Phototherapy: Theory and practice.

Despite the development of highly effective biologics for skin diseases such as psoriasis or atopic dermatitis, UVA and UVB therapy, alone or in combination, are still essential components of various guidelines. Phototherapy is not only a first-line treatment and highly effective for a number of skin diseases, but is also economical and has few side effects. The targeted use of UVA and UVB, if necessary, in combination with the photosensitizer psoralen in the context of PUVA therapy, enables the dermatologist to effectively treat a wide variety of skin diseases. Indications for phototherapy include epidermal diseases such as atopic dermatitis, psoriasis and vitiligo, as well as photodermatoses, mycosis fungoides, graft-versus-host disease and deep dermal diseases such as scleroderma. This article reviews the physical principles, molecular mechanisms, current treatment regimens, and individual indications for phototherapy and photochemotherapy.

Importance of diagnostics and risk of secondary malignancies in primary cutaneous lymphomas.

BACKGROUND AND OBJECTIVES: Primary cutaneous lymphomas (PCL) often strongly differ in clinical behavior and prognosis from systemic lymphomas of the same histopathologic type. The aim of the study was to investigate the distribution of PCL subtypes, the average time from disease manifestation to diagnosis, the importance of diagnostic procedures, the occurrence of secondary malignancies and the different treatment modalities. PATIENTS AND METHODS: Retrospective analysis of 152 patients with PCL examined at the Department of Dermatology of the University Hospital Tübingen from 2010-2012. RESULTS: 105 patients with CTCL (69.1 %) and 47 patients with CBCL (30.9 %) were included. The average time from disease manifestation to diagnosis was four years. The most common diagnosed lymphoma was mycosis fungoides (MF) (47.4 %). First-line therapies here include phototherapy only (psoralen-UV-A [PUVA], n = 48; UVB 311 nm, n = 7) or combination therapies primarily phototherapy with systemic retinoids (n = 18). Most frequent second-line therapy was interferon (INF)-α plus PUVA (n = 15). The outcome was favorable (45.2 % remission, 28.6 % stable disease, 22.6 % progressive disease). Malignant comorbidities were observed more frequently compared to a healthy control group. CONCLUSIONS: The diagnosis of lymphoma often takes several years. The value of staging procedures is still low and the treatment modalities for MF in earlier stages are mainly based on phototherapy.

Biological effects of a new ultraviolet A1 prototype based on light-emitting diodes on the treatment of localized scleroderma.

Ultraviolet A1 (UVA1 ) phototherapy (spectral range 340-400 nm) is a well-established treatment option for various skin diseases such as localized scleroderma. Recent improvements of conventional UVA1 light sources (metal-halide or fluorescent lamps) have brought attention to a new light-emitting diode (LED) technology with remarkable advantages in handling and clinical routine. This study provides a preclinical histological and molecular evaluation of an LED-based UVA1 prototype with a narrower spectral range (360-400 nm) for treating localized scleroderma. Scleroderma mouse models and fibroblasts in vitro were exposed to LED-based UVA1 phototherapy or to irradiation with a commercially available metal-halide lamp emitting low-dose (20, 40 J/cm2 ), medium-dose (60 J/cm2 ) and high-dose (80, 100 J/cm2 ) UVA1 light. Both UVA1 light sources affected inflammatory genes (IL-1α and IL-6) and growth factors (TGFß-1 and TGFß-2). Increased collagen type 1 was reduced after UVA1 phototherapy. Matrix metalloproteinase-1 was more enhanced after a medium dose of LED-based UVA1 phototherapy than after conventional treatment. In vivo, dermal thickness and the amount of collagen were reduced after both treatment methods. Remarkably, myofibroblasts were more effectively reduced by a medium dose of LED-based UVA1 phototherapy. The study indicates that LED-based UVA1 phototherapy yields similar or even better results than conventional treatment. In terms of biosafety and patient comfort, LED-based UVA1 phototherapy offers clear advantages over conventional treatment because of the use of a narrower and less harmful UVA1 spectrum, less heat generation and shorter treatment times at the same irradiation intensity. Clinical studies are required to confirm these results in patients with localized scleroderma.

Phototherapy-induced elevation of serum level of melanoma inhibitory activity.

