Treatment Of Systemic Sclerosis Research Articles

The use of “Acellbia” – a biosimilar of rituximab in systemic sclerosis

Introduction. The possibilities of modern therapy for systemic sclerosis (SSc) remains limited, since most of the used drugs do not have a diseasemodifying effect. This encourages the study of new approaches that potentially affect the fundamental pathological processes underlying the disease. One example is anti-B cell therapy, in particular rituximab (RTX). Until now RTX do not have a registration for the treatment of SSc, but there is a large positive experience of its use, which is reflected in recent meta-analyses and clinical recommendations. Complicated and expensive methods for obtaining genetically engineered biological preparations have contributed to the emergence of more accessible biosimilars, one of which is the RTX biosimilar, Acellbia (Biocad, Russian Federation). The “biosimilar” versions of RTX might reduce the cost of therapy and increase patients accessibility to this treatment option. The RTX biosimilar Acellbia (ACB) has received approval in Russian Federation in 2014 for all indications held by reference RTX (including rheumatoid arthritis and ANCA-associated vasculitis).The aim of this study was to investigate the efficacy and safety of Acellbia in patients with systemic sclerosis.Material and methods. Our prospective uncontrolled study included 20 patients (14 women) aged 50±14 years, with a disease duration of 3.5±2.7 years. Indications for the prescribing of ACB were high disease activity and the presence of risk factors for progression. All patients had radiological signs of interstitial lung disease, 13 (65%) were positive for antibodies to topoisomerase 1. None of the patients had previously been treated with biological therapy. All patients received glucocorticoids in low doses and 15 (75%) patients were not on concomitant immunosuppressants during the study. ACB was administered in doses of 2 g (two doses of 1 g with a weekly interval) at inclusion of the study and after 6–8 months according to the same scheme, cumulative dose – 4 g. An assessment of basic measurements was obtained at baseline (Point 0), before the second course (after 7.2±1.7 mo, Point 1) and at the end of follow-up (13.4±1.6 mo, Point 2). The results are presented in the form of mean values and standard deviations.Results. There was a positive effect on the main manifestations of the disease, which accompanied by stable depletion of CD19+ B lymphocytes in the peripheral blood. At the intermediate assessment (between points 0–1), no significant changes were observed, with the exception of the skin score. At the end of the study, most of the parameters showed a significant improvement between points 0–2. The activity of the disease (EScSG-AI) decreased, and the skin score decreased from 12.8±11 to 6.2±5.6 (p=0.002). The forced vital capacity (% of predicted) increased from 89±18.2 to 98.26±16.13% (p=0.0002), and the diffusion capacity of the lungs (% of predicted) increased from 56.8±15.7 to 61.9±17.2% (p<0.019). A significant decrease in CRP, antitopoisomerase-1 antibodies, as well as IgG (from 12.6±2.6 to 10.2±2.2 g/l) was noted. Repopulation to normal level of B lymphocytes did not occur in any case, and complete depletion of B lymphocytes at the end of the study was maintained in 83% of patients (15 of 18). The quality of life questionnaire SHAQ improved (p=0.0001), and the average dose of prednisolone was reduced from 11.0±2.7 to 9.4±2.3 mg/day (p=0.03). Positive changes according to HRCT was evident in 9 (45%) patients due to a decrease in ground glass opacity. The frequency and spectrum of adverse events (AEs) corresponded to those already known for RTX. Of the 20 patients who received 2 courses of ACB, two withdrew from the evaluation at Point 2 due to pregnancy (1) and lung cancer (1). A total of 11 (55%) AEs were reported in 9 (45%) patients, most of them were classified as mild. Infectious complications developed in 7 (35%) patients: respiratory infections of the upper respiratory tract (4), positivity in the TB skin test (2), otitis (1), cystitis (1) and cholecystitis (1). One patient developed calf vein thrombosis and lung cancer was diagnosed in one case.Conclusion. Our data suggest that Acellbia could be used for the treatment of SSc. A short-term, prospective, uncontrolled study showed good efficacy and acceptable safety of the ACB biosimilar in SSc. A significant decrease of skin fibrosis and improvement of lung functions have been proven. The clinical effect of ACB manifested by the 6th month from the start of therapy and reached its maximum one year after its initiation. Due to the positive efficacy of ACB, it can be prescribed for the patients with SSc with ineffectiveness and/or intolerance to immunosuppressants, and could be considered as a first-line therapy. Our data should be confirmed by the results of controlled clinical trials.

