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Drug-induced scleroderma-like lesion is a condition in which administration of a drug induces skin sclerotic lesions similar to systemic sclerosis or morphea. The clinical manifestations of drug-induced scleroderma-like lesion can be divided into two types: scleroderma-like lesions and morphea-like plaques. A wide variety of drugs can cause drug-induced scleroderma-like lesion. Bleomycin, L-tryptophan, vinyl chloride, and phytonadione (vitamin K1) have been reported, but in recent years, cases due to chemotherapeutic agents, such as taxane-based agents, gemcitabine, and tegafur-uracil, and immune checkpoint inhibitors have increased. Drug-induced scleroderma-like lesion differs from systemic sclerosis in that it does not include Raynaud's phenomenon, nail-fold capillary abnormality, organ involvement, such as reflux esophagitis, interstitial pneumonia, renal crisis, or anti-nuclear Abs. On the other hand, there are reports of cases in which Raynaud's phenomenon, positive conversion of anti-nuclear Abs, and development of skin sclerosis from the fingers developed after initiation of the drug. Whether the skin sclerosis improves after discontinuation of the drug depends on the patient. In patients with severe skin sclerosis, functional impairment, such as flexion contracture of the fingers, may occur, and systemic therapy, such as steroids, may be necessary. When treating patients with skin sclerosis, it is important to keep in mind the possibility that the sclerotic lesion may be induced by a drug.

Drug-induced scleroderma-like lesion is a condition in which administration of a drug induces skin sclerotic lesions similar to systemic sclerosis or morphea. The clinical manifestations of drug-induced scleroderma-like lesion can be divided into two types: scleroderma-like lesions and morphea-like plaques. A wide variety of drugs can cause drug-induced scleroderma-like lesion. Bleomycin, L -tryptophan, vinyl chloride, and phytonadione (vitamin K 1) have been reported, but in recent years, cases due to chemotherapeutic agents, such as taxane-based agents, gemcitabine, and tegafur-uracil, and immune checkpoint inhibitors have increased. Drug-induced scleroderma-like lesion differs from systemic sclerosis in that it does not include Raynaud's phenomenon, nail-fold capillary abnormality, organ involvement, such as reflux esophagitis, interstitial pneumonia, renal crisis, or anti-nuclear Abs. On the other hand, there are reports of cases in which Raynaud's phenomenon, positive conversion of anti-nuclear Abs, and development of skin sclerosis from the fingers developed after initiation of the drug. Whether the skin sclerosis improves after discontinuation of the drug depends on the patient. In patients with severe skin sclerosis, functional impairment, such as flexion contracture of the fingers, may occur, and systemic therapy, such as steroids, may be necessary. When treating patients with skin sclerosis, it is important to keep in mind the possibility that the sclerotic lesion may be induced by a drug. [ABSTRACT FROM AUTHOR]

Vasohibin‐1 (VASH‐1) is a potent anti‐angiogenic factor mainly produced by endothelial cells. In addition, VASH‐1 prevents TGF‐β–dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH‐1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH‐1 in SSc by evaluating the clinical correlation between serum VASH‐1 levels and the expression of VASH‐1 in SSc‐involved skin. Serum VASH‐1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH‐1 as compared to those without. Importantly, serum VASH‐1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL‐6 levels, but not serum surfactant protein D levels. In SSc‐involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH‐1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc‐like endothelial properties, did not affect VASH‐1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH‐1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH‐1 to SSc vasculopathy seems to be limited. [ABSTRACT FROM AUTHOR]

Objective: To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. Methods: A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration <60 months, and valid mRSS data at one year. Worsening of skin thickness was defined as an increase in mRSS ≥3 points and an increase ≥25% from baseline to one year. Initial demographic and clinical parameters useful for predicting the progression of skin thickness were identified using univariate and multivariable analysis, and prediction models of skin thickening progression were built based on combinations of independent predictive parameters. Results: Only 23 patients (13.5%) experienced worsening mRSSs at one year. Short disease duration, low mRSS, absence of nailfold bleeding, arthritis, and a high erythrocyte sedimentation rate at diagnosis were identified as predictors of subsequent worsening of the mRSS even after adjusting for the treatment. Assessment of the best predictive model revealed that patients with a disease duration ≤12 months and mRSS ≤19 had a risk of mRSS worsening within one year, with a sensitivity of 73.9% and specificity of 81.1%. Conclusion: Identification of predictors of subsequent worsening of skin thickness in dcSSc patients is useful for identifying patients who require intensive treatment with potential disease-modifying agents and for improving clinical trial design by characterizing eligible progressors in the Japanese population. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). Methods: We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n=150) and limited cutaneous SSc (lcSSc) with ILD (n=57) in 10 medical centers every year for 7 consecutive years. Results: Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. Conclusion: In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non‐invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc. [ABSTRACT FROM AUTHOR]

Systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is the most frequent cause of death for SSc but there is still no sufficient treatment available. Although cyclophosphamide (CYC) therapy is a common treatment which has shown statistical efficacy against SSc‐ILD to date, its effects are temporary and not enough. Rituximab (RTX), the anti‐CD20 monoclonal antibody, has recently shown efficacy in many autoimmune diseases. In SSc‐ILD, RTX is also considered to be one of the novel treatment candidates. However, studies of SSc‐ILD in Japanese treated with RTX have only a few case reports. Therefore, in this study, we retrospectively compared nine patients treated with RTX and 30 patients treated with CYC to investigate the efficacy of RTX treatment for Japanese anti‐topoisomerase I‐positive SSc‐ILD patients. At the 24‐month evaluation, the improvement rates of percent predicted of forced vital capacity and percent predicted of diffusing capacity of the lung carbon monoxide in the RTX‐treated group were significantly higher than those in the CYC‐treated group (20.6 ± 8.8% vs 1.1 ± 3.9%; P < 0.05 and 34.0 ± 6.0% vs −1.5 ± 2.8%; P < 0.01, respectively). In addition, skin thickness scores also showed a marked improvement from 13.5 points before the start of treatment to 5.8 points after 24 months by RTX therapy (P < 0.05). These results suggest that RTX treatment is more effective for Japanese SSc‐ILD patients than CYC treatment. In the future, it is expected that large‐scale clinical trials will show the usefulness of RTX treatment for SSc‐ILD. [ABSTRACT FROM AUTHOR]

Abstract Skin fibrosis is a devastating clinical condition commonly seen in skin-restricted and systemic disorders. The goal of skin fibrosis treatment is the restoration of abnormally activated dermal fibroblasts producing the excessive amount of extracellular matrix, which is generally a final consequence of the complex disease process including the activation of vascular and immune systems. Among various skin fibrotic conditions, the molecular mechanisms underlying dermal fibroblast activation have been mostly well studied in systemic sclerosis (SSc). SSc is a multisystem autoimmune and vascular disease resulting in extensive fibrosis of the skin and various internal organs. Since SSc pathogenesis is believed to include all the critical components regulating tissue fibrosis, the studies on anti-fibrotic drugs against SSc provide us much useful information regarding the strategy for the treatment of various skin fibrotic conditions. In the recent decade, as is the case with other autoimmune and inflammatory diseases, the molecular targeting therapy with monoclonal antibody has been clinically well examined in SSc. Promising clinical outcomes are so far reported in tocilizumab (an anti-IL-6 receptor antibody), rituximab (an anti-CD20 antibody), and fresolimumab (an anti-TGF-β antibody). The analysis of gene expression profiles in skin lesions of SSc patients treated with tocilizumab or fresolimumab revealed a critical role of monocyte-macrophage lineage cells in the development of skin fibrosis and the involvement of IL-6 and TGF-β in the activation of those cells. Considering that B cells modulate the differentiation and activation of macrophages, favorable clinical outcomes of rituximab treatment imply the central role of B cell/monocyte-macrophage lineage cell axis in the pathogenesis of SSc. This scenario may be applicable at least partly to other skin fibrotic conditions. In this review article, the currently available data on these drugs are summarized and the future directions are discussed.

CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T‐helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14‐mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17‐skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2‐skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc. [ABSTRACT FROM AUTHOR]

