Sophie C.
Weatherhead
*ab,
Peter M.
Farr
ab and
Nicholas J.
Reynolds
ab
aDepartment of Dermatology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
bDermatological Sciences, Newcastle University, Newcastle-upon-Tyne, UK. E-mail: sophie.weatherhead@ncl.ac.uk
First published on 18th September 2012
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.
The action spectrum for clearance of psoriasis can be defined as the relative effectiveness of different wavelengths in achieving clearance of plaques. To optimise the efficacy of phototherapy for psoriasis it is important to know which wavelengths are the most effective in plaque clearance. However, our current phototherapy treatments are based on the action spectrum derived from studying just four patients with psoriasis. In 1981, Parrish and Jaenicke published their landmark study examining four male Caucasian patients with psoriasis.12 Seven plaques were chosen from each subject and irradiated daily in localised areas with wavelengths of UV ranging from 254 nm to 320 nm and the clinical response recorded. The authors showed that wavelengths over 300 nm and less that 320 nm were effective in clearing plaques at doses equal to or less than the MED, but those less than 300 nm were ineffective even at doses of up to 28 times the MED. Around this time, a phosphor coating on low-pressure mercury bulbs was developed that resulted in an emission of UVB peaking at 311 nm +/−2 nm, and therefore these lamps were developed commercially to treat psoriasis (narrowband UVB). Whether the optimal therapeutic wavelength shows inter-individual variation remains to be determined. However, by gaining insight into the mechanism of plaque clearance,13 we hypothesise that characteristics of psoriatic plaques may contribute to variation in therapeutic responses to UVB. Together, these factors suggest that further treatment benefit could be obtained by optimising wavelengths of UV radiation delivered to individual patients. Further research in this area is warranted.
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Fig. 1 Known action spectra within the skin. Three action spectra are shown: non-melanoma skin cancer (blue), DNA damage (black) and erythema (red). These follow a similar pattern, suggesting that they may have a common chromophore. They peak within the UVC/UVB range and decline as the wavelength increases. It should be noted however, that the action spectrum for DNA damage is calculated using data from cultured cell and adjusted for transmission through the human epidermis. This makes it difficult to directly compare with the other 2 in vivo spectra as the optics of the epidermis will affect transmission and some chromophores (e.g. DNA) can act as “sunscreens” to UVR. |
The DNA damage action spectrum was defined by Setlow in 1974 to identify which wavelengths are most carcinogenic to the skin (Fig. 1).20 Affected epidermal cells are predominantly basal, however, the action spectrum parallels that of the erythema action spectrum for wavelengths greater than 300 nm, suggesting a possible common chromophore. This is supported by studies looking at the action spectrum of UVB (290–320 nm) for the production of the proinflammatory cytokine TNFα, within human epidermis in vivo.21,22 Young et al. showed that DNA is likely to be a major chromophore for erythema in the UVB range.21 Walker and Young later showed that the action spectrum of soluble TNFα production, which is thought to play a role in UV-induced skin cancer, closely paralleled the action spectrum of erythema and DNA damage in the basal layer.22 It has maximum efficacy at 300 nm, suggesting that cyclobutane pyrimidine dimers trigger TNFα production and release within human epidermis. The action spectrum for mammalian non melanoma skin cancer, which was defined by de Gruijl and van der Leun in 1994,23 lies between the erythemal and DNA-damage action spectra and the erythema action spectrum within the UVB range, but show a sine-like effect at longer wavelengths, between 340–400 nm (see Fig. 1). This spectrum was calculated using mice studies and human epidermis ex vivo, although it was noted that the action spectra can vary between individuals.
Other action spectra in the skin include the effects of UV on immunosuppression, which shows a peak at 300 nm and a further peak at 370 nm; although the UVA peak is likely to be the greatest contributor to immunosuppression due to the far greater amount of UVA contributing to total daily UV exposure.24 UV has also been shown to activate the transcription factor Nuclear Factor of Activated T cells (NFAT),25 which regulates COX-2 production and may thereby contribute to UV-induced skin cancer formation.26 The action spectrum for NFAT activation has only been derived in cultured keratinocytes where it was shown to be inversely related to wavelength. It is distinct to the DNA damage/erythema action spectra,26 although it is not possible to directly compare in vivo and in vitro systems as the absorption spectrum of single cells in vitro will not be complicated by the differing optics of the skin, and hence penetration into the epidermis.
Because UVB exerts a multitude of effects, it cannot be assumed that the action spectrum for psoriasis will depend on basal layer DNA damage and follow a similar plot to those shown in Fig. 1, as this is dependent on the depth of UV penetration required for maximal biological activity. Therefore, only if the biological target for psoriasis clearance by UV is within the basal layer (as for DNA damage and skin cancer induction), would the action spectrum be expected to be similar.
