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.
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.
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-c 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.
Objective We undertook this study to investigate the effect of B cell depletion on fibrosis in systemic sclerosis (SSc) and its mechanism of action. Methods Mice with bleomycin‐induced SSc (BLM‐SSc) were treated with anti‐CD20 antibody, and skin and lung fibrosis were histopathologically evaluated. T cells and macrophages were cocultured with B cells, and the effect of B cells on their differentiation was assessed by flow cytometry. We also cocultured B cells and monocytes from SSc patients and analyzed the correlation between fibrosis and profibrotic macrophage induction by B cells. Results B cell depletion inhibited fibrosis in mice with BLM‐SSc. B cells from mice with BLM‐SSc increased proinflammatory cytokine–producing T cells in coculture. In mice with BLM‐SSc, B cell depletion before BLM treatment (pre‐depletion) inhibited fibrosis more strongly than B cell depletion after BLM treatment (post‐depletion) (P < 0.01). However, the frequencies of proinflammatory T cells were lower in the post‐depletion group than in the pre‐depletion group. This discrepancy suggests that the effect of B cell depletion on fibrosis cannot be explained by its effect on T cell differentiation. On the other hand, profibrotic macrophages were markedly decreased in the pre‐depletion group compared to the post‐depletion group (P < 0.05). Furthermore, B cells from mice with BLM‐SSc increased profibrotic macrophage differentiation in coculture (P < 0.05). In SSc patients, the extent of profibrotic macrophage induction by B cells correlated with the severity of fibrosis (P < 0.0005). Conclusion These findings suggest that B cell depletion inhibits tissue fibrosis via suppression of profibrotic macrophage differentiation in mice with BLM‐SSc, providing a new rationale for B cell depletion therapy in SSc.
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