Vera H. Price

Genome-wide association study in alopecia areata implicates both innate and adaptive immunity

Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P ≤ 5 × 10−7). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (Treg cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.

Alopecia areata investigational assessment guidelines

From Duke University Medical Center, Durhama; University of Minnesota, Minneapolisb; Pontefract General Infirmaryc; University of California at San Franciscod; Northwest Cutaneous Research Specialists, Portlande; The University of British Columbia, Vancouverf; and Johnson & Johnson, Skin Biology Research Center, Skillman.g Reprint requests: Elise A. Olsen, MD, Professor of Medicine, Duke University Medical Center, Box 3294, Durham, NC 27710. J Am Acad Dermatol 1999;40:242-6. *Developed from the Alopecia Areata Consensus meeting sponsored by the National Alopecia Areata Foundation at the First Tricontinental Meeting of the Hair Research Societies, Brussels, Belgium, Oct 8, 1995. Participants are listed at the end of the guidelines. Copyright

Hair Follicle Stem Cell-Specific PPARγ Deletion Causes Scarring Alopecia

Primary cicatricial or scarring alopecias (CA) are a group of inflammatory hair disorders of unknown pathogenesis characterized by the permanent destruction of the hair follicle. The current treatment options are ineffective in controlling disease progression largely because the molecular basis for CA is not understood. Microarray analysis of the lymphocytic CA, Lichen planopilaris (LPP), compared to normal scalp biopsies identified decreased expression of genes required for lipid metabolism and peroxisome biogenesis. Immunohistochemical analysis showed progressive loss of peroxisomes, proinflammatory lipid accumulation, and infiltration of inflammatory cells followed by destruction of the pilosebaceous unit. The expression of peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor that regulates these processes, is significantly decreased in LPP. Specific agonists of PPARgamma are effective in inducing peroxisomal and lipid metabolic gene expression in human keratinocytes. Finally, targeted deletion of PPARgamma in follicular stem cells in mice causes a skin and hair phenotype that emulates scarring alopecia. These studies suggest that PPARgamma is crucial for healthy pilosebaceous units and it is the loss of this function that triggers the pathogenesis of LPP. We propose that PPARgamma-targeted therapy may represent a new strategy in the treatment of these disorders.

Genomewide Scan for Linkage Reveals Evidence of Several Susceptibility Loci for Alopecia Areata

Alopecia areata (AA) is a genetically determined, immune-mediated disorder of the hair follicle that affects 1%-2% of the U.S. population. It is defined by a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body. In an effort to define the genetic basis of AA, we performed a genomewide search for linkage in 20 families with AA consisting of 102 affected and 118 unaffected individuals from the United States and Israel. Our analysis revealed evidence of at least four susceptibility loci on chromosomes 6, 10, 16 and 18, by use of several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint LOD score of 3.93 on chromosome 18, a two-point affected sib pair (ASP) LOD score of 3.11 on chromosome 16, several ASP LOD scores >2.00 on chromosome 6q, and a haplotype-based relative risk LOD of 2.00 on chromosome 6p (in the major histocompatibility complex locus). Our findings confirm previous studies of association of the human leukocyte antigen locus with human AA, as well as the C3H-HeJ mouse model for AA. Interestingly, the major loci on chromosomes 16 and 18 coincide with loci for psoriasis reported elsewhere. These results suggest that these regions may harbor gene(s) involved in a number of different skin and hair disorders.

Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and 2% topical minoxidil, placebo, or no treatment

Quantitative estimation of hair growth using hair weight and number was recorded for 120 weeks in 4 groups of 9 men with androgenetic alopecia. Three double-blind groups applied either 2% or 5% minoxidil solution, or vehicle. The fourth group, unblinded, received no treatment. Measurements of hair weight and number were continued for 96 weeks, when treatment (if any) was stopped, though measurements were continued for another 24 weeks. Although not compared statistically, the placebo and untreated groups behaved in a similar fashion. In contrast, the 5% and 2% minoxidil treatment groups showed a statistically significant increase in mean percentage change in interval weight from baseline compared with placebo; results for number counts were usually less significant. Over 96 weeks, topical minoxidil induced and maintained an increase in interval weight over baseline of about 30%. After treatment was stopped, hair weight and number counts for the minoxidil groups returned to about the same levels as placebo in 24 weeks.

