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It's official: full data from a randomized trial evaluating safety of the oral JAK inhibitor tofacitinib (Xeljanz), approved for treating rheumatoid arthritis and related disorders as well as ulcerative colitis, are now published -- and they are not good.

Patients assigned to tofacitinib developed major adverse cardiovascular events (MACE) at a rate of 3.4% and new cancers were seen in 4.2% during a median 4 years of follow-up; for those treated with either adalimumab (Humira) or etanercept (Enbrel), the corresponding rates were 2.5% and 2.99%, respectively, according to a report in the .

This worked out to hazard ratios of 1.33 for MACE (95% CI 0.91-1.94) and 1.48 for incident cancers (95% CI 1.04-2.09), reported investigators led by Steven Ytterberg, MD, of the Mayo Clinic in Rochester, Minnesota. Neither met prespecified criteria for noninferiority, which the trial's sponsor -- tofacitinib manufacturer Pfizer -- had hoped to achieve.

Moreover, MACE and incident cancers were not the only adverse events that occurred more frequently with tofacitinib: opportunistic infections such as herpes zoster and tuberculosis also had increased rates. And the higher of two tofacitinib doses tested in the study (10 mg twice daily) was associated with increased all-cause mortality (2.7% vs 1.8% for 5 mg twice daily and 1.2% for tumor necrosis factor [TNF] inhibitors).

Pfizer had released topline results from the study , leading to substantial upgrades to the boxed warning that tofacitinib and related drugs already carried. The FDA considers the increased adverse event rates to be a class effect for all JAK inhibitors.

Efficacy data in the new report were limited, mainly showing that all three arms got the same benefit, an approximately 30-point average reduction in Simplified Disease Activity Index (SDAI) scores, which run from 0 to 100 -- a clinically significant improvement, though short of remission for most patients.

In their paper, Ytterberg and colleagues stuck to reporting the trial's results, offering no advice to patients or clinicians on how to interpret them.

That was Jasvinder Singh, MBBS, MPH, of the University of Alabama at Birmingham. He noted that the drug -- along with its chemical cousins baricitinib (Olumiant) and upadacitinib (Rinvoq) -- already come with boxed warnings about the risk, which were . The agency also tightened eligibility criteria for tofacitinib and upadacitinib to allow the drugs only in patients failing on TNF inhibitors; previously, patients could receive them after failing nonbiologic drugs.

So what do the new data mean? "In patients with rheumatoid arthritis who have an incomplete response to methotrexate and have active disease, a TNF inhibitor will be preferred to tofacitinib for a new start, especially in persons 65 years of age or older," Singh wrote.

But the drug could still be considered for younger patients who "strongly prefer or are only willing to take an oral DMARD [disease-modifying anti-rheumatic drug]," he added.

"JAK inhibitors are among important oral treatment options for rheumatoid arthritis," Singh concluded -- but only for patients who understand the risks and participate actively in treatment decisions.

Study Details

Called , the multinational trial began in 2014, as ordered by the FDA when the drug was first approved for rheumatoid arthritis in 2012. The FDA had already mandated a boxed warning based on findings from the agent's registration trials, pointing to higher rates of infections and certain malignancies, but wanted Pfizer to produce a clearer picture of the risks.

The safety study randomized 4,362 patients at a 1:1:1 ratio to tofacitinib at 10 or 5 mg twice daily or to one of two TNF inhibitors. Patients were enrolled at 323 sites in 30 nations. In North America, the assigned TNF inhibitor was adalimumab; etanercept was used elsewhere. After an for the higher tofacitinib dose, that arm was terminated and its patients were shifted to the lower dosage. Adalimumab and etanercept doses were the customary standards, and all patients continued on methotrexate.

Only individuals 50 and older with rheumatoid arthritis not responding to methotrexate were enrolled (approvals for other indications, including ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, and ulcerative colitis, all came after the trial was designed). Patients also were required to have at least one cardiovascular risk factor beyond age. Those with current or previous cancers were excluded, although those with "adequately treated" non-melanoma skin cancers (NMSC) were allowed.

Mean patient age was about 61, and close to 80% were women. SDAI values averaged about 42 at baseline.

Crude adverse event rates for major outcomes were as follows:

• Serious adverse events: 24.1% for tofacitinib low dose, 26.8% for tofacitinib high dose, 21.1% for TNF inhibitors
• Serious infection: 9.7%, 11.6%, and 8.2%, respectively
• MACE: 3.2%, 3.5%, and 2.5%, respectively
• Incident cancers (excluding NMSC): 4.3%, 4.1%, and 2.9%, respectively

Extrapolating these data, Ytterberg and colleagues estimated that 6.1% of patients receiving tofacitinib would develop cancers over 5.5 years versus 3.8% of those on TNF inhibitors. Similarly, the estimated cumulative 5.5-year rate for MACE was 5.8% for tofacitinib and 4.3% with TNF inhibitors. (The researchers noted that people with rheumatoid arthritis already face increased rates of cardiovascular disease and cancer relative to the general population.)

Herpes zoster accounted for most of the opportunistic infections seen in participants. Only 11 cases of tuberculosis occurred and were not more common with tofacitinib.

The higher tofacitinib dose was associated with increased rates of several other adverse effects, including liver abnormalities and thromboembolic events. Ulcerative colitis is the only indication for which the 10-mg twice-daily dose was ever approved, but only for a few weeks to induce remission, which is still allowed; the recommended maintenance dose is 5 mg twice daily, or once daily for certain patients at special risk. (An 11-mg extended-release pill for once-daily dosing in arthritic conditions -- twice daily for ulcerative colitis induction -- remains available.)

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