Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides

The aim of this study was to evaluate new and previously hypothesised non-genetic risk factors for serologic subtypes of rheumatoid arthritis ( RA) defined by the presence or absence of auto-antibodies to cyclic citrullinated peptides (CCP). In a national case-control study, we included 515 patients recently diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and 769 gender- and age-matched population controls. Telephone interviews provided information about non-genetic exposures, and serum samples for patients were tested for anti-CCP-antibodies. Associations between exposure variables and risk of anti-CCP-positive and anti-CCP-negative RA were evaluated using logistic regression. A series of RA subtype-specific risk factors were identified. Tobacco smoking ( odds ratio [ OR] = 1.65; 95% confidence interval: 1.03 - 2.64, for > 20 versus 0 pack-years) was selectively associated with risk of anti-CCP-positive RA, whereas alcohol consumption exhibited an inverse dose-response association with this RA subtype ( OR = 1.98, 1.22 - 3.19, for 0 versus > 0 - 5 drinks per week). Furthermore, coffee consumption ( OR = 2.18; 1.07 - 4.42, for > 10 versus 0 cups per day), ever use of oral contraceptives ( OR = 1.65; 1.06 - 2.57) and having a first-degree relative with schizophrenia ( OR = 4.18; 1.54 - 11.3) appeared more strongly associated with risk of anti-CCP-positive RA. Obesity was selectively associated with risk of anti-CCP-negative RA, with obese individuals being at more than 3-fold increased risk of this subtype compared with normal-weight individuals ( OR = 3.45; 1.73 - 6.87). Age at menarche was the only examined factor that was significantly associated with both serologic subtypes of RA (p-trends = 0.01); women with menarche at age = 15 years had about twice the risk of either RA subtype compared with women with menarche at age = 12 years. Major differences in risk factor profiles suggest distinct etiologies for anti-CCP-positive and anti-CCP-negative RA.