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

Photochemotherapy (Psoralen Plus Ultraviolet A Radiation)

Naturally occurring psoralens and sunlight have been used for thousands of years in the treatment of skin disorders.[25] Modern photochemotherapy involves oral or topical administration of a photosensitizing psoralen followed by exposure to long-wavelength (320-400 nm) UVA irradiation.[25] Systemic psoralen formulations are most frequently used,[26] and will be the focus of the present discussion. The mechanism of action of PUVA therapy in patients with psoriasis has not been fully elucidated; however, PUVA is known to have antiproliferative, anti-inflammatory and immunosuppressive effects.[25,26] PUVA is approved in several European countries and the U.S.A. for the treatment of severe psoriasis ( Table 1 ).

The most commonly used systemic psoralen for the treatment of dermatological disease is oral methoxsalen (8-methoxypsoralen), available in hard or soft gelatine capsule formulations (8-MOP® and Oxsoralen-Ultra®, respectively; ICN Pharmaceuticals).[17,25] Current guidelines for patients with psoriasis recommend an initial oral methoxsalen dose of 0·5 mg kg-1.[25,27] The minimum phototoxic dose and phototoxic peak time should be determined for each patient following methoxsalen administration.[27] The bioavailability and onset of photosensitization for each methoxsalen formulation are unique; therefore, formulations cannot be substituted without reassessment of dosage.[27,28]

The efficacy of PUVA in patients with psoriasis is widely accepted, and guidelines for PUVA psoriasis therapy have been developed.[25,26] Clinical trials suggest that PUVA therapy is effective for most forms of psoriasis and induces complete or partial remission in 70-90% of patients with psoriasis.[26,29] A recent systematic review identified 23 randomized controlled trials of systemic PUVA monotherapy or combination therapy for psoriasis; however, the heterogeneity of trials with respect to patient population, baseline psoriasis characteristics, treatment regimen and duration, and outcome measures meant that data could not be pooled and only 'tentative' conclusions could be drawn.[11] Overall, PUVA therapy with oral methoxsalen 0·6-1·0 mg kg-1 was found to be highly effective in clearing psoriasis.[11] Combination retinoid plus PUVA therapy appeared to be more effective in clearing psoriasis than either regimen alone, and the efficacy of PUVA therapy was increased by concomitant use of topical treatments such as corticosteroids and vitamin D3 analogues, a common clinical practice.[11] Research has shown that combination PUVA-methotrexate therapy may also be highly effective;[7,25] however, this combination may be limited by the risk of excessive immunosuppression and additive carcinogenesis.[24,26]

PUVA therapy may be associated with several immediate and delayed adverse effects ( Table 2 ). The primary safety concerns associated with PUVA relate to long-term effects such as skin cancer, photodamage and premature ageing of the skin, including an increased incidence of irregular pigmentation, lentigines and actinic keratoses.[25,26] Notably, there is a clear relationship between cumulative PUVA exposure and an increased risk of skin cancer.[25,26,27,30] One long-term, prospective study of 1380 patients found that during the 10 years following first PUVA exposure, patients who received more than 260 PUVA treatments had an 11-fold greater risk of cutaneous squamous cell carcinoma than patients who received 160 or fewer PUVA treatments.[30] There was also a modest increase in the incidence of basal cell carcinoma in patients who received prolonged PUVA therapy.[30] In addition, recent data from the same patient cohort suggest that PUVA-treated patients may be at increased risk of developing melanoma.[27,31] Although UVA doses administered in the study were probably higher than those used today, the evidence of increased cancer risk was sufficient for current PUVA treatment guidelines to recommend minimization of cumulative UVA exposure.[29] The carcinogenic mechanism has not been elucidated; however, there is evidence that PUVA has both mutagenic and immunological effects.[30]

As many of the long-term effects of PUVA therapy may be dose related, minimizing cumulative PUVA exposure may reduce the risk of adverse events.[26,29] The use of combination treatment regimens such as retinoid-PUVA may be another approach to minimizing cumulative exposure; however, retinoid therapy is associated with unique safety issues (see 'Oral retinoids').

