Photodiagnostic services in the UK and Republic of Ireland: a British Photodermatology Group Workshop Report.

BACKGROUND: Photodiagnostic investigations are essential for the accurate diagnosis of abnormal cutaneous photosensitivity and provide important information for the management of patients with photodermatoses (cutaneous photosensitivity disorders). Although photodiagnosis has been undertaken since the early 1970s, specialist services in the United Kingdom (UK) and Republic of Ireland are limited and there is no formal guidance on diagnostic approach. Indeed, there is a limited literature in this area of methodology and diagnostic practice. OBJECTIVES: The primary objective was to undertake a British Photodermatology Group Workshop to review the role and activities of specialist centres in the UK and Republic of Ireland in order to ascertain whether there were consensus practices. Secondary objectives were to identify key priorities for service, training and research. METHODS: An initial detailed survey review of current activities was undertaken prior to the Workshop and data from this survey were used to inform discussion at the Workshop, which was attended by key photodermatology experts from the UK and Republic of Ireland. RESULTS/CONCLUSIONS: We have undertaken a detailed review of current Photodiagnostic Services in the UK and Republic of Ireland and report on our findings from the 12 centres and we have identified key areas of consensus practice. This is an important step in the process of standardising and optimising procedures and protocols and defining minimum clinical standards for photodiagnostic investigations, which are of such diagnostic importance in Dermatology.

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.

NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure.

The nuclear factor of activated T cells (NFAT) transcription factors are regulated by calcium/calcineurin signals and play important roles in T cells, muscle, bone, and neural tissue. NFAT is expressed in the epidermis, and although recent data suggest that NFAT is involved in the skin's responses to ultraviolet radiation (UVR), the wavelengths of radiation that activate NFAT and the biological function of UV-activated NFAT remain undefined. We demonstrate that NFAT transcriptional activity is preferentially induced by UVB wavelengths in keratinocytes. The derived action spectrum for NFAT activation indicates that NFAT transcriptional activity is inversely associated with wavelength. UVR also evoked NFAT2 nuclear translocation in a parallel wavelength-dependent fashion and both transcriptional activation and nuclear translocation were inhibited by the calcineurin inhibitor cyclosporin A. UVR also evoked NFAT2 nuclear translocation in three-dimensional skin equivalents. Evidence suggests that COX-2 contributes to UV-induced carcinogenesis. Inhibiting UV-induced NFAT activation in keratinocytes, reduced COX-2 protein induction, and increased UV-induced apoptosis. COX-2 luciferase reporters lacking functional NFAT binding sites were less responsive to UVR, highlighting that NFAT is required for UV-induced COX-2 induction. Taken together, these data suggest that the proinflammatory, antiapoptotic, and procarcinogenic functions of UV-activated COX-2 may be mediated, in part, by upstream NFAT signaling.

The quality of life of 790 patients with photodermatoses.

BACKGROUND: Polymorphic light eruption and erythropoietic protoporphyria (EPP) have been demonstrated to have a moderate and large impact on the quality of life (QoL) of patients, respectively. However, there is little information available about the impact of other photodermatoses on QoL. OBJECTIVES: To assess and compare the impact of all forms of photodermatoses on patients' QoL using the standard 1-week Dermatology Life Quality Index (DLQI) questionnaire and a modified questionnaire to assess the impact over the previous year. METHODS: All patients with photodermatoses seen between 2001 and 2005 at five U.K. photobiology centres were contacted by post on the same day during a forecasted sunny week across the U.K. and asked to complete DLQI questionnaires. RESULTS: A total of 1877 patients were contacted. Seven hundred and ninety-seven (42%) patients replied, with a range from 30% to 48% for the five individual centres. Nearly two-thirds of patients with actinic prurigo (AP) and more than one-third of patients with photoaggravated dermatoses (PAD), chronic actinic dermatitis, EPP and solar urticaria had a DLQI of > 10, confirming a very large effect of the disorders on QoL. Of the cutaneous porphyrias, both variegate porphyria (median DLQI 3) and porphyria cutanea tarda (median DLQI 1.5) had a much lower impact on QoL than EPP. CONCLUSION: This is the first large-scale study to attempt to measure the impact of a range of photodermatoses on QoL. Photodermatoses have a major impact on QoL. This impact is highest in AP and PAD.

Wavelength specific patterns of p53 induction in human skin following exposure to UV radiation.

