Ruxolitinib For Alopecia Areata

This academic Alopecia Areata clinical study by Columbia University, has finally been released in full to the public.  I highlighted what I believe are the important points to consider regarding this study.  The complete study can be found here JCI.  

Abstract

BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA.

METHODS. We initiated an open-label clinical trial of 12 patients with moderate-to-severe AA, using oral ruxolitinib, 20 mg twice per day, for 3–6 months of treatment followed by 3 months follow-up off drug. The primary endpoint was the proportion of subjects with 50% or greater hair regrowth from baseline to end of treatment.

RESULTS. Nine of twelve patients (75%) demonstrated a remarkable response to treatment, with average hair regrowth of 92% at the end of treatment. Safety parameters remained largely within normal limits, and no serious adverse effects were reported. Gene expression profiling revealed treatment-related downregulation of inflammatory markers, including signatures for CTLs and IFN response genes and upregulation of hair-specific markers.

CONCLUSION. In this pilot study, 9 of 12 patients (75%) treated with ruxolitinib showed significant scalp hair regrowth and improvement of AA. Larger randomized controlled trials are needed to further assess the safety and efficacy of ruxolitinib in the treatment of AA.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01950780.

FUNDING. Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award (CUMC CTSA).

Introduction

Alopecia areata (AA) is a major medical problem and is among the most prevalent autoimmune disease in the US, with a lifetime risk of 1.7% (1). AA affects both sexes across all ethnicities and represents the second most common form of human hair loss, second only to androgenetic alopecia (2). AA usually presents with patchy hair loss. One-third of these patients will experience spontaneous remissions within the first year. However, many patients’ disease will progress to alopecia totalis (AT, total scalp hair loss) or alopecia universalis (AU, loss of all body hair). Persistent moderate-to-severe AA causes significant disfigurement and psychological distress in affected individuals (3). In clinical practice, there are no evidence-based treatments for AA (4), yet various treatments are offered, most commonly topical and intralesional steroids, which have limited efficacy.

Our recent mechanistic studies demonstrated a dominant role for type I cellular immunity in AA pathogenesis, mediated by IFN-γ–producing NKG2D-bearing CD8+ cytotoxic T lymphocytes (CTLs) (5). The central role of type I cellular immunity is also reflected in the transcriptional landscape of AA lesional skin in humans and mice, which is dominated by IFN response genes and a CTL signature. These findings provided the rationale for therapeutically targeting JAK1/2 kinases in AA, and, indeed, we showed that treatment with JAK inhibitors reversed AA in C3H/HeJ mice and eliminated the type I inflammatory response in the skin (6).

On the basis of our preclinical findings, we initiated a phase II efficacy signal-seeking clinical trial in moderate-to-severe AA, assessing the clinical and immunopathological response to treatment with oral ruxolitinib, a JAK1/2 inhibitor currently FDA approved for the treatment of myeloproliferative disorders.

Results

Efficacy. This study was an open-label clinical trial to investigate ruxolitinib (Jakafi, Incyte Pharmaceuticals), 20 mg orally twice daily, in the treatment of moderate-to-severe AA (Table 1 and Figure 1A). All patients received ruxolitinib for 3–6 months, followed by a 3-month observational phase to assess treatment response durability.

Figure 1

Hair regrowth during and following discontinuation of ruxolitinib treatment. (A) Patient enrollment flow chart. (B) Severity of alopecia tool (SALT) scores for individual patients during (solid lines) and following cessation of (dashed lines) ruxolitinib treatment. (C) Percentage regrowth for individual patients during and following cessation of ruxolitinib treatment. (D) Predicted (black lines) and actual patient regrowth trajectories (blue lines) from regression models presented in Supplemental Table 1.

Table 1

Demographic and treatment time variables overall and by responder status

Nine of twelve patients (75%) had significant hair regrowth and achieved the primary outcome of at least 50% regrowth (Table 2). The mean baseline severity of alopecia tool (SALT) score of 65.8% ± 28.0% decreased to a score of 24.8% ± 22.9% at 3 months and to a score of 7.3% ± 13.5% at the end of 6 months of treatment (P < 0.005, Table 2). As a group, the responders exhibited a 92% reduction in hair loss from baseline (Figure 1, B–D;Figure 2; and Supplemental Table 1; supplemental material available online with this article; doi:10.1172/jci.insight.89790DS1), with 7 of the 9 responders achieving over 95% regrowth by end of treatment.

