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Background: Results from the double-blind phase 2 DESIRES trial showed that rituximab improves skin thickening in systemic sclerosis. Here, we present the findings of a subsequent 24-week open-label extension phase., Methods: Patients with systemic sclerosis aged 20-79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria, with a baseline modified Rodnan Skin Score (mRSS) of 10 or greater were enrolled into the DESIRES trial, which was an investigator-initiated, phase 2, double-blind, randomised controlled trial of rituximab versus placebo conducted at four sites in Japan. After completion of 24 weeks of treatment with either rituximab or placebo, patients in both groups received a further 24 weeks of rituximab (375 mg/m 2 intravenously, once per week for 4 consecutive weeks) in an open-label extension. The primary endpoint of the double-blind trial was mRSS at week 24, which was reassessed at week 48 in the open-label extension. All endpoints were exploratory. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses included those who had received at least one dose and undergone efficacy assessment at 24 weeks in the double-blind phase and at 48 weeks in the extension phase. The DESIRES study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139., Findings: Between Nov 28, 2017, and Nov 6, 2018, 56 patients were randomly assigned to either rituximab (n=28) or placebo (n=28) in a double-blind study. 26 patients initially assigned to rituximab and 20 assigned to placebo transitioned to the open-label extension and all received at least one dose of rituximab; 24 participants in the rituximab-rituximab group and 19 in the placebo-rituximab group completed the extension phase. In the rituximab-rituximab group, there was an improvement in mRSS from baseline at week 24 (-5·81 [SD 3·16]), with further improvement at week 48 (-8·88 [3·10]). In the placebo-rituximab group, mRSS worsened at week 24 (2·14 [SD 5·51]) but improved at the week 48 assessment (-6·05 [4·43]). One patient each in the rituximab-rituximab and placebo-rituximab groups experienced one serious adverse event during the open-label phase (cholangitis and pneumococcal pneumonia, respectively). There were no deaths during follow-up., Interpretation: Two courses of rituximab is a safe treatment that can provide sustained improvement in systemic sclerosis for at least 48 weeks., Funding: Japan Agency for Medical Research and Development., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b-C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms., Methods: Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay., Results: Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis., Conclusion: Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment., (© 2020 Japanese Dermatological Association.)

Background: Previous studies have shown the relationship between higher skin thickness score and the existence of organ involvements in systemic sclerosis (SSc). Here, we firstly investigated the correlation between skin thickness score and quantitative measurements of each organ involvement in Japanese patients with SSc., Methods: All Japanese SSc patients hospitalized to our clinic for initial evaluation of SSc were selected. Skin thickness was evaluated by modified Rodnan total skin thickness score (mRSS). Relationship between mRSS and prevalence or incidence of organ involvements was examined by logistic analyses. Correlation between mRSS and quantitative measurements of organ involvements was examined by correlation analyses and regression analyses., Results: We recruited 198 patients into our study. The mean disease duration was 7.3 years with the mean follow-up duration of 3.2 years. Multivariate logistic regression analyses revealed that higher mRSS is related to higher prevalence of interstitial lung disease (P < 0.05), restrictive impairment (P < 0.01), and diffusion impairment (P < 0.05) of the lung. Correlation analyses revealed mRSS negatively correlates with forced vital capacity (P < 0.001) and diffusing capacity (P < 0.001) of the lung. Correlation between longitudinal change of mRSS and that of forced vital capacity (P < 0.05) or diffusing capacity (P < 0.001) of the lung was also demonstrated., Conclusions: Skin thickness score significantly correlates with quantitative measurements of lung involvement in Japanese patients with SSc.