Emerging cellular and immunotherapies for systemic sclerosis: from mesenchymal stromal cells to CAR-T cells and vaccine-based approaches.

Although two targeted therapies have received recent approval for systemic sclerosis (SSc)-associated interstitial lung disease, they do not show major disease-modifying activity, highlighting the need for novel therapies and innovative paradigms. To that end, cellular therapies may represent a new opportunity for the treatment of SSc. The purpose of this review is to provide an up-to-date overview of emerging cell-based disease-modifying therapies in SSc. Initial small studies in patients with severe refractory systemic lupus erythematosus (SLE) using engineered regulatory cells show promising results. CD19-directed CAR-T have shown promising results in one case report of refractory diffuse cutaneous SSc patients. T cells engineered to express a chimeric autoantibody receptor (CAAR-T cells) may be even more relevant via the specific elimination of auto-reactive B cells. Targeting pro-fibrotic or senescence-related pathways may also constitute promising approaches in SSc. Building on the classification of the clinical phenotype and prediction of clinical trajectory based on individual patients' autoantigen and/or autoantibody profile, cellular therapies targeting the same autoantigen or related autoreactive cells may represent an unprecedented opportunity to implement personalized medicine in SSc.

Treatable Traits in Systemic Sclerosis.

Systemic sclerosis (SSc) is a chronic systemic disease within the spectrum of connective tissue diseases, specifically characterized by vascular abnormalities and inflammatory and fibrotic involvement of the skin and internal organs resulting in high morbidity and mortality. The clinical phenotype of SSc is heterogeneous, and serum autoantibodies together with the extent of skin involvement have a predictive value in the risk stratification. Current recommendations include an organ-based management according to the predominant involvement with only limited individual factors included in the treatment algorithm. Similar to what has been proposed for other chronic diseases, we hypothesize that a "treatable trait" approach based on relevant phenotypes and endotypes could address the unmet needs in SSc stratification and treatment to maximize the outcomes. We provide herein a comprehensive review and a critical discussion of the literature regarding potential treatable traits in SSc, focusing on established and candidate biomarkers, with the purpose of setting the bases for a precision medicine-based approach. The discussion, structured based on the organ involvement, allows to conjugate the pathogenetic mechanisms of tissue injury with the proposed predictors, particularly autoantibodies and other serum biomarkers. Ultimately, we are convinced that precision medicine is the ideal guide to manage a complex condition such as SSc for which available treatments are largely unsatisfactory.

A randomized clinical trial of bermekimab treatment for clinical improvement of systemic sclerosis

Increased concentrations of interleukin (IL)-1α have been recently described in tissues of patients with systemic sclerosis (SSc) suggesting that IL-1α inhibition may be a target for treatment. We conducted a double-blind, placebo-controlled study to assess the safety and efficacy of the fully humanized IL-1α blocking monoclonal antibody bermekimab in SSc. To evaluate response to treatment, we developed the score of inhibition of progression of SSc which was validated using the CRISS index and the modified CRISS index. The primary endpoint was met in 80% of bermekimab-treated patients vs. 20% of placebo-treated patients (p: 0.023). Most of efficacy was found for increase of carbon monoxide lung diffusion capacity. Production of IL-1α and TNF by circulating mononuclear cells was decreased and the absolute count of CD42/Cd62-platelets was decreased. Results suggest that bermekimab is a promising treatment for SSc.

ATRA ameliorates fibrosis by suppressing the pro-fibrotic molecule Fra2/AP-1 in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.

The Role of CCL24 in Systemic Sclerosis.

