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.     

PUVA erythemal sensitivity depends on plasma psoralen concentration and UVA sensitivity

The variation in erythemal sensitivity of the skin during PUVA therapy with oral 8-methoxypsoralen (8-MOP) was examined by measuring both UVA and PUVA erythemal responses, together with plasma 8-MOP concentration, in 27 patients about to start PUVA therapy for psoriasis. The erythema responses were judged visually, and also measured using a reflectance instrument in order to construct dose-response curves. No significant association was found between the UVA and PUVA minimal erythema responses. The plasma psoralen concentration showed significant association with the slope of the PUVA erythema dose-response curve. The slopes of the UVA and PUVA erythema dose-response curves were significantly associated, and this association became much stronger when allowance was made for plasma psoralen concentration. These results show that erythemal sensitivity during PUVA therapy is related to both plasma psoralen concentration and inherent UVA sensitivity, but that this relationship is not apparent when sensitivity is judged visually as the minimal erythema response. The association between PUVA and UVA erythemal sensitivity suggests a common pathway in the vascular response induced hy UVA radiation, with or without psoralen.     

A case of actinic prurigo showing hypersensitivity of skin fibroblasts to ultraviolet A (UVA)

We here report a patient with actinic prurigo. He had had erythematous papulovesicular eruptions on the sun-exposed sites from fall to early summer for 4 years. The lesions healed leaving atrophic scars. The histology showed epidermal necrosis and dermal dense perivascular lymphohistiocytic infiltration and edema. His minimal erythema doses to ultraviolet B (UVB) and UVA were normal and lowered, respectively. Skin lesions were produced by repeated irradiation with UVA plus UVB, but not with UVA alone. Then he was diagnosed as having actinic prurigo. Skin fibroblasts from the patient were hypersensitive to UVA. We believe that the hypersensitivity relates to the pathomechanisms of the photosensitivity in the case. UVA sensitivity of fibroblasts may be useful for differentiating actinic prurigo, hydroa vacciniforme, and other similar photosensitive disorders.     

Mechanisms of phototherapy and photochemotherapy for photodermatoses

Most photodermatoses represent indications for preventive ultraviolet (UV) phototherapy and/or psoralen plus ultraviolet A (PUVA) photochemotherapy. The aim of treatment is to prevent the outbreak of disease by increasing the patient's tolerance to sunlight. The mechanisms by which ultraviolet B (UVB) and PUVA induce such tolerance are not completely understood. Pigmentation and skin thickening may be important factors in the protective effect, but they cannot sufficiently explain the degree of protection induced. Other mechanisms that may be of critical importance for the therapeutic efficacy encompass a variety of immunomodulatory effects on human skin known to be induced by UVA, UVB, and PUVA. Obviously the mechanisms of prophylactic phototherapy are strongly intertwined with the pathogenesis of the photodermatoses. The possible mechanisms of photoprevention are discussed for polymorphic light eruption (PMLE), actinic prurigo, chronic actinic dermatitis, and solar urticaria.     

Erythema action spectrum in xeroderma pigmentosum group A patients

Twenty patients with xeroderma pigmentosum group A (XP-A) and 30 healthy controls were studied to determine the energy requirements for UV-erythema with monochromatic light between 255 and 340 nm. As test sites, unexposed skin on the upper back was selected for irradiation using a prism monochromator and a 1 kW xenon arc source. The minimal erythema doses (MEDs) were determined at each erythemal response peak, at 24 hours post irradiation in normal controls and at 72 hours in XP-A patients, respectively. Compared with normal subjects, XP-A patients had extremely low MEDs at all wavelengths tested. The erythema action spectrum showed 2 peaks at 265 and 290 nm in XP-A patients and the greatest effectiveness at 290 nm. These results indicate that XP-A patients should be protected strongly against not only UVB but also UVA, because the photo-hypersensitivity in XP-A patients has been extended from the UVB to UVA region.     

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 possible role of prostaglandins in PUVA-induced inflammation: implication by organ cultured skin

