Alopecia areata: light at the end of the tunnel

Alopecia areata (AA) has lacked effective treatment options for decades, and there is an unmet medical need for a reliable therapy in moderate-to-severe cases. With the approval of the first JAK inhibitor pending, there is a treatment for severe cases, “enfin”.

AA is a chronic relapsing inflammatory disorder characterised by a non-scarring hair loss on the scalp and/or body. “Being able to do something for these patients has been life-altering for them,” said Prof. Maryanne Senna (Harvard Medical School, MA, USA) [1]. Hair loss has important implications regarding self-image, attractiveness, desirability, youthfulness, and self-esteem. “There is an insufficient acceptance that hair loss is an important medical problem,” she said.

With a global prevalence of 2%, AA affects both sexes and has an initial onset typically before age 30. Around 10–20% of the patients will develop alopecia totalis. “In the US, until June 2022, no approved treatments for AA were available. Prior to this, we did not really have options for these patients,” Prof. Senna said.

2014-2022: An eight-year success story of JAK inhibitors

A breakthrough in therapy was a publication in 2014, where in a patient with plaque psoriasis, the oral JAK inhibitor tofacitinib reversed alopecia universalis [2]. “This set the wheels in motion,” Prof. Senna explained. But why are JAK inhibitors so successful? According to a simplified overview of AA pathogenesis, cytotoxic T cells penetrate the proximal anagen hair bulb and initiate an autoimmune attack in response to a still unrecognised antigen. Both CD8-positive and NKG2D-positive T-cells are the major effectors in AA pathogenesis. Cytokines involved in AA pathogenesis, including IFN-y and IL-15, activate signalling via the JAK-STAT pathway. Modulating the signalling at the point of JAKs decreases the inflammatory response. The recent FDA approval was the consequence of the positive results of the oral selective JAK1/2 inhibitor baricitinib in 2 phase 3 trials, BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) [3]. In these trials, participants had a Severity of Alopecia Tool (SALT) ≥50, and 44% had alopecia totalis at baseline. All 1,200 participants were randomised to once-daily placebo, 2 mg or 4 mg of baricitinib. At week 36, the primary endpoint, a SALT ≤20, was achieved overall by 38.8% (baricitinib 4 mg), 22.8% (baricitinib 2 mg), and 6.2% (placebo) participants in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. “A subgroup analysis revealed that those with very severe AA showed higher efficacy rates. It provides confidence that even in our most severe patients, we can have a response,” Prof. Senna commented. The most common adverse events were acne, increased creatine kinase, and elevations of LDL and HDL cholesterol. Notably, there was only 1 cardiovascular event, a case of myocardial infarction in a 44-year-old with multiple risk factors.

As Prof. Brett King (Yale University School of Medicine, CT, USA) emphasised in his virtual lecture on JAK inhibitors in AA, baricitinib also leads to a regrowth of eyebrow and eyelash hair [4]. “In severe AA, JAK inhibitors should be our first-line treatment option, and we have far more data than with all the other agents,” he said. Intralesional steroid injection is the mainstay of therapy for adults with limited disease (e.g. ≤20% scalp hair loss), but for severe AA, systemic therapy is warranted (see Figure).

Unfortunately, therapy with topical JAK preparations proved ineffective for the treatment of AA [5,6].

Figure: Alopecia areata treatment algorithm [4]



AA, alopecia areata; CS, corticosteroids.

Dupilumab: another star on the horizon

The story does not end with the JAK inhibitors. “An atopic background might also play a role in some of our patients,” Prof. Senna continued. A phase 2 trial published last year showed the efficacy of the IL-4/13 inhibitor dupilumab [7]. In this trial, 60 adult participants with SALT ≥50 were included and randomised to dupilumab or placebo. Among them, 38% had a history of atopic dermatitis (AD), 11% had active AD, 45% had a family history of AD, and 30% had total IgE levels ≥200 IU/mL. Interestingly, the effect of dupilumab differed according to the baseline IgE levels of the patients: 22.5% of those with IgE <200 reduced their scalp hair loss by 50% compared with 46.2% of those with baseline IgE ≥200. “Baseline IgE may aid in dupilumab treatment selection for AA patients,” Prof. Senna commented.

1. Senna M. Alopecia areata: treatments enfin! OS, SPIN 2022 Congress, 06–08 July, Paris, France.
2. Craiglow BG, King BA. J Invest Dermatol. 2014;134:2988-90.
3. King B, et al. N Engl J Med. 2022:386:1687-99.
4. King B. JAK inhibitors for the treatment of alopecia areata. FS4, SPIN 2022 Congress, 06–08 July, Paris, France.
5. Olsen E, et al. J Am Acad Dermatol. 2020;82:412-9.
6. Mikhaylov D, et al. Arch Dermatol Res. 2022 [online ahead of print].
7. Guttman-Yassky E, et al. 2022:77:897-906.

 

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Posted on 26 August 202217 May 2024