Psoralen UVA Research Articles

Papular dermatitis (subacute prurigo, “itchy red bump” disease): Pilot study of phototherapy

Background: Some patients with a subacute or chronic pruritic erythematous papular eruption are refractory to treatment. We previously described a number of these patients with papular dermatitis or subacute prurigo. Objective: The purpose of this study was to examine the effectiveness of different types of phototherapy for treatment of papular dermatitis. Methods: We reviewed the medical records of 11 patients who were diagnosed with papular dermatitis and who underwent phototherapy within the last 5 years. Results: Eleven patients had a total of 17 phototherapy courses: psoralen–UVA (PUVA; 9), UVA/UVB light (3), and UVB alone (5). Within the PUVA treatment group, three of nine patients experienced total clearing, and six of nine patients experienced partial improvement. Although patients in all groups relapsed with time, overall the PUVA-treated patients had the best response rate and the best chance of the condition remaining clear after treatment was stopped. Conclusion: PUVA may be an effective treatment for papular dermatitis. The frequency of relapse indicates that maintenance treatments may be necessary for long-term control of the disease. (J Am Acad Dermatol 1998;38:929-33.)

Narrow band UVB (311 nm) phototherapy and PUVA photochemotherapy: A combination

Background: Psoralen-UVA (PUVA) photochemotherapy is widely used for the treatment of psoriasis despite concerns of skin carcinogenesis from high cumulative UVA doses and number of treatments. Objective: We attempted to determine whether combined bath-PUVA with narrow-band (311 nm) phototherapy improves efficacy and reduces long-term toxicity. Methods: Twelve psoriatic patients underwent phototesting with 311 nm lamps and, after topical bath-water psoralen sensitization, with 311 nm, UVA, or both radiations. Patients were treated with bath-PUVA on one side of the body and with bath-PUVA plus 311 nm exposures (bath-PUVA–311 nm) on the other side. On both sides, four weekly treatments were delivered and UVA doses were increased once weekly whereas 311 nm doses were adjusted at each exposure. Results: Psoralen sensitization did not modify the erythematous threshold to 311 nm radiation. However, 311 nm exposures enhanced the phototoxic activity of bath-PUVA. Bath-PUVA–311 nm cleared psoriasis with fewer exposures and lower cumulative UVA doses under the same minimally erythemogenic conditions. Conclusion: Combination with 311 nm exposures enhanced the phototoxic and therapeutic activities of bath-PUVA. (J Am Acad Dermatol 1998;38:687-90.)

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.

The psoriatic patient and the use of topical antipsoriatics

Psoriasis is a chronic disease with profound social implications. When patients are asked about the worst aspect of having psoriasis, most of them answer that it is the appearance and consequent embarrassment. Dermatological diseases all have a strong impact on the patient's psyche because of their visibility. The onset of psoriasis in childhood or adolescence can magnify the psychological aspects of the disease. Attempts have been made to quantify stress and to identify its relationship to skin disease. Although studies on the relationship between stress and psoriasis are often at variance, there seems to be a subgroup of patients in whom stress is a precipitating factor. Psoriasis for most patients requires regular treatment. There are types of the disease which respond very well to certain treatments with long-term remission. However, psoriasis is a disease which can be koebnerized by internal and external triggers, may vary in its life cycle and may relapse frequently. There are still disadvantages with all available therapies. They may have serious side-effects during or after treatment or the treatment protocol may be difficult to follow. Treatments such as short-contact dithranol, ultraviolet (UV) A/B radiation and psoralen/UVA (PUVA) are either difficult to use at home or require special equipment and experienced personnel. In general, severe psoriasis requires the facilities of a hospital or a daycare clinic. However, mild psoriasis mostly does not need these specialist facilities. The patient is able to perform the treatment at home. In the last 5 years psoriatic patients have experienced a marked increase in their quality of life as a result of the introduction of balneophototherapy, bath PUVA and, in particular, new topical treatments with vitamin D3 derivatives (calcipotriol, tacalcitol) and very recently a topical retinoid. Combination of the topical agents with other treatment modalities such as UVA/B, bath-PUVA or balneophototherapy can increase efficacy by lowering the side-effects and shortening the treatment time. A treatment with tacalcitol, for example, once daily significantly decreases the time needed for selfcare at home. In a very recent nonrandomized study, 5205 patients with mild to moderate psoriasis were treated with tacalcitol once daily alone or in combination with UV or other treatments. Over 90% showed a good to very good compliance and reported very good to good local tolerability. More than 80% of the patients improved markedly during a treatment course of 8-12 weeks. Systemic adverse events such as an increase in plasma calcium could not be detected.

