UVA1 irradiation attenuates collagen production via Ficz/AhR/MAPK signaling activation in scleroderma.

Scleroderma is an autoimmune disease mainly characterized by progressive fibrosis of the skin. There are two types of scleroderma, namely localized scleroderma (LS) and systemic sclerosis (SSc); skin lesions in both types of scleroderma are histologically identical. Progressive skin sclerosis induces psychological and ecological burden for scleroderma patients. However, there is no effective treatment for scleroderma due to its unclear etiology. Aryl hydrocarbon receptor (AhR) is recognized as an environmental chemical effector that can respond to ultraviolet radiation, which has been demonstrated to participate in the pathogenesis of SSc in our previous study. In this study, we verify whether the anti-fibrosis effect of ultraviolet A1 (UVA1) phototherapy could be partially induced through Ficz/AhR/MAPK signaling activation for fibrotic lesions in both SSc and LS patients. This is the first study to show the association between the AhR pathway and the anti-fibrotic mechanism of UVA1 phototherapy, which provides additional evidence of the role of AhR in the fibrotic mechanism of systemic scleroderma from different perspectives. Ficz and other AhR agonists may replace UVA1 phototherapy as anti-fibrotic agents in scleroderma.

Phototherapy for sclerosing skin conditions.

Phototherapy is an effective treatment strategy for a variety of sclerosing skin conditions. There are a number of phototherapeutic modalities used for the treatment of sclerosing skin conditions, including ultraviolet (UV)A1, broadband UVA, psoralen plus UVA, and narrowband UVB phototherapy. As controlled trials with validated outcome measures are lacking for these therapies, existing evidence is largely level II for morphea and is even more minimal for scleroderma and other sclerosing disorders (scleroderma, lichen sclerosus, and chronic graft-versus-host disease, among others). Studies do suggest that phototherapy may be effective for many of these disorders, including those that have been unresponsive to other therapies. Phototherapy remains an attractive therapeutic option for patients due to its efficacy and favorable risk-versus-benefit profile. Phototherapy also offers a therapeutic alternative to systemic immunosuppressives for patients who cannot tolerate these medications.

Ultraviolet phototherapy for cutaneous diseases: a concise review.

Phototherapy is the use of non-ionizing radiation, primarily in the ultraviolet spectrum, to treat disease. In dermatology, ultraviolet (UV) phototherapy remains an established, lower cost, and often preferred option for many common skin conditions, despite the introduction of newer potent biologics. This article introduces a principal therapeutic modality in the treatment of psoriasis, atopic dermatitis (eczema), vitiligo, and morphea among other diseases where oral manifestations may be present, providing basic information about the use of UVA, UVB, and PUVA. Practical considerations and side effects of phototherapy are described. Phototherapy is an effective treatment for many illnesses and carries a relatively benign side-effect profile.

Ultraviolet A1 phototherapy beyond morphea: experience in 83 patients.

BACKGROUND/PURPOSE: Ultraviolet A1 (UVA1) phototherapy has been used for over 15 years in the United States, primarily for the treatment of localized sclerosis and various sclerosing disorders. The objective was to describe use of UVA1 for dermatoses beyond localized sclerosis at two academic institutions. METHODS: Data from 83 patients treated with low- (20-40 J/cm(2) ), medium- (>40-80 J/cm(2) ), and high- (>80-120 J/cm(2) ) dose UVA1 phototherapy was retrospectively analyzed. The mean individual treatment dose (J/cm(2) ), the mean number of sessions, and the mean total dose (J/cm(2) ) were evaluated. Effectiveness was assessed by reviewing clinical examination notes from office visits. RESULTS: Good therapeutic efficacy was seen in patients with systemic sclerosis (SS, 16 patients), graft-versus-host disease (GVHD, 25 patients), and nephrogenic systemic fibrosis (NSF, 17 patients). A statistically significant a dose-response association was observed in the cases of SS, GVHD and NSF. Likelihood of clinical improvement from UVA1 phototherapy was very likely for medium- and high-dose regimens in SS, while this level of improvement was only observed in GVHD and NSF patients receiving high-dose UVA1. CONCLUSION: UVA1 phototherapy is effective and safe in the treatment of GVHD, NSF, SS, and mast cell disorders. High-dose regimens appear to be more effective than medium- and low-dose regimens for NSF and GVHD, while medium- and high-dose regimens outperform low-dose UVA1 in SS.

Low-dose UVA1 phototherapy for scleroderma: what benefit can we expect?

