Traditional Therapies in the Management of Moderate to Severe Chronic Plaque Psoriasis: An Assessment of the Benefits and Risks

L. Naldi; C.E.M. Griffiths

Disclosures

The British Journal of Dermatology. 2005;152(4):597-615. 

In This Article

Ciclosporin

Ciclosporin was first used (inadvertently) for the treatment of psoriasis in 1979,[36] and as early as 1983 received approval for this indication in some European countries. Ciclosporin therapy for psoriasis is now approved throughout most European countries and the U.S.A. ( Table 1 ). Ciclosporin (Neoral®; Novartis)[37] is a potent immunosuppressant used worldwide to treat psoriasis. Ciclosporin therapy should be carefully tailored for individual patients.[38] The recommended initial ciclosporin dosage for patients with psoriasis is 2·5 mg kg-1 daily taken as a divided oral dose (1·25 mg kg-1 twice daily).[37,38] If necessary, the dose may be gradually increased every 2-4 weeks by 0·5-1·0 mg kg-1 daily.[37,38] The internationally recognized maximum dose for dermatology patients is 5 mg kg-1 daily.[20,38,39] Intermittent short courses of an average of 12 weeks' duration are considered preferable. Patients who fail to respond satisfactorily after 6 weeks of treatment at either the maximum dose or their maximum tolerated dose should discontinue ciclosporin therapy.[37]

The efficacy of ciclosporin in the treatment of psoriasis has been well established in clinical trials.[11,20] A systematic review of the literature identified 18 randomized clinical trials of ciclosporin therapy for psoriasis.[11] Ciclosporin doses ranged from 1·25 to 14 mg kg-1 daily, with the majority of studies evaluating doses higher than the current maximum dose of 4-5 mg kg-1 daily.[20,37,39] There was considerable heterogeneity in the data with respect to baseline disease severity, ciclosporin dose, success criteria and treatment duration. The short duration of treatment (4-10 weeks) and generally small sample sizes in placebo-controlled clinical trials probably contributed to the variability of results reported. Despite these limitations, the data showed that ciclosporin administered at doses of 2·5-5·0 mg kg-1 daily for 12-16 weeks was highly effective in inducing the rapid remission of psoriasis, while longer-term treatment at doses of approximately 3·0 mg kg-1 daily was effective in maintaining remission.[11,38]

Despite numerous studies, none included large sample sizes, which results in an imprecise treatment effect estimate. The size of the treatment effect is quite variable between the trials, with the mean rate difference (RD) in studies of ciclosporin induction therapy ranging from slightly greater than zero to more than 0·8; the highest value occurred in a trial that required only a 50% improvement in Psoriasis Area and Severity Index (PASI) (PASI-50 response) as a measure of treatment success.[40] The range of RD values observed reflects the high degree of variability in treatment response in patients with psoriasis. When data from studies assessing the approved dose of ciclosporin (5 mg kg-1 daily) were retrospectively evaluated, the overall RD was 0·28 [95% confidence interval (CI) 0·21-0·35]. It is important to acknowledge the limitations in retrospectively combining heterogeneous data.

Ciclosporin (Neoral®) prescribing guidelines indicate that 51% and 79% of patients in a dose-titration trial achieved at least a 75% improvement from baseline in PASI (PASI-75 response) after 8 weeks and 16 weeks of treatment, respectively. Recently, a randomized controlled clinical trial by Heydendael et al . compared the efficacy of ciclosporin vs. methotrexate in 85 patients with moderate to severe plaque psoriasis.[41] Patients received ciclosporin 3 mg kg-1 daily ( n = 42) or methotrexate 15 mg weekly ( n = 43) for 16 weeks, with dose escalation as required. During the treatment period, 71% of ciclosporin-treated patients and 60% of methotrexate-treated patients achieved a PASI-75 response (no significant difference, P = 0·29). Overall, ciclosporin and methotrexate were found to induce psoriasis remission with similar efficacy, and there was no statistical difference between treatment groups in terms of the duration of remission.[41] However, the sample size was limited and a small difference between the two treatments cannot be ruled out. Similarly, a small prospective clinical trial by Sandhu et al . in 30 consecutive patients with severe psoriasis showed that treatment with ciclosporin 3-4 mg kg-1 daily (mean 196·6 mg daily) or methotrexate 0·5 mg kg-1 weekly (mean 27·7 mg weekly) produced a comparable clinical response after 8 weeks of treatment (90·6% vs. 94·3% reduction in PASI, respectively), although patients treated with methotrexate achieved a more rapid clinical response.[42] Overall, the data support similar activity of ciclosporin and methotrexate in moderate to severe psoriasis; however, larger studies are required to confirm these findings.

