Ciclosporin is a highly effective and rapidly acting systemic treatment for psoriasis. This drug was first discovered in 1970, and was developed as an immunosuppressant for use in organ transplantation. The first controlled trial in psoriasis was published in 1986, and a license was granted in the for the treatment of severe psoriasis in 1992.
The main side effects are renal impairment and hypertension, both of which are largely reversible provided that guidelines regarding monitoring and dosage are followed. In other situations such as transplantation, the incidence of lymphoma is increased in patients receiving long-term ciclosporin. However, these individuals are much more intensively immunosuppressed than those taking ciclosporin for treatment of psoriasis.
Dosage regimens
For treatment of psoriasis the dose should not normally exceed 5 mg/kg/day and this is usually divided into two daily doses. Ciclosporin may be employed either as a maintenance treatment, using long term continuous therapy, or as a short course of treatment for 4 to 12 weeks, to induce remission, which might then be repeated later following relapse. Less severe cases are best treated with intermittent therapy which causes less toxicity and side effects. Patients with the more active disease require maintenance therapy and long-term continuous ciclosporin therapy may be appropriate in a subgroup of patients; however, duration of treatment should normally be kept below 2 years whenever possible. Treatment needs to be tailored to individual patients and when long-term continuous ciclosporin therapy is necessary, annual evaluation of glomerular filtration rate may be useful to accurately monitor renal function.
The starting dose ranges from 2.5 to 5 mg/kg/day. If improvement is not apparent after 2 weeks the dose can be increased by 0.5 to 1 mg/kg/day at fortnightly intervals provided that the maximum dose rate of 5 mg/kg/day is not exceeded. Once adequate improvement has occurred either the drug can be stopped in less severe cases or the dose can be reduced in steps of 0.5 to 1 mg/kg day, at fortnightly intervals to determine the lowest dose at which adequate control of the psoriasis can be maintained. The maintenance dose required may vary over time with disease activity. The aim of maintenance treatment should not be to maintain the patient completely clear of psoriasis, but rather to keep the disease activity at a level tolerable for the patient.
Efficacy
The efficacy of ciclosporin has been demonstrated in double-blind, placebo controlled trials. The effect of the ciclosporin can be maintained by long-term treatment.
Response to cyclosporin has been reported for all the clinical variants and manifestations of psoriasis including erythrodermic psoriasis, generalised pustular psoriasis, palmoplantar pustulosis and acrodermatitis continua of Hallopeau.
Although ciclosporin is currently licensed for treatment of severe psoriasis, it has also been suggested that treatment of more moderate forms of chronic plaque psoriasis may be appropriate.
Safety and side effects
The most frequent problem requiring withdrawal of cyclosporin is renal impairment, which is related to dose and duration of treatment. Even short courses of treatment at the dose of 5 mg/kg/day may produce a measurable effect on renal function. This appears to be largely reversible provided that the recommended dose rate of 5 mg/kg/day is not exceeded and that the dose is reduced, and treatment stopped if required, to prevent the serum creatinine rising to more than 130% of baseline. After prolonged treatment nephrotoxicity will not be completely reversible. However, renal impairment does not become progressive after treatment is discontinued. Hyperkalaemia is a manifestation of renal impairment, which is occasionally problematic. Serum potassium should therefore be monitored in conjunction with the serum creatinine.
Treatment with ciclosporin results in an increase in blood pressure. Significant hypertension may develop at any time during treatment and this is probably a dose dependent effect. Hypertension resulting from ciclosporin therapy can either be treated or the dose of ciclosporin can be reduced. Nifedipine is the drug of first choice if it is considered necessary to treat hypertension. It should be noted that other calcium antagonists are known to increase the plasma level of ciclosporin.
An increase in serum bilirubin is often observed during cyclosporin treatment. Isolated increases in serum bilirubin do not usually require cyclosporin dose adjustment. Other side effects include myalgia, arthralgia, gastrointestinal disorders (nausea, abdominal pain and diarrhoea), gingival hyperplasia, headache, hypertrichosis, paraesthesiae and tremor. Nausea is most frequently encountered after the first few doses and usually resolves. Gum hypertrophy may respond to improved dental hygiene or a reduction in dose. Hypertrichosis is often seen to some degree and may be a particular problem in female patients with dark hair. Ciclosporin can raise serum cholesterol and triglyceride levels and urate levels, and may also mildly impair glucose tolerance.
Infections, including herpes simplex, have not been a prominent problem during treatment of psoriasis. However, ciclosporin can be hazardous in patients who have suffered from hepatitis B or C.
The risk of malignancy developing as a result of long term immunosuppression is significantly increased. Although there is no doubt that the risk of diverse malignancies, including cutaneous tumours and lymphomas, is increased in transplant patients, this group undergo immunosuppression of a different order of magnitude to dermatological patients. Cutaneous malignancy may be a particular hazard because patients with psoriasis will often have received therapeutic ultraviolet irradiation. Squamous cell carcinomas have been reported in these circumstances.
Contraindications
These include patients with renal disease; hypertension; hyperlipidaemia; impaired glucose tolerance; active chronic infection or evidence of previous infection with hepatitis B or C; history of malignancy. Ciclosporin is not known to be teratogenic. Although its use cannot be recommended in pregnancy, it would seem preferable to using cytotoxic drugs, retinoids and perhaps PUVA. In the elderly, the usefulness of ciclosporin tends to be restricted by a lower renal reserve.