The objective of this study is to investigate the impact of skin sclerosis burden on an internal organ involvement over a 1-year period, as measured by time-adjusted accrual-modified Rodnan skin score (TA-mRSS), and to evaluate association between TA-mRSS patterns and laboratory tests in patients with systemic sclerosis (SSc). This prospective study was conducted at Siriraj Hospital (Bangkok, Thailand) during the November 2013-November 2016. SSc patients by ACR/EULAR 2013 or ACR 1980 criteria were eligible. TA-mRSS was classified as low, intermediate, or high, and then compared between groups. Correlation between the arithmetic mean of laboratory tests and TA-mRSS was assessed by multiple linear regression analysis. A total of 118 patients, with 81.4% women, median (IQR) age 49.8 (43.8, 55.1) years, disease duration from onset of non-Raynaud symptoms to first visit of 3.3 (1, 6.8) years, 78% dcSSc, and 75.3% anti-Scl-70 positivity, were analyzed. TA-mRSS over 1 year ranged from 0 to 37.44. The high skin sclerosis burden group had a median TA-mRSS > 7.26 (> 67th percentile). Patients with high TA-mRSS were dcSSc, high initial and average mRSS, and had tendon friction rub, digital ischemic complications, usual interstitial pneumonia, diastolic dysfunction, gastrointestinal dysmotility, and low serum albumin. In multiple linear regression analysis, the arithmetic mean of hemoglobin (B = − 1.007, 95% CI − 1.779 to − 0.236), erythrocyte sedimentation rate (B = − 0.078, 95% CI − 0.126 to − 0.029), serum glutamic oxaloacetic transaminase (B = 0.073, 95% CI 0.026-0.12), creatine phosphokinase (B = 0.012, 95% CI 0.003-0.021), and albumin (B = − 4.117, 95% CI − 6.958 to − 1.276) were associated with TA-mRSS. This study found a higher cumulative course of mRSS over a 1-year period to be significantly associated with severe internal organ involvement. [ABSTRACT FROM AUTHOR]

Objectives This case series explores the potential efficacy of Abatacept in patients presenting with morphea subtypes and deep tissue involvement. Methods Three patients with established morphea subtypes and deep tissue involvement and with no contraindication to Abatacept were included in this prospective open-label study. The index patient was exceptionally severely affected with a mean Modified Rodnan Skin Score (MRSS) of 38/51. At baseline, whole-body MRI and skin biopsy were performed which confirmed classical deposition of dense fibrous tissue in the appropriate layer of the skin. MRSS was performed independently by three clinicians and VAS scores (10 cm) were measured at baseline for Patient Global Disease Activity (PGDA), Patient Global Pain (PGP), Patient Day Pain (PDP), Patient Night Pain (PNP), and Physician Global Disease Activity (PhGDA). Patients 2 and 3 were similarly screened at baseline except for MRI. Patients were commenced on Abatacept as per body weight (10 mg/kg) given intravenously with concomitant tapering dose of oral prednisolone. All three were re-assessed at 6 months and the index case was further re-assessed at 18 months. Results All patients tolerated the Abatacept well and showed dramatic improvement. The index patient’s clinical signs and symptoms, whole-body MRI, and mean Modified Rodnan Skin Score improved dramatically from baseline by 37% at 6 months and by 74% at 18 months. There were no clinically significant adverse outcomes noted. Conclusion We present three cases, one with exceptionally severe disease, which demonstrated excellent clinical response to Abatacept. Abatacept is a promising option for the treatment of severe or resistant morphea, especially in those with deep tissue involvement. [ABSTRACT FROM AUTHOR]

Collagen type IV is the primary collagen in the basement membranes around blood vessels and in the dermoepidermal junction in the skin. Perivascular collagen type IV is synthesized by endothelial cells and pericytes, and contributes to the homeostasis and remodeling of blood vessels. It has been well recognized that elevated serum collagen type IV levels are associated with the liver fibrosis. The objective was to examine serum collagen type IV levels and their clinical associations in patients with systemic sclerosis ( SSc), and to examine the expression of collagen type IV in the fibrotic skin in SSc. Serum collagen type IV levels in SSc patients and diffuse cutaneous type SSc patients were significantly higher than those in healthy individuals. Serum collagen type IV levels were positively correlated with modified Rodnan total skin score. Serum collagen type IV levels in early stage (disease duration ≤3 years) diffuse cutaneous SSc patients were significantly elevated. Serum collagen type IV levels in SSc patients with digital ulcers ( DU) were significantly elevated. In immunohistochemical staining, the expression of collagen type IV around dermal small vessels in the affected skin was reduced compared with those of normal individuals. These results suggest that elevated serum collagen type IV levels may be associated with the skin sclerosis in the early stage of SSc. The measurement of serum collagen type IV levels in SSc patients may be useful as a disease activity marker in skin sclerosis and DU. [ABSTRACT FROM AUTHOR]

