Allergic contact and photocontact dermatitis due to psoralens in patients with psoriasis treated with topical PUVA

The incidence and clinical features of allergic contact and/or photocontact dermatitis due to psoralens were examined in 371 patients with psoriasis treated with topical PUVA. The psoralen derivatives used in the study were 8-methoxypsoralen (8MOP), 3-carbethoxypsoralen (3CPs), 4,6,4'-trimethylangelicin (TMA) and 7-methyl pyridopsoralen (MPP). Of 371 patients treated with 8MOP, three (0.8%) developed an acute dermatitis in the PUVA-treated areas. This incidence was significantly lower (P less than 0.01) than that for 3CPs (four of 10 patients) or that for TMA (six of 17 patients). None of the seven patients receiving MPP on PUVA had a reaction. It was confirmed that these dermatitis reactions were due to contact and/or photocontact allergy to psoralens by several methods that include patch and photopatch tests, photopatch test mapping, determination of the minimal erythema dose (MED) and immunohistochemistry.     

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.     

5‐Methoxypsoralen plus ultraviolet (UV) A is superior to medium‐dose UVA1 in the treatment of severe atopic dermatitis: a randomized crossover trial

Background Ultraviolet (UV) A1 and psoralen plus UVA (PUVA) are effective treatment options for severe atopic dermatitis (AD); however, their relative efficacy has not yet been determined in a head‐to‐head study. Objectives To compare UVA1 and oral 5‐methoxypsoralen (5‐MOP) plus UVA with respect to efficacy, tolerability and duration of response in patients with severe generalized AD. Methods Forty patients were included in this randomized observer‐blinded crossover trial. The patients received either 15 exposures to medium‐dose UVA1 as the first treatment and, in cases of relapse, another 15 exposures to 5‐MOP plus UVA as the second treatment, or vice versa. All patients were followed until 12 months after discontinuation of the last treatment. The SCORAD score was determined by a blinded investigator at baseline, after 10 and 15 treatments each and during the follow‐up period. In addition, all adverse events were recorded during the whole study period. Results Twenty‐three patients completed the crossover treatment. Both phototherapies resulted in clinical improvement; however, PUVA reduced the baseline SCORAD score to a significantly greater extent than UVA1 (mean ± SD 54·3 ± 25·7% vs. 37·7 ± 22·8%; P = 0·041). The median length of remission was 4 weeks (interquartile range 4–12) after UVA1 and 12 weeks (interquartile range 4–26) after PUVA therapy (P = 0·012). Conclusions PUVA provides a better short‐ and long‐term response than medium‐dose UVA1 in patients with severe AD.     

Suppressive effect of ultraviolet (UVB and PUVA) radiation on superantigen production by Staphylococcus aureus

It is well known that Staphylococcus aureus (S. aureus) proliferates on the moist skin lesion of atopic dermatitis. Reduction of bacteria colonization from skin lesions by antibiotics has been reported to be effective for the treatment of atopic dermatitis. S. aureus produces superantigens which can activate T cells and possibly enhance the inflammatory reaction. Photo(chemo)therapy has been successfully used for the treatment of severe cases of atopic dermatitis. We have previously reported that photo(chemo)therapy had bacteriostatic effect on S. aureus. Now we examined the effect of UVB and psoralen plus UVA (PUVA) on superantigen production from S. aureus. We isolated S. aureus from six atopic dermatitis patients. S. aureus was irradiated in vitro with UVB (0, 5, 10 mJ/cm²) or PUVA (0.001% psoralen plus 0, 5, 10 mJ/cm² UVA) and incubated 4 h with 100 strokes per min. After incubation, the amounts of superantigens in the supernatant were measured using ELISA kit. The production of superantigens decreased in an ultraviolet dose-dependent manner. The suppressive effects of UV radiation on superantigen production may be involved in the therapeutic efficacy of photo(chemo)therapy for atopic dermatitis.     

