The benefits and risks of long-term PUVA photochemotherapy.

In 1974 a new photobiologic principle i.e. light + drug, called photochemotherapy was discovered in Boston and immediately confirmed in Vienna. Psoralen + UVA (PUVA) photochemotherapy has now been applied to the treatment of more than 24 heterogeneous groups of diseases, especially psoriasis and mycosis fungoides. After 24 years of experience in thousands of patients with psoriasis and 23 other skin disorders, virtually the only risk is the development of squamous-cell carcinomas. This risk is low with two exceptions: previous history of treatment with ionizing radiation or inorganic trivalent arsenic, and patients with recalcitrant psoriasis who require continuous treatment for many years. In a recent report from a large USA clinical trial, melanoma developed in a few patients with psoriasis treated with PUVA. This prospective clinical trial did not have a control population, and therefore, the conclusion that PUVA can cause melanoma is tentative.

Topical or oral administration with an extract of Polypodium leucotomos prevents acute sunburn and psoralen-induced phototoxic reactions as well as depletion of Langerhans cells in human skin.

Sunburn, immune suppression, photoaging, and skin cancers result from uncontrolled overexposure of human skin to solar ultraviolet radiation (UVR). Preventive measures, including photoprotection, are helpful and can be achieved by topical sunscreening agents. Polypodium leucotomos (PL) has been used for the treatment of inflammatory diseases and has shown some in vitro and in vivo inmunomodulating properties. Its beneficial photoprotective effects in the treatment of vitiligo and its antioxidant properties encouraged us to evaluate in vivo the potentially useful photoprotective property of natural extract of PL after topical application or oral ingestion. Twenty-one healthy volunteers [either untreated or treated with oral psoralens (8-MOP or 5-MOP)] were enrolled in this study and exposed to solar radiation for evaluation of the following clinical parameters: immediate pigment darkening (IPD), minimal erythema dose (MED), minimal melanogenic dose (MMD), and minimal phototoxic dose (MPD) before and after topical or oral administration of PL. Immunohistochemical assessment of CD1a-expressing epidermal cells were also performed. PL was found to be photoprotective after topical application as well as oral administration. PL increased UV dose required for IPD (P < 0.01), MED (P < 0.001) and MPD (P < 0.001). After oral administration of PL, MED increased 2.8 +/- 0.59 times and MPD increased 2.75 +/- 0.5 and 6.8 +/- 1.3 times depending upon the type of psoralen used. Immunohistochemical study revealed photoprotection of Langherhans cells by oral as well as topical PL. The observed photoprotective activities of oral or topical PL reveal a new avenue in examining the potentially useful field of systemic photoprotection and suggests that PL can be used as adjunct treatment and can make photochemotherapy and phototherapy possibly safe and effective when the control of cutaneous phototoxicity to PUVA or UVB is a limiting factor in such phototherapies.

Total body heliotherapy.

Sunlight has long been known to be beneficial for a variety of skin diseases. Patients with psoriasis and eczema frequently employ ambient heliotherapy to control their conditions. However, social norms do not permit a person to expose the entire body in public, thus placing severe restrictions on the utility of this modality for the treatment of generalized psoriasis, for example. Tan-Thru bathing suits, designed to attract those who wish to tan without an accentuated "tan line", are reported to absorb ultraviolet (UV) rays up to a maximum equivalent of a sun protection factor (SPF) 10 sunblock, thus offering approximately 89% protection while in use, according to their manufacturer. If so, this bathing suit may allow patients with UV-responsive skin dermatoses to achieve full body exposure in a socially acceptable manner. The objective of this study was to verify the SPF and to determine the actual transmittance to skin covered by a Tan-Thru bathing suit. Ten healthy adult subjects were recruited for this investigation. UVB minimal erythema dose (MED) was determined on unaffected gluteal or lower back skin, once with and once without the swimsuit on. Our results showed that the mean SPF afforded by the bathing suit was in fact 4.9 (range 4.5-5.6). In conclusion, theoretically, the Tan-Thru bathing suits could allow enough UVB penetration under ambient conditions to be beneficial for patients with UVB responsive conditions.

