FDA Updates Side Effects For 3 Rheumatoid Arthritis Drugs

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Lara Antal / Verywell

Key Takeaways

  • A study mandated by the Food and Drug Administration found that older patients with rheumatoid arthritis who took Xeljanz (tofacitinib) have an increased risk of having a heart attack or stroke or of developing cancer. 
  • The FDA changed the labeling of Xeljanz and two similar drugs to reflect these findings. 
  • Olumiant (baricitinib) and Rinvoq (upadacitinib) should be prescribed for patients with rheumatoid arthritis only after other medications to control the condition have been tried, according to the FDA.

A four-year study of a medication called Xeljanz (tofacitinib) found that it increased the risk of a major cardiovascular event and the risk of developing cancer in older patients with rheumatoid arthritis. Specifically, Xeljanz increased risk of a cardiovascular event like a heart attack or stroke by 33% and of developing cancer by 48%. 

The study published in the New England Journal of Medicine in January 2022, was mandated by the Food and Drug Administration (FDA) in order to continue evaluating Xeljanz's safety after it was approved. The agency requires such post-approval safety studies for some drugs. 

Xeljanz suppresses the immune system and is approved to treat three autoimmune diseases: rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. The study only included patients with rheumatoid arthritis.

The FDA approved Xeljanz to treat rheumatoid arthritis in 2012, “but had concerns enough to not give it a blanket approval, but to say we want to see some further evidence,” Steven Ytterberg, MD, lead study author, told Verywell. Ytterberg is a consultant emeritus and associate professor of medicine emeritus at the Mayo Clinic.

Drugs that suppress the immune system are known to increase the risks of developing cancer, Ytterberg noted. These drugs can also increase lipid levels in patients who take them, which raises the risk of cardiovascular events like heart attack and stroke. 

On the basis of this study, the FDA added warnings to the prescribing instructions for Xeljanz and two similar drugs, Olumiant and Rinvoq.

Reevaluating JAK Inhibitors

Xeljanz, Olumiant, and Rinvoq each belong to a class of drugs called janus kinase (JAK) inhibitors. JAK inhibitors treat inflammatory diseases and cancer by disrupting the signaling of enzymes that normally promote inflammation and autoimmunity. Because JAK inhibitors can be taken in pill form, they may be more convenient for patients than other disease-modifying antirheumatic drugs (DMARDs), which need to be injected or administered via infusion.

However, because of the new Xeljanz findings, the FDA is advising physicians to considering prescribing other medications for rheumatoid arthritis ahead of JAK inhibitors in certain patients, switching to a JAK inhibitor only if other treatments don't work. Examples of other treatments include a class of drugs called tumor necrosis factor (TNF) inhibitors, like Humira (adalimumab) and Enbrel (etanercept). Many TNF inhibitors are administered via self-injection.

When Xeljanz was originally approved to treat rheumatoid arthritis, there had been a push to use it earlier in treatment because it is an oral drug, Ytterberg said.

Now, Ytterberg says a good course of action is to start a patient with rheumatoid arthritis on methotrexate, the most common first-line DMARD, which can be taken by mouth or by injection. The second-line choice would be a TNF inhibitor, he added. 

The Study 

More than 6,500 patients at least 50 years old from 30 countries were enrolled in the New England Journal of Medicine study. Each participant had active rheumatoid arthritis that had not responded to treatment with methotrexate, as well as at least one risk factor for cardiovascular disease.

Patients were divided into three groups and randomly assigned to receive two daily doses of 5 milligrams or 10 milligrams of Xeljanz or a TNF inhibitor. Researchers then evaluated them for a median of four years. 

The incidence of major cardiovascular events—like heart attack or stroke—was higher (3.4%) for patients taking either dose of Xeljanz than for patients who took a TNF inhibitor (2.5%). Incidence was higher in patients who were over 65 years old than those who were younger than 65.

The incidence of cancers, not including melanoma, was higher in both Xeljanz dose groups (4.2%)  than among patients receiving the TNF inhibitor (2.9%). 

All three treatments were found to be effective in treating rheumatoid arthritis. 

Several of the authors of the study are employees of Pfizer, the maker of Xeljanz. Pfizer funded the study.

What Should Patients Do?

What should patients who are taking Xeljanz do with this information?

“For patients on Xeljanz who are doing well on it, [this study] is probably something they should note,” Nilanjana Bose, MD, a rheumatologist with Lonestar Rheumatology in Houston, Texas, and a member of the American College of Rheumatology, told Verywell.

A patient with other cardiovascular risk factors should have a talk with their primary care physician and cardiologist, as well as their rheumatologist, about whether to take or continue with Xeljanz, she said. 

Rheumatoid arthritis causes permanent damage to joints and loss of function for many patients. The risks of using a drug that raises the risks of heart attack and stroke have to be balanced against the risks of rheumatoid arthritis.

“I tell my patients that just having [rheumatoid arthritis] puts you at a higher risk for both vascular disease and cancer,” Bose said. 

Finding the right medications that work to treat and control flares of rheumatoid arthritis is a balancing act, said Ytterberg. A physician has to balance the risk of undertreating the disease—leading to flares and progressive problems—and the risks of medications, he noted. 

What This Means For You

Older patients with rheumatoid arthritis who take Xeljanz appear to have an increased risk of having a heart attack or stroke or of developing cancer. Based on information from a large study, the Food and Drug Administration has added warnings to the labeling for Xeljanz and two similar drugs reflect these findings. If you're taking these medications, talk to your primary care provider and your rheumatologist about your specific risks.

2 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritisN Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927

  2. U.S. Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions.

By Valerie DeBenedette
Valerie DeBenedette has over 30 years' experience writing about health and medicine. She is the former managing editor of Drug Topics magazine.