Risks of cancer associated with long-term exposure to PUVA in humans: current status--1991.

Since 1975 oral 8-methoxypsoralen administered in association with ultraviolet-A radiation (UVA), (PUVA) has been widely used to treat psoriasis and other cutaneous diseases. PUVA is mutagenic, and in animals carcinogenic. Prospective study of a cohort of patients with psoriasis who were first treated with PUVA in 1975-1976 has provided data on the carcinogenic risk of this treatment. There is a dose-dependent increase in the risk of squamous cell cancer of the skin associated with exposure to PUVA. A recent large-scale Swedish study confirmed this association. The risk of squamous cell cancer of the genitals of males exposed to high doses of PUVA is especially high. A consistent, confirmed, and significant relationship of exposure to PUVA to other types of malignancies in man has not been established. Although highly effective in the treatment of psoriasis, the risk of squamous cell cancer associated with long-term therapy with PUVA must be considered in determining when this therapy is appropriate for an individual patient. Additional study of PUVA-treated patients will better define the full spectrum of the carcinogenic risk of PUVA therapy and the clinical behavior of tumors that arise in association with this treatment.     

PUVA (8-methoxy-psoralen plus ultraviolet A) induces the formation of 8-hydroxy-2'-deoxyguanosine and DNA fragmentation in calf thymus DNA and human epidermoid carcinoma cells.

The objective of this study is to investigate if 8-methoxy-psoralen (8-MOP) plus ultraviolet A (UVA) radiation (PUVA) induces oxidative DNA damage. When calf thymus DNA was incubated with 8-MOP and irradiated with UVA (335-400 nm), the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was substantially increased by approximately 6-fold. Formation of 8-OHdG proportionally correlated with both UVA fluence and 8-MOP concentrations. Human epidermoid carcinoma cells were incubated with 10 microg 8-MOP per milliliter, followed by irradiation of 25 kJ/m2 UVA. The level of 8-OHdG increased by nearly 3-fold in PUVA-treated cells compared to 8-MOP and UVA controls. The formation of 8-OHdG correlated with DNA fragmentation as determined by spectrofluorometry. To investigate the reactive oxygen species (ROS) involved in PUVA-induced oxidative DNA damage, less or more specific ROS quenchers were added to DNA solution prior to PUVA treatment. The results showed that only sodium azide and genistein significantly quenched PUVA-induced 8-OHdG, whereas catalase, superoxide dismutase, and mannitol exhibited no effect. The quencher study with cultured cells indicated that N-acetyl-cysteine and genistein protected oxidative DNA damage as well as DNA fragmentation by PUVA treatment. Our studies show that PUVA treatment is able to induce the formation of 8-OHdG in purified DNA and cultured cells and suggest that singlet oxygen is the principle reactive oxygen species involved in oxidative DNA damage by PUVA treatment.     

Antiapoptotic role of p38 mitogen activated protein kinase in Jurkat T cells and normal human T lymphocytes treated with 8-methoxypsoralen and ultraviolet-A radiation

A combination of 8-methoxypsoralen and ultraviolet-A radiation (320–400 nm) (PUVA) is used for the treatment of T cell-mediated disorders, including chronic graft-versus-host disease, autoimmune disorders, and cutaneous T-cell lymphomas. The mechanisms of action of this therapy, referred to as extracorporeal phototherapy, have not been fully elucidated. PUVA is known to induce apoptosis in T lymphocytes collected by apheresis, however no information is available concerning the underlying signaling pathways which are activated by PUVA. In this study, we found that PUVA treatment of Jurkat cells and human T lymphocytes up-regulates the p38 MAPK pathway but not the p42/44 MAPK or the SAPK/JNK signaling networks. The use of a pharmacological inhibitor selective for the p38 MAPK pathway, SB203580, allowed us to demonstrate that this network exerts an antiapoptotic effect in PUVA-treated Jurkat cells and T lymphocytes from healthy donors. Moreover, the effect of SB203580 was not due to a down-regulation of the Akt survival pathway which was not activated in response to PUVA. These results may suggest that p38 MAPK-dependent signaling is very important for the regulation of survival genes after exposure to PUVA. Since the therapeutic effect of PUVA seems to depend, at least in part, on apoptosis, further studies on the apoptosis signaling networks activated by this treatment might lead to the use of signal transduction modulators in combination with PUVA, to increase the efficacy of this form of therapy.     

