Results of cyclosporin treatment of severe, chronic psoriasis vulgaris

Controlled double-blind studies have demonstrated the efficacy of 14 mg/kg per day cyclosporin A (CsA) in patients with severe psoriasis. Recently a placebo-controlled double-blind randomized study confirmed that CsA therapy (mean dose 5.5 mg/kg/day improves psoriasis significantly. We have carried out a placebo-controlled, double-blind, randomized trial involving 12 patients suffering from severe psoriasis resistant to local therapy. Within 4 weeks, 5 mg/kg per day CsA resulted in 6 patients in a mean reduction of 72.5% of the PASI score, which differed significantly from the mean reduction of 18.1% in 6 patients receiving placebo. The most important side-effect was reversible hypertension in 1 patient. The preliminary results of a dose-finding study that started recently indicate that 1-3 mg/kg per day CsA results in a significant improvement in the patient's condition.     

A multicentre evaluation of the guidelines for the use of cyclosporin A in severe psoriasis

Background Controversy still exists as lo whether a dosage scheme for the treatment of severe psoriasis with cyclosporin A (CsA) should start with low dosages (3 mg/kg/day) or rather with high dosages (5 mg/kg/day). Aims In this open prospective multi-centre trial guidelines for the use of CsA in psoriasis beginning with low dosages were evaluated. A secondary aim of the study was to elucidate factors predicting efficacy of CsA treatment. Methods Efficacy and tolerability of CsA were evaluated monthly during 16 weeks in 86 patients (56 males, 30 females, mean age 43,0 ± 14,9 years) suffering from chronic severe plaque-type psoriasis, not responding to topical therapy (mean PASI 18.0 ± 8.1). All patients started with 3 mg/kg/day. Patients were defined as responders with a PASI reduction > 25% at month 1, ≥ 25% at month 1, ≥ 60% at month 3 and ≥ 70% at month 4. When a patient was a failure, the dose was increased by 1 mg/kg/day lo a maximum of 5 mg/kg/day. Results A gradual mean PASI reduction of 38%. 59%, 72% to 76% was reached with a mean CsA dose of 3.0, 3.2, 3.5, and 3.6 mg/kg/day at weeks 4, 8, 12 and 16. respectively. At the end of the study period, 39 patients were still on 3, 24 patients were on 4 and 15 patients were on 5 mg/kg/day. Due to subjective side-effects 6 patients dropped out on 3 mg/kg/day and 2 on 4 mg/kg/day. Diastolic and systolic blood pressure and creatinine levels were stable. Overall, CsA was relatively well tolerated. Absence of previous therapies, low baseline PASI and failure at week 4 were predictive for higher drop-out and failure rate and lower PASI at the end of study. Conclusions This study shows that a significant proportion of severe psoriasis patients can be treated with 3 mg/kg/day CsA with good tolerability and excellent clinical results. It is concluded that a treatment scheme with an optimal risk-benefit ratio should start with low dosages of CsA (3 mg/kg/day).     

Cyclosporin maintenance therapy for severe atopic dermatitis.

Twelve patients with chronic severe atopic dermatitis were treated with cyclosporin A (CsA) in a dose of 5.0 mg/kg/day. All patients except one showed a good therapeutic response. After week six, the CsA dose was reduced until an increased activity of atopic dermatitis was noticed (minimal effective dose). The minimal effective dose fluctuated with the severity of the atopic dermatitis. The mean minimal effective dose was approximately 4.0 mg/kg/day. Maintenance therapy with CsA for atopic dermatitis seems to be effective but may be hampered by side effects in the same way as CsA therapy is hampered by side effects in the treatment of psoriasis.     

Three cases of pityriasis rubra pilaris successfully treated with cyclosporin A

BACKGROUND: Pityriasis rubra pilaris (PRP) is reported to respond poorly to cyclosporin A (CsA). OBJECTIVE: We attempted to determine the efficacy of CsA in the treatment of classic adult-type PRP. METHODS: Three patients with classic adult-type PRP were treated with 5 mg/kg/day CsA. RESULTS: A sustained clinical response was achieved within 2-4 weeks of therapy. Relapses were noted when the CsA dose was decreased to 1.2 mg/kg/day. CONCLUSION: CsA should be considered in the treatment of classical adult-type PRP.     

