Lose Your Inhibitions: Expanding Use of JAK Inhibitors

JAK inhibitors continue to make inroads into dermatology, often with life-changing benefits to patients. In multiple clinical trials, use of Janus kinase (JAK) inhibitors has yielded a range of benefits including reduced itching for individuals with eczema, hair regrowth in alopecia areata, and restoration of skin color for patients with vitiligo, according to the American Academy of Dermatology (AAD)’s patient education section.1

Some of the key benefits JAK inhibitor treatment include the rapid response and noninjectable delivery, both of which appeal to patients as well as clinicians, the AAD website explains, and many patients who failed on other treatments have seen significant improvements in their disorder with JAK inhibitors; however, safety concerns persist.1

In the wake of data on cardiovascular concerns and cancer risk associated with tofacitinib in patients with rheumatoid arthritis, the US Food and Drug Administration (FDA) mandated a black box warning, not only for tofacitinib, but also on two JAK inhibitors with current dermatologic indications: upadacitinib and baricitinib.

Currently, FDA-approved JAK inhibitors for dermatology include the oral medications upadacitinib and abrocitinib for moderate-to-severe atopic dermatitis (AD), baricitinib for severe alopecia areata, and the topical ruxolitinib for mild-to-moderate AD and nonsegmental vitiligo according to the AAD.1

In a review published in the Journal of Drugs in Dermatology in 2022, Stefano G. Daniele, PhD, and Christopher G. Bunick, MD, both of Yale University, New Haven, CT, noted that “this class-based boxed warning is not unusual or specific to JAK inhibitors but is in accordance with routine FDA procedures to maintain medication safety.” Safety concerns associated with JAK inhibitor use in studies of tofacitinib included increased risk for major adverse cardiovascular events (MACE), blood clots, cancer, and death compared with tumor necrosis factor-alpha inhibitors. The study authors conducted a review of adverse event data associated with methotrexate, cyclosporine, and systemic corticosteroids, and found that traditional systemic therapies for AD showed equal or higher incidence rates for malignancy other than nonmelanoma skin cancer (NMSC), nonmelanoma skin cancer, major adverse cardiac events, and venous thromboembolism compared to upadacitinib and abrocitinib.2

In a review published in Dermatologic Therapy, Christeen Samuel, MD, of Johns Hopkins University, Baltimore, MD, detailed FDA approvals of JAK inhibitors for dermatology indications and discussed safety profiles. Overall, the review found that dermatology clinical trial data showed patients on oral JAK inhibitors had low rates of venous thromboembolism, MACE, and malignancy similar to the rates in patients on placebo.3

Specifically, the researchers found rates of venous thromboembolism ranging from 0% to 0.1-0.5% in dermatology patients receiving JAK therapy compared with no events in patients given placebo.

Similarly, the rates of cardiovascular events ranged from no events in patients administered JAK inhibitor to 0.4%-1.2% compared with no events to 0.5%-1.2% in patients receiving placebo. The rates of serious infections were 0.4%-4.8% compared with no events to 0.5%-1.3% in the placebo. The rates of nonmelanoma skin cancer ranged from no event to 0.6%-0.9% compared with no events in the placebo. The rates of nonNMSC ranged from no event to 0.2%-0.7% compared with no event to 0.6% in the placebo.3

“Most patients who developed these adverse events had risk factors for the specific event,” and therefore dermatologists should consider patients’ baseline risk factors for these complications before opting for oral JAK inhibitors, the researchers noted. Overall, the most common treatment-emergent adverse events (those seen in 5% or more of patients on oral JAK inhibitors) included upper respiratory infections, nasopharyngitis, nausea, headache, and acne, they said.

