Photoallergic contact dermatitis to 8-methoxypsoralen in Ficus carica.

BACKGROUND: Photocontact dermatitis to Ficus carica is induced by furocoumarins present in sap. These substances are generally considered to cause phototoxic reactions. OBJECTIVES: We conducted a patch test and histopathological study of patients with phytophoto contact dermatitis from the fig tree to evaluate the mechanism underlying the photoreaction. PATIENTS AND METHODS: Patch and photopatch testing with serial dilutions of two natural furocoumarins [5-methoxypsoralen and 8-methoxypsoralen (8-MOP)] contained in plant sap were performed in 47 patients. A synthetic furocoumarin, 4,5',8-trimethylpsoralen, was also tested. Histopathological analyses were made of some positive photoreactions. RESULTS: Positive photopatch tests reactions to 8-MOP were obtained in 12 of 47 patients, in 4 of them down to a concentration of 0.0001%. Patch tests and photopatch tests to the other two furocoumarins were negative. Histopathological findings on biopsies from positive photopatch tests to 8-MOP showed a dermatitis. CONCLUSIONS: Allergic photoreactions induced by contact with plants containing coumarins are generally regarded as chance findings. This study has demonstrated that phytophoto allergic contact dermatitis resulting from furocoumarins is not an exceptional finding, and should be suspected in subjects with diffuse clinical manifestations in photo-exposed but also non-exposed sites. To differentiate allergic from toxic photoreactions, patch tests need to be performed with serial dilutions of furocoumarins. Histological analysis of a biopsy sample from a positive test site will reveal alterations compatible with a photoallergic contact dermatitis.

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.

Kinetics of phototoxicity in trioxysalen bath psoralen plus ultraviolet A photochemotherapy.

A trioxysalen bath is a safe alternative to systemic 8-methoxypsoralen in long-term psoralen plus ultraviolet A (PUVA) treatment. The kinetics of its main side-effect, the strong phototoxicity, has not been thoroughly studied. This study determined the degree and persistence of phototoxicity after a single 10 min bath at a trioxysalen concentration of 0.33 mg/l. The buttock skin of 16 healthy volunteers was irradiated with UVA 10 min, and 1, 3, 9 and 24h after the bath. The minimal phototoxic dose (MPD) was assessed 48, 72 and 96h after the bath. In general, the 96 h reading showed the lowest values of MPD; for example, a median of 0.14 J/cm2 (95% confidence interval 0.10-0.14 J/cm2) at sites irradiated 10 min after the bath. The values increased progressively with later irradiation, and the maximum dose applied, 18.32 J/cm2, failed to produce any redness when irradiation was given 24 h after the bath. Substantial phototoxicity persists up to at least 9h after the trioxysalen bath, making it wise for patients to avoid sunshine for at least the rest of the day.

Concentration-dependent phototoxicity in trimethylpsoralen bath psoralen ultraviolet A.

BACKGROUND: Long-term use of topical trimethylpsoralen (TMP) psoralen bath plus ultraviolet A (bath PUVA) is considered safe with regard to the risk of skin cancer. However, the potential for severe phototoxicity limits its use. OBJECTIVES: To study the effect of dilution of the TMP bath on the minimal phototoxic dose (MPD). METHODS: Fifteen volunteers participated in the study. The MPD tests were performed for three TMP concentrations: 0.33 mg L-1, 0.1 mg L-1 and 0.033 mg L-1 at 2-week intervals. Geometric UVA dose series increasing by a factor of radical2 were used for the testing on the previously unexposed buttock skin. The MPD72 h was assessed at 72 h from the bath. RESULTS: For the highest TMP concentration of 0.33 mg L-1, the median MPD72 h was 0.14 J cm-2 (95% confidence interval (CI), 0.10-0.14 J cm-2). For the diluted TMP bath concentration of 0.1 mg L-1, the median MPD72 h increased to 0.29 J cm-2 (95% CI, 0.2-0.41 J cm-2) and for 0.033 mg L-1 to 0.81 J cm-2 (95% CI, 0.57-1.15 J cm-2), respectively. Thus, diluting the labelled concentration of 0.33 mg L-1 1 : 10 increased the median MPD72 h 5.6-fold. CONCLUSIONS: With regard to the safety and practicality of the TMP bath PUVA, the lower concentrations of TMP may be of clinical importance, and this needs to be validated in future controlled clinical trials.

