Background:Rheumatoid arthritis (RA) has been described in virtually every ethnic population. Most RA patients harbor anti-modified protein antibodies (AMPAs), including anti-citrullinated protein (ACPA), anti-carbamylated protein (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (AAPA). However, it is unclear whether differences exist in the AMPA response between different ethnic groups. Such differences could provide new clues to genetic and environmental factors contributing to autoantibody development.Objectives:To investigate the prevalence of different AMPA in four ethnically diverse RA populations, and their association with smoking.Methods:Enzyme-linked immunosorbent assays were used to measure anti-CarP IgG, anti-MAA IgG (both in-house), and anti-acetylated vimentin IgG (Orgentec) in ACPA-positive sera of Dutch (NL, n=103), Japanese (JP, n=174), Canadian First Nations People (FN, n=100), and black South Africans (SA, n=67) fulfilling the 1987 ACR classification criteria for RA. Ethnicity-matched local healthy controls were used to calculate cohort-specific cut-offs. Logistic regression was used to identify whether ever-smoking was associated with AMPA seropositivity in each cohort, corrected for age, gender, and disease duration. Random-effects meta-analysis was used to pool the resulting odds ratios (OR).Results:For all three AMPAs, median levels were higher in FN and especially SA than NL and JP patients (Figure 1). The median autoantibody levels in arbitrary units (in % of patients positive) for NL, JP, FN and SA RA patients were: anti-CarP IgG: 1157 (47%), 994 (43%), 1642 (58%) and 2336 (76%) (p<0.001); anti-MAA IgG: 131 (29%), 179 (22%), 251 (29%) and 257 (53%) (p<0.001); AAPA: 133 (20%), 136 (17%), 153 (38%) and 316 (28%) (p<0.001). Prevalence, meaning positivity, also differed significantly between cohorts for all AMPAs (p<0.001).There were also marked differences in total IgG levels in mean (SD) g/L: 13 (4) for NL, 17 (6) for JP, 18 (6) for FN, and 25 (8) for SA (p<0.001). When the autoantibody levels were normalized to total IgG, the differences in became less pronounced between cohorts (Figure 2). The median arbitrary units per g/L Total IgG for NL, JP, FN and SA RA patients were: anti-CarP IgG: 54, 25, 53, and 79; anti-MAA IgG: 6, 5, 8, and 9; and AAPA: 2, 2, 2, and 3, suggesting that autoantibody level differences may partly correspond to cohort-specific differences in total IgG, although the overall trend of higher levels in SA persisted. There was no association between smoking and anti-CarP or anti-MAA positivity, with pooled OR (95% CI) of 1.31 (0.79-2.18) and 0.85 (0.46-1.56), respectively. However, smoking was positively and consistently associated with AAPA positivity in each cohort: pooled OR (95% CI) of 2.01 (1.06-3.81).Conclusion:In these ACPA-positive ethnically diverse RA populations, levels and prevalence of various AMPAs differ, suggesting that ethnic background and environment may influence the development of the autoantibody response in RA. Despite these differences, our results imply smoking as a consistent risk factor for AAPA across different ethnic backgrounds.Disclosure of Interests:Emma C. de Moel: None declared, Veerle Derksen: None declared, Leendert A Trouw: None declared, Chikashi Terao: None declared, Mohammed Tikly: None declared, Hani El-Gabalawy: None declared, Holger Bang Grant/research support from: Employee of Orgentec Diagnostika, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Rene Toes: None declared, Diane van der Woude: None declared
Population-specific diversity of the immunoglobulin constant heavy G chain (IGHG) genes