Figure 2

Clinical photographs of responder AA patients on ruxolitinib. Pairs of photographs for subjects 1, 2, 3, 4, 8, 9, 10, 11, and 12 are shown as labeled. Photographs labeled “a” in each pair were taken at baseline, and those labeled “b” were taken at the end of treatment with ruxolitinib.

Table 2

Description of variables at baseline and end of treatment, among all subjects, responders only, or nonresponders only

Regrowth was seen in responders as soon as 4 weeks after study medication was initiated and initially presented as variably subtle patchy areas of regrowth, consisting of pigmented terminal hairs, with the exception of one patient (subject 4) with concurrent vitiligo, who exhibited primarily gray hair regrowth. Of note, the areas of vitiligo in this patient were also noted to improve with ruxolitinib treatment (7). Hair regrowth for all responders increased steadily, with substantial increases each month, resulting in the majority (8 of 9) of responders achieving at least 50% regrowth by the week 12 visit. Responding patients with evidence of regrowth at 3 months continued treatment until they had either achieved 95%–100% regrowth or completed 6 months of treatment.

Durability of responses was assessed in the 3-month follow-up period off treatment. Three of nine responders noted shedding, beginning at week 3 following ruxolitinib discontinuation, and had marked hair loss at week 12 off drug (Supplemental Figure 1); however, hair loss did not reach baseline levels (Figure 1, B and C). Six of nine responders reported increased shedding without major hair loss.

Biomarker and clinical correlative studies. Gene expression profiling was performed on skin biopsies taken at baseline and following 12 weeks of treatment, with additional optional biopsies performed earlier in the treatment course. Baseline scalp samples exhibited a distinct gene expression profile when compared with samples taken from unaffected patients (Figure 3Aand Supplemental Table 2). Following ruxolitinib treatment, gene expression profiles of AA patient scalp samples clustered more closely with healthy control scalp samples than with baseline AA samples (Figure 3B), indicating global normalization of the AA pathogenic response. Gene expression profiles attributed to the IFN, CTL, and hair keratin (KRT) signatures were assessed in the trivariate AA disease activity index (ALADIN, Figure 3C), a summary index of the AA pathogenic inflammatory response and hair regrowth (8). Importantly, eventual AA responders clustered together on the ALADIN matrix at baseline, sharing high IFN and CTL scores (Figure 3, C and D).

Figure 3

Biomarkers based on skin gene expression correlate with clinical response. (A) Heatmap and clustering dendrogram of samples from patients at baseline (nresponders = 9,nnonresponders = 2) and week 12 of treatment (nresponders = 9, nnonresponders = 1) and healthy controls (n = 6) using differentially expressed genes between baseline responder and healthy control samples (Supplemental Table 2). Black, normal subjects; red, AA responder patient at baseline; purple, AA responder patient after 12 weeks treatment; yellow, AA nonresponder patient at baseline; blue, AA nonresponder patient after 12 weeks treatment. (B) Principal components plots of samples taken from subjects at 12 weeks after treatment and at baseline. Principal components are labeled PC1, PC2, and PC3. (C) Heatmap of AA disease activity index (ALADIN) genes. (D) Three-dimensional plot of ALADIN signatures. (E) ALADIN component signature scores. Left panel, cytotoxic T lymphocyte (CTL) signature scores; middle panel, IFN signature scores; right panel, hair keratin (KRT) signature scores. R, responders; NR, nonresponders; HC, healthy controls. *P < 0.05, **P < 0.01, ***P <0 .001.="" 0="" 12="" and="" by="" compare="" compared="" followed="" kruskal-wallis="" ranked-sum="" samples.="" samples="" signed-rank="" strong="" style="box-sizing: inherit;" test.="" test="" the="" to="" used="" using="" was="" week="" were="" wilcoxon="">F

Adverse events. Ruxolitinib was well tolerated and safely administered in all 12 patients. There were no serious adverse effects, and no patients required discontinuation of therapy.Observed adverse effects were infrequent and included 3 minor bacterial skin infections (in the same patient), 9 episodes of upper respiratory tract infection/allergy symptoms in 7 patients, 1 urinary tract infection, 1 case of mild pneumonia, 1 conjunctival hemorrhage following a surgical procedure, and mild gastrointestinal symptoms. One patient developed lowered hemoglobin, which resolved with dose modification. 
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