Tofacitinib (XELJANZ, XELJANZ ER) for Rheumatoid Arthritis Increases Risk of Infections

Public Citizen’s Health Research Group (HRG) has designated the oral drug tofacitinib (XELJANZ, XELJANZ ER) as Do Not Use for rheumatoid arthritis since 2017 because other very effective and safer drugs for this autoimmune disease existed. Since then, further evidence has emerged that tofacitinib has unique risks of several serious adverse effects, including infections, cancers, blood clots and cardiovascular events (heart attack and stroke) (see the text box, below, for excerpts of important warnings found in the product labeling for tofacitinib).[1],[2]

A study published in the November 2022 issue of the Annals of Rheumatic Diseases confirmed that tofacitinib increases the risk of severe and other infections compared to treatment with the tumor necrosis factor (TNF) blocker drugs that demonstrate similar effectiveness for treating rheumatoid arthritis.[3]

Excerpts from Black-Box Warnings in the FDA- Approved Product Labeling for Tofacitinib*

SERIOUS INFECTIONS: Patients treated with tofacitinib are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

MORTALITY: In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day.

MALIGNANCIES: Malignancies, including lymphomas and solid tumors, have occurred in patients treated with tofacitinib.

THROMBOSIS: Thrombosis, including blood clots in the lungs, large veins in the legs and arteries have occurred in patients treated with tofacitinib. Many of these events were serious and some resulted in death.

*Some of these warnings have been paraphrased.

About tofacitinib and TNF blockers

Tofacitinib is a potent immune-suppressing drug known as a Janus kinase (JAK) inhibitor.[4] It was first approved by the Food and Drug Administration (FDA) in 2012 for the treatment of moderate-to-severe rheumatoid arthritis in adults who experience an inadequate response to methotrexate (TREXALL, XATMEP).[5] Other JAK inhibitors approved later are baricitinib (OLUMIANT) and upadacitinib (RINVOQ); because the FDA considers them to have similar risks to those seen with tofacitinib, HRG also designates them as Do Not Use for rheumatoid arthritis.[6] JAK inhibitors are more generally classified as “disease-modifying antirheumatic drugs” (DMARDs).[7] DMARDs are used to reduce signs and symptoms of rheumatoid arthritis and in some cases even slow or arrest the joint damage that is the hallmark of that disease.

When the FDA approved tofacitinib, the agency required that the drug’s manufacturer, Pfizer, conduct a postmarketing trial to further consider safety concerns that emerged during the trials that led to the drug’s approval.[8],[9] On Sept. 1, 2021, the FDA announced that it had completed its review of that postmarketing trial’s results and concluded that tofacitinib increased the risk of serious cardiovascular events, cancer, blood clots and death enough to warrant a change in the product labeling for the drug.[10],[11] That change limited the approved use to patients who have not responded to or cannot tolerate TNF blockers, which are commonly prescribed injectable drugs that are FDA-approved to treat rheumatoid arthritis and other inflammatory diseases.

TNF blockers act by suppressing the activity of a substance in the body (TNF) that causes inflammation and contributes to immune system diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis.[12] Drugs in the TNF blocker class include infliximab (REMICADE), etanercept (ENBREL), adalimumab (HUMIRA), certolizumab pegol (CIMZIA) and golimumab (SIMPONI).

The recently published results comparing the infection risk of JAK inhibitors with that of TNF blockers come from the same postmarketing trial that led to the Sept. 1, 2021, label change.

New study on infection risk

The Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study was designed to compare the safety of tofacitinib with that of TNF blockers in patients who had active rheumatoid arthritis despite methotrexate treatment, were age 50 years or older and had at least one added cardiovascular risk (such as smoking, hypertension, low high-density lipoprotein level [sometimes called “good cholesterol”], diabetes mellitus, family history of premature coronary heart disease or a personal history of any coronary heart disease).[13] A key exclusion for this study were patients with a history of cancer (excluding adequately treated nonmelanoma skin cancer). Results from that study were published in the Jan. 27, 2022, issue of the New England Journal of Medicine. That publication focused on the primary outcomes of cardiovascular and cancer risks. Those results were the basis for an FDA 2019[14] warning and the 2021 label change described above.

The ORAL Surveillance study also evaluated serious and other infections (including herpes zoster [chickenpox, shingles] and tuberculosis) as secondary outcomes, and those results are detailed in the November 2022 issue of Annals of Rheumatic Diseases and described briefly below. Note that prior to this study it was already known that the risk of infection is elevated with rheumatoid arthritis because of many factors, including disease activity, age, other related illnesses and adverse treatment effects.[15]

The ORAL Surveillance study population was composed of individuals with active rheumatoid arthritis randomized into three groups as follows: 1,455 individuals received 5 milligrams (mg) of tofacitinib twice per day, 1,456 received 10 mg of tofacitinib twice per day and 1,451 received injections of one of two TNF blockers (40 mg of subcutaneous adalimumab once every two weeks or 50 mg of etanercept once weekly).[16] The trial ran from March 2014 to July 2020 and the median follow-up period was four years.

The most frequent infections (at least 4% new cases for each infection type, across all treatment groups) observed in this surveillance study were upper respiratory tract, bronchitis, urinary tract, herpes zoster, nasopharyngitis, pneumonia, sinusitis, pharyngitis, influenza and latent tuberculosis.[17]

The results of the ORAL Surveillance study revealed that serious and other infections were more likely to occur with tofacitinib treatment than with TNF-blocker therapy.[18] These differences were especially strong for the twice-daily 10-mg dosage of tofacitinib but were often significant even for the twice-daily 5-mg dosage.[19] Further analyses demonstrated that across all three groups, the risk of serious infections was especially evident with increasing age, opioid use, chronic lung disease history and oral corticosteroid use.[20] By comparison, nonserious infections, again across all three treatment groups, were significantly more likely to occur in females, past smokers, those with a history of chronic lung disease/infections and persons with high disease-activity scores (indicating joint-function impairment or inflammation).

What You Can Do

If you have rheumatoid arthritis, you should avoid starting tofacitinib if you are not currently taking it. If you are already taking tofacitinib for rheumatoid arthritis, consult with your doctor about switching to another DMARD. Do not stop taking any drug before consulting your doctor.

If you are taking tofacitinib for any other condition, talk to your doctor about the risks and benefits of the drug compared with those of alternative treatments.

If you notice any signs of infection (for example, fever, rash, cough or sore throat) while taking tofacitinib or any immune-suppressing therapy, contact your doctor immediately.
 

References

[1] Worst Pills Best Pills News. Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. October 2017. https://www.worstpills.org/newsletters/view/1155. Accessed December 7, 2022.

[2] Worst Pills Best Pills News E-alert. FDA warns tofacitinib (XELJANZ, XELJANZ XR) increases risk of serious heart-related adverse effects and cancer. March 1, 2021. https://www.worstpills.org/e-alerts/view/134. Accessed December 7, 2022.

[3] Balanescu AR, Citera G, Pascual-Ramos V, et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2022;81(11):1491-1503.

[4] Worst Pills Best Pills News. FDA limits approved uses of tofacitinib (XELJANZ, XELJANZ XR) because of serious adverse effects. January 2022. https://www.worstpills.org/newsletters/view/1444. Accessed December 7, 2022.

[5] Worst Pills Best Pills News. Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. October 2017. https://www.worstpills.org/newsletters/view/1155. Accessed December 7, 2022.

[6] Worst Pills Best Pills News. FDA limits approved uses of tofacitinib (XELJANZ, XELJANZ XR) because of serious adverse effects. January 2022. https://www.worstpills.org/newsletters/view/1444. Accessed December 7, 2022.

[7] Worst Pills Best Pills News E-alert. FDA warns tofacitinib (XELJANZ, XELJANZ XR) increases risk of serious heart-related adverse effects and cancer. March 1, 2021. https://www.worstpills.org/e-alerts/view/134. Accessed November 16, 2022.

[8] Worst Pills Best Pills News. FDA limits approved uses of tofacitinib (XELJANZ, XELJANZ XR) because of serious adverse effects. January 2022. https://www.worstpills.org/newsletters/view/1444. Accessed December 7, 2022.

[9] Worst Pills Best Pills News. Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. October 2017. https://www.worstpills.org/newsletters/view/1155. Accessed December 7, 2022.

[10] Worst Pills Best Pills News. FDA limits approved uses of tofacitinib (XELJANZ, XELJANZ XR) because of serious adverse effects. January 2022. https://www.worstpills.org/newsletters/view/1444. Accessed December 7 , 2022.

[11] Food and Drug Administration. FDA drug safety communication: 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. September 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed December 12, 2022.

[12] Food and Drug Administration. Information on tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). February 25, 2021. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-tumor-necrosis-factor-tnf-blockers-marketed-remicade-enbrel-humira-cimzia-and-simponi. Accessed December 7, 2022.

[13] Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326.

[14] Food and Drug Administration. FDA drug safety communication: Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. February 25, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-xr. Accessed December 12, 2022.

[15] Balanescu AR, Citera G, Pascual-Ramos V, et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2022;81(11):1491-1503.

[16] Ibid.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] Ibid.