Development of the alopecia areata scale for clinical use: Results of an academic-industry collaborative effort.

BACKGROUND: The current classification for alopecia areata (AA) does not provide a consistent assessment of disease severity. OBJECTIVE: To develop an AA severity scale based on expert experience. METHODS: A modified Delphi process was utilized. An advisory group of 22 AA clinical experts from the United States was formed to develop this AA scale. Representatives from the pharmaceutical industry provided feedback during its development. RESULTS: Survey responses were used to draft severity criteria, aspiring to develop a simple scale that may be easily applied in clinical practice. A consensus vote was held to determine the final AA severity statement, with all AA experts agreeing to adopt the proposed scale. LIMITATIONS: The scale is a static assessment intended to be used in clinical practice and not clinical trials. CONCLUSION: The final AA disease severity scale, anchored in the extent of hair loss, captures key features commonly used by AA experts in clinical practice. This scale will better aid clinicians in appropriately assessing severity in patients with this common disease.

High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata.

Alopecia areata (AA) is an autoimmune disease in which cytotoxic T cells specifically target growing hair follicles. We used high-throughput TCR sequencing in the C3H/HeJ mouse model of AA and in human AA patients to gain insight into pathogenic T cell populations and their dynamics, which revealed clonal CD8+ T cell expansions in lesional skin. In the C3H/HeJ model, we observed interindividual sharing of TCRß chain protein sequences, which strongly supports a model of antigenic drive in AA. The overlap between the lesional TCR repertoire and a population of CD8+NKG2D+ T cells in skin-draining lymph nodes identified this subset as pathogenic effectors. In AA patients, treatment with the oral JAK inhibitor tofacitinib resulted in a decrease in clonally expanded CD8+ T cells in the scalp but also revealed that many expanded lesional T cell clones do not completely disappear from either skin or blood during treatment with tofacitinib, which may explain in part the relapse of disease after stopping treatment.

Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Aberrant hedgehog signalling underlies the development of basal-cell carcinomas. We previously reported the interim analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial in patients with the basal-cell nevus (Gorlin) syndrome indicating that the smoothened inhibitor vismodegib reduces basal-cell carcinoma tumour burden and prevents new basal-cell carcinoma growth in patients with basal-cell nevus syndrome. We report the final results of this 36 month trial. METHODS: In our multicentre, randomised, double-blind, placebo-controlled, phase 2 trial we enrolled patients aged 35-75 years with basal-cell nevus syndrome with at least ten surgically eligible basal-cell carcinomas at the Children's Hospital Oakland, Columbia University outpatient dermatology clinic (NY, USA) and a private practice outpatient dermatology office in Newport Beach (CA, USA). Patients were assigned to vismodegib or placebo (2:1) according to a randomisation sequence generated by computer code. The primary endpoint of the trial of 41 patients was to compare the effect of oral vismodegib (150 mg/day) versus placebo on the incidence of new surgically eligible basal-cell carcinomas after 3 months of treatment. In the subsequent, open-label phase (n=37) patients continued vismodegib at two sites for as long as month 36 (n=25) and at the third site were monitored up to month 36 (n=12). Additional endpoints for this phase were: whether continuous versus interrupted dosing differentially affected tumour burden; time to reach various levels of reduction in tumour burden; reduction in tumour size in patients who took less than 50% of the expected number of vismodegib tablets; reduction in the number of surgical excisions required per year before, during, and after treatment; and the effect of vismodegib on hedgehog target gene expression. We monitored patients at visits every 3 months for up to 36 months. The primary endpoint was analysed on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00957229. FINDINGS: Between Sept 22, 2009, and Jan 24, 2011, 41 patients were monitored for a median of 36 months (IQR 36-36). Patients treated with vismodegib (n=26) had a mean reduced rate of new surgically eligible basal-cell carcinomas compared with patients randomly assigned to placebo (n=15; two [SD 0·12] new surgically eligible basal-cell carcinomas per patient per year vs 34 [1·32] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). In the 11 patients initially assigned to placebo, mean cross over to vismodegib reduced the development of new surgically eligible basal-cell carcinomas compared with placebo (0·4 [SD 0·2] new surgically eligible basal-cell carcinomas per patient per year vs 30·0 [7·8] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). Only three (17%) of 18 patients tolerated vismodegib continuously for the full 36 months. Fewer new surgically eligible basal-cell carcinomas developed in patients receiving vismodegib continuously than in those who interrupted dosing (mean 0·6 [0·72] new surgically eligible basal-cell carcinomas per patient per year vs 1·7 [1·8] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). Treatment-related grade 3-4 adverse events included weight loss of 20% or more (n=6) and muscle cramps (n=2). Two patients died during the course of the trial, one each from laryngeal and metastatic prostate cancer, deemed probably unrelated to drug. INTERPRETATION: Vismodegib reduces basal-cell carcinoma tumour burden in patients with basal-cell nevus syndrome. Adverse events associated with vismodegib frequently led to interruption of treatment, which is followed by basal-cell carcinoma recurrence. FUNDING: Genentech investigator-initiated trial funding, Clinical and Translational Science Award from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, Damon Runyon Cancer Research Foundation Clinical Investigator Award, Swim across America Foundation, and Michael J Rainen Family Foundation.

Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.

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).

Molecular signatures define alopecia areata subtypes and transcriptional biomarkers.

Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis.

From Targets to Treatments: Bridging Autoimmune Research to Advance Understanding of Alopecia Areata.

Alopecia areata is a common autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body that affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation (NAAF) is a nonprofit organization that supports research to find a cure or acceptable treatment for alopecia areata, supports those with the disease, and educates the public about alopecia areata. NAAF conducts research summits every 2 years that are central to achieving the goals of a major strategic initiative, the Alopecia Areata Treatment Development Program, which are: to accelerate progress toward a safe, effective, affordable treatment or a cure for alopecia areata. These summits have played a key role in transforming the understanding of alopecia areata from largely inflammatory and dermatological perspectives to a focus on the genetic and immunological factors that are now recognized as driving and active determinants of the disease process.

Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.

Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.

Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.

Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8(+)NKG2D(+) T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing CD8(+)NKG2D(+) effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor ß (IL-15Rß) prevented disease development, reducing the accumulation of CD8(+)NKG2D(+) T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.

Basal cell carcinoma: an evidence-based treatment update.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer. Surgical excision remains the standard of treatment, but several alternative treatment modalities exist. OBJECTIVES: This review aims to provide a current analysis of evidence for the treatment of BCC; specifically, which treatments have the lowest recurrence rates and the best cosmetic outcomes. METHODS: We searched PubMed (January 1946 to August 2013), Ovid MEDLINE (2003-August 2013), the Cochrane Central Register of Controlled Trials (January 1993 to August 2013), and the Cochrane Database of Systematic Reviews (The Cochrane Library Issue 9, 2013) databases for randomized controlled trials, systematic reviews, or comparative studies for the treatment of BCC. RESULTS: We found 615 potential articles. Two independent reviewers selected 40 studies: 29 randomized controlled trials (RCTs), seven systematic reviews, and four nonrandomized prospective trials. Treatment modalities reviewed include surgical therapy, radiotherapy and cryotherapy, photodynamic therapy (PDT), topical imiquimod, topical 5-fluorouracil (5-FU), topical solasodine glycoalkaloids, topical ingenol mebutate, intralesional 5-FU, intralesional interferon (IFN), and oral hedgehog pathway inhibitors. CONCLUSIONS: The available data suggest that surgical methods remain the gold standard in BCC treatment, with Mohs micrographic surgery typically utilized for high-risk lesions. Suitable alternate treatment options for appropriately selected primary low-risk lesions may include PDT, cryotherapy, topical imiquimod, and 5-FU. Radiotherapy is a suitable alternate for surgical methods for treatment in older patient populations. Electrodesiccation and curettage (ED&C) is a commonly used primary treatment option for low-risk lesions; however, there were no RCTs examining ED&C that met our inclusion criteria. New hedgehog pathway inhibitors are promising for the management of advanced BCC; however, side effects are a concern for some patients, and much remains to be learned regarding optimal treatment length, risk of recurrence, and potential development of resistance. There is insufficient evidence at present to make recommendations on topical solasodine glycoalkaloids, topical ingenol mebutate, and intralesional 5-FU and IFN-α. Overall continued research on the efficacy of treatment modalities is needed. In particular, studies should include histologic ascertainment of clearance, long-term follow-up, stratification based on tumor subtype, and comparison with surgical outcomes.

The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome.

IMPORTANCE: Keratocystic odontogenic tumors (KCOTs) of the jaw affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog signaling pathway. OBSERVATIONS: We examined the effect of vismodegib (an oral Hedgehog pathway inhibitor) on KCOT size in patients with BCNS enrolled in a clinical trial testing vismodegib for basal cell carcinoma prevention (NCT00957229), using pretreatment and posttreatment magnetic resonance imaging. Four men and 2 women had pretreatment KCOTs (mean longest diameter, 2.0 cm; range, 0.7-3.3 cm), occurring primarily in the mandible. Patients were treated with vismodegib, 150 mg/d, for a mean (SD) of 18.0 (4.8) months (range, 11-24 months). Four patients experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all patients by 1.0 cm (95% CI, 0.03-1.94; P = .02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development. CONCLUSIONS AND RELEVANCE: Vismodegib shrinks some KCOTs in patients with BCNS and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.

Tazarotene: randomized, double-blind, vehicle-controlled, and open-label concurrent trials for basal cell carcinoma prevention and therapy in patients with basal cell nevus syndrome.