T-cell immunoglobulin and mucin domain 3 ( TIM-3) has been thought to play a crucial role in the negative regulation of immune responses. Here, we examined the levels of serum soluble TIM-3 ( sTIM-3) in patients with systemic sclerosis ( SSc) and evaluated the results with respect to the clinical features of the disease. Patients with diffuse cutaneous SSc (dc SSc) had higher levels of sTIM-3 than those with limited cutaneous SSc and healthy individuals. Serum sTIM-3 levels were positively correlated with the severity of skin sclerosis in early phase dc SSc. Moreover, serum sTIM-3 levels were increased more often in patients with renal crisis and cardiac involvement than in those with normal sTIM-3 levels. These results suggest that serum sTIM-3 levels may be increased in patients with early phase dc SSc and associated with cardiac involvement and renal crisis. Measurement of serum sTIM-3 may be useful for risk stratification in the early stage of the disease. [ABSTRACT FROM AUTHOR]

The interaction of programmed death-1 ( PD-1) with its ligand, programmed death ligand-1 ( PD-L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis ( SSc) had higher levels of soluble PD-1 ( sPD-1) than those with limited cutaneous SSc and healthy individuals. Serum sPD-1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD-L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD-L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD-1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD-1/ PD-L1 interaction may contribute to the development of skin sclerosis in SSc. [ABSTRACT FROM AUTHOR]

Background The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities. Methods Here, we describe a series of 10 SSc patients (4 M and 6 F, mean age 46 ± 13.5SD years, mean disease duration 6.3 ± 2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375 mg/m 2 ). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6 months of the first cycle and at the end of long-term follow-up period (37 ± 21SD months, range 18–72 months). An updated review of the world literature was also done. Results RTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6 months evaluation (modified Rodnan skin score from 25 ± 4.3 to 17.2 ± 4.6; p = .022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle. These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study. Conclusion The present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis. [ABSTRACT FROM AUTHOR]

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease ( PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon ( RP), digital ulcers ( DU) in systemic sclerosis ( SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti-topoisomerase I antibody positivity, complications of DU, acro-osteolysis ( AO) and interstitial lung disease ( ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness ( IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO. [ABSTRACT FROM AUTHOR]

Angiopoietin-like protein 3 (ANGPTL3), which is part of a family of secreted glycoproteins that are structurally similar to angiopoietins, is principally expressed in the liver and is involved in lipid metabolism and angiogenesis. The aim of this study was to determine the clinical significance of serum ANGPTL3 levels, measured with a specific enzyme-linked immunosorbent assay, in patients with systemic sclerosis. Serum ANGPTL3 levels correlated positively with skin score in diffuse cutaneous systemic sclerosis with a disease duration ≤ 6 years. Furthermore, the prevalence of digital ulcers was significantly higher in patients with elevated serum ANGPTL3 levels than in other patients. Moreover, among patients excluding diffuse cutaneous systemic sclerosis with disease duration ≤ 6 years, serum ANGPTL3 levels correlated positively with estimated right ventricular systolic pressure. In conclusion, ANGPTL3 may contribute to the development of progressive skin sclerosis and proliferative obliterative vasculopathy, such as digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, in systemic sclerosis. [ABSTRACT FROM AUTHOR]

ABSTRACT We report a case of a 64-year-old man with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome that had been previously misdiagnosed as systemic sclerosis. He had typical symptoms of POEMS syndrome, however, the existence of skin sclerosis, contracture of fingers and pigmentation were similar to that of systemic sclerosis. Ten patients, including the patient discussed in this case, visited our department between 1990 and 2011. Among them, five patients had skin sclerosis. Therefore, we compared skin lesions and clinical/laboratory features of POEMS syndrome and systemic sclerosis in an attempt to distinguish these disorders. Regarding the cutaneous and laboratory findings, the existence of hemangioma or hypertrichosis is indicative of POEMS syndrome. By contrast, the existence of systemic sclerosis-specific autoantibodies, nail fold bleeding, digital ulcer/digital pitting scar or telangiectasia is highly suggestive of systemic sclerosis. To our knowledge, this is the first report to discuss in detail the differentiation between POEMS syndrome and systemic sclerosis. [ABSTRACT FROM AUTHOR]