A modified dosage schedule for increased efficiency in PUVA treatment of psoriasis

Ten patients with chronic widespread plaque psoriasis, all of whom had previously completely cleared and suffered a subsequent widespread relapse after conventional PUVA therapy, were treated with a modified UVA dosage schedule, with psoralen formulation and dosage unchanged. Initial and incremental UVA doses were maximized to near-erythemogenic levels as determined by weekly testing for minimal phototoxic dose (MPD), treatment being given three times a week. A comparison of complete psoriasis clearing between the modified treatment and the last PUVA course showed a geometric mean reduction in treatment duration of 55% (P less than 0.001) for a similar number of treatments each week, and a cumulative UVA dose of 31% (P less than 0.05), representing a reduction in treatment duration from 9.1 to 4.1 weeks and cumulative UVA dose reduction of 100.8 to 69.9 J/cm2. Such an improvement in efficiency permits a marked increase in treated patient numbers for the same cost, and is more convenient. The reduction in the total cumulative UVA dose given as larger individual doses also seems likely to lead to a lower incidence of cutaneous long-term, especially carcinogenic, adverse effects.     

Cell kinetic studies of the effect of 8-methoxypsoralen with long wave ultraviolet irradiation on human melanoma cell line (SEKI, II)

The growth inhibition and cell cycle phase distribution of a human malignant melanoma cell line (SEKI, II) treated with 8-methoxypsoralen (8MOP) and UVA irradiation (PUVA) were investigated in vitro. A growth inhibition effect was observed in 8 methoxypsoralen (8MOP) 0.1 μg/ml + UVA 1 J/cm² group, and a strong cytocidal effect was noted in the 8MOP 1 μg/ml + UVA 3 J/cm² groups. Continued accumulation was observed at 24 to 72 hours in the following phases: G₂M phase in the 8MOP 0.1 μg/ml + UVA 1 J/cm² group; middle S phase in the 8MOP 0.1 μg/ml + UVA 3 J/cm² group; and early S phase in the 8MOP 1 μg/ml + UVA 1 J/cm² group. It appeared that 8MOP with UVA irradiation acts mainly on the S phase to block the cell cycle progression between the S and G₂M phases. The variation of cell cycle phase distribution under the effect of 8MOP with UVA irradiation was similar to that observed with the alkylating agent, ACNU, suggesting a possible similarity of the mechanism of action between them. The reaction in the dark was vital for the onset of action of 8MOP with UVA irradiation; as is the case for DTIC with UVA irradiation (32).     

A new psoralen-containing gel for topical PUVA therapy: development,and treatment results in patients with palmoplantar and plaque-type psoriasis,and hyperkeratotic eczema

Summary Topical photochemotherapy with psoralen and its derivatives 4.5′,8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP), with UVA irradiation, was evaluated with regard to minimum phototoxic dose, concentration, timing of UVA irradiation and systemic and local side-effects, in healthy volunteers. Psoralen (0.005%) in aqueous gel was found to be superior to TMP and 8-MOP in aqueous gel. No hyperpigmentation was seen after topical PUVA treatment with psoralen in aqueous gel. Patients with plaque-type psoriasis (n = 7), palmoplantar psoriasis (n = 7) and hyperkeratotic eczema (n = 2) were treated. Topical PUVA therapy was effective in most psoriasis patients, without the occurrence of local or systemic side-effects. Moreover, hyperkeratotic eczema patients who did not respond to conventional therapy showed partial remission. These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.     

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.     