Monochromatic excimer lasers (308 nm) can be effective as a treatment for localised psoriasis8,10,11,29 and have been demonstrated to be as effective as 311 nm UVB in clearing psoriasis.11 Over recent years, the 308 nm excimer laser has been used to effectively clear individual plaques using doses of 3–6 MEDs.30 One study showed that irradiation of matched psoriatic plaques in 15 patients with the 308 nm excimer laser, 308 nm UVB lamp and 311 nm UVB lamp resulted in similar efficacy for all three irradiation sources over a 10 week period, with a mean of 24 treatments required for clearance.11 More recently, an open, single-blinded right/left comparison trial compared the 308 nm excimer laser and 311 nm UV lamp in 16 patients and again found similar efficacy overall although nine patients responded better to the 308 nm excimer laser and four to the 311 nm lamp.31 Therefore, although these treatments are highly effective in clearing psoriasis, they clear psoriasis to varying extents in different patients, are not effective in all patients and show inter-individual variation in efficacy.
Designing experiments to investigate which wavelengths most effectively clear psoriasis and the factors regulating response may include expanding the original studies of Parrish and Jaenicke using a large sample size. Plaques would need to be matched within patients for size, thickness and location, across a range of age groups in men and women. However, such experiments are very time consuming for both patient and investigator and require the use of a calibrated monochromator, which are only available in a few specialised centres. It is unlikely that such an experiment would be undertaken today, particularly in view of alternative therapeutic modalities available. Moreover, initial doses used in treatment are usually based on the patients’ MED for a given wavelength, and would therefore need to be measured for each wavelength prior to irradiation. Whether or not relating response to a patient's MED is the best way to compare doses will remain unclear until the exact mechanism of plaque clearance is defined. Only if the biological effect of clearance occurs in the same location (depth) of the epidermis as inducing factors for erythema, can the use of MED as a way of equating doses be justified. Our recent work has shown that keratinocyte apoptosis is an important mechanism of psoriatic plaque remodelling in response to UVB, and that this occurs predominantly in the basal and suprabasal epidermis of psoriatic plaques.13 Moreover, by adopting a systems biology approach we created a mathematical model of psoriatic epidermis and its response to UVB that allowed us to make predictions about effects of specific input variables on the defined outcomes.13 This approach will facilitate the design of specific intervention studies in humans to address some remaining unanswered questions.
The erythema action spectrum is similar to that of the DNA damage and skin cancer action spectra which affect the basal layer, suggesting that MED is likely to be a good way of determining equal dose between different wavelengths. UV-induced keratinocyte apoptosis may therefore be a good biomarker to predict plaque clearance.
In normal skin, UV-induced damage can be limited by apoptosis, and both UVB and UVC have been shown to induce apoptosis of normal human keratinocytes in vitro, although UVC appears to cause significantly more (6–4) photoproducts and cyclobutane pyrimidine dimers than UVB in cultured keratinocytes.33 When equal levels of keratinocyte apoptosis are generated with UVC and UVB, greater release of mitochondrial apoptotic pathway factors (such as cytochrome c) has been shown following UVC, with UVB inducing more apoptosis via the extrinsic pathway.33 This suggests that effects of UV on keratinocytes are at least in part, wavelength specific, irrespective of differences in penetration.
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Fig. 2 Interactive model of psoriatic epidermis, which can be adapted to incorporate different action spectra The model interface consists of buttons, sliders, and monitors to allow easy adjustment of parameters by the user, and observation of the result of these adjustments. Each ‘tick’ represents one hour, and is displayed at the top of the interface. ‘Start-with-psoriasis-phenotype on/off’ allows the user to choose whether to start the model as normal or psoriatic phenotype, but does not affect the running of the model in any way. The positions monitor goes from ‘1’ (normal) to ‘7’ (maximal psoriatic phenotype for this model), and will change according to the number of cells and proliferation rate within the model. ‘Cytokine-stimulus’ allows the user to choose to ‘switch on a stimulus’ to increase the proportion of actively proliferating stem and TA cells. Note that it takes approximately 600 h for the model to start to reach equilibrium (as shown in the overview display window), which is then self-sustaining until irradiated with UVB. Yellow patches represent the basement membrane, dermis and below. Stem cells are shown as blue, TA cells as pink (light pink when actively dividing and darker pink when resting), and green cells are differentiated. |
An important observation was that keratinocyte apoptosis does not occur in psoriatic plaques in vivo in response to doses of up to 3 MEDs of 290 nm UVB at time-points between 4 and 48 h (n = 26).13 Extending this observation further, the biological effects of five different wavelengths of UVB (296 nm, 301 nm, 306 nm, 311 nm and 320 nm) were examined in matched psoriatic plaques in vivo from 18 patients (Weatherhead et al., unpublished data). This study showed that keratinocyte apoptosis occurs in psoriatic plaques following irradiation with wavelengths between 300 and 320 nm only, fitting well with Parrish and Jaenicke's original study which showed that only these wavelengths are clinically effective in clearing psoriasis.12 Interestingly, this study showed wide inter-patient variation, with peak keratinocyte apoptotic response in 50% of the patients following 311 nm, 17% of patients following 301 nm and 22% of patients had a peak following 306 nm UVB. Apoptotic counts in plaques following irradiation with these 3 wavelengths were all significantly greater than following irradiation with 296 nm or 320 nm UV (p = 0.0314). Longer wavelengths of UV penetrate deeper into the epidermis, and as apoptosis is seen in the lower epidermis, it could be argued that the optimal wavelength for apoptosis induction will be dependent on epidermal thickness within the plaque. However, although a positive correlation was shown between epidermal thickness and optimal wavelength for apoptosis induction, this was not statistically significant amongst this relatively small sample. The apoptotic response of the 5 wavelengths studied was also independent of patients’ skin type and the administered irradiation dose. It is therefore unclear from this work why some patients have a differential apoptotic response to wavelengths which induce keratinocyte apoptosis in other subjects. One possible explanation is that this arises due to sample error and chance observation of transient events (apoptosis; which can be completed within 20 min),13 with larger numbers of patients being required to reduce this potential bias.
