PracticalDermatology

The growth, so to speak, of Janus kinase inhibitors (JAK) to treat severe alopecia areata (AA) has been life-changing for many patients with no other option, according to Joel Schlessinger, MD, a board-certified dermatologist and cosmetic surgeon in Omaha, NE.

Although JAK inhibitors have been used off-label in topical form to treat hair loss, the positive results of clinical trials with oral JAK inhibitors for alopecia areata and alopecia universalis “were simply remarkable,” said Dr. Schlessinger, who has been involved the trials. “It has been gratifying to be a part of these research endeavors, and to have the ability to offer a treatment for people who had no other effective options,” he told Practical Dermatology.

JAK inhibitors work by interfering with the inflammatory process that fuels hair loss. Baricitinib (Olumiant) was approved by the US Food and Drug Administration in 2022 for the treatment of severe alopecia areata (AA) in adults aged 18 years and older. In June 2023, it was joined by ritlecitinib (Litfulo). The ritlecitinib approval extends the use of JAK inhibitors to younger patients (aged 12 years and older) with severe AA.

Approval Studies Offer Encouragement

The ritlecitinib approval was based on data from a randomized, double-blind phase 2b-3 trial conducted in 118 locations in 18 countries. In the results, published the Lancet, patients aged 12 years and older with alopecia areata and scalp hair loss of at least 50% received oral ritlecitinib or a placebo daily for 24 weeks. At the end of this period, significantly more patients who received either 30 mg or 50 mg of the drug (with or without a 200-mg loading dose) compared to patients assigned placebo met the primary endpoint of Severity of Alopecia Tool (SALT) scores of 20 or less, which is 80% or more scalp hair coverage.

The most common adverse events in both younger (12 to 17 years of age) and older patients (18 years and older) included headache, diarrhea, acne, rash, and urticaria.

In March 2023, extended long-term safety and efficacy results for baricitinib were published. The two studies, BRAVE-AA1 and BRAVE-AA2, were the basis for baricitinib’s 2022 approval, with data from 36 weeks of treatment. In the initial BRAVE-AA1, 35% and 22% of patients who received 4 mg and 2 mg, respectively, met the SALT criteria, as did 32% and 17% of those treated with 4 mg and 2 mg, respectively, in the initial BRAVE-AA2 study.1

The updated studies showed increased response rates for hair regrowth increased over 52 weeks. After 52 weeks of continuous baricitinib therapy, 40.9% of patients who received 4 mg and 21.2% of those who received 2 mg achieved SALT scores of 20 or less. Results were similar in the BRAVE-AA2 study, with 36.8% and 24.4% of patients in 4-mg and 2-mg dose groups, respectively, meeting the primary outcome at 52 weeks. In these studies, the most frequently reported treatment-emergent adverse events were upper respiratory tract infection, headache, nasopharyngitis, acne, and urinary tract infection, as well as creatine phosphokinase elevation and COVID-19 infection.

Implications for Skin of Color

Recent research, including a cross-sectional study of data from the National Alopecia Areata Registry, suggests that African Americans have increased odds of AA. In that study, the population included 9,340 individuals with AA and 2,064 without. Overall, African Americans had a significantly increased risk of AA (odds ratio 1.77) compared to White individuals, while the risk of AA among Asian individuals was lower compared to White individuals (OR 0.40).2

African American patients were underrepresented in the baricitinib and ritlecitinib studies.

“As far as we know, there is every reason that patients of color will respond to JAK inhibitors in the same manner as Caucasian patients, though the clinical trials included mainly Caucasian patients,” Amy McMichael, MD, of Wake Forest School of Medicine, Winston-Salem, NC, told Practical Dermatology. “For those of us who have been able to use both FDA approved and non-FDA-approved JAK inhibitors in our AA patients of color, we have found excellent response and safety with the use of these medications,” she said.

“However, there is no substitute for performing studies in skin of color populations to prove what we see in clinical practice is absolutely true,” Dr. McMichael continued. “Barriers to the use of JAK inhibitors in AA patients can include delayed diagnosis due to misdiagnosis, delayed referral to dermatology, and/or under- or uninsured status,” she said.

“It is imperative for any future clinical trials to include patients who are skin of color. Also, retrospective studies must be performed in skin of color patients with AA who are treated with JAK inhibitors,” said Dr. McMichael. “Finally, future studies are needed to determine which patients with AA (in general) will respond to which JAK inhibitor for a more personalized approach to treatment,” she added.

Don’t Discount Black Box Warnings

However, JAK inhibitors are not without more serious safety concerns, and Dr. Schlessinger noted some of the persistent risk factors that should be considered.

The full prescribing information for both baricitinib and ritlecitinib contains black box warnings of the potential for serious infections, mortality, malignancy, thrombosis, and major adverse cardiovascular events (MACE).

“We expect to have some serious infections and malignancy with almost any biologics, but the Achilles heel of the JAK inhibitors is the risk of thrombotic and cardiac events,” Dr. Schlessinger said.

However, for many patients with alopecia totalis or alopecia universalis, this is a set of risks they are willing to accept, he said. Other treatment options are “nearly ineffective and terribly dangerous,” he added.

The greatest challenge to successful treatment of hair loss with JAK inhibitors is for patients with an ongoing set of risk factors that predispose them to the conditions in the black box, said Dr. Schlessinger. Many patients come to the dermatologist seeking treatment for hair loss, but they may have concomitant morbidities and other risk factors that render them ineligible, he said.

“It is important that any physician prescribing these drugs understands the risks associated with them and the significant black box warnings,” Dr. Schlessinger emphasized. “Consent forms should be explained and signed prior to prescribing, and appropriate follow-up should be conducted. “In our office, we conduct patient follow-up after one month, and then every 3 months to obtain blood work and check for issues of clotting and thrombosis,” he said.

The incidence of thrombotic events during the research period for JAK inhibitors for severe AA may have been impacted by the COVID-19 pandemic, Dr. Schlessinger noted. Overall, the incidence of thrombotic events in the population increased during the pandemic, among those who may not have known that they were infected, and among those who experienced a known COVID-19-related thrombotic event. Time will tell, but some of the safety data on many of the drugs approved during the COVID time period may normalize, and many of these drugs have better safety profiles than expected, Dr. Schlessinger believes.

Looking ahead, Dr. Schlessinger sees the addition of JAK inhibitors as powerful tools in the treatment of severe hair loss.

“It is a very exciting time for those of us who witnessed disease states that were previously nearly hopeless in terms of therapeutic options to now see the benefits of solid clinical research and massive investments by pharmaceutical research companies to bring new treatments for these conditions,” said Dr. Schlessinger. “When I started my practice 30 years ago, psoriasis was one of my dreaded diseases, but now it is incredibly rewarding to have effective treatments for psoriasis, alopecia, and so many other conditions.”

Disclosures

Dr. Schlessinger participated in clinical trials for JAK inhibitors, but had no relevant financial conflicts to disclose. Dr. McMichael disclosed consulting or grant funding from Pfizer, Janssen, Incyte, Sun Pharma, and Lilly.

1. Kwon O, Senna MM, Sinclair R, et al. Efficacy and safety of baricitinib in patients with severe alopecia areata over 52 weeks of continuous therapy in two Phase III trials (BRAVE-AA1 and BRAVE-AA2). Am J Clin Dermatol. 24, 443–451 (2023). https://doi.org/10.1007/s40257-023-00764-w.

2. King B, Zhang X, Harcha WG, et al. Efficacy and safety of ritlecitinib in adults and adolescents with alopecia areata: a andomized, double-blind, multicentre, phase 2b-3 trial. Epub 2023 Apr 14. Lancet. 2023 May 6;401(10387):1518-1529. doi: 10.1016/S0140-6736(23)00222-2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2823%2900222-2/fulltext

3. Lee H, Jung SJ, Patel AB, et al. Racial characteristics of alopecia areata in the United States. J Am Acad Dermatol. 2020;83:1064-1070. doi: 10.1016/j.jaad.2019.06.1300