Systemic suppression of contact hypersensitivity in mice by psoralen plus UVA radiation (PUVA)

Treatment of mice with 8-methoxypsoralen plus longwave UV radiation (UVA, 320-400 nm) decreased their response to contact sensitizers applied subsequently to unirradiated skin. This decreased reactivity exhibited a delayed time course, it affected the afferent but not the efferent phase of the reaction, and it was associated with the development of splenic suppressor cells. These suppressor cells were antigen-specific T lymphocytes, and they prevented the induction, but not the elicitation, of contact hypersensitivity in recipient mice. In all of these characteristics, the decreased reactivity induced by treatment with psoralen plus UVA radiation (PUVA) resembled that produced by UV radiation of shorter wavelengths (less than 320 nm). These studies suggest that PUVA treatment may initiate the same sequence of cellular events as does exposure to sunlamp (UVB, 280-320 nm) radiation, leading to preferential activation of the suppressor cell pathway.     

The relationship between plasma psoralen concentration and psoralen-UVA erythema

The plasma 8-methoxypsoralen (8-MOP) concentration was measured in 60 patients commencing psoralen photochemotherapy (PUVA). At the time of blood sampling each patient was phototested using a series of 10 exposures to UVA. The resulting erythema was measured objectively 72 h after irradiation and dose-response curves for psoralen-UVA erythema were constructed. Although the dose of 8-MOP was calculated according to body weight, patients receiving 30 mg of 8-MOP had a significantly lower mean plasma concentration than those receiving higher doses. There was no significant correlation between plasma 8-MOP concentration and minimal phototoxic dose, either estimated visually or calculated from the dose-response curves. However the slope of the dose-response curve showed significant correlation with plasma 8-MOP concentration. The variation between patients in the rate of increase of the erythemal response, but not the variation in threshold sensitivity, can be explained by difference in plasma psoralen concentration.     

Skin cancer and psoralen plus UVA: a retrospective study of 106 patients exposed to a great number of PUVA treatments

INTRODUCTION: The benefits of PUVAtherapy in many dermatological affections are well known. Its carcinogenic role in the long term has been assessed varyingly in American and European series. OBJECTIVE: The aim of this study was to assess the role of PUVA in the onset of cancers of the skin. METHODS: Retrospective study of patients presenting with psoriasis and followed-up in the phototherapy unit of the Michallon Hospital in Grenoble since 1976 and having received more than 150 sessions of PUVA. The parameters studied were: age, gender, phototype, age at the time of the first irradiation, type of phototherapy administered, total number of sessions, concomitant treatments, administration of retinoids and the appearance of skin cancers with the interval before their onset after the first session, their localization and their histological type. RESULTS: One hundred six patients were retained among the 152 who replied to the inclusion criteria. Having died or been lost to follow-up, forty-six patients were excluded. Fourteen patients had presented at least one cutaneous tumor with a total number of 35. Excluding the keratoacanthomas, 13 patients had a non-melanic cutaneous cancer with a total number of 32 tumors. Ten out of the 14 were phototype III, 3 were phototype II and one was phototype IV. Nine out of 14 had received PUVAtherapy alone and 5 PUVAtherapy and broad spectrum UVB. The number of sessions of PUVA received in all the cases was more than 200 (220 to 780), corresponding to a total dose of UVA comprised between 1460 and 3882 Joules. The delay before onset of the tumors varied from 6 to 27 years after the first PUVAtherapy. The mean age at the time of the first irradiation was of 50.2 years (14-75 years). The mean duration of phototherapy was of 10 years (2.23 years).     

Environmental UVA radiation and eye protection during PUVA therapy

Experimental and clinical evidence suggests that patients receiving psoralens plus UVA radiation (PUVA) therapy for the treatment of psoriasis or other skin diseases run the risk of developing cataracts. The total exposure to UVA radiation of these patients has been difficult to quantify because they are exposed to UVA radiation in the environment as well as during PUVA therapy. In our studies, the spectral irradiances of possible environmental sources of UVA radiation (sunlight, daylight and cool white fluorescent bulbs, and incandescent bulbs) were measured and compared to the spectral irradiance of a bank of PUVA bulbs. Sunlight and PUVA bulbs were found to have similar irradiances in the UVA waveband. Window glass reduced the UVA irradiance from sunlight. Artificial sources of illumination had a very low UVA irradiance compared with PUVA bulbs and sunlight. These results indicate that patients should protect their eyes from sunlight both outdoors and indoors after ingestion of psoralens; however, protection from incandescent bulbs or cool white and daylight fluorescent bulbs is much less important, and possibly unnecessary.     

