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How can physicians help patients with rheumatoid arthritis when methotrexate fails? It was hoped that a new class of oral medication held the answer, but the FDA issued a black box warning for JAK inhibitors last year citing major adverse cardiac events and cancer as safety concerns. UAB’s Dr. Jasvinder Singh is seeking a definitive answer.

Patients with rheumatoid arthritis, or RA, often respond well to methotrexate—the most commonly prescribed oral medication for the condition. Thanks to a widely available, inexpensive pill, they experience relief from disabling joint pain and enjoy a robust quality of life. For those who have an incomplete response to this antimetabolite drug, the road to remission is a bit more challenging.

One safe and effective alternative is a different class of drug known as TNF inhibitors. Unfortunately, these types of biologics don’t come in a pill. They are administered with an injection, a method many patients are uncomfortable choosing.

In 2012, another class of therapeutics arrived on the scene: JAK inhibitors. As an oral medicine, they promised both results and easy adoption for patients. Unfortunately, late last year, the FDA responded to a post-marketing clinical follow-up trial by issuing black box warning label for the JAK inhibitors tofacitinib, upadacitinib and baricitinib. The FDA also changed the indications for tofacitinib and upadacitinib from “incomplete response to methotrexate” to “incomplete response to a TNF inhibitor.”

They cite the results of the ORAL Surveillance study, a 4-year randomized trial in which patients 50 years of age or older with active rheumatoid arthritis and at least one additional cardiovascular risk factor were randomly assigned to receive oral tofacitinib or an injection of a TNF inhibitor. The risks of major adverse cardiovascular events (MACE) and cancers were higher with the combined tofacitinib doses than with a TNF inhibitor.

Whether the higher MACE risk associated with tofacitinib as compared to a TNF inhibitor comes from a reduced risk caused by the TNF inhibitor or from an increased risk from tofacitinib is still unknown, as UAB rheumatologist Jasvinder Singh, M.D., recently commented in the New England Journal of Medicine.

Singh also noted the limits of the study, as results do not apply to subpopulations of patients who are younger than 50 years old, who had no cardiovascular risk factors, or for whom a TNF inhibitor caused unacceptable side effects or was not therapeutic.

The current debate reveals a definite gap in the knowledge that leaves patients who don’t respond completely to methotrexate struggling with their next treatment decision. Fortunately, the Patient-Centered Outcomes Research Institute has funded a $7 million grant to explore these concerns: A Real-World Comparative Effectiveness Trial of Treatment Strategies in Patients with Rheumatoid Arthritis with Active Disease Despite Methotrexate.

Singh, who is principal investigator on the grant, says, “Ongoing or previous studies have excluded most real-world RA patients and have not compared the effectiveness of these treatment options for patient reported outcomes in RA. Our study findings of varying effects of medications on outcomes in patients with RA will make personalized treatment options possible.”