Psoralen bath plus UV-A therapy. Possibilities and limitations

Psoralen bath plus UV-A therapy. Possibilities and limitations

Psoralen UVA therapy for linear and generalized morphea

APL is characterized histologically by delicate, thin-walled, vascular spaces lined by endothelium in the papillary dermis. The vascular spaces form channels that run horizontally and have a dissection of appearance. There is no cellular atypia. In some cases the lesion extends to the mid and reticular dermis and even to the subcutis, and the vascular spaces in the deep tissue are smaller and have irregular appearance. 5 Immunohistochemical studies have given inconsistent results. Wilson Jones et al. 5 found that the lesional endothelial cells were UEA-1 positive and factor VIII-related antigen negative. Rosso, Gianelli, and Carnevali 9 found that factor VIII-related antigen was positive, whereas UEA1 was inconsistently reactive in the endothelial cells. Tadaki et al. 4 reported that in their case endothelial cells did not stain with either factor VIII-related antigen or UEA-1. Zhu et al. 6 found type IV collagen and desmin surrounding the vascular channels, suggesting that APL is a hamartoma that contains blood and lymphatic vessels as well as smooth muscle.

Photogenotoxicity of Skin Phototumorigenic Fluoroquinolone Antibiotics Detected Using the Comet Assay

The fluoroquinolone (FQ) antibiotics photosensitize human skin to solar UV radiation and are reported to photosensitize tumor formation in mouse skin. As tumor initiation will not occur without genotoxic insult, we examined the potential of ciprofloxacin, lomefloxacin, fleroxacin, BAYy3118 (a recently developed monofluorinated quinolone) and a nalidixic acid to photosensitize DNA damage in V79 hamster fibroblasts in vitro. Cells were exposed to 37.5 kJ/m2 UVA (320-400 nm; glass filtered Sylvania psoralen + UVA (PUVA) tubes; calibrated Waldmann radiometer) at 4 degrees C in the presence of FQ and immediately afterwards embedded in agarose, lysed and placed in an electrophoretic field at pH 12. Under these denaturing conditions, the presence of DNA single-strand breaks (SSB), alkali-labile sites (ALS) and double-strand breaks (DSB) can be visualized as DNA migrating away from the nucleus (characteristic "comet" appearance) after staining with a specific fluorochrome. At FQ concentrations that induced minimal loss of cell viability (neutral red uptake assay) the compounds tested induced comets with a rank order of BAYy3118 > norfloxacin > ciprofloxacin > lomefloxacin > fleroxacin > nalidixic acid. If cells were incubated after treatment for 1 h at 37 degrees C, the comet score decreased, suggesting efficient removal of SSB/ALS/DSB. Addition of the DNA polymerase(alpha) inhibitor, aphidicolin, to cells treated with either ciprofloxacin alone or ciprofloxacin + UVA resulted in an accumulation of SSB due to the endo/exonuclease steps of excision repair. We have demonstrated that the FQ are photogenotoxic in mammalian cells but the FQ-photosensitized SSB are efficiently repaired. Preliminary evidence that ciprofloxacin photosensitizes the formation of DNA lesions warranting excision repair may indicate production of more mutagenic lesions.