Objective. To clarify the clinical course of SSc in Japanese patients with early-onset disease. It is well known that ethnic variations exist in the clinical features and severity of SSc. However, neither the clinical course nor prognostic factors have been thoroughly investigated in the Japanese population.Methods. Ninety-three Japanese patients of early-onset SSc (disease duration: <3 years) with diffuse skin sclerosis and/or interstitial lung disease were registered in a multi-centre observational study. All patients had a physical examination with laboratory tests at their first visit and at each of the three subsequent years. Factors that could predict the severity of skin sclerosis and lung involvement were examined statistically by multiple regression analysis.Results. Two patients died from SSc-related myocardial involvement and four patients died from other complications during the 3-year study. Among various clinical data assessed, the initial modified Rodnan total skin thickness score (MRSS) and maximal oral aperture were associated positively and negatively with MRSS at Year 3, respectively. Additionally, initial ESR tended to be associated with final MRSS. Pulmonary vital capacity (VC) in the third year was significantly associated with initial %VC. Furthermore, patients with anti-topo I antibody tended to show reduced %VC at Year 3.Conclusions. Several possible prognostic factors for skin sclerosis and lung function were detected in Japanese patients with early SSc. Further longitudinal studies of larger populations will be needed to confirm these findings. [ABSTRACT FROM PUBLISHER]

Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme involved in production of the PGD and J series, which have various role in inflammation and immunity. We evaluated the effect of treatment with 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or the injection of prostaglandin D2 synthase (PGDS) cDNA expressing-retrovirally transfected fibroblasts on bleomycin (BLM)-induced scleroderma-like skin sclerosis. Daily injection of BLM (30 μg) for 4 weeks induced histological evidence of dermal sclerosis in C3H mice. We examined the effect of injection of 15d-PGJ2 (30 ng twice a day) or PGDS expressing-retrovirally transfected fibroblast on BLM-induced dermal sclerosis. Administration of 15d-PGJ2 (a nonenzymatic metabolite of PGD2) injection of PGDS cDNA-expressing fibroblasts significantly reduced dermal sclerosis, the hydroxyproline content, and dermal thickness. Moreover, 15-d PGJ2 down-regulation of the expression of transforming growth factor β1 and connective tissue growth factor which had been induced by BLM. Mast cells were also increased in the skin by BLM injection and there was prominent degranulation of these mast cells along with elevated plasma histamine levels. 15-d PGJ2 and PGDS-expressing cells also suppressed degranulation of cultured mast cells and histamine release by these cells. These results show that 15-d PGJ2 and PGDS-expressing cells can prevent experimental skin sclerosis induced by BLM and raise the possibility of therapeutic approaches targeting of PPARγ for the skin lesion of scleroderma. [Copyright &y& Elsevier]

Recent studies have shown that collagen-degrading matrix metalloproteinase (MMP)-1 and MMP-3 are produced by fibroblasts in response to photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) and are considered to be involved in the antisclerotic effects of ALA-PDT observed in the treatment of localized scleroderma.As the primary target of topical PDT is epidermal keratinocytes, we studied the indirect participation of keratinocytes in the production of MMPs and collagen by dermal fibroblasts.Keratinocytes were treated with sublethal doses of ALA (100 µmol L−1) and red light. The conditioned media were collected 24 h after PDT and primary human fibroblasts were exposed to these media for 6–48 h. Further, a coculture model, keratinocytes seeded on to collagen type IV-coated transwells in the upper chamber and fibroblasts in the lower chamber, was used to study paracrine effects of keratinocytes after PDT.Keratinocyte supernatants after PDT showed a significant, up to 10-fold increase of interleukin (IL)-1α and a 2·5-fold increase of tumour necrosis factor-α as determined by enzyme-linked immunosorbent assay, while IL-6, MMP-1 and MMP-3 were not altered significantly. Fibroblasts treated with keratinocyte-conditioned media after PDT showed an induction of MMP-1 and MMP-3 protein levels up to threefold in both models used, suggesting that ALA-PDT modulates MMP-1 and MMP-3 production via indirect mechanisms. Collagen type I mRNA expression by fibroblasts was not altered significantly in either model. The addition of an IL-1 receptor antagonist to the keratinocyte-conditioned media completely inhibited the induction of MMP-1 and MMP-3 in stimulated fibroblasts, suggesting that IL-1 is mainly responsible for the observed paracrine effects.We present evidence that PDT can trigger MMP production in dermal fibroblasts not only directly as has been already shown, but also by an indirect paracrine loop mediated by soluble factors released by epidermal keratinocytes. [ABSTRACT FROM AUTHOR]