Psoralen/UVA treatment and chromosomes

Summary Treatment of human lymphocytes in vitro with trimethylpsoralen or 8-methoxypsoralen and UVA irradiation (PUVA) induced chromosome damage, mainly constrictions and gaps, but also breaks and exchanges, and increased the frequency of sister chromatid exchange (SCE). The localization of the chromosome aberrations was nonrandom. The coincidence of many PUVA hits with mercaptoenthanol hits suggests that PUVA may have other targets in the cell than the DNA, perhaps the folding proteins of the chromosomes and the nuclear membrane/chromatin attachment organelles.Caffeine increased in a synergistic way the chromosome aberration yield if added after PUVA treatment, but there was no effect when caffeine was present before and during PUVA treatment. The SCE frequency was increased in the presence of caffeine.     

Small molecular antioxidants effectively protect from PUVA-induced oxidative stress responses underlying fibroblast senescence and photoaging

Exposure of human fibroblasts to 8-methoxypsoralen plus ultraviolet-A irradiation (PUVA) results in stress-induced cellular senescence in fibroblasts. We here studied the role of the antioxidant defense system in the accumulation of reactive oxygen species (ROS) and the effect of the antioxidants alpha-tocopherol, N-acetylcysteine, and alpha-lipoic acid on PUVA-induced cellular senescence. PUVA treatment induced an immediate and increasing generation of intracellular ROS. Supplementation of PUVA-treated fibroblasts with alpha-tocopherol (alpha-Toc), N-acetylcysteine (NAC), or alpha-lipoic acid (alpha-LA) abrogated the increased ROS generation and rescued fibroblasts from the ROS-dependent changes into the cellular senescence phenotype, such as cytoplasmic enlargement, enhanced expression of senescence-associated-beta-galactosidase and matrix-metalloproteinase-1, hallmarks of photoaging and intrinsic aging. PUVA treatment disrupted the integrity of cellular membranes and impaired homeostasis and function of the cellular antioxidant system with a significant decrease in glutathione and hydrogen peroxide-detoxifying enzymes activities. Supplementation with NAC, alpha-LA, and alpha-Toc counteracted these changes. Our data provide causal evidence that (i) oxidative stress due to an imbalance in the overall cellular antioxidant capacity contributes to the induction and maintenance of the PUVA-induced fibroblast senescence and that (ii) low molecular antioxidants protect effectively against these deleterious alterations.     

Mutagenicity of 8-methoxypsoralen and long-wave ultraviolet irradiation in diploid human skin fibroblasts: an improved risk estimate in photochemotherapy

Cell killing and the induction of mutation were studied in dividing and non-dividing human skin fibroblasts as a result of treatment by 8-methoxypsoralen (8-MOP) and long-wave UV irradiation (UVA). The cytotoxic effect was highly dependent upon the duration of the UVA exposure. The frequency of mutations increased linearly with the UVA dose at concentrations of 10 and 0.25 microliter 8-MOP/ml, the latter representing the concentration in the skin during PUVA treatment. The number of mutations induced per unit dose (= per microgram 8-MOP/ml per joule UVA/m2) was calculated: for dividing cells this value was 3.3 X 10(-8) per cell and for non-dividing cells 0.6 X 10.8(-8) per cell. On the basis of these values the expected number of induced mutants in the human skin per session of photochemotherapy is 1.2 X 10(-5), and per 30 years of maintenance therapy 1.3 X 10(-2) per cell. A comparison was made between this frequency and the frequency to be expected from spontaneous mutation. In addition the significance of absence in patients of SCE induction by photochemotherapy is discussed.     

p53 and Fas ligand are required for psoralen and UVA-induced apoptosis in mouse epidermal cells

A combination of 8-methoxypsoralen (8-MOP) and ultraviolet-A (UVA) radiation (320-400 nm) (PUVA) is widely used in the treatment of psoriasis and other skin diseases. PUVA is highly effective in eliminating hyperproliferative cells in the epidermis, but its mechanism of action has not been fully elucidated. In this study, we used immortalized JB6 mouse epidermal cells, p53(-/-), and Fas ligand deficient (gld) mice to investigate the molecular mechanism by which PUVA induces cell death. The results indicate that PUVA treatment induces apoptosis in JB6 cells. In addition, PUVA treatment of JB6 cells results in p53 stabilization, phosphorylation, and nuclear localization as well as induction of p21(Waf/Cip1) and caspase-3 activity. In vivo studies reveal that PUVA treatment induces significantly less apoptosis in the epidermis of p53(-/-) mice compared to p53(+/+) mice. Furthermore, FasL-deficient (gld) mice are completely resistant to PUVA-induced apoptosis compared to wild-type mice. These results indicate that PUVA treatment induces apoptosis in mouse epidermal cells in vitro and in vivo and that p53 and Fas/Fas ligand interactions are required for this process, at least in vivo. This implies that similar mechanisms may be involved in the elimination of psoriatic keratinocytes from human skin following PUVA therapy.     

