## Janus kinase inhibitors for alopecia areata

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Brett A. King, MD, PhD, and Brittany G. Craiglow, MD

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Janus kinase (JAK) inhibitors have ushered in a new era in alopecia areata (AA). Historically, moderate-tosevere AA was refractory to treatment. JAK inhibitors have changed that; now, treatment of moderate-tosevere AA is possible. Here, we briefly review the history of and rationale for JAK inhibitor treatment of AA, phase 3 clinical trial data, and considerations regarding differences among JAK inhibitors, safety, and patient selection. ( J Am Acad Dermatol 2023;89:S29-32.)

Key words: alopecia; alopecia areata; alopecia totalis; alopecia universalis; baricitinib; deuruxolitinib; hair loss; JAK; JAK inhibitor; Janus kinase; Janus kinase inhibitor; ritlecitinib; ruxolitinib; tofacitinib.

### BACKGROUND

Alopecia areata (AA) is an autoimmune disease that causes hair loss. It is the second most common form of alopecia, usually causing round patches of alopecia and, less commonly, complete loss of all body hair. Moderate-to-severe AA is notoriously refractory to treatment.[1](#page-2-0)

In June 2014, we reported the first patient with AA successfully treated with the Janus kinase (JAK) inhibitor (JAKi) tofacitinib.[2](#page-2-1) Subsequently, open-label clinical trials, case series, and reports of tofacitinib and ruxolitinib supported use of JAKi for

From the Department of Dermatology, Yale School of Medicine, Yale University, New Haven, Connecticut.

Funding sources: Dr King received funding from the Poddar Fund to understand autoimmunity in alopecia areata.

Author Disclosures: Dr King has served on advisory boards and/or is a consultant and/or is a clinical trial investigator for AbbVie, AltruBio Inc, Almirall, AnaptysBio, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol-Myers Squibb, Concert Pharmaceuticals Inc, Equillium, Horizon Therapeutics, Eli Lilly and Company, Incyte Corp, Janssen Pharmaceuticals, LEO Pharma, Otsuka/Visterra Inc, Pfizer Inc, Regeneron, Sanofi Genzyme, TWi Biotechnology Inc, and Viela Bio and has been on speaker bureaus for AbbVie, Incyte, Eli Lilly, Pfizer, Regeneron, and Sanofi Genzyme. Dr Craiglow has served on advisory boards and/or is a consultant for Concert Pharmaceuticals, Eli Lilly, Pfizer, Regeneron, and Sanofi Genzyme and is on speaker bureaus for AbbVie, Eli Lilly, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.

Reviewer Disclosures: Kenneth Tsai, MD, PhD disclosed the following relevant relationship e Sun Pharmaceutical Industries AA. Industry-sponsored clinical trials followed and in June 2022, history was made with the first-ever Food and Drug Administration approval of a treatment for AA, baricitinib, followed a year later by the second one, ritlecitinib. Here, we briefly review JAKi treatment of AA.

### RATIONALE FOR JAKi TREATMENT OF AA

Immune activation and hair follicle attack in AA involves the cytokines interferon-gamma and interleukin-15.[3](#page-2-2)[,4](#page-2-3) Signaling by interferon-gamma and interleukin-15 requires JAK proteins; therefore, JAKis

Ltd. (Advisory Board/Fees). In accordance with the ACCME Standards for Integrity and Independence in Accredited Continuing Education, the American Academy of Dermatology has implemented mechanisms, prior to the planning implementation of this activity, to identify and mitigate conflicts of interest for all individuals in a position to control the content. IRB approval status: Not applicable.

Accepted for publication May 18, 2023.

<https://doi.org/10.1016/j.jaad.2023.05.049> Date of release: August 2023.

Expiration date: August 2026.

Correspondence to: Brett A. King, MD, PhD, Department of Dermatology, Yale School of Medicine, Yale University, PO Box 208059, New Haven, CT 06520. E-mail: [brett.king@yale.edu](mailto:brett.king@yale.edu), Twitter: [@Brett\\_King\\_](https://twitter.com/Brett_King_).

0190-9622/\$36.00

2023 Published by Elsevier Inc. on behalf of the American Academy of Dermatology, Inc.

modulate the activity of important drivers of AA, leading to hair regrowth.

### ORAL JAKis FOR AA

There are numerous publications of off-label use of JAKis for AA, usually of tofacitinib and, to a much lesser extent, ruxolitinib, because these were

**CAPSULE SUMMARY** 

treat.