BACKGROUND: The first reports of the application of ultravioletA1 (UVA1) phototherapy for scleroderma go back only to 1995, but since then, several studies have proven its effectiveness in this disease. OBJECTIVES: To evaluate the effectiveness of low-dose (35 J/cm(2) ) UVA(1) phototherapy in patients with scleroderma, trying to define the subgroups that benefit most from this treatment. METHODS: Retrospective analysis of patients diagnosed with clinical and/or histological scleroderma, undergoing low-dose UVA(1) phototherapy between 2003 and 2010. RESULTS: We studied 21 patients (20 women and one man) aged 10-75 years (mean 50). Eighteen with morphea performed a total of 29 treatments, with an average of 33 sessions per treatment per patient, a mean dose of 31 J/cm(2) per session and an average cumulative dose of 1662 J/cm(2) (310-4270). The three patients with systemic scleroderma underwent a total of five treatments, with an average of 26 sessions per treatment per patient, a mean dose of 29.5 J/cm(2) per session and an average cumulative dose of 1160 J/cm(2) (660-1695). Using the modified Rodnan skin score, in the group of patients with morphea, a marked improvement was found in 77.8% patients and a moderate improvement was found in 11.1% patients. In the systemic scleroderma group, a patient with complete remission of the skin sclerosis is emphasized. CONCLUSIONS: Our experience allows us to conclude that low-dose UVA(1) phototherapy is a well tolerated option, with excellent results mainly in patients with morphea. This treatment is a valuable contribution to these patients, given the limited therapeutic options available.

Immunomodulatory effects of extracorporeal photochemotherapy in systemic sclerosis.

The aim of this study was to evaluate the clinical and immunomodulatory effects of extracorporeal photochemotherapy (ECP) in systemic sclerosis (SSc). We enrolled 16 patients with diffuse cutaneous SSc, who received 12 ECP treatments in total. After ECP treatments, the dermal thickness reduced and the mobility of joints improved. Internal organ involvement did not deteriorate. The percentages and numbers of peripheral Th17 cells decreased, the values of Tr1 and Treg cells increased, and the suppressor capacity of Treg cells improved. Interestingly, we found a positive correlation between the reduction of IL-17 levels and skin thickness measured by ultrasound. Moreover, levels of CCL2 and TGF-beta decreased, while the concentration of IL-1Ra, IL-10 and HGF elevated during the therapy. ECP treatments contribute to the restoration of disproportional autoimmune responses and attenuate fibrotic processes, thus decelerate the disease progression. Accordingly, ECP can be a useful element of novel treatment modalities proposed for SSc.

Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial.

PURPOSE: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol. METHODS AND MATERIALS: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34(+) selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered. RESULTS: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 ± 18.1 cGy, with an average dkB of 5.0 ± 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 ± 5.1 cGy. CONCLUSIONS: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.

Period of remission after treatment with UVA-1 in sclerodermic skin diseases.

BACKGROUND: Sclerodermic skin diseases can cause severe morbidity and disability. UVA-1 has shown to be an effective therapy for sclerodermic skin diseases. However, the period of remission in these patients is not clear. In this study, the effect and remission period of UVA-1 phototherapy in various sclerotic skin diseases is described using a semiquantitative clinical score combined with the durometer score as an objective apparatus to measure the hardness of the skin. OBJECTIVE: Our purpose was to determine the effectiveness of UVA-1 phototherapy and the duration of remission in sclerodermic skin diseases. METHODS: In this prospective study, 10 patients with various sclerodermic skin diseases were treated with UVA-1 phototherapy. The durometer was used to observe the hardness of the skin. Hardness of the skin was measured by one investigator at 10 locations, distributed evenly on the representative sclerotic skin. Each spot was measured three times, and the average of each of these measurements was summed to give the total durometer score. Durometer scores were recorded weekly until the final treatment date and 4 weeks after treatment. Clinical scores were carried out at the end date of the treatment using a 6-point scale semiquantitative score. Long-term effects were evaluated up to 29-46 months. RESULTS: The patients were treated with UVA-1 in a cumulative dose of 1286 +/- 58.8 (SEM) J/cm(2) (range, 846-1470 J/cm(2)) divided over five times a week for 4 weeks. In all patients studied, the sclerotic skin lesions were markedly softer after UVA-1 treatment. All durometer scores improved highly significant during the first 3 weeks of treatment and borderline significant during the last week of treatment. There was no significant improvement between the end of UVA-1 phototherapy and 1 month after ending the therapy (P > 0.05). All patients noted improvement of the semiquantitative clinical score during treatment. Clinical improvement was associated with improvement of the durometer score (95% confidence interval). With a follow-up until 46 months, the remission period was stable up to 26 months in six patients. The duration of sclerodermic skin diseases before start of treatment did not influence improvement in the clinical or durometer score. One patient had an acute side effect of minimal erythema. No other side effects, except tanning and fatigue, were noted. LIMITATIONS: This is an open-label uncontrolled study. CONCLUSION: UVA-1 is an effective treatment for sclerodermic skin diseases with a long period of remission and clinical improvement even in patients with a long history of a sclerotic skin disease. UVA-1 should be considered among the first approaches in the management of sclerotic skin diseases.

