Tacrolimus ointment improves psoriasis in a microplaque assay

Tacrolimus (FK506) is an effective and well tolerated immunosuppressant used to prevent allograft rejection. We describe the evaluation of two tacrolimus ointment formulations for treatment of chronic plaque-type psoriasis. This was a microplaque assay with randomized, double-blind design. Sixteen patients (15 men, one woman, all white and 28-69 years old) with chronic plaque-type psoriasis participated. Six different ointments were applied to discrete microplaques, 17 mm in diameter, on a descaled psoriasis lesion: these were tacrolimus ointment with diisopropyl adipate as penetration enhancer, tacrolimus ointment without diisopropyl adipate, 0.1% betamethasone 17alpha-valerate ointment, 0.005% calcipotriol ointment and, as controls, the ointment bases for tacrolimus and betamethasone. Ointments were reapplied and the area was sealed every 2-3 days during the 14-day treatment period. After 7 and 14 days, erythema and infiltration were graded on a scale of 0-4, and superficial blood flow was measured with a laser Doppler flowmeter. Epidermal thickness was measured histologically at the end of treatment. Compared with the vehicle controls, sites treated with tacrolimus ointment (with or without penetration enhancer) showed a significant reduction in erythema and infiltration (P < 0. 001), a significant reduction in superficial blood flow (P < 0.01) and a significant decrease in epidermal thickness (P < or = 0.001). Results for betamethasone and calcipotriol, when compared with the vehicle controls, were similar. These results suggest that, under conditions of descaling and occlusion, tacrolimus ointment is effective in the treatment of psoriasis.     

Membrane and cytosolic interleukin-1 alpha and beta in normal human epidermal cells: variability of epitope exposure in immunohistochemistry.

Previous studies have shown that interleukin-1 (IL-1) is present in normal human epidermis. However, with immunohistochemical techniques, epidermal IL-1 immunoreactivity has been found in only a limited number of epidermal cells. In the present study, we show that both IL-1 alpha and beta immunoreactivities can be detected in all epidermal cell layers, provided optimal processing of tissue samples is used. The use of isolated epidermal cells showed that keratinocytes at various stages of maturation display both membrane-associated and cytosolic IL-1 alpha and beta immunoreactivities. After protease treatment of tissue sections, the IL-1 beta immunoreactivity of the granular cell layer was enhanced by some antibodies used, whereas in the other cell layers it was clearly lower. We a) suggest a different cellular localization, processing, and/or binding to subcellular structures of IL-1 during the differentiation process of human keratinocytes and b) outline the technical difficulties in any immunohistologic approach to IL-1 status in diseased skin.     

Book Review

Book reviewed in this article:
Nicholas J. Lowe & Nadim A. Shaath (eds): Sunscreens: development, evaluation and regulatory aspects.     

Intermittent short courses of cyclosporin (Neoral®) for psoriasis unresponsive to topical therapy: a 1-year multicentre, randomized study

We performed a 1-year study to determine whether intermittent short courses of the microemulsion formulation of cyclosporin (Neoral) could effectively control plaque psoriasis and whether tapering or abrupt cessation of cyclosporin therapy would influence time to relapse. Four hundred patients with plaque psoriasis were included in this open, multicentre, randomized study. All patients commenced cyclosporin at a dose of 2.5 mg/kg daily. Cyclosporin dosage could be increased to a maximum of 5 mg/kg daily. Treatment was continued until clearance of psoriasis or for a maximum of 12 weeks. Patients were then randomly assigned either to stop cyclosporin abruptly or to have the dose reduced by 1 mg/kg daily each week until cessation. On relapse, patients were given another course of cyclosporin. Patients were followed for at least 1 year, during which they could receive as many treatment courses as necessary. The number of patients who required one, two, three and four treatment courses was 400, 259, 117 and 26, respectively. The median time to relapse after the end of the first treatment period was 109 days in the group of patients randomized to stop cyclosporin abruptly and 113 days in patients randomized to taper off cyclosporin (P = 0.038). More than 30% of patients had not relapsed 6 months after having stopped treatment. After each treatment course, the Kaplan-Meier probability of achieving 75% or more reduction in disease area by day 84 of treatment was 83%, 76%, 73% and 66%, respectively. Mean serum creatinine concentration and blood pressure did not show any clinically significant changes over time. Our results show that intermittent short-course therapy with Neoral, when used in conjunction with topical therapy, is well tolerated and provides effective control of plaque psoriasis for 1 year. Tapering off cyclosporin on treatment cessation induces a slight delay in psoriasis relapse.     

Immunocompetent cells of fixed drug eruption

The positive provocation test reactions of the skin of six patients with fixed drug eruption (FDE) were studied from timed skin biopsies taken between 2 hours and 9 days after the appearance of FDE. Monoclonal antibodies to the following immunocompetent cell surface epitopes were used: T3, T4, T6, T8, T9, M1, Ia1, Drc, Leu7 and B cell. The dermal infiltrate comprised 60-80% of T lymphocytes at all the times studied. Cells with T4 and T8 epitopes were displayed in similar numbers. A transient decrease in the number of T6+ cells of the epidermis could be detected with a simultaneous and also transient increase of the T6+ cells in the dermis, which suggests a possible traffic of Langerhans' cells from the epidermis to the dermis. The epidermal Ia1+ cells showed changes similar to but less marked than the T6+ cells. The number of the dermal Ia1+ cells increased continuously. In the late biopsies these Ia1+ cells comprised up to 90% of the infiltrating cells. Except for the finding of a reduction of T6+ and Ia1+ epidermal cells, the cellular kinetics of FDE are similar to those seen in both cutaneous immunological and irritant reactions.     

Suction blister fluid histamine in fixed drug eruption.

The histamine concentration was measured from suction blister fluid obtained from normal and lesional skin of 8 patients with fixed drug eruption (FDE) caused by phenazone salicylate and from that of 2 healthy control subjects. In blister fluid samples obtained before peroral challenge with phenazone salicylate, the histamine concentrations were below 5 nmol/l both in uninvolved skin and in sites of previous FDE lesion (sample 0). After challenge, samples were taken from the incipient reaction that was visible after an average of 155 min. Histamine levels were significantly elevated in the blister fluid of 2 out of 8 FDE lesions (200 and 640 nmol/l) but in none of the uninvolved skin (sample 1). Two hours later (sample 2) the histamine levels were elevated in both uninvolved (mean 51.4 nmol/l) and lesional skin (mean 168 nmol/l). After 24 h (sample 3) the corresponding mean value was 25.4 nmol/l for uninvolved skin and 108 nmol/l for lesional skin. The histamine values in the blister fluid from FDE lesions in samples 2 and 3 were significantly higher (p less than 0.05) than those in the control blisters of uninvolved skin. An elevation of histamine levels comparable to that in the uninvolved skin of FDE patients was seen in the 2 healthy control subjects studied. The present study provides direct evidence of early release of histamine from mast cells or basophils in FDE and suggests that histamine is one of the mediators of clinical symptoms of FDE.     

Use of the Newer Immunosuppressive Agents in Dermatology

Immune mechanisms play a central role in various diseases such as eczema and psoriasis, and in the past treatment tended to involve corticosteroids and cytostatic drugs. Organ transplantation has stimulated the development of newer immunosuppressants, some of which have also been found to be efficacious in the inflammatory dermatoses. The best studied such immunosuppressant is cyclosporin, which has shown efficacy especially in psoriasis and atopic dermatitis. The major limiting factor in the use of cyclosporin is its adverse effects, especially nephrotoxicity and hypertension. Therefore the risk : benefit ratio should always be considered before initiation of cyclosporin therapy, and the patient should be carefully followed for such adverse effects. Tacrolimus seems to share the efficacy and most of the adverse effects of cyclosporin when used systemically, presumably because of its similar intracellular mechanism of action. Unlike cyclosporin, tacrolimus is efficacious topically, which may allow lower systemic adverse effects to be combined with higher local efficacy. Other newer immunosuppressants include sirolimus (rapamycin) and monoclonal antibodies. Their use in dermatology is still in the research phase, and no conclusions about their clinical potential can yet be made.