Effects of in vitro PUVA treatment on adenylate cyclase responses of epidermis

We investigated the effect of 8-methoxypsoralen (8-MOP) plus long wave ultraviolet irradiation (PUVA) on the pig skin epidermal cyclic AMP (cAMP) system. Following PUVA treatment in vitro, pig skin squares were incubated in RPMI 1640 medium, and the cAMP accumulation by various adenylate cyclase stimulators was determined. A significant increase of the beta-adrenergic adenylate cyclase response was observed as early as 6-h following PUVA treatment; the maximal effect was reached at 24-h and lasted at least for 72-h. This augmentation effect of PUVA treatment was potentiated by increasing the 8-MOP concentration (0.5–160 μg/ml) and UVA irradiation dose (0.05–1.4 J/cm²). At higher irradiation doses (2.1–2.8 J/cm²), the beta-adrenergic augmentation effect was less marked. There were no significant differences in the adenosine-and histamine-adenylate cyclase response up to 1.4 J/cm² irradiation; however, the latter was decreased at a higher irradiation dose (2.8 J/cm²). Although UVA irradiation alone had no effect on the beta-adrenergic response, 8-MOP treatment alone increased this receptor response at higher concentrations; this effect was much weaker than that induced by PUVA treatment. Cyclic AMP phosphodiesterase activities were not affected by PUVA treatment. These results indicate that epidermal adenylate cyclase response is affected by in vitro PUVA treatment.     

Comparison of turbo‐PUVA and conventional American‐style PUVA in the treatment of psoriatic patients

Background: Ultraviolet (UV)A protective properties of dihydroxyacetone (DHA) have been used as a topical UV‐resisting barrier to optimize psoralens and UVA (turbo‐PUVA). Starting doses and increments were based on the DHA diffuse reflectance spectroscopy‐derived protection factor. Objective: To evaluate the efficacy of turbo‐PUVA in psoriatic patients using a simpler method for determining starting doses and increments, in comparison to the conventional American‐style PUVA photochemotherapy. Methods: Thirty psoriasis patients (15 on American‐style PUVA and 15 on turbo‐PUVA) were evaluated, each receiving PUVA twice weekly. Starting UVA dose was determined according to skin phototype for the American‐style PUVA group and according to the patient's skin phototype × DHA SPF 3 in turbo‐PUVA group. UVA increments used were 0.5–1.5 J/cm² per treatment in American‐style PUVA and 25% of the previous dose in turbo‐PUVA. Results: Turbo‐PUVA group showed a significantly lower mean cumulative dose, a significantly higher psoriasis area and severity index score reduction, lesser mean number of treatment sessions, and less duration of treatment till remission (188.44±106.2 J/cm², 92.164±1.975%, 11.2±3.52 session, and 1.4±0.44 months, respectively) than conventional American‐style PUVA group (255.13±18.304 J/cm², 74.725±10.976%, 30±0.00 sessions, and 3.75±0.00 months, respectively). Conclusion: Turbo‐PUVA is more effective and time convenient for the treatment of psoriasis with less cumulative dose than the conventional American‐style PUVA.     

PUVA and PUVB in vitiligo – are they equally effective?

BACKGROUND/AIMS: The combination of psoralens with different types of ultraviolet (UVL) sources in the treatment of vitiligo has led to different reports of success. The purpose of this trial is to compare in a random right-left comparison study the efficacy and side effects of oral 8-MOP plus UVA (PUVA) and oral 8-MOP plus UVB (broadband, 290-320 nm P-UVB) in the treatment of vitiligo. METHODS: The study included 24 cases of extensive vitiligo involving more than 30% of the body surface area in a bilateral symmetrical distribution. Each patient received 0.7 mg/kg 8-MOP orally 2 h before the light session. The right side of the body was exposed to UVA (320-400 nm), while the left half was exposed to UVB (290-320 nm). The patients received 3 sessions/week for a total of 30 sessions. RESULTS: Both PUVA and PUVB produced moderate (50-60%) improvement, with similar incidences of phototoxic reaction and skin thickening. However, the study revealed a significant difference in the number of sessions needed to improve produce erythema and perifollicular pigmentation as well as a moderate response, the response on the UVA side always being earlier. Furthermore, the amount of joules needed to achieve the same response was 10 times greater on the UVA side than on the UVB side. CONCLUSION: The use of psoralen plus broadband UVB is as effective as PUVA in the treatment of vitiligo. However, the long-term side effects of psoralen plus UVB are unknown.     