Backgrounds: Stratified epithelia have caught much attention as potential contributors to the development of dermal and oesophageal fibrosis in systemic sclerosis (SSc). Galectin-7 is a marker of all types of stratified epithelia, which is involved in the maintenance of epidermal homeostasis. So far, the role of galectin-7 has not been studied in SSc., Objectives: To investigate the potential contribution of galectin-7 to the development of clinical manifestations in SSc., Methods: Galectin-7 expression was examined in skin samples and cultured keratinocytes by immunostaining and/or quantitative reverse transcription PCR. Serum galectin-7 levels were determined by enzyme-linked immunosorbent assay in 63 SSc and 20 healthy subjects., Results: Galectin-7 expression was markedly decreased in the epidermis of SSc lesional skin compared with that of healthy control skin. Serum galectin-7 levels were significantly lower in SSc patients than in healthy controls and inversely correlated with skin score. In addition, SSc patients with diffuse pigmentation and those with oesophageal dysfunction had significantly decreased serum galectin-7 levels as compared to those without each symptom. Importantly, endothelin-1 stimulation suppressed galectin-7 expression in normal human keratinocytes, and bosentan, a dual endothelin receptor antagonist, reversed circulating galectin-7 levels and epidermal galectin-7 expression in SSc patients., Conclusions: Galectin-7 downregulation in stratified epithelia, which is mediated at least partially by autocrine endothelin stimulation, may contribute to the development of cutaneous manifestations and oesophageal dysfunction in SSc patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Aquaporin-1 (AQP1), a water channel protein controlling the water contents of cells and tissues, exerts pleiotropic effects on various biological activities, including inflammation, angiogenesis, and extracellular matrix remodeling, by regulating cell behaviors and tissue water balance., Objective: To investigate AQP1 roles in systemic sclerosis (SSc) which is characterized by autoimmune inflammation, vasculopathy, and tissue fibrosis., Methods: AQP1 expression was evaluated by immunohistochemistry and quantitative reverse transcription PCR in skin samples from human and animal models and by immunoblotting in cultured cells. Fli1 binding to the AQP1 promoter was evaluated by chromatin immunoprecipitation. Cell migration was assessed by scratch assay., Results: Dermal fibroblasts and endothelial cells highly expressed AQP1 in SSc lesional skin, and AQP1 expression in dermal fibroblasts and endothelial cells positively correlated with the degrees of tissue fibrosis and edema, respectively. Consistently, SSc dermal fibroblasts up-regulated AQP1 compared with normal dermal fibroblasts in vitro. Furthermore, TGF-β stimulation induced AQP1 expression in normal dermal fibroblasts, while TGF-β1 antisense oligonucleotide suppressed AQP1 expression in SSc dermal fibroblasts. In endothelial cells, Fli1 deficiency resulted in AQP1 up-regulation in vivo and in vitro and Fli1 bound to the AQP1 promoter. Importantly, SSc dermal fibroblasts and FLI1 siRNA-treated endothelial cells had a pro-migratory property, which was remarkably diminished by gene silencing of AQP1., Conclusion: AQP1 is up-regulated in SSc dermal fibroblasts and SSc endothelial cells at least partially due to autocrine TGF-β stimulation and Fli1 deficiency, respectively, possibly contributing to inflammation, vasculopathy, and tissue fibrosis by regulating tissue edema and cell migration., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

CXCL13, a chemokine for B cells, follicular T cells, T helper 17 cells, and regulatory T cells, is reported to contribute to the development of systemic sclerosis (SSc), reflecting aberrant activation of immune system. To better understand the role of CXCL13 in SSc, we investigated the influence of Fli1 deficiency, a potential predisposing factor of this disease, on CXCL13 expression and assessed the clinical correlation of serum CXCL13 levels by multivariate regression analysis. Haploinsufficient loss of Fli1 remarkably induced CXCL13 expression in murine peritoneal macrophages, while gene silencing of FLI1 did not affect the expression of CXCL13 in human dermal fibroblasts and human dermal microvascular endothelial cells. Serum CXCL13 levels were elevated in SSc patients compared with healthy controls and correlated positively with skin score and negatively with pulmonary function test results. SSc patients with elevated serum CXCL13 levels had longer disease duration, diffuse cutaneous involvement, interstitial lung disease (ILD), heart involvement, pulmonary arterial hypertension, Raynaud's phenomenon, pitting scars, digital ulcers, telangiectasia, and high serum IgG levels more frequently than the other patients. In particular, serum CXCL13 levels were associated with ILD and digital ulcers by multivariate regression analysis. Taken together, these results indicate that CXCL13 expression is upregulated by Fli1 deficiency in macrophages, potentially contributing to the development of tissue fibrosis, vasculopathy and immune activation in SSc, especially ILD and digital ulcers., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-β in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family growth factors, which affects multiple aspects of the wound healing process such as epithelialization, wound contraction and angiogenesis. In our study, we measured the serum HB-EGF levels of 51 systemic sclerosis (SSc) patients, which showed a significant increase compared with those of 20 normal subjects. Further analysis revealed a positive correlation between the HB-EGF level and pulmonary ground-glass score but no correlation between the former and pulmonary fibrosis score. Other findings include: a significant increase of serum sialylated carbohydrate antigen KL-6 levels and significant shortness of disease duration in the diffuse cutaneous SSc patients with elevated HB-EGF levels; and significantly higher HB-EGF levels in the presence of Raynaud's phenomenon, in that of telangiectasia, and in the absence of contracture of phalanges in all SSc patients. We then evaluated HB-EGF mRNA levels of fibroblasts harvested from skin samples of the SSc patients and those of foreskin-derived fibroblasts treated with transforming growth factor-β, both of which were significantly higher than each control. In conclusion, we speculate that HB-EGF plays a pro-inflammatory role in the active skin and lung lesions of SSc., (© 2017 Japanese Dermatological Association.)

