An observer-blinded randomized controlled pilot trial comparing localized immersion psoralen-ultraviolet A with localized narrowband ultraviolet B for the treatment of palmar hand eczema.

BACKGROUND: Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. OBJECTIVES: To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB-UVB for the treatment of chronic hand eczema unresponsive to topical steroids. METHODS: Sixty patients with hand eczema unresponsive to clobetasol propionate 0·05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary outcome measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). RESULTS: In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to-treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9·5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. CONCLUSIONS: In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.

Investigation of cutaneous photoadaptation to narrowband ultraviolet B.

BACKGROUND: Photoadaptation describes the skin's ability to withstand an increased dose of ultraviolet (UV) radiation with repeated exposure, and this is the reason for exposure doses being increased during a course of phototherapy. However, directly measured data on photoadaptation are available only for broadband (BB) and not narrowband (NB)-UVB. OBJECTIVES: To measure photoadaptation to narrowband UVB. METHODS: We measured the degree of photoadaptation in patients with psoriasis during a standard course of NB-UVB phototherapy. The minimal erythemal dose (MED) was measured before and towards the end of a course of phototherapy. An adaptation factor (AF) was calculated for each patient using the ratio of final MED to initial MED. Sigmoid dose-response curves were also constructed. RESULTS: MED results were available for 50 patients (mean age 44 years, 28 female). The mean AF was 2·7 (95% confidence interval 2·4-3·0). There was no significant correlation between AF and skin type or initial MED. Dose-response curves were right shifted and parallel after phototherapy, and there was no significant difference in the maximum slope (P = 0·73). CONCLUSIONS: The photoadaptation caused by NB-UVB is considerably less than that reported for BB-UVB. The variation in photoadaptation between patients was not explained by skin type or baseline MED. Physical factors (such as tanning and epidermal thickening) are probably sufficient to account for photoadaptation, rather than downregulation of the inflammatory response. These data should help in the design of phototherapy protocols for NB-UVB to achieve optimal clearance of psoriasis.

Glutathione S-transferase genotype is associated with sensitivity to psoralen-ultraviolet A photochemotherapy.

BACKGROUND: There is marked interpatient variation in responses to psoralen-ultraviolet A (PUVA) photochemotherapy. Identification of molecular biomarkers of PUVA sensitivity may facilitate treatment predictability.The glutathione S-transferases (GSTs) influence cutaneous defence against UV radiation-induced oxidative stress and are therefore candidate biomarkers of PUVA sensitivity. Several human GSTs, including GSTM1 and GSTT1, are polymorphic, and null polymorphisms have been associated with increased UVB erythemal sensitivity and skin cancer risk. PUVA also increases skin cancer risk. OBJECTIVES: To investigate the effect of GST genotype on PUVA sensitivity. METHODS: We investigated GST genotype in patients starting PUVA (n=111) and the effects of 8-methoxypsoralen (8-MOP) on antioxidant response element (ARE)-regulated gene expression in mammalian cells. RESULTS: Lower minimal phototoxic doses (MPD) (P=0·022) and higher serum 8-MOP concentrations (P=0·052) were seen in GSTM1-null allele homozygotes compared with patients with one or two active alleles. In a subset of patients with psoriasis (n=50), the GSTM1 genotype was not associated with PUVA outcomes, although MPD [hazard ratio (HR) 1·37; 95% confidence interval (CI) for HR 1·15-1·64] and GSTT1-null (HR 2·39; 95% CI for HR 1·31-4·35) and GSTP1b (HR 1·96; 95% CI for HR 1·10-3·51) genotypes were associated with clearance of psoriasis in this patient group. Exposure of mammalian cells to 8-MOP induced gene expression via the ARE, a regulatory sequence in promoters of cytoprotective genes including GSTs, suggesting that these genes may be implicated in 8-MOP metabolism. CONCLUSION: The polymorphic human GSTs are associated with PUVA sensitivity. Further studies are required to examine the clinical relevance of these preliminary findings.

Melanocortin 1 receptor (MC1R) genotype influences erythemal sensitivity to psoralen-ultraviolet A photochemotherapy.

