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Cyclosporine increases the risk of skin and lymphoid tissue malignancies in organ transplant patients. A similar increase has been shown among psoriasis patients, but no data exist on the carcinogenic risk of cyclosporine monotherapy in skin diseases. We conducted a retrospective cohort study of 272 patients, all of whom had received at least one month of cyclosporine treatment. The cancer information on these patients was obtained from the Finnish Cancer Registry. The median follow-up time was 10.9 years and the median treatment time with cyclosporine was 8 months. We did not detect any increase in the risk of skin malignancies or lymphoma. The overall risk of cancer was almost identical to that expected in the general population (standardized incidence ratios (SIR) = 1.31, 95% confidence interval (CI) = 0.70-2.23). This study shows that short-term cyclosporine treatment is probably not related to subsequent malignancy. Since the CI of the SIR estimate was rather wide, larger studies are needed in the future.

Atopic dermatitis often requires long-term treatment. This European, multicentre, non-comparative, 24-month, follow-up study investigated the efficacy and safety of 0.1% tacrolimus ointment applied to adults with atopic dermatitis. Patients (n=672) applied a thin layer of 0.1% tacrolimus ointment twice daily for 3 weeks to all affected body areas. After 3 weeks, ointment was applied once daily. Clinical improvement became apparent after 2 weeks of treatment and 65.5% of patients had a rating of clearance, excellent or marked improvement by month 3. Skin burning (31.7%) was the most common causally-related adverse event, followed by pruritus (11.3%) folliculitis (6.4%), alcohol intolerance (5.7%), herpes simplex (5.7%), skin infection (4.6%), skin erythema (3.3%) and hyperaesthesia (2.4%). The most commonly reported infections were flu syndrome (12.9%), skin infection (9.8%), folliculitis (7.4%) and herpes simplex (7.0%). Long-term treatment up to 24 months with 0.1% tacrolimus ointment is safe and efficacious in adults with atopic dermatitis.

We performed a cost-effective evaluation of cyclosporin A versus UVAB phototherapy in the treatment of severe atopic dermatitis. The analysis was based on a one-year open prospective clinical trial conducted in Finland and showed that patients who received intermittent cyclosporin A therapy had on average 191 remission days per year, i.e. where disease activity was reduced by 50% or more. Patients receiving UVAB phototherapy had on average 123 remission days per year. All costs were estimated for the one-year period. Health service utilization of the 2 treatment groups was estimated based on the data gathered during the clinical study. Total costs were USD 5,438 in the cyclosporin A group and USD 5,635 in the UVAB group. Direct health-care costs were USD 4,935 in the cyclosporin A group and USD 3,124 in the UVAB group. The cost of a remission day was USD 28 in the cyclosporin A group and USD 46 in the UVAB group. In terms of direct health-care costs, the cost of a remission day was USD 26 in the cyclosporin A group and USD 25 in the UVAB group. Our results demonstrate that cyclosporin A therapy is similarly cost-effective as UVAB phototherapy in terms of total cost in the treatment of atopic dermatitis unresponsive to topical treatment. In terms of direct health-care costs, i.e. treatment and health services utilization costs, however, UVAB is significantly less costly, but side effects are frequent.

Although cyclosporin is effective for the treatment of severe atopic dermatitis, phototherapy is the standard second-line treatment for this disease. An open, randomized, controlled, parallel-group study was conducted to compare the efficacy, influence on quality of life and safety of cyclosporin and UVAB phototherapy during 1 year of intermittent treatment of atopic dermatitis in adult patients. The main endpoints of the study were the number of days in remission and the influence on quality of life. Seventy-two patients were treated, 36 in each group. Cyclosporin produced significantly more days in remission than UVAB phototherapy during the 1-year study period. At the end of the study no difference between the 2 groups was noted in terms of quality of life. A significant increase in serum creatinine occurred in 2 patients and 7 patients developed mild or moderate hypertension during cyclosporin treatment. It can be concluded that intermittent cyclosporin seems to be more effective than UVAB and is reasonably safe for the treatment of atopic dermatitis over a 1-year treatment period.