Treatment of nickel dermatitis with Trientine

23 nickel-sensitive patients with hand eczema were treated with Trientine 300 mg daily and a placebo in a double-blind, crossover trial. No significant improvement occurred in the hand eczema. A surprising finding was that there was no detectable increase in urinary nickel excretion, in contrast to animal studies.     

The effect of a corticosteroid cream and a barrier‐strengthening moisturizer in hand eczema. A double‐blind,randomized, prospective,parallel group clinical trial

Background Hand eczema is a common and persistent disease with a relapsing course. Clinical data suggest that once daily treatment with corticosteroids is just as effective as twice daily treatment. Objectives The aim of this study was to compare once and twice daily applications of a strong corticosteroid cream in addition to maintenance therapy with a moisturizer in patients with a recent relapse of hand eczema. Methods The study was a parallel, double‐blind, randomized, clinical trial on 44 patients. Twice daily application of a strong corticosteroid cream (betamethasone valerate 0.1%) was compared with once daily application, where a urea‐containing moisturizer was substituted for the corticosteroid cream in the morning. The investigator scored the presence of eczema and the patients judged the health‐related quality of life (HRQoL) using the Dermatology Life Quality Index (DLQI), which measures how much the patient’s skin problem has affected his/her life over the past week. The patients also judged the severity of their eczema daily on a visual analogue scale. Results Both groups improved in terms of eczema and DLQI. However, the clinical scoring demonstrated that once daily application of corticosteroid was superior to twice daily application in diminishing eczema, especially in the group of patients with lower eczema scores at inclusion. Conclusions Twice daily use of corticosteroids was not superior to once daily use in treating eczema. On the contrary, the clinical assessment showed a larger benefit from once daily treatment compared with twice daily, especially in the group of patients with a moderate eczema at inclusion.     

Maintenance treatment with cyclosporin in atopic eczema

Summary We have studied two reducing-dose regimens intended to minimize toxicity of cyclosporin A (CyA) while maintaining its capacity to control atopic eczema following induction of remission. Twenty-four patients with severe chronic atopic eczema were first treated in a double-blind randomized placebo-controlled cross-over study of CyA (5 mg/kg/day). All 19 who completed the study showed the expected highly significant improvements, compared with placebo, in area involved, erythema, excoriation, lichenification, itch and requirement for topical steroid. In 17 of the 19 patients, control was re-established with CyA 5 mg/kg/day, and they were then re-randomized to stepwise reduction at 2-week intervals in either (i) the dose of CyA given daily, or (ii) the frequency with which the 5 mg/kg dose was given. Fifteen patients (seven continuous reducing dose, eight intermittent fixed dose) completed the planned reduction to either 1 mg/kg/day or 5 mg/kg every fifth day. In both groups the response was sustained despite dose reduction, although control was less good at a continuous dose of 1 mg/kg. Intermittent treatment was as good as or better than continuous reducing dosage in this study, and in both groups there was further deterioration after the drug was stopped. The findings suggest that the dose of CyA required to control atopic eczema is less than that required to achieve remission, and that the therapeutic index can be further improved by alternative dosing strategies. This offers a new approach to maintenance treatment of eczema and other chronic refractory dermatoses.     

Verruca Vulgaris Developing during Cyclosporin Therapy for Psoriasis Vulgaris

Several kinds of side effects have recently been reported with cyclosporin (CsA) therapy. We describe two patients with psoriasis vulgaris who developed verrucae vulgaris during systemic CsA therapy. In one case, a verrucous nodule appeared on the scalp and grew rapidly in a 54-year-old male with psoriasis vulgaris 29 months after starting CsA therapy. The total dose of CsA was 87.5 g, and average dose of CsA was 2 mg/kg/day. In the other case, multiple verrucae vulgaris developed on the scalp, face, knee, and inguinal region in a 54-year-old male. He had been given CsA for 10 months, the total dose was 45.5 g, and the average dose was 3 mg/kg/day. He also had Sjögren's syndrome. Most of the verrucae vulgaris lesions spontaneously disappeared after stopping the CsA.     