Major toxicities associated with ciclosporin therapy include nephrotoxicity, hypertension and immunosuppression ( Table 2 ).[37] Renal toxicity is perhaps of greatest concern for patients with psoriasis. Renal toxicity is dose related and almost always occurs in patients receiving prolonged and/or high-dose ciclosporin therapy.[38] Ciclosporin can effect acute changes in renal function due to vasoconstriction of the afferent arterioles, leading to a reduction in the glomerular filtration rate and increases in serum urea and creatinine.[43,44] Changes in renal function, notably increased serum creatinine, are relatively common and are reversible with a reduced ciclosporin dosage or periods off treatment to allow recovery.[38,43,44] Less frequently, structural changes may occur within the proximal tubule or afferent arteriole, the latter changes being irreversible.[43]

Hypertension is a common adverse effect of ciclosporin therapy in patients with psoriasis.[20,37,43] The incidence of hypertension increases with both cumulative ciclosporin dose and prolonged therapy. Hypertension is generally mild or moderate in severity and resolves in most patients with psoriasis following cessation of ciclosporin treatment. Should antihypertensive therapy be required, calcium channel antagonists (e.g. nifedipine) are generally recommended.[43,44,45] However, some calcium channel antagonists (e.g. diltiazem, nicardipine and verapamil) may alter ciclosporin metabolism.[20,37]

As an immunosuppressant, ciclosporin may increase the risk of infection and is associated with an increased incidence of malignancy. The occurrence of malignancy in transplant patients receiving ciclosporin is well established, and there is evidence of an increased risk of malignancy in patients with psoriasis treated with ciclosporin. In clinical trials, 32 (2·2%) of 1439 patients with psoriasis treated with ciclosporin (Neoral®) developed malignancies, including squamous cell carcinoma, basal cell carcinoma and lymphoproliferative malignancies.[37] In a prospective, 5-year study of 1252 patients with psoriasis who received ciclosporin for an average of 1·9 years, malignancies were reported in 47 (3·8%) patients. The overall incidence of malignancy in this study was approximately twofold higher compared with the general population, driven primarily by a sixfold increase in nonmelanoma skin cancers, most of which were squamous cell carcinomas.[46] The increase in nonmelanoma skin cancers occurred only in patients with a history of PUVA therapy, and multivariate analysis showed that previous exposures to PUVA, methotrexate or other immunosuppressant agents were significant risk factors for nonmelanoma skin cancer.[38,46] Overall, the incidence of cutaneous malignancy in ciclosporin-treated patients was considered comparable to that observed in patients with severe psoriasis, and there was no increase in noncutaneous malignancies compared with the general population.[38,46]