Systemic sclerosis (SSc) is a chronic immune-mediated disease characterized by microangiopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Though not fully understood, the pathogenesis of SSc is dominated by microvascular injury, endothelial dysregulation, and immune response that are thought to be associated with fibroblast activation and related fibrogenesis. Among the main clinical subsets, diffuse SSc (dSSc) is a progressive form with rapid and disseminated skin thickening accompanied by internal organ fibrosis and dysfunction. Despite recent advances and multiple randomized clinical trials in early dSSc patients, an effective disease-modifying treatment for progressive skin fibrosis is still missing, and there is a crucial need to identify new targets for therapeutic intervention. Eotaxin-2 (CCL24) is a chemokine secreted by immune cells and epithelial cells, which promotes trafficking of immune cells and activation of pro-fibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the skin and sera of patients with SSc compared with healthy controls; elevated levels of CCL24 and CCR3 were associated with fibrosis and predictive of greater lung function deterioration. Growing evidence supports the potency of a CCL24-blocking antibody as an anti-inflammatory and anti-fibrotic modulating agent in multiple preclinical models that involve liver, skin, and lung inflammation and fibrosis. This review highlights the role of CCL24 in orchestrating immune, vascular, and fibrotic pathways, and the potential of CCL24 inhibition as a novel treatment for SSc.

Pharmacological inhibition of TAK1 prevents and induces regression of experimental organ fibrosis.

Multi-organ fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of transforming growth factor-β (TGF-β) and toll-like receptor (TLR) signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc, and investigate pharmacological TAK1 blockade using a novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc, and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.

Systemic sclerosis associated myopathy: how to treat.

Systemic sclerosis (SSc) and myositis are two different entities that may coexist as an overlap syndrome. Immunological biomarkers such as anti-PM/Scl or anti-Ku reinforce the syndrome. This review is focused on the treatment of different and characteristic manifestations of this syndrome. Among the different phenotypes of muscle involvement in patients with SSc, the fibrotic pattern and the sporadic inclusion body myositis must be identified early to avoid a futile immunosuppressive treatment. Other forms such as dermatomyositis, non-specific myositis and immune-mediated necrotizing myopathy need to receive conventional immunosuppressive therapy considering that high dose of glucocorticoids may induce a scleroderma renal crisis in patients with SSc. Physicians must be aware of the existence of a "double trouble" association of hereditary myopathy with an autoimmune phenomenon. Several autoantibodies, mainly anti-PM/Scl and anti-Ku may help to define specific phenotypes with characteristic clinical manifestations that need a more specific therapy. Vasculopathy is one of the underlying mechanisms that link SSc and myositis. Recent advances in this topic are reviewed. Current treatment of SSc associated myopathy must be tailored to specific organs involved. Identifying the specific clinical, pathological, and immunological phenotypes may help to take the correct therapeutic decisions.

VITAMIN D3 AND Α-TOCOPHEROL ACETATE AMELIORATE INFLAMMATORY AND FIBROTIC PROCESSES IN SYSTEMIC SCLEROSIS: PRECLINICAL EVIDENCE

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vascular abnormalities. Despite extensive research, there is currently no effective treatment for SSc. This study aimed to investigate the effects of α-tocopherol acetate and vitamin D3 on the levels of surfactant protein D (SP-D), interleukin-13 (IL-13), and vascular cell adhesion molecule-1 (VCAM-1) in a preclinical model of SSc.
 The study included an intact group (IG) (15 animals) with no interventions, control group (CG) (20 animals) injected with isotonic solution, an experimental group #1 (EG#1) (25 animals) that were induced with SSc by injecting them subcutaneously with 0.5 ml of 5% (NaClO) three times a week for six consecutive weeks; and experimental group #2 (EG#2) (25 animals) with correction provided by injections of vitamin D (1000 IU / 100 g) and α-tocopherol acetate (10 mg / 100 g ) intramuscularly for 3 weeks.
 The serum concentrations of IL-13, SP-D, and VCAM-1 were significantly higher in the EG#1 compared to the control group (109.35 (93,23-199.05) vs 8.50 (5.60-14.20), p=0.004; 490.20 (156.20-605.70) vs 78.10 (40.80-100.40), p=0.004; 91.25 (85.00 -264.98) vs 19.50 (13.53-22.20), p=0.004 respectively). The administration of vitamin D3 and α-tocopherol acetate was found to have a positive effect on all three parameters investigated. The SP-D level in the EG#2 was significantly lower than that in the EG#1 (490.20 (156.20-605.70) vs 123.75 (108.80-145.03), p=0.004). The concentration of IL-13 and VCAM-1 were also lower in the EG#2.
 In conclusion, this study provides evidence of the beneficial effects of vitamin D3 and α-tocopherol acetate in reducing the levels of SP-D, IL-13, and VCAM-1 in a preclinical model of systemic sclerosis.