Cyclosporin A in the treatment of chronic dermatitis of the hands

Summary The efficacy of cyclosporin A (CyA) treatment was studied in seven patients with chronic dermatitis of the hands. CyA was started at a daily dose of 2·5 mg/kg in five patients, and 1·25 mg/kg in two patients. In patients who responded to the treatment at 2·5 mg/kg/day, the daily CyA dose was reduced stepwise, to the lowest maintenance dose of 1·25 mg/kg. In patients who did not respond, the dose was increased, to a maximum of 5 mg/kg/day. The patients were treated for 2–16 weeks. In six of the seven patients the dermatitis responded to CyA treatment within a few weeks. No response was seen with a starting dose of 1·25 mg/kg/day. In three of the five patients with a starting dose of 2·5 mg/kg/day, the daily CyA dose could be reduced to 1·25–2 mg/kg/day. After stopping CyA treatment, the dermatitis recurred during follow-up in three patients, three remained in remission, and one patient was not available for study. Treatment-related side-effects occurred in three patients. CyA treatment had to be stopped in one patient due to headache. The present study suggests that CyA could be a useful treatment for chronic dermatitis of the hands not responding to conventional therapy.     

Cyclosporin A inhibits directly in vivo keratinocyte proliferation of living human skin

A direct in vivo antiproliferative effect of cyclosporin A (CsA) on human epidermal keratinocytes (EK) grafted onto nude mice was evaluated. Using pulse-labeling of 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue incorporated into the nuclei of DNA-synthesizing (S-phase) cells, the antiproliferative effect of CsA was revealed as a decrease in the number of BrdU-positive human EK grafted onto nude mice receiving a daily subcutaneous injection of 50 mg/kg of CsA. The blood level of CsA in the treated mice, evaluated by a radioimmunologic assay, was 679 +/- 501 ng/ml (n = 3). Using an antibody to leukocyte common antigen, it was shown that no human lymphocytes were present in the grafted skin. Therefore, this antiproliferative effect of CsA on human EK seems to be due to a direct effect on EK rather than to lymphocyte regulation.     

Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study

Combination therapy is a common approach to psoriasis, aimed at improving clinical response and minimizing the risk of side effects. The aim of this pilot randomized open-label study was to evaluate the efficacy and safety of the combination of low-dose cyclosporine (CsA) with calcipotriol-betamethasone dipropionate (CBD) ointment in the treatment of psoriasis. Sixty patients with moderate-to-severe plaque psoriasis were randomized to receive CsA, 2 mg/kg/day, combined with CBD ointment (n = 30) or CsA, at the same daily dosage, in combination with an emollient (n = 30), for 8 weeks. The primary efficacy parameter was the Psoriasis Area and Severity Index (PASI) 75 response rate at 8 weeks. Combination therapy with CsA and CBD ointment was more effective than CsA and emollient treatment, with statistically significant results, particularly less itching after 4 and 8 weeks and PASI reduction at all post-baseline visits. Significantly more patients treated with CsA + CBD achieved the PASI 75 at 8th week (87% vs 37% in the CsA-emollient group; p = 0.0001). The efficacy results were paralleled by the investigator and patient's global assessment of disease severity at the end of study. Our results suggest that the addition of CBD ointment to low-dose CsA enhances clinical response and improves the risk/benefit ratio.     

