Cyclosporine for the treatment of chronic idiopathic urticaria

Journal of Drugs in Dermatology, Feb, 2007 by Isaac Brownell

Cyclosporine for the Treatment of Chronic Idiopathic Urticaria

Commentary on:

Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. Vena GA, et al. J Am Acad Dermatol. 2006;55:705-709.

Summary

The authors present a multicenter, double-blinded, placebo-controlled trial of combination cyclosporine and cetirizine for the treatment of chronic idiopathic urticaria (CIU). Inclusion criteria included adult patients with severe relapsing CIU and persistence of symptoms on cetirizine (Zyrtec, Pfizer, Inc, New York, NY). Exclusion criteria included other forms of urticaria, contraindications to cetirizine or cyclosporine (CsA), or any significant illness. Patients were randomized to receive CsA for 16 weeks, CsA for 8 weeks followed by placebo for 8 weeks, or placebo for 16 weeks. CsA was started at 5 mg/kg/day for days 0 to 13, then reduced to 4 mg/kg/day for days 14 to 27, then tapered to 3 mg/kg/day from day 28. All patients also received cetirizine 10 mg daily for the duration of the study. The primary endpoint was change in urticaria severity score at 8 weeks. Secondary endpoints included change in severity score at 16 and 24 weeks, number of patients requiring rescue therapy, subject's global assessment (SGA, 5-point scale), Dermatology Life Quality Index (DLQI) scores, laboratory parameters, and adverse events.

A total of 99 patients were enrolled to receive CsA for 16 weeks (n=31), CsA for 8 weeks and placebo for 8 weeks (n=33), or placebo for 16 weeks (n=35). The treatment arms were similar with respect to patient characteristics and baseline disease severity. There was significant improvement in urticaria severity scores and DLQI scores in the CsA treatment arms compared to placebo at both 8 and 16 weeks. SGA scores were better with CsA treatment versus placebo only at 8 weeks. Fewer people in the 16-week CsA group required rescue therapy (19%) or withdrew from the study due to lack of efficacy (10%) compared to the other 2 treatment groups (42%, 24% and 31%, respectively). This was the only notable difference between the 16-week and 8-week course of CsA. A total of 60 patients (60%) reported adverse events (69% of CsA-treated, 46% of placebo). Gastrointestinal disturbances, paresthesias, infections, and elevated serum creatinine were the most common events in the CsA-treated patients. The only serious adverse events were not drug related. Adverse events, including hypertension, resulted in discontinuation of drug in 6% of CsA-treated patients.

Comment

CIU is defined by the regular presence of hives for more than 6 weeks without an identifiable eliciting stimulus. (1) A portion of patients with CIU (40%-50%) have an associated autoimmune component. CIU has significant impact on patient quality of life and management can be challenging. (2) There is good evidence to support the use of nonsedating [H.sub.1] antihistamines as first-line therapy in the treatment of CIU. When treating this condition, antihistamines are sometimes combined and the dosage is often increased beyond the recommended doses. (2) Nonetheless, in individual patients or during exacerbations of the disease alternative immunosuppressive agents such as corticosteroids or cyclosporine A (CsA) are required. CsA (Neoral, Novartis, Basel, Switzerland) is a systemic calcineurin-inhibitor immunosuppressant approved for the treatment of transplanted organ rejection, rheumatoid arthritis, and plaque psoriasis. It is also commonly used for graft versus host disease and ulcerative colitis. There are abundant case reports, open-label trials, and a single randomized controlled trial (n=29) (3) that suggest CsA is effective in some patients with CIU.

In this larger controlled trial, the authors confirm previous findings about the efficacy of CsA in the treatment of CIU. They find that CsA started at 5 mg/kg/day and progressively reduced to 3 mg/kg/day for periods of 8 or 16 weeks in combination with cetirizine can provide improvement in 63% of adult patients with CIU. However, the therapeutic effect is largely lost after discontinuation of the drugs. In light of the potentially severe adverse effect profile of CsA, its use in CIU should be limited to short courses of therapy. The potential for mycophenolate mofetil (CellCept, F. Hoffmann-La Roche Ltd, Basel, Switzerland) as an alternative immunosuppressant with a seemingly better safety profile merits further investigation. (4)

Novartis, the manufacturer of Neoral, sponsored this trial.

References

1. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol. 2004;114:465-474; quiz 475.

2. Zuberbier T, Bindslev-Jensen C, Canonica W, et al. EAACI/GA2LEN/EDF guideline: management of urticaria. Allergy. 2006; 61:321-331.

3. Grattan CE, O'Donnell BF, Francis DM, et al. Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria. Br J Dermatol. 2000;143:365-372.

4. Shahar E, Bergman R, Guttman-Yassky E, Pollack S. Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids. Int J Dermatol. 2006;45:1224-1227.