Time course of skin photosensitivity following trimethylpsoralen bath PUVA.

One aspect of bath photochemotherapy (PUVA) that requires clarification is the duration of psoralen-induced cutaneous photosensitisation under conditions simulating clinical use. Using a half back comparison study technique, we investigated the persistence of trimethylpsoralen (TMP)-induced photosensitivity in skin irradiated to simulate a first PUVA exposure compared with un-irradiated skin. Baseline UVA minimal erythema dose and minimal phototoxic dose (MPD) were determined in 13 healthy volunteers. After readings at 72 h, subjects were bathed in TMP bath water for 15 min and one half of the back was immediately exposed to 40% of the MPD. Test sites (1.5 cm2) on both halves of the back were then irradiated with a UVA dose series at 15 min, 5, 10, 24, 34, 48 and 72 h after the bath. MPD readings were recorded visually at 72 h after each UVA exposure. The UVA MED was >25 J/cm2 in all the subjects. At each time point, a phototoxic index (PI) was calculated as UVA MED/MPD. In un-irradiated skin, photosensitivity returned to normal (PI=1) within 24 h after the TMP bath. In contrast, skin pre-irradiated to simulate the first PUVA treatment was still significantly photosensitive (PI=2.3; P=0.002) at 48 h. Contrary to previous recommendations, these data suggest that patients should be advised to avoid ambient or artificial sources of UVA throughout their course of TMP bath PUVA to reduce the risk of phototoxic erythema.

Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis.

It has been suggested that trioxsalen bath and ultraviolet (UV) A (PUVA) is associated with a very low or no risk of non-melanoma skin cancer, but the numbers of patients in individual studies have been limited. In order to attain statistically relevant information about the cancer risk associated with trioxsalen bath PUVA, two follow-up studies were combined and the joined cancer incidence was analysed among 944 Swedish and Finnish patients with psoriasis. The mean follow-up time for skin cancer was 14.7 years. Standardized incidence ratios (SIR) were calculated as a ratio of observed and expected numbers of cases. The expected numbers of cases were based on the national cancer incidence rates in the respective countries. There was no excess of squamous cell skin carcinoma [SIR 1.1, 95% confidence interval (CI) 0.2-3.2] or malignant melanoma (SIR 0.9, 95% CI 0.1-3.2) in the combined cohort. Basal cell skin carcinoma was not studied. The incidence of all non-cutaneous cancers was not increased (SIR 1.1, 95% CI 0.8-1.4). A threefold excess risk of squamous cell skin carcinoma after trioxsalen bath PUVA could therefore be excluded, which is a markedly lower risk than that associated with oral 8-methoxypsoralen PUVA. The result needs to be confirmed in a future follow-up, however, as the number of patients with high PUVA exposures was low.

Carcinogenic risk of bath PUVA in comparison to oral PUVA therapy.

The potential carcinogenic risk of bath PUVA therapy was compared to that of systemic (oral) PUVA. An analysis of the epidemiological data on cancer risk following bath PUVA with trimethylpsoralen does not support the conclusion that bath PUVA per se is less carcinogenic than systemic PUVA with 8-methoxypsoralen (8-MOP). Pharmacokinetic studies indicate that both the concentration of 8-MOP in the target organ for PUVA carcinogenicity (skin) at the relevant time point (time point of UVA irradiation) and the extents of biological effects in the skin are comparable following bathwater or systemic 8-MOP administration. Furthermore, the therapeutic effects of PUVA arise from the same photochemical reaction mechanisms as do the carcinogenic effects. Theoretically, the ratio of (desired) cytotoxic versus (undesired) mutagenic effects could increase with increasing efficiency of the PUVA therapy itself. On the basis of the available evidence, it is concluded that all forms of PUVA therapy, independently of the route of 8-MOP administration, contribute to a small but dose-dependent increase in nonmelanoma skin cancer risk.

Bath PUVA--an investigation of the distribution of trioxsalen (TMP) and 8-methoxypsoralen (8-MOP) in bathwater.

