Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism

To the Editor: Alopecia areata (AA) is a prevalent (approximately 1.7% lifetime risk) disease.1 Although it has a large effect on patients' quality of life and poses a large economic burden, treatment options for patients with AA are limited.2,3 For more extensive alopecia forms, such as total scalp (totalis) or body (universalis) AA, for which spontaneous regrowth is rare,1 immunosuppressants (systemic corticosteroids, cyclosporine A, and Janus kinase inhibitors) have shown some efficacy but are associated with side effects that preclude long-term use.2,3 Furthermore, hair loss recurs shortly after cessation of treatment.3 Cytokines driving hair loss are not well understood,1 hindering the targeted therapeutic development seen with other skin diseases.4 Our recent study in a well-characterized group of 27 patients with AA associated the AA signature with robust TH2 and IL-23p19 and IL-23/IL-12p40 activation in addition to the TH1 skewing that has been the previous focus.5,6 This provides a rationale for exploring cytokine-targeted therapeutics in patients with AA, which are approved or tested for psoriasis or atopic dermatitis.4 Our data show a large and significant increase in IL-12/IL-23p40 cytokine levels in scalp from patients with lesional AA versus normal scalp.5 Ustekinumab, an IL-12/IL-23p40 blocker that is US Food and Drug Administration approved for psoriasis, induces high-grade improvement in 70% to 80% of patients with psoriasis.4 Here we show that ustekinumab has impressive ability to improve hair growth in patients with extensive AA. Substantial TH2 downregulation was observed in the 2 patients with dramatic clinical improvement, whereas all patients had reduction of PDE gene expression (Fig 2, C). Because PDE genes were significantly upregulated at baseline and downregulated with treatment, a PDE score might also provide insights into disease resolution with treatment.