HAIR REGROWTH: Therapeutic Agents

Today there are new classes of hair growth promotors with proven efficacy. This article reviews the current state of the art agents for treatment of two of the most common forms of hair loss encountered in clinical practice, androgenetic alopecia and alopecia areata. Current therapeutic strategies are based on recent advances in the understanding of disordered hair growth. Practical treatment protocols are presented.

Loose anagen syndrome

A distinctive new hair condition, the loose anagen syndrome, features anagen hairs that are loosely anchored and easily pulled from the scalp. The children studied had sparse hair that did not grow long and that pulled easily from the scalp. The majority of patients were blond girls, aged 2 to 5 years, but both sexes and those with dark hair can be affected. The hair was not fragile, and easily pulled hairs were misshapen anagen hairs without external root sheaths. Histologic examination of the hair showed abnormal premature keratinization of Huxleys and Henles layers of the inner root sheath in some samples. Length and density of hair gradually increased with age, but anagen hairs remained loosely anchored in adulthood. This report describes findings in 22 children and five adults with the loose anagen syndrome.

Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss

BACKGROUND Androgenetic alopecia is a common condition of adult men. Finasteride, a type 2 5alpha-reductase inhibitor, decreases the formation of dihydrotestosterone from testosterone. OBJECTIVE Two separate clinical studies were conducted to establish the optimal dose of finasteride in men with this condition. METHODS Men from 18 to 36 years of age with moderate vertex male pattern hair loss received finasteride 5, 1, 0.2, or 0.01 mg/day or placebo based on random assignment. Efficacy was determined by scalp hair counts, patient self-assessment, investigator assessment, and assessment of clinical photographs. Safety was assessed by clinical and laboratory measurements and by analysis of adverse experiences. RESULTS Efficacy was demonstrated for all end points for finasteride at doses of 0.2 mg/day or higher, with 1 and 5 mg demonstrating similar efficacy that was superior to lower doses. Efficacy of the 0.01 mg dose was similar to placebo. No significant safety issues were identified in the trials. CONCLUSION Finasteride 1 mg/day is the optimal dose for the treatment of men with male pattern hair loss and was subsequently identified for further clinical development.

Frontal fibrosing alopecia: a clinical review of 36 patients

Background  Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia with a distinctive clinical pattern of progressive frontotemporal hairline recession. Currently, there are no evidence‐based studies to guide treatment for patients with FFA; thus, treatment options vary among clinicians.

Double-blind, placebo-controlled evaluation of topical minoxidil in extensive alopecia areata

The safety and efficacy of 3% topical minoxidil were evaluated in the treatment of extensive patchy alopecia areata, alopecia totalis, and alopecia universalis. Patients with extensive patchy alopecia areata had greater than 50% scalp hair loss. In this double-blind study, thirty subjects applied minoxidil or placebo to half of the afflicted scalp area twice daily, with overnight petrolatum occlusion, for 1 year. Both male and female subjects, ranging in age from 9 to 65 years, were enrolled, fifteen subjects to each treatment group. Minoxidil applications were generally well tolerated except for three instances of scalp itching and dermatitis, two of which necessitated discontinuing the medication. Hair growth was seen in seven of eleven evaluable subjects (63.6%) in the minoxidil group and in five of fourteen evaluable subjects (35.7%) in the placebo group. Excellent, cosmetically acceptable hair growth was seen in three of eleven minoxidil-treated subjects (27.3%) and in one of fourteen placebo-treated subjects (7.1%). Examination of vital signs and laboratory measurements revealed no evidence of systemic effects of minoxidil. Seven of the twelve subjects assayed in the minoxidil group had detectable minoxidil serum levels, ranging from 0.4 to 7.5 ng/ml.