Trioxsalen (TMP) bath PUVA avoids the side effects of nausea and headache associated with oral 8-methoxypsoralen (8-MOP) treatment and allows shorter irradiation times that can be advantageous in some patients. However we noted that a number of patients developed unusual patterns of phototoxic burning. We thought that this was related to an uneven distribution of the TMP in the bathwater and for this reason, a study of bath water TMP concentrations achieved using different TMP preparations was undertaken. The distribution of 8-MOP in an 8-MOP bath was also measured for comparison. Our results confirm that an uneven distribution of TMP is achieved using TMP capsules or suspension and would explain our observed patterns of burning. With an ethanolic solution of TMP, or the commercial equivalent Tripsor, or with Puvasoralen-8 (an 8-MOP preparation), a homogeneous psoralen distribution is achieved, and they are therefore preferable for use in bath PUVA.

Cancer incidence among Finnish patients with psoriasis treated with trioxsalen bath PUVA.

BACKGROUND: Systemic methoxsalen PUVA increases nonmelanoma skin cancer risk in a dose-dependent manner, whereas trioxsalen bath PUVA treatment has been suggested to be less carcinogenic. OBJECTIVE: Our purpose was to study the carcinogenicity of topical trioxsalen PUVA. METHODS: We performed a record linkage study of 337 male and 190 female patients with psoriasis treated with trioxsalen bath PUVA during the period 1977 to 1988 and the Finnish Cancer Registry (cancer incidence in the period 1977 to 1993). The mean follow-up period per person was approximately 11 years. Data on the total cumulative UVA dose and other potentially carcinogenic treatments were collected from the patients' files. The standardized incidence ratio (SIR) was calculated, in which the expected number of cases was based on the national cancer incidence rates. RESULTS: During the follow-up, 26 cancer cases were observed in the cohort versus 30 expected (SIR, 0.88; 95% confidence interval [CI], 0.57-1.28). The only primary sites showing high SIRs were cancer of the kidney (SIR, 3.56; 95% CI, 0.97-9.10) and non-Hodgkin's lymphoma (SIR, 2.94; 95% CI, 0.36-10.6). There was only one case of nonmelanoma skin cancer; the expected number was 0.8 (SIR, 1.26; 95% CI, 0.03-7.04). The average cumulative UVA dose was 65 J/cm2; 40 patients had received more than 200 J/cm2. The average number of treatments was 112; 65 patients had received more than 200 treatments. CONCLUSION: No excess of squamous cell carcinoma of the skin was found in patients treated with trioxsalen bath PUVA. However, because of the small size of the cohort, only a sevenfold excess risk can be excluded. The possible associations between psoriasis or its treatment and kidney cancer and lymphoma need to be studied further in larger series.

Elimination of potential mutagenicity in platelet concentrates that are virally inactivated with psoralens and ultraviolet A light.

BACKGROUND: For virus sterilization of platelet concentrates (PCs), treatment with aminomethyltrimethyl psoralen (AMT) and long-wavelength ultraviolet A light (UVA) has shown efficacy. It has been found that treatment with 50 micrograms per mL of AMT and 38 J per cm2 of UVA in the presence of 0.35-mM rutin efficiently kills viruses while maintaining platelet integrity. There is, however, concern about the mutagenic potential of psoralens and UVA (PUVA)-treated PCs. STUDY DESIGN AND METHODS: Adsorption of PUVA-treated PCs with a hydrophobic resin containing C18 as the ligand was used for AMT removal, which was quantitated by the use of radioactive AMT. PUVA-treated PCs, with and without C18 treatment, were examined for solution pH and platelet aggregation response to agonists. In addition, residual AMT activity was determined by AMT's virucidal activity or incorporation into cellular DNA upon a second UVA irradiation and by its mutagenic potential in the Ames test. RESULTS: After PUVA treatment of PCs, residual AMT retained virucidal and adduct-forming ability upon re-exposure to UVA, but activities were less than those observed originally. As has been found previously, AMT had mutagenic potential following incubation in the dark with rat liver S9 microsomal enzymes. The PUVA treatment reduced this potential by 90 percent. C18 adsorption following PUVA treatment had no negative effect on platelet integrity and eliminated 50 percent of the added radioactive AMT. In addition, all detectable virucidal, nucleic acid-modifying, and mutagenic activities of AMT-treated PCs were removed by C18. CONCLUSION: These results suggest that hydrophobic resin adsorption of PUVA-treated PCs will conveniently remove functional psoralens and eliminates their mutagenic potential.

