JAK Inhibitor Safety Warnings Drawn From Rheumatologic Data May Be Misleading in Dermatology

Ted Bosworth

March 18, 2023

Dr Brett A. King

NEW ORLEANS — All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a black box warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis (RA) study, according to a critical review at the American Academy of Dermatology (AAD) 2023 Annual Meeting.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is "not necessarily data-driven," said Brett A. King, MD, PhD, associate professor of dermatology, Yale School of Medicine, New Haven, Connecticut.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published last year in the New England Journal of Medicine, the US Food and Drug Administration requires a black box warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, King said. The same language has even been applied to topical ruxolitinib cream. 

Basis of Black Box Warnings

In ORAL Surveillance, about 4300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m2.

After a median 4 years of follow-up (about 5000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that "JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients."

Evidence of Difference in Dermatology

There is some evidence to back this up. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib now is indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared to methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were < 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again < 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, King emphasized that it is essential to consider how the black box warning for JAK inhibitors was generated before applying them to dermatologic indications.

"Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no," he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of "where the black box warning comes from."

"We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes," he said. But the safety profile of JAK inhibitors "is almost certainly better" than the profile suggested in black box warnings applied to JAK inhibitors for dermatologic indications, he advised.

Risk-Benefit Considerations in Dermatology

This position was supported by numerous other experts when asked for their perspectives. "I fully agree," said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine at Mount Sinai, New York City.

Like King, Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

"While JAK inhibitors need monitoring as advised, adopting a black box warning from an RA study for patients who are older [is problematic]," she commented. A study with the nonselective tofacitinib in this population "cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis."

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine at Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

"The comments about the ORAL Surveillance study are salient," he said in an interview. "This kind of data should not directly be extrapolated to other patient types or to other medications." However, one of Han's most important caveats involves long-term use.

"JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids," he said. While doses used in dermatology "are generally below the level of any major concern," Han cautioned that "we lack definitive data" on long-term use, and this is important for understanding "any potential small risk of rare events, such as malignancy or thromboembolism."

Saakshi Khattri, MD, a colleague of Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk "needs to be delivered in the right context." Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense.

"Different diseases, different age groups," she said.

King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

American Academy of Dermatology (AAD) 2023 Annual Meeting. Abstract S005. Presented March 17, 2023.

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