Helger Stege

High-dose UVA1 radiation therapy for localized scleroderma

BACKGROUNDnFibrotic 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.nnnOBJECTIVEnOur purpose was to assess whether UVA1 radiation therapy is effective for patients with localized scleroderma.nnnMETHODSnPatients 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.nnnRESULTSnIn 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.nnnCONCLUSIONnHigh-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.

High-dose UVA1 therapy for atopic dermatitis: Results of a multicenter trial

BACKGROUNDnThe 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).nnnOBJECTIVEnThe 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.nnnMETHODSnPatients 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).nnnRESULTSnWith 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.nnnCONCLUSIONnThis study confirms the therapeutic effectiveness of high-dose UVA1 monotherapy for treatment of severe exacerbations of AD.

Infrared radiation-induced matrix metalloproteinase in human skin: implications for protection.

Human skin is exposed to infrared radiation (IR) from natural and artificial sources. In previous studies, near IR radiation (IRA; 760-1,440 nm) was shown to elicit a retrograde mitochondrial signaling response leading to induction of matrix metalloproteinase-1 (MMP-1) expression. These studies, however, have exclusively employed cultured human skin fibroblasts ex vivo. Here, we have assessed the in vivo relevance of these observations by exposing healthy human skin in vivo to physiologically relevant doses of IRA. Eighty percent of the tested individuals responded to IRA radiation by upregulating of MMP-1 expression. Specifically, IRA irradiation caused increased expression of MMP-1 in the dermis, but not in the epidermis. Raman spectroscopy revealed that IRA radiation also caused a significant decrease in the antioxidant content of human skin. In vitro studies had previously shown that IRA-induced MMP-1 expression was mediated through an oxidative stress response, which originates from the mitochondrial electron transport chain. We now report that incubation of cultured human dermal fibroblasts or treatment of human skin with specific antioxidants prevented IRA radiation-induced MMP-1 expression in vitro and in vivo. Thus, IRA irradiation most likely promotes premature skin aging and topical application of appropriate antioxidants represents an effective photoprotective strategy.

Chronically Ultraviolet-exposed Human Skin Shows a Higher Mutation Frequency of Mitochondrial DNA as Compared to Unexposed Skin and the Hematopoietic System

Normal ageing processes are associated with an accumulation of mutations within the mitochondrial (mt) DNA. The most frequent mutation is a 4977 base pair (bp) deletion known as common deletion. In order to test the hypothesis that chronically sun‐exposed skin is characterized by an increased mutation frequency of mtDNA, the mutation frequency of the common deletion between skin and another replicating tissue (the hematopoietic system) and chronically sun‐exposed versus sun‐protected skin was compared in the same individuals. This was done by comparing the amount of mutated mtDNA molecules with the whole mitochondrial genome in the same specimen with a semiquantitative polymerase chain reation method, thus allowing direct comparison of different tissues. In all skin specimens the common deletion could be observed. In contrast only 3 of 10 blood samples revealed detectable amounts of the common deletion. Comparison of sun‐exposed versus sun‐protected skin exhibited a higher content of the common deletion in sun‐exposed skin in 7 of 10 individuals. Additionally, a hitherto undescribed mtDNA mutation was detected exclusively in human skin. These studies indicate that exposure of human skin to solar radiation leads to an accumulation of mtDNA mutations, possibly via oxidative damage, which may play an important role in photoageing.

Ultraviolet A1 (340-400 nm) phototherapy for cutaneous T-cell lymphoma

BACKGROUNDnThe 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.nnnOBJECTIVEnThe purpose of this open pilot study was to assess the therapeutic effectiveness of UVA1 phototherapy for cutaneous T-cell lymphoma (CTCL).nnnMETHODSnUVA1 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.nnnRESULTSnIn 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.nnnCONCLUSIONnThese studies suggest that patients with CTCL stages IA and IB can be treated effectively with UVA1 phototherapy.

Green light is effective and less painful than red light in photodynamic therapy of facial solar keratoses

Photodynamic therapy (PDT) with topically applied δ‐aminolevulinic acid (ALA) is increasingly employed to treat patients with multiple solar keratoses and superficial skin tumors. For these indications, ALA‐PDT has been shown to be highly efficient. Treatment of multiple or extended lesions, however, is substantially hampered by the fact that ALA‐PDT is associated with burning pain during the irradiation procedure. The standard irradiation devices commonly used for ALA‐PDT emit red light around 630 nm. In the present half‐side comparison study we have observed that ALA‐PDT employing a green light irradiation device (543–548 nm) is equally effective, as compared with standard red light ALA‐PDT. In contrast to red light ALA‐PDT, however, green light ALA‐PDT caused only little tingling and burning but no pain. These observations indicate that green light ALA‐PDT is superior to standard ALA‐PDT, because it is associated with less unwanted side effects.

