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/antiproliferative agent with an acceptable toxicity profile has long been a goal for the management of severe plaque psoriasis.


OBJECTIVE
To investigate the efficacy and safety of sirolimus (Rapamune) 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) daily the negative control. The primary efficacy variable was the mean percentage reduction in Psoriasis Area and Severity Index (PASI). Safety assessments included monitoring of adverse events, clinical laboratory parameters and sirolimus/cyclosporin blood concentrations.


RESULTS
The greatest mean percentage decreases in PASI were seen with cyclosporin 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 significantly better results than cyclosporin 1.25 mg kg(-1) daily (mean decrease 33.4%). Serum creatinine levels were significantly lower for groups with sirolimus 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 included hot flushes (12%), hyperlipidaemia (9%) and increased serum creatinine (9%).


CONCLUSIONS
The concomitant administration of sirolimus with a subtherapeutic dose of cyclosporin in severe psoriasis may permit a reduction in their respective toxicities, notably cyclosporin-induced nephrotoxicity.
Reitamo
S
S
Department of Dermatology, Skin and Allergy Hospital, University of Helsinki, Meilahdentie 2, 00250 Helsinki, Finland. sakari.reitamo@hus.fi
Spuls
P
P
Sassolas
B
B
Lahfa
M
M
Claudy
A
A
Griffiths
C E
CE
D000293:Adolescent; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D003879:Dermatologic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011565:Psoriasis / Q000188:drug therapy*; D012720:Severity of Illness Index; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome
D003879:Dermatologic Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus