Guidelines for clinical trials of frontal fibrosing alopecia: consensus recommendations from the International FFA Cooperative Group (IFFACG).

BACKGROUND: Frontal fibrosing alopecia (FFA) has become one of the most common causes of cicatricial alopecia worldwide. However, there is a lack of clear aetiology and robust clinical trial evidence for the efficacy and safety of agents currently used for treatment. OBJECTIVES: To enable data to be collected worldwide on FFA using common criteria and assessment methods. METHODS: A multicentre, international group of experts in hair loss was convened by email to create consensus recommendations for clinical trials. Consensus was defined at > 90% agreement on each recommended part of these guidelines. RESULTS: Standardized diagnostic criteria, severity rating, staging, and investigator and patient assessment of scalp hair loss and other clinical features of FFA were created. CONCLUSIONS: These guidelines should allow the collection of reliable aggregate data on FFA and advance efforts in both clinical and basic research to close knowledge gaps in this condition.

Small-fibre neuropathy in a patient with dermatomyositis and severe scalp pruritus.

Dermatomyositis (DM) is commonly associated with scalp pruritus that can be severe. In addition, significant crawling and burning sensations have been reported in these cases. The aetiology of these scalp sensations in the context of DM is not fully understood. We report a 42-year-old female with treatment-resistant DM and structural changes in scalp epidermal and dermal nerve fibres. The patient presented with characteristic skin manifestations (Gottron's papules and poikiloderma), severely pruritic scalp, intermittent muscle weakness on neurological exam with electrodiagnostically confirmed myositis, and joint pain. Structural changes in scalp epidermal and dermal nerve fibres were discovered in a skin biopsy, suggesting that small-fibre neuropathy associated with scalp pruritus may be a manifestation of the DM syndrome. Further clinical experience combined with selective skin biopsy in patients with DM and symptomatic scalp will help determine the frequency of coexistent small nerve fibre involvement. Based on our limited findings, we suggest that pruritus in DM may be associated with abnormal epidermal and dermal nerve fibre structure.

Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome?

Two half brothers (maternally related) had a similar syndrome of microhydrocephaly in both brothers and dilatation of the spinal canal with fusion of thalami in one brother. Primordial growth delay was noted in both brothers, with severe mental retardation in the surviving brother. Both had ectodermal dysplasia with scaling, hyperkeratosis, and generalized alopecia, but normal sweat and sebaceous glands. Skeletal anomalies included hemivertebrae with abnormal segmentation in one and scoliosis with polydactyly in the other. Ears were apparently low set, large, and protruding, with mixed hearing loss in the brother who survived. Eye anomalies included maldevelopment of one eye in Patient 1 and small optic nerves more noticeable on one side in Patient 2. Both had cryptorchidism and dysplastic/hypoplastic kidneys of varying severity that resulted in the early postnatal death of one sib. Manifestations present in only one or the other sib included submucous cleft palate, aganglionosis of the rectum and colon, agenesis of one testicle, and single umbilical artery. This syndrome has not been described previously and may be due to an X-linked mutation. The acronym BRESEK reflects the common findings, whereas BRESHECK denotes all manifestations of both patients: brain, retardation, ectodermal dysplasia, skeletal deformities, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia. In addition to an X-linked mutation, a contiguous gene deletion or maternal mosaicism of an autosomal dominant gene must be considered.

Abnormal nevoblast migration mimicking neurofibromatosis.

A patient appeared to have von Recklinghausen type I neurofibromatosis, but her numerous cutaneous tumors were intradermal nevi and not neurofibromas. The patient had hundreds of 1- to 3-cm firm, flesh-colored, dome-shaped papules and pedunculated nodules on her buccal mucosa, eyelids, face, extremities, and trunk as well as a large, confluent, cerebriform tumor extending from the 12th thoracic vertebra to the sacrum. No cafe au lait macules, freckles, or Lisch nodules were present. Several hundred lesions were removed using the carbon dioxide laser. Histopathologic examination of all of the lesions revealed all of them to be intradermal nevi. Our patient's skin disease was clinically very similar to neurofibromatosis. We suggest our patient represents a distinct clinical entity that is related to environmental factors or a mutation that affected nevoblasts or melanoblasts and their derivatives during early embryo development.

