Transient Efficacy of Tofacitinib in Alopecia Areata Universalis.

Introduction
Alopecia areata (AA), a nonscarring type of hair loss, is the most prevalent autoimmune disease, with a lifetime prevalence of 1.7% [1, 2]. Men and women are equally affected, and onset of the disease can occur at any age; however, most cases start before the age of 30 [3]. Fifty percent of children and adolescents with AA suffer from depression [4]. Autoimmune diseases such as vitiligo, thyroid disease and atopic diseases have been associated with AA [5]. The genetic architecture has also been described [6]. A high concordance rate among monozygotic twins was reported [7, 8], and a positive family history is linked to AA [9, 10, 11]. Additionally, human leukocyte antigen (HLA)-DQB1, HLA-DRB1, HLA-A, HLA-B, HLA-C and also the genes NOTCH4, MICA, PTPN22 and AIRE were found to be associated with AA [2, 12]. The first genome-wide association study found 8 loci (table 1) with genome-wide significance containing multiple genes involved in the adaptive T cell-driven immune response [2]. The current view is that both genetic and immune factors contribute to the development of AA (fig. 1). In addition, much less well-defined environmental and psychologic elements are sure to have some influence as well.
A Cochrane review analyzing 17 randomized controlled trials concluded that there is currently no effective evidence-based treatment for AA. Even though topical minoxidil, cyclosporine, corticosteroids (as well as systemic corticosteroids) and photodynamic therapy are used, there is no firm evidence of superiority compared to placebo [13]. However, in daily clinical use, all these drugs are used with apparent success. Recently, Suarez-Farinas et al. [14] performed microarray and RT-PCR of 27 lesional and 17 nonlesional samples of patients with AA. It was shown that TH1, TH2, and IL-23 cytokine were increased, while TH17/TH22 skewing was lacking [14]. Additionally, also ustekinumab, a monoclonal IL-12/23 inhibitor, is of interest as a potential treatment of AA. There have been case reports that ustekinumab causes AA [15, 16, 17], but in contrast, successful treatments with significant increase of hair growth were reported [18, 19].
The possibility of reversal of AA by Janus kinase (JAK) inhibitors was successfully shown in the murine model [20]. Additionally, Craiglow and King [21] published a case of a 25-year-old patient with psoriasis vulgaris and alopecia universalis, a type of AA in which complete loss of hair of the entire body is observed. After treatment with tofacitinib, a JAK1/3 inhibitor approved for the treatment of rheumatoid arthritis, complete regrowth of hair was observed [21]. Also, one case from Germany responded well to tofacitinib (U. Mrowietz, personal communication). In another case report, 3 patients suffering from AA were successfully treated with ruxolitinib, a JAK1/2 inhibitor approved for myelofibrosis [20].

Case
A 51-year-old businessman with alopecia universalis presented to our clinic. His past medical history revealed a bilateral chronic retinal vasculitis and uveitis, for which he had been treated in the past with various drugs such as methotrexate, azathioprine, oral prednisolone and infliximab. Two years before, while receiving infliximab and azathioprine, sudden loss of hair had occurred on the temples, and drug-induced AA was suspected. Even though the drug treatment was stopped, the AA worsened. Four months later, the retinal vasculitis showed progression of disease as well, so infliximab and azathioprine were started again. A dermatologic consultation was sought. Subsequently, treatment with topical and oral steroids, followed by topical diphenylcyclopropenone as well as oral methotrexate (up to 30 mg per week) was initiated. However, no regrowth of hair was observed after 6 months.
Upon his first consultation in our clinic, a skin biopsy was performed on the scalp. A biopsy confirmed sparse lymphocytic infiltrates along nonsclerotic fibrous tracts extending along the site of previous follicles. The diagnosis of a nonfibrosing AA was confirmed. Compassionate use of tofacitinib 5 mg twice daily was initiated. Methotrexate was continued at 15 mg per week. The scalp remained unchanged for 2 months (fig. 2a), but after 3 months of treatment, growth of short terminal pigmented hair was detected (fig. 2b). These, however, disappeared again within a single month, resulting in renewed complete alopecia (fig. 2c).

Discussion
The efficacy of tofacitinib has been suggested by murine experiments and by one case presentation [20, 21]. Tofacitinib citrate (Xeljanz®) abrogates IL-15 signaling [22] and thus mediates IL-15 activation of lymphocytes [14]. Even though the initial clinical results were promising, the efficacy of tofacitinib waned again in our patient. This was even more striking when considering that the patient had additional immunosuppression by methotrexate for his retinal vasculitis. Notably, methotrexate monotherapy has been shown to be a safe treatment option for AA as well [15]. Another potential reason for treatment failure could have been the presence of antibodies specific for hair follicles [23, 24]; however, we were unable to measure and rule them out.
The clinical observation in this patient could be interpreted as follows: suppression of AA by tofacitinib is an active process that, if too weak, may not tip the balance towards stable hair regrowth but instead allow a reversion to a completely alopecic state. Although here we report only on a single case with all its limitations, it will be interesting to analyze the outcome of randomized clinical trials, especially in patients not showing efficacy to tofacitinib. Also, our observation may prompt the question whether combinations of immunosuppressive drugs potentiate or inhibit each other in AA.

Statement of Ethics
The authors state that the patient gave informed consent to have his photographs published.

Disclosure Statement
F.A. is funded by a HSM2 (Hochspezialisierte Medizin) grant awarded by the Kanton of Zurich, Switzerland. A.A.N. is funded by the Promedica and Bruno-Bloch Foundation.