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Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers

Year: 2016

Type: article

Abstract: Alopecia areata (AA) is a highly prevalent autoimmune disease in the United States with a lifetime risk of 1.7%. However, AA remains a significant unmet need in dermatology, and treatments are lacking. Janus kinase inhibitors are emerging as potential therapies for many autoimmune conditions, including most recently AA 1, 2. We report a patient who was treated with oral tofacitinib citrate, a preferential JAK3/JAK1 inhibitor, for AA, resulting in significant hair regrowth and concurrent skin and blood biomarker changes. We hypothesized that effective tofacitinib treatment of alopecia areata would be accompanied by changes in expression of AA-associated genes in skin as well as circulating serum CXCL10 levels. Punch biopsies were taken at baseline and after four weeks of treatment. Total RNA was extracted, reverse-transcribed, amplified, biotinylated and then hybridized to Human U133 Plus 2.0 gene chips (Affymetrix, Santa Clara, CA) as previously described 3. ALADIN scores were calculated as previously described relative to healthy controls at baseline 3. Serum from blood draws taken prior to the initiation of tofacitinib treatment and after four weeks of treatment were assayed for CXCL10 levels using the Human IP-10/CXCL10 ELISA kit (Sigma-Aldrich, St. Louis, MO) according to the manufacturer's instructions. A 40-year-old Caucasian woman with persistent moderate/severe AA was enrolled in our open-label pilot study to test the efficacy of oral tofacitinib for AA (https://clinicaltrials.gov/NCT02299297). Her AA began on her scalp 5 years prior to enrolment and resolved completely within 1 year in the setting of pregnancy. A few months after delivery, her AA recurred as patchy disease. Treatment with topical corticosteroids, anthralin cream and intra-lesional corticosteroids was of limited benefit. Her AA progressed to involve all extremities, eyelashes and eyebrows with patchy scalp involvement and remained stable until her enrollment into the clinical trial (Fig. 1). Her past medical history was unremarkable, and she denied a family history of AA. The patient began treatment with tofacitinib 5 mg twice daily. Patchy regrowth was noted at month 1. After two and three months of treatment, she had scalp hair regrowth of 62.5% and 94%, respectively. Significant regrowth of her eyebrows and eyelashes was noted. Scalp hair regrowth was nearly complete 4 months after initiating treatment (Fig. 1). There were no adverse events reported and no laboratory abnormalities in her complete blood count, complete metabolic panel or lipid profile. Cessation of treatment with tofacitinib resulted in near-complete hair loss (Fig. S1). Punch biopsies of the scalp (Fig. S2) and blood draws were performed at baseline and after 4 weeks of treatment to monitor gene expression and biomarker changes. Serum levels of CXCL10, an interferon (IFN)-induced chemokine found at high levels in AA skin 3, decreased after 4 weeks of treatment (Fig. S2). In addition, microarray analysis was performed on the skin biopsy samples. Based on the AA Disease Activity Index (ALADIN) 3, the patient exhibited high IFN and cytotoxic T lymphocyte (CTL) signatures at baseline that decreased by 4 weeks of treatment, although not to the level of normal controls (Fig. S2). Alopecia areata is an autoimmune disease with strong associations with genetic loci in close proximity to genes with immune functions 4. Targeting candidate immune pathways that may be contributing to disease pathogenesis is an active area of investigation 5, and JAK inhibitors target multiple immune signalling pathways involved in AA. We have previously shown systemic and topical tofacitinib to be effective in preventing the development of AA, as well as reversing established AA, in the graft model of AA in C3H/HeJ mice 3. We report here effective treatment of a human subject with persistent patchy AA, correlating with a diminished ALADIN profile compared to baseline. Larger clinical studies are needed to assess the safety, efficacy and durability of tofacitinib and other JAK inhibitors in the treatment of AA and to correlate response to biomarkers identified for AA. JAK inhibitors are a promising class of drugs for treatment of AA; however, further work is needed to determine optimal dose and administration regimens to generate durable responses. See Supporting information file (contains Figures S1 and S2 also) for Acknowledgements. A Jabbari, N Nguyen, J Cerise, G Ulerio, A de Jong and J Mackay-Wiggan performed the research. A Jabbari, N Nguyen, J Cerise, G Ulerio, A de Jong, J Mackay-Wiggan, R Clynes and A Christiano designed the research study. A Jabbari, N Nguyen, J Cerise, G Ulerio, A de Jong and J Mackay-Wiggan analysed the data, and A Jabbari, N Nguyen and J Mackay-Wiggan wrote the manuscript. The authors have declared no conflicting interests. Data S1. Acknowledgement. Figure S1. Hair loss recurrence following cessation of oral tofacitinib treatment. Figure S2. Scalp biopsy specimens from an alopecia areata patient treated with oral tofaicitinib. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Source: Experimental Dermatology

DOI: 10.1111/exd.13060