Antiproliferative, antiangiogenic and apoptotic effect of photochemotherapy (PUVA) in psoriasis patients

The aim of the study was to investigate the antiproliferative, antiangiogenic and apoptotic effect of photochemotherapy (PUVA) in psoriatic patients, and to compare it with a control group of psoriatics treated with local corticosteroid therapy. The study included 60 psoriasis patients, 30 of them allocated to PUVA therapy and local corticosteroid each. Immunohistochemical methods of staining with Ki-67, F-8 and bcl-2 antibodies were used to determine proliferative keratinocyte count, to visualize the number of blood vessels in the dermis, and to determine the number of cells exhibiting expression of the antiapoptotic oncoprotein bcl-2, respectively. In all study patients, the values of Ki-67, F-8, bcl-2 and PUVA score were recorded pre- and at six weeks post-therapeutically. Study results showed a statistically significant decrease in the epidermal proliferative keratinocyte count and dermal number of blood vessels after both therapeutic modalities (p < 0.001 both). The value of bcl-2 showed a statistically significant increase in the group of patients treated with PUVA therapy (p = 0.001) and an increase in the control group, demonstrating enhanced keratinocyte apoptosis after treatment. Accordingly, study results demonstrated the antiproliferative, antiangiogenic and apoptotic effect of both PUVA and local corticosteroids. These very mechanisms appear to play a key role in the action of most antipsoriatic therapies.     

Soluble tumour necrosis factor-alpha receptor type 1 as a biomarker of response to phototherapy in patients with psoriasis.

The purpose of the study was to analyze the relationship between the serum concentration of soluble tumour necrosis factor-alpha type 1 (sTNF-R1), the severity of plaque-type psoriasis and therapeutic response. We compared sTNF-R1 in 25 patients treated with narrowband ultraviolet B (NB-UVB) radiation and 25 patients treated with systemic photochemotherapy (psoralen plus UVA-PUVA). The pretreatment Psoriasis Area and Severity Index (PASI) score and sTNF-R1 concentration were 16.32+/-5.26 and 1.99+/-0.40 ng ml(-1), respectively, in the group treated with NB-UVB, and 17.22+/-3.48 and 2.07+/-0.31 ng ml(-1), respectively, in the group treated with PUVA. The concentration of sTNF-R1 in healthy controls was 1.49+/-0.34 ng ml(-1) (p<0.05 compared with patients with psoriasis). The pretreatment PASI score correlated with sTNF-R1 in both treatment groups (r=0.46 and r=0.44, p<0.05). NB-UVB and PUVA gave similar therapeutic effects (the PASI score after 20 treatments was 4.42+/-1.67 in the NB-UVB-treated group and 5.55+/-2.10 in PUVA-treated patients); however, the sTNF-R1 concentration at the same time differed significantly: 1.52+/-0.37 ng ml(-1) and 1.98+/-0.39 ng ml(-1) (p<0.001), respectively. Moreover, the decline in sTNF-R1 in both treatment groups was significant only in patients in whom the duration of skin lesions was less than 3 months. The results suggest that the value of serum sTNF-R1 concentration as a marker of response to phototherapy may depend on duration of skin lesions and the treatment method.     

Breast cancer cell survival signal is affected by bergapten combined with an ultraviolet irradiation

In this study we have reported that bergapten (B) and bergapten plus UV (PUVA) are able to significantly affect MCF-7, ZR-75 and SKBR-3 breast cancer cell proliferations.B induced a lowering of PI3K/AKT survival signal in MCF-7 cells even in presence of IGF-I stimulation. Furthermore, B and in a higher extent, PUVA up-regulated the p53 mRNA and the protein content. An increased co-association between p21 WAF and proliferating cell nuclear antigen (PCNA) has been observed in PUVA-treated MCF-7 cells, thus inhibiting DNA replication. These results highlight how B, and its photoactivated compound, exert antiproliferative effects and induce apoptotic responses in breast cancer cells.     

Soluble tumour necrosis factor-α receptor type 1 as a biomarker of response to phototherapy in patients with psoriasis

Abstract

The purpose of the study was to analyze the relationship between the serum concentration of soluble tumour necrosis factor-α type 1 (sTNF-R1), the severity of plaque-type psoriasis and therapeutic response. We compared sTNF-R1 in 25 patients treated with narrowband ultraviolet B (NB-UVB) radiation and 25 patients treated with systemic photochemotherapy (psoralen plus UVA – PUVA). The pretreatment Psoriasis Area and Severity Index (PASI) score and sTNF-R1 concentration were 16.32±5.26 and 1.99±0.40 ng ml^?1, respectively, in the group treated with NB-UVB, and 17.22±3.48 and 2.07±0.31 ng ml^?1, respectively, in the group treated with PUVA. The concentration of sTNF-R1 in healthy controls was 1.49±0.34 ng ml^?1 (p<0.05 compared with patients with psoriasis). The pretreatment PASI score correlated with sTNF-R1 in both treatment groups (r=0.46 and r=0.44, p<0.05). NB-UVB and PUVA gave similar therapeutic effects (the PASI score after 20 treatments was 4.42±1.67 in the NB-UVB-treated group and 5.55±2.10 in PUVA-treated patients); however, the sTNF-R1 concentration at the same time differed significantly: 1.52±0.37 ng ml^?1 and 1.98±0.39 ng ml^?1 (p<0.001), respectively. Moreover, the decline in sTNF-R1 in both treatment groups was significant only in patients in whom the duration of skin lesions was less than 3 months. The results suggest that the value of serum sTNF-R1 concentration as a marker of response to phototherapy may depend on duration of skin lesions and the treatment method.     

Angiopoietin 1 promotes tumor angiogenesis and tumor vessel plasticity of human cervical cancer in mice

We have previously shown that following psoralen photoactivation (PUVA treatment) human dermal fibroblasts undergo long-term growth arrest as well as morphological and functional changes reminiscent of cellular senescence [ 1 ]. In the absence of molecular data on what constitutes normal senescence, it has been difficult to decide whether these PUVA-induced changes reflect cellular senescence or rather a mimic thereof. We herein report that PUVA-induced growth arrest, the senescent phenotype with long-term induction of senescence-associated beta-galactosidase, as well as increased expression of matrix metalloprotease-1 are fully reversible at days 100 to 130 post PUVA treatment in four independently tested fibroblast strains. The late returning growth capacity in PUVA-treated fibroblasts is not due to immortalization, as shown by continued lack of telomerase activity, accelerated telomere shortening, and a decrease in overall growth rates in fibroblasts in their regrowing phase post PUVA treatment. Lack of anchorage-independent growth additionally suggests that the cells are also not tumorigenically transformed. Collectively, our data suggest that PUVA-induced changes do not fully reflect replicative senescence but rather represent a long-term transient phenocopy of senescence. The model reported here is particularly suited to elucidating mechanisms underlying long-term transient growth arrest, the related functional changes, and the release of cells thereof.     

Chromosome studies on lymphocytes of patients under cytostatic therapy

Summary Lymphocyte cultures from the peripheral blood of 38 patients undergoing a cytostatic interval therapy with a regimen of methyl-CCNU (1-[2-chloroethyl-3-(4-methyl-cyclohexyl)]-1-nitrosourea), 5-fluorouracil, and vincristine (each 5-day course of therapy was followed by a therapy interval of 4 weeks) were supplied with 5-bromodeoxyuridine (BUDR) for the whole culture time to determine the sister chromatid labelling pattern. From a total of 92 individual blood samples sister chromatid exchange (SCE) studies were performed including analyses before the start of the therapy, and immediately and 4 weeks after each course of therapy. In addition, the frequency of first, second, and third metaphases in the 72-h cultures was estimated using the characteristic labelling patterns.A distinct increase of SCE frequency over the control level (i.e., lymphocyte cultures of patients before the start of therapy) was observed at all phases of therapy. It was clearly correlated with the number of courses of therapy up to course 7, later on the SCE rate remained more or less at the level reached. The influence of the composition of each drug regimen on the SCE rate was less pronounced than it was on the breakage rate. Moreover, although a clear correlation existed between the individual rates of breakage and SCE, the formation of the latter appeared to reflect a long-term effect of the therapy rather than did the formation of break aberrations. In addition, as the intercellular variability of the number of SCEs per cell was much higher than that of breaks, the interindividual variability (variation of the mean values for each patient) was small compared to the respective variability of breakage rates.The proportion of first, second, and third metaphases present in 72-h cultures evidently was influenced by single courses of therapy. The observed delay of proliferation was also reflected in different amounts of chromosome damage. Although the BUDR treatment enhanced the cytostatic effect of the therapy on the lymphocytes in culture rendering SCE analysis rather difficult in several cases, the other data of this study and in particular the experiences with the long-term effect make it imperative to include BUDR-labelling in further cytogenetic studies in subjects with exceptional exposure to chemicals. However, the SCE method can by no means, replace the classic cytogenetic analysis.     