BACKGROUND: Phototherapy is a frequently used treatment modality for a variety of dermatologic diseases. UV radiation has different effects on the skin, for example increased production and release of cytokines and other proteins, and is involved in the initiation and progression of skin cancer. Objective of this clinical trial was to investigate potential systemic effects of UV phototherapy on cytokine profiles in blood. METHODS: In a prospective, mono-centric, one-armed study, the serum levels of the melanoma tumour marker "melanoma inhibitory activity" (MIA), Il-1α, Il-4, Il-6, Il-10, TNF-α and IFN-γ of 115 patients with different skin diseases were compared before and 24-48 hours as well as 2-4 weeks after the first phototherapy with PUVA (psoralen and ultraviolet A), UVA or UVB, or both. Data were analysed using linear mixed models. RESULTS: Estimated marginal means of MIA levels were 6.05 ng/mL (95%-CI: 5.37-6.72, range: 2.83-14.49) before the first treatment, which had significantly increased to 6.79 ng/mL 2-4 weeks after the first phototherapy (CI 95%: 6.12-7.47, range: 3.09-15.45; P = 0.0042). MIA levels 2-4 weeks after the first phototherapy were significantly higher than 24-48 hours after the first phototherapy (P = 0.0083). 2-4 weeks after the first treatment, TNF-α levels had decreased significantly (P = 0.033) more in patients with psoriasis who had responded well to phototherapy than in patients unresponsive to treatment. Serum levels of the other cytokines had not changed significantly. CONCLUSIONS: Short-term phototherapy significantly increased the serum levels of the melanoma tumour marker MIA. The potential clinical relevance of these findings (ie an increased risk of melanoma) is unclear and should be further investigated.

Phototherapy.

The efficacy of phototherapy is based on the interaction between ultraviolet (UV) radiation and the skin. The photobiological effects thus achieved depend on the wavelengths used. Targeted use of UVA and UVB, where indicated in combination with a photosensitizer such as psoralen, provides the dermatologist with a broad armamentarium for the treatment of a multitude of skin diseases. The spectrum of indications ranges from superficial dermatitis, psoriasis, and malignancies, such as cutaneous T-cell lymphoma, to deep sclerosing conditions such as morphea. The objective of the present review is to highlight the photobiological effects of the various types of UV radiation as well as the resultant clinical indications for phototherapy.

S1-Guidelines on UV phototherapy and photochemotherapy.

Known in part since antiquity, the salutary effects of sunlight again garnered increasing attention in the second half of the 19(th) century. The development of a device for ultraviolet irradiation of cutaneous tuberculosis by Finnsen at the onset of the twentieth century truly marked the beginning of modern phototherapy. In dermatology, treatment methods almost exclusively use wavelengths below the visible light range (ultraviolet light). Since the early 1970s, increasingly powerful artificial light sources have become available for UVB and UVA therapy as well as the combination of UVA and photosensitizers (photochemotherapy). High structural and procedural quality standards are an essential prerequisite for the implementation of effective as well as safe phototherapy. The following guidelines outline the current consensus of leading experts in the field of phototherapy with respect to indications, contraindications, and side effects of various treatment options available. Particular focus is also on adequate UV doses at the beginning and over the further course of treatment as well as on management of side effects.

S1-Leitlinie zur UV-Phototherapie und Photochemotherapie.

Die heilsame Wirkung des Sonnenlichts war teilweise schon im Altertum bekannt und fand in der zweiten Hälfte des 19. Jahrhunderts wieder zunehmend Beachtung. Den Beginn der modernen Phototherapien markiert die Entwicklung einer Apparatur zur ultravioletten Bestrahlung der Hauttuberkulose durch Finnsen zu Beginn des zwanzigsten Jahrhunderts. Zur Therapie von Hauterkrankungen finden beinahe ausschließlich die spektralen Bereiche unterhalb des sichtbaren Lichtes (ultraviolett) Anwendung. Seit den 1970er Jahren stehen zunehmend leistungsfähige künstliche Strahlenquellen bereit für die Therapie mit UVB, UVA und die Kombination von UVA mit Photosensibilisatoren (Photochemotherapie). Hohe strukturelle und prozedurale Qualitätsstandards sind unabdingbare Voraussetzung für die Durchführung einer gleichermaßen wirkungsvollen wie auch sicheren Phototherapie. Die Leitlinie formuliert den aktuellen Konsens führender Experten auf dem Gebiet der Phototherapie in Bezug auf die Indikationen für die jeweiligen Therapieverfahren, deren Gegenanzeigen und Nebenwirkungen und insbesondere für die Wahl der korrekten Dosis zu Beginn und im Verlauf einer Therapie sowie das Management von Nebenwirkungen.