Treatment of skin symptoms of Beh?et's disease with low dose cyclosporin A

We treated six patients with moderate to severe skin symptoms of Beh?et's disease with oral administration of Cyclosporin A (CsA). During the first two weeks, 5 mg/kg/day CsA twice a day was given and then the dose was reduced to 3 mg/kg/day. Erythema nodosum like eruptions, oral aphtha, and thrombophlebitis began to improve within three days, and four patients had complete remission by two weeks after the start of treatment. In one patient, a genital ulcer took almost three months to disappear. In peripheral blood of patients treated with CsA 5 mg/kg/day for two weeks, there were decreases in the OKT4/OKT8 ratio. After the reduction of the dosage, the ratio was temporarily increased, but it decreased to the normal range around the twelfth week of the treatment. No clinically important side effects were seen.     

Treatment with disulfiram in chronic nickel hand dermatitis

Eleven patients with nickel allergy and hand eczema of the pompholyx type were treated with disulfiram 200 mg daily for 8 weeks. 2 patients healed and 8 improved considerably. Mild relapses were observed in all patients within 2–16 weeks after discontinuation of treatment. Liver enzymes should be carefully monitored during disulfiram therapy.     

Lichenoid nail changes as sole external manifestation of graft vs. host disease

A 56-year-old-man who had refractory anemia with an excess of blasts underwent an allogeneic peripheral blood stem cell transplantation (PBSCT) from his brother after preparation with melphalan and fludarabin. He received GvHD (graft-vs.-host disease) prophylaxis with cyclosporine from day -1 at a daily dose of 5 mg/kg of body weight. The daily dosage was tapered gradually from day +20. On post-PBSCT day 68 he developed acute cutaneous GvHD grade 3 and acute gastrointestinal GvHD grade 2-3, which was resolved with a daily dose of 1 mg/kg of body weight of prednisone. The patient was discharged in good clinical condition and without signs of GvHD, and he started tapering his immunosuppressive treatment. By day 160 he developed oral lichen planus-like changes, with several reticulate white lesions on the oral mucosa. A biopsy specimen was microscopically consistent with lichenoid GvHD (Fig. 1). By day 150 after PBSCT, when he was being treated with CsA 100 mg once daily and prednisone 10 mg once daily, his fingernails started to grow abnormally and gradually became dystrophic and painful. Two months later his toenails became similarly affected. Although affecting all finger and toe nails, the lesions were especially important in both thumbs. Physical examination revealed multiple findings on his nails (Fig. 2): thickening, fragility, onycholysis, longitudinal striations, and even pterygium. The micological cultures were negative. A biopsy specimen showed an sparse papillary dermis lymphoid infiltrate with focal exocytosis and presence of isolated multiple necrotic keratinocytes (Fig. 3). These findings were interpreted as a lichenoid GvHD with oral and nail involvement. The patient did not have other associated cutaneous lesions. He did not develop signs or symptoms consistent with hepatic GvHD. In May 2000 thalidomide was added to the immunosuppressive therapy, at a daily dose from 100 to 300 mg according to tolerance (constipation, sedation, ...). The lesions on the oral mucous showed a substantial improvement, but the nail changes remained more or less stable. Thalidomide was discontinued after 7 months because the patient displayed numbness and tingling in the hands and feet consistent with a peripheral neuropathy. Twenty days later he stopped taking thalidomide and the oral lichenoid lesions worsened, resulting in difficulty in eating. He also developed periungueal erythema, swelling and intense pain after minimal trauma. The daily dose of prednisone increased to 20-30 mg with moderate improvement. However, the dose could not be increased because of the secondary immunosuppressive effects. Twenty-three months post-PBSCT the patient remains with intense oral and nail lichenoid lesions.     

Therapie berufsbedingter Hauterkrankungen

Hand eczema is one of the most frequent skin diseases. About 5-10% of population has chronic hand eczema. In addition, hand eczema accounts for more than 90% of occupational skin diseases. The therapy of hand eczema is expensive and often leads to a loss in quality of life. The therapy is complex, not always successful and can lead in the worst case to the patient being forced to give up or change their profession. We review the therapeutic options to treat occupational hand eczema.     

Successful etanercept therapy in therapy refractory acrodermatitis continua suppurativa Hallopeau

A 50-year-old patient presented with erythema, vesicles and pustules as well as interphalangeal joint pain. Acrodermatitis continua suppurativa Hallopeau was diagnosed. She was treated topically with glucocorticos-teroids, calcitriol, calcipotriol, tacrolimus and bath-PUVA therapy without any clear benefit. Systemic acitretin 0.75 mg/kg daily led to improvement but complete resolution could never be achieved.Because of acitretin-induced mucosal side effects and hair loss, the dose was reduced to 20 mg/d alternating with 10 mg/d. The disease flared again. Additional therapy with etanercept 2 x 25 mg subcutaneously weekly was started. Within four weeks all symptoms resolved. The joint pain disappeared and the nail growth improved. After six months, etanercept therapy was discontinued. Two weeks later the first rebound of pustules occurred. Etanercept was restarted and the patient cleared rapidly. Etanercept therapy can be a useful therapeutic approach in refractory acrodermatitis continua suppurativa Hallopeau.     

Rapidly developing giant sized lupus vulgaris on the chest associated with bilateral scrofuloderma on the neck

Lupus vulgaris and scrofuloderma are the opposite poles of cutaneous tuberculosis. Lupus vulgaris of a giant size and scrofuloderma in the vicinity of this lesion were both present in a 70-year-old female patient. The purified protein derivative of tuberculin (PPD) skin test was strongly positive. In histopathological examination, granulomatous infiltration without caseation necrosis was seen in the dermis. The patient was treated with a four-drug therapy consisting of pyrazinamide (25 mg/kg), isoniazid (5 mg/kg), rifampin (10 mg/kg) and ethambutol (15 mg/kg) daily for 2 months, followed by dual therapy with isoniazid and rifampin for 6 months. Her cutaneous lesions significantly regressed after 4 months, leaving keloid scars.     

External and internal exposure to the antigen in the hand eczema of nickel allergy

A provocation study was performed in twelve female patients with contact allergy to nickel and hand eczema of the pompholyx type. Intense handling of nickel-contaminated metal objects did not induce any visible eczematous activity. Oral administration of nickel in a double-blind test provoked an aggravation of the hand eczema in nine of the twelve patients, and in seven of the patients this was accompanied by secondary eruptions including outbreaks of earlier, healed eczema. The nickel dose given is probably in the upper limit of the presently known daily intake of the metal, but should be considered to be within the physiologic range. It is concluded that ingestion of small amounts of nickel may be of greater importance in maintaining the hand eczema than external contacts with the metal.     

Therapie von Handekzemen

Hand eczema is a very common skin disease, which can be induced by different causes. Although many interventions ranging from topical corticosteroids and UV therapy to oral cyclosporine and retinoids are available, the treatment of hand eczema can be very difficult and frustrating. The objective of our study was to assess the external evidence of different treatment modalities for hand eczema. Electronic databases (Cochrane, MEDLINE, Embase, Pascal, Jicst-Eplus, Amed) were systematically searched for clinical trials on therapy for hand eczema. Additionally, four general medical journals (BMJ, JAMA, Lancet, NEJM) and 17 specialists dermatological journals were hand searched from 1977 to August 2004. A total of 100 studies were found and 31 identified as randomised clinical trials (RCTs) dealing with different interventions. Due to the poor quality of most of these RCTs, they are inadequate as a guide to clinical practice. There is a need for high-quality RCTs on therapy for hand eczema regarding established as well as new treatment options taking different subgroups of hand eczema into consideration.     

Nickel-sensitive patients with vesicular hand eczema: oral challenge with a diet naturally high in nickel

Oral challenge with nickel sulphate indicated that vesicular hand eczema in nickel-sensitive patients may be exacerbated by nickel occurring naturally in the diet. Twelve nickel-sensitive females with vesicular hand eczema were challenged with a supplementary high nickel diet for 4 days in a single-blind cross-over study. The diet had about five times the average nickel content of the daily Danish diet. An aggravation of the hand eczema was observed in six out of 12 patients on day 4 after the start of the challenge. By day II, the hand eczema was worse in 10 out of 12 patients, and remained unchanged in two.