Modifications of PUVA.

The goal of photochemotherapy in psoriasis is to attempt to lower the number of exposures and the total cumulative doses while still maintaining good control of the disease. PUVA has been modified by using better psoralen preparations and more effective light sources, and it also has been combined with other treatment modalities. The objectives in modifying PUVA and combining PUVA with other treatment modalities are to increase efficacy, to reduce short- and long-term adverse effects, and to reduce the cost of treatment. Modalities that have been combined with PUVA include topical corticosteroids, anthralin, calcipotriene ointment, methotrexate, UVB, retinoids, and cyclosporine.

Ocular findings in patients treated with PUVA.

This 5-year prospective study of ophthalmologic findings in 1299 patients treated with oral 8-methoxypsoralen photochemotherapy (PUVA) for psoriasis failed to demonstrate a significant dose-dependent increase in the risk of developing symptomatic cataracts. These patients were instructed to wear UVA-blocking eyeglasses when exposed to sunlight and during treatment for a 12-h period beginning from the time of 8-methoxypsoralen ingestion. However, we did observe a small increase in the risk for development of nuclear sclerosis and posterior subcapsular opacities among patients who received at least 100 PUVA treatments, compared to patients with fewer than 100 treatments (relative risk = 2.3 and 3.0, respectively; p less than .05 both comparisons). We compared our results to those of a large, population-based study and found, after adjusting for differences in methods, that the prevalence of cataracts in our study patients, aged 52-75 years, was not significantly different. Since the latency period for development of symptomatic ocular abnormalities may be longer than 5 years, continued surveillance of our cohort and continued use of appropriate ocular protection by all patients treated with PUVA is indicated.

Actinic degeneration in association with long-term use of PUVA.

To determine the extent of clinical actinic damage that occurred in association with exposure to oral methoxsalen photochemotherapy (PUVA), dermatologists at 16 university centers assessed the wrinkling, telangiectasia, and altered skin markings on the buttocks and the dorsa of the hands among 1380 patients treated with PUVA. These changes are similar to those seen in skin that is chronically exposed to sunlight. After more than 5 years of prospective study, patients with psoriasis exposed to PUVA showed a significant dose-dependent increase in the prevalence of clinical actinic degeneration of the skin of the buttocks (p less than .05, F-test). The prevalence of moderate or severe change among those patients exposed to high doses of PUVA (more than 160 treatments) was low (11%). The degree of increased clinical actinic degeneration noted on the dorsa of the hands was also significantly related to total exposure to PUVA (p less than .05, F-test). Our findings indicate that long-term PUVA exposure is associated with an increase in clinical actinic degeneration of the skin. However, the magnitude of this increase is small and, after more than 5 years, is of limited clinical consequence to most patients.

Chronic cutaneous effects of long-term psoralen and ultraviolet radiation therapy in patients with vitiligo.

Vitiligo is refractory to most therapeutic modalities. To assess the efficacy of a variety of PUVA therapies, we enrolled 596 subjects in a prospective study, and 230 were followed for up to 55 months. Various psoralen derivatives and dosage schedules were used. Each subject was examined at yearly intervals for therapeutic response and evidence of chronic PUVA toxicity. At 4 years after therapeutic inception, 29 (13%) developed lesions in remaining vitiliginous macules. Clinically, hyperkeratotic macules and hyperkeratotic, lichenoid, and telangiectatic papules were discerned. Histologic examination of these lesions revealed them to be actinic and lichenoid keratoses, verruca vulgaris, and hyperkeratosis with either hyperplasia or atrophy. No tumors were present. In perilesional skin, dermal collagen and elastic tissue degeneration, much greater in degree than reported in psoriatic skin, was observed. In this group of PUVA-treated patients, no increased risk of carcinoma was apparent during the follow-up period.