Cyclosporine is efficacious in short-term treatment of various eczematous disorders. In a follow-up study we have evaluated the long-term efficacy of cyclosporine in 75 patients, who in previous studies had been treated with cyclosporine for chronic actinic dermatitis (6 patients), atopic dermatitis (42 patients) and chronic hand eczema (27 patients), 4, 2 and 1 year after the initial treatment, respectively. Three out of 6 patients with chronic actinic dermatitis showed long-term efficacy. Two years after the initial treatment with cyclosporine (5 mg/kg/day for 1-2 treatment periods of 6 weeks) for atopic dermatitis the mean disease activity was significantly lower compared to baseline (58% decrease), and compared to the time of treatment stop no significant change had occurred. Of 37 evaluable patients 35 were still in remission. One year after the initial treatment with cyclosporine (3 mg/kg/day for 6 weeks) for chronic hand eczema the mean disease activity was significantly lower than at baseline (54% decrease), and compared to the time of treatment stop no significant change had occurred. Of 27 evaluable patients 21 patients were still in remission. The study suggests that long-term remissions are possible in eczematous diseases treated with cyclosporine, even for a relatively short treatment period. It must be stressed, however, that we did not have control groups for any of the studied patient groups.

In a randomized, controlled parallel group study we have shown that cyclosporine at 3 mg/kg/day is as effective as topical betamethasone-17,21-dipropionate in the treatment of chronic hand eczema. In this study we compared the influence of these therapies on the quality of life. Forty-one patients were treated with either treatment for 6 weeks, after which patients with failure were switched to the other treatment for another 6 weeks. Quality of life was assessed with the Eczema Disability Index (EDI) at baseline and at the end of both treatment periods. The total EDI score decreased significantly and to the same degree in both groups, i.e. from the mean value of 30.5 to 20.9 in the cyclosporine group and from 27.2 to 18.9 in the betamethasone-17,21-dipropionate group. Irrespective of the dimension of the EDI (daily activity, school/work, personal relationship, leisure, treatment), the difference between the treatment groups at the end of the first treatment period was not significant. In the second part of the study a slight further decrease in total score was observed, but without any difference between the groups. There was a significant correlation between changes in the total EDI score and changes in all the clinical assessments, i.e. disease activity, extent of the disease, itch, sleep disturbances and use of emollients. Though the significant correlation between the total EDI and clinical assessments makes quality of life assessments in hand eczema questionable, the missing correlation between some clinical assessments and dimensions of the EDI suggests that EDI views aspects of the disease not covered by clinical measures.

Topical corticosteroids are the standard treatment for hand eczema. However, in chronic forms of the disease they are often ineffective or lose their efficacy due to tachyphylaxis. In a previous open study cyclosporine showed efficacy in chronic hand eczema. The aim of this study was to compare oral cyclosporine at 3 mg/kg/day with topical 0.05% beta-methasone-17,21-dipropionate (BDP) cream in the treatment of chronic hand eczema. In a randomized, double-blind study 41 patients with chronic hand eczema resistant to conventional treatment were assigned to either cyclosporine or BDP for 6 weeks. Both cyclosporine and BDP improved the eczema. The total disease activity score decreased to 57% of baseline in the cyclosporine group (mean change -6, SD 4.3; p < 0.001) and to 58% of baseline in the BDP group (mean change -5.7, SD 4; p < 0.001) at the end of treatment. However, between the groups there was no significant difference. Adverse events occurred in 68% of the patients during cyclosporine and in 56% during BDP treatment. With cyclosporine no case of hypertension or increase in serum creatinine above normal levels was recorded. In two patients the serum creatinine levels increased to values 30% above their own baseline values. Relapses occurred to the same extent in both groups. Cyclosporine at 3 mg/kg/day is as effective as topical BDP in the treatment of chronic hand eczema. Low-dose cyclosporine could be useful as an alternative treatment for severe chronic hand eczema in patients unresponsive to conventional treatment.

Delayed-type hypersensitivity reactions to skin antigens are an indirect measure of cellular immune response. We studied in a double-blind manner whether clinically effective doses of cyclosporin A in palmoplantar pustulosis would diminish delayed-type hypersensitivity reactions in vivo. For testing delayed-type hypersensitivity, we applied intradermally a standardized panel of seven recall antigens and a vehicle control in 30 patients with palmoplantar pustulosis, and 28 were tested both at baseline and after 4 weeks. For 4 weeks 14 patients were treated with 2.5 mg/kg/day cyclosporin A and 14 patients with placebo. Cyclosporin A but not placebo caused a significant decrease in clinical disease parameters. In contrast, no significant differences in delayed-type hypersensitivity reactions between treatment groups were observed. The results do not support the view that the efficacy of low-dose cyclosporin A in dermatological disorders can be entirely explained by cyclosporin A's inhibitory actions on effector T-cells.

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.

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.