Thioredoxin reductase. Role in free radical reduction in different hypopigmentation disorders.

Membrane-associated thioredoxin reductase (TR) has been discovered to reduce free radicals at the surface of the skin. An accurate bioassay for this enzyme has been developed by using a spin-labeled quaternary ammonium salt as a free radical substrate. Enzyme activity has been correlated with the surface area, and units of specific activity have been determined as the sequential decrease in nitroxide radical reduction per 3-mm punch biopsy per ten minutes. The TR activity in a random population of 30 healthy volunteers with different skin types (Fitzpatrick classification I through VI) could be correlated to the skin type. Ten patients with untreated vitiligo, two with piebaldism, three with albinism, and two with postinflammatory leukoderma were examined and the findings were compared with the expected rates for the individuals' skin types. The results from this survey on the human population support our previous molecular experiments on the control of melanin biosynthesis by TR in the epidermis.

Alopecia areata. Autoreactive T cells are variably enriched in scalp lesions relative to peripheral blood.

BACKGROUND AND DESIGN: Alopecia areata is a condition characterized by hair loss in association with perifollicular infiltration of T cells and antigen-presenting cells. Autoreactive T cells are postulated to amplify this abnormality by interacting with DR+ follicular epithelium. These cells may recognize either autologous major histocompatibility complex class II antigen or an autoantigen restricted by major histocompatibility complex class II. Limiting dilution analysis was used to determine the frequency of autoreactive lymphocytes in scalp biopsy specimens and peripheral blood from seven adult patients with alopecia areata. Autoreactive T cells are defined for this study as those that proliferate in response to autologous irradiated peripheral blood mononuclear cells. RESULTS: Autoreactive lymphocytes were enriched in scalp biopsy specimens relative to peripheral blood in five of seven patients. This enrichment was statistically significant in four of five patients. Five autoreactive T-cell clones derived from lesional scalp were characterized. Four of these clones were CD3+CD4+CD8- and one clone was CD3+CD4-CD8+. CONCLUSIONS: Enrichment of autoreactive cells in lesions of alopecia areata supports a role for these cells in the pathogenesis of this condition. Enrichment of autoreactive lymphocytes is also found in allergic contact dermatitis. Thus, these autoreactive lymphocytes may have a general role in inflammation.

Familial alopecia areata. HLA antigens and autoantibody formation in an American family.

Ten members of a white American family, spanning three generations, were studied. Three family members from two different generations were affected with hair loss. Two had alopecia universalis; one had alopecia areata. All subjects were HLA-typed using 131 antiserum samples obtained from multiparous female donors defining 41 HLA-A and HLA-B antigen specificities. Six haplotypes were identified. The affected persons and four other family members shared a common haplotype, HLA-A2,B40. The OKT4 (helper), OKT8 (suppressor-cytotoxic) cells, OKT4-OKT8 (helper-suppressor-cytotoxic) ratios and the percentage of B cells found were comparable for both the 12 control subjects and the family members studied. However, family members showed increased autoantibody formation, decreased T-cell percentages, and concanavalin A-induced suppression of the normal lymphocyte response to mitogens.

Suppressor cell number and function in alopecia areata.

Several values of immunologic function were studied and correlated with disease activity and extent in 14 patients with alopecia areata, alopecia totalis, or alopecia universalis and in a concurrently studied age- and sex-matched control group. As compared with the control group, the patients showed a significantly increased incidence of autoantibody formation, increased concanavalin A-induced suppression of the normal lymphocyte response to mitogens, an increased proportion of suppressor-cytotoxic cells in the peripheral blood, and a decrease in the absolute B-cell count. Absolute total T-cell counts, quantitative serum immunoglobulin determinations, and lymphocyte proliferation after exposure to the mitogens--concanavalin A, phytohemagglutinin, and pokeweed--and to tetanus antigen were comparable for both groups. Neither the percentage of concanavalin A-induced suppression of the normal lymphocyte response to mitogens nor the helper-suppressor ratio correlated significantly with the extent of hair loss. However, patients, particularly those who demonstrated spontaneous regrowth of hair, had increased concanavalin A-induced suppression in conjunction with an increase in the proportion of peripheral suppressor cells.

Evidence for eosinophil degranulation in the pathogenesis of herpes gestationis.

Herpes gestationis is a pregnancy-related bullous dermatosis of unknown origin with associated tissue and peripheral blood eosinophilia. In this report, eosinophil degranulation in herpes gestationis was studied, and the role that the eosinophil may have as an effector cell that induces tissue damage through deposition of toxic cationic proteins is discussed. Using indirect immunofluorescence with antibody to human eosinophil granule major basic protein, major basic protein was observed both within tissue eosinophils and deposited extracellularly outside eosinophils in the dermis of eight patients with herpes gestationis. Possible mechanisms whereby eosinophils might be activated to degranulate in herpes gestationis are reviewed.

HLA-D locus associations in alopecia areata. DRw52a may confer disease resistance.

Because predisposition to autoimmunity has been associated with HLA-D alleles and alopecia areata is hypothesized to be a T-cell mediated autoimmune hair loss, we determined DR and DQ alleles in 88 white and 10 American black patients with alopecia areata as well as controls with the use of restriction fragment length polymorphism typing with cDNA probes. White patients with alopecia areata have an increase in the phenotype frequencies of DR4 and DQw8 and an increase in genotype frequencies of DR4 and DR5 (now DRw11[5]). These associations are in agreement with those reported in two other studies but are not significant when corrected by the number of HLA antigens tested. Sixty-one percent of all patients with AA have DR4 and/or DRw11(5) specificities vs 40% of controls, with more DR4,DRw11(5) and DQw7(w3), DQw8(w3) heterozygotes among patients. DQw6(w1) phenotype frequencies and DRw52a phenotype and genotype frequencies are significantly decreased in patients with alopecia areata relative to controls. This highly significant negative association with the HLA DRB3 allele DRw52a in whites persisted even when DR4- or DRw11(5)-positive individuals were excluded from the patient and control groups. These data suggest that HLA-DR4 and DRw11(5) with their associated DQw7(w3) and DQw8(w3) specificities may confer susceptibility to alopecia areata, while DRw52a may confer resistance.

General evaluation of the patient with alopecia.

The evaluation of the patient with alopecia is a multistep process that comprises obtaining a good medical history, performing the clinical examination with a special emphasis on the examination of cut and plucked hair, doing a scalp biopsy, and ordering appropriate laboratory studies. Genetic counseling may be given if it is requested.

The antiandrogens. When and how they should be used.

This article is a useful guide for treating androgen-related skin disorders such as androgenetic alopecia, acne, and hirsutism. All available antiandrogens are discussed, as well as treatment doses, efficacy, and mode of action.

Relationship between follicular nerve supply and alopecia.

The emergence of new technologies such as the combination of immunohistochemical techniques with laser scanning confocal microscopy allows one to observe and project the three-dimensional perifollicular innervation in tissue sections measuring up to 200 microns. This technology opens the door to making new discoveries about the innervation of the hair follicle. As new information is generated about the cutaneous sensory nervous system, neuropeptide expression, and the modulation of inflammatory and proliferative processes by the nervous system in the skin, it is likely this knowledge will be applied to enhance our understanding of the biology of the hair follicle in both the normal and diseased state.

Skin diseases of the external genitalia. Recognition and treatment.

Dermatologic diseases of the genitalia are of several types: congenital diseases, acquired diseases (those caused by viruses, bacteria, fungi, or physical or chemical toxins), tumors, and atrophic dermatoses. The methods available to diagnose these diseases vary. Some conditions may be recognized by appearance alone, whereas others require histopathologic examination of involved skin for correct diagnosis. Some do not need treatment, while others call for an aggressive approach. Some types of genital dermatologic diseases, such as herpes infections and condylomata acuminata, appear to be associated with genital carcinogenesis. Patients with these diseases should be carefully examined.