Assessing effectiveness in acne clinical trials: steps towards a core outcome measure set.

BACKGROUND: Acne ranks second to dermatitis in terms of global burden of skin disease. As such, it is essential that data on treatment efficacy are generated in a way that maximizes the opportunity for comparison among treatments. Interest in developing core outcome sets for use in clinical trials to standardize data collection in skin disease is surging. OBJECTIVES: The goal of this review is to provide an update on the efforts underway, challenges encountered and future directions in the development of an acne core outcome measure set for use in clinical trials. METHODS: The activities of the Acne Core Outcomes Research Network (ACORN) are presented in the context of currently acceptable methodologies for core outcome set development. CONCLUSIONS: Emphasis is placed on following a rigorous methodology, involving patients and recognizing a role for emerging technologies.

TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells.

BACKGROUND: The full mechanism of action of isotretinoin [13-cis retinoic acid (13-cis RA)] in treating acne is unknown. 13-cis RA induces key genes in sebocytes that are involved in apoptosis, including Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL). OBJECTIVES: In this study, we investigated the role of 13-cis RA-induced TRAIL within SEB-1 sebocytes. METHODS: Using 13-cis RA and recombinant human TRAIL (rhTRAIL) protein, we assessed induction of TRAIL and apoptosis in SEB-1 sebocytes, normal keratinocytes and patient skin biopsies. RESULTS: Treatment with rhTRAIL protein increased TUNEL-positive staining in SEB-1 sebocytes. TRAIL siRNA significantly decreased the percentage of TUNEL-positive SEB-1 sebocytes in response to 13-cis RA treatment. Furthermore, TRAIL expression increased in the skin of patients with acne after 1 week of isotretinoin therapy compared with baseline. TRAIL expression localized within sebaceous glands. Unlike sebocytes, TRAIL protein expression was not increased in normal human epidermal keratinocytes in response to 13-cis RA, nor did rhTRAIL induce apoptosis in keratinocytes, suggesting that TRAIL is key in the sebocyte-specific apoptotic effects of 13-cis RA. CONCLUSIONS: Taken together, our data suggest that TRAIL, like the neutrophil gelatinase-associated lipocalin, is involved in mediating 13-cis RA apoptosis of sebocytes.

Isotretinoin increases skin-surface levels of neutrophil gelatinase-associated lipocalin in patients treated for severe acne.

BACKGROUND: A clear-cut need exists for safe and effective alternatives to the use of isotretinoin in severe acne. Lack of data regarding the specifics of isotretinoin's mechanism of action has hampered progress in this area. Recently, the protein neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a mediator of the apoptotic effect of isotretinoin on sebocytes. OBJECTIVES: To establish further the clinical relevance of NGAL and to elucidate the factors that induce NGAL expression in sebocytes. METHODS: Methods were developed to isolate and quantify skin-surface levels of NGAL from normal subjects and patients with acne undergoing treatment with isotretinoin. RESULTS: Patients with acne were found to have higher skin levels of NGAL compared with normal subjects. Studies in SEB-1 sebocytes indicate that NGAL expression is increased in response to Propionibacterium acnes and interleukin (IL)-1ß. In patients, isotretinoin increases NGAL levels by 2·4-fold on the skin surface and this increase precedes decreases in sebum and P. acnes counts. CONCLUSIONS: These data support the hypothesis that NGAL is an important mediator of the early effects of isotretinoin on the sebaceous glands and provide insights into the mechanisms that regulate NGAL expression in the skin.

Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe?

Sebaceous glands are intriguing glands that are found throughout the human body except on the palms of the hands and soles of the feet. The true function of these glands has yet to be determined, but there are several theories, including antioxidant effects, antibacterial effects, and transport of pheromones. Sebaceous glands produce lipids that are involved in the pathogenesis of one of the most prevalent diseases of adolescence, acne. Although the majority of lipids produced by the sebaceous gland are also produced in other areas of the body, there are two that are characteristic of the sebaceous gland, wax esters and squalene. This review seeks to present an update on the physiology of the sebaceous glands, with particular emphasis on the production of sebaceous lipids.

Endocrinological evaluation and hormonal therapy for women with difficult acne.

