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Notes: 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).

Notes: General description Atopic dermatitis is a common disease with a genetic background known as atopic syndrome. New findings as to possible genes involved are in accordance with a suspected pathogenesis of immune dysregulation. A preferential outgrowth of IL-4 secreting Th2 cells upon stimulation with relevant allergens results in B cell stimulation and the production of allergen-specific IgE. Non-specific and specific immunological and inflammatory processes form the pathological basis of the clinical condition eczema. Therapeutical options include general measures such as allergen avoidance, prescription of emollients, and the use of (sedating) antihistamines. Specific topical agents are tar preparations, corticosteroids and possibly topical non-steroidal anti-inflammatory drugs. Systemic therapy is sometimes required and corticosteroids and cyclosporin are available for that purpose. Photo(chemo)therapy is another modality and long-wave UVA seems to be promising in that respect. Learning objective The reader will have knowledge of new developments in the genetics and immunopathology of atopy and atopic dermatitis. Knowledge of the imniunodiagnosis and management of atopic dermatitis as well as its complications will be reviewed and updated with insights in new therapeutic modalities as well as in the changes of how the existing modalities should be used.

Notes: An open, randomized trial was performed to determine the optimal dosage schedule with regard to the efficacy and safety of cyclosporin in severe atopic dermatitis. The study also provided clinical experience with regard to the efficacy and safety of long-term cyclosporin treatment. During a 2-month dose-finding period. 78 patients with severe, long-standing atopic dermatitis received cyclosporin at a dose of either 5 mg/kg per day, decreasing to 3 mg/kg per day (Group A), or 3 mg/kg per day, increasing to 5 mg/kg per day (Group B). Patients were maintained on their optimal dose for a further 10 months. Patients in Group A showed a significantly greater improvement in efficacy parameters over the first 2 weeks than with patients in Group B, but as the dose was decreased in Group A and increased in Group B, these differences were minimized. After 1 year, cyclosporin showed an efficacy of 59.8% in Group A and 51.7% in Group B, assessed by a severity score. Assessed in terms of an area score, these figures were 48.7% and 40%, respectively. Cyclosporin demonstrated a good safety profile during long-term treatment and was generally well tolerated. The lower starting dosage was not associated with higher dropout rates. This study showed no differences in efficacy or adverse events between the two dosage schedules in long-term treatment.

Notes: Summary Background Cyclosporin is an effective treatment for severe plaque psoriasis. Unfortunately, its use may be limited by time- and dose-related nephrotoxicity. Serum trough levels may be useful for monitoring the risk of nephrotoxicity. Objectives To determine whether monitoring of trough levels is necessary in psoriasis patients undergoing short-term treatment with cyclosporin. Methods A computerized and manual literature search identified studies on adults with plaque-type psoriasis treated with cyclosporin ≤ 5 mg kg−1 daily, in which trough levels were measured in whole blood. Number of patients, treatment duration, formulation and dosage, renal function tests and trough levels were extracted. The association between renal function and trough levels was investigated. Additionally, in a randomized controlled trial on cyclosporin vs. methotrexate in moderate to severe psoriasis, cyclosporin trough levels were measured frequently in 20 patients during 12 weeks of treatment. The Pearson correlation coefficient between serum creatinine and cyclosporin trough levels was calculated. Results Fifty-six articles were found concerning cyclosporin trough level measurements in psoriasis patients, of which eight were analysed. Many studies were excluded due to inappropriate cyclosporin dosages used. As data were heterogeneous and lacked various key parameters, a correlation study and a meta-analysis could not be performed. Instead, a quantitative description of the literature was given. No high mean trough levels or elevations of serum creatinine were described. In our clinical study, all the mean trough levels in 17 patients treated with cyclosporin 3 mg kg−1 daily were within the therapeutic range (〈 200 ng mL−1). Elevated trough levels were found in two of three patients treated with cyclosporin 3–5 mg kg−1 daily. No signs of renal dysfunction were seen. Conclusions The literature does not provide a definitive answer on whether monitoring cyclosporin trough levels in patients with psoriasis should be standard practice. Our own data show no need for cyclosporin trough level monitoring during short-term treatment with cyclosporin 3 mg kg−1 daily. However, when cyclosporin doses are 〉 3 mg kg−1 daily, monitoring may be indicated.

Notes: Background SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. Objectives This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0·05%, 0·2%, 0·6% and 1·0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. Methods This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0·05%, 0·2%, 0·6%, or 1·0%, matching vehicle cream, or the internal control 0·1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. Results A clear dose–response relationship for SDZ ASM 981 was evident, with 0·2%, 0·6% and 1·0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0·041, 0·001 and 0·008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1·0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0·6% and 1·0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42·9%, 48·9% and 34·9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1·0% cream was similar to that of the lower concentrations. Conclusions 1·0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.

Notes: This is a review of the clinical studies performed so far in The Netherlands of the treatment of psoriasis with cyclosporin A (CyA), a selective immunosuppressive drug that has caused a major breakthrough in transplant medicine. Data derived from a double-blind placebocontrolled study (5 mg/kg/day of CyA), dose-finding studies (2.5 mg vs 5 mg/kg/day and 1 mg, 2 mg or 3 mg/kg/day), and long-term treatment of chronic plaque-type psoriasis (1.1–7.2 mg/kg/day) suggest an initial starting dose of 3 mg/kg/day irrespective of the severity of the disease. Long-term treatment brought about dose- and time-dependent (reversible) side effects, including renal dysfunction and hypertension. Efforts to reduce the dose included concomitant administration of drugs known to have anti-psoriatic efficacy. Only combination with topical steroids appeared to add to the clinical efficacy of CyA, but did not allow a dose reduction sufficient to restore renal function. Dose reduction through intermittent treatment, however, postponed exacerbations sufficiently to permit at least partial normalization of serum creatinine levels. A similar effect was seen in the treatment of pustular palmoplantar psoriasis, which responded to doses of 1.1–6–1 mg/kg/day.

Notes: Twenty patients with severe plaque psoriasis were selected to receive either low-dose cyclosporin A (CyA) or placebo (CyA vehicle) in a double-blind randomized trial at two centres.Within 4 weeks the mean reduction in the Psoriasis Area and Severity Index (PASI) in 10 patients receiving CyA (mean dose 5.5 mg/kg/day) differed significantly from the mean reduction in 10 patients receiving placebo. In eight patients given placebo a switch to CyA therapy resulted within 4 weeks in a mean reduction in PASI of 90%. In a total 15 out of 18 patients given CyA (83%) (mean dose 5.6 mg/kg/day) there was an improvement of ≥ 75% in PASI within 4 weeks. In a 2-month tapering off phase a lower mean CyA dose (3 mg/kg/day) was effective in maintaining the reduced PASI scores in seven of nine patients. Four out of five CyA treated patients who entered a post-treatment observation phase had a relapse (PASI score ≥ 50% of score at baseline) after a mean interval of 6.5 weeks.The most important side-effects were mild reversible hypertension in 5 of 18 patients (28%), and reversible elevated serum creatinine levels in 7 of 18 patients (39%). We consider that further studies are justified in severe chronic psoriasis to establish suitable regimens for maintenance of remission in psoriasis with low-doses of CyA or a combination of CyA with other anti-psoriatic agents.

Notes: A 49-year-old patient developed generalized pustular psoriasis after tapering off the methotrexate therapy he had been receiving for severe psoriasis and arthralgia. Treatment with cyclosporin A produced a dramatic reduction of the cutaneous lesions and the joint symptoms.