In general, the incidence and severity of adverse events in patients with psoriasis appear to be related to the cumulative dose and/or duration of ciclosporin treatment.[47] One retrospective analysis of long-term ciclosporin therapy for psoriasis ( n = 122) showed that the percentage of patients who discontinued treatment due to adverse events increased from 14% at 12 months to 41% at 48 months.[48] Common reasons for discontinuation included renal dysfunction and hypertension (28% and 19% of all patients, respectively).[48] Due to the risk of potentially serious cumulative toxicities, current guidelines recommend that patients with psoriasis should receive continuous ciclosporin therapy for no more than 1-2 years.[37,38] Intermittent short-term ciclosporin therapy is an effective means of inducing psoriasis remission while minimizing toxicity and is the recommended treatment approach;[11,38,47] alternatively, short-term therapy may be incorporated into a sequential treatment regimen involving a less toxic maintenance treatment such as oral retinoid therapy.[39]

The safety concerns associated with ciclosporin therapy necessitate careful patient selection and regular monitoring during treatment.[47,49] Ciclosporin is contraindicated in patients with abnormal renal function, uncontrolled hypertension or malignancies, and should be avoided in patients with active infection, immunodeficiency or severe chronic organ dysfunction ( Table 2 ).[20,37,43] Ciclosporin is not absolutely contraindicated in pregnancy, although prescribing guidelines recommend serious consideration of discontinuation, due to the potential for adverse effects.[37] As ciclosporin is excreted in breast milk, treatment is contraindicated during breastfeeding.[37]

Current consensus guidelines recommend that a range of laboratory values, in particular blood pressure and serum creatinine, should be monitored prior to treatment, biweekly during treatment for the first 2 months, and monthly thereafter ( Table 3 ).[38] Patients should also be examined at baseline and throughout treatment for ciclosporin-related adverse events, including infection and malignancy. Particular care should be taken with elderly patients due to the possibility of renal impairment and with patients receiving concomitant nephrotoxic drugs.[20,37]

Numerous drugs interact with ciclosporin, including some over-the-counter formulations; therefore, careful consideration of concurrent medications is required ( Table 4 ). Drug interactions may be of particular concern for elderly patients with psoriasis, many of whom have a large number of concomitant medications. Several medications (e.g. nonsteroidal anti-inflammatory drugs administered long-term) may potentiate renal dysfunction in patients receiving concomitant ciclosporin therapy. In addition, drugs that modulate the activity of cytochrome P-450 3A, the enzyme system largely responsible for ciclosporin metabolism, can shift ciclosporin concentrations outside the narrow therapeutic range. Interactions that increase serum levels of ciclosporin (e.g. erythromycin, methylprednisone and amiodarone) or decrease ciclosporin concentration (e.g. phenobarbital, orlistat and St John's wort) are well documented. Some interactions should be avoided, while others may be managed by careful monitoring of serum ciclosporin concentrations and appropriate dose modification.[37]

Ciclosporin treatment can produce rapid clearance of psoriasis, and its benefit/risk ratio is considered acceptable for short-term treatment.[50] For example, ciclosporin may be particularly beneficial as an induction therapy[39] or for short-term treatment of psoriasis flare.[33] However, the clear relationship between cumulative ciclosporin exposure and serious toxicity prohibits continuous treatment for more than 1-2 years in almost all patients.[37,38,45] Intermittent short courses of around 12 weeks' duration are considered preferable.[38] The impact of serious ciclosporin-induced toxicities, such as impaired renal function and hypertension, can often be minimized by careful monitoring and dose reduction or discontinuation of treatment as necessary.[20,50] In some cases, however, renal toxicity or hypertension may persist after discontinuation of ciclosporin.[50]

The risks of ciclosporin treatment may be less of a concern for patients whose quality of life is severely affected by psoriasis. The benefit/risk ratio may also be more acceptable for patients with limited treatment options; for example, Lebwohl et al . recommended short-term ciclosporin therapy for a young woman whose alcohol use and failure to use reliable contraception ruled out methotrexate or acitretin therapy (see 'Methotrexate' and 'Oral retinoids').[33] Conversely, the benefit/risk ratio may be less acceptable in patients predisposed to ciclosporin-induced toxicity, for example due to advanced age, pre-existing renal impairment or hypertension,[50] or a prior history of immunosuppressive therapy.[37]

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