INTRODUCTION
Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It forms a complex with cyclophilin, a cytoplasmic immunophilin. This
complex inactivates calcineurin phosphorylase, preventing the phosphorylation of nuclear factor of activated T-cells (NFAT) and, therefore, the production of NFAT-
dependent cytokine such as interleukin-2, which is required for full activation of the T-cell pathway. Cyclosporine was the first immunosuppressive drug found to act
selectively on T-cells. It was isolated in 1970 from the soil fungus Tolypocladium inflatum Gams by Borel at Sandoz Laboratories in Basel, Switzerland, while looking
for novel antifungal agents.1
In 1979, cyclosporine was first observed to improve psoriasis during a pilot study undertaken to investigate the efficacy of cyclosporine in rheumatoid arthritis and
psoriatic arthritis,2 but was not approved by the US Food and Drug Administration for the treatment of psoriasis until 1997. Since then, the FDA has not approved
cyclosporine for the treatment of any other clinical condition in dermatology; however, it has been approved for use in atopic dermatitis in other countries (Europe)
and it has been used off-label for the treatment of multiple inflammatory skin conditions including blistering disorders, and connective tissue diseases.
Cyclosporine in Psoriasis
Nowadays, even in the age of biologics, cyclosporine remains as one of the most effective treatments for psoriasis because of its efficacy and rapid onset of action. Multiple dose-finding studies have been performed in order to elucidate the optimal dose for cyclosporine that achieves clearance with minimal toxicity.3-7 The initial dose of cyclosporine recommended by the American Academy of Dermatology is 2.5 mg per kg daily, administered in two divided doses (every twelve hours). In patients with severe psoriasis, in which a rapid response is needed, an initial dose of 5 mg per kg daily is usually a better option. Although the higher dose is associated with a faster and more efficacious response, it is also associated with a higher rate of adverse reactions. Clinical improvement of the cutaneous lesions occurs after approximately 4 weeks, and maximum response is seen after 8 to 16 weeks. If a satisfactory response is not achieved after 4 to 6 weeks of initial therapy with the lower dose (2.5 mg per kg daily), the dose can be increased gradually by 0.5 to 1.0 mg/kg/day at 2- to 4-week intervals, to a maximum of 5 mg/kg/day, as long as, the laboratory parameters remain satisfactory.8 If response is still unsatisfactory after 3 months of treatment with the higher doses, then cyclosporine should be discontinued.
Nowadays, even in the age of biologics, cyclosporine remains as one of the most effective treatments for psoriasis because of its efficacy and rapid onset of action. Multiple dose-finding studies have been performed in order to elucidate the optimal dose for cyclosporine that achieves clearance with minimal toxicity.3-7 The initial dose of cyclosporine recommended by the American Academy of Dermatology is 2.5 mg per kg daily, administered in two divided doses (every twelve hours). In patients with severe psoriasis, in which a rapid response is needed, an initial dose of 5 mg per kg daily is usually a better option. Although the higher dose is associated with a faster and more efficacious response, it is also associated with a higher rate of adverse reactions. Clinical improvement of the cutaneous lesions occurs after approximately 4 weeks, and maximum response is seen after 8 to 16 weeks. If a satisfactory response is not achieved after 4 to 6 weeks of initial therapy with the lower dose (2.5 mg per kg daily), the dose can be increased gradually by 0.5 to 1.0 mg/kg/day at 2- to 4-week intervals, to a maximum of 5 mg/kg/day, as long as, the laboratory parameters remain satisfactory.8 If response is still unsatisfactory after 3 months of treatment with the higher doses, then cyclosporine should be discontinued.
Long-Term Therapy
Currently, long-term therapy of psoriasis (> 1 year) with cyclosporine is not a common approach and should be prescribed only after other therapeutic options have been considered. This is because of possible adverse effects, including renal toxicity and arterial hypertension.9,10 There is also the possibility for an increased risk of developing lymphoproliferative disorders and other malignant tumors, especially squamous cell carcinomas of the skin (more common in patients with high cumulative doses of phototherapy in combination with psoralen — UV-A (PUVA) (>1000 J per cm2).11,12 Current guidelines limit the continuous use of cyclosporine in the United States to 1 year,13 whereas in Europe the recommended limit is 2 years.8,14
Currently, long-term therapy of psoriasis (> 1 year) with cyclosporine is not a common approach and should be prescribed only after other therapeutic options have been considered. This is because of possible adverse effects, including renal toxicity and arterial hypertension.9,10 There is also the possibility for an increased risk of developing lymphoproliferative disorders and other malignant tumors, especially squamous cell carcinomas of the skin (more common in patients with high cumulative doses of phototherapy in combination with psoralen — UV-A (PUVA) (>1000 J per cm2).11,12 Current guidelines limit the continuous use of cyclosporine in the United States to 1 year,13 whereas in Europe the recommended limit is 2 years.8,14
Short-Term Therapy
The use of intermittent short-term therapy is currently the most commonly recommended regimen of cyclosporine for the treatment of psoriasis.8,13,15-17 Patients are treated until an adequate response is achieved, which generally requires 8 to 16 weeks. Subsequently, cyclosporine is discontinued or slowly tapered by 1 mg per kg every week over 4 weeks9.
The use of intermittent short-term therapy is currently the most commonly recommended regimen of cyclosporine for the treatment of psoriasis.8,13,15-17 Patients are treated until an adequate response is achieved, which generally requires 8 to 16 weeks. Subsequently, cyclosporine is discontinued or slowly tapered by 1 mg per kg every week over 4 weeks9.
A short course of cyclosporine can be used in severe flares of psoriasis because of its rapid onset of action until a better long-term alternative treatment is
instituted. This is particularly useful in the treatment of erythrodermic or generalized pustular psoriasis where cyclosporine remains as the treatment of choice
despite the new biologic medications.8,13,18
