Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial

Background The identification of a highly potent immunosuppressive/antiprol iferative agent with an acceptable toxicity profile has long been a goal fo r the management of severe plaque psoriasis. Objectives To investigate the efficacy and safety of sirolimus (Rapamune(R) ) for severe psoriasis when given alone or in association with cyclosporin. Methods In a randomized, double-blind, eight parallel group, pilot study in 24 out-patient centres in seven European countries, 150 patients, 18 years and older, with severe chronic plaque psoriasis were given sirolimus 0.5, 1.5 and 3.0 mg m(-2) daily for 8 weeks, either alone or in association with a subtherapeutic dose of cyclosporin (1.25 mg kg(-1) daily). Cyclosporin 5 mg kg(-1) daily was the positive control and cyclosporin 1.25 mg kg(-1) da ily the negative control. The primary efficacy variable was the mean percen tage reduction in Psoriasis Area and Severity Index (PASI). Safety assessme nts included monitoring of adverse events, clinical laboratory parameters a nd sirolimus/cyclosporin blood concentrations. Results The greatest mean percentage decreases in PASI were seen with cyclo sporin 5.0 mg kg(-1) daily (70.5%) and with sirolimus 3.0 mg m(-2) daily cyclosporin 1.25 mg kg(-1) daily (63.7%). Both groups demonstrated signific antly better results than cyclosporin 1.25 mg kg(-1) daily (mean decrease 3 3.4%). Serum creatinine levels were significantly lower for groups with sir olimus alone and sirolimus plus reduced-dose cyclosporin when compared with cyclosporin 5.0 mg kg(-1) daily. Adverse events associated with sirolimus included thrombocytopenia (5%), hyperlipidaemia (9%), aphthous stomatitis ( 9%) and acne (13%), whereas adverse events associated with cyclosporin incl uded hot flushes (12%), hyperlipidaemia (9%) and increased serum creatinine (9%). Conclusions The concomitant administration of sirolimus with a subtherapeut ic dose of cyclosporin in severe psoriasis may permit a reduction in their respective toxicities, notably cyclosporin-induced nephrotoxicity.