Iguratimod as an alternative therapy for systemic sclerosis and prevention of the occurrence of ischemic digital ulcer.

This study aimed to assess the effectiveness of iguratimod (IGU) as an alternative treatment for systemic sclerosis (SSc), especially in the prevention of ischemic digital ulcers (DUs). We constructed two cohorts from the Renji SSc registry. In the first cohort, SSc patients receiving IGU were observed prospectively with effectiveness and safety. In the second cohort, we picked up all the DU patients with at least a 3-month follow-up to investigate the prevention of IGU on ischemic DU. From 2017 to 2021, 182 SSc patients were enrolled in our SSc registry. A total of 23 patients received IGU. With a median follow-up of 61 weeks (IQR: 15-82 weeks), the drug persistence was 13/23. In total, 91.3% of the patients (21/23) became free of deterioration in the last visit with IGU. Of note, 10 patients withdrew from the study due to the following reasons: two patients withdrew due to deterioration, three due to incompliance, and five due to mild-to-moderate side effects. All the patients with side effects recovered fully after stopping IGU. Of note, 11 patients had ischemic DU, and 8 out of 11 (72.7%) patients had no new occurrence of DU during the follow-up. In the second cohort of 31 DU patients receiving a combination of vasoactive agents with a median follow-up of 47 weeks (IQR, 16-107 weeks), IGU treatment was protective of new DU occurrence (adjusted risk ratio = 0.25; 95% CI, 0.05-0.94; adjusted odds ratio = 0.07; and 95% CI, 0.01-0.49). Our study for the first time describes the potential of IGU possibly as an alternative treatment for SSc. To our surprise, this study provides a hint that IGU treatment can be used for the prevention of the occurrence of ischemic DU and merits further investigation.

Role of rituximab in the treatment of systemic sclerosis: A literature review.

To evaluate the effectiveness of rituximab (RTX) in patients with systemic sclerosis (SSc). PubMed was searched for articles, published through March 31, 2022, on any controlled studies using RTX in the treatment of SSc. Of 85 identified articles, nine were selected by title/abstract screening and full text examination. All nine articles reported outcomes of forced vital capacity (%FVC), and seven reported those of modified Rodnan skin scores (mRSS). Among the seven controlled studies evaluating skin lesions in patients with SSc, four showed a significant improvement of mRSS by RTX when compared with a control group, whereas three show no significant effect. Among the nine controlled studies evaluating lung lesions, five showed a significant improvement of %FVC compared with a control group, whereas four showed no significant effect. RTX may be effective in the treatment of skin and lung lesions in patients with SSc. The profiles of SSc patients for whom RTX is indicated were unclear, although patients with diffuse cutaneous SSc and those positive for anti-topoisomerase I antibody were considered potential targets. Additional studies are needed to assess the long-term effectiveness of RTX in the treatment of patients with SSc.

Identification of Mechanisms by Which Genetic Susceptibility Loci Influence Systemic Sclerosis Risk Using Functional Genomics in Primary T Cells and Monocytes.

Systemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the genes associated with the disease are still unknown because associated variants affect mostly noncoding intergenic elements of the genome. We used functional genomics to translate the genetic findings into a better understanding of the disease. Promoter capture Hi-C and RNA-sequencing experiments were performed in CD4+ T cells and CD14+ monocytes from 10 SSc patients and 5 healthy controls to link SSc-associated variants with their target genes, followed by differential expression and differential interaction analyses between cell types. We linked SSc-associated loci to 39 new potential target genes and confirmed 7 previously known SSc-associated genes. We highlight novel causal genes, such as CXCR5, as the most probable candidate gene for the DDX6 locus. Some previously known SSc-associated genes, such as IRF8, STAT4, and CD247, showed cell type-specific interactions. We also identified 15 potential drug targets already in use in other similar immune-mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions were directly correlated with the expression of important genes implicated in cell type-specific pathways and found evidence that chromatin conformation is associated with genotype. Our study revealed potential causal genes for SSc-associated loci, some of them acting in a cell type-specific manner, suggesting novel biologic mechanisms that might mediate SSc pathogenesis.