The effect of psoralen photochemotherapy (PUVA) on symptomatic dermographism

A controlled trial of 4-weeks oral photochemotherapy (PUVA) on 14 patients with severe symptomatic dermatographism produced a clinically useful reduction in itching in five patients. In four of these patients itching had relapsed to pre-treatment levels within 3 months of finishing the PUVA course. A comparison of the weal and flare responses on exposed and covered (control) skin using a calibrated dermographometer showed no significant change in skin reactivity, even in the patients who experienced symptomatic relief. While PUVA may temporarily reduce itching in some patients with symptomatic dermographism, its use cannot generally be justified for treating this type of physical urticaria.     

Ultrastructural modification of the plasma membrane in HUT 102 lymphoblasts by long-wave ultraviolet light, psoralen, and PUVA

Ultrastructural alterations of the plasma membrane in HUT 102 lymphoblasts were assessed after a 2-h interaction with a suprapharmacologic (15 micrograms/ml) concentration of 8-MOP, 2-h irradiation with UVA (2.1 mW/cm2), and the exposure of the HUT 102 cells to PUVA under the same conditions. The dark reaction of HUT cells with 8-MOP resulted in the disappearance of microvilli, the emergence of plasma-membrane-associated spherical bodies, formation of lamellar fungiform membrane evaginations, and, in approximately 1% of the cells, formation of uropods and cell capping. Except for uropod formation and cell capping, UVA has induced the same plasma-membrane alterations, and was more deleterious to structural cytoplasmic integrity than 8-MOP. Morphologic changes of the plasma membrane in PUVA-exposed cells tended to replicate structural alterations elicited independently during the dark reaction by suprapharmacologic 8-MOP concentrations. Partial retention of microvilli by cells after PUVA was the sole exception. In light of all available evidence we conclude that psoralen during the dark reactions interacts with plasma membrane lipids by as yet undisclosed mechanisms and that in addition to lipids, membrane proteins are also the primary target of the initial interaction of HUT 102 cells with psoralen during PUVA treatment.     

Evaluation of time-dependent response to psoralen plus UVA (PUVA) treatment with topical 8-methoxypsoralen (8-MOP) gel in palmoplantar dermatoses

BACKGROUND: Topical psoralen plus UVA (PUVA) is an effective treatment for localized forms of eczema, psoriasis, and palmoplantar pustulosis, which avoids some of the undesirable side-effects of systemic psoralens. Aims In this study, the efficacy of topical PUVA treatment with 8-methoxypsoralen (8-MOP) gel was compared with placebo plus UVA in chronic recurrent palmoplantar dermatoses. METHODS: Twenty-two patients with palmoplantar disease (11 with psoriasis vulgaris, six with eczema, and five with pustulosis) were enrolled in the study. The study design was a left-right comparison: one hand or foot was treated with 8-MOP 0.01% gel plus UVA, whilst the contralateral hand or foot received placebo and UVA for 6 weeks. Twenty minutes after application of the gel, both sides were exposed to UVA. The treatment regimen was three times a week, and the UVA dose was increased weekly by 20%. RESULTS: A comparison of the pre- and post-treatment scores with regard to the severity of the clinical picture and the infiltration of plaques showed a significant decrease (from 7.5 +/- 2.0 to 2.5 +/- 2.1 and from 2.0 +/- 0.7 to 0.3 +/- 0.5, respectively) in the sites treated with 8-MOP gel compared with placebo after 6 weeks. CONCLUSION: The results of the study indicate that at least 18 courses of local PUVA within 6 weeks, with a cumulative dose of 87 J/cm(2), are required to induce a significant decrease in the disease severity and an improvement in the infiltration of plaques due to 8-MOP gel at a concentration of 0.01% when treating chronic recurrent palmoplantar dermatoses.     

Erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA

In PUVA treatment of psoriasis, clinical observation suggests that uninvolved skin is more susceptible to PUVA erythema than lesions of psoriasis. If this is the case, then the efficacy of PUVA treatment might be increased by using localized high-dose UVA restricted to lesional skin. We have therefore studied the erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA and, for comparison, the erythemal response to UVB. In 14 patients, an area of psoriasis and adjacent uninvolved skin were exposed to a series of UVA doses (350 ± 30 nm, 1–16 J/cm²), using an irradiation monochromator. Six other patients were similarly phototested with a series of UVB doses (300 ± 5 nm, 20–112 mJ/cm²) to both uninvolved and lesional skin. Erythema was judged visually at 72 h for psoralen–UVA, and at 24 h for UVB, and measured using a scanning laser–Doppler velocimeter. In 10 patients, PUVA therapy using high-dose UVA was subsequently given to lesional skin (8–16 J/cm² twice weekly) in addition to conventional whole-body PUVA. For psoralen–UVA, the minimal phototoxic dose within psoriasis was increased by a factor of 4 compared with non-lesional skin (P < 0.01, Wilcoxon signed-rank test). For UVB, the minimal erythema dose within psoriasis was higher than that for non-lesional skin (medians > 112 and 28 respectively, P < 0.05). Laser–Doppler measurements confirmed that the reduced erythemal sensitivity was not due to masking of response by pre-existing increased blood flux within psoriasis. In six patients, the sites subsequently treated twice weekly with PUVA, using high-dose UVA, cleared faster (median number of treatments 3), but with a similar cumulative UVA dose, compared with adjacent lesional skin treated with conventional PUVA (median number of treatments 12). This study demonstrates that psoriasis may clear rapidly, without burning, using high-dose UVA. Availability of a suitable irradiation apparatus would allow rapid and effective PUVA treatment to be used for localized, resistant disease.     

A comparison of psoralen plus ultraviolet A (PUVA) monotherapy,tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis

BACKGROUND: Numerous studies have shown that the additional administration of topical or systemic antipsoriatic agents might serve as an effective means to increase the efficacy of photochemotherapy [psoralen plus ultraviolet (UV) A (PUVA)] for psoriasis. OBJECTIVES: To compare the therapeutic response to tacalcitol plus PUVA, tazarotene plus PUVA and PUVA monotherapy in patients with chronic plaque-type psoriasis. In addition, we also assessed the duration of remission induced by each regimen and the tolerability of the two combination treatments. METHODS: Thirty-one patients with chronic plaque-type psoriasis were included in this observer-blinded, intrapatient comparison trial. PUVA treatment was given four times weekly. Additionally, tacalcitol ointment and 0.1% tazarotene gel were applied separately on two target areas once daily in the evening. At the onset of therapy and every 2 weeks thereafter the response to treatment was determined by the Psoriasis Severity Index score, which assesses the degree of erythema, infiltration and scaling of the psoriatic lesions. After complete or near complete clearing patients were followed-up until relapse. RESULTS: Twenty-four patients completed the study. The treatment requirements to induce complete or near complete clearing were significantly lower for both combination treatments than for PUVA monotherapy (P < 0.01). The median cumulative UVA dose and number of exposures were 30.6 J cm-2 (95% confidence interval, CI 22.5-71.2) and 14 (95% CI 11-16) for tacalcitol plus PUVA, 32.3 J cm-2 (95% CI 22.5-73.8) and 14 (95% CI 11-19) for tazarotene plus PUVA, and 37.0 J cm-2 (95% CI 29.5-83.9) and 16 (95% CI 14-22) for PUVA monotherapy. No difference between the three regimens was observed with regard to duration of remission. Adverse reactions occurred more often with 0.1% tazarotene than with tacalcitol but were in general mild and completely reversible upon using a lower concentration of 0.05% tazarotene. CONCLUSIONS: Tacalcitol ointment and tazarotene gel are both comparably effective in improving the therapeutic result of PUVA therapy in patients with chronic plaque-type psoriasis. Besides accelerating the treatment response, both agents, by virtue of their UVA dose-sparing effect, might also help to reduce possible long-term hazards of PUVA treatment.     

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review

Background  

Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare.     

Treatment of vitiligo with local khellin and UVA: comparison with systemic PUVA

Vitiligo is an idiopathic leukoderma often with a progressive course causing destruction of melanocytes. The best methods for achieving cosmetically acceptable re-pigmentation of affected skin appear to be both local and systemic PUVA. They may, however, cause serious side effects, which is an argument for conducting research into new, equally effective photo-chemotherapeutic agents. One of these agents is khellin. We conducted a pilot study in 33 patients to evaluate the effectiveness of local KUVA and systemic PUVA therapy for vitiligo and to compare them in terms of the degree of re-pigmentation, duration of treatment, number of procedures, total UVA dose and side effects. Local KUVA required longer duration of treatment and higher UVA doses. KUVA-induced re-pigmentation depended on the age of the patients (r = -0.61, P = 0.001), and better results were achieved with younger individuals [% re-pigmentation = 81.76 - (1.48 x age in years)]. No side effects were observed in cases of local KUVA treatment. Erythema, itching and gastro-intestinal disturbances occurred with some patients treated with PUVA. The results demonstrate that local KUVA may effectively induce re-pigmentation of vitiligo-affected skin areas to a degree comparable to that achieved when using systemic PUVA, provided that treatment duration is long enough.     

