Ultraviolet erythema: dose response and mediator diffusion.

The earliest contribution made by Jan van der Leun to the field of photobiology was studying the mechanism of UV-induced erythema in human skin - a subject he chose for his PhD in the 1960s. His contribution to this topic encouraged us to continue this work and over a number of years in the 1980s and 1990s, we carried out several studies on quantitative aspects of UV erythema. A major part of Jan's thesis focused on diffusion processes in UV erythema and his observations led him to conclude that erythema induced by radiation with wavelengths of around 300 nm was due to the actions of a diffusing mediator arising in the epidermis, whereas radiation at shorter wavelengths around 254 nm, caused erythema by exerting a direct effect on the dermal blood vessels. By taking his data and combining them with our own studies on the dose response of UV erythema to radiation of different wavelengths, we were able to show that, contrary to Jan's conclusions, the mediator diffusion theory he developed did indeed predict that both UVB and UVC induced erythema could be explained by the action of diffusing mediators.

Spectral effects of UV on psoriasis.

Ultraviolet B (UVB) is a highly effective, relatively safe, affordable and widely used therapeutic option for moderate psoriasis. Several types of UVB lamp are available to treat psoriasis, both broadband and narrowband, allowing a choice of spectral emission. However despite years of clinical use, the mechanism of action of UVB in clearing psoriasis remained incompletely understood. Moreover, there has been little insight into how the relative effectiveness of different UVB wavelengths linked to the mechanism of action, although it is known that the action spectrum for clearance of psoriasis differs from the action spectrum of erythema. This paper examines the existing literature from which our current treatments have evolved, and offers new insight into the use of keratinocyte apoptosis as a biomarker which may help to optimise UV treatment in the future. When combined with a systems biology approach, this potential biomarker may provide insight into which wavelengths of UV are the most effective in clearing psoriasis, allowing a more rational and potentially an individually tailored approach to optimising phototherapy for psoriasis.

Keratinocyte apoptosis in epidermal remodeling and clearance of psoriasis induced by UV radiation.

Psoriasis is a common chronic skin disorder, but the mechanisms involved in the resolution and clearance of plaques remain poorly defined. We investigated the mechanism of action of UVB, which is highly effective in clearing psoriasis and inducing remission, and tested the hypothesis that apoptosis is a key mechanism. To distinguish bystander effects, equal erythemal doses of two UVB wavelengths were compared following in vivo irradiation of psoriatic plaques; one is clinically effective (311 nm) and one has no therapeutic effect on psoriasis (290 nm). Only 311 nm UVB induced significant apoptosis in lesional epidermis, and most apoptotic cells were keratinocytes. To determine clinical relevance, we created a computational model of psoriatic epidermis. Modeling predicted apoptosis would occur in both stem and transit-amplifying cells to account for plaque clearance; this was confirmed and quantified experimentally. The median rate of keratinocyte apoptosis from onset to cell death was 20 minutes. These data were fed back into the model and demonstrated that the observed level of keratinocyte apoptosis was sufficient to explain UVB-induced plaque resolution. Our human studies combined with a systems biology approach demonstrate that keratinocyte apoptosis is a key mechanism in psoriatic plaques clearance, providing the basis for future molecular investigation and therapeutic development.

Seasonal palmar keratoderma in erythropoietic protoporphyria indicates autosomal recessive inheritance.

Erythropoietic protoporphyria (EPP) is an inherited disorder that results from partial deficiency of ferrochelatase (FECH). It is characterized clinically by acute photosensitivity and, in 2% of patients, liver disease. Inheritance is usually autosomal dominant with low penetrance but is recessive in about 4% of families. A cross-sectional study of 223 patients with EPP in the United Kingdom identified six individuals with palmar keratoderma. We now show that these and three additional patients, from six families, have an inherited subtype of EPP which is characterized by seasonal palmar keratoderma, relatively low erythrocyte protoporphyrin concentrations, and recessive inheritance. No patient had evidence of liver dysfunction; four patients had neurological abnormalities. Patients were hetero- or homoallelic for nine different FECH mutations; four of which were previously unreported. Prokaryotic expression predicted that FECH activities were 2.7-25% (mean 10.6%) of normal. Neither mutation type nor FECH activity provided an explanation for the unusual phenotype. Our findings show that palmar keratoderma is a clinical indicator of recessive EPP, identify a phenotype that occurs in 38% of reported families with recessive EPP that to our knowledge is previously unreported, and suggest that patients with this phenotype may carry a lower risk of liver disease than other patients with recessive EPP.

Positive photocontact responses are not elicited to sunscreen ingredients exposed to UVA prior to application onto the skin.

Photocontact allergic reactions to sunscreen chemicals are investigated by photopatch testing. It has generally been assumed that for photocontact allergy to be shown, the putative pro-allergen must be in the skin at the time of ultraviolet A (UVA) exposure. However, this assumption has not, to our knowledge, been tested. The objective of this study was to determine whether positive photocontact responses can still be elicited when sunscreen chemicals are exposed to UVA prior to application onto the skin. 3 patients known to have positive photocontact reactions to a total of 6 sunscreen chemicals were studied. For conventional photopatch testing, patch test strips were applied onto the back and removed 1 D later, and the area was irradiated with UVA (5 J/cm(2)). For pre-irradiated testing, patches were exposed to the same dose of UVA immediately before application onto the back and then removed 1 D later. Skin responses were visually assessed by a blinded investigator 1 and 2 D after patch test removal. The same photocontact responses of the same magnitude, as previously documented for each patient, were seen at each of the conventional UVA-exposed patch test sites. However, in no patient was a positive response elicited at any of the sites where pre-irradiated patches had been applied. This study shows that positive photocontact responses to sunscreen chemicals do not occur when the putative pro-allergen is irradiated prior to application onto the skin. This suggests that for a photoallergic reaction to occur, the sunscreen chemical needs to be within the skin when activated by UVA.

A randomized comparison of selective broadband UVB and narrowband UVB in the treatment of psoriasis.

UVB is widely used to treat psoriasis. Conventional broadband UVB lamps are less effective than narrowband UVB lamps, which have an emission peak at 311 nm. The long-term safety of narrowband UVB phototherapy is uncertain. "Selective" broadband UVB lamps, which have little emission <290 nm, are also available, but have not been adequately compared to narrowband UVB lamps. We performed a randomized comparison of narrowband UVB (TL-01 lamps) and selective broadband UVB (UV6 lamps) in 100 patients with psoriasis. The median number of exposures for clearance was 28.4 for TL-01 and 30.4 for UV6 (ratio of the medians 0.93; 95% confidence interval (CI) 0.80, 1.09; P=0.39). No significant difference was found in the proportion of patients achieving clearance: TL-01 56%, UV6 40% (odds ratio for clearance with TL-01 relative to UV6 was 2.00 (95% CI 0.87, 4.62), P=0.10). Side effects, including the development of erythema during phototherapy, were similar for the two lamp types. Risk estimates based on the human photocarcinogenesis action spectrum predict that narrowband UVB lamps will be 50% more carcinogenic for equal erythemal doses than selective broadband lamps (UV6). As these two lamp types appear to be of similar efficacy, phototherapy using a selective broadband source may be a safer option than use of narrowband UVB.