Ultraviolet A1 phototherapy for the treatment of localized scleroderma

Ultraviolet (UV)A1 phototherapy is effective for T-cell-mediated skin diseases such as atopic dermatitis and mast cell-mediated skin diseases such as mastocytoma. UVA1 phototherapy is also effective against the sclerotic lesions of systemic sclerosis and morphea. Currently, in Japan, access to UVA1 phototherapy is limited because the UVA1 phototherapy device has not yet been approved. On the basis of our experience, we report three patients with localized scleroderma who responded successfully to UVA1 phototherapy. Efficacy was assessed by histological analysis and elastography. UVA1 successfully ameliorated sclerotic lesions, including morphea, linear scleroderma and morphea lesions in a patient with limited cutaneous systemic sclerosis. No side-effects were observed during UVA1 phototherapy.     

Case of localized scleroderma successfully treated with bath psoralen and ultraviolet A therapy

The patient was a 12-year-old girl with linear scleroderma distributed on the right abdomen, dorsal aspect of the right thigh, lower leg and foot. The initial regimen of oral prednisolone and methotrexate, or i.v. methylprednisolone failed in the treatment of the scleroderma. Then bath psoralen and ultraviolet A therapy (bath-PUVA) therapy of 0.2 J–4.0 J/cm² daily to total doses 62.8 J/cm² combined with oral prednisolone was started. After bath-PUVA therapy, regression of the skin sclerosis was observed, the possible mobile range of the right ankle was increased and histological examination confirmed improvement of the sclerosis. The successful results of bath-PUVA therapy in this case suggest its utility for localized scleroderma.     

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.     

Ultraviolet A1 phototherapy

Long-wavelength ultraviolet A (340-400 nm; UVA1) therapy is currently available in only a few dermatology departments. Equipment capable of delivering this waveband has been available since 1981, but it is only over the past decade that increasing numbers of studies assessing the potential of this as a therapy have been published. High-dose UVA1, which requires expensive and space-occupying apparatus, is effective as a monotherapy for acute flares of atopic dermatitis, but it has not yet been formally assessed as an adjunct, rather than as an alternative to conventional therapies including potent and very potent topical corticosteroids. Low-dose (which can be administered using a standard phototherapy cubicle fitted with appropriate lamps) and medium-dose UVA1 may be less effective for this indication. Another condition for which UVA1 is effective, and is particularly promising because we have no reliably effective treatment already, is localized scleroderma. It also appears to be effective in systemic lupus erythematosus (although it is not yet clear when it is indicated, and its safety needs to be assessed in more patients) and in polymorphic light eruption (although there have been no studies suggesting that UVA1 will have any advantages over standard prophylactic phototherapies). Open studies and case series suggest that UVA1 may prove beneficial for various other diseases, including cutaneous T-cell lymphoma, lichen sclerosus, keloids, systemic sclerosis and hand dermatitis. In the centres where it is available, UVA1 has already proved a useful addition to the range of phototherapies previously available. However, much more research is needed to confirm its efficacy for many of its potential indications, and to determine when and how it should be used.     

局限性硬皮病的UVA-1和PUVA治疗进展

局限性硬皮病是一种结缔组织病,以局限性或弥漫性皮肤硬化或伴有内脏器官纤维化为特征,治疗方法包括物理治疗、药物治疗、紫外线和光化学疗法.其中紫外线和光化学疗法由于效果明显且不良反应小而成为近期研究的热点.大量临床及基础试验证明,紫外线可阻止纤维化进程,使硬化的皮肤斑块变软,尤其是UVA-1(340～400 nm)和光化学治疗PUVA更是取得了很好的效果.但是,目前的大多数试验在实验设计和效果评价方面尚没有统一的标准.

Abstract：

Localized scleroderma (LS) is a connective tissue disease characterized by localized or diffused sclerosis of skin with or without the fibrosis of various internal organs.The management of LS includes physical treatment,drugs and phototherapy.Because of high efficiency and few side effects,phototherapy has become a hot spot of recent researches.Numerous clinical and basic researches have proved that phototherapy can block fibrosis progression,induce softening of already existing sclerotic lesions by suppressing inflammatory cell infiltration.In particular,long wave ultraviolet A1 (340-400 nm) and photochemotherapy (PUVA) have shown a satisfactory effect.However,no uniform standard is available for the design of trials and evaluation of efficacy.     

