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

Discussion

Based on clinical experience, it is widely accepted that traditional systemic therapies are effective in the treatment of moderate to severe psoriasis; however, the paucity of well-designed, comparative clinical trials limits rigorous evidence-based evaluation of their efficacy. There is marked heterogeneity in published clinical trials, with inconsistent study design, patient population and efficacy endpoints, compounded by small sample sizes.[1,11,12] Estimates of treatment effect are therefore imprecise, as evidenced by a range of RD values and wide CIs.

In a systematic review of the literature, NBUVB phototherapy was an effective treatment for psoriasis; however, comparative trials were limited.[11] A more recent review estimated that between 63% and 80% of patients achieve clearance with NBUVB phototherapy.[14] Only tentative conclusions could be drawn regarding the efficacy of PUVA therapy.[11] Other reviewers have estimated that PUVA therapy may be effective in 70-90% of patients, with poor results or failures in the remaining 10-30% of patients.[26] No definitive conclusions could be drawn regarding methotrexate due to the limited evidence available.[11] Two small trials support similar efficacy of methotrexate and ciclosporin in patients with moderate to severe psoriasis, however. Ciclosporin was found to be highly effective in the treatment of psoriasis, although there was wide variation in the estimated treatment effect, limiting accurate assessment of efficacy.[11] Oral retinoids appeared to be somewhat less effective than other systemic therapies for psoriasis, and it has been suggested that acitretin may be best suited to maintenance therapy as part of a sequential treatment regimen.[11,39] Placebo-controlled clinical trials supported the efficacy of FAE therapy, but no comparative trials were available.[11]

Photochemotherapy and each of the widely used traditional systemic treatments for psoriasis are associated with potentially serious toxicities that may limit their long-term use. As discussed earlier, such toxicities contributed to study dropouts during longer-term studies.[48,56] The primary safety concerns for patients with psoriasis include increased risk of malignancy (PUVA and possibly NBUVB), cumulative renal toxicity and hypertension (ciclosporin), haematological and liver toxicity (methotrexate), or hypervitaminosis A-like symptoms and prolonged teratogenicity (oral retinoid therapy). Because psoriasis is a chronic disease often requiring lifelong treatment, the risk of these treatment-related toxicities must be managed throughout a patient's lifetime. It is also important to consider concurrent illnesses or concomitant medications that might be contraindicated with certain systemic therapies. These considerations potentially limit the number of patients eligible for certain systemic therapies. This is illustrated in the study by Heydendael et al. demonstrating that of 111 patients screened, 11 were excluded due to liver abnormalities, two for hypertension, and two for low creatinine clearance.[41] There is currently no standard therapeutic approach for patients with moderate to severe disease, as the benefits and risks of treatment must be weighed for each patient, taking into consideration past treatment history, concomitant illness and current medications.

Strategies such as rotation of systemic therapies, combination therapy, sequential therapy, and treatment regimens incorporating periods off therapy may be used in an attempt to reduce patients' cumulative exposure to each of the traditional systemic agents. Although it is intuitive that reduced cumulative exposure may help to minimize treatment-related toxicity, there are few long-term data to support this hypothesis.[29] Such complicated treatment regimens require skilful management on the part of the physician, particularly when overlapping treatment is required.[39]

A large survey of patient members of the U.S. National Psoriasis Foundation recently reported a high level of dissatisfaction with treatment, particularly among those patients with clinically defined severe disease.[90] It was noted that effective treatments such as PUVA and methotrexate were discussed with patients more often than they were prescribed, perhaps contributing to patients' feelings of frustration and the perception that their treatment was not sufficiently aggressive.[90] Similar results were reported in a survey of patient members of the European Federation of Psoriasis Patient Organizations (EUROPSO), in which only 27% of patients expressed a high level of satisfaction with their prescription treatments for psoriasis or psoriatic arthritis. Notably, satisfaction was higher among the small proportion of patients receiving systemic therapies. Patients with self-reported moderate to severe psoriasis indicated that their treatment was time consuming (50%), ineffective (32%), expensive (30%), caused side-effects (23%) and was unpleasant (3%); side-effects were more common (31%) among patients with self-reported severe psoriasis.[91] It has been suggested that the relatively low usage of systemic therapies reported in the U.S. survey may reflect physicians' reluctance to prescribe potentially toxic agents.[92]

Based on an improved understanding of the immunopathogenesis of psoriasis,[93] new therapeutic agents described as 'biologicals' or 'biological response modifiers' are being developed, some of which are already available in parts of Europe and in the U.S.A. Of particular interest are new agents that inhibit the activity of tumour necrosis factor-α or target T-cell functions in the pathogenesis of psoriasis. To date, the efficacy of these new agents has been evaluated primarily in the context of short-term randomized placebo-controlled clinical trials.[94,95,96,97,98,99,100] The role of these new drugs in the long-term management of psoriasis remains under evaluation. Long-term, pragmatic, comparative clinical trials with clinically relevant endpoints (e.g. duration of remission) represent the best way to define the role of these promising new agents in the clinical management of psoriasis.

In summary, the available clinical data show that traditional therapies are effective in the treatment of moderate to severe psoriasis. Potentially serious toxicities associated with these treatments limit their long-term use for this chronic disease, necessitating complex therapeutic regimens and periods off treatment. Currently, there is no universal standard of care for patients with moderate to severe psoriasis, and the benefits and risks of systemic therapy must be weighed carefully for each patient to ensure optimal management of psoriasis symptoms and minimization of acute and cumulative toxicities.


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