BACKGROUND: The melanocortin 1 receptor (MC1R) is a highly polymorphic G protein-coupled receptor. Inheritance of various MC1R alleles has been associated with a red hair/fair skin phenotype, increased incidence of skin cancer and altered sensitivity to ultraviolet (UV) radiation. OBJECTIVES: To investigate whether MC1R genotype influences erythemal sensitivity to psoralen-UVA photochemotherapy (PUVA) in patients with psoriasis and other common skin diseases. METHODS: Patients (n = 111) about to start PUVA were recruited to the study. Erythemal responses were assessed visually at 72 h and 96 h following PUVA by assessment of the minimal phototoxic dose (MPD). MC1R genotype was determined by direct sequencing. RESULTS: Inheritance of the MC1R Arg(151)Cys allele was associated with a red hair phenotype (odds ratio 25.19, P = 0.0004). In contrast, inheritance of the Val(60)Leu and Arg(163)Gln SNPs was associated with increased PUVA erythemal sensitivity (reduced MPD) 72 h following treatment in all patients (n = 111; Val(60)Leu chi(2) = 5.764, P = 0.016; Arg(163)Gln chi(2) = 5.469, P = 0.019) and in a subset of patients with psoriasis (n = 55; Val(60)Leu chi(2) = 4.534, P = 0.033; Arg(163)Gln chi(2) = 7.298, P = 0.007). Inheritance of two or more MC1R SNPs was also associated with increased PUVA erythemal sensitivity (reduced MPD) in both patient groups (n = 111; chi(2) = 8.166, P = 0.017; n = 55; chi(2) = 10.303, P = 0.016). CONCLUSIONS: Our data demonstrate that MC1R genotype influences PUVA erythemal sensitivity in patients with psoriasis and other common skin diseases.

The challenge of follow-up in narrowband ultraviolet B phototherapy.

BACKGROUND: The use of narrowband ultraviolet (UV) B phototherapy to treat psoriasis and other disorders has increased markedly since the TL-01 lamps were introduced in the 1980s. While broadband UVB phototherapy has generally been considered to be a relatively safe treatment, some concern has been raised about the potential increased skin cancer risk with narrowband UVB. OBJECTIVES: The likelihood of a patient who is free of nonmelanoma skin cancer (NMSC) at the start of phototherapy developing a malignancy after a certain follow-up period will be dependent not only on the carcinogenic potential of the treatment but also on the age-conditional probability of natural occurrence. We were interested to explore the potential difficulty of designing studies to separate these two events. Methods Mathematical models were developed that combined age-conditional probabilities of developing NMSC due to natural causes with the risk of inducing these cancers from narrowband UVB phototherapy in order to estimate the excess number of cancers resulting from this therapeutic intervention in a cohort of patients. RESULTS: Within-department studies will be most unlikely to demonstrate that the number of NMSCs observed in follow-up studies is significantly different from that expected in an untreated population, even for a follow-up period of 20 years. CONCLUSIONS: Determination of the carcinogenic potential associated with narrowband UVB will require large multicentre studies typically involving several thousand new patients per year and followed up for 10 years or more.

An update and guidance on narrowband ultraviolet B phototherapy: a British Photodermatology Group Workshop Report.

Summary These guidelines for use of narrowband (TL-01) ultraviolet B have been prepared for dermatologists by the British Photodermatology Group on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment of patients with a variety of dermatoses and photodermatoses, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of background photobiology.

Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial.

BACKGROUND: Narrow-band ultraviolet B (UVB) is an effective treatment for psoriasis, and open studies suggest that this phototherapy might improve atopic eczema. We did a randomised controlled trial to compare narrow-band UVB, UVA, and visible light phototherapy as second-line, adjunctive treatments in adult patients with moderate to severe atopic eczema. METHODS: Phototherapy was administered twice a week for 12 weeks. 26 patients were randomly assigned narrow-band UVB, 24 were assigned UVA, and 23 visible fluorescent light. The primary endpoints were change in total disease activity (sum of scores at six body sites) and change in extent of disease after 24 treatments compared with baseline. Data were analysed by the method of summary measures. FINDINGS: 13 patients withdrew or were excluded from analysis. Mean reductions in total disease activity over 24 treatments in patients who received narrow-band UVB and UVA, respectively, were 9.4 points (95% CI 3.6 to 15.2) and 4.4 points (-1.0 to 9.8) more than in patients who received visible light. Mean reductions in extent of disease after 24 treatments with narrow-band UVB and UVA were 6.7% (1.5 to 11.9) and -1.0% (-5.3 to 3.3) compared with visible light. A small proportion of patients developed erythema after phototherapy or had a flare in their eczema sufficient to withdraw from treatment. INTERPRETATION: Narrow-band UVB is an effective adjunctive treatment for moderate to severe atopic eczema, and the treatment is well tolerated by most patients.

The effect of methoxsalen dose on ultraviolet-A-induced erythema.