Managing Risks and Maximizing Benefits

JAK inhibitors are potential game-changers in dermatology because of their unique mechanism of action, said Peter Lio, MD, founding director of the Chicago Integrative Eczema Center, in an interview with Practical Dermatology. This mechanism “falls somewhere between the overly broad classical immunosuppressants such as cyclosporine and prednisone, and the highly selective biologic agents such as dupilumab and tralokinumab,” he said. “They are oral agents, which is a huge plus, they are taken once daily, and they work incredibly quickly.” In fact, JAK inhibitors work so quickly that experts talk about the possibility of using them as “just in time” treatments for a flare up rather than as chronic therapies, he noted. However, “we don’t have much research on short-term use, and they are not FDA-approved for use in such a manner at this time,” he added.

JAK inhibitors now include a black box warning that discusses risks including infection, malignancy, cardiovascular events, and blood clots, Dr. Lio noted. “While we think that these risks are relatively low, and much of this comes from work from another JAK inhibitor, tofacitinib, that is actually less selective than the ones we have for atopic dermatitis, and was studied in rheumatoid arthritis,” he said. Additionally, since tofacitinib was studied in a very specific patient population of adults aged 50 years and older with at least one cardiac risk factor, “it is off-putting and frankly difficult to counsel patients,” since data in other populations and with other products are lacking, he said.

In a recent presentation at the Interdisciplinary Autoimmune Summit, held virtually, Dr. Lio outlined his personal approach to monitoring patients on JAK inhibitors. He starts at baseline with a complete blood count, comprehensive metabolic panel, lipid profile, hepatitis screen, tuberculosis test, and HIV screen, and these tests are repeated annually. At 1 month and 3 months, Dr. Lio orders a CBC, CMP, and lipid profiles, then repeats them every 2 to 3 months if the results are reassuring.

The greatest barriers to expanding the use of JAK inhibitors in dermatology include hesitation on the part of clinicians to start patients on them, given the risk potential and need for laboratory monitoring, Dr. Lio said.

Other potential barriers include patient trepidation surrounding frequent labs and side effects, and the cost/insurance coverage for JAK inhibitors, he noted.

However, “I think that with good education, appropriate patient selection, and good documentation, these barriers are largely surmountable,” said Dr. Lio. “I think that the drug companies also have generally helpful patient support programs for coverage, although they do add administrative burdens for the prescribers.”

Overall, clinicians are quite convinced of the effectiveness of JAK inhibitors, Dr. Lio told Practical Dermatology. “What we need now are longer-term safety data, data on best practices for monitoring, how to deal with necessary vaccinations, and ideally, finding biomarkers so we can avoid or at least minimize the more concerning side effects,” he said.

Disclosures

Dr. Lio disclosed research grants/funding from Regeneron/Sanofi Genzyme, and AbbVie; serving on the speaker’s bureau for Regeneron/Sanofi Genzyme, Pfizer, Incyte, Eli Lilly, LEO, Galderma; and serving on consulting/advisory boards for Almirall, ASLAN Pharmaceuticals, Bristol-Meyers, UCB, Dermavant, Regeneron/Sanofi Genzyme, Merck, Pfizer, LEO Pharmaceuticals, AbbVie, Eli Lilly, Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, Galderma, Arbonne, Amyris, Bodewell, Burt’s Bees, My-Or Diagnostics, Sibel Health, and Kimberly-Clark.

1. American Academy of Dermatology. JAK inhibitors: What your dermatologist wants you to know. Accessed May 9, 2023. https://www.aad.org/public/diseases/a-z/jak-inhibitors

2. Daniele SG, Bunick CG. JAK inhibitor safety compared to traditional systemic immunosuppressive therapies. J Drugs Dermatol. Epub November 18, 2022. 2022;21(12):1298-1303. doi:10.36849/JDD.7187

3. Samuel C, Cornman H, Kambalka A, Kwatra SG. A review on the safety of using JAK inhibitors in dermatology: Clinical and laboratory monitoring. Dermatol Ther (Heidelb). 2023 Mar;13(3):729-749. doi: 10.1007/s13555-023-00892-5. https://link.springer.com/article/10.1007/s13555-023-00892-5