Cutaneous squamous-cell carcinoma in patients treated with PUVA.

A 5.7-year prospective study of 1380 patients treated for psoriasis with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA) revealed that after adjustment for exposures to ionizing radiation and topical tar preparations, the risk that cutaneous squamous-cell carcinoma would develop at least 22 months after the first exposure to PUVA was 12.8 times higher in patients exposed to a high dose than in those exposed to a low dose (95 per cent confidence interval, 5.8 to 28.5). No substantial dose-related increase was noted for basal-cell carcinoma. The dose-dependent risk of cutaneous squamous-cell carcinoma suggests that PUVA can act as an independent carcinogen. In our study, morbidity associated with these tumors has been limited, but further follow-up is needed. Meanwhile, patients treated with PUVA should be followed closely for the possible development of cutaneous squamous-cell carcinoma.

Morphologic alterations of epidermal melanocytes and melanosomes in PUVA lentigines: a comparative ultrastructural investigation of lentigines induced by PUVA and sunlight.

Ultrastructural studies were conducted in order to determine morphologic and functional differences in melanocytes and melanosomes in PUVA lentigines and solar lentigines, and light-protected buttock skin. Compared to melanocytes in solar lentigines from 7 subjects and light-protected buttock skin from 5 subjects (none of these subjects had received UV radiation therapy), melanocytes in PUVA lentigines from 6 subjects generally had longer and more numerous dendrites, and showed more active melanogenesis. Basal keratinocytes in PUVA lentigines had a significantly increased frequency of large, single melanosomes, and revealed significantly larger individual melanosomes within compound melanosomes. Other findings in some PUVA lentigines included the close apposition of Langerhans cells to melanocytes, and atypical nuclear, cytoplasmic and melanosomal alterations, including melanosomal pleomorphism and melanin macroglobules. The presence of relatively large and predominantly single melanosomes in basal keratinocytes of PUVA lentigines suggests more active melanogenesis and/or an irreversible somatic alteration. It will be important to determine the clinical course and ultrastructural findings of PUVA lentigines that persist long after PUVA is discontinued.

Combined methotrexate-PUVA therapy in the treatment of psoriasis.

Thirty patients with psoriasis were treated with a 3-week course of methotrexate followed by a combination of PUVA therapy and methotrexate. When lesions cleared to less than 1% UVA-exposed body involvement, the methotrexate was stopped and PUVA therapy alone was used as maintenance therapy. This protocol achieved clearance of disease in twenty-eight of the thirty patients in a mean of 5.7 (+/- 1.0) weeks, with 9.3 (+/- 3.0) exposures to PUVA therapy and a final UVA radiation dose at clearance of 6.2 (+/- 2.5) J/cm2. The mean total dose of methotrexate was 93.0 mg (range, 67.5-127.5 mg). The only significant adverse effect seen was prolonged phototoxicity in eight patients. By reducing the total cumulative exposure dose of PUVA therapy, this treatment may reduce long-term side effects.

Effect of methoxsalen photochemotherapy on cost of treatment for psoriasis. An example of technological assessment.

In 1974 a new therapy that employs methoxsalen and ultraviolet A irradiation (PUVA) was introduced as an outpatient treatment for severe psoriasis. To study the effect of this therapy on the cost of treatment, we documented for 1,320 patients two major components of cost--hospitalization and PUVA treatments. When the one-year period before initiation of PUVA therapy was compared with a one-year period after initiation of PUVA therapy, average hospital days per person per year declined 77% (5.1 vs 1.2). This decrease in hospitalization was most notable among patients who continued to use PUVA therapy. Largely offsetting the reduction in cost from reduced hospitalization was the cost of PUVA treatments. Our data confirm the previously known effectiveness of PUVA therapy, and they provide no support for the hypothesis that PUVA substantially increases the cost of treating patients with severe psoriasis.