Wilcoxon rank-sum tests to compare anti-MAA antibody concentrations between RA and controls and assessed associations with smoking, alcohol, chronic lung disease, and gender; Wilcoxon signed-rank tests to compare paired sputum and serum concentrations; and SpearmanÕs correlations to assess correlations between sputum anti-MAA and RA autoantibodies.

Results: Mean (SD) age was 50 (13) years with 75% female, 71% Caucasian, 11% current and 29% former smokers, and 18% with chronic lung disease. Sputum anti-MAA antibody concentrations in RA and HC are shown in Table 1. Sputum IgA and IgG anti-MAA were higher in RA than HC. After adjusting for total Ig, in both RA and HC, IgG anti-MAA antibody was higher in sputum than serum (P < 0.001), while IgM anti-MAA was higher in serum (P<0.001), and IgA anti-MAA did not differ (P = 0.58). In RA subjects, sputum IgM anti-MAA antibody correlated with sputum CCP3.1 (r = 0.42, P = 0.03) and marginally correlated with sputum RF IgA (r = 0.38, P = 0.052). Sputum IgA anti-MAA antibody correlated with serum RF level (r = 0.46, P = 0.02) and sputum IgG anti-MAA antibody did not correlate with other autoantibodies. Sputum IgA anti-MAA antibody, but not IgM or IgG, was higher in current smokers vs non-smokers. There were no other associations between anti-MAA antibody and smoking status, alcohol use, chronic lung disease, or gender.

Conclusion: IgG and IgA anti-MAA antibody are enriched in the sputum of RA subjects, with relative concentrations of IgG higher in paired sputum than serum. These data suggest MAA modification and anti-MAA immune responses within the airways could contribute to disease pathogenesis. Additional studies will be needed to examine the relationship of anti-MAA antibody with measures of airway inflammation and lung function in RA and to determine mechanisms underpinning these associations.