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Entwicklungen und praktische Anwendungen in der Photo(chemo)therapie
Abstract
Seit Jahrzehnten stellen photo- und photochemotherapeutische Verfahren etablierte dermatologische Behandlungsregime dar. Die enge Verzahnung von dermatologischer, photobiologischer und photoimmunologischer Forschung mit strahlenphysikalischen und technischen Innovationen haben der Photodermatologie in den letzten Jahren wichtige Impulse gegeben, die sich rasch in der Therapie niedergeschlagen haben. Einerseits ist auf die Einführung neuer selektiver Spektren im UVB- und UVA-Bereich, z.B. auf die 311 nm-UVB-oder die UVA1-Phototherapie, andererseits auf neue Indikationen, z.B. die Behandlung von Bindegewebserkrankungen und der GvHD, hinzuweisen. Im Folgenden wird Neues und Bewährtes in der Photo(chemo)-therapie sowohl in Bezug auf klinische als auch auf wissenschaftliche Relevanz dargestellt.
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Photodermatologische Verfahren sind von zentraler Bedeutung in der heutigen Dermatologie. Dieses Handbuch ist ein praxisbezogener Leitfaden durch die moderne dermatologische Phototherapie und Photodiagnostik. Es finden sich ausführliche Darstellungen bewährter und neuester photo(chemo)therapeutsicher und photodiagnostischer Verfahren. Im Vordergrund steht die zu behandelnde Hauterkrankung. Das praxisorientierte Lehrbuch richtet sich gleichermaßen an den in der Weiterbildung befindlichen Arzt wie an den erfahrenen, in der Klinik oder in der Praxis tätigen Dermatologen. So finden sich Informationen zum gegenwärtigen Wissensstand klinisch bedeutsamer photobiologischer Prozesse neben ausführlichen Darstellungen praxisrelevanter Themen, z.B. technische Hinweise zur praktischen Durchführung, Abrechnungsdetails im Zeitalter des Gesundheitsstrukturgesetzes, Maßnahmen zur Qualitätssicherung etc. Die langjährige Erfahrung der Herausgeber und Autoren in Klinik, Forschung und Lehre hat aus der Fülle der dargebotenen Informationen ein von fachlicher und didaktischer Kompetenz geprägtes Handbuch zum Thema entstehen lassen.
Ultraviolet A (UVA) irradiation is effectively used to treat patients with atopic dermatitis and other T cell mediated, inflammatory skin diseases. In the present study, successful phototherapy of atopic dermatitis was found to result from UVA radiation-induced apoptosis in skin-infiltrating T helper cells, leading to T cell depletion from eczematous skin. In vitro, UVA radiation-induced human T helper cell apoptosis was mediated through the FAS/FAS-ligand system, which was activated in irradiated T cells as a consequence of singlet oxygen generation. These studies demonstrate that singlet oxygen is a potent trigger for the induction of human T cell apoptosis. They also identify singlet oxygen generation as a fundamental mechanism of action operative in phototherapy.
Narrow-band (312 nm) ultraviolet B light (UVB) is a new form of therapy for psoriasis, but its mechanism of action is unknown. In a bilateral comparison clinical study, daily exposure of psoriatic plaques to broad-band UVB (290-320 nm) or 312-nm UVB depleted T cells from the epidermis and dermis of psoriatic lesions. However, 312-nm UVB was significantly more depleting in both tissue compartments. To characterize the mechanism of T cell depletion, assays for T cell apoptosis were performed on T cells derived from UVB-irradiated skin in vivo and on T cells irradiated in vitro with 312-nm UVB. Apoptosis was induced in T cells exposed to 50-100 mJ/cm2 of 312-nm UVB in vitro, as measured by increased binding of fluorescein isothiocyanate (FITC)-Annexin V to CD3(+) cells and by characteristic cell size/granularity changes measured by cytometry. In vivo exposure of psoriatic skin lesions to 312-nm UVB for 1-2 wk also induced apoptosis in T cells as assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) reaction in tissue sections, by binding of FITC-Annexin V to CD3(+) T cells contained in epidermal cell suspensions, and by detection of apoptosis-related size shifts of CD3(+) cells. Induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions.
Dieses Kapitel beschäftigt sich mit der Anwendung von Photochemotherapie und Phototherapie bei Vitiligo. Zunächst wird die Krankheit definiert und werden Differentialdiagnosen und assoziierte Phänomene beschrieben. Allgemeine therapeutische Maßnahmen und Alternativen zu phototherapeutischen Verfahren folgen. Den Hauptteil bildet die Beschreibung der praktischen Durchführung und Wirkung der Bestrahlungsbehandlung mit oder ohne Photosensibilisator sowie von kombinierten Therapieformen.
