Concerns, Conflicting Studies Dog JAK Inhibitors

Despite FDA warnings, these drugs may not be risky for all people.

By Linda Rath | Updated Jan. 19, 2023

In September 2021, the Food and Drug Administration revised the safety and treatment recommendations for tofacitinib (Xeljanz and Xeljanz XR), baricitinib (Olumiant) and upadacitinib (Rinvoq) — medications called Janus kinase (JAK) inhibitors used to treat inflammatory forms of arthritis and other conditions. The drugs’ boxed warnings — the agency’s strongest cautions — were updated to include information about the serious risk of heart-related problems, blood clots, cancer and death. Use of the medications was limited to patients who hadn’t been helped by one or more drugs called tumor necrosis factor (TNF) blockers, or anti-TNFs. 

Tofacitinib is approved to treat polyarticular juvenile idiopathic arthritis, psoriatic arthritis, rheumatoid arthritis (RA) and ankylosing spondylitis as well as ulcerative colitis. It’s sometimes used off-label for psoriasis patients. Baricitinib is approved to treat RA, alopecia areata (hair loss) and has emergency use authorization for certain patients hospitalized with COVID-19. Upadacitinib is approved to treat RA and atopic dermatitis.

The revised warnings were prompted by the results of a post-marketing safety trial comparing 5 mg and 10 mg of tofacitinib to anti-TNFs for RA. The trial found a greater risk of heart attack, stroke, blood clots, cancer and death with tofacitinib. Herpes zoster, tuberculosis and non-melanoma skin cancer also occurred more often in the tofacitinib group. Patients at higher risk were over 65, smokers and those who had previously had a heart attack, stroke or cancer. 

Although tofacitinib was the only drug studied in the post-marketing trial, the FDA extended its warnings to baricitinib and upadacitinib because they’re in the same drug class and work the same general way.

Study Analysis Finds Different Results

The trial received some criticism. Among other things, most participants were white women over 50 who had at least one heart disease risk factor, ranging from high blood pressure to diabetes. This compromised the ability to extend the findings to younger adults, people with no heart disease risk factors and other races and ethnicities.

To get a better handle on the study results, a team of researchers from NYU Langone Health in New York City analyzed 66 randomized controlled trials that looked at complications of JAK inhibitors in more than 38,000 participants. Although the trials differed considerably in the type of JAK inhibitors and the diseases studied, there was a clear association between serious blood clots (venous thromboembolism or VTE) and JAK inhibitors, especially when taken for a year or more. However, there was less association with heart problems than in the original trial.

Michael Garschik, MD, a cardiologist at NYU Langone and one of the researchers involved in the meta-analysis, said the data doesn’t mean JAK inhibitors should never be used but that more caution is warranted for high-risk patients.  

The View from Europe

The European Medicines Agency, which is the European Union’s equivalent of the FDA, continues to rely on the findings of the original post-marketing study as well as a preliminary observational trial of baricitinib to make policy decisions. The baricitinib trial found the same increased risk of heart attack, stroke and blood clots vs. anti-TNFs seen with tofacitinib. Like the FDA, the EMA concluded that all JAK inhibitors have the same risks and should be avoided as much as possible in people over 65, current and former smokers and anyone with risk factors for heart disease or cancer. Agreeing with the NYU researchers, the EMA says the drugs should be used with caution or at a reduced dose in people at risk of blood clots “when possible.” The EMA issued its recommendations on January 13, 2023.

One thing health care providers on both sides of the Atlantic agree on is that any use of JAK inhibitors should be contingent on shared decision-making, where patients fully understand the drugs’ risks and have equal say in their treatment.  

What Should You Do?

JAK inhibitors are not a first-line therapy for inflammatory forms of arthritis. Only a small percentage of people take them, either because anti-TNFs haven’t worked or stopped working or because they want an oral medication rather than an injection or infusion.

If you take one of these medications, don’t stop taking it without talking to your rheumatologist. Several options are available if you and your doctor decide switching is right for you.