Advances in biological and targeted therapies for systemic sclerosis

Introduction Systemic sclerosis (SSc) is a severe, and often life-threatening, autoimmune disease which causes inflammation and fibrosis of the skin and internal organs. There are currently limited effective therapeutic options for patients with SSc. There are recently completed and ongoing phase 2 and 3 studies looking at biologic therapies for SSc that target underlying pathogenesis of the disease. Areas covered The purpose of this review is to describe completed and ongoing trials of different biologic therapies for the treatment of SSc. This review discusses biologic therapy directed at multiple pathways that are believed to contribute to inflammation and fibrosis in SSc including T cell, B cell, direct cytokines, and JAK signaling. Data presented is based on authors’ expertise of completed and ongoing trials. Expert opinion Tocilizumab and rituximab have supporting data to advocate for use in early SSc. Data from tocilizumab showed preservation of forced vital capacity (FVC) and beneficial effects on global composite measure. Recent data from different trials with rituximab in SSc (with and without interstitial lung disease) show beneficial effects on skin and FVC with good tolerability. We highlight the molecular heterogeneity in early SSc phenotype and the need to account for this in future trials.

State-of-the-art evidence in the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Identification of lncRNA-miRNA-mRNA networks in circulating exosomes as potential biomarkers for systemic sclerosis.

This study aimed to analyze potential biomarkers for systemic sclerosis (SSc) by constructing lncRNA-miRNA-mRNA networks in circulating exosomes (cirexos). Differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in SSc cirexos were screened using high-throughput sequencing and detected with real-time quantitative PCR (RT-qPCR). Differentially expressed genes (DEGs) were analyzed using the DisGeNET, GeneCards, GSEA4.2.3, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Receiver operating characteristic (ROC) curves, correlation analyses, and a double-luciferase reporter gene detection assay were used to analyze competing endogenous RNA (ceRNA) networks and clinical data. In this study, 286 DEmRNAs and 192 DElncRNAs were screened, of which 18 DEGs were the same as the SSc-related genes. The main SSc-related pathways included extracellular matrix (ECM) receptor interaction, local adhesion, platelet activation, and IgA production by the intestinal immune network. A hub gene, COL1A1, was obtained by a protein-protein interaction (PPI) network. Four ceRNA networks were predicted through Cytoscape. The relative expression levels of COL1A1, ENST0000313807, and NON-HSAT194388.1 were significantly higher in SSc, while the relative expression levels of hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p were significantly lower in SSc (P < 0.05). The ROC curve showed that the ENST00000313807-hsa-miR-29a-3p-COL1A1 network as a combined biomarker of SSc is more valuable than independent diagnosis, and that it is correlated with high-resolution CT (HRCT), Scl-70, C-reactive protein (CRP), Ro-52, IL-10, IgM, lymphocyte percentage, neutrophil percentage, albumin divided by globulin, urea, and RDW-SD (P < 0.05). Double-luciferase reporter gene detection showed that ENST00000313807 interacts with hsa-miR-29a-3p, which interacts with COL1A1. The ENST00000313807-hsa-miR-29a-3p-COL1A1 network in plasma cirexos represents a potential combined biomarker for the clinical diagnosis and treatment of SSc.

Long-term Outcomes After Rituximab Treatment for Patients With Systemic Sclerosis