The cerebro-morphological fingerprint of a progeroid syndrome: white matter changes correlate with neurological symptoms in xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive progeroid syndrome. It has recently been shown that the underlying DNA repair defect plays a central role in the aging process. In addition to skin symptoms, various premature neurological abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: We present the clinical neurological phenotype in 14 XP patients (seven subtypes), in seven of these patients together with conventional and multiparametric advanced MRI data to assess the macrostructural and microstructural cerebral morphology in comparison to controls, including volumetric measurements, MR spectroscopy ((1)H MRS), and diffusion tensor imaging (DTI). Clinical hallmarks were spinocerebellar ataxia, pyramidal tract signs, and mild cognitive deficits. DTI demonstrated significantly reduced WM directionality in all regions investigated, i.e. the thalamus, the corticospinal tracts and the dorsal corpus callosum. Single patients showed a marked relative hippocampal volume reduction, but the patients were not different from controls in the volumetric measurements of hippocampal and whole brain volumes at group level. However, (1)H MRS demonstrated that the hippocampal formation was metabolically altered. CONCLUSIONS: The most prominent feature was the white matter affectation, as assessed by DTI, with volume and directionality reductions of the fiber projections involving both the craniocaudal fibers and the interhemispheric connections. These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients.

Phototherapy and photochemotherapy.

The treatment of skin diseases with ultraviolet radiation represents an important therapeutic modality in clinical dermatology, and the number of skin diseases that improve under the phototherapeutic modalities of today is still growing. While clinical phototherapy was originally based on empirical observations, our present understanding of the underlying mechanisms has improved substantially due to important progress in photobiological science. The better understanding of this scientific basis of treatment allows to both choose the correct phototherapeutic modality and determine the most effective treatment regimen. The aim of this article is to discuss the appropriate indications for phototherapy as well as its safe and effective employment, providing practical help in daily clinical phototherapeutic practice.

UV-A induced oxidative stress is more prominent in naturally pigmented aged human RPE cells compared to non-pigmented human RPE cells independent of zinc treatment.

To investigate the effects of zinc supplementation on human amelanotic (ARPE-19) and native pigmented retinal pigment epithelial cells (hRPE) under normal light conditions and after ultraviolet A light exposure. hRPE cells, containing both melanin and lipofuscin granules, were prepared from human donor eyes of 60-70 year old patients. Cells of the amelanotic ARPE-19 cell line and pigmented hRPE cells were treated with zinc chloride and subjected to oxidative stress by UV-A irradiation. Intracellular H(2)O(2) formation was measured using a fluorescence oxidation assay. Additionally, apoptosis and viability assays were performed. Control cells were treated identically except for irradiation and zinc supplementation. Under normal light conditions, zinc treated hRPE cells produced less H(2)O(2) than unsupplemented hRPE cells. Viability and apoptosis events did not change. After UV-A irradiation, ARPE and hRPE cells were greatly impaired in all tests performed compared to the non-irradiated controls. No differences were found after zinc supplementation. hRPE cells showed a higher apoptosis and mortality rate than non-pigmented cells when stressed by UV-A light. ARPE cells never showed any zinc related effects. In contrast, without irradiation, zinc supplementation reduced H(2)O(2) production in pigmented hRPE cells slightly. We did not find any zinc effect in irradiated hRPE cells. After UV light exposure, pigmented cells showed a higher apoptosis and mortality than cells lacking any pigmentation. We conclude that cells with pigmentation consisting of melanin and lipofuscin granules have more prooxidative than antioxidative capacity when stressed by UV light exposure compared to cells lacking any pigmentation.

[New and established indications for phototherapy with narrowband UVB]. / Neue und etablierte Indikationen der UV-B-311-nm-Phototherapie.

Phototherapy with ultraviolet (UV) irradiation of wavelengths between 280 and 320 nm (UV-B) is a safe and effective treatment for a variety of inflammatory skin diseases. In addition to standard broad band UVB, narrow band phototherapy with fluorescent bulbs emitting near monochromatic UV between 310-315 nm has become an important treatment for diseases such as psoriasis, atopic dermatitis or vitiligo. Other diseases respond favorably to narrow band UV-B phototherapy, the number of potential indications for such phototherapy is continuously growing. The differential effects of narrow band UV-B phototherapy in comparison to other UV phototherapies, as well as new and established indications for this treatment modality are reviewed.

Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.

Mutations of mitochondrial (mt) DNA play a role in neurodegeneration, normal aging, premature aging of the skin (photoaging), and tumors. We and others could demonstrate that mtDNA mutations can be induced in skin cells in vitro and in normal human skin in vivo by repetitive, sublethal ultraviolet (UV)-A-irradiation. These mutations are mediated by singlet oxygen and persist in human skin as long-term biomarkers of UV exposure. Although mtDNA exclusively encodes for the respiratory chain, involvement of the energy metabolism in mtDNA mutagenesis and a protective role of the energy precursor creatine have thus far not been shown. We assessed the amount of a marker mutation of mtDNA, the so-called common deletion, by real-time PCR. Induction of the common deletion was paralleled by a measurable decrease of oxygen consumption, mitochondrial membrane potential, and ATP content, as well as an increase of matrix metalloproteinase-1. Mitochondrial mutagenesis as well as functional consequences could be normalized by increasing intracellular creatine levels. These data indicate that increase of the energy precursor creatine protects from functionally relevant, aging-associated mutations of mitochondrial DNA.

Phototherapy with narrowband vs broadband UVB.

Phototherapy with ultraviolet (UV) radiation of wavelengths between 280 and 320 nm (UVB) is a safe and effective treatment for a variety of diseases. In addition to standard broadband UVB (bUVB), narrowband phototherapy with fluorescent bulbs emitting near monochromatic UV around 311 nm (nUVB) has become an important treatment for diseases such as psoriasis, atopic dermatitis and vitiligo. In addition to these indications, the number of diseases for which nUVB phototherapy is reported to be effective is continuously growing. The differential effects of nUVB phototherapy in comparison to other UV wavelengths as well as established and new indications for this treatment modality are reviewed.

No evidence for increased skin cancer risk in psoriasis patients treated with broadband or narrowband UVB phototherapy: a first retrospective study.

Phototherapy of skin diseases such as psoriasis is an effective and safe treatment modality. However, increasing the risk of skin cancer by phototherapy is a serious concern. An increased skin cancer risk occurs after prolonged photochemotherapy (PUVA). In contrast, the role of broadband UVB or narrowband UVB therapy in skin carcinogenesis of humans with psoriasis is less clear. Therefore, we investigated the incidence of skin tumours in a total of 195 psoriasis patients, receiving broadband (n=69) or narrowband (n=126) UVB from 1994 to 2000 with follow-up until 2003. Data were raised from the regional interdisciplinary cancer centre of the University of Tuebingen, Germany and compared with the tumour incidences given for the German population. In this study, with 80% statistical power to detect a 6-7-fold increase in skin cancer with broadband UVB and 83% power to detect a 5-6-fold increase with narrow band UVB at p=0.05, only one patient developed skin cancer - an in situ melanoma. The tumour occurred within the same year that phototherapy was initiated. Thus, the present study does not provide evidence for an increased skin cancer risk for patients treated with either broadband or narrowband UVB phototherapy

Betacarotene supplementation protects from photoaging-associated mitochondrial DNA mutation.

Mutations of mitochondrial DNA accumulate during normal aging and can be detected at elevated levels in skin prematurely aged by chronic exposure to ultraviolet (UV) light (photoaging). In normal human fibroblasts, we have previously demonstrated that mtDNA deletions are induced by repetitive exposure to sublethal doses of UVA radiation mediated through singlet oxygen. Betacarotene is a known quencher of ROS and singlet oxygen in particular, and it is widely applied in photoprotective compounds. Therefore we investigated whether in our in vitro system, betacarotene is capable of protecting from the induction of photoaging-associated mtDNA deletions. All-E (trans) betacarotene was tested at doses from 0.25 to 3.0 microM for uptake into cells as well as its protective capacity. Assessment of cellular uptake of all-E betacarotene measured by HPLC revealed a dose dependent increase of intracellular concentrations, as well as an increase in oxidative metabolites. UVA-exposure led to a decrease of all-E-betacarotene, its Z-isomers and oxidative metabolites. Assessment of mtDNA deletions by PCR revealed reduced levels of mtDNA mutagenesis in cells coincubated with betacarotene at concentrations of 0.5 microM and higher. Taken together, these results indicate that betacarotene (i) is taken up into the cell in a dose dependent manner, (ii) interacts with UVA radiation in the cell and (iii) shows protective properties from the induction of a photoaging-associated mtDNA mutation.