Endocan is a novel human endothelial cell-specific molecule and is mainly expressed in endothelial cells in various tissues. Endocan has the capacity to inhibit leukocytes binding to the vascular endothelium. It also can promote the angiogenesis alongside vascular endothelial growth factor A. Through these functions, endocan has been implicated in the pathogenesis of various inflammatory diseases. To investigate the possible roles of endocan in atopic dermatitis (AD), we examined endocan expression in lesional skin and sera in patients with AD. Endocan mRNA and protein levels were increased in lesional skin of AD compared with healthy skin and endocan was expressed on epidermal keratinocytes and dermal endothelial cells. On the other hand, serum endocan levels in patients with AD were significantly lower than those in healthy controls. Our results suggest that elevated endocan expression in lesional skin may be associated with development of AD through angiogenesis and that decreased endocan expression in sera may be associated with increased leukocyte recruitment in AD., (© 2017 Japanese Dermatological Association.)

Objective: CXCL6, a chemokine with proangiogenic property, is reported to be involved in vasculopathy associated with systemic sclerosis (SSc). We investigated the contribution of CXCL6 to SSc development by focusing on the association of friend leukemia virus integration 1 (Fli1) deficiency, a potential predisposing factor of SSc, with CXCL6 expression and clinical correlation of serum CXCL6 levels., Methods: mRNA levels of target genes and the binding of Fli1 to the CXCL6 promoter were evaluated by quantitative reverse transcription-PCR and chromatin immunoprecipitation, respectively. Serum CXCL6 levels were determined by ELISA., Results: FLI1 siRNA significantly enhanced CXCL6 mRNA expression in human dermal fibroblasts and human dermal microvascular endothelial cells, while Fli1 haploinsufficiency significantly suppressed CXCL6 mRNA expression in murine peritoneal macrophages stimulated with lipopolysaccharide. Supporting a critical role of Fli1 deficiency to induce SSc-like phenotypes, CXCL6 mRNA expression was higher in SSc dermal fibroblasts than in normal dermal fibroblasts. Importantly, Fli1 bound to the CXCL6 promoter in dermal fibroblasts, endothelial cells, and THP-1 cells. In patients with SSc, serum CXCL6 levels correlated positively with the severity of dermal and pulmonary fibrosis and were elevated in association with cardiac and pulmonary vascular involvement and cutaneous vascular symptoms, including Raynaud phenomenon, digital ulcers (DU)/pitting scars, and telangiectasia. Especially, serum CXCL6 levels were associated with DU/pitting scars and heart involvement by multiple regression analysis., Conclusion: CXCL6 expression is upregulated by Fli1 deficiency in fibroblasts and endothelial cells, potentially contributing to the development of fibrosis and vasculopathy in the skin, lung, and heart of SSc.

Cathepsin L (CTSL) is a lysosomal proteolytic enzyme involved in inflammation and vascular and extracellular matrix remodelling, which are the three cardinal pathological events associated with systemic sclerosis (SSc). To elucidate the potential role of CTSL in the development of SSc, we here investigated CTSL expression in the lesional skin of patients with SSc and SSc animal models and the clinical correlation of serum CTSL levels. CTSL expression was elevated in dermal small vessels of SSc patients compared with those of healthy controls. Consistently, CTSL mRNA levels were increased in SSc lesional skin samples, but not in cultivated SSc dermal fibroblasts, compared with corresponding control samples from healthy individuals. Serum CTSL levels were significantly higher in SSc patients than in healthy controls and inversely correlated with skin score. Furthermore, the elevation of serum CTSL levels was linked to SSc vasculopathy. Supporting these results, Ctsl mRNA levels were decreased in the skin of bleomycin-treated mice, an SSc animal model recapitulating its fibrotic aspect, and CTSL expression was enhanced in dermal small vessels of endothelial cell-specific Fli1 knockout mice, reminiscent of SSc vasculopathy. Importantly, gene silencing of FLI1 induced CTSL mRNA expression and Fli1 occupied the CTSL promoter in human dermal microvascular endothelial cells. Collectively, these results suggest that endothelial CTSL up-regulation partially due to Fli1 deficiency may contribute to the development of vasculopathy, while the decrease in dermal CTSL expression is likely associated with dermal fibrosis in SSc., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

H2S has been highlighted recently as an endogenous, gaseous signaling molecule, especially in inflammations. The deposition of IC induces an acute inflammatory response with tissue injury. To assess the roles of H2S in the IC-induced diseases, the cutaneous, reverse passive Arthus reaction was conducted using NaHS as a H2S donor. Furthermore, we conducted similar experiments using selectin(-/-) mice to determine the involvement of selectin molecules in the H2S-mediated pathway. Exogenous application of NaHS dramatically attenuated inflammatory reactions in WT mice associated with Arthus reaction. Namely, mRNA expressions of TNF-α, IFN-γ, and neutrophil numbers were reduced significantly in the lesional skins of NaHS-treated WT mice relative to untreated ones. NaHS treatment significantly reduced these three parameters in the lesional skins of E- and P-selectin(-/-) mice but not in those of L-selectin(-/-) mice. Quite similar results were obtained in the blocking study using WT mice injected with mAb to E-, P-, and L-selectin. Our results indicated that the exogenous application of NaHS attenuates inflammatory responses in reverse passive Arthus reaction through a L-selectin-involved pathway but not through E- or P-selectin pathways.

Objective: Patients with systemic sclerosis (SSc) exhibit enhanced production of free radicals due to ischemia and reperfusion injury following Raynaud's phenomenon, an initial clinical manifestation. Oxidative stress induces cytokine production, inflammatory cell recruitment, and tissue injury in several inflammatory diseases. The aim of this study was to examine the effect of edaravone, a free radical scavenger, on the development of fibrosis and autoimmunity in two different mouse models of SSc., Methods: The bleomycin-induced SSc model in mice and the tight skin mouse model were used to evaluate the effect of edaravone on fibrosis and immunologic abnormalities. To assess the reaction of fibroblasts to stimulation with free radicals, fibroblasts from these mice were cultured with NONOate, a nitric oxide-releasing agent, and hydrogen peroxide., Results: Treatment with edaravone reduced fibrosis in mice with bleomycin-induced SSc and in TSK/+ mice. The production of free radicals was also attenuated by edaravone in both models. In addition, production of fibrogenic cytokines such as interleukin-6 and transforming growth factor β1, production of anti-topoisomerase I antibody, and the degree of hypergammaglobulinemia were reduced by edaravone. Furthermore, bleomycin induced the production of H2O2 and nitric oxide from inflammatory cells, and collagen production was increased in fibroblasts cultured with H2O2 and NONOate., Conclusion: This study is the first to show that edaravone has a significant inhibitory effect on fibrosis both in the bleomycin-induced SSc model and in TSK/+ mice. These results indicate that edaravone should be further evaluated for potential use as an antifibrotic agent in SSc., (Copyright © 2011 by the American College of Rheumatology.)

To determine serum interleukin-33 (IL-33) levels and their associations with clinical parameters in patients with systemic sclerosis (SSc). Serum IL-33 levels were examined by enzyme-linked immunosorbent assay in 69 patients with SSc and 30 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (follow-up, 1-7 years). Serum IL-33 levels were elevated in SSc patients (261.7 ± 141.9 pg/ml) compared with healthy individuals (174.9 ± 72.4 pg/ml; P < 0.001). Patients with diffuse cutaneous SSc had higher levels of IL-33 (287.5 ± 146.6 pg/ml) than those with limited cutaneous SSc (221.5 ± 126.5 pg/ml; P < 0.05). Pulmonary fibrosis and decreased forced vital capacity were more commonly found in patients with elevated IL-33 levels than in those with normal IL-33 levels. IL-33 levels correlated positively with the extent of skin sclerosis, and inversely with percent predicted forced vital capacity. IL-33 levels were increased in SSc patients and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. Therefore, IL-33 possibly plays a role in cutaneous and pulmonary fibrosis in SSc patients.

Objective: Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice., Methods: Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts., Results: Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor beta1, was attenuated by rapamycin. Hypergammaglobulinemia and anti-topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner., Conclusion: This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients.

Objective: To determine serum concentrations of soluble CXCL16 and its clinical associations in patients with systemic sclerosis (SSc)., Methods: Serum CXCL16 levels from 89 patients with SSc were examined by ELISA. In a retrospective longitudinal study, 68 sera from 28 patients with SSc were analyzed (followup 1.3 to 7.3 yrs)., Results: Serum CXCL16 levels were elevated in patients with SSc compared with healthy controls (n = 42). Patients with diffuse cutaneous SSc (n = 52) had higher levels of CXCL16 than those with limited cutaneous SSc (n = 37). Serum CXCL16 levels correlated positively with the extent of skin sclerosis. In the longitudinal study, CXCL16 levels generally decreased on a parallel with the improvement in skin sclerosis., Conclusion: CXCL16 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis, suggesting that CXCL16 may have a role in the development of skin fibrosis in SSc. Blockade of CXCL16 interaction might be a potential therapeutic target in patients with SSc.

Introduction: The high mobility group box 1 protein (HMGB-1)/advanced glycation end products (RAGE) system is recently shown to play an important part in immune/inflammatory disorders. However, the association of this system in systemic sclerosis (SSc) remains unknown., Materials and Methods: To determine clinical association of serum levels of HMGB-1 and soluble RAGE (sRAGE) in patients with SSc, sera from 70 patients with SSc and 25 healthy controls were examined by enzyme-linked immunosorbent assay. Sera from tight-skin mice and bleomycin-induced scleroderma mice, animal models for SSc, were also examined. Skin HMGB-1 and RAGE expression was assessed by immunohistochemistry., Results and Discussion: Serum HMGB-1 and sRAGE levels in SSc were higher than those in controls. Similarly, HMGB-1 and sRAGE levels in animal SSc models were higher than those in control mice. SSc patients with elevated HMGB-1 and sRAGE levels had more frequent involvement of several organs and immunological abnormalities compared to those with normal levels. Furthermore, HMGB-1 and sRAGE levels correlated positively with modified Rodnan total skin thickness score and negatively with pulmonary function test., Conclusions: HMGB-1 and sRAGE expression in the sclerotic skin was more intense than normal skin. These results suggest that elevated serum HMGB-1 and sRAGE levels are associated with the disease severity and immunological abnormalities in SSc.

Objective: To determine any clinical association of serum levels of hyaluronan in patients with systemic sclerosis (SSc)., Methods: Hyaluronan levels in serum samples from patients with SSc (n = 66) and hyaluronan expression in skin were assessed., Results: Serum hyaluronan levels in SSc patients were higher than those in healthy controls. SSc patients with elevated hyaluronan levels had more frequent involvement of several clinical manifestations and immunological abnormalities compared to those with normal levels. Thus, hyaluronan levels correlated with disease severity. Hyaluronan expression in the sclerotic skin from SSc patients was more intense, relative to expression in normal skin., Conclusion: These results suggest that elevated serum hyaluronan levels are associated with disease severity and immunological abnormalities in patients with SSc.

Mice subcutaneously injected with bleomycin, in an experimental model of human systemic sclerosis, develop cutaneous and lung fibrosis with autoantibody production. CD19 is a general "rheostat" that defines signaling thresholds critical for humoral immune responses, autoimmunity, and cytokine production. To determine the role of CD19 in the bleomycin-induced systemic sclerosis model, we investigated the development of fibrosis and autoimmunity in CD19-deficient mice. Bleomycin-treated wild-type mice exhibited dermal and lung fibrosis, hyper-gamma-globulinemia, autoantibody production, and enhanced serum and skin expression of various cytokines, including fibrogenic interleukin-4, interleukin-6, and transforming growth factor-beta1, all of which were inhibited by CD19 deficiency. Bleomycin treatment enhanced hyaluronan production in the skin, lung, and sera. Addition of hyaluronan, an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, stimulated B cells to produce various cytokines, primarily through TLR4; CD19 deficiency suppressed this stimulation. These results suggest that bleomycin induces fibrosis by enhancing hyaluronan production, which activates B cells to produce fibrogenic cytokines mainly via TLR4 and induce autoantibody production, and that CD19 deficiency suppresses fibrosis and autoantibody production by inhibiting TLR4 signals.

As the clinical course of systemic sclerosis (SSc) varies widely, prognostic indicators have been sought to predict the outcomes of individual patients. Racial differences in SSc render it necessary to validate prognostic indicators in different patient cohorts. In this study, we aimed to assess clinical and laboratory parameters in Japanese patients with early‐stage SSc with diffuse cutaneous involvement and/or interstitial lung disease, and identify predictive factors for disease progression. We performed multivariate analyses of baseline clinical information to estimate symptoms 4 years later in Japanese patients with diffuse cutaneous SSc and/or SSc with interstitial lung disease. Patients were enrolled in the study within 5 years of disease onset at 10 Japanese SSc centers. Over 12 years, 115 patients followed up for 4 years were included in this study. The modified Rodnan skin score (mRSS) at 4 years correlated with the baseline mRSS and finger‐to‐palm distance, defined as the average length from the distal tip of the fourth finger to the distal palmar crease. The percentage predicted vital capacity (%VC) in year 4 positively and negatively correlated with initial %VC and the presence of anti‐topoisomerase I antibodies, respectively. The Health Assessment Questionnaire Disability Index (HAQ‐DI) at 4 years was positively and negatively associated with baseline HAQ‐DI and %VC, respectively. The occurrence of digital ulcers within 4 years was associated with the initial presence of digital ulcers, finger‐to‐palm distance, and the presence of digital pitting scars and anti‐topoisomerase I antibodies. This study identified several factors that may predict the progression of early‐stage SSc in Japanese patients. Finger‐to‐palm distance may be a useful tool for predicting the progression of skin thickening and the development of digital ulcers in the early stages of severe SSc, but larger, long‐term prospective studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

• RALDH1+CD11b−CD103− murine dermal DCs regulate skin fibrosis via Treg induction. • RALDH1-producing dermal DCs are decreased in the involved skin of SSc patients. • RALDH1-producing dermal DCs may regulate inducible Tregs in skin fibrotic disorders. Skin fibrosis of systemic sclerosis (SSc) is believed to be driven by complex processes including immune abnormalities, but the underlying immune response remains enigmatic. In particular, the role of dermal dendritic cells (DCs) is totally unknown. We investigated the impact of CD103 loss on bleomycin-induced skin fibrosis because CD103 is a critical molecule determining DC phenotypes. Bleomycin-induced skin fibrosis was generated with Cd103 −/− mice. The alterations of tissue fibrosis and related inflammation were investigated by histologic examination, hydroxyproline assay, quantitative reverse transcription PCR and flow cytometry. SSc skin samples were evaluated by immunofluorescence. CD103 loss decreased bleomycin-induced dermal thickness and collagen contents, along with TGF-β1 and CTGF suppression. Treg proportion was increased, while Th1/Th2/Th17 cell proportions were decreased in the skin of bleomycin-treated Cd103 −/− mice. Bleomycin injection enhanced CD11b-CD103- DC proportion in wild-type mice, which was further augmented in Cd103 −/− mice. Importantly, RALDH1/ALDH1A1 enzyme oxidizing retinaldehyde to retinoic acid, an inducer of Tregs, was preferentially expressed by CD11b-CD103- DCs and its expression levels were elevated in bleomycin-injected skin lesions, to a greater extent in Cd103 −/− mice than in wild-type mice. Importantly, the number of RALDH1-positive DCs was decreased in the lesional skin of SSc patients and tended to inversely correlate with skin fibrosis severity. This study identified a critical role of dermal DCs as a regulator of Treg development through RALDH1 in bleomycin-treated mice and possibly in human SSc. This finding sheds new light on dermal DCs as a new therapeutic target of SSc. [ABSTRACT FROM AUTHOR]