Vincent C. Ho

Guidelines of care for the management of primary cutaneous melanoma.

The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up.

Summary Background  Long‐term safety evaluations of biologics are needed to inform patient management decisions.

Treatment of pyoderma gangrenosum

Critical to the proper management of pyoderma gangrenosum are correct diagnosis, identification and treatment of any underlying disorder, and the proper choice of topical and systemic therapy. Many agents are available for the treatment of pyoderma gangrenosum. We review the current therapeutic options, their efficacy and side effects, and we offer some guidelines for their proper selection.

Oral cyclosporine for the treatment of alopecia areata: A clinical and immunohistochemical analysis

Cyclosporine inhibits the activation of helper T cells that may be pathogenic in alopecia areata. Therefore we treated six patients with alopecia areata (five men, one woman) with oral cyclosporine, 6 mg/kg/day for 12 weeks. Three patients had alopecia universalis, one had alopecia totalis, and two had patchy alopecia areata of the scalp. Hair regrowth in the scalp of all patients occurred within the second and fourth weeks of therapy, followed by hair regrowth of the face and chest (in the male patients), pubic area, extremities, and axillae. Overall, the site of best response was the scalp. Cosmetically acceptable terminal hair regrowth on the scalp occurred in three of six patients. Significant hair loss, however, occurred in all patients within 3 months of discontinuation of cyclosporine treatment. Clinical response correlated with changes in immune cell infiltration of the hair follicles. The number of leukocytes per hair follicle was quantified in transverse scalp biopsy sections stained with a panel of monoclonal antibodies. The degree of terminal hair regrowth correlated significantly with decreases in follicular epithelial human lymphocyte antigen-DR and intercellular adhesion molecule-1 expression, T cells, helper/inducer (CD4) T cells, suppressor/cytotoxic (CD8) T cells and Langerhans cells (CD1+DR+) from the hair follicles during cyclosporine therapy. A significant decrease in the CD4/CD8 ratio occurred early in the course of treatment and was maintained throughout the therapy. This decrease suggests that cyclosporine not only cleared immune cells from the hair follicles but also altered the balance of regulatory lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous manifestations of gastrointestinal disorders. Part I

This article reviews the cutaneous manifestations of gastrointestinal tract diseases. In part I, the gastrointestinal tract polyposis syndromes and gastrointestinal tract malignancies will be discussed. The cutaneous manifestations of inflammatory bowel disorders, vascular disorders of the gastrointestinal tract, celiac disease and bowel-associated dermatosis-arthritis syndrome will be discussed in part II. For each entity, a brief summary of the gastrointestinal tract (and other extracutaneous) manifestations is given. This is followed by a detailed discussion of the cutaneous signs. Current guidelines for the investigation and management of these diseases are presented.

Treatment of severe lichen planus with cyclosporine

Two patients with severe chronic lichen planus were successfully treated with oral cyclosporine (6 mg/kg/day). A response was noted within 4 weeks, and complete clearing was achieved after 8 weeks of treatment. No significant adverse effect was noted. The patients have remained in remission 3 and 10 months after therapy, respectively. Clinical improvement was accompanied by significant reduction in the T cell infiltrate in the skin. Abnormal expression of keratinocyte intercellular adhesion molecule-1 (ICAM-1), which was present before therapy, became undetectable after 1 week of cyclosporine therapy, before any significant clinical and histologic change.

p53-regulated apoptosis is differentiation dependent in ultraviolet B-irradiated mouse keratinocytes.