Rituximab is emerging as a promising therapeutic option for systemic sclerosis (SSc), but its long-term outcomes and response markers are unknown. To evaluate the long-term outcomes after rituximab treatment for SSc and identify potential response markers. In this single-center cohort study, patients with SSc who continued to receive rituximab after the DESIRES trial were analyzed with a median follow-up of 96 weeks. Among the 43 patients who completed the DESIRES trial, 31 continued to receive rituximab, of which 29 with complete data were included in this study. Rituximab treatment. A post hoc analysis of the clinical and laboratory data. In 29 patients with SSc (27 female [93%]; median [IQR] age, 48 [35-45] years), significant improvement in modified Rodnan skin score (MRSS) and percentage of predicted forced vital capacity (FVC%) were observed after 1 (median [IQR] change in MRSS, -7 [-8.5 to -4]; P < .001) and 3 (median [IQR] change in FVC% predicted, 1.85 [0.13-5.68]; P < .001) courses of rituximab, respectively, both of which were sustained during follow-up. High responders (MRSS improvement of ≥9; n = 16) experienced a greater decrease in serum levels of IgG (median [IQR] change in IgG, -125 [-207 to -83] vs 7 [-120 to 43]; P = .008) and IgA (median [IQR] change in IgA, -45 [-96 to -32] vs -11 [-20 to 3]; P < .001) compared with low responders (MRSS improvement of ≤8; n = 13). In particular, decrease in serum IgA levels significantly correlated with the improvement in MRSS (r = 0.64; P < .001). At the last follow-up, low IgM, low IgA, and low IgG was observed in 7, 1, and 1 patient, respectively, of which low IgM was associated with greater improvement in FVC% predicted (median [IQR] change in FVC% predicted, 7.2 [3.8-8.9] vs 3.6 [1.4-6.2]; P = .003). In this cohort study, rituximab treatment was associated with significantly improved skin and lung fibrosis in SSc in a long-term follow-up. Decrease in serum immunoglobulins was associated with greater clinical response.

Autologous fat or adipose-derived stem cell grafting in systemic sclerosis treatment: a systematic review and meta-analysis.

Systemic sclerosis (SSc) is characterised by vasculopathy and progressive fibrosis of the skin. The aim of this article is to analyse and summarise the efficacy and safety of autologous fat (AF), stromal vascular fraction (SVF) and adipose-derived stem cell (ADSC) grafting in the treatment of SSc, providing evidence for clinical application. The research involves the efficacy and safety of AF, SVF and ADSC grafting in the treatment of patients with SSc. The studies were screened and selected independently by two authors based on pre-specified criteria. The data extraction and quality assessment were also performed independently by two authors. Fifteen studies were eligible for inclusion. Skin thickness reduced following SVF or AF therapy, but there was no significant difference. All measures used to assess fingertip symptoms revealed a significant improvement. Notably, SVF and AF were found to have the most impact on Raynaud's phenomenon improvement. The ADSC group improved the most in terms of finger pain alleviation. SVF reported the highest proportion of adverse events, accounting for approximately half of the cases. AF, SVF, and ADSC all displayed therapeutic effects of improving SSc, but differences existed in the effects on different symptoms. Plastic surgeons should choose the most suitable treatment strategy after comprehensively evaluating the patient's clinical manifestations.