We report that, in human skin, exposure to equally erythemogenic doses of UVA, UVB, and UVC increases immunocytochemically detected p53 in a wavelength-specific pattern. UVC produced immunostaining confined to the upper epidermis. With UVB, staining was seen throughout the epidermis, whereas with UVA staining predominated in the basal layer. The results with UVB and UVC are understandable on the basis of their known differences in penetration, whereas those with UVA are not. This suggests that within one cell type the pattern of p53 response to UV radiation is wavelength dependent.

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.

A quantitative study of the effect of terfenadine on cutaneous erythema induced by UVB and UVC radiation.

Terfenadine, given in sufficient dose to cause maximum H1 receptor blockade, had no effect on the intensity of UVB or UVC erythema measured with a reflectance instrument at 4, 8, and 24 h after irradiation. Histamine, acting on the H1 receptor, is not a significant mediator of UVB or UVC erythema.

Similar dose-response and persistence of erythema with broad-band and narrow-band ultraviolet B lamps.

Psoriasis may be treated with ultraviolet B from lamps that have a broad emission spectrum or, more effectively, with lamps that have a narrow emission spectrum at 311 +/- 2 nm. There are conflicting reports of either greater or lesser burning episodes with narrow-band compared to broad-band ultraviolet B, even when treatments are based on predetermined minimal erythema dose measurements. This suggests that either the characteristics of the dose-response curve for erythema or the time course for erythema may be different for the two lamps. We examined the erythemal response to narrow-band and broad-band ultraviolet B in 12 patients with psoriasis. A geometric series of 10 doses from each lamp type were used on nonlesional skin on the back. Dose-response curves were constructed from reflectance measurements of erythema at 24 h and 72 h after irradiation. No significant difference was found in steepness of the erythema dose-response curve for the two lamps at 24 or 72 h. Persistence of erythema was assessed as the percentage of erythema remaining at 72 h. The mean persistence was 63% for narrow-band and 64% for broad-band lamps (p = 0.94). Therefore, in terms of erythemal response, no evidence has been found for a difference in burning potential for the two lamps.

The time course of UVB and UVC erythema.

The time course of ultraviolet erythema was measured using six different exposure doses of UVC and UVB radiation in each of eight adult subjects. The intensity of erythema was measured by reflectance spectrophotometry at 4, 8, 24, 36, and 48 h after irradiation. In five subjects there was no significant difference between the form of the UVB and UVC erythema time-course. In three subjects a significant difference was observed, but this was random rather than systematic between subjects. The results do not confirm the previously reported major differences in time course between the two qualities of radiation.

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.

Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, and induction of p53 protein and mRNA following application of skin irritants.

The mechanisms mediating the varied effects of ultraviolet radiation (UVR) on human skin are unclear, although a relationship between erythema and DNA damage is suggested by photosensitivity in xeroderma pigmentosum. Increased p53 expression in response to UVR is thought to reflect direct DNA damage, but recent evidence indicates that UVR also activates membrane and cytosolic signal transduction pathways. In this study, we have investigated the relationship between erythema and p53 induction following UVB and whether this p53 response is specific to UVR. p53 protein expression was determined by immunocytochemistry using the monoclonal antibody DO7, and p53 mRNA expression was examined by non-isotopic in situ hybridization. Incremental doses of UVB were administered to the lower back of eight subjects. Immunostaining revealed that p53 positive nuclei were significantly increased 8 h after suberythemogenic doses of UVB (79 +/- 12), compared to normal unirradiated skin (8 +/- 6, p < 0.0005), but no change in p53 mRNA was seen. Higher UVB doses, which resulted in moderate erythema, resulted in a similar or greater induction of p53 protein. Indomethacin (1% w/v), applied immediately after UVB irradiation, significantly inhibited UVB erythema at 8 h in six subjects (p < 0.005), but did not reduce p53 immunostaining. Dithranol (1 microgram/microliter, n = 8), sodium dodecylsulphate (5%, n = 4), and retinoic acid (0.5%, n = 4), applied for 48 h, caused erythema, significantly increased p53 protein levels (p < 0.05), and also increased p53 mRNA. Our results show that in human skin, UVB-induced p53 elevation can be dissociated from erythema and skin irritants can also induce p53 protein. The induction of p53 mRNA by irritants but not UVR suggests different mechanisms of action.

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.