The effect of amelogenins (Xelma™) on hard-to-heal venous leg ulcers

With an aging population venous ulceration is likely to become an increasing problem. Despite improvements in care and the widespread introduction of compression bandaging, the mainstay of current management, a significant proportion of venous leg ulcers remain hard to heal. Therefore, a single‐blinded, randomized multicenter study was performed to compare wound size reduction using amelogenin proteins (Xelma™) formulated into a solution which forms a temporary extracellular matrix on contact with the wound bed. Propylene glycol alginate 7% served as a control. Patients were randomized to receive either amelogenin protein or control treatment. The investigational products were applied weekly under soft silicone secondary dressings for up to a maximum of 12 weeks. Compression therapy was maintained throughout the investigation. Wound size reduction was measured by tracing and all wounds were photographed. In total 123 patients were recruited, 62 patients in the amelogenin group, and 61 in the control group, respectively. Subgroup analyses were performed for ulcers with a size >10 cm2 at baseline and for ulcers of duration of >12 months. The wound size reduction was greatest in the group treated with amelogenin (33.8 vs. 25.6%, n= 117), this difference being greatest for larger ulcers (25 vs. 7.9% for ulcers>10 cm2, n= 61) and those of long duration (29.3 vs. 10.9% for ulcers >12‐month duration, n= 61).We conclude that this product may be clinically useful in the treatment of these venous leg ulcers.

Evaluation of the capacity of sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test.

Although sunscreens are widely used to photoprotect patients with photosensitive lupus erythematosus (LE), standardized controlled studies that can prove their efficacy for this indication have been lacking. Therefore, in the present study, the capacity of three different, commercially available sunscreens to prevent the development of skin lesions that have been induced in LE patients under standardized, reproducible conditions by employing a provocative phototest was assessed. In a double blind, intraindividual comparative study, 11 patients with LE were photoprovoked according to a standard protocol. All patients developed LE‐specific skin lesions upon photoprovocation with a combination of UVA plus UVB radiation. Each of the sunscreens tested prevented the development of skin lesions in this assay, but to various extents. Suncreen A (UVB: Octocrylene; UVA: Mexoryl SX, Mexoryl XL, Parsol 1789; TiO2) was by far the most effective by protecting in 11/11 patients. This protective capacity was corroborated by studies in which strong ICAM‐1 mRNA expression was found in unprotected test areas, but not in sunscreen A pretreated sites. In contrast to sunscreen A, sunscreen B (UVB: Eusolex 6300, Parsol MCX, Uvinul T150, Neohelipan; UVA: Parsol 1789; TiO2) protected in 5 patients and sunscreen C (Eusolex 6300, Parsol MCX, Uvinul T150; UVA: Parsol 1789; TiO2) in 3 out of 11 patients. These studies indicate that the use of sunscreens is beneficial to LE patients because it can prevent the development of UV radiation‐induced skin lesions. Effective protection, however, might vary considerably between different sunscreens.

Successful monotherapy of severe and intractable atopic dermatitis by photopheresis

BACKGROUNDnPatients with chronic atopic dermatitis can become unresponsive to standard immunosuppressive therapy and thus pose a serious therapeutic problem.nnnOBJECTIVEnOur purpose was to evaluate the therapeutic effectiveness of photopheresis in the management of patients with severe and intractable atopic dermatitis.nnnMETHODSnPhotopheresis was used as monotherapy in patients (n = 3) who previously did not respond to treatment with glucocorticosteroids, cyclosporine, phototherapy, or photochemotherapy. Patients were treated at 2-week intervals (total number of treatments = 10).nnnRESULTSnIn all patients, photopheresis induced clinical improvement and reduction of elevated serum levels of eosinophil cationic protein and total IgE. Prolongation of the intervals between treatments from 2 to 4 weeks caused worsening in one patient, whereas shortening of treatment-free intervals improved both clinical and laboratory findings.nnnCONCLUSIONnThese studies indicate that photopheresis may be used as monotherapy for the treatment of patients with severe atopic dermatitis that has become intractable to standard therapeutic modalities.

Creme-PUVA-Photochemotherapie

ZusammenfassungTrotz unbestrittener Vorteile wie z.B. dem Fehlen systemischer Nebenwirkungen oder niedriger kumulativer UVA-Dosen wird die Durchführung der Bade-PUVA-Photochemotherapie in der dermatologischen Praxis durch die mit dem Badevorgang verknüpften räumlichen und personellen Anforderungen erschwert. Wir haben daher eine topische Photochemotherapie entwickelt, bei der 8-Methoxypsoralen (8-MOP) in einer Konzentration von 0.0006% in einer Wasser-in-Öl Emulsion (30% Wasser) angewendet wird (Creme-PUVA- Photochemotherapie). Unter diesen Bedingungen führte eine Ganzkörperbehandlung nicht zu messbaren 8-MOP-Serumspiegeln. Eine Photosensibilisierung der Haut war hingegen 1u2005h nach Applikation der 8-MOP-haltigen Creme maximal ausgeprägt und bestand für 3u2005h. Die therapeutische Effektivität der Creme-PUVA- Photochemotherapie wurde an 10 Patienten mit chronisch rezidivierenden, hyperkeratotisch-rhagadiformen Hand- und/oder Fußekzemen untersucht. Nach 40 Behandlungen zeigten 7 Patienten komplette und 2 Patienten partielle Remissionen. Die Creme-PUVA- Photochemotherapie ist somit ein effektiv, sicher, einfach und damit kostengünstig durchführbares photochemotherapeutisches Verfahren, das die topische PUVA-Therapie der Wahl für die dermatologische Praxis darstellen könnte.SummaryBath-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 1u2005hour after cream application and persisted for 3u2005hours. 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.