Previous studies from our laboratory, using p53 transgenic mice, have suggested that ultraviolet (UV) light-induced keratinocyte apoptosis in the skin is not affected by overexpression of mutant p53 protein. To further elucidate a possible role for p53 in UV-induced keratinocyte cell death, we now examine apoptosis in skin and isolated keratinocytes from p53 null (-/-) mice and assess the influence of cell differentiation on this process. In vivo, using this knockout model, epidermal keratinocytes in p53-/- mice exhibited only a 5.2-fold increase in apoptosis after 2000 J/m2 UVB irradiation compared with a 26.3-fold increase in normal control animals. If this p53-dependent apoptosis is important in elimination of precancerous, UV-damaged keratinocytes, then it should be active in the undifferentiated cells of the epidermal basal layer. To test this hypothesis, we examined the effect of differentiation on UV-induced apoptosis in primary cultures of murine and human keratinocytes. Apoptosis was p53-independent in undifferentiated murine keratinocytes, which exhibited relative resistance to UVB-induced killing with only a 1.5-fold increase in apoptosis in p53+/+ cells and a 1.4-fold increase in p53-/- cells. Differentiated keratinocytes, in contrast, showed a 9.4-fold UVB induction of apoptosis in p53+/+ cells, almost three times the induction observed in p53-/- cells. This UV-induced difference in apoptosis was observed when keratinocytes were cultured on type IV collagen substrate, but not on plastic alone. Western blotting of UV-irradiated, differentiated keratinocytes did not support a role for either Bax or Bcl-2 in this process. In support of these findings in mice, cell death in human cultured keratinocytes also occurred in a differentiation-associated fashion. We conclude that p53-induced apoptosis eliminates damaged keratinocytes in the differentiated cell compartment, but this mechanism is not active in the basal, undifferentiated cells and is therefore of questionable significance in protection against skin cancer induction.

Intralesional cyclosporine in the treatment of psoriasis. A clinical, immunologic, and pharmacokinetic study

In a double-blind, vehicle-controlled study, all of six psoriatic plaques treated with intralesional cyclosporine administered three times weekly for 4 weeks showed complete clearing or incomplete but significant clearing in comparison with vehicle-treated plaques (p less than 0.01). Epidermal thickness decreased from 0.42 +/- 0.07 to 0.27 +/- 0.08 mm at 4 weeks (p less than 0.03). Biopsy specimens obtained on day 5, before any clinical improvement, revealed a significant reduction of epidermal DR+CD1- antigen-presenting cells, epidermal and dermal monocytes, and keratinocyte intercellular adhesion molecule-1 expression. By day 5 the stratum corneum reverted to normal in the plaques receiving cyclosporine. Pain at the injection site was the major side effect. Steady-state blood cyclosporine levels ranged from 20 to 30 ng/ml during the first 12 hours after injection and became undetectable at 48 hours. These data suggest that cyclosporine improves the skin of patients with psoriasis by a local mechanism of action.

IMMUNOSUPPRESSIVE AGENTS IN DERMATOLOGY: An Update

Azathioprine, cyclophosphamide, methotrexate, and cyclosporine are the immunosuppressive agents most commonly used by dermatologists. Azathioprine has a relatively good safety profile and is therefore often preferred for the treatment of chronic eczematous dermatitides and bullous disorders. Awareness of the role of genetic polymorphisms in its metabolism can increase the efficacy and safety of this drug. Cyclophosphamide is an antimetabolite that has a more rapid onset of immunosuppressive effect than azathioprine, but has significant short-term and long-term toxicity. It is of use in fulminant, life-threatening cutaneous disease. Methotrexate is an antimetabolite that has significant anti-inflammatory activity. Despite its hepatotoxicity, its role in inflammatory dermatoses is broadening. Likewise, the role of cyclosporine is being expanded. This drug has potent T-cell inhibitory effects secondary to interference with intracellular signal transduction. Given the evidence for cumulative renal toxicity, it currently has a role in the short-term treatment of refractory psoriasis and atopic dermatitis, as well as in select inflammatory dermatoses. Familiarity with disease-specific clinical efficacy, side-effect profile, and dosage allows the successful and judicious use of these drugs in dermatologic disorders.

Update on the use of ciclosporin in immune-mediated dermatoses

Immune‐mediated dermatoses, such as psoriasis and atopic dermatitis, affect a significant proportion of the population. Although most cases are not life threatening, these diseases can have a profound effect on the sufferers quality of life and that of their family. Systemic therapy, such as ciclosporin, is often indicated for severe or recalcitrant disease. The efficacy of ciclosporin in the treatment of psoriasis and atopic dermatitis has been established and clinical data also demonstrate its efficacy in treating less common but equally challenging conditions such as pyoderma gangrenosum, lichen planus, autoimmune bullous disease, recalcitrant chronic idiopathic urticaria and chronic dermatitis of the hands and feet. The risk of potential adverse events associated with ciclosporin is greatly reduced if current treatment and monitoring guidelines are followed.