P53 Mutation in Squamous Cell Carcinomas from Psoriasis Patients Treated with Psoralen + UVA (PUVA)

Individuals suffering from psoriasis are treated with a combination of psoralen and UVA radiation, commonly referred to as "PUVA" therapy. Epidemiologic studies have shown that PUVA therapy is a risk factor for skin cancer in psoriasis patients. Although PUVA treatment induces skin cancer in laboratory animals, it is unknown whether the increased incidence of skin cancer reported in PUVA-treated psoriasis patients is due to the carcinogenic effects of PUVA or due to other factors such as UVB. Because UV and PUVA induce different types of DNA damage resulting in unique types of p53 mutation, we investigated whether skin cancers from PUVA-treated psoriasis patients have PUVA-type or UV-type p53 mutations. Analysis of 17 squamous cell carcinomas (SCCs) from Austrian PUVA-treated patients revealed a total of 25 p53 mutations in 11 SCCs. A majority of p53 mutations occurred at 5'TpG sites. Although previous studies have shown that 5'TpA sites are the primary targets for PUVA mutagenesis, substitutions at 5'TpG sites are also quite common. Interestingly, a sizable portion of p53 mutations detected were C-->T or CC-->TT transitions, characteristic of UV-induced mutations. Because some psoriasis patients had substantial exposure to UVB before PUVA therapy and because the light sources used in PUVA therapy contained small but significant wavelengths in the UVB region, it is possible that the C-->T and CC-->TT transitions detected in SCCs from PUVA-treated patients were induced by UVB. Nonetheless, our results indicate that both PUVA and UVB may play a role in the development of skin cancer in Austrian psoriasis patients who undergo PUVA therapy.

Viral attenuation of labile blood products

Viral inactivation is one of the possibilities to reduce the residual risk of blood products. It is now applied to all plasma derived products (PDP). Application of such techniques to labile blood products (LBP) is difficult for two main reasons: any method should inactivate cell-associated viruses and should avoid any injury of the cells constituting the active ingredient. Physical techniques may reduce the viral content of cellular BPL (leucodepletion, washing, gamma irradiation), but none of them is active enough to comply with the present requirements for efficacy. An important work has been dedicated to the development of virus photoinactivation techniques. They consist of the addition of a photoreagent followed by illumination at an appropriate wavelength which results in a photochemical reaction responsible for the viral inactivation. Treatment of platelet concentrates by psoralen derivatives and UV-A illumination significantly inactivate in vitro enveloped and naked viruses, free and cell-associated viruses and also sequences integrated in the viral genome. Recent progresses have led to these results without detectable functional alteration of platelets and mutagenicity. Viral inactivation of red blood cells yet did not reach the same level because hemoglobin does not allow the use of the photoreagent compounds applicable to platelet concentrates. Viral decontamination of fresh frozen plasma by solvent and detergent, active on enveloped viruses, has been used in France since 1992. Other techniques of comparable efficacy, have received an agreement in other countries. The research on viral inactivation of LBP could prove to be of great importance in the near future in bringing additional safety to patients not only for the residual viral risk but maybe also for the residual bacterial risk of LBP.

Complete Remissions in Psoralen and UV-A (PUVA)-Refractory Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma With Combined Interferon Alfa and PUVA

BACKGROUND AND DESIGN--The optimal therapy for the mycosis fungoides type of cutaneous T-cell lymphoma has yet to be determined. Based on recent reports on the efficacy of high-dose interferon alfa in cutaneous T-cell lymphoma, we chose to test the hypothesis that systemic adjunctive therapy with low-dose interferon alfa along with psoralen and long-wave UV-A radiation (PUVA) could decrease the amount of PUVA necessary to achieve the best response, as well as improve the therapeutic effect of PUVA. Five patients with cutaneous T-cell lymphoma (mycosis fungoides type) were initially treated unsuccessfully with PUVA alone (three times a week for at least 3 months); PUVA was stopped, patients' diseases were re-staged, then interferon alfa (3 x 10(6) U/d for 1 week, then 6 x 10(6) U/d for 1 week) was initiated 2 weeks prior to restarting PUVA. Responses to treatment were graded as complete remission (skin clear, or negative biopsy specimens of remaining dermatitic lesions), partial remission (> 50% improvement), progression (> 25% worsening), or no change (failure to qualify for other categories) at 4, 8, 12, and 16 weeks. OBSERVATIONS--After 3 to 5 months of treatment with PUVA thrice weekly, none of the patients treated with PUVA alone had achieved complete remission. By contrast, systemic adjunctive therapy with low-dose interferon alfa along with PUVA resulted in complete remissions in all five (100%) patients in an average of 3.2 months (in three patients, lesions were cleared by 3 months). Average of 107 additional joules (68% more) and 1.6 additional months of PUVA administered thrice weekly was required to achieve the best response attainable with PUVA alone compared with complete remissions achieved with combined interferon alfa and PUVA therapy. --These data indicate that patients with disease refractory to PUVA alone can achieve a complete remission if they restart treatment with PUVA in combination with well-tolerated low doses of interferon alfa. In addition, the duration of PUVA exposure can be reduced with the addition of low-dose interferon alfa to the conventional PUVA treatment of cutaneous T-cell lymphoma of the mycosis fungoides type in such patients.