The role of arachidonate metabolites in UV-induced inflammation was analyzed by measuring the amounts of prostaglandins or leukotrienes released into a culture medium in the organ culture of biopsied guinea pig skin following UV exposure. Increased concentrations of prostaglandin E2, F2 alpha, and 6-oxo-F1 alpha were found in the medium subjected to UVB radiation followed by 24 h incubation in the organ culture, compared to medium from non-exposed skin, whereas LTC4 was at an undetectable level in both. This release occurred in UVB dose-dependent fashion and was completely inhibited by the addition of indomethacin to the medium. Exposure to monochromatic UV light of 250, 300, and 350 nm released prostaglandin E2, F2 alpha, and 6-oxo-F1 alpha, in increasing order of 250, 300, and 350 nm, but not LTC4. This order of amount released almost paralleled the intensity of inflammation that occurred with each wavelength. Exposure of skin to UVA following intraperitoneal injection of 8-methoxypsoralen (PUVA) was also found to stimulate the synthesis of prostaglandin E2 in UVA dose-dependent fashion, and the stimulation through an increasing dose of UVA occurred more significantly than UVB exposure. The time course of prostaglandin release following UVB and PUVA exposures was found to have a pattern similar to their dynamics in association with erythema and edema, conditions which could be significantly diminished by the topical application of indomethacin. The present studies demonstrate that prostaglandins play an important role in the production of inflammation by UVB as well as UVA and PUVA.     

Narrowband UVB and psoralen-UVA in the treatment of early-stage mycosis fungoides: a retrospective study

BACKGROUND: Treatment of early-stage mycosis fungoides (MF) consists of topical steroids, phototherapy (UVB), photochemotherapy (psoralen plus UVA [PUVA]), topical nitrogen mustard, or total skin electron-beam irradiation. It has been reported that the same effective UVB dose is safer than PUVA regarding carcinogenicity and produces fewer side effects. Narrowband UVB (311 nm) results in less irritation and erythema and is more effective compared with broadband UVB. OBJECTIVE: Our purpose in this retrospective study was to analyze the response to treatment, relapse-free interval, and irradiation dose in 56 patients with early-stage MF (stage Ia and Ib). A total of 21 patients were treated with narrowband UVB (311 nm); 35 patients were treated with PUVA. RESULTS: Narrowband UVB treatment led to complete remission in 17 of 21 patients (81%), partial remission in 4 of 21 (19%), and none showed progressive disease. PUVA treatment led to complete remission in 25 of 35 patients (71%), partial remission in 10 of 35 (29%), and none showed progressive disease. The mean relapse-free interval for patients treated with UVB was 24.5 months (range, 2-66 months) and for patients treated with PUVA, 22.8 months (range, 1-43 months). CONCLUSION: Narrowband UVB therapy for patients with early-stage MF is an effective treatment modality. It has several advantages over treatment with broadband UVB and PUVA. When treating patients with early-stage MF it may be beneficial to start with narrowband UVB therapy and, if there is progression or no response, switch to PUVA therapy.     

Effect of cutaneous hypoxia upon erythema and pigment responses to UVA, UVB, and PUVA (8-MOP + UVA) in human skin

The effect of oxygen deprivation upon UVA-, UVB-, and PUVA-induced pigment and erythema responses in normal human skin was examined. Before exposure, varying degrees of hypoxia in the skin of the forearm were achieved by inflating a sphygmomanometer cuff applied to the upper arm. After the transcutaneously measured pO2 had stabilized, sites on the inner forearm were exposed to UVA, UVB, or 8-MOP + UVA radiation, to determine dose thresholds for the induction of erythema and pigmentation at different cuff pressures. Inflation of the cuff to greater than systolic pressure completely inhibited immediate and delayed pigment responses (IPD, DT) to UVA doses greater than 10 times the normal pigmentation threshold dose. UVA-induced delayed erythema responses were partially inhibited by cuff inflation: 2.7 times the minimal erythema dose of UVA was necessary to cause an erythema response when exposure occurred during vascular occlusion. In contrast, erythema and pigment responses to UVB and PUVA were unaltered by cuff pressures exceeding systolic pressure during exposure. Inhibition of UVA-induced erythema and pigment responses by vascular occlusion were reversed by the transcutaneous diffusion of 100% O2. These findings indicate that the cutaneous responses to UVA and UVB occur by separate pathways differing with respect to O2 dependence. Our findings agree with those of other studies which indicate that PUVA-induced phototoxicity and melanogenesis are not O2-dependent.     

Actinic prurigo, tropical (South-East Asian) variant.

Actinic prurigo is a chronic familial photodermatitis found predominantly among the Amerindians. It has been reported from North and South America, Britain and Japan. We report a case of actinic prurigo seen in Singapore. A 20-year-old Malay female presented with a persistent pruriginous eruption in the sun-exposed parts and on her abdomen. She also had lower lip cheilitis and thinning of the outer eyebrows, features often seen in actinic prurigo. The minimal erythema dose to ultraviolet A (UVA) and UVB were persistently lowered. We propose that this condition be called actinic prurigo, tropical (South-East Asian) variant.     

Can ultraviolet erythema be used to identify the basal cell carcinoma phenotype?

Since a prolonged duration of a strong UBV erythema has been suggested as a marker for propensity to develop skin cancer, we objectively followed the duration and intensity of erythemas induced by UVB and UVA radiation for 28 days in 18 patients with basal cell carcinoma (BCC), and in 15 healthy controls using reflectance spectrophotometry. The erythema index, defined as the difference in redness between UV-exposed skin and normal, adjacent skin on the lower abdomen, did not differ significantly between the two groups at 24 h, when the reaction was maximal, following a dose of 6 MED of UVB. Erythema values after 7 and 14 days were slightly higher in the BCC group, but this difference did not reach statistical significance. At day 7 some patients in the BCC group showed very strong erythemas. At days 21 and 28 the two groups had almost identical erythemal reactions. Following a standard dose of UVA of 100 J/cm², patients with BCC and healthy controls both showed weak erythemal reactions, which declined somewhat over the study period. No significant differences in pigmentary response were noted between the BCC and the control group, neither following UVB nor UVA. Although individual patients with BCC deviate from the normal erythemal curve for UVB, the UVB response is not a suitable predictive instrument in screening patients with the basal cell carcinoma phenotype.     

DNA repair elicited by UVB during PUVA therapy for psoriasis

Summary The skin of patients receiving psoralen and UVA (PUVA) therapy for psoriasis is exposed to trace amounts of UVB radiation emitted by PUVA irradiators in addition to UVA. DNA repair activity was measured using autoradiography in the uninvolved skin of PUVA-treated patients in order to determine whether 8-methoxypsoralen (8-MOP) plus UVA elicits repair, inhibits the skin repair response to UVB, or protects epidermal-cell DNA from UVB damage by promoting a tan. Epidermal-DNA repair activity was observed in 27 out of 37 patients following the first PUVA treatment. Phototesting with multiples of the initial UV dose elicited a linear increase in repair activity. Glass-filtered radiation failed to stimulate repair, indicating that the reaction was due to UVB, not to 8-MOP plus UVA. The same amount of repair activity was observed in the skin of patients irradiated either before or after 8-MOP ingestion, demonstrating that the drug did not interfere with the response of the skin to UVB. At clearing, however, the repair activity was never greater than that elicited at the initial treatment and was often undetectable despite a tenfold increase in UV exposure. It is proposed that DNA damage should be measured to determine whether epidermal cells are entirely protected from UVB radiation at the completion of therapy.     

A case of actinic prurigo in Thailand

Actinic prurigo is a separate entity from the polymorphous light eruption that affects American Indians. It has been reported mainly from North and South America, with only few reported cases from Britain or Asia. We report a case of actinic prurigo in a Thai girl who showed cheilitis and pruritic papules on exposed areas for three years. We were able to induce populovesicular lesions by three consecutive irradiations with 100 J/cm2 UVA and 2 minimal erythematous dose of UVB. However, three weeks after irradiation, a prurigo papule developed at the UVB irradiated site.     

An intraindividual comparative study of psoralen-UVA erythema induced by bath 8-methoxypsoralen and 4, 5', 8-trimethylpsoralen

BACKGROUND: Limited work has been conducted on the characteristics of topical trimethylpsoralen (TMP) psoralen-UVA (PUVA) erythema. OBJECTIVE: We sought to determine the time-course and dose-response characteristics of erythema induced by topical TMP, and to compare these parameters with those for topical 8-methoxypsoralen (MOP) within patients. METHODS: After photosensitization of one forearm with topical TMP, test sites were exposed to a UVA dose series. The procedure was repeated on the other forearm using 8-MOP solution. Erythema was assessed visually and with a reflectance instrument every 24 hours for 7 days. RESULTS: TMP PUVA erythema followed a similar time course to 8-MOP PUVA erythema. The majority of patients were at maximal erythema at or beyond 96 hours. TMP PUVA had a significantly steeper dose-response curve at 48, 72, and 96 hours compared with 8-MOP PUVA. CONCLUSION: On the basis of these data, the optimal time to read the TMP minimal phototoxic dose is 96 hours. In view of the steeper dose-response curve for TMP PUVA, a lower UVA incremental regimen should be considered compared with that for 8-MOP PUVA.     

The Relationship among Minimal Erythema Dose,Minimal Delayed Tanning Dose,and Skin Color

The relationship among minimal erythema dose (MED), minimal delayed tanning dose (MDTD), and skin color was examined in 16 healthy volunteers using three different spectra. The subjects were exposed to UVB, UVA+B, and UV+Visible light (UV+Visible) with a xenon arc solar simulator as a light source. The MEDs for UVB and UVA+B were less than the MDTDs, whereas the MED for UV+Visible was higher than the MDTD. There was no significant correlation between the MED and the MDTD for UVB or UVA+B. The MED for UV+Visible was significantly correlated to the MDTD (p<0.01). Skin color significantly correlated with MEDs for UVB and UVA+B (p<0.01), but not for UV+Visible. There was no significant correlation between skin color and the MDTD for any spectra. From these results, it is suggested that the relationship between erythemal and melanogenic responses is dependent on spectral bands of the light source and that skin color is a predictor of UV-induced erythema.     

Reduction in 8-methoxypsoralen immersion time alters the erythemal response to bath PUVA

Topical psoralen plus ultraviolet A (PUVA) using 8-methoxypsoralen (8-MOP) bath solution is a well established and effective treatment in dermatology. The standard immersion time in the UK is 15 min, but a shorter bathing period could potentially increase treatment convenience. In order to examine the effect of reduction in immersion time on skin phototoxicity, we compared the erythemal response to UVA following 5 min and 15 min psoralen baths. The study was performed on the forearm skin of 7 healthy volunteers using an 8-MOP psoralen concentration of 2.6 mg/l. One forearm of each volunteer was soaked for 15 min and the other for 5 min, followed by immediate irradiation with a series of 10 doses of broadband UVA ranging from 0.1 J/cm2 to 6.9 J/cm2. At 72 h, the minimal phototoxic doses (MPDs) were noted and erythema readings (erythema index) were taken in triplicate with a reflectance instrument. The median MPD following 5 min immersion was 1.7 (range 0.7-2.7) J/cm2 compared with 1.0 (range 0.4-1.7) J/cm2 after 15 min treatment, with no significant difference. However, the mean slope of erythema dose-response on the 15-min treated side was significantly steeper than on the 5-min treated side, 0.036 and 0.021 respectively, P < 0.05. Hence, this preliminary work shows that reducing 8-MOP immersion time to 5 min reduces the erythemal response to UVA. It will clearly be necessary to examine the effect of a shortened immersion period on disease clearance before considering such a change to the topical PUVA regime.     

Dietary fish oil as a photoprotective agent in hydroa vacciniforme

Hydroa vacciniforme is a troublesome and scarring photosensitivity disorder for which treatment is unsatisfactory. Dietary fish oil rich in ω-3 polyunsaturated fatty acids reportedly increases the resistance to ultraviolet-induced erythema and rash provocation in polymorphic light eruption. We report for the first time the response of hydroa vacciniforme to dietary fish oil. Three Caucasian boys with the condition were placed on MaxEPA, five capsules daily. Phototesting was performed at baseline and after 3 months supplementation. At baseline, low erythemal thresholds were seen to monochromated UVA at 350 and 370 nm in all three boys, while one also had a low threshold to 320 nm (UVA) and another showed a low threshold to 300 nm (UVB). Broad-band UVA provocation challenge produced typical skin lesions in all the subjects. Following fish oil, all the boys showed reduced erythemal sensitivity to UVA and one also showed reduced sensitivity to UVB. Provocation challenge revealed a reduced response in all three children. Clinically, these changes were accompanied by pronounced improvement in one child, mild improvement in the second child, but no improvement in the third. The third boy subsequently showed good clinical response to azathioprine.     

Cutaneous carcinoma and 8-methoxypsoralen and ultraviolet A (PUVA) lentigines in Japanese patients with psoriasis treated with topical PUVA: a follow-up study of 214 patients

A total of 214 Japanese patients with psoriasis, under treatment with topical 8-methoxypsoralen and ultraviolet A (PUVA), were examined for malignant skin tumors and pigmented lesions during a follow-up period of up to 17 years (mean 5.8 years). One patient had developed multiple superficial basal cell carcinomas, and the remaining 213 patients had neither cutaneous carcinomas nor actinic keratoses. PUVA lentigines were seen in 89 patients (42%) and the incidence of lentigines increased as the number of PUVA treatments and the cumulative UVA dose increased. Melanocytic atypia was not observed histologically in 24 pigmented lesions examined. This report suggests that this topical PUVA regimen may not be highly carcinogenic in the Asian population.     

Chronic actinic dermatitis developed during phototherapy for psoriasis

A patient with psoriasis vulgaris had been successfully treated with PUVA and UVB therapy. During maintenance phototherapy, he suddenly became photosensitive and developed eczematous eruption. Minimal response doses to UVB and UVA were extremely low--1.09 mJ/cm2 and 0.3 J/cm2, respectively. No chemical substances were identified as the responsible photosensitizer. The condition was diagnosed as chronic actinic dermatitis (CAD). PUVA therapy was unsatisfactory because it was not possible to administer an adequate dose of UVA. Oral cyclosporine, topical corticosteroid and sunscreen were used with beneficial therapeutic effects on psoriasis and CAD. As far as we know, the development of CAD during phototherapy has not been previously reported.