Patients with localized scleroderma receiving topical photodynamic therapy with 5-aminolevulinic acid show a reduction in skin tightness, suggesting that this therapy reduces skin sclerosis. To investigate potential mechanisms, the effects of 5-aminolevulinic acid and light on collagen metabolism were studied in vitro . Normal and scleroderma fibroblasts were treated with sublethal doses of 5-aminolevulinic acid and red light and transferred to three-dimensional collagen lattices. Cell supernatants were taken 6–72 h after photodynamic therapy to determine protein levels of the matrix metalloproteinases 1, 2, and 3, and of their inhibitors, tissue inhibitor of metalloproteinase 1 and 2 by enzyme-linked immunosorbent assay. Cellular mRNA expression of these proteins and of collagen type I and III was measured by quantitative real-time polymerase chain reaction. A significant, time-dependent induction of matrix metalloproteinase 1 (up to 2.4-fold after 48 h) and matrix metalloproteinase 3 (up to 4.3-fold after 48 h) protein levels was seen after 5-aminolevulinic acid-photodynamic therapy. Irradiation with ultraviolet A light, used as a positive control, showed a similar induction of matrix metalloproteinase 1 (2.3-fold after 48 h). The mRNA levels of matrix metalloproteinase 1 and matrix metalloproteinase 3 were significantly increased 12 h after irradiation, whereas collagen type I mRNA was strongly decreased already 6 h following irradiation. Collagen type III, tissue inhibitor of metalloproteinase 1, and matrix metalloproteinase 2 did not change after photodynamic therapy. Addition of nontoxic concentrations of sodium azide, a singlet-oxygen quencher, significantly inhibited induction of matrix metalloproteinase 1 by 5-aminolevulinic acid and light. These data show that 5-aminolevulinic acid and light induce matrix metalloproteinase 1 and matrix metalloproteinase 3 expression in normal and scleroderma fibroblasts in a singlet oxygen-dependent way while... [ABSTRACT FROM AUTHOR]

To determine the role of chemokines in the pathogenesis of systemic sclerosis (SSc), we examined serum levels, spontaneous production by peripheral blood mononuclear cells (PBMC), and histological distribution in the affected skin, of MCP-1, MIP-1α and MIP-1β in SSc patients. Serum levels of these chemokines were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels of these chemokines in culture supernatants from PBMC were also measured by ELISA. Serum levels and spontaneous production levels by PBMC of MCP-1, MIP-1α, and MIP-1β were significantly elevated in patients with SSc compared with normal controls. Elevated serum levels of MCP-1 and MIP-1α significantly correlated with the presence of pulmonary fibrosis. MCP-1 expression in the skin of SSc was immunohistochemically examined using anti-MCP-1 MoAb. MCP-1 was strongly expressed in the epidermis, inflammatory mononuclear cells, and vascular endothelial cells in the sclerotic skin of SSc patients, but not expressed in any control skin. Furthermore, the MCP-1 expression in inflammatory mononuclear cells and endothelial cells significantly correlated with earlier onset of SSc. Thus, MCP-1, MIP-1α and MIP-1β may be involved in the disease process, possibly by augmenting leucocyte migration into the affected tissues in SSc. Furthermore, MCP-1 and MIP-1α may play an important role in the development of pulmonary fibrosis in SSc. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis and vasculopathy in various organs with a background of inflammation initiated by autoimmune abnormalities. Calponin 3 plays a role in the cell motility and contractibility of fibroblasts during wound healing in the skin. We aimed to evaluate serum calponin 3 levels in SSc patients and their association with clinical manifestations of SSc. Serum samples were collected from 68 patients with SSc and 20 healthy controls. Serum calponin 3 levels were examined using enzyme-linked immunosorbent assay kits, and their association with clinical features of SSc was statistically analyzed. The upper limit of the 95% confidence interval of serum calponin 3 levels in healthy controls was utilized as the cut-off value when dividing SSc patients into the elevated and normal groups. Serum calponin 3 levels were significantly higher in SSc patients than in healthy controls (mean (95% confidence interval), 15.38 (14.66–16.11) vs. 13.56 (12.75–14.38) ng/mL, p < 0.05). The modified Rodnan total skin thickness score was significantly higher in the elevated serum calponin 3 level group than in the normal level group (median (25–75th percentiles), 10.0 (2.0–16.0) vs. 6.5 (3.25–8.75), p < 0.05). Moreover, SSc patients with increased serum calponin 3 levels also had a higher frequency of arthralgia (40% vs. 9%, p < 0.05). Elevated serum calponin 3 levels were associated with skin sclerosis and arthralgia in SSc patients. Serum calponin 3 levels might be a biomarker that reflects the severity of skin sclerosis and joint involvement in SSc. [ABSTRACT FROM AUTHOR]