8-Methoxypsoralen and longwave ultraviolet irradiation are a novel antiproliferative combination for vascular smooth muscle.

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Although the effects of arterial exposure to high-energy radiation sources such as laser have been investigated in detail, the effects on vascular cells of low-intensity radiant energy in combination with photoactive agents have not been extensively characterized. Psoralens are photoactive agents that are known to be well tolerated when used in conjunction with local exposure to ultraviolet light in the A band (UVA) for the treatment of various dermatologic proliferative disorders. We have investigated the effects of psoralen/UVA (PUVA) exposure on the proliferation of bovine aortic smooth muscle cells. Proliferation and viability were assessed over a 14-day period by trypan blue exclusion counts. Cell cycle effects were evaluated by thymidine incorporation and flow cytometry with DNA quantitation after addition of serum or platelet-derived growth factor B-chain (PDGF-BB) to subconfluent cells synchronized by serum withdrawal. No effect was observed after exposure to 8-methoxypsoralen (8-MOP) at concentrations up to 10 microM or UVA irradiation at energies up to 2.5 J/cm2. Longwave ultraviolet light and 8-MOP were found to behave synergistically as potent inhibitors of DNA synthesis in bovine aortic smooth muscle cells with the EC50 in combination ranging from 7 microM at 0.35 J/cm2 to 0.2 microM at 2.1 J/cm2. Similar antiproliferative effects were obtained by an inverse variation of dose and energy delivered. After serum stimulation, inhibition of DNA synthesis was found with either an immediate or delayed (16-hour) application of PUVA. This effect was independent of subsequent 8-MOP washout. Flow cytometry of cells treated with PUVA at several times after serum stimulation demonstrated for each time point a block in further cell cycle progression for cells in all phases of the cell cycle. Evaluation of [125I]-labeled PDGF and epidermal growth factor (EGF) binding revealed no effect of PUVA on the apparent number or affinity of PDGF binding sites present but did reveal a dose-dependent inhibition by PUVA of EGF binding. This inhibition of EGF binding occurred increasingly at higher PUVA doses than the cell cycle inhibition and accordingly did not appear to represent a critical mechanism for the antiproliferative effect. Cell counting after a single exposure to PUVA (1 microM, 1.5 J/cm2) revealed complete stasis of cell proliferation over a 28-day period without recurrent exposure. No increase in trypan-positive cells was noted over this period. PUVA treatment represents a novel method for locally inhibiting proliferation of vascular smooth muscle cells without producing cytolysis.

Doses of ultraviolet radiation that modulate accessory cell activity and ICAM-1 expression are ultimately cytotoxic for murine epidermal Langerhans cells.