Ultraviolet A1 phototherapy for treatment of acrosclerosis in systemic sclerosis: controlled study with half-side comparison analysis.

BACKGROUND: Treatments currently used in acrosclerosis for patients with systemic sclerosis (SS) are not very efficient and are associated with adverse effects. Several reports concern the efficacy of ultraviolet A1 (UVA1) phototherapy for localized scleroderma. Recent studies appear to indicate the interest of UVA1 in acrosclerosis for patients with SS. However, these studies are uncontrolled. OBJECTIVE: To determine whether UVA1 phototherapy is effective for acrosclerosis in SS with a randomized, investigator-blinded, controlled study. METHODS: Nine patients with SS completed the study. The duration of disease ranged from 6 to 21 years. None of them had received glucocorticoids or immunosuppressive agents. Low-dose UVA1 phototherapy (40 J/cm(2)) of the randomized hand was performed three times weekly over a period of 14 weeks. The other hand served as control. The clinical evaluation used a modified semiquantitative skin scoring system, the index flexion and extension, and a visual analog scale (VAS) was performed at baseline and after treatment. RESULTS: The mean of skin score and VAS improved significantly (P<0.05), but this improvement does not appear to be different between the treated or the untreated hands. There was no modification of the index flexion or extension. Two patients noticeably improved the functions of the treated hand. No side effects were observed. CONCLUSIONS: These results suggest that UVA1 phototherapy does not improve cutaneous thickness in acrosclerosis even if few functional improvements, and some ulcerations healings can be occasionally observed. However, a larger scale trial is necessary to confirm this inefficiency.

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review.

BACKGROUND: Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. METHODS: Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. RESULTS: Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. CONCLUSIONS: Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications.

Modulation of endothelial dysfunction and apoptosis: UVA1-mediated skin improvement in systemic sclerosis.

UVA1-mediated effects regarding vascular dysregulation as a primary pathogenetic factor of systemic sclerosis skin lesions have so far not been investigated. Pre- and posttherapy skin biopsies of four patients were evaluated immunohistochemically for angiostatic, angiogenic and angioapoptotic features. Immunohistochemistry revealed a partial pretherapy loss of endothelial CD31 and CD34 expression accompanied by a posttherapy increase of CD34(+) cells. Simultaneously, VEGF and M30 CytoDEATH immunolabeling demonstrated UVA1-induced neovascularization and decreased endothelial apoptosis. Our results suggest that UVA1 irradiation exerts its positive effects by a modulation of endothelial regulation/transformation beside the proposed induction of T cell apoptosis and collagenases.

UVA1-induced decrease in dermal neuron-specific enolase (NSE) in acrosclerosis.

Besides its role in small-cell carcinoma of the lung, elevated serum levels of neuron-specific enolase (NSE) have recently been reported to be associated with autoimmune rheumatic disorders such as systemic sclerosis. Serum NSE seems to correlate with disease activity as well as Rodnan skin score. The aim of the study was to assess the neuromodulatory effects of conventional UVA1 phototherapy on acrosclerosis as an additional mechanism besides an assumed T cell apoptosis, collagenase induction and angiogenesis. Punch skin biopsies of acrosclerotic skin lesions taken before and after treatment from four patients were evaluated immunohistochemically for the presence of NSE, S100 and neurofilament. Immunolabeling revealed a UVA-induced decrease in dermal NSE expression. In contrast, no alteration in neurofilament+ cells could be detected. In line with the findings of a previous investigation, a high number of S100+ cells were detected in most specimens. We demonstrated a UVA1-induced reduction in dermal NSE levels correlating with a softening of former sclerotic lesions. Even though the origin and the functional mechanisms remain obscure, NSE might be relevant directly within sclerotic skin lesions and may possibly be used as a diagnostic marker at least in SSc-associated acrosclerotic skin.

Low-dose UVA1 phototherapy in systemic sclerosis: effects on acrosclerosis.

