In September 2021, the US Food and Drug Administration (FDA) updated their Boxed Warning on Janus kinase (JAK) inhibitors tofacitinib, baricitinib, and upadacitinib to reflect findings from their recent review on a safety clinical trial on tofacitinib.1,2

The FDA concluded that these JAK inhibitors, used to treat certain autoimmune conditions, may increase the risk for heart attack, stroke, cancer, blood clots, and death. These conditions were previously associated with taking larger doses of the medications; however, what is significant now is that they are also associated with a lower dose of the medications.1,2

JAK Inhibitors Carry Risk for Side Effects in Autoimmune Diseases

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The news of the additional FDA warnings for JAK inhibitors may not have come as a surprise to clinicians. We know that medications that are designed to interfere with the immune system can have unintended consequences for patients. Although that may be alarming, it does not negate the value of these medications in the management of disease.

Targeted small-molecule drugs, like JAK inhibitors, and biologics, have undoubtedly changed the face of rheumatic disease in a positive way. They provide lifesaving solutions to some patients. The reality, however, is that warnings on any of the medications used to treat autoimmune diseases are side effects. We’re probably not going to develop a drug (at least in the near future) that can manipulate the immune system in a way that treats the disease and doesn’t carry risks for side effects.

Nicole Bundy, MD, MPH, is a board-certified internist and rheumatologist, and the chief medical officer at Mymee.

The recent FDA warning also serves as a stark reminder that there’s never going to be a “magic bullet” for autoimmune or any other chronic diseases. We need to understand that along with the benefits that we can anticipate from these types of drugs, there will always be the risk for unintended consequences.

Need for Nonpharmacologic Treatments in the Management of Autoimmune Diseases

The goal should be to minimize our reliance on medications like tofacitinib so that we can decrease these serious risks. Fortunately, this is in our power. We can look for nonpharmacologic ways to augment treatments.

For patients receiving JAK inhibitors, a careful and ongoing assessment of individual risks and benefits is needed to determine whether this continues to be the best choice of treatment. Ideally, clinicians would identify the patients at greatest risk for these side effects and adhere to careful prescribing practices. That is personalized medicine at its best.

In light of the recent FDA warning, patients receiving treatment with JAK inhibitors should make an appointment with their providers for further evaluation.

What both physicians and patients can take away from the new FDA warnings is that this is not an indictment of a particular drug, but instead a wakeup call that warrants more attention to overall personal wellness, as part of pharmacologic treatment. Care for autoimmune diseases, which can be complicated and require a variety of drugs, needs to be given on the foundation of a more comprehensive approach to treatment that includes diet and lifestyle factors. This is the standard-of-care in other disciplines, such as cardiovascular and cancer medicine, where patients are encouraged to incorporate better diet and lifestyle habits into their treatment plan. This rarely happens in rheumatology, which needs to change.

Of note, benefits of JAK inhibitors for many patients often reach a “ceiling.” Some patients still experience lingering symptoms, most notably fatigue. These symptoms are often not improved by these JAK inhibitors and continue to be debilitating for patients and affect their quality of life. It’s beyond that ceiling— the gap between the impact of the drug and how patients want to feel — where thoughtfully prescribed personalized interventions, which include diet and lifestyle changes, can make a big difference.

With regard to autoimmune diseases, the best course of action is to encourage patients to practice healthy lifestyle habits that improve the body’s resilience. Doing so — through adequate sleep, a nutritious diet with whole foods (and removal of foods that may act as triggers for a patient’s unique immune cells), physical activity, and stress management strategies — has numerous indispensable benefits that extend from prevention to treatment.

For patients who may carry additional risk factors for autoimmunity, such as a family history, these lifestyle habits may minimize the chance of developing these diseases. A healthy foundation makes it more likely that disease will be adequately controlled using less medications, reduces the risks for certain side effects, and increases the chances of experiencing more complete symptom relief and a better quality of life. .

The bottom line is that helping patients with rheumatic diseases achieve and maintain a better baseline of health decreases vulnerabilities and increases resilience. In the face of the FDA warnings about the ever-evolving risks and side effects related to pharmacologic treatment, rheumatologists and their patients can consider lifestyle interventions.


1. US Food & 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. Updated September 16, 2021. Accessed October 13, 2021.

2. US Food & Drug Administration. FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). February 4, 2021. Accessed October 13, 2021.

This article originally appeared on Rheumatology Advisor