Mechanisms that underlie immunomodulatory properties of ultraviolet (UV) radiation remain incompletely characterized. Recently, we have studied effects of UV on the functional activity of epidermal Langerhans cells (LC) and have attempted to relate inhibitory effects of UV on LC function to modulatory effects of UV on adhesion molecule expression by LC. Exposure of LC in vitro to amounts of UVB, UVC, or psoralen+UVA (PUVA) radiation that inhibited LC function also prevented increased expression of intercellular adhesion molecule-1 by LC in vitro. Subsequent studies revealed that amounts of UV radiation that inhibited LC function and modulated ICAM-1 expression also decreased LC survival in vitro, although UV-induced LC cytotoxicity did not become apparent until 48-72 h after UV exposure. Our results are consistent with those of previous studies that suggested that low doses of UV radiation were cytotoxic for LC in situ. The potential cytotoxicity of UV radiation for LC should be considered when studies of effects of UV radiation on immune responses in skin are interpreted.

Cyclosporin A Suppresses ICAM-1 Expression by Papillary Endothelium in Healing Psoriatic Plaques

To analyze the mode of action of Cyclosporin A (CsA) in psoriasis, we examined the phenotypic profile of resident and passenger skin cells in seven psoriatic patients before and after 2 weeks of CsA treatment using a large panel of monoclonal antibodies in a three-step immunoperoxidase technique. For comparison, skin biopsies from psoriatic patients receiving psoralen + UVA (PUVA) therapy were examined. Although both treatment protocols were equally effective in inducing resolution of psoriatic lesions, the phenotypic changes induced by CsA differed greatly from those seen after PUVA. In CsA-treated patients there was a dramatic reduction in the ICAM-1 expression by papillary endothelial cells, but density, pattern, and phenotype of infiltrating inflammatory cells remained essentially unchanged. In contrast, PUVA therapy had no visible effect on ICAM-1 expression by papillary endothelial cells, but resulted in a significant reduction of the hemopoietic resident and infiltrating mononuclear cells within the epidermis. These results favor, but do not prove, the assumption that the CsA regimen chosen in this study exerts its anti-psoriatic effect primarily at the level of the keratinocyte, i.e., by inhibiting events leading to keratinocyte proliferation as well as by interfering with the secretion of mediators responsible for ICAM-1 expression by papillary endothelial cells.

A comparison of the dose-response relationship for psoralen-UVA erythema and UVB erythema

Twenty patients with psoriasis were phototested to determine their erythemal responses to UVB and psoralen-UVA (PUVA) (oral 8-methoxypsoralen). The smallest ultraviolet radiation doses to produce erythema (minimal erythema dose and minimal phototoxic dose, respectively) were recorded and dose-response curves were constructed for UVB (24 hours after irradiation) and PUVA (48 hours) using objective measurement. The choice of a 48-hour measurement was validated by phototesting an additional 11 subjects to determine the time course of PUVA erythema. No correlation was demonstrated between minimal erythema dose for UVB, minimal phototoxic dose for PUVA, and sun-reactive skin type. The mean slope of the dose-response curve for UVB erythema was four times steeper than that for PUVA. Psoralen-UVA erythema reached a broad maximum between 48 and 96 hours after irradiation. Using objective methods we have demonstrated that the commonly accepted view of a steep dose-response relationship for PUVA erythema is not valid.

A Comparison of the Dose-Response Relationship for Psoralen-UVA Erythema and UVB Erythema

Twenty patients with psoriasis were phototested to determine their erythemal responses to UVB and psoralen-UVA (PUVA) (oral 8-methoxypsoralen). The smallest ultraviolet radiation doses to produce erythema (minimal erythema dose and minimal phototoxic dose, respectively) were recorded and dose-response curves were constructed for UVB (24 hours after irradiation) and PUVA (48 hours) using objective measurement. The choice of a 48-hour measurement was validated by phototesting an additional 11 subjects to determine the time course of PUVA erythema. No correlation was demonstrated between minimal erythema dose for UVB, minimal phototoxic dose for PUVA, and sun-reactive skin type. The mean slope of the dose-response curve for UVB erythema was four times steeper than that for PUVA. Psoralen-UVA erythema reached a broad maximum between 48 and 96 hours after irradiation. Using objective methods we have demonstrated that the commonly accepted view of a steep dose-response relationship for PUVA erythema is not valid.