There is considerable interindividual variation in bioavailability of Methoxsalen (8-methoxypsoralen) after ingestion of the standard dose used in photochemotherapy (psoralen plus ultraviolet A). A dose change may be used to alter the degree of photosensitivity, although there is limited information on the effect of 8-methoxypsoralen dose alterations on phototoxicity within individuals. We studied the effect of changes of 8-methoxypsoralen dose over a narrow range in 15 subjects with psoriasis. Two hours after ingestion, serum 8-methoxypsoralen concentration was determined and phototesting was performed at 350 +/- 30 nm (0.45-14 J per cm2). The minimal phototoxic dose at 72 h was recorded, erythema was measured using a reflectance instrument, and dose-response curves were constructed. Each subject was tested on three occasions using doses of 25 mg per m2 (conventional dose) or conventional dose +/- 10 mg. Median serum 8-methoxypsoralen concentration increased from 96 to 143 to 229 ng per ml with dose increases from conventional dose - 10 mg to conventional dose and conventional dose + 10 mg, respectively (p < 0.001). The median minimal phototoxic dose and D0.025 (the objective equivalent of the minimal phototoxic dose derived from the dose-response curve) were significantly reduced with increasing 8-methoxypsoralen dose from conventional dose minus 10 mg (minimal phototoxic dose 1.7 J per cm2; D(0.025) 2.8 J per cm2) to conventional dose (1.2; 1.4 J per cm2) and conventional dose plus 10 mg (0.9; 1.0 J per cm2) (p < 0.001). Change in 8-methoxypsoralen dose had no detectable effect on the maximum slope of the psoralen plus ultraviolet A erythema dose-response curve. Thus, 8-methoxypsoralen dose changes within individuals, over a narrow but clinically relevant range, significantly altered the threshold response to psoralen plus ultraviolet A erythema but not the rate of increase in erythema with increasing ultraviolet A dose.

PUVA-related punctate keratoses of the hands and feet.

BACKGROUND: We have observed, in patients undergoing high-dose PUVA treatment, a type of keratosis not previously described. The lesions usually occur on the sides of the palms or soles and are clinically distinct. They are generally painless and often go unnoticed by patients. OBJECTIVE: We sought to further characterize these lesions both clinically and histologically. METHODS: Patients attending a PUVA clinic were screened for these keratoses. Other PUVA-related complications were recorded. Representative lesions were photographed, and biopsy specimens were taken. RESULTS: Biopsy specimens were taken from lesions in 10 patients. All had plaque psoriasis and had received high UVA doses (>1000 J/cm(2)) through PUVA therapy. All patients had PUVA-induced keratoses elsewhere, but the number varied greatly between patients. The hand and foot keratoses were well defined and circular and had a characteristic histologic appearance, with a sharp demarcation between normal and abnormal markedly pale-staining epidermis. CONCLUSION: These lesions are a further cutaneous manifestation of prolonged PUVA therapy.

Guidelines for topical PUVA: a report of a workshop of the British photodermatology group.

Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] plays an important part in dermatological therapeutics, being an effective and generally safe treatment for psoriasis and other dermatoses. In order to maintain optimal efficacy and safety, guidelines concerning best practice should be available to operators and supervisors. The British Photodermatology Group (BPG) have previously published recommendations on PUVA, including UVA dosimetry and calibration, patient pretreatment assessment, indications and contraindications, and the management of adverse reactions.1 While most current knowledge relates to oral PUVA, the use of topical PUVA regimens is also popular and presents a number of questions peculiar to this modality, including the choice of psoralen, formulation, method of application, optimal timing of treatment, UVA regimens and relative benefits or risks as compared with oral PUVA. Bath PUVA, i.e. generalized immersion, is the most frequently used modality of topical treatment, practised by about 100 centres in the U.K., while other topical preparations tend to be used for localized diseases such as those affecting the hands and feet. This paper is the product of a recent workshop of the BPG and includes guidelines for bath, local immersion and other topical PUVA. These recommendations are based, where possible, on the results of controlled studies, or otherwise on the consensus view on current practice.

A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis.

BACKGROUND: Although PUVA treatment of psoriasis is more effective than conventional or broad-band UVB phototherapy, two small studies have suggested that narrow-band or TL-01 phototherapy may have a therapeutic effect equal to PUVA. If confirmed, this would be of considerable importance as TL-01 therapy is likely to be considerably safer in the long term than PUVA. OBJECTIVE: The purpose of this study was to compare PUVA with narrow-band (TL-01) phototherapy in psoriasis. METHODS: We studied 100 patients with plaque-type psoriasis who were randomly allocated to twice-weekly treatment with PUVA or narrow-band UVB. RESULTS: Clearance of psoriasis was achieved in a significantly greater proportion of patients treated with PUVA (84%) than with TL-01 (63%) (P =.018), and with significantly fewer treatments (median number of treatments for clearance with PUVA, 16.7; with TL-01, 25.3; P =.001). Only 12% of those treated with TL-01 were clear of psoriasis 6 months after finishing treatment compared with 35% for PUVA (P =.002). CONCLUSION: When given twice weekly, PUVA is more effective for psoriasis than narrow-band UVB phototherapy.