Historically, moderate-to-severe alopecia

areata was notoriously refractory to

· Janus kinase inhibitors have changed

to-severe disease possible. Baricitinib

deuruxolitinib is advancing toward

and improving the care of patients.

approval, and drugs with novel

and ritlecitinib are approved,

this, making the treatment of moderate-

mechanisms of action are in clinical trials,

expanding our understanding of disease

approved in 2011-2012, several years ahead of other JAKis. Because neither of these medicines has been studied in large, randomized, controlled trials, data regarding their overall efficacy in AA are lacking.

To date, results of phase 3, randomized, controlled trials of 3 oral JAKis have been published and/or presented—baricitinib,5 ritlecitinib, and deuruxolitinib (CTP-543). Enrollment criteria and patient characteristics across these trials have been similar. Patients have $\geq$ 50% scalp

hair loss, with average scalp hair loss of 80% to 90%; approximately half of patients have nearcomplete or complete scalp hair loss (ie, alopecia totalis and alopecia universalis), and 60% to 70% of patients have involvement of eyebrows and about 60% to 70% of patients have involvement of eyelashes. The ritlecitinib trial was in patients aged 12 years and older while the trials of baricitinib and deuruxolitinib were in adults only.

### Baricitinib

In 2 trials of baricitinib,5 39% and 23% of patients treated with baricitinib 4 mg and 2 mg daily, respectively, achieved $\leq 20\%$ scalp hair loss during 36 weeks of treatment, and the majority of those patients achieved $\leq 10\%$ scalp hair loss. Approximately a third of patients with severe eyebrow loss achieved normal or near-normal eyebrows and, similarly, a third of patients with severe eyelash loss achieved normal or near-normal eyelashes during the 36-week period. Over an additional 16 weeks of treatment (52 weeks total), the proportion of patients achieving $\leq 20\%$ scalp hair loss continued to increase.

Baricitinib was the first medicine approved for treatment of adults with severe AA.

### Ritlecitinib

In a trial of ritlecitinib,6 23% of patients treated with ritlecitinib 50 mg daily achieved $\leq$ 20% scalp hair loss during 24 weeks of treatment, and the majority of

those patients achieved ≤10% scalp hair loss. Similar proportions of patients with any eyebrow involvement or any eyelash involvement achieved normal or near-normal eyebrows or eyelashes, respectively, during the 24-week period. Over an additional 24 weeks of treatment (48 weeks total), the proportion of patients achieving ≤20% scalp hair loss increased to 40%.

Ritlecitinib is approved for treatment of patients aged 12 years and older with severe AA.

### Deuruxolitinib

In a trial of deuruxolitinib,7 30% to 42% of patients treated with 2 doses of deuruxolitinib achieved $\leq$ 20% scalp hair loss during 24 weeks of treatment, the majority of whom achieved $\leq$ 10% scalp hair loss.

# TOPICAL JAKIS ARE INEFFECTIVE FOR

### **MODERATE-TO-SEVERE AA**

Although there are case reports of topical JAKi for AA, topical JAKi have not demonstrated efficacy in AA clinical trials of ruxolitinib 1.5% cream,8 delgocitinib ointment,9 or tofacitinib 2% ointment.10

### SAFETY OF JAKis IN AA

JAKis have a boxed warning for malignancy, infection, mortality, major adverse cardiovascular events, and thrombosis. The warning is a class warning born of a long-term safety study of tofacitinib in rheumatoid arthritis that was enriched in patients with baseline increased risk of these adverse events.11 At least in the case of baricitinib, for which there are data across rheumatoid arthritis, atopic dermatitis, and AA, the safety profile in AA (and atopic dermatitis) is favorable and better than in rheumatoid arthritis,12 supporting the notion that risk is different in different patient populations. Ultimately, the safety profile of different JAKis in AA will be assessed in clinical trials and, possibly, registries that follow patients long-term. Necessarily, when deciding if JAKi treatment is appropriate for any patient, potential risk factors such as smoking, obesity, hypertension, etc will need to be considered.

### JAKI SELECTIVITY AND EFFICACY IN AA

Different JAKis have selectivity for 1 or more of the 4 JAK enzymes (JAK1, JAK2, JAK3, and tyrosine

### Abbreviations used:

- AA: alopecia areata
- AD: atopic dermatitis JAK: Janus kinase
- JAK: Janus kinase JAKi: JAK inhibitor

kinase 2), and to some degree-likely much less than is commonly said-this selectivity impacts the efficacy and safety profile of individual drugs. Acknowledging the shortcomings of comparing data from different trials as well as notable differences between drugs and clinical trials (eg, ritlecitinib is not just a JAKi but also a TEC inhibitor, and there are only 24-week data for deuruxolitinib but 48- to 52-week data for the others), the efficacy of baricitinib (JAK1/2 inhibitor), ritlecitinib (JAK3/TEC inhibitor), and deuruxolitinib (JAK1/2 inhibitor) are not very different, which may suggest that JAKi selectivity is relatively unimportant to efficacy. Although only case reports, there is compelling evidence that failure of one JAKi does not predict failure of another JAKi.13