Acne vulgaris is the most common skin condition observed in the medical community. Convention is to treat this condition with a combination of comedolytics, anti-inflammatory and antibacterial topical agents, or if indicated, oral antibiotics or retinoids. In addition to these therapies, hormonal therapy is potentially an option in women whose acne is not responding to conventional treatment or if signs of endocrine abnormalities are present. This paper focuses on the use of hormonal therapy in women with severe or recalcitrant acne. After a brief description of the pathogenesis of acne vulgaris, and the conventional treatment modalities, indications for hormonal therapy are discussed. This is followed by an outline of a suggested endocrine evaluation, and interpretation of the evaluation test results. Various options for hormonal therapy are then described, including a further discussion of oral contraceptives (OCs) in the treatment of acne.

Acne and rosacea. New and emerging therapies.

The goal of this article is to highlight recent developments in the treatment of acne and rosacea. An update on the use of isotretinoin, minocycline, topical retinoids, and hormones in the treatment of acne are presented. Highlights of research findings that may lead to future acne therapies are discussed. New in the management of rosacea are studies demonstrating the efficacy of 1% topical metronidazole in the treatment of rosacea, reports on the successful maintenance of remissions of rosacea with 0.75% metronidazole gel, and data regarding the controversial association of rosacea with Helicobacter pylori infection.

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia.

BACKGROUND: Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE: We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS: Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS: Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION: In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

Activity of type 1 5 alpha-reductase is greater in the follicular infrainfundibulum compared with the epidermis.

The enzyme 5 alpha-reductase converts testosterone (T) to dihydrotestosterone (DHT). Although this enzyme has been localized to various regions of the pilosebaceous unit, its activity has not been studied in the follicular portion of either vellus or sebaceous follicles. The goal of our study was to determine the relative activities of 5 alpha-reductase within various regions of these follicles with particular emphasis on the infrainfundibulum. A finding of increased 5 alpha-reductase activity in upper follicles compared to epidermis might support the hypothesis that increased follicular production of DHT is involved in the hyperkeratinization observed in this region of the follicle in acne vulgaris. 5 alpha-reductase activity was determined at pH 5 (optimal for the type 2 isozyme) and pH 7 (optimal for the type 1 isozyme) in isolated infrainfundibular segments from sebaceous and vellus follicles, homogenized epidermis from various anatomical areas and in microdissected segments of the pilosebaceous unit from breast skin of normal subjects. Enzyme activity was also determined at pH 7 in cultured infrainfundibular keratinocytes and in interfollicular epidermal keratinocytes. Homogenates of infrainfundibular segments demonstrated significantly greater activity at pH 7 compared to pH 5 (P < 0.001), confirming activity of the type 1 5 alpha-reductase in this region. Activity of 5 alpha-reductase was much lower in homogenized epidermis and did not demonstrate a clear pH preference. Keratinocytes cultured from the infrainfundibulum demonstrated significantly greater 5 alpha-reductase activity compared to keratinocytes from interfollicular epidermis (P = 0.04). In the dissected segments of pilosebaceous units from breast skin, 5 alpha-reductase activity was greatest in the sebaceous gland followed by the sebaceous duct, infrainfundibulum, whole skin and epidermis. These data indicate that 5 alpha-reductase activity varies within regions of the pilosebaceous unit and compared with interfollicular epidermal cells, infrainfundibular keratinocytes have an increased capacity for producing androgens which may play a role in the follicular hyperkeratinization seen in acne.

Acne. An overview of clinical research findings.

Although acne represents the most common chronic skin condition seen by dermatologists, there are still many unanswered questions regarding its pathophysiology, and patients are still in need of more effective therapies, particularly those aimed at the hormonal aspects of acne. Recent clinical research has led to advances in our understanding of factors such as cytokines in follicular hyperkeratinization and the role of androgens in acne, the emergence and significance of antibiotic resistance of P. acnes, the long-term safety and efficacy of isotretinoin, and the safety and efficacy of new topical retinoids, such as tazarotene and adapalene. Fruitful interactions between basic scientists and clinical researchers within medicine and the pharmaceutical industry will, it is hoped, provide for future advances in this area.

Interstitial granulomatous dermatitis with arthritis.

BACKGROUND: Interstitial granulomatous dermatitis with arthritis is an uncommon systemic disorder involving the cutaneous and musculoskeletal systems. The eruption may mimic other dermatoses including granuloma annulare, erythema chronicum migrans, and the inflammatory stage of morphea. Key histopathologic characteristics, along with clinical correlation, allow accurate diagnosis. OBJECTIVE: We describe the clinical, serologic, and histologic features in three patients with interstitial granulomatous dermatitis with arthritis. METHODS: Skin biopsy specimens were examined and correlated with the clinical and laboratory findings. RESULTS: Erythematous, annular, indurated plaques on the extremities were present in two women. An erythematous, papular eruption on the head and neck was present in a third patient. All patients had myalgia and migratory polyarthralgias of the extremities along with various serologic abnormalities. Histologic examination revealed a dense lymphohistiocytic interstitial infiltrate involving primarily the reticular dermis. Foci of necrobiotic collagen were present. Vasculitis was absent. CONCLUSION: Interstitial granulomatous dermatitis with arthritis is unique multisystem disease with variable cutaneous expression. Abnormal serologic findings indicate a possible connection to collagen vascular disease.

An overview of acne and its treatment.

The pathophysiology of acne vulgaris results from the interplay of follicular hyperkeratinization, the presence of Propionibacterium acnes bacteria in the follicular canal, and sebum production. Several anti-acne agents are currently available that affect one or more of these pathogenic factors and are effective against one or more acne lesion types. The only currently available agent that is directly effective against comedones is tretinoin. Agents effective against inflammatory lesions include tretinoin, benzoyl peroxide, and topical and systemic antibiotics. Agents effective against nodules and cysts include oral antibiotics and isotretinoin. However, the successful utilization of the available agents and techniques is highly dependent on an accurate and thorough assessment of each patient's needs and concerns, followed by the implementation of an individualized treatment program that has been clearly communicated to the patient. Such a program may employ several different anti-acne agents and adjunctive treatments such as comedo extraction or intralesional injection.

Acne rosacea.

Rosacea is a multifactorial skin disorder that usually affects middle-aged persons. Little is known about the etiology of rosacea, although the disease most likely represents a vascular anomaly occurring in patients with fair skin. The mainstay of treatment for inflammatory lesions has been oral antibiotics, but topical metronidazole also may be effective. Because recurrences are common after discontinuation of therapy, doses should be tapered as tolerated. Antibiotics are more effective for inflammatory lesions than for erythema and telangiectasia. Isotretinoin may be effective for inflammatory lesions, edema and rhinophyma in some resistant cases, but its use is limited by its side effects and teratogenicity. Ablation of telangiectasia with the tunable dye laser and various surgical approaches to rhinophyma are effective newer treatments but are more expensive and less available than conventional therapy.

Cytomegalovirus diaper dermatitis.

Cytomegalovirus inclusions have been reported in perineal ulcers from immunosuppressed adults. The importance of this finding is unknown. We report the first pediatric case of cutaneous cytomegalovirus infection in an infant with congenital human immunodeficiency virus infection, presenting as a diaper dermatitis. Cytomegalovirus was cultured from the skin biopsy specimen, and characteristic inclusions were seen on hematoxylin-eosin-stained sections. Results of this biopsy specimen analysis prompted further investigation revealing disseminated cytomegalovirus infection, including retinitis. Aggressive pursuit of a pathogen in common conditions such as diaper dermatitis is strongly recommended in immunosuppressed pediatric patients.

Dermatoses among floral shop workers.

Concern about the increasing incidence of hand dermatitis in floral shop workers in the United States and its possible association to the plant Alstroemeria, a flower that has become popular since its introduction in 1981, prompted investigation of the prevalence and cause of hand dermatitis in a sample of floral workers. Fifty-seven floral workers were surveyed, and 15 (26%) reported hand dermatitis within the previous 12 months. Sixteen floral workers (eight with dermatitis) volunteered to be patch tested to the North American Contact Dermatitis Group Standard and Perfume Trays, a series of eight pesticides and 20 plant allergens. Of four of seven floral designers and arrangers who reported hand dermatitis, three reacted positively to patch tests to tuliposide A, the allergen in Alstroemeria. Patch test readings for all other plant extracts were negative. A positive reading for a test to one pesticide, difolatan (Captafol), was noted, the relevance of which is unknown.