Can I take my rheumatoid arthritis (RA) medication with statins?

Statins are recommended by the 2018 American Heart Association/American College of Cardiology guideline for the management of blood cholesterol to lower low-density lipoprotein cholesterol and cardiovascular (CVD) risk.¹ Similar to the general population, statins reduce CVD risk in patients with rheumatoid arthritis (RA).²

There are insufficient randomized controlled studies to date that have specifically assessed the safety of anti-rheumatic medications given concomitantly with statins. Manufacturer’s package inserts for statins do not identify any specific drug-drug interactions between statins and medications used to treat RA.^3–8 However, many of the drugs used to treat RA have been developed since statins were approved for use. There are no drug-drug interactions with statins listed in the package inserts for most anti-rheumatic drugs. This includes methotrexate, sulfasalazine, tumor necrosis factor inhibitors, hydroxychloroquine, rituximab, and abatacept.^9–18

Several small single-center studies of statin use in patients with RA provide some evidence of statin safety in this population. The Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients with Rheumatoid Arthritis (TRACE RA) study, a randomized, double-blind, placebo-controlled study, followed 3,002 patients with RA for a mean of 2.51 years and found no significant difference in adverse events between those taking atorvastatin 40 mg (19.8%) and those taking placebo (19.5%) (p=0.854).¹⁹ The study was discontinued early because of lower than expected cardiovascular event rates and the risk of concomitant RA medication use was not analyzed in the study, but these safety data were encouraging.

Toms et al sought to determine if patients with RA were predisposed to develop statin-associated myopathy (SAM) and to identify known genetic markers of risk for the development of SAM among patients with RA.²⁰ In this study, 90% of 74 RA patients taking statins has at least one risk factor for SAM. The frequency of genetic markers among 396 patients with RA did not differ significantly among patients with RA compared to the 438 non-RA controls. No cases of SAMS were reported in those taking statins over a four-year follow-up period.

Another concern when statins are used in patients with RA is the risk of incident diabetes. The risk of developing diabetes is already increased among patients with RA compared to the general population.²¹ Ozen et all compared the risk of developing diabetes among patients with RA taking different medication regimens.²² Hydroxychloroquine and abatacept were associated with a decreased risk of incident diabetes; glucocorticoids and statins were associated with an increased risk. In a randomized double-blind comparison study, Pareek and Chandurkar evaluated the efficacy and safety of an atorvastatin-hydroxychloroquine combination with atorvastatin alone among 328 patients with dyslipidemia.²³ The combination therapy showed a statistically significant percentage reduction in cholesterol levels compared to monotherapy. Eight patients in the monotherapy group who had pre-diabetes at baseline developed diabetes within six months compared to only one in the combination therapy group (p=0.034). The authors suggest that concomitant use of hydroxychloroquine with atorvastatin could mitigate the risk of statin-induced diabetes.

Some medications, called CYP inhibitors, can interfere with the metabolism of other drugs that are metabolized by the same CYP pathways in the liver. Tocilizumab, tofacitinib, and leflunomide interact with the CYP3A4 system when metabolized and should be used with caution when administered with the specific statins that are metabolized by the same system.^24–26 This includes simvastatin, lovastatin, and atorvastatin. Dosage adjustments of the statins may be necessary. The package insert for leflunomide also specifies that when it is given concomitantly with rosuvastatin, the dosage of the statin should not exceed 10 mg per day.²⁴

Liver Function, RA Medications, and Statins

Many medications used to treat RA are associated with some degree of abnormal liver function tests (LFTs), particularly methotrexate, sulfasalazine, leflunomide, tocilizumab, and tofacitinib.^27,28  

All statins approved for use in the US have been associated with mild-to-moderate elevations of LFTs during therapy. These changes generally resolve even when the statin is continued without dose adjustment.²⁷ It is difficult to prove hepatotoxicity is caused by a specific drug unless the patient has a positive response to a re-challenge with the same drug, something rarely done in clinical practice. Rarely, however, liver injury attributable to statin use has been reported.²⁹

Although routine monitoring of LFTs is no longer routinely recommended for patients on statin therapy, clinical and biochemical monitoring of liver function is recommended to promote safe use of anti-rheumatics that are associated with elevated liver function tests, which would identify any potential hepatotoxicity when used in combination with statins.^{25,26,30–32} Monitoring of liver function would seem to be particularly important when statins are administered with those anti-rheumatics listed in the Drug-Induced Liver Injury Database (Table 1).

Rituximab and Statins

Rituximab is a monoclonal antibody used to treat RA when other medications have not been effective. It relies on lipids in the plasma membrane for its action.  Because cholesterol levels drop as an outcome of the use of statin drugs, statins theoretically may reduce rituximab efficacy.^33,34

There are conflicting results from small studies in patients taking rituximab plus statins compared to rituximab alone.^35–37 Arts et al. found that combination therapy with rituximab and statins diminished the efficacy of rituximab on RA disease activity after six months measured by the Disease Activity Score of 28 joints (DAS28) as an outcome measure.³⁵ Das et al. found no significant difference among patients taking statins with rituximab versus rituximab monotherapy using a cellular biomarker (plasmablast number) and clinical response (DAS28) as the outcome measures.³⁶ Neither the specific statins used nor dosages were given for either study.

One industry-supported retrospective analysis pooled data from four placebo-controlled phase II/III randomized clinical trials of patients with moderate to severe RA (1,460 rituximab-treated and 778 placebo-treated).³⁸ All patients were receiving methotrexate and many were also receiving prednisolone or NSAIDS. Multiple outcomes (DAS28 using erythrocyte sedimentation rates, American College of Rheumatology (ACR) 20% or 50% response, and peripheral blood CD19+ B-cell counts) at 24 weeks were compared among patients taking one course of rituximab alone, those taking the course of rituximab plus statins for eight or more weeks, and those taking placebo with or without statins. These authors concluded that concomitant use of statins did not significantly alter patient response to rituximab treatment over a 24-week placebo-controlled period.

The potential effect of statins on the efficacy of rituximab does not preclude their concomitant use. The ACR 2015 guideline for treatment of rheumatoid arthritis does not provide guidance with respect to the concomitant use of rituximab and statins.³¹ The European League Against Rheumatism recommendations for cardiovascular disease risk management in patients with RA recommends statins generally for patients with RA who otherwise qualify for their use as in the general population.³⁹ The same document points to the inconsistency in the literature with respect to the use of statins with rituximab and encourages more study before the issue is fully understood.

^References

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2. An J, Alemao E, Reynolds K, et al. Cardiovascular outcomes associated with lowering low-density lipoprotein cholesterol in rheumatoid arthritis and matched nonrheumatoid arthritis. J Rheumatol 2016; 43 (11): 1989-1996.
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