Bestrahlung mit verschiedenartig zusammengesetzten UVB- und UVA- Strahlen sowie die Photochemotherapie, bei der eine UVA-Bestrahlung der systemischen oder kutanen Applikation von Photosensibilisatoren folgt, sind häufig genutzte, elegante und effiziente Therapieverfaren für eine große Anzahl vorweigend entzündlicher, aber auch einiger neoplastischer Hautkrankheiten [3]. Seit einigen Jahren gewinnen die verschiedenen Formen der Balneophototherapie, die bis vor kurzem wenig beachtet wurden, in der Dermatotherapie zunehmend an Bedeutung. Die Balneophototherapie läßt sich in 2 Gruppen unterteilen: die vor gut 20 Jahren in Skandinavien entwickelte Bade-PUVA-Photochemotherapie (Balneophotochemotherapie) und die verschiedenen Formen der Sole-UV-Therapie die sich aus der Salwasserklimatherapie entwickelt haben [10, 11, 27, 28, 46, 49, 51].
Dr. M. Kerscher, Dermatologische Klinik und Poliklinik der Ludwig-Maximilians-Universität, Frauenlobstraße 9, D-80337 München
Zusammenfassung. Während die systemische PUVA-Therapie (8-Methoxypsoralen und UV-A) zur Behandlung verschiedener Hauterkrankungen vor etwa
20 Jahren etabliert wurde, wurden PUVA-Bäder mit 8-Methoxypsoralen bisher nicht in größerem Umfang therapeutisch eingesetzt.
Aufgrund des Fehlens von systemischen Nebenwirkungen und der deutlich geringeren UV-A-Dosis stellt die PUVA-Bad-Therapie eine
interessante Alternative zur systemischen PUVA-Therapie dar. Eine Variante der PUVA-Bad-Therapie sind die PUVA-Hand- und Fußbäder.
Da derzeit keine einheitlichen Therapierichtlinien für die PUVA-Bad-Therapie vorgegeben sind, werden die aktuellen therapeutischen
Möglichkeiten sowie die praktische Durchführung dieser Therapieform beschrieben.
Bath-PUVA-photochemotherapy lacks systemic side effects and requires low cumulative UVA dosis, but a major disadvantage is the logistical requirement for bath tubs in a practice. We have developed an alternative form of topical PUVA therapy using a lipophilic emulsion vehicle for the photosensitizer 8-MOP (cream-PUVA-photochemotherapy). A 0.0006% 8-MOP containing water-in-oil emulsion (30% H2O) was optimal for inducing photosensitivity in treated skin areas without increasing 8-MOP plasma levels. Increased skin photosensitivity was maximal 1 hour after cream application and persisted for 3 hours. We next assessed the effectiveness of cream-PUVA-photochemotherapy in the treatment of patients with chronic recalcitrant palmoplantar eczema (n=10). In seven patients complete, and in two patients partial, remissions were observed after 40 treatments. Thus, cream-PUVA-photochemotherapy, which is easier to perform than bath-PUVA-photochemotherapy, is an effective, safe and low-cost modality, which may prove to become the topical PUVA therapy of choice for dermatological practioners.
Besides glucocorticosteroids, there is currently no known effective therapy for patients with acute atopic dermatitis.
The therapeutic effectiveness of high-dose UVA1 irradiation in the management of patients with acute exacerbation of atopic dermatitis was examined.
Patients in the high-dose UVA1 group (n = 15) were irradiated with 130 joules/cm2 UVA1; the control group (n = 10) was treated with UVA-UVB therapy in a minimal erythema dose-dependent manner (total number of treatments 15).
High-dose UVA1 irradiation was found to induce a significant clinical improvement of atopic dermatitis (p less than 0.001). In comparison with UVA-UVB therapy, significant differences in favor of high-dose UVA1 were observed (p less than 0.01). High-dose UVA1, but not UVA-UVB treatment, significantly reduced the elevated serum level of eosinophil cationic protein in patients with atopic dermatitis (p less than 0.003).
These studies indicate that high-dose UVA1 irradiation may represent a novel phototherapeutic modality for the treatment of patients with an acute exacerbation of atopic dermatitis.
We report the effect of UVA irradiation on collagen metabolism of fibroblasts, including both synthesis of the collagen degrading enzyme collagenase and de novo synthesis of type I collagen as the major structural component of the dermis. For this purpose confluent fibroblast monolayers were irradiated under standardized conditions (5, 15, 35, 60 J/cm2 using UVASUN 3000, Mutzhas, Munich, FRG, and UV source Sellas sunlight type 2.001, Sellas, Gevelsberg, FRG). Subsequently, total RNA was isolated and subjected to dot blot and northern blot analysis using oligolabelled cDNA clones for human type I collagen, collagenase and beta-actin. Collagen type I and beta-actin mRNA levels remained unaltered following irradiation, suggesting that the synthetic pathway of collagen metabolism at the pretranslational level is not affected by short-term UVA irradiation. However, collagenase mRNA was found to be dose-dependently induced in fibroblasts after irradiation, thus probably contributing to the actinic damage to the dermis. These in vitro data were confirmed in vivo using in situ hybridization on frozen sections of biopsy material obtained from UVA irradiated patients.