Topical tacrolimus 0.1% ointment in the treatment of localized scleroderma. An open label clinical and histological study

Localized scleroderma or morphea, although a self‐limited and benign disease, may leave substantial physical and cosmetic deformity necessitating treatment but treatment remains to date unsatisfactory. The aim of our study was to evaluate the efficacy of topical tacrolimus ointment in the treatment of morphea. Thirteen patients with morphea used tacrolimus 0.1% cream b.i.d. without occlusion for 4 months. Patients were followed up for up to a year. A 4‐mm biopsy was taken before starting treatment in seven patients and 4 months after continuous use of tacrolimus 0.1% ointment, next to the previous biopsy site. Masson trichrome and elastica stains were performed to evaluate the distribution of elastic fibers as well as the streptavidin‐biotin horseradish peroxide immunohistochemical method for the detection of CD20/L‐26, CD3, CD8, CD4, CD1a, human leukocyte antigen‐DR and CD25. Four patients had a less than 25% improvement, two patients responded by 50–70% and the remaining seven by more than 70%. Patients with thick, well‐established lesions responded poorly in comparison to others with less thick and more erythematous ones. Patients with mild‐to‐moderate fibrosis histologically were more likely to improve after treatment, while the lymphocytic infiltrate decreased regardless of initial degree before treatment. It was concluded that topical tacrolimus 0.1% cream may be used in patients with morphea, particularly with early inflammatory lesions, even as a first‐line treatment.     

Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children

BACKGROUND: Localized scleroderma (LS) or morphoea is often considered to be a benign self-limiting condition confined to the skin and subcutaneous tissue. However, the course of the disease is unpredictable and severe functional and cosmetic disability may result. Drug treatment with systemic corticosteroids in combination with methotrexate has been reported to be beneficial in LS, but data in children is limited. OBJECTIVES: To evaluate the efficacy and tolerability of systemic corticosteroids in combination with methotrexate in children with LS. METHODS: Treatment and outcome of 34 patients with LS were retrospectively analysed. Pulsed intravenous methylprednisolone was given, followed by oral prednisolone on a reducing regimen and maintenance treatment with methotrexate. We assessed treatment outcome clinically and by thermography and monitored adverse events. RESULTS: From the onset of treatment, the disease stopped progressing in 94% of the patients. All patients demonstrated significant clinical improvement within a mean time of 5.7 +/- 3.9 months. Mean duration of follow-up over the treatment period and beyond was 2.9 +/- 2.0 years. In 16 (47%) patients therapy was discontinued when the disease was considered to be inactive clinically; however, seven (44%) of the 16 developed a relapse, necessitating repeat treatment. At last follow-up (range 0.2-7.0 years), 24 (71%) of the 34 patients had completely inactive disease. Observed adverse events were moderate and transient and no patient had to stop therapy. CONCLUSIONS: These data suggest that systemic corticosteroids and methotrexate in combination are beneficial and well tolerated in the treatment of children with LS. Because of the risk of relapse after discontinuing therapy, long-term monitoring is mandatory.     

Effectiveness, side-effects and period of remission after treatment with methotrexate in localized scleroderma and related sclerotic skin diseases: an inception cohort study

Background  Detailed information is lacking on effectiveness of methotrexate (MTX) in sclerotic skin diseases, side-effects, and duration of remission after discontinuation.
Objectives  To determine effectiveness, side-effects and period of remission gained by use of MTX in sclerotic skin diseases.
Methods  All patients with a sclerotic skin disease who were treated with MTX (group A) or MTX with corticosteroids (CS) (group B) between 1995 and 2007 were evaluated. Detailed information was collected on dosage and duration of MTX treatment, concomitant immunosuppressive medication and CS treatment, effectiveness, side-effects, duration of the remission period, and time until restart.
Results  Fifty-eight patients (A, n  =   47; B, n  =   11) were evaluated. Clinical assessment revealed that 38 patients (81%) treated with MTX and 11 patients (100%) treated with MTX + CS showed improvement of sclerotic skin. After one treatment course 51% of the patients treated with MTX and 73% treated with MTX + CS reached remission status with a median follow-up time of 55 and 58 months. Patients showing relapse still responded to a second and even to a third course of MTX. Patients who showed a relapse had received a lower cumulative dose, due to a shorter period of treatment with MTX in the first course. Serious side-effects were seen in six patients (10%).
Conclusions  MTX was an effective treatment for various sclerotic skin diseases with a long period of remission and relatively low toxicity. Patients showing relapse still responded to a second and third course of MTX.     

