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The use of statins did not increase the risk for the development of rheumatoid arthritis (RA) after adjustment for the important confounder of hyperlipidemia, a large nationwide U.S. study found.

A modest increased risk for RA was observed among patients taking statins after adjustment for age, sex, index year, region of residence, and race/ethnicity (OR 1.12, 95% CI 1.06-1.18), and also after adjustment for the Charlson comorbidity index (OR 1.14, 95% CI 1.08-1.20), reported Elena Myasoedova, MD, PhD, and colleagues from the Mayo Clinic in Rochester, Minnesota.

However, the association was no longer significant after further adjustment for hyperlipidemia (OR 0.95, 95% CI 0.90-1.01), as shown in the study online in .

Statins are known to have pleiotropic effects and "have been shown to modify a range of non-lipid-related cell signaling pathways, including those involved in eliciting inflammatory responses," the team wrote.

And while statins have been shown to reduce inflammation among RA patients, an older of patients with extensive statin exposure suggested that statins might actually induce autoimmunity. But the literature to date includes conflicting results, with some studies finding protective effects against RA, others showing an increased risk for RA, and still others suggesting neutral effects.

Therefore, to clarify the potential influence of statin use on RA development, as well as to consider the effects of statin duration and intensity and the potential confounding effects of comorbidities, the Mayo team analyzed data from the OptumLabs Data Warehouse, which includes de-identified information for more than 51 million individuals enrolled in commercial and Medicare Advantage plans from 2010 to 2019.

The analysis included 16,363 cases and the same number of matched controls. Both groups were predominantly white women, and mean age was 58.

The most common comorbidities were hyperlipidemia, reported in 48% of cases and 42.4% of controls; hypothyroidism, in 21.3% of cases and 16.4% of controls; and diabetes, in 20.4% and 18.9%, respectively.

A total of 33.7% of RA cases were statin users, as were 31.6% of controls.

Most statin users in both groups had been taking the drugs for at least a year, and the majority had been on medium-intensity statins, such as atorvastatin (10-20 mg/day) or simvastatin (20-40 mg/day).

Former users of statins were found to be at increased risk for RA compared with never users (OR 1.21, 95% CI 1.13-1.28), while current users had no increase (OR 1.03, 95% CI 0.97-1.10). However, after the researchers adjusted for hyperlipidemia, again no increase in RA risk was seen for former statin users (OR 1.03, 95% CI 0.96-1.10), and the risk was slightly lower for current users (OR 0.87, 95% CI 0.81-0.93).

Patients whose statin use was less than a year had a slight increase in risk, but this was not statistically significant. Risks also were not statistically significant when comparing dose response relationships and statin intensity.

In a sensitivity analysis that included only patients who had laboratory data for low-density lipoprotein cholesterol (6,948 in each group), the risk again was not elevated (OR 1, 95% CI 0.93-1.08), the researchers reported.

They noted that the reduced risk observed after statistical adjustment for hyperlipidemia was of interest because have suggested that hyperlipidemia itself may be a risk factor for RA. The new study supported the concept that the risk for RA may relate to the lipid levels rather than statin use, Myasoedova and co-authors suggested.

They pointed out, however, that if the reduction in RA risk observed after adjustment for hyperlipidemia was a statistical artifact, potential mechanisms by which statins influence RA development should be addressed.

One possible mechanism, the researchers said, was that statins might cause a shift from Th1 to Th2 immune responses, which could upregulate B cells and trigger the release of autoantibodies. That shift also might increase the risk of infections, leading to loss of self-tolerance. Moreover, statins are pro-apoptotic, and increased cell death could lead to excessive release of antigens and further encourage the production of autoantibodies.

Nonetheless, "the results of this nationwide study suggest there is no significant increase in the risk of RA occurrence in statin users, adjusting for hyperlipidemia in addition to other relevant confounders," the investigators stated. The results do not "support any change to the current clinical recommendations for prescribing statins."

In addition, the team said, "the current body of conflicting data on this topic [the risk of RA in statin users] demonstrates the challenge of performing a retrospective analysis on the relationship between a prescription drug and an unrelated medical disease."

A limitation of the study, the researchers said, was its observational, nonrandomized, design.

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