Fibrotic skin lesions in patients with localized scleroderma can cause muscle atrophy, disfigurement, and flexion contractures. There is no effective therapy for this disease. Skin fibrosis is thought to be caused by decreased collagenase activity. Collagenase activity can be induced in dermal fibroblasts by UVA1 irradiation.
Our purpose was to assess whether UVA1 radiation therapy is effective for patients with localized scleroderma.
Patients with localized scleroderma (n = 17) were exposed 30 times to 130 J/cm2 UVA1 (high-dose UVA1 therapy; n = 10) or 20 J/cm2 UVA1 (low-dose UVA1 therapy; n = 7). Therapeutic effectiveness was assessed by evaluation of (1) clinical features, (2) thickness of sclerotic plaques, and (3) cutaneous elastometry. Sequential biopsy specimens from treated lesions were analyzed for collagenase I messenger RNA (mRNA) expression by semiquantitative reverse transcriptase-polymerase chain reaction.
In all patients, high-dose UVA1 therapy softened sclerotic plaques, and complete clearance was observed in four of 10 patients. High-dose UVA1 therapy significantly reduced thickness and increased elasticity of plaques. These changes could not be detected in unirradiated control plaques and were still present in 9 of 10 patients 3 months after cessation of therapy. For all factors assessed, high-dose UVA1 was superior to low-dose UVA1 therapy (p = 0.001). High-dose UVA1 therapy increased collagenase I mRNA expression about 20-fold in treated plaques.
High-dose UVA1 therapy is effective in the treatment of localized scleroderma. Effectiveness is UVA1 dose dependent and is associated with induction of collagenase I expression.
The results of an open, single-center study suggested that phototherapy with high doses of UVA1 radiation (UVA1R; 340-400 nm) is effective for acute, severe exacerbations of atopic dermatitis (AD).
The purpose of this study was to assess the effectiveness of high-dose UVA1 phototherapy for acute, severe AD in a randomized multicenter trial in direct comparison with topical glucocorticoid therapy.
Patients were treated with high-dose UVA1R (10 days, 130 J/cm2/day; n = 20), topically with fluocortolone (10 days, 1 x daily; n = 17), or with UVA-UVB therapy (10 days, 1 x daily, minimal erythema dose-dependent; n = 16).
With a clinical scoring system, significant differences in favor of high-dose UVA1R and fluocortolone therapy were observed (p < 0.0001), as compared with UVA-UVB therapy. At day 10, high-dose UVA1R was superior to fluocortolone (p < 0.002) therapy. Serum levels of eosinophil cationic protein and the blood eosinophil count were significantly reduced after high-dose UVA1 or fluocortolone, but not UVA-UVB therapy.
This study confirms the therapeutic effectiveness of high-dose UVA1 monotherapy for treatment of severe exacerbations of AD.
The results of a recent study suggested that ultraviolet A1 radiation (UVA1R; 340-400 nm) phototherapy for atopic dermatitis works through induction of apoptosis in skin-infiltrating helper T cells, indicating the possibility that other helper T cell-mediated skin diseases may respond to UVA1R as well.
The purpose of this open pilot study was to assess the therapeutic effectiveness of UVA1 phototherapy for cutaneous T-cell lymphoma (CTCL).
UVA1 phototherapy was used as monotherapy in patients (n = 3) with histologically proven CTCL (stages IA and IB). For daily whole body UVA1 irradiations, either a high-dose (n = 2; 130 J/cm2 UVA1 per exposure) or medium-dose (n = 1; 60 J/cm2 UVA1) regimen was used. Therapeutic effectiveness was assessed clinically and histologically.
In each of the 3 patients, skin lesions began to resolve after only a few UVA1 radiation exposures. Complete clearance was observed between 16 and 20 exposures, regardless of whether the high- or medium-dose regimen had been employed.
These studies suggest that patients with CTCL stages IA and IB can be treated effectively with UVA1 phototherapy.
Therapeutic photomedicine: Phototherapy
- J Krutmann
- Im Freedberg
- Az Eisen
- K Wolff
- Kf Austen
- La Goldsmith
- Si Katz
- Tb Fitzpatrick
nm UVB (narrow band UVB) induces apoptosis of T cells within psoriatic lesions
- M Ozawa
- K Ferenci
- T Kikuchi
- I Cardinale
- L M Austin
- T R Coven
- L H Burack
- J G Krueger
High-dose ultraviolet (UV) AI therapy works through induction of apoptosis in skin-infiltrating T-helper cells: Analysis of the photobiological and molecular mechanisms
- A Morita
- T Werfel
- H Stege
- C Ahrens
- M Grewe
- T Ruzicka
- S Grether-Beck
- H Sies
- H Krüger
- A Kapp
- J Krutmann