# WHEN TO CONSIDER JAKI TREATMENT OF AA, AND OPTIMIZING EFFICACY

Clinical trials of JAKis have involved adolescent and adult patients with 50% to 100% scalp hair loss (see above) whose current episode of severe hair loss is 6 months to 7 to 10 years. Certainly, in clinical practice treatment may also be considered when there is less severe scalp hair loss - such as when there is noticeable eyebrows/eyelashes involvement, disease that is refractory to treatment, significant psychosocial impact, and/or diffuse positive hair pull test14 - or when the current episode of severe hair loss is longer than 10 years.

Analyses from clinical trials have revealed 2 patient/disease characteristics that impact efficacy, sometimes dramatically. The first is the duration of current episode of severe disease, that is the amount of time a patient has had severe scalp hair loss. Treatment in the first 3 to 4 years of severe scalp hair loss greatly improves efficacy. The second characteristic is the presence of scalp hair, that is efficacy is much greater for patients who have some scalp hair at the time of treatment initiation than for those with near-complete or complete scalp hair loss.

It may be possible to enhance JAKi treatment responses with combination therapy. Building on earlier data showing that oral minoxidil 5 mg twice daily is sometimes effective as monotherapy for AA, there is limited data showing that JAKis in combination with oral minoxidil 2.5 to 5 mg once or twice daily increases treatment responses.15

### SUMMARY

JAKis have forever changed AA, providing the first two approved medicines, baricitinib and ritlecitinib, for severe AA, with not only other JAKis but hopefully other treatments with novel mechanisms of action to follow. These advances portend a bright future for patients.

### REFERENCES

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academic-industry collaborative effort. J Am Acad Dermatol. 2022;86(2):359-364. <https://doi.org/10.1016/j.jaad.2021.08.043>

15. Wambier CG, Craiglow BG, King BA. Combination tofacitinib and oral minoxidil treatment for severe alopecia areata. J Am Acad Dermatol. 2021;85(3):743-745. [https://doi.org/10.1016/j.](https://doi.org/10.1016/j.jaad.2019.08.080) [jaad.2019.08.080](https://doi.org/10.1016/j.jaad.2019.08.080)

Journal of the American Academy of Dermatology

publisher

articletitle

journaltitle

articlelink

content_type

copyright

Pfizer

Utility of azathioprine, methotrexate and cyclosporine as steroid-sparing agents in chronic alopecia areata: a retrospective study of continuation rates in 138 patients

J Eur Acad Dermatol Venereol

Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis

J Invest Dermatol

Lymphocytes, neuropeptides, and genes involved in alopecia areata

J Clin Invest

Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition

Nat Med

Two phase 3 trials of baricitinib for alopecia areata

N Engl J Med

Ruxolitinib cream for the treatment of patients with alopecia areata: a 2-part, double-blind, randomized, vehicle-controlled phase 2 study

J Am Acad Dermatol

A phase 2a randomized vehicle-controlled multi-center study of the safety and efficacy of delgocitinib in subjects with moderate-to-severe alopecia areata

Arch Dermatol Res

Tofacitinib 2% ointment, a topical Janus kinase inhibitor, for the treatment of alopecia areata: a pilot study of 10 patients

Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis

A review of safety outcomes from clinical trials of baricitinib in rheumatology, dermatology and COVID-19

Adv Ther

Less is more? Failure of one JAK inhibitor does not predict failure of another one in a patient with alopecia areata

Dermatol Ther

Development of the alopecia areata scale for clinical use: results of an academic-industry collaborative effort

Combination tofacitinib and oral minoxidil treatment for severe alopecia areata

Janus kinase (JAK) inhibitors have ushered in a new era in alopecia areata (AA). Historically, moderate-to-severe AA was refractory to treatment. JAK inhibitors have changed that; now, treatment of moderate-to-severe AA is possible. Here, we briefly review the history of and rationale for JAK inhibitor treatment of AA, phase 3 clinical trial data, and considerations regarding differences among JAK inhibitors, safety, and patient selection.

Janus kinase inhibitors for alopecia areata.

Janus kinase inhibitors for alopecia areata

Janus kinase inhibitors for alopecia areata

Clinical Summary

What was studied

Key findings

Study limitations

Clinical implications

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