Statins have anti-inflammatory/immunomodulatory effects that may be useful in preventing rheumatoid arthritis (RA), but previous observational studies about the risk of RA with statin use yielded conflicting results.
Background: Two population-based studies showed a reduced risk of RA with statin use, while a case–control study showed an increased risk. Two cohort studies investigating overall unintended effects of statins revealed no change in the risk of RA, among a number of other outcomes, with statin use. The discrepancies may have resulted from small numbers of exposed cases, improper case validation or study designs comparing effects in statin users vs. nonusers or adherers vs. non-adherers, which, in the case of the pleiotropic benefits of statins, have been shown to pose challenges concerning bias eradication. [See the full article for references and sources.]
Goal: Therefore, these researchers undertook a nested case–control analysis in a large population-based cohort of new statin users to define the relationship between the intensity of statin treatment and the risk of RA. They hypothesized that the immunomodulatory effect would be more pronounced, and the risk of RA would be lower, in high-intensity statin users compared with low-intensity users.
Methods: Using data from the UK Clinical Practice Research Datalink, they performed a nested case–control analysis in a population-based cohort of patients who began receiving statins between 1997 and 2009 and were followed up until a first diagnosis of RA, death, end of registration with the physician’s practice, or end of January 2011. For each case of RA, 10 age-, sex- and calendar year–matched controls were randomly selected from risk sets. They estimated the hazard ratio (HR) of incident RA in the highest quintile of duration-weighted average statin intensity compared with the lowest, using conditional logistic regression. Models were adjusted for smoking status, total cholesterol level, obesity, history of cardiovascular disease, coexistent autoimmune disease, hypothyroidism, and persistence with treatment.
Results: The cohort included 528,654 new users of statins, with 1,357 new cases of RA occurring during a mean follow-up of 3.3 years, for an incidence rate of 7.9 per 10,000 person-years. Cases were more likely to be smokers, to have other autoimmune diseases and to have had lower total cholesterol levels at baseline. The incidence of RA was lower in the highest statin intensity quintile (adjusted HR 0.77 [95% confidence interval 0.63–0.95]) compared with the lowest quintile.
Conclusion: In this large population-based study, high-intensity statin treatment was associated with a 23% reduced risk of RA when compared with low-intensity statin treatment. The highest quintile of duration-weighted average statin intensity corresponded to daily treatment with atorvastatin 20–80 mg, rosuvastatin 5–40 mg, or simvastatin 80 mg. The association appeared most pronounced six months after initiation of statin treatment, continued up to three years, and gradually abated after longer-term treatment, although the confidence intervals were very wide. This is the largest study on the association of statins with RA risk to date, and the first to assess the effect of relative statin strength.