Comparison of cyclosporin and UVAB phototherapy for intermittent one-year treatment of atopic dermatitis.

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.

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.

Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial.

We conducted a randomized, double-blind, placebo-controlled trial to assess the atrophogenicity of tacrolimus ointment. In a combined group of atopic dermatitis patients (n = 14) and healthy volunteers (n = 12), 0.3% tacrolimus, 0.1% tacrolimus, betamethasone-valerate, and a vehicle control were applied in a randomized order to nonsymptomatic, 4 cm x 4 cm regions of abdominal skin. After 7 d of treatment under occlusion, the carboxy- and amino-terminal propeptides of procollagen I (PICP, PINP) and the amino-terminal propeptide of procollagen III (PIIINP) were measured from suction blister fluid with specific radioimmunoassays. In addition, ultrasound measurements of skin thickness were taken. Betamethasone-treated areas showed median PICP, PINP, and PIIINP concentrations of 17.0%, 17.6%, and 39.5% of the vehicle control at the end of the treatment period, respectively, whereas the 0.1% and 0.3% tacrolimus-treated areas showed median concentrations of approximately 100% of the vehicle control (p < 0.001). Betamethasone was also the only treatment to reduce skin thickness; the median decrease in skin thickness was 7.4% relative to 0.1% tacrolimus, 7.1% relative to 0.3% tacrolimus, and 8.8% relative to the vehicle control (p < 0.01). Results for atopic dermatitis patients and healthy volunteers were similar. These findings suggest that tacrolimus does not cause skin atrophy.

Long-term follow-up of eczema patients treated with cyclosporine.

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.

Double-blind placebo-controlled study of long-term low-dose cyclosporin in the treatment of palmoplantar pustulosis.

We previously showed in a double-blind, placebo-controlled study that cyclosporin at a dose of 2.5 mg/kg per day is an effective treatment for palmoplantar pustulosis (PPP). In the present randomized, double-blind, placebo-controlled multicentre study we treated 58 PPP patients with placebo or cyclosporin at an initial dose of 1 mg/kg per day. Disease activity was calculated from the number of fresh pustules. Treatment success was defined as the number of fresh pustules not exceeding 50% of the patients' own baseline pustule number. In cases of treatment success the dose of the test medication was not increased and the treatment was kept blinded for a maximum of 12 months. Blinding was broken only on treatment failure of the initial test medication dose. The mean blinded treatment time was 5.1 months for the patients receiving cyclosporin and 2.1 months for placebo (P < 0.01). Treatment was kept blinded for 12 months for seven patients in the cyclosporin and two in the placebo group (P < 0.05). Patients whose treatment code was broken continued in an open dose-finding part of the study with dose adjustments of cyclosporin every second month. In cases of treatment failure the dose of cyclosporin was increased in steps of 1 mg/kg per day; in cases of treatment success the cyclosporin dose was decreased by 1 mg/kg per day. The minimum and maximum doses were 1 and 4 mg/kg per day, respectively. The mean effective dose during the dose-finding part was between 1.2 and 1.7 mg/kg per day. Two patients did not respond to the highest dose of 4 mg/kg per day. In two patients serum creatinine levels increased by > 30% of their own baseline. The other main adverse events were hypertension (seven patients) and hypertrichosis (six patients). After stopping cyclosporin treatment the mean number of fresh pustules showed a maximum after 2 weeks with a continuous decline after that. Twelve months after completing the treatment the mean number of pustules was reduced to 20.0 compared with 63.6 at baseline (P < 0.001); 11 patients were free from pustules and two of these were totally cleared. We conclude that cyclosporin at 1-2 mg/kg per day is an effective and well tolerated treatment for PPP in most patients.

Comparison of the influence of cyclosporine and topical betamethasone-17,21-dipropionate treatment on quality of life in chronic hand eczema.

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.

Comparison of cyclosporin A pharmacokinetics of a new microemulsion formulation and standard oral preparation in patients with psoriasis.

Cyclosporin A (CyA) is a potent immunosuppressive drug which has shown efficacy in various skin disorders. The bioavailability of the oral CyA formulation (Sandimmun) is approximately 30%, showing high interpatient and intrapatient variability. The steady-state pharmacokinetics, efficacy and tolerability of CyA in two formulations: commercial Sandimmun soft gelatin capsules (CyA-SGC) and a newer oral formulation (Sandimmun Neoral: CyA-NOF), were compared in an open prospective study with a crossover between the two treatments in 19 patients with psoriasis. Each patient received a twice-daily treatment of CyA with a clinically effective dose of 2-5 mg/kg per day. The individual dosages were kept unchanged for at least 2 weeks before study entry and over the 42-day course of the study. At entry, patients were switched to CyA-NOF for 4 weeks and then back to CyA-SGC for another 2 weeks. Pharmacokinetic profiles were assessed at steady-state on day 14 while the patients were on CyA-NOF, and on day 42 while on CyA-SGC. Switching from CyA-SGC to CyA-NOF using 1:1 dose conversion resulted in an increased absorption of the drug. On average there was a 61% increase in maximum drug concentration (Cmax) and a 32% increase in the area under the steady-state blood concentration-time curve (AUC): Cmin was comparable in the two formulations. The increases in Cmax and AUC were associated with some increase in the clinical efficacy of the treatment. The number of adverse events reported by the patients and observed by the investigators were increased during CyA-NOF; the mean serum creatinine levels were not affected. An increased and a more consistent and predictable absorption of CyA is achieved with the new oral microemulsion formulation.

Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema.

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 in palmoplantar pustulosis: effect of cyclosporin A treatment on skin testing with recall antigens.

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.

Cyclosporin in atopic dermatitis: time to relapse and effect of intermittent therapy.

The efficacy of cyclosporin (CyA) in the induction of remission in atopic dermatitis has been documented in controlled studies. However, little information is available on the duration of remission after CyA treatment. We studied the length of remission in 43 patients with severe atopic dermatitis after a 6-week treatment period with CyA at 5 mg/kg per day. After a follow-up of 6-26 weeks, depending on the time-point of relapse, a second treatment period with CyA, identical to the first, was performed. Disease activity was evaluated bi-weekly, using six different parameters: 1, a total body disease activity score; 2, the extent of the disease; 3, the occurrence of itch; 4, the occurrence of sleep disturbance; 5, the use of topical emollients; and 6, the use of topical hydrocortisone. A significant decrease in disease activity was observed. The total body disease activity score decreased from the baseline score of 31 to 11.6 at the end of the first part and to 13.4 at the end of the second part of the study. An almost maximal response to treatment was already apparent after 2 weeks of treatment. All the other efficacy parameters studied also showed a significant response to CyA treatment. A similar response to CyA was seen when the patients were re-treated. After both treatment periods, approximately half of the patients relapsed after 2 weeks (42% first part; 54% second part). After 6 weeks follow-up, the relapse rates were 71 and 90%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study.

BACKGROUND AND DESIGN: Palmoplantar pustulosis (PPP) is an inflammatory skin disease characterized by pustule formation, erythema, induration, and scaling of the affected skin of the palms and soles. Palmoplantar pustulosis is usually resistant to treatment. In a double-blind study (phase 1) of 4 weeks, 40 patients with PPP were randomized to receive oral cyclosporine, 2.5 mg/kg per day, or placebo. An open-label dose-finding phase 2 with cyclosporine doses of 1.25, 2.5, and 3.75 mg/kg per day was performed in the following 3 months. The patients were then followed for at least 2 months after termination of cyclosporine treatment. Response to treatment was judged by the number of fresh pustules. Patients displaying a reduction of 50% or greater in the number of pustules, compared with baseline, were defined as responders. RESULTS: Of the patients who completed phase 1, 17 of 19 patients in the cyclosporine group and four of 15 in the placebo group were classified as responders (P < .001). Cyclosporine, but not placebo, significantly reduced formation of new pustules (P = .001). In the subsequent open phase, a daily cyclosporine dose of 1.25 mg/kg appeared to be an effective treatment of PPP in approximately half of the treated patients. Many patients relapsed after initial success with cyclosporine. However, only one patient studied totally failed to respond to cyclosporine treatment. At the end of phase 3, most of the studied parameters had returned to pretreatment levels. The most common side effect was headache in the 2.5 mg/kg per day dosage group; no significant side effects were observed in the 1.25 mg/kg per day dosage group. CONCLUSIONS: Low-dose cyclosporine treatment (1.25 to 2.5 mg/kg per day) is effective in PPP.

Cyclosporin for palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is a chronic skin disease characterized by persistent erythematous, scaly plaques incorporating sterile pustules on palms and soles, which is resistant to most treatments. Recently, two published uncontrolled studies suggested that cyclosporin (CsA) could be an effective treatment for PPP. Similarly, an unpublished, randomized, placebo-controlled study showed that CsA is effective in preventing new pustule formation in PPP. In the present paper we review the treatment of PPP with special emphasis on CsA treatment.

Interleukin-8 immunoreactivity in the skin of healthy subjects and patients with palmoplantar pustulosis and psoriasis.

Previous studies have shown that neutrophil-activating peptide 1/interleukin-8 (IL-8) is present in psoriatic scales and to a lesser extent in normal human epidermis. A panel of monoclonal antibodies and polyclonal antisera raised against IL-8 was used to localize IL-8 with immunoperoxidase techniques in non-lesional and lesional skin of patients with psoriasis and palmo-plantar pustulosis (PPP), and in corresponding sites from healthy subjects. Intracellular IL-8 immunoreactivity was found in all epidermal cell layers in biopsies of healthy subjects and in non-lesional and lesional skin in both PPP and psoriasis. The most intense immunolabeling was regularly found in the basal cell layer. Intercellular epidermal IL-8 immunolabeling was regularly detected in lesional biopsies in PPP and psoriasis, but not in healthy subjects or non-lesional skin in PPP and psoriasis. No intercellular immunolabeling was detected after successful treatment of lesional skin. The majority of cells along the eccrine sweat glands, dermal mononuclear cell infiltrates, and endothelial cells were IL-8 immunoreactive in all biopsies studied. The present study suggests that IL-8, its precursor form, or, alternatively, a degradation product is present in normal human epidermis.

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.