In our prospective analyses involving women followed for up to 24 years, we found no evidence of associations between intake of antioxidants from foods and supplements and the risks of RA and SLE. No clear trends of increasing or decreasing risk of either of these autoimmune diseases were found in relation to a range of antioxidant intakes nor to a summary measure of antioxidant intake. In our sensitivity analyses, we investigated whether the timing of nutrient intake, either remote intake from cohort baseline only or more recent intake in the most current questionnaire cycle only, could be related to risk, but we found no indication that either was true.
The impetus for this study was that, in several past studies, blood levels of antioxidants were found to have decreased in RA and SLE subjects both before and after diagnosis (15
), and an inverse relation between systemic inflammation and antioxidant blood levels has been reported (16
). Associations between baseline intake of antioxidant nutrients from foods and supplements and RA development up to 11 years later were investigated in the Iowa Women's Health Study, a prospective cohort study involving 29,368 women aged 55–69 years when the study started (19
). High intakes of β-cryptoxanthin and supplemental (but not total) zinc were found to be potentially protective against RA. In the Norfolk Arthritis Registry, those in the highest compared with the lowest tertiles of zeaxanthin and β-cryptoxanthin were at lower risk of developing inflammatory polyarthritis (20
). However, in the Women's Health Study, a randomized, double-blind, placebo-controlled trial of 39,876 female health professionals, supplementation with 600 IU of vitamin E a day for a mean of 10.1 years was not associated with a significant reduction in the risk of developing RA (47
Our study included a large number of incident cases, as well as detailed, repeated assessments of exposures, allowing for assessment of average and more recent diet, time-varying covariates, prospective assessment of most exposures, and long follow-up. The accuracy and validity of the semiquantitative FFQ have been well studied, and, in past NHS and NHSII analyses, associations between antioxidant intake and risks of lung cancer (48
) and breast cancer (49
) have been observed. Our 2-stage validation process includes careful medical record reviews, and all women who self-reported any connective tissue disease not confirmed as definite RA or SLE were excluded to reduce misclassification. We controlled for cigarette smoking, alcohol intake, and physical activity; none were related to RA or SLE risk, and none confounded observed associations. We examined antioxidant intakes individually and calculated an overall antioxidant FRAP score. We performed a variety of sensitivity analyses, including stratifying the RA analyses by pack-years of smoking. Smoking creates oxidative stress, inducing free radicals and decreasing blood antioxidant levels (50
), which could modify the relation between antioxidant intake and risk of disease. No associations between intakes of any of these vitamins and risks of these autoimmune diseases were found, however.
Potential limitations of the current study include the observational study design and use of self-reported exposure data; low correlations between FFQ-based intakes of lycopene, lutein, and β-carotene and plasma levels in past validation studies; and limited generalizability of results to non-Caucasian or male populations. With 787 validated cases of incident RA and 192 cases of incident SLE, we had limited power to detect small effects of antioxidant intake, and these results do not rule out the possibility that profound deficiencies of one or more of these antioxidants contribute to the pathogenesis of these autoimmune diseases. Similarly, many factors other than dietary intake (such as genetic differences in absorption or homeostatic mechanisms, and environmental exposures) may influence between-person variations in plasma antioxidant levels and oxidative stress (51
Oxidative stress may be involved in the pathogenesis of one or both of these diseases. However, the current prospective, longitudinal cohort study does not support the hypothesis that regular intake of a range of antioxidants in foods and supplements is related to future risk of developing either RA or SLE in women.