In the short term, PUVA is frequently associated with acute adverse reactions such as pruritus, nausea and delayed sunburn-like erythema.[25,26] Acute ocular reactions (i.e. conjunctival hyperaemia and decreased lacrimation) have been described in patients refusing to wear adequate eye sun-protection during treatment;[27,32] it is therefore recommended that patients use UVA-blocking plastic lens spectacles during the 24 h following oral PUVA therapy.[26] Because of the risk of sun damage associated with photosensitization following treatment, patients should also protect their skin from the sun.[26]

Careful selection of patients likely to benefit from, and comply with, treatment may enhance the safety of PUVA therapy.[26] According to oral methoxsalen prescribing guidelines, systemic PUVA therapy is contraindicated in patients who may have a history of photosensitive disease, certain skin cancers, aphakia (due to the increased risk of retinal damage), or idiosyncratic reactions to psoralen compounds ( Table 2 ).[25,27] Additionally, general PUVA treatment guidelines suggest that therapy should be avoided in immunosuppressed patients because of the risk of cancer.[26] The potential effects of systemic methoxsalen on the fetus and/or female reproductive capacity are not known; therefore, oral methoxsalen is contraindicated during pregnancy and should be administered to women of reproductive potential only when treatment is clearly justified.[27] As it is not known whether methoxsalen is excreted in human milk, oral methoxsalen is contraindicated during breastfeeding.[27]

There are relatively few monitoring requirements associated with oral PUVA compared with other systemic antipsoriatic therapies ( Table 3 ); however, it is important that patients undergo ophthalmological and routine laboratory evaluation prior to treatment and at regular intervals during therapy. Early detection of skin cancers, especially melanoma, is essential for their successful treatment; therefore, physicians and patients must be vigilant in monitoring skin lesions.[27,29] Patients with a history of prolonged coal tar and UVB therapy, ionizing radiation or arsenic exposure may be at increased risk of skin cancer and should be examined with particular care.[27] Caution should be exercised for patients receiving oral methoxsalen and concomitant photosensitizing medications because of the potential for enhanced phototoxicity ( Table 4 ). In addition, care should be taken with elderly patients and those who may be unable to tolerate PUVA therapy, for example, due to pre-existing hepatic insufficiency or cardiac disease.

A consensus workshop of international dermatologists concluded that in general PUVA has one of the most acceptable benefit/risk ratios of all treatments for moderate to severe psoriasis.[29] However, the risks and benefits of treatment must be weighed carefully for each individual. The benefit/risk ratio may appear particularly favourable for patients severely disabled by psoriasis who may be prepared to endure the acute adverse effects of PUVA therapy.[25] PUVA may be a favourable therapeutic option for elderly patients for whom ageing of the skin and skin cancers with prolonged latency represent less of a clinical concern.[29] Patients with skin types V and VI have a lower risk of skin cancer.[29] Conversely, the benefits of PUVA therapy may be reduced in patients who are noncompliant with therapy (e.g. due to frequent visits to the phototherapy clinic), patients whose tolerance to PUVA is limited by comorbid conditions or fair skin and patients with disease subtypes such as eruptive psoriasis.[25,26,33]

The acute and long-term risks of PUVA therapy can be minimized by careful monitoring.[25,34] However, research has shown that the risk of squamous cell carcinoma associated with PUVA therapy for psoriasis persists for at least 15 years after discontinuation of treatment, while the risk of basal cell carcinoma continues to increase after discontinuation.[35] Therefore, patients treated with PUVA require prolonged and rigorous follow-up,[35] and in contrast to some of the partially reversible toxicities associated with other systemic therapies for psoriasis, discontinuation may not be sufficient to limit the long-term impact of PUVA therapy, should monitoring reveal adverse effects.[29]

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