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Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc., Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

Cutaneous arteritis (CA) is necrotizing vasculitis invading the small- to medium-sized arteries of the skin. The majority of patients can be favorably managed by low- to medium-dose systemic corticosteroids (prednisolone

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) is myositis-specific autoantibody associated with rapidly progressive interstitial lung disease (ILD) and poor prognosis. In this retrospective observational study, we aimed to verify the efficacy and safety of introducing combined immunosuppressive therapy for anti-MDA5 Ab-positive dermatomyositis (DM) from their early stage. We recruited all Japanese patients diagnosed with DM in our clinic between January 2011 and October 2018, who had anti-MDA5 Ab, anti-aminoacyl transfer RNA synthetase Ab or anti-transcriptional intermediary factor 1-γ Ab. Combined immunosuppressive therapy was defined as combination of systemic corticosteroids, i.v. cyclophosphamide and tacrolimus. The difference of clinical features among the three groups was analyzed by multiple comparison analysis. The longitudinal change of the measurements from baseline was examined by Wilcoxon signed-rank test. Association between therapeutic regimens and adverse events was examined by logistic regression analysis. As a result, combined immunosuppressive therapy was most frequently used in the anti-MDA5 Ab-positive group, which significantly improved their forced vital capacity of the lung. Interval time since initial visit until starting treatment was the shortest in the anti-MDA5 Ab-positive group. There was no significant difference in the incidence of death and recurrence among the three groups. Cytomegalovirus reactivation was most common in the anti-MDA5 Ab-positive group, associated with combined immunosuppressive therapy. Collectively, early introduction of combined immunosuppressive therapy was effective for DM patients with anti-MDA5 Ab. At the same time, clinicians should be aware of the risk of cytomegalovirus reactivation during the treatment.

The benefit of rituximab (RTX) for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has been shown in previous clinical trials. However, predictors of RTX efficacy have not been clarified. We investigated whether B-cell responsiveness to RTX is related to therapeutic effect. Ten SSc-ILD patients treated with RTX in an independent clinical trial (Japan Registry of Clinical Trials, jRCTs031180373) were included in this analysis. Peripheral B-cell counts were examined retrospectively before RTX administration (baseline) and at 2, 4, 12, and 24 weeks after the first RTX administration, along with percent-predicted forced vital capacity (%FVC) before and 24 weeks after RTX treatment. Relative to baseline, the percentage of residual peripheral blood B cells at 2 weeks after RTX was negatively correlated with the %FVC improvement at the 24-week assessment (r = -0.41, p = 0.04). In the subgroup with less than 5% B-cell persistence at week 2, %FVC at the 24-week assessment was significantly improved compared to baseline (p = 0.02). In another subgroup with more than 5% residual B cells, %FVC was not significantly different after 24 weeks compared to baseline (p = 0.41). In conclusion, the removal rate of B cells after 2 weeks of RTX treatment may be a useful surrogate marker of subsequent SSc-ILD improvement.

Background: Sarcoidosis is a relatively rare, systemic granulomatous disease that occurs in approximately 1–40 per 100,000 individuals but affects Japanese people disproportionately. While sarcoidosis may affect any organ, morbidity and mortality is worst for cases of cardiac sarcoidosis, which is also difficult to diagnose. In this study, we investigated whether cutaneous sarcoidosis, particularly cutaneous sarcoidosis of the face, which is visible and more easily diagnosable, can be a predictor for the development of cardiac sarcoidosis. Method: We retrospectively examined patients with cutaneous sarcoidosis seen at the Department of Dermatology at the JR Tokyo General Hospital and the Department of Dermatology at the University of Tokyo Hospital between April 1, 2005 and March 31, 2019. Results: Our study found that sarcoid lesions on the face increased the risk for cardiac sarcoidosis (p = 0.0090, odds ratio 20), whereas, sarcoid lesions on the extremities decreased the risk for cardiac sarcoidosis (p = 0.0387, odds ratio 0.0961). Conclusion: Cutaneous sarcoidosis of the face is a strong predictor of cardiac sarcoidosis.

Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis and vasculopathy of the skin and internal organs against a background of autoimmune abnormalities. In recent years, the importance of the interleukin (IL)-17 family for inflammatory diseases has received much attention, but autoimmune diseases have not yet been fully explored. As for SSc, there is also no unified perspective on the involvement of the IL-17 family in its development, and few studies have been conducted linking IL-17F and IL-17E particularly to the disease severity. In the present study, we examined the correlation between serum IL-17F and IL-17E levels and disease severity in SSc patients. Moreover, the expression of the receptors for these cytokines, IL-17RB and IL-17RC, in skin tissues obtained by skin biopsy was examined by immunohistochemistry. Both cytokines were significantly elevated in the sera of patients with diffuse cutaneous SSc patients compared with healthy controls. Serum IL-17F levels correlated with modified Rodnan total skin thickness score, a semiquantitative measure of skin sclerosis, percent predicted forced vital capacity, percent predicted carbon monoxide lung diffusion capacity and serum levels of Krebs von den Lungen-6 and surfactant protein-D, serological markers of interstitial lung disease. Serum IL-17E levels were significantly correlated with percent predicted forced vital capacity and serum Krebs von den Lungen-6 levels. Serum levels of IL-17F and IL-17E also correlated with the prevalence of digital ulcers, and serum IL-17F levels were associated with elevated right ventricle systolic pressure values. In addition, IL-17RC and IL-17RB expression was increased in the skin tissues of diffuse cutaneous SSc patients. These results suggested that IL-17F and IL-17E could be involved in fibrosis and vasculopathy in SSc through their respective receptors in the affected organ tissues.

Coexistence of anti-topoisomerase (topo) I antibody (Ab) and anti-U1 ribonucleoprotein (RNP) Ab is occasionally observed among patients with systemic sclerosis (SSc). To clarify the clinical significance of anti-U1 RNP Ab in patients with anti-topo I Ab-positive SSc, we conducted a retrospective review of SSc patients initially arrived at our clinic since April 2011 until March 2020. Serum levels of anti-topo I Ab were examined by enzyme-linked immunosorbent assay, and anti-topo I Ab-positive patients were recruited into the study. Serum anti-U1 RNP Ab positivity was explored by chemiluminescent enzyme immunoassay. In total, 92 patients were enrolled into our study. Of these, 11 cases were anti-U1 RNP Ab-positive (anti-U1RNP+) and 81 patients were anti-U1 RNP Ab-negative (anti-U1RNP-). Age of SSc onset was significantly lower in anti-U1RNP+ group than in anti-U1RNP- group (median [25-75th percentiles], 26.8 [20.3-39.6] vs 45.1 [31.5-56.8] years, P < 0.01). Additionally, serum levels of anti-topo I Ab were significantly higher among anti-U1RNP+ patients compared to the others (166 [124-195] vs 135 [104-174] U/mL, P < 0.05). Moreover, concurrence of systemic lupus erythematosus and Sjogren’s syndrome was more common in anti-U1RNP+ group than in anti-U1RNP- group (45.5% vs 1.2%, P < 0.001; 54.5% vs 12.3%, P < 0.01). In conclusion, anti-U1 RNP Ab is associated with early disease onset, reduced vital capacity of the lung, and concurrence of systemic lupus erythematosus and Sjogren’s syndrome among SSc patients with anti-topo I Ab.

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD.