1. Patients with rheumatoid arthritis (RA) treated with tofacitinib showed a higher risk of developing major adverse cardiovascular events and cancers, compared to those treated with a tumor necrosis factor (TNF) inhibitor.
2. Efficacy was similar between tofacitinib and TNF inhibitor in treating RA.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Rheumatoid arthritis is a systemic, chronic autoimmune disorder. Treatments include disease-modifying antirheumatic drugs (DMARDs), such as methotrexate; biologics, such as TNF inhibitors; and targeted DMARDs, such as tofacitinib, which selectively inhibits Janus kinase (JAK) 1, 2, and 3. During development, increases in serum lipids and cancers prompted the FDA to require a safety trial comparing tofacitinib with TNF inhibitor. The current study was a randomized, post-authorization, noninferiority trial evaluating the safety and efficacy of tofacitinib compared with a TNF inhibitor in RA patients with elevated cardiovascular risk. Tofacitinib was given at 5mg or 10mg twice daily. The TNF inhibitor comparators were either adalimumab or etanercept. During a follow-up of 4 years, the incidences of major cardiovascular adverse events (MACE) and cancer were higher with tofacitinib than adalimumab. Efficacy was similar across all groups and noninferiority of tofacitinib was not shown. The study only investigated one specific drug from the JAK inhibitor group (tofacitinib). Therefore, it is unclear if the risk profiles are specific to tofacitinib or generalizable to the broader category of JAK-targeting DMARDs.
In-Depth [randomized controlled trial]: This randomized, open-label, post-authorization, noninferiority trial investigated the safety and efficacy of tofacitinib in the treatment of RA. Patients above the age of 50 with active RA despite methotrexate who had at least 1 additional cardiovascular risk factor (such as cigarette smoker, hypertension, diabetes mellitus, low high-density lipoprotein cholesterol level, family history of cardiovascular diseases) were enrolled. A key exclusion criterion was a current or previous cancer diagnosis, except non-melanoma skin cancer. Overall, 1455 patients received oral tofacitinib at 5mg twice daily, 1456 received oral tofacitinib at 10mg twice daily, and 1451 received either subcutaneous adalimumab 40mg every 2 weeks or etanercept 50mg once weekly. Background methotrexate was continued unless otherwise indicated. The primary outcomes were adjudicated MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and cancers, excluding nonmelanoma skin cancers. Secondary outcomes include adverse events, including serious infections, opportunistic infections, non-melanoma skin cancer, and thromboembolism. Noninferiority was defined if the upper limit of the 95% confidence interval (CI) for the hazard ratio was less than 1.8 for combined tofacitinib doses compared to TNF inhibitors. During a median follow-up of 4.0 years, the incidence of MACE was higher with the combined tofacitinib doses (3.4%, 98 patients) than with a TNF inhibitor (2.5%, 37 patients). The hazard ratio for combined tofacitinib compared to TNF inhibitor was 1.33 (95% CI, 0.91 to 1.94) and noninferiority was not shown. The incidence of cancers, during the same period, was higher with the combined tofacitinib doses (4.2%, 122 patients) than with a TNF inhibitor (2.9%, 42 patients). The corresponding hazard ratio for combined tofacitinib compared to TNF inhibitor was 1.48 (95% confidence interval [CI], 1.04 to 2.09) and noninferiority was not shown. For secondary outcomes, the incidences of adjudicated opportunistic infections, all herpes zoster, and nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar across all treatment groups, with improvements in Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index observed from month 2 and sustained through trial completion. In the number-needed-to-harm analysis, 113 and 55 patients would need to be treated with tofacitinib, rather than a TNF inhibitor, for 5 years for one additional MACE and cancer, respectively. With a large patient cohort and extensive follow-up, this trial provided clear evidence for the relative risks of tofacitinib compared to TNF inhibitors in this patient population.
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