Rochester, MN—While tofacitinib and TNF inhibitors both are effective in treating RA, patients on tofacitinib had higher risk of MACEs and cancers than those taking TNF inhibitors, according to a new study.

The report in The New England Journal of Medicine points out that the trial was prompted by increases in lipid levels and cancers with tofacitinib.

Mayo Clinic–led researchers conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial including patients who had active RA despite treatment with methotrexate. All participants were aged 50 years or older and had at least one additional cardiovascular risk factor.

Patients were randomly assigned in a 1:1:1 ratio with 1,455 receiving doses of tofacitinib 5 mg twice daily, 1,456 receiving tofacitinib 10 mg twice daily, and 1,451 being treated with a TNF inhibitor. Defined as the coprimary endpoints were adjudicated MACE and cancers, excluding nonmelanoma skin cancer.

Approved for the treatment of RA by the FDA at doses of 5 mg twice daily or 11 mg once daily (extended-release formulation), tofacitinib is a targeted synthetic disease-modifying antirheumatic drug that selectively inhibits Janus kinase (JAK)1, JAK3, and, to a lesser extent, JAK2.

Background information in the article recounts how, during drug development, increases in serum lipid levels and the incidence of cancers, including lymphoma, were observed. That prompted the FDA to require a prospective, head-to-head safety trial comparing tofacitinib with TNF inhibitors.

The result was the Oral Rheumatoid Arthritis Trial Surveillance, which assessed the hypothesis that the risk of MACE or cancers, excluding nonmelanoma skin cancer, would not be at least 1.8 times higher with tofacitinib (combined doses of 5 mg and 10 mg twice daily) than with a TNF inhibitor in this patient population.

Results indicated that, during a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]).

Researchers calculated the hazard ratios as 1.33 (95% CI, 0.91-1.94) for MACE and 1.48 (95% CI, 1.04-2.09) for cancers. As a result, they pointed out, the noninferiority of tofacitinib was not shown.

The report also noted that incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor.

The authors added that efficacy was similar in all three groups, with improvements from Month 2 that were sustained through trial completion.

"In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk–enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria," the study concluded. "Several adverse events were more common with tofacitinib."

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