Sporadic human basal cell carcinomas (BCC) are generally well managed with current surgical modalities. However, in the subset of high-risk patients predisposed to developing large numbers of BCCs, there is an unmet need for effective, low-morbidity chemoprevention. This population includes fair-skinned patients with extensive sun exposure and those with genodermatoses such as the basal cell nevus (Gorlin) syndrome (BCNS). Tazarotene (Tazorac, Allergan) is a topical retinoid with relative specificity for RAR-ß and RAR-γ receptors. We previously demonstrated tazarotene's robust anti-BCC efficacy in Ptch1(+/-) mice, a murine equivalent of BCNS, and others have found it to have some efficacy against sporadic human BCCs. We report here results of a randomized, double-blind, vehicle-controlled study in patients with BCNS evaluating the efficacy of topically applied tazarotene for BCC chemoprevention (N = 34 subjects), along with an open-label trial evaluating tazarotene's efficacy for chemotherapy of BCC lesions (N = 36 subjects) for a maximum follow-up period of 3 years. We found that only 6% of patients had a chemopreventive response and that only 6% of treated BCC target lesions were clinically cured. Our studies provide no evidence for either chemopreventive or chemotherapeutic effect of tazarotene against BCCs in patients with BCNS.

Topical cyclosporine versus emulsion vehicle for the treatment of brittle nails: a randomized controlled pilot study.

BACKGROUND: Limited options are available for the treatment of brittle nail syndrome. OBJECTIVE: To assess the efficacy and safety of topical cyclosporine emulsion (CsAE) versus emulsion (vehicle) alone in the treatment of brittle nail syndrome. RESULTS: Twenty-four patients were randomized to topical CsAE emulsion or emulsion (vehicle) for 24 weeks. Four fingernails of each patient were included; the 2 most severe brittle nails and the second most normal nail were treated with the same medication. The fourth nail, the most normal nail, remained untreated and was used to assess nail growth. The prespecified primary endpoint was change from baseline in Physician Global Assessment (PGA) score (0 to 5 scale) at each follow-up visit. Safety evaluations were conducted at each visit. RESULTS: In the intent-to-treat population (n=12 for each treatment arm), the PGA score for treated nails improved from baseline (CsAE, 0.7 to 1.4; emulsion, 0.7 to 1.5; P<0.05 for each), with no significant between-group differences. Untreated nails did not improve in overall appearance (0.0 to 0.3 grade; P>0.05). Statistically and clinically significant improvement from baseline was reported for nail length/appearance in both CsAE and vehicle groups. LIMITATIONS: Sample size was relatively small. The difference in PGA between treated and untreated nails was not analyzed. Baseline disease severity may have been too mild, limiting detection of efficacy. CONCLUSIONS: Both CsAE and emulsion vehicle applied topically appeared to improve signs and symptoms of brittle nail syndrome and were well tolerated. These findings warrant corroboration in a larger population and inclusion of comparison with an inactive control and a higher concentration of CsAE, the former which may help in distinguishing the efficacy of vehicle emulsion from CsAE.

Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.

BACKGROUND: Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS: We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS: In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS: Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

The genetics of alopecia areata: What's new and how will it help our patients?

In the United States, alopecia areata (AA) is the most prevalent autoimmune disease, affecting approximately 5.3 million people, including males and females of all ages and across all ethnic groups. AA affects more individuals than most other autoimmune diseases combined, and yet despite its prevalence, there is little information on the underlying pathogenesis and there are currently no evidence-based treatments available to treat or cure this disease. Genetics has provided a valuable tool for gaining insight into disease pathology. We recently completed the first genome-wide association study (GWAS) in AA and successfully identified at least eight regions in the genome with evidence for association to AA. Importantly, this work identifies a discrete set of genes, some of which have been well studied within the context of other autoimmune diseases and already have targeted therapies available or in development. The insight that we have gained through our GWAS sets the stage for the rational development of novel effective therapeutic approaches and heralds in an exciting new era with the commencement of translational research in AA based on genetic findings.

Efficacy and safety study of tazarotene cream 0.1% for the treatment of brittle nail syndrome.

Brittle nail syndrome refers to nails that exhibit surface roughness, raggedness, and peeling. It is a common problem, with a higher prevalence among elderly patients. The goal of this study was to determine if tazarotene cream 0.1% ameliorates the signs and symptoms of brittle nails. In this open-label, single-center trial, participants applied tazarotene cream to the nails twice daily for 24 weeks. Signs and symptoms were rated by the investigators and by the participants during treatment and 12 weeks after discontinuation. Twenty participants were enrolled in the study; 1 participant withdrew prior to the 4-week followup visit. Of the 18 participants available for analysis (1 participant was excluded because baseline photographs were not available) for the primary end point of improvement in the physician global improvement assessment (PGIA), all 18 participants achieved improvement of the target nails at week 12 as well as 16 participants (88.9%) at week 24. All 18 participants had improvement in the PGIA score 12 weeks posttreatment at week 36. The physician global assessment (PGA) improved for 14 of 19 participants (73.7%) at both weeks 12 and 24; at week 24, 4 of 19 participants had achieved a PGA score of none. At week 36, 17 of 19 participants (89.5%) agreed that their nails had improved overall. Only 1 participant (5.3%) reported mild local irritation. This study demonstrated that tazarotene improves some of the changes noted in conjunction with brittle nail syndrome with minimal to no irritation.