Changes in collagen I and collagen III metabolism in patients with generalized atopic eczema undergoing medium-dose ultraviolet A1 phototherapy

Fourteen patients suffering from acute, exacerbated atopic eczema were screened for changes in collagen I and collagen III metabolism in serum (n = 11), urine (n = 11) and skin biopsies (n = 9) before and after medium-dose ultraviolet (UV) A1 phototherapy (15 exposures of 50 J/cm2 over a 3-week period, total dose 750 J/cm2). Mature collagen I and, to a lesser extent, mature collagen III were found to be decreased after the therapy in skin samples from the irradiated patients. As markers of collagen I degradation, the cross-links pyridoline and deoxypyridoline were analysed in urine using high-performance liquid chromatography. Both cross-links were found to be mildly increased after UVA1 phototherapy, without reaching statistical significance. As markers of de novo collagen synthesis we screened for the procollagen I-carboxyterminal peptide (PICP) and procollagen III-aminoterminal peptide (PIIINP) levels in serum and skin. The ratio of PICP to PIIINP in serum dropped significantly after the UVA1 phototherapy, suggesting a different impact of UVA1 on the two collagens. These findings were paralleled by a diminished ratio of PICP to PIIINP in tissue samples. Staining for matrix metalloproteinase 1 (MMP-1) and its specific counterpart, tissue inhibitor of MMP-1 (TIMP-1), showed slight increases for both proteins by therapeutic UVA1; this was also seen in serum for TIMP-1 but not MMP-1. In our study, high-energy UVA1 doses induced changes of the skin collagens in patients with atopic eczema which are measurable by their metabolites in serum and urine.     

A study of the correction factor for ultraviolet phototherapy dose measurements made by the indirect method

BACKGROUND: Optimization of ultraviolet (UV) phototherapy for treatment of psoriasis and other skin conditions requires accurate dosimetry. One factor involved in whole body treatments is the correction that needs to be applied to radiometer measurements of irradiance made remotely without a person in the phototherapy cabin. OBJECTIVES: To evaluate the correction factor for cabins of different design and to consider whether different factors should be used for different phototherapy cabins and radiometers. METHODS: An automated UV dosimetry system capable of recording irradiances at positions around the circumference of a circle equating to a human trunk has been developed. The system has been combined with a phantom to derive values for the ratio between irradiance measurements made by the direct method with a person in a cabin, and indirect measurements recorded remotely. In addition, values for the ratio in UVA cabins have been derived from comparisons between measurements made directly by persons in a cabin and indirect measurements. RESULTS: Variations in direct to indirect ratio (DIR) with cabin type were less than between individual sets of measurements. The mean DIR obtained for cabins with TL01 lamps was 0.85 +/- 0.02, while that for UVA cabins was 0.80 +/- 0.05. The DIR for dual lamp (TL01/UVA) cabins, when TL01 lamps were illuminated, was higher (0.92). CONCLUSIONS: The DIR should be applied to any measurements made using radiometers without a person or equivalent phantom in a cabin. It is proposed that standard values are appropriate for groups of cabins with a single type of lamp and similar reflectors.     

The expression of matrix metalloproteinase-1 mRNA induced by ultraviolet A1 (340-400 nm) is phototherapy relevant to the glutathione (GSH) content in skin fibroblasts of systemic sclerosis

The excessive deposition of collagen in systemic sclerosis (SSc) is thought to be due to an abnormal function of fibroblasts, which may be the result of an immune dysregulation in skin. Ultraviolet A1 (UVA1) irradiation has been shown to be an effective therapy. This is thought to be due to its capacity to induce matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. In the present in vitro study, the effect of UVA1 irradiation on MMP-1 was studied using skin fibroblasts from healthy controls (n=5) and patients with systemic sclerosis (n=5). In vitro irradiation studies showed that gene expression for MMP-1 after UVA1 irradiation (p<0.05) was induced in all the fibroblasts studied, but that the induction rate was greater in SSc fibroblasts than in normal ones (p<0.05). The glutathione (GSH) level was lower in SSc fibroblasts than in controls before UVA1 irradiation. However, after UVA1 irradiation, GSH levels were increased and equivalent between normal and SSc fibroblasts. These findings indicated that the relatively stronger increase in MMP-1 expression in SSc fibroblasts was due to the lower antioxidant capacity. These data support the concept that clinical responses to UVA1 radiation are influenced by the antioxidative state of the patients' skin.     

