Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata

Abstract

Background: Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined.

Methods: This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome.

Results: Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment.

Conclusions: At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease.

Trial registration: ClinicalTrials.gov NCT02197455 and NCT02312882.

Funding: This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

Figures

Figure 1. Seventy patients were enrolled in the trial, of which 68 received medication.

Two patients dropped out of the trial prior to receiving medication due to inability to attend trial visits. Two additional patients withdrew from the study prior to completing 3 months of tofacitinib citrate.

Figure 2. Clinical response and associations.

(A) Distribution of percentage change in SALT score for all patients: 24 patients (36%) were nonresponders (NRs) with percentage change in SALT score below 5%, 21 patients (32%) were intermediate responders (IRs) with percentage change in SALT score between 5% and 50%, and 21 patients (32%) were strong responders (SRs) with percentage change in SALT score >50%. (B) The median percentage change in SALT score was 23.7% (range, 0%–94.4%) for men (n = 35) and 13.9% (range, 0%–91.4%) for women (n = 31), but the difference between groups was not significant (P = 0.2256) according to the Wilcoxon rank-sum test. (C) There was a difference in median percentage change in SALT score based on subtype: AA (70.0%, n = 11), ophiasis (68.0%, n = 3), AT (11.8%, n = 6), and AU (10.5%, n = 46) (P = 0.0024) based on the Wilcoxon rank-sum test. (D) There was a significant negative correlation, as measured by Spearman correlation test, between duration of current episode of AA and percentage change in SALT score (–0.35559, P = 0.0034). (E) Principal component analysis of genome-wide RNA sequencing demonstrated that the pretreatment signature of SRs with more longstanding disease (SR >20 years) more closely matched that of SRs with less longstanding disease (SR <10 years) rather than the disease duration-matched NRs (NR >20 years). (F) Peribulbar inflammation was seen on initial scalp biopsy in 23 of 28 patients and corresponded to a median percentage change in SALT score of 32.9% (range, 1.2%–87.4%) compared with 5 of 28 patients without peribulbar inflammation with median percentage change in SALT score of 1.2% (range, 0%–65%), which was not found to be significant (P = 0.0512) based on the Wilcoxon rank-sum test. In B, C, and F, lines denote median, and error bars denote 95% confidence interval.

Figure 3. Association of disease response and inflammation.

(A) A representative nonresponder had minimal peribulbar inflammation on initial scalp biopsy (original magnification, ×4 [top], ×10 [bottom]). Histopathology with hematoxylin and eosin stain was performed for all 28 patients who consented to scalp biopsy submission for histopathology. (B) Representative nonresponder with SALT score of 100 prior to treatment and (C) 100 at 3 months. (D) A representative strong responder displayed brisk peribulbar lymphocytic infiltrate on initial scalp biopsy (original magnification, ×10 [top], ×20 [bottom]), and (E) immunofluorescence of pretreatment scalp biopsy demonstrated strong follicular staining for STAT3 (red), (F) which was diminished after 2 months of tofacitinib (original magnification ×10 [top], ×63 [bottom]). Immunofluorescence for STAT3 was performed on 3 randomly selected strong responders and 3 randomly selected nonresponders. (G) The representative strong responder had a SALT score that decreased from 100 prior to treatment (H) to 13 at 3 months. Immunofluorescence: red = pSTAT3, green = β4-integrin, gray = DNA.

Figure 4. Heatmap of alopecia areata disease activity index gene Z scores in scalp biopsies of strong responders (n = 9) at baseline and week 8 and nonresponders (n = 9) at baseline and week 8.

Figure 5. Unsupervised biomarker signature predicting nonresponse to tofacitinib.

(A) Differences between patient-paired samples revealed the existence of 2 subclusters of nonresponders. One of these subclusters had a molecular behavior similar to that in the SR group, and the other had a molecular behavior discordant with response. This was used to partition the nonresponders into presumptive slow responders, who may eventually respond to treatment and are simply delayed, and likely true nonresponders, who exhibit no indication of improvement at a molecular level. Unsupervised hierarchical clustering of the tofacitinib patients using the “slow responder versus nonresponder” gene signature is shown. This gene signature was derived from the top 50 most differentially expressed genes when comparing true nonresponders and slow responders (P < 0.05). The clustering demonstrates that the signature is capable of robustly separating molecular true nonresponders (red patients, n = 8) from slow responders (orange patients, n = 11), which in turn segregated with the molecular true responders (blue patients, n = 9). White lines are superimposed as a visual aid to demarcate the primary superclusters in both gene and sample clustering. (B) A 3-dimensional representation of the first 3 principal components underlying the clustering results provides a spatial representation of the molecular divergence between patients based on predicted molecular response. The true nonresponders (red spheres, n = 8) segregate from a second cluster consisting of a mix of true responders (blue spheres, n = 9) and slow responders (orange spheres, n = 11).