Narrowband UVB as an effective substitute for psoralen plus UVA: lessons from a psoralen shortage

From March to August 2010, there was a shortage of encapsulated liquid 8-methoxypsoralen (8-MOP), the psoralen used for bath psoralen plus UVA (PUVA) in Toronto, Canada. Patients were forced to discontinue bath PUVA treatment and were transitioned to other therapeutic modalities, including narrowband UVB (nbUVB). A retrospective chart review was conducted of all patients who discontinued bath PUVA due to the unavailability of 8-MOP, with a focus on those who were switched to nbUVB. Sixty-three patients discontinued PUVA, 39 of whom were switched to nbUVB. Fifteen of 17 patients with mycosis fungoides (MF) who were switched to nbUVB improved, and patients with earlier-stage disease were more likely to improve. Ten of 13 (77%) psoriasis patients improved with nbUVB, including two patients whose psoriasis cleared completely. All three small-plaque parapsoriasis patients who switched to nbUVB had complete clearance of their lesions. In conclusion, nbUVB may be a suitable alternative for patients with MF, small-plaque parapsoriasis and psoriasis who cannot access PUVA therapy.     

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.     

Narrowband UVB phototherapy for the treatment of psoriasis: a review and update.

An advance in UVB-based phototherapy has been the introduction of fluorescent lightbulbs (Philips TL-01) that deliver monochromatic light at 311-nm UVB, a narrowband wavelength that seems to maximize clearing of plaques relative to its erythrogenic potential. Narrowband UVB phototherapy has considerable advantages over traditional treatment options such as broadband UVB and psoralen plus UVA (PUVA). It is clearly more effective than broadband UVB, safer than PUVA, and well tolerated by patients when taken at suberythemogenic doses. Narrowband UVB represents an important new therapy for psoriasis.     

The efficacy of localized PUVA therapy for chronic hand and foot dermatoses

The response to treatment of all patients enrolled over an 18-month period for localized oral or topical psoralen photochemotherapy (PUVA) of chronic hand and foot dermatoses was retrospectively reviewed. There were broadly similar success rates for the two groups for complete clearance: 61.5% (eight of 13 patients who completed therapy)—oral PUVA, 47.8% (11 of 23 patients who completed therapy)—topical PUVA, and for significant improvement: 23.1% (three of 13 patients)—oral PUVA, 30.4% (seven of 23 patients)—topical PUVA; there were no significant differences in response when diagnostic subgroupings of the hand dermatoses were taken into account. The mean number of treatments (22 for oral PUVA and 24 for topical), treatment durations (122 and 129 days), maximum UVA doses (11.2 and 12.3J/cm²) and to a lesser extent cumulative UVA doses (189.3 and 237.0 J/ cm²) for the therapies were similar in the two groups; adverse effects were minimal for both treatment protocols. However, at least five of the eight patients in the oral PUVA group and five of the 11 in the topical group who cleared completely relapsed after a mean 86 (range 19.245) and 174 (range 23-596) days, respectively. These findings are in broad agreement with those of previous studies. Therefore to avoid generalized photo-sensitivity and a higher likelihood of adverse effects with systemic therapy, as well as a possible slower relapse rate, topical therapy seems preferable.     

Controlled study of PUVA and adjunctive topical therapy in the management of psoriasis

In a random study of 116 patients with psoriasis vulgaris, oral psoralen photochemotherapy (PUVA) used alone was compared to PUVA plus adjunctive topical therapy with tar, dithranol, or topical corticosteroids. PUVA plus topical corticosteroids produced more rapid clearing of psoriasis but despite maintenance therapy, the frequency of recurrences of the disease during the early phase of follow-up was significantly higher with that treatment, as compared to all other treatments. Dithranol plus PUVA also cleared psoriasis quicker than PUVA alone but patient acceptability for that regimen was low. The addition of tar to PUVA therapy appeared to have little influence on results.     