If results of this study are representative of the general psoriatic population, it follows that UVB lamps with emission in the 301–311 nm range (and no significant emission of highly erythemal wavelengths < 301 nm) would appear the most efficient in inducing epidermal keratinocyte apoptosis, and therefore potentially would result in the best clinical outcome for patients if apoptosis is an important mechanism of psoriasis clearance. Broadband UVB lamps used to treat psoriasis may be “selective” (with little emission at 300 nm or shorter wavelengths, e.g. UV6), or “conventional” (with significant emission < 300 nm, e.g. TL12, FS40). It would therefore follow that narrowband UVB (TL01; 311 nm +/−2 nm)/selective broadband UVB should be more effective for a given erythemal dose than conventional broadband UVB, as a greater proportion of the output is within the apoptosis-inducing spectrum. Several small half-body studies have shown a significantly greater efficacy for narrowband rather than conventional broadband UVB,5,34–36 and a further study found no significant difference in psoriasis clearance between TL01 and UV6 in a large randomised study of 100 patients.7 There has not been any demonstrated difference in skin cancer risk between narrowband and broadband UVB in humans,37 but mouse studies suggest a 2–3 times greater risk of SCC per MED with TL01 compared to TL12 lamps.38
The above data assume that peak erythemal response occurs 18–24 h (peak is around 12–15 h but we measure MED at 24 h for convenience) following UVB irradiation in non-lesional psoriatic epidermis, as in normal skin the peak in erythemal time-course has been demonstrated to be similar for UVA, UVB and UVC.39,40 Ideally an erythema time-course should be obtained for each wavelength to exclude a different time-course in psoriatic skin, however, when patients were reviewed at 48 h following initial MED irradiations there was no suggestion of a delayed erythemal response for any wavelength tested.
Overall, these results suggest that keratinocyte apoptosis is important in UVB-induced clearance of psoriasis, and this may be useful as a biomarker to further investigate which wavelengths of UVB are most effective in clearing psoriasis and to investigate factors that contribute to inter-individual variation in response. An intriguing possibility is to develop biomarkers of response that allow assessment of wavelength specificity in individual patients with the ultimate aim of individualising therapeutic delivery of UVB.
The thickness of psoriasis plaques will differ significantly between body sites and individuals, and clinical observation shows that UV penetration through hyperkeratotic plaques will be limited. However, although penetration of UV is important in determining which wavelengths can have biological effects on the lower epidermis, it is likely that other wavelength specific factors (e.g. activation of the intrinsic versus extrinsic pathways) will be important in influencing clearance.
Several action spectra have been well defined within the normal epidermis, but only one study has attempted to examine the action spectrum for UV-induced clearance of psoriasis.12 This landmark study helped define the range of UVB wavelengths which can clear psoriasis, and showed that the action spectrum for UV-induced clearance of psoriasis is clearly distinct from the erythema action spectrum, but did not distinguish the optimal wavelength for clearance. Defining this more precisely would be laborious and difficult to perform clinically, but may be possible if directed using a biomarker. In this paper, we have described UV-induced keratinocyte apoptosis occurring following irradiation of psoriatic plaques in vivo and suggest that this may be a useful biomarker of clinical response. Early data indicate that this could potentially be useful to help define the action spectrum for plaque clearance, which combined with a systems biology approach would allow a more targeted and feasible clinical study to be undertaken. A further interesting study would be to compare the efficacy of these narrowband UVB sources compared to broadband UVB (in particular filtering out wavelengths below 300 nm, which induce erythema but are ineffective in clearing psoriasis), which may allow tolerance of greater UV doses while allowing for individual peak responses at wavelengths between 300 and 320 nm.
Footnote |
† This article is published as part of a themed issue on current topics in photodermatology. |
This journal is © The Royal Society of Chemistry and Owner Societies 2013 |