Lysosomes: A possible target for psoralen photodamage

Treatment in vitro of Ehrlich ascites tumor cells or human fibroblasts with 8-methoxypsoralen (8-MOP, 2.4 μM) and UVA irradiation results in a 30% and 60% respectively reduction in lysosomal β-galactosidase activity in situ. Under identical conditions one 8-MOP adduct was formed per 2 × 10 4 bases of DNA, one 8-MOP adduct was formed per ∼ 10 4 tRNA molecules and one per ∼ 100 ribosomes. It is suggested that the decrease in lysosomal β-galactosidase activity is a result of leakage through the lysosomal membrane caused by psoralen—UVA damage of the lipids in the membrane, since no effect was found on β-galactosidase in vitro. These results indicate that the lysosomes may also be a target for cellular photodamage by 8-methoxypsoralen.

In vitro dissolution rates of six 8-methoxypsoralen formulations.

Dissolution rates in water of six oral 8-methoxypsoralen formulations were determined with both the rotating basket method and a column type flow-through method. Comparable and reproducible results were obtained with both methods. In view of the necessity in psoralen-UVA (PUVA) therapy that effective tissue concentrations of the drug be present in the skin during the irradiation period, we propose a requirement for a dissolution rate of 8-MOP tablets or capsules of at least 80% within 25 min. None of the three preparations registered in The Netherlands met this requirement. However, two preparations from abroad and a new capsule formulated in our pharmacy department with solid 8-MOP dispersed in polyethylene glycol 6000 showed satisfactory dissolution profiles.

Depletion of Cutaneous Glutathione and the Induction of Inflammation by 8-Methoxypsoralen Plus UVA Radiation

The purpose of this study was to examine the dose response and time course relationships between PUVA (psoralen + UVA) depletion of skin glutathione (GSH) and the induction of inflammation. Dorsal skin fold thickness (DSFT), an index of cutaneous edema, was used as a noninvasive measure of inflammation. Ornithine decarboxylase (ODC) was used as a measure of epidermal damage. Female hairless mice were given 8-methoxypsoralen (8-MOP) (dissolved in corn oil) by gavage at different doses, and 2 h later the mice were irradiated with 5 J/cm2 UVA. At 24 h, DSFT measurements were taken, the mice were killed, and reduced GSH, glutathione disulfide (GSSG), and glutathione-S-transferase were measured in the epidermis and dermis. Epidermal GSH was depleted 0, 11, 45, 87, and 98% from vehicle and/or UVA-treated levels (0.7 mM) after 0.1, 0.5, 5, 25, and 50 mg/kg, respectively. In the dermis GSH decreased from 0.3 mM by 47, 87, and 91% after 5, 25, and 50 mg/kg 8-MOP, respectively. Increases in DSFT of 20, 141, and 242% were observed after 5, 25, and 50 mg/kg doses, respectively. GSSG accounted for a small portion of total GSH in the skin after PUVA treatment. The maximal decreases in GSH were not observed until 24-48 h after PUVA treatment. PUVA treatment leads to dose-related increases in dermal edema, epidermal ODC, and depletion of GSH levels from both compartments in the skin. The time course of glutathione loss suggests that PUVA may interfere with its resynthesis or utilization from the circulation.

Problèmes posés par l'utilisation thérapeutique des photosensibilisateurs en dermatologie

Three phototherapeutic regimens with photosensitization are now used in dermatology: PUVA (psoralen + UVA), TUV (crude coaltar + UV), PRT (phototherapy with hematoporphyrin derivative). The efficiency of PUVA and TUV is well known in several dermatoses. PRT is now being tested experimentally. For TUV, the lack of a standardized regimen does not allow a clear-cut evaluation of the therapy. For PUVA, late side-effects, particularly carcinogenicity have to be considered. To improve efficiency and minimize the side-effects of PUVA some procedures, such as association with retinoïds, pharmaco-kinetic studies for individual adaptation of the therapeutic regimen and the use of new less mutagenic psoralens are helpful. The persistent phototoxicity following treatments with hematoporphyrin derivative constitutes the major side-effect observed, for this phototherapy.

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.