The Role of PUVA in the Treatment of Psoriasis

Photochemotherapy with methoxsalen (8-methoxypsoralen) and long wavelength ultraviolet (UV) radiation (referred to as ‘PUVA’ for psoralen plus UVA) is commonly used to treat psoriasis and vitiligo. These vastly different diseases respond to the therapy by different mechanisms even though the immediate effects of the therapy — the photomodification of cellular biomolecules — is the same for each. Because psoriasis is not cured by PUVA, patients receive many treatments over their lifetime and have a significantly increased risk for the development of skin cancers (primarily squamous cell carcinomas). In this article the basic aspects of psoralen photobiology are reviewed briefly. Several recent studies describing the incidence of skin cancer in UVA treated psoriasis cohorts are comparatively reviewed. In addition the impact of the analysis of mutations in the tumor suppressor gene, p53, are summarized. An unexpected mutation spectrum (very few PUVA type T→A transversions and frequent UVB solar signature C→T transitions) suggest that effects other than direct DNA photoadduct formation may be at play. These analyses suggest that it may be possible to improve the therapeutic efficacy of PUVA by a careful evaluation of the mode of delivery. In this review the science behind PUVA is summarized. In addition, the incidence of skin cancer as a long term consequence of repeated treatments is surveyed. To relate clinical observations to molelcular events, the nature of p53 mutations found in skin cancers from psoriasis patients is also analyzed. Finally some suggestions for improving the delivery of PUVA therapy are presented.     

窄谱UVB治疗寻常性银屑病的临床研究

目的　评价窄谱UVB治疗寻常性银屑病的疗效及安全性,并与改良PUVA(PUVA+UVB)疗法比较方法　108例患者,其中50例单纯照射窄谱UVB; 58例口服8 甲氧补骨脂素片, 0. 6mg/kg/次, 2h后照射UVA和UVB;每周3次,疗程8周,观察疗效与安全性。结果　经过8周治疗,窄谱UVB组基愈率为70. 0%,显效率为20. 0%。改良PUVA组基愈率为96. 6%,显效率为3. 4%;不良反应:窄谱UVB组仅个别患者出现轻度红斑、色素沉着及皮肤瘙痒。改良PUVA组发生率为40. 3%,多为轻中度消化道反应及皮肤瘙痒、色素沉着等。照射时间窄谱UVB组最长不超过7min,改良PUVA组最长需30min以上。结论　窄谱UVB治疗寻常性斑块型银屑病具有良好疗效,与改良PUVA疗法相比,虽然疗效略逊,但方法简便,患者无需服药,照光时间短,不良反应发生率亦低。     

Phototherapy in pediatric patients

The treatment of children with psoriasis, atopic dermatitis (AD), pityriasis lichenoides, and scleroderma poses a therapeutic problem because all therapeutic options are associated with numerous side effects. Therefore ultraviolet A and B (UVA and UVB) phototherapy is presented as a possible alternative to some of these therapies, primarily topical and systemic corticosteroids, in children. Our results in treating children with phototherapy and psoralen plus UVA (PUVA) bath phototherapy over the past 5 years are reported. UVB therapy (TL01) was used in 20 psoriatic children (6 boys, 14 girls; ages 6-14 years) during the stage of disease exacerbation and in 9 children (3 boys, 6 girls; ages 8-16 years) with pityriasis lichenoides. Combined UVA/UVB phototherapy was applied in 21 AD children (7 boys, 14 girls; ages 4-15 years). Photochemotherapy with local application of a PUVA bath was used in six children (2 boys, 4 girls; ages 9-16 years) with circumscribed scleroderma and in one girl with systemic scleroderma. All children received short courses of phototherapy with either no maintenance or short maintenance. All three therapeutic protocols resulted in a certain degree of improvement in most of the study patients. None of the patients exhibited any early phototherapy side effects. We conclude that phototherapy and PUVA bath are valuable and safe therapeutic options for selected children who do not respond to other treatments.     

Psoralen/UVA treatment and chromosomes

Summary Five psoriasis patients treated with 8-methoxypsoralen and UVA (PUVA) were studied by lymphocyte cultures at the 1st, 5th, 10th and 20th treatment and at a maintenance treatment 6 months later. Abnormal amounts of chromosome aberrations were not found, and the frequency of sister chromatid exchange (examined at the last treatment) was not increased. In vitro experiments with nanogram doses of psoralen (similar to plasma levels in patients) showed no increase in chromosome aberration or SCE frequency.The results indicate that therapeutic doses of PUVA have no clastogenic effect.