In this large randomized, double-blind, placebo-controlled study of 100 mg of aspirin or placebo on alternate days we found no significant effect of low-dose aspirin on the incidence of definite RA in women. We also did not find an increased incidence of other types of RA, defined using several different case definitions, including seropositive and seronegative RA, inflammatory polyarthritis, or self reported RA.
We were interested in examining the role of aspirin in preventing the development of RA because several plausible biological mechanisms exist. Previous studies have demonstrated that low-dose aspirin is effective in preventing other diseases where prostaglandin pathways are involved, such as colorectal adenomas and cancers. In colorectal neoplasia, COX-2 is responsible for the production of prostaglandins that impact proliferation of tumor tissues [11
]. Inhibition of COX-2 restores apoptosis and inhibits angiogenesis, which also may delay or ameliorate synovitis in early RA[17
]. Similarly, prostaglandin E2 increases estrogen production in cultured cells [8
] and the use of aspirin may inhibit prostaglandin-driven estrogen and progesterone production. This may explain aspirin’s potential ability to reduce hormonally affected cancers such as breast cancer and prostate cancer as well [18
]. Aspirin may influence RA incidence by modulating estrogen biosynthesis [20
] as well as by its ability to restore apoptosis and inhibit angiogenesis [21
It is also possible that aspirin may reduce the risk of RA via its role as an antioxidant. Salicylate inhibits cytokine-dependent induction of NOS-II gene expression, through nuclear factor-kB activation [22
], which reduces the nitrosative stress of cytokine production. Aspirin also has antioxidant effect on proteins and scavenges hydroxyl radicals [6
]. An antioxidant effect could prevent or delay RA onset, although a recent report from this trial demonstrated that vitamin E, a dietary antioxidant, did not significantly reduce risk of RA[23
A recent analysis from the WHS trial demonstrated lower incidence of asthma among women randomized to aspirin, possibly explained by an anti-inflammatory effect of aspirin [24
]. Aspirin inhibits IL4 gene expression in T cells, as well as promotes IL-4 and IL-13 induced activation of STAT6 via non-COX dependent pathways, which may also explain its role in reducing asthmatic symptoms[7
]. In this report, administration of 100 mg of aspirin reduced the risk of newly reported asthma by 10%. This study had 872 new cases of asthma in the aspirin group, thus providing sufficient power to detect small reductions in risk.
We had limited power to detect moderate reductions in risk of RA, and in seropositive or seronegative disease subtypes because of the relatively small number of incident RA cases. Previous observational studies of low-dose aspirin supplement use in the prevention of cancer and asthma have reported between a 10% and 30% reduction in disease risk. In the present study, with 106 cases of definite RA, we would have only 40% power to detect a 30% reduction in risk but would have 86% power to detect a 50% reduction in risk. For the self reported and CSQ positive endpoints, however, we would have adequate power to detect moderate-sized risk reductions. In addition, while we ascertained RA cases based on self-reports, followed by CSQ screening and the medical record review, our use of strict ACR criteria when reviewing medical records may have resulted in labeling some RA cases as controls. However, analyses of other less stringent diagnostic groups demonstrated no associations as well. Furthermore, our cohort consisted of female health professionals who differ from the general population in some characteristics. For example, study subjects were less likely to smoke than the general population, and more likely to take post-menopausal hormone therapy, but showed similar proportions of elevated blood pressure and obesity. While the differences may affect the generalizability of our findings, they do not by themselves compromise the validity of the results. Finally, the annual incidence rate of definite RA in this study was 27.1 per 100,000 person-years, which is similar to one population based study[25
] but lower than rates reported by other studies [1
]. Incidence rates in the present study may be lower because individuals who choose to participate in research studies tend to be healthier than the general population.
We were not able to evaluate every participant’s medical record to confirm RA. Twenty eight percent of women who self-reported RA did not respond to requests for further information so how many of these participants may have had RA is unknown. However, we did analyze all self-reported RA as a secondary endpoint, where we also observed no association with aspirin. While there were a large number of women who initially reported a diagnosis of RA, but then denied this diagnosis upon further follow-up, this is comparable to two similar studies, the Iowa Women’s Health Cohort Study [27
] and the Nurse’s Health Study where only 7% of original self reports were confirmed as RA[28
]. An initial diagnosis of RA later refuted by a rheumatologist is a common experience in community health care settings.
We cannot comment on whether higher doses of aspirin than in the present trial might have a protective effect on the development of RA. Higher doses may mask symptoms of joint pain and delay the diagnosis of RA. Or, higher doses may exert more anti-oxidant, COX-2 inhibition and/or anti-inflammatory effect. Randomized trials using higher doses of aspirin can provide additional data. Observational studies of higher doses of aspirin are limited, in that there is potential for confounding by indication. Individuals with early RA might take NSAIDS more frequently to alleviate their symptoms, potentially masking an inverse association.
In conclusion, low-dose aspirin through anti inflammatory, anti apoptotic or antioxidant effects may potentially reduce the risk of developing RA. Despite these plausible biological mechanisms, as well as data from this trial and others of a reduction in inflammatory diseases such as colorectal neoplasia and asthma, the present study demonstrated no reduction in risk of RA with aspirin. It is possible that higher dose aspirin may prevent the diagnosis of RA or that studies with higher numbers of RA cases may demonstrate a significant result with the modest risk reduction observed in the present study. Given the frequency of aspirin use in the general population, this question deserves further study.