We evaluated associations with the presence of rheumatoid factor, rather than clinical disease. Studies showing rheumatoid factor antecedent to the onset of clinical disease support this approach.1
Our findings are consistent with previous studies that found a protective effect of oral contraceptive use on the development of rheumatoid arthritis.3,4,5,6,7
Our unique finding that oral contraceptives are inversely associated with the presence of rheumatoid factor in healthy women suggests that these exogenous hormones may act very early in the development of the immune dysregulation that occurs in rheumatoid arthritis.
We did not find a significant “dose–response” effect with the duration of oral contraceptive use in our population, although in oral contraceptive users, rheumatoid factor‐positive women had used oral contraceptives for a slightly shorter duration than rheumatoid factor‐negative women. This may suggest a threshold effect, whereby the longer durations reported by the women carried little influence beyond the threshold duration.
The precise mechanism behind the protective effect of oral contraceptives on rheumatoid arthritis is unknown, but it may be that oral contraceptives, which are largely synthetic hormones, drive the immune system towards T helper 2 cytokine responses, and decreased production of proinflammatory and other cytokines leading to T helper 1‐associated rheumatoid arthritis‐specific cellular autoimmunity.13
We observed an association between rheumatoid factor positivity and smoking only in the heaviest smokers. Previous studies that have examined an association between rheumatoid factor and cigarette smoking in individuals without rheumatoid arthritis are conflicting.10,11
However, studies on seropositive rheumatoid arthritis and smoking reported associations between pack‐years smoked and rheumatoid factor levels14
; and another study found an association between smoking and seropositive rheumatoid arthritis only in subjects who had smoked
20 years at an intensity of 6–9 cigarettes/day.15
Although our study was limited by the small number of heavy smokers, our results, considered in combination with the findings from previous studies, indicate that there might be a cumulative or threshold dose effect of smoking.
Our study population was selected through children at increased risk for type 1 diabetes, and thus enriched with HLA‐DR4. However, because the DAISY cohort was identified and assembled during a population‐based screening, it was therefore established without prior bias relative to rheumatoid arthritis. Also, rheumatoid factor‐positive and rheumatoid factor‐negative women for this study were drawn from the same healthy cohort, thus minimising selection bias. Additionally, our study was not susceptible to recall and interviewer bias because the exposure data were collected without knowledge of the autoantibody status by the individual or the interviewer.
Given that all the women in this study were selected from a cohort of largely Caucasian parents who had given birth to at least one child, wider applicability of these results may be limited. Although these results are consistent with the findings of previous investigators, studies showing a protective effect of oral contraceptive use on rheumatoid factor status in a more ethnically mixed population and in nulliparous women would further support our findings. Given that our study was cross sectional, we cannot discern the temporal sequence between exposure and outcome needed to establish causality. Prospective studies designed to follow‐up individuals for the development of rheumatoid factor and rheumatoid arthritis are necessary to evaluate these hypotheses further. Nevertheless, our results support the hypotheses that oral contraceptive use is protective, and that cigarette smoking may confer increased risk very early in the rheumatoid arthritis disease course.