Drug interactions
Potassium-sparing diuretics may exacerbate ciclosporin-induced hyperkalaemia and should only be initiated with regular monitoring of U&E’s.
St Johns Wort is known to decrease ciclosporin levels. Herbal medicines may have an effect on drug levels. Avoid concomitant use.
Ciclosporin should not be taken within one hour of grapefruit juice as this increases drug absorption
Numerous drugs affect the hepatic metabolism of cyclosporin by inhibiting or inducing cytochrome P450 3A and these may reduce the efficacy or increase the toxicity of cyclosporin. Important examples of drugs inhibiting ciclosporin metabolism are diltiazem, erythromycin, itraconazole, and verapamil. Drugs, which may induce increased ciclosporin metabolism, include carbamazepine, phenytoin rifampicin and orlistat.
It is best to avoid ciclosporin, if possible, in patients requiring any other nephrotoxic drugs, including non-steroidal anti inflammatory agents (particularly diclofenac: Half dose of diclofenac if given concomitantly). An up to date reference list, such as that found in the British National Formulary, should always be consulted when prescribing concomitant systemic medication.
Ciclosporin can increase the risk of myositis with statins. Simvastatin can be used but not more than 10mg daily.
Monitoring
Before starting ciclosporin, blood pressure should be recorded and examination performed for any evidence of lymphadenopathy, malignancy or infection. Female patients should be encouraged to attend for a cervical smear if this has not been performed within the last three years. Serum creatinine should be measured to establish a baseline. Since this may vary considerably from day to day, it is recommended that two estimations be performed, at intervals of a few days, and the mean should be used as the baseline value. A baseline creatinine clearance is useful. Other useful investigations at baseline are liver function tests, serum electrolytes and urate, fasting blood sugar and lipid levels, and urinalysis.
Blood results should be repeated fortnightly for 8 weeks after achieving a stable dose and then monthly, After a period of six months, if the ciclosporin has been well tolerated, it is possible to extend the review interval to six or eight weeks in some patients.
Serum creatinine and electrolytes should be checked at each visit. Small reductions in glomerular filtration rate (GFR) in the normal kidney are not detected by monitoring serum creatinine. However, in subjects in whom renal function is already impaired, the creatinine rises much more promptly with small changes in the GFR. This investigation is therefore most sensitive in the circumstances where it is most important. Experience in the treatment of psoriasis suggests that changes in renal function are largely reversible after stopping treatment provided that the dose is reduced as required to prevent a sustained rise in serum creatinine of more than 30%. If there is a sustained rise in serum creatinine exceeding 30% above the baseline value the dose should be reduced by 0.5 to 1 mg/kg/day and review intervals should not exceed one month. If the creatinine has risen by more than 50% larger dose reductions may be required, and if the creatinine fails to return to within 130% of baseline consideration should be given to use of an alternative treatment. Measurement of the GFR using radioisotope excretion studies is not essential.
Blood pressure should also be monitored at each review. Fasting serum lipids should be checked on treatment. It is probably not mandatory to monitor these after the first three months. At intervals of three to six months, complete medical examination is recommended particularly to seek evidence of neoplasia.
Patient acceptability
Ciclosporin is generally well tolerated. The reduction in disease activity is often rapid. The most significant side effects, hypertension and renal impairment, are asymptomatic in the early stages and other side effects are not usually troublesome.
Synergy with other treatments
It is likely that a certain level of dose sparing can be achieved by using topical treatment concomitantly with ciclosporin. Very satisfactory control of psoriasis can be achieved, at least in some patients, using a very low dose of ciclosporin, 2 mg/kg/day. Ciclosporin can be effective with relative dose sparing in combination with methotrexate or hydroxycarbamide. Greater care with monitoring is required if combining therapies.
References
van Joost T. Bos JD. Heule F. Meinardi MM. Lowdose cyclosporin A in severe psoriasis. A doubleblind study. Br J Dermatol 1988; 118: 18390.
Ellis CN, Fradin MS, Messana JM et al. Cyclosporine for plaquetype psoriasis. Results of a multidose, doubleblind trial. N Engl J Med 1991; 324: 27784.
Ho VC. The use of ciclosporin in psoriasis: a clinical review. Br J Dermatol. 2004 May;150 Suppl 67:1-10.
Griffiths CE, Dubertret L, Ellis CN, Finlay AY, Finzi AF, Ho VC, Johnston A, Katsambas A, Lison AE, Naeyaert JM, Nakagawa H, Paul C, Vanaclocha F. Ciclosporin in psoriasis clinical practice: an international consensus statement. Br J Dermatol. 2004 May;150 Suppl 67:11-23.
Clark CM, Kirby B, Morris AD, Davison S, Zaki I, Emerson R, Saihan EM, Chalmers RJ, Barker JN, Allen BR, Griffiths CE. Combination treatment with methotrexate and cyclosporin for severe recalcitrant psoriasis. Br J Dermatol. 1999 Aug;141(2):279-82
Paul C, Hornig F. Risk of malignancy associated with cyclosporin use in psoriasis. Dermatology. 1999;198(3):320-1
This information forms part of the current BAD guidance document for the general management of psoriasis. Other sections in the document comprise: