NEW ORLEANS – All but one of the Janus kinase (JAK) inhibitors with dermatologic indications carry a black box warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), although the The basis of all risks is a study of rheumatoid arthritis (RA), according to a critical review at the 2023 annual meeting of the American Academy of Dermatology (AAD).
Since the postmarketing RA study was specifically enriched for high-risk patients by requiring an age of at least 50 years at enrollment and the presence of at least one cardiovascular risk factor, extrapolation of these risks to dermatologic indications “is not necessarily data-based,” 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. In contrast, according to the ORAL Surveillance study, published last year in it New England Journal of Medicine, the US Food and Drug Administration requires a black box warning in nearly identical language for all other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ in JAK selectivity and other characteristics likely relevant to adverse event risk, King said. The same language has even been applied to ruxolitinib topical cream.
Basis of black box warnings
In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to receive 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 approximately 30 kg/m2.
After a median of 4 years of follow-up (approximately 5,000 patient-years), the incidence of many of the adverse events tracked in the study was higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. King did not question the significance of these data, but questioned whether they are reasonably extrapolated to dermatologic indications, particularly since many of those treated are younger than are common in an RA population.
In fact, despite a study enriched by an increased risk of many events tracked, most adverse events were only slightly elevated, King pointed out. For example, the incidence of MACE during the 4-year follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% among those randomized to the TNF inhibitor. Cancer rates were 4.2% vs. 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to the TNF inhibitor.
King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than the TNF inhibitor in patients with RA, but believes that “the safety of the JAK inhibitor is almost certainly not the same in dermatology as it is in patients of rheumatology”.
Evidence of difference in dermatology
There is some evidence to back this up. King cited a recently published study in open DMR who evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients during 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 across the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis) and the fourth was atopic dermatitis (AD). Fourteen outcomes, including multiple types of infection, MACE, liver complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.
For RA diseases, upadacitinib was associated with a higher 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 the comparators.
When assessing the risk of adverse events across all indications, for MACE, the exposure-adjusted event rates for upadacitinib were < 0.1 in patients treated for AD during the observation period vs 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, upadacitinib rates were again <0.1 in AD patients versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.
Referring to the post-marketing study, King stressed that it is essential to consider how the black box warning for JAK inhibitors was generated before applying them to dermatological indications.
“Is it possible that a 30-year-old patient with a skin disorder is at the same risk as the patients in the study for whom we received the boxed warning? The answer is simply no,” he said.
Similar to the tofacitinib data in the ORAL Surveillance study, the data from the upadacitinib clinical trial are not necessarily relevant to other JAK inhibitors. Indeed, King noted that the safety profiles of available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity having implications for off-target events.
King doesn’t discount the potential risks outlined in current regulatory warnings about the use of JAK inhibitors, but he thinks dermatologists should be aware “where the black box warning is coming from.”
“We need to think carefully about the risk-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 the black box warnings applied to JAK inhibitors for dermatologic indications, she advised.
Risk-benefit considerations in dermatology
This position was supported by many other experts when asked for their perspectives. “I totally agree,” said Emma Guttman-Yassky, MD, PhD, chair of the system of dermatology and immunology at the Icahn School of Medicine at Mount Sinai, New York City.
Like King, Guttman-Yassky did not rule out the potential risks of JAK inhibitors in the treatment of skin diseases.
“While JAK inhibitors need to be monitored as recommended, adopt black box warning from RA study for older patients [is problematic]commented. A study with non-selective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those being treated [for] alopecia areata or atopic dermatitis”.
George Z. Han, MD, PhD, 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 feedback on the ORAL Surveillance study is outstanding,” he said in an interview. “This type of data should not be directly extrapolated to other types of patients or to other medications.” However, one of Han’s biggest caveats involves long-term use.
“JAK inhibitors remain drugs with a relatively narrow therapeutic window that, in a dose-dependent manner, could cause negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While the doses used in dermatology are “generally below the level of any significant concern,” Han cautioned that “we lack definitive data” on long-term use, and this is important to understand “any small potential risk of rare events such as malignancy or thromboembolism”.
Saakshi Khattri, MD, a colleague of Guttman-Yassky’s at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but also agreed that the risk “must be presented in the right context.” Khattri, who is board-certified in both dermatology and rheumatology, noted that the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications is meaningless.
“Different diseases, different age groups,” he 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) Annual Meeting 2023. AbstractS005. Submitted March 17, 2023.
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