Suggested mechanisms of action of UVA phototherapy in morphea: a molecular study

BACKGROUND: Ultraviolet A (UVA) phototherapy proved to be an efficient line of treatment of scleroderma. The mechanism through which it acts is still not clear. OBJECTIVES: To detect the mechanism of action of UVA phototherapy in morphea through measuring its effect on the levels of different parameters related to collagen metabolism. METHODS: Twenty-one cases of morphea were treated with low-dose broad-band UVA for 20 sessions. Twelve cases received 20 J/cm(2)/session with a cumulative dose of 400 J/cm(2) and nine cases received 10 J/cm(2)/session with a cumulative dose of 200 J/cm(2). The response was assessed clinically every week. Two skin biopsies were taken from the lesional skin of each patient before starting and after the end of therapy. Paraffin sections were examined for quantitative polymerase chain reaction measurement of collagen I, collagen III, collagenase, transforming growth factor-beta (TGF-beta) and interferon gamma (IFNgamma). RESULTS: Eighteen patients reported remarkable softening of the skin lesions, with variable degrees ranging from moderate in 57.1% of them good in 19% to very good response in 9.5%. After treatment, all the studied parameters revealed statistically significant changes. There was a significant decrease in collagen I, collagen III and TGF-beta and a significant increase in collagenase (MMP-1) and IFNgamma. The relative change was found to be greatest in collagenase, followed by IFNgamma then TGF-beta and finally collagen I. The changes in collagen I, collagenase, IFNgamma and TGF-beta were found to increase gradually with the degree of clinical response. In all the parameters studied the relative change was significantly higher in cases treated with 20 J/cm(2)/session in contrast to those treated with 10 J/cm(2)/session although no statistically significant difference could be detected in the clinical response to those doses. CONCLUSIONS: The efficacy of low-dose UVA phototherapy in the treatment of localized scleroderma is mainly obtained by the increased production of MMP-1 and IFNgamma, and to a lesser extent by decreasing TGF-beta and collagen production. Concerning the use of 10 or 20 J/cm(2)/session those effects are dose dependent, but the clinical response does not significantly differ.     

Comparison of 2‐D shear wave elastography with clinical score in localized scleroderma: A new method to increase the diagnostic accuracy

There is no established diagnostic criteria or widely accepted severity classification of localized scleroderma (LS) by imaging. Acoustic radiation force impulse (ARFI) technology by normalized mean shear wave velocity (SWV) may be as a probing tool for diagnosing and staging LS accurately and objectively. Fifty‐six patients with LS of inflammatory (n = 21), sclerotic (n = 24) and atrophic (n = 11) stage and 30 healthy controls were evaluated on the basis of pathological results. Dermal thickness, ARFI quality (elastography score) and quantity (mean SWV) were measured by ultrasonography (US), diagnosis and stage performances of LS using the dermal thickness, elastography score and mean SWV compared with modified localized scleroderma skin severity index (mLoSSI) were evaluated. Significant differences in the dermal thickness, elastography score and mean SWV were found between the normal adult and LS patients; for diagnosing LS, the area under the receiver–operator curves (AUROC) of the dermal thickness, elastography score, mean SWV and mLoSSI were 0.93 ± 0.03, 0.95 ± 0.01, 0.93 ± 0.03 and 0.93 ± 0.02, respectively. Compared with the dermal thickness, the elastography score and mLoSSI, the AUROC and the specificities of mean SWV for differentiating sclerotic from inflammatory stage and atrophic from sclerotic LS increased significantly, especially by normalized mean SWV (AUROC, 0.84 ± 0.06 and 0.83 ± 0.07; specificity, 85.71% and 91.67%). As non‐invasive methods, mean SWV and dermal thickness by US may provide reliable information to diagnose and stage LS compared with mLoSSI especially by normalized mean SWV.