Background and Objectives Rheumatoid arthritis (RA) is characterised by antibodies to citrullinated proteins (ACPA) which may be present several years before development of clinical symptoms. Smoking is a known risk factor for the development of RA, but data is scarce on the relationship of smoking with specific subsets of ACPA in the years before disease onset. In this study we examined the immune response to citrullinated antigens and a detailed smoking history, in a nested case-control study of subjects enrolled in the European Prospective Investigation into Cancer (EPIC) project who later developed RA.
Materials and Methods The study sample included 412 participants from EPIC centres in Italy and Spain. Serum from 103 individuals who would eventually develop RA (pre-RA cases) were compared with three age-, sex- and centre-matched controls (n = 309). Antibodies to CCP, citrullinated-α-enolase peptide-1 (CEP-1; CKIHACitEIFDSCitGNPTVEC), citrullinated-fibrinogen (cFIB; CNEEGFFSACitGHRPLDKKC) and citrullinated-vimentin (cVIM; CVYATCitSSAVCitLCitSSVPC) were analysed by ELISA with positivity defined by 98th percentile of the controls.
Results The median time to diagnosis in the pre-RA cases was 7 years (1.7–15.8 years). The frequency of positive antibodies (cases vs. controls) were: anti-CCP2 (20%; p < 0.001), anti-cFIB (18%; p < 0.001), anti-CEP-1 (15%; p < 0.001), and anti-cVIM (6%; p < 0.006). All of the antibodies increased in frequency closer to diagnosis and with no specificity being particularly prominent in very early presymptomatic autoimmunity. The frequency of ever smoking was higher amongst pre-RA cases compared with controls (59% vs. 47%, p = 0.02). Pre-RA cases who smoked had higher levels of ACPA by all measures, which reached statistical significance when comparing former smokers to other groups. Pre-RA former smokers were 2.5 times more likely to develop RA (OR 2.50, 95% CI: 1.28, 4.89; p = 0.007) and were four times more likely to have positive anti-CEP-1 (OR 4.06, 95% CI 1.02, 16.2) than pre-RA never smokers.
Conclusions This is the first study of Pre-RA from a Southern European population in which we show that smoking is a risk factor not only for RA but for the development of presymptomatic autoimmunity, with citrullinated enolase being prominent. This strengthens the hypothesis that smoking is of aetiological importance in the very early stages of generating the autoantibodies that ultimately drive the disease.