Sister-chromatid exchanges in lymphocytes from infants with Down's syndrome

Sister-chromatid exchange (SCE) frequencies were studied in blood lymphocytes from 12 patients (3 females and 9 males) with Down's syndrome (DS). The mean frequency of SCE per metaphase for the patients (both sexes) was 9.2 +/- 0.8 which was significantly higher (P less than 0.01) than the mean SCE value (5.1 +/- 0.2) scored for 16 healthy infants (8 females and 8 males). A significant increase in the mean frequency of SCE in 12 parents of infants with DS (8.7 +/- 0.9 SCE/cell) was noticeable when compared with 20 parents of normal infants (6.3 +/- 0.1 SCE/cell). Increases in cellular division with reduction in their replication were also observed in patients with DS. Treatment with mitomycin C (0.05 micrograms/ml), hycanthone (0.1 micrograms/ml) and gamma-radiation (0.1 Gy) revealed a significant (P less than 0.01) increase in frequencies of SCE in DS lymphocytes and in those of their parents as compared to controls. These data may reveal a familial hypersensitivity reaction to these agents. The results indicate a genomic instability and deranged DNA-repair mechanisms which are accentuated by exposure to mutagenic agents, the underlying causal factor for which might be genetic.     

Biochemical Changes Observed After PUVA Versus PUVA Plus Methotrexate Therapy in Mycosis Fungoides Using Synchrotron Infrared Microspectroscopy

Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma in which the distinction between early stage MF and other inflammatory dermatosis remains difficult. Twenty patients of early stage MF and nine patients with psoriasis and lichen planus were included in this study. Ten MF patients were treated with psoralen plus UVA (PUVA) and the other 10 MF patients were treated with PUVA plus methotrexate (MTX) until complete clinical remission. Synchrotron infrared microspectroscopy (SIRM) found that MF lesions were biochemically different compared to inflammatory diseases. After treating MF with either therapeutic modality, the lymphocytic count decreased significantly in both the epidermis and dermis (P < 0.001) but no biochemical changes were observed in the remaining lymphocytes after treatment, indicating the disease process was slowed by treatment but not eradicated. In conclusion SIRM is a promising method for distinguishing MF from other inflammatory diseases such as psoriasis and lichen planus. A significant reduction in lymphocyte count indicated that PUVA therapy is an effective treatment for early stage MF, and MTX could be reserved for more advanced cases that are not PUVA responsive. However, SIRM evidence of persistent disease suggests that maintenance therapy is recommended after clinical remission.     

Photopheresis with UV-A light and 8-methoxypsoralen leads to cell death and to release of blebs with anti-inflammatory phenotype in activated and non-activated lymphocytes

Background: Extracorporeal photopheresis is a therapy for treatment of autoimmune diseases, cutaneous T-cell lymphoma, organ graft rejection as well as graft-versus-host diseases. The exact mechanism how the combination of 8-methoxypsoralen plus UV-A irradiation (PUVA) acts is still unclear. We investigated the cell death of activated and non-activated lymphocytes after PUVA treatment as well as the rate of released blebs and their antigen composition. Results: In presence of 8-MOP, UV-A light highly significantly increased the cell death of activated lymphocytes. The same was observed to a lesser extent in non-activated cells. Blebs derived from activated lymphocytes after PUVA treatment showed the highest surface exposition of phosphatidylserine. These blebs also displayed a high exposure of the antigens CD5 and CD8 as well as a low exposure of CD28 and CD86. Conclusion: PUVA treatment exerts anti-inflammatory effects by inducing apoptosis and apoptotic cell-derived blebs with immune suppressive surface composition.     

