Background Previous studies indicate that several different isotypes of circulating anti-citrullinated peptide antibodies (ACPAs) and rheumatoid factors (RF) can be detected in individuals who later develop rheumatoid arthritis (RA) years before onset, and that smoking is a predictor of RA.
Objectives To investigate isotypes of antibodies to cyclic citrullinated peptides (CCP) and RF, and their relation to smoking, before the clinical onset of RA.
Methods Incident cases of RA were identified among participants (n=30447) in a community based health survey, which was linked to local and national registers, followed by a structured review of the medical records. One control from the health survey, matched for age, sex and year of inclusion, was selected for each validated case.
IgG anti-CCP2 antibodies were determined by standard ELISA methods (Euro-Diagnostica; locally defined cut off 20 U/L). IgA and IgM anti-CCP2, and IgA, IgM and IgG RF were detected using the EliA assay on the Phadia 2500 (Phadia/Thermofisher AB, Uppsala, Sweden). The standard anti-CCP antigen (the same as for the IgG anti-CCP2 measurements) was used. Cut offs for these assays were set at the 98th percentile, based on investigation of sera from the matched controls. Analyses were stratified by time from inclusion in the health survey to RA diagnosis (1-3, 4-5, 6-8 and 9-13 years, respectively), and by history of current or ever smoking.
Results Serum was available from 166 cases (78% women), who were diagnosed with RA a median of 5 years (IQR 3-8; range 1-13) after inclusion in the health survey. The most frequently detected isotypes in the pre-RA individuals were IgM RF (24%) and IgG anti-CCP2 (22%). Among the IgM RF positive individuals who later developed RA, 56% were positive for IgA RF and 46% were positive for IgG RF, and among those positive for IgG anti-CCP2, 73% were IgA anti-CCP2 positive and 19% were IgM anti-CCP positive. All isotypes were observed in a limited number of cases sampled >9 years before RA diagnosis (n=33) (anti-CCP2: 12% IgG, 12% IgA, 6% IgM; RF: 18% IgM, 15% IgG, 12% IgA). The proportions with positive tests increased significantly with shorter time to diagnosis for IgG anti-CCP2 (p=0.026), IgA anti-CCP2 (p=0.046) and IgM RF (p=0.029), with a similar trend for IgA RF (p=0.09). Current (p<0.001) and ever smoking (p=0.003) were associated with subsequent development of RA. There were no major differences in detected anti-CCP2 or RF isotypes before RA diagnosis between current smokers and current non-smokers, whereas ever smokers were more likely than never smokers to be positive for IgG anti-CCP2 (28% vs 13%; p=0.02) and IgG RF (15% vs 6%; p=0.09), but not for the other isotypes. The time to RA diagnosis was similar in ever smokers and never smokers.
Conclusions Different patterns in isotype distribution are seen for anti-CCP2 antibodies and RF in the pre-clinical phase of RA. A history of smoking may contribute to the development of in particular IgG ACPA and IgG RF before the clinical onset of RA, suggesting a role for smoking in the very early pathogenesis of the IgG seropositive RA phenotype.
Disclosure of Interest None declared
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