The time-course of psoralen ultraviolet A (PUVA) erythema.

The time-course for the development of ultraviolet A-induced erythema in psoralen-sensitized skin differs from that caused by ultraviolet B or ultraviolet A but objective data are not available. During psoralen ultraviolet A therapy, the minimal phototoxic dose is determined 72 h after exposure, when psoralen ultraviolet A erythema is assumed to be maximal. This measurement is of fundamental importance in optimizing the therapeutic regimen. We examined a detailed time-course for development of psoralen ultraviolet A erythema in 16 subjects. The erythemal responses to ultraviolet B, ultraviolet A and psoralen ultraviolet A were assessed visually and using a reflectance device. Ultraviolet B erythema was maximal 24 h after exposure compared with subsequent time-points. Psoralen ultraviolet A erythema was evident at 24 h, with reduction in the median ultraviolet A minimal erythema dose from 14 to 5 J per cm2 in the presence of psoralen (p < 0.01; n = 9). Peak psoralen ultraviolet A erythema, assessed by minimal phototoxic dose, did not occur until 96 h or later in 75% of subjects. Using individual dose- response curves, we determined that only 67% of mean maximum psoralen ultraviolet A erythemal intensity had developed by 72 h. Furthermore, at the time of maximal erythema, the slope of the psoralen ultraviolet A dose-response curve was approximately 2-fold shallower than that for ultraviolet B-induced erythema. If assessment of psoralen ultraviolet A erythemal sensitivity had been made at 96 h instead of the conventional 72 h time-point, peak erythemal responses would not have been missed in any of the subjects. Based on these findings, it seems appropriate to consider whether psoralen ultraviolet A minimal phototoxic dose measurements should be performed 96 h after exposure.

Phototesting prior to narrowband (TL-01) ultraviolet B phototherapy.

A device for phototesting patients prior to narrowband phototherapy is described. One hundred and fifty patients (130 with psoriasis and 20 with eczema) of skin types I-IV were phototested on the forearm and 22 on both forearm and back. The minimal erythema dose (MED) was judged visually 24 h after irradiation, and in those patients who were tested at two body sites, objective measurement of the erythema was made using a reflectance instrument. The MED values on the arm showed a fivefold range. There was no significant association between skin type and MED. The MED values on the arm were significantly higher than those measured on the back, although the differences were small in the majority of cases. No significant difference was found between the slopes of the dose-response curves measured on the arm and on the back.

Comparison of psoralen-UVB and psoralen-UVA photochemotherapy in the treatment of psoriasis.

BACKGROUND: PUVA treatment of psoriasis is usually given with broad-band fluorescent UVA lamps. Narrow-band UVB exposure after oral methoxsalen has been shown to achieve a greater therapeutic response in psoriasis than identical UVB exposure given without psoralen. OBJECTIVE: The purpose of this study was to compare conventional PUVA with psoralen-UVB therapy in psoriasis. METHODS: We studied 100 patients with plaque-type psoriasis who were randomly selected to receive either conventional psoralen-UVA or psoralen-UVB treatment. RESULTS: No significant difference was found between the two treatments in the proportion of patients whose skin cleared during treatment or in the number of exposures required for clearance of psoriasis. As expected, the cumulative UV dose for clearance was smaller in the group treated with UVB compared with those receiving UVA. Side effects and disease status at 3 months after the end of treatment were similar for the two groups. CONCLUSION: Psoralen-UVB treatment of psoriasis is as effective as conventional PUVA. The mechanism of psoralen-311 nm UVB action on psoriasis requires study to predict the long-term safety of this treatment.

Calculation of 8-methoxypsoralen dose according to body surface area in PUVA treatment.

In 41 patients about to start PUVA, the dose of 8-methoxypsoralen (8-MOP) was calculated conventionally according to body weight (0.6 mg/kg), or according to body surface area (25 mg/m2) predicted from height and weight measurements. The two different methods of dosing were used on consecutive treatment days and the plasma 8-MOP concentration was measured on each occasion 2 h after ingestion of the crystalline form of 8-MOP, given to the nearest 10 mg. Body weight calculated doses ranged from 30 to 60 mg with a significant difference in the plasma 8-MOP concentration between the dose groups, indicating a systematic variation according to the weight of the patient. When calculated according to body surface area, only two doses were used (40 or 50 mg), and there was no significant difference in plasma 8-MOP concentration between the groups. Calculation of the dose of 8-MOP using body surface area may be performed quickly and simply provided the height and weight of individual patients is known. We provide evidence that this method of dosing will improve the therapeutic effect of PUVA in psoriasis.