Urinary thymine dimers and 8-oxo-2′-deoxyguanosine in psoriasis

Psoralen in conjunction with UVA (PUVA) is perhaps the most effective treatment for psoriasis. It is, however, a risk factor for skin cancer in these patients and there is a need to develop non-invasive assays reflective of treatment-induced DNA damage. We report here the assessment of two important lesions, thymine dimer (T<>T) and 8-oxo-2'-deoxyguanosine (8-OHdG), in the urine of psoriasis patients. It was found that, once corrected for urine concentration, the psoriatic group had significantly higher (P<0. 0001) urinary levels of thymine dimers compared to the control group. No significant differences in urinary 8-OHdG levels were noted between the psoriatic, atopic dermatitis and control groups. Therefore biomonitoring of therapy from the very start with this simple and non-invasive assay could perhaps be an effective measure of the risk involved with the treatment allowing optimization for minimal-risk therapy.     

Comparison of sister-chromatid exchange induced by photoactivated 3-carbethoxypsoralen and 8-methoxypsoralen in human blood lymphocytes

The induction of sister-chromatid exchange (SCE) by a photoactivated monofunctional derivative of psoralen, 3-carbethoxypsoralen (3-CPs) was compared with that of the bifunctional compound, 8-methoxypsoralen (8-MOP). Lymphocytes were exposed in vitro to a series of equimolar concentrations of the drugs as well as to increasing doses of long-wave ultraviolet light (UVA) and second-division metaphases examined for SCE. The drugs or UVA per se did not influence the incidence of SCE. However, combination of the drug and UVA exposure resulted in a dose-dependent increase in SCE and such elevation was less pronounced with 3-CPs as compared to 8-MOP. This difference between 3-CPs and 8-MOP could be due to the difference in the types of lesions induced/repaired in DNA.     

Modulation of PPARγ Provides New Insights in a Stress Induced Premature Senescence Model

Peroxisome proliferator-activated receptor gamma (PPARγ) may be involved in a key mechanism of the skin aging process, influencing several aspects related to the age-related degeneration of skin cells, including antioxidant unbalance. Therefore, we investigated whether the up-modulation of this nuclear receptor exerts a protective effect in a stress-induced premature senescence (SIPS) model based on a single exposure of human dermal fibroblasts to 8-methoxypsoralen plus + ultraviolet-A-irradiation (PUVA). Among possible PPARγ modulators, we selected 2,4,6-octatrienoic acid (Octa), a member of the parrodiene family, previously reported to promote melanogenesis and antioxidant defense in normal human melanocytes through a mechanism involving PPARγ activation. Exposure to PUVA induced an early and significant decrease in PPARγ expression and activity. PPARγ up-modulation counteracted the antioxidant imbalance induced by PUVA and reduced the expression of stress response genes with a synergistic increase of different components of the cell antioxidant network, such as catalase and reduced glutathione. PUVA-treated fibroblasts grown in the presence of Octa are partially but significantly rescued from the features of the cellular senescence-like phenotype, such as cytoplasmic enlargement, the expression of senescence-associated-β-galactosidase, matrix-metalloproteinase-1, and cell cycle proteins. Moreover, the alterations in the cell membrane lipids, such as the decrease in the polyunsaturated fatty acid content of phospholipids and the increase in cholesterol levels, which are typical features of cell aging, were prevented. Our data suggest that PPARγ is one of the targets of PUVA-SIPS and that its pharmacological up-modulation may represent a novel therapeutic approach for the photooxidative skin damage.     

The importance of patient selection for photochemotherapy in psoriasis.

Twenty-four patients with psoriasis were treated with orally administered 8-methoxypsoralen followed by exposure to high-intensity long-wavelength ultraviolet radiation (PUVA) at a psoriasis day care centre. Among the 20 with plaque type psoriasis the condition cleared in 13 (65%), after a mean of 20.7 treatment sessions, and improved but failed to clear in 4 (20%); the treatment failed in the other 3 (15%). The other four patients had erythrodermic, pustular or inflammatory psoriasis, and all failed to respond to PUVA therapy. Factors to be considered in patient selection for this form of therapy are the type of psoriasis, the patient''s skin type and th proportion of the body surface area involved.