Cutaneous carcinoma following psoralen and long-wave ultraviolet radiation (PUVA) therapy for psoriasis

Multiple basal cell epitheliomas developed in two psoriatic patients during treatment with orally administered 8-methoxypsoralen and long-wave ultraviolet radiation (PUVA). Twenty-two basal cell epitheliomas (BCEs) were seen in the two patients, 80% occurring in non-sun-exposed areas. Since neither patient had any historical or clinical evidence of arsenic intake or the basal cell nevus syndrome, PUVA therapy may have been of pathogenetic responsibility for the development of these lesions.     

Inhibitory effect of 8-methoxysporalen plus UVA (PUVA) on the systemic induction of contact sensitivity to dinitrochlorbenzene (DNCB) in guinea pigs

Summary To investigate the influence of 8-MOP and UVA on the induction of cell-mediated immunity, guinea pigs, sensitized with a single injection of dinitrofluorbenzene (DNFB) in Freund's complete adjuvant (FCA) in all footpads and the nuchal skin, were treated with 8-MOP, UVA, or 8-MOP+ UVA on days 0, 2, and 5 and tested with dinitrochlorbenzene (DNCB) on day 14 after sensitization. Two control groups, exposed in a covered condition to the PUVA 4000 lamp, to observe the heat effect, showed a slightly enhanced contact sensitivity in comparison to the only sensitized control group. No altered reactivity was observed after irradiation with longwave UV light alone, whereas a statistically significant enhanced resp. reduced contact sensitivity was obtained after the treatment with 8-MOP alone and the combined action of 8-MOP +UVA, respectively.Dedicated to Prof. Dr. P. Laugier, Chairman of the Department of Dermatology, University of Geneva, Switzerland, on the occasion of his 70th anniversary     

Photoageing: the role of UVB, solar-simulated UVB, visible and psoralen UVA radiation

We have studied the morphological and histological effects of chronic exposure of two strains of haired mice (albino Balb/c and pigmented C3H-) to various types of radiation. UVB (280-320 nm) radiation from unfiltered sunlamp bulbs for 20 and 30 weeks produced marked epidermal acanthosis and dyskeratosis which was reversible in mice exposed for 20 weeks followed by a 20-week rest. In the dermis the elastic fibres were altered and in the pigmented mice these changes had almost completely reversed 29 weeks after cessation of exposure. Cellulose acetate-filtered sunlamp bulbs (greater than 289 nm) produced similar but less marked changes. Chronic exposure to UVA (320-400 nm) radiation produced minimal alterations in the dermis while the epidermis was normal. Visible (greater than 400 nm) radiation in large doses produced no degenerative changes. Methoxsalen/UVA radiation produced epidermal acanthosis, dermal sclerosis, and alteration of elastic fibres, which was prominent in both strains at 40 weeks. These findings suggest that the UVB component of sunlight is largely responsible for photoageing of the skin. Furthermore, chronic exposure to methoxsalen/UVA therapy is likely to potentiate solar-induced photoageing.     

Topical psoralen photochemotherapy (PUVA) and superficial radiotherapy in the treatment of chronic hand eczema

The therapeutic efficacy of conventional superficial radiotherapy and topical psoralen photochemotherapy (topical PUVA) administered over a 6 week period was compared in a double-blind study of 21 patients with chronic bilateral constitutional hand eczema. One hand was treated with conventional superficial radiotherapy and the other with topical 8-methoxy-psoralen and long-wave ultraviolet light (topical PUVA). Significantly better clinical improvement was seen in superficial radiotherapy treated hands over topical PUVA treated hands after 6 weeks of treatment, but this difference was not maintained at 9 or 18 weeks. There was no significant difference in symptom severity between the two treatments after 6 weeks, but superficial radiotherapy produced significantly more symptomatic improvement at 9 and 18 weeks. Superficial radiotherapy is a less time consuming procedure than topical PUVA and leads to more rapid improvement.