Ultraviolet A phototherapy and trimethylpsoralen UVA photochemotherapy in polymorphous light eruption--a controlled study.

Twenty-two patients with polymorphous light eruption were prophylactically treated with ultraviolet A (UVA) with and without trimethylpsoralen in the first randomized double-blind study in this subject. Twelve of the patients were treated during 2 consecutive springs with placebo during one spring and psoralens during the other. Eighteen of the patients improved after the therapy, but there was no clear-cut difference between the 2 regimens. As many as 12 patients got light eruptions during the treatment, but all but one continued with the therapy. This study indicates that UVA alone is as good prophylactic therapy for polymorphous light eruption as PUVA with trimethylpsoralen. However, because of the high incidence of provoked eruptions during therapy, the treatment may be difficult to handle for the patients themselves, at least during the initial treatment.

Comparison of the carcinogenic potential of trioxsalen bath PUVA and oral methoxsalen PUVA. A preliminary report.

BACKGROUND AND DESIGN: There is an increasing concern about the long-term carcinogenic effect of oral psoralen with long-wave UV radiation in the A range (PUVA). Most follow-up investigations indicate a definite risk of squamous cell carcinoma of the skin with long-term PUVA treatment. In a recently published study of 4799 Swedish patients who had received PUVA, it was noted that 833 patients who had received trioxsalen bath or oral trioxsalen did not show any increased risk of skin cancer in contrast to oral methoxsalen. This finding has been further investigated in this study. We compared four dermatologic university clinics in Sweden with regard to the carcinogenic potential of the PUVA regimen used. One clinic used trioxsalen bath PUVA exclusively and the other three used oral methoxsalen. Information on their PUVA-treated patients was collected and linked with information from the Swedish Cancer Registry to identify individuals with squamous cell carcinoma of the skin. RESULTS: A total of 18 squamous cell carcinomas of the skin were reported in 2975 PUVA-treated patients until 1987. The expected number was 3.1. The center using bath PUVA only had no increased risk of squamous cell carcinoma of the skin in contrast to the three centers using oral methoxsalen-PUVA. The increased risk for male subjects from those centers varied from six to 13 times that in the general population, but for female subjects a significant increased relative risk was found only at one center. CONCLUSION: In this preliminary report, PUVA treatment with trioxsalen bath seems to be less carcinogenic than the oral dosage. However, differences in the patient populations might also have affected the outcome of the study. More information on this field is needed.

Drug-induced photo-onycholysis. Three subtypes identified in a study of 15 cases.

We have studied 15 patients with photo-onycholysis induced by tetracyclines, psoralens, or fluoroquinolones. Three distinct clinical subtypes of onycholysis were seen. Type I showed a half-moon-shaped separation that was concave distally. Type II had a circular notch opened distally and shaped as if the distal nail plate had acted as a convex lens. In type III the changes were located in the central part of the nail bed with no connection to the margins. Ultraviolet (UV) irradiation of normal fingernails with various wavelengths showed that 3% to 20% of the irradiation could penetrate the nail. The different patterns of photodamage might be caused by the nail acting as a lens. Less protection by lack of melanin and absence of sebum and stratum granulosum may favor penetration of UV irradiation and explain why the skin was not always affected.

Case report: malignant melanoma arising during drug therapy for vitiligo.

A 30-year-old white male developed cutaneous patches of depigmentation which were treated with Trioxsalen ingested before daily sunbathing. A darkly pigmented lesion which appeared three weeks later on his back was widely excised and classified as a low-grade malignancy. Although the treatment of vitiligo with plants containing photodynamically active compounds dates back as far as 1400 BC, the modern period of research began only in the 1930's leading to the development of oral psoralens, a coumarin derivative. In early tests, patients showed increased sunlight tolerance and repigmentation of vitiliginous areas. Although some patients have developed uveitis and vitiligo while being treated for melanoma, previous published reports deny any cutaneous malignancy arising during drug therapy of vitiligo. The associations between vitiligo and melanoma are discussed. The possible causative role of Trioxsalen in etiology of the case presented is discussed.