BACKGROUND: Increased collagen synthesis, vascular damage, and T-lymphocytic infiltration contribute to the development of systemic sclerosis. Preliminary studies revealed the effectiveness of low-dose UVA1 phototherapy in acrosclerosis. OBJECTIVE: We sought to confirm data of a pilot study revealing the efficacy of low-dose UVA1 irradiation in acrosclerosis in a larger number of patients. METHODS: Symptoms of 18 patients receiving low-dose UVA1 phototherapy were evaluated clinically and biometrically in an open, nonrandomized study. A number of pretherapeutic and posttherapeutic biopsy specimens were tested immunohistochemically for matrix-metalloproteinase-1. RESULTS: UVA1 irradiation led to softening of former stiffness reflected by a significant decrease of the hand score, increase of total skin distension, and reduction of skin thickness. Posttherapeutically, matrix-metalloproteinase-1 immunolabeling revealed a significant dermal elevation of collagenase. CONCLUSION: Low-dose UVA1 phototherapy is a capable treatment option for acrosclerosis. Its beneficial effect may be mediated by the induction of collagenases and a reduction of collagen deposition and cellular infiltration.

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.

Treatment of scleroderma: an update.

The goal of this article is to update the reader and focus on novel therapies and clinical trials published since our last review [6]. Evidence suggests that drug intervention should target one or all of three biological processes: vascular disease, autoimmunity and tissue fibrosis. Efforts should be made to classify the subtype of scleroderma, to determine the activity of the disease process and the degree of specific organ involvement before specific treatment decisions are made. Cyclophosphamide in fibrosing alveolitis, intravenous prostaglandins and other vasodilators for the vascular disease, endothelin-1 inhibition in pulmonary hypertension and immunosuppressive therapy for early inflammatory disease, all appear to have benefit. Several agents used in vitro and in animal models of fibrosis also show promise including anti-transforming growth factor-beta, the statins and anti-integrins. More experience in well-designed clinical trials is needed to define the role of these agents in treating scleroderma.

Matched-control retrospective study of the acute and late complications in patients with collagen vascular diseases treated with radiation therapy.

BACKGROUND: Controversy surrounds the potential complication rate of patients with collagen vascular diseases (CVD) after radiation. We assess the acute and late complications (based on Radiation Therapy Oncology Group criteria) by a matched-control retrospective study. PATIRNTS/METHODS: The charts of 12,000 patients treated with radiation therapy at the University of Louisville from 1982 to 2001 were reviewed for CVD. A total of 38 patients with documented CVD were compared with a matched-control group of 38 patients without CVD. Median follow-up for patients with CVD was 35 months. The patients were matched on the basis of site treated, age, dose, date of treatment, sex, treatment goal, follow-up, tumor site and histology, therapeutic technique, and general treatment method. The patients with CVD included 21 patients with systemic lupus erythematosus (55%), two with scleroderma (5%), four with Raynaud's phenomena (11%), three with fibromyalgia (8%), three with polymyalgia rheumatica (8%), three with Sjögren's syndrome (8%), and two with polymyositis-dermatomyositis (5%). Twenty-nine patients received curative doses, and nine patients received palliative doses. RESULTS: No difference was observed in the incidence of acute or late complications between the two groups. For CVD and matched-control patients receiving curative doses, the incidence of acute reaction for grade II was 49% versus 58% and for grade III was 7% versus 7%, respectively. The incidence of late reactions for patients with CVD and the matched control patients for grade I was 3% versus 7%, for grade II was 7% versus 3%, and for grade III was 7% versus 7%, respectively. The patients treated with palliation had a similar incidence of acute reaction in the CVD and the matched-control groups. No patients in the CVD or matched-control group had fatal complications. Only patients with scleroderma had a slight increase in acute and late complications. CONCLUSION: This is the largest matched-control study thus far in the literature. In the comparison between the patients with CVD and the matched-control patients, there was no significant difference in the incidence of acute or late complication. However, there was a higher incidence of radiation complications in patients with scleroderma. Importantly, no fatal complication was noted in any of the patients with CVD.

Phototherapy for scleroderma: biologic rationale, results, and promise.

Scleroderma is a chronic disease of connective tissue characterized by deposition of large amounts of collagen. Localized scleroderma affects only the skin, whereas systemic disease, systemic sclerosis, may affect the lungs, gastrointestinal tract, kidneys, and heart in addition to the skin. Although the various forms of localized scleroderma are not life threatening, they result in considerable morbidity owing to joint contracture, loss of flexibility, and disfigurement. Although many different treatments have been attempted, until now none has proven to be effective. Accumulating evidence indicates that UVA irradiation offers a genuine opportunity to ameliorate localized scleroderma and the cutaneous manifestations of systemic sclerosis.