Nuclear IL-33 in Fibroblasts Promotes Skin Fibrosis

Systemic sclerosis (SSc) is a complex and poorly understood connective tissue disease characterized by diffuse fibrosis in several organs, especially the skin ( Asano, 2017 Asano Y. Recent advances in the treatment of skin involvement in systemic sclerosis. Inflamm Regen. 2017; 37: 12 Crossref Scopus (6) Google Scholar , Bhattacharyya et al., 2012 Bhattacharyya S. Wei J. Tourtellotte W.G. Hinchcliff M. Gottardi C.G. Varga J. Fibrosis in systemic sclerosis: common and unique pathobiology. Fibrogenesis Tissue Repair. 2012; 5: S18 Crossref Scopus (30) Google Scholar , Denton et al., 2006 Denton C.P. Black C.M. Abraham D.J. Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol. 2006; 2: 134-144 Crossref Scopus (156) Google Scholar ). Interleukin (IL)-33 is found to regulate tissue fibrosis in multiple organs ( Kotsiou et al., 2018 Kotsiou O.S. Gourgoulianis K.I. Zarogiannis S.G. IL-33/ST2 Axis in Organ Fibrosis. Frontiers in immunology. 2018; 9: 2432 Crossref PubMed Scopus (96) Google Scholar , Xu et al., 2016 Xu J. Zheng J. Song P. Zhou Y. Guan S. IL33/ST2 pathway in a bleomycininduced pulmonary fibrosis model. Mol Med Rep. 2016; 14: 1704-1708 Crossref Scopus (13) Google Scholar ). However, the exact role of IL-33 in fibrosis remains controversial ( Kotsiou et al., 2018 Kotsiou O.S. Gourgoulianis K.I. Zarogiannis S.G. IL-33/ST2 Axis in Organ Fibrosis. Frontiers in immunology. 2018; 9: 2432 Crossref PubMed Scopus (96) Google Scholar ). Previous studies have shown a pro-fibrotic role for IL-33 cytokine through its receptor, interleukin-1 receptor-like 1(IL1RL1 or ST2), regulating the secretion of pro-fibrotic cytokine, IL-13, from eosinophils, M2 macrophages and type 2 innate lymphoid cells (ILC2) ( Li et al., 2014 Li D. Guabiraba R. Besnard A.G. Komai-Koma M. Jabir M.S. Zhang L. et al. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. The Journal of allergy and clinical immunology. 2014; 134: 1422-1432 e11 Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar , Rankin et al., 2010 Rankin A.L. Mumm J.B. Murphy E. Turner S. Yu N. McClanahan T.K. et al. IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol. 2010; 184: 1526-1535 Crossref PubMed Scopus (188) Google Scholar , Wu et al., 2018 Wu L. Luo Z. Zheng J. Yao P. Yuan Z. Lv X. et al. IL-33 Can Promote the Process of Pulmonary Fibrosis by Inducing the Imbalance Between MMP-9 and TIMP-1. Inflammation. 2018; 41: 878-885 Crossref PubMed Scopus (30) Google Scholar ). However, IL-33 can also play an anti-fibrotic role through the induction of ILC2 cells and regulatory T cells in several organs including the skin ( Cheon et al., 2022 Cheon S.Y. Park J.H. Ameri A.H. Lee R.T. Nazarian R.M. Demehri S. IL-33/Regulatory T-Cell Axis Suppresses Skin Fibrosis. The Journal of investigative dermatology. 2022; Google Scholar , Garbern et al., 2019 Garbern J.C. Williams J. Kristl A.C. Malick A. Rachmin I. Gaeta B. et al. Dysregulation of IL-33/ST2 signaling and myocardial periarteriolar fibrosis. J Mol Cell Cardiol. 2019; 128: 179-186 Abstract Full Text Full Text PDF Scopus (12) Google Scholar , Riedel et al., 2017 Riedel J.H. Becker M. Kopp K. Duster M. Brix S.R. Meyer-Schwesinger C. et al. IL-33-Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis. J Am Soc Nephrol. 2017; 28: 2068-2080 Crossref Scopus (71) Google Scholar ). Thus, it is critical to determine the full spectrum of IL-33 effect in fibrosis to develop optimal therapies for its utilization in the treatment of SSc and other fibrosis-associated diseases.

Comprehensive analysis of ferroptosis-related hub gene signatures as a potential pathogenesis and therapeutic target for systemic sclerosis: A bioinformatics analysis.

Introduction: The molecular mechanism of systemic sclerosis (SSc) remains unclear. Ferroptosis participates in a series of cell activities, such as inflammatory progression, by regulating cell death; unfortunately, there aren't many research that discuss the connection between ferroptosis and SSc.Objectives: This study used bioinformatics analysis to report a potential relationship between ferroptosis and SSc.Methods: The SSc and control datasets GSE125362 and GSE76807 were obtained from the gene expression omnibus database. The differentially expressed genes (DEGs) were identified using the R software. By the Venn diagram, ferroptosis DEGs were detected. The chosen candidate genes were then subjected to analyses of protein-protein interactions, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. With the Molecular Complex Detection plugin program, the hub genes were investigated. A multifactor regulatory network was constructed depending on key hub genes, and immune infiltration was also evaluated. Finally, quantitative real-time polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay were used to validate the bioinformatic results.Results: Twenty-four ferroptosis-related differentially expressed genes were detected in patients with SSc versus the normal controls. The biological processes of FRGs in patients with SSc focused on the negative regulation of cell proliferation and inflammatory response. The signaling pathways were enriched in necroptosis. The core genes of SSc were CYBB, IL-6, NOX4,TLR4, CXCL2, JUN, and LY96. Three miRNAs, two lncRNAs, and five transcription factors were predicted. The evaluation of immune infiltration showed that the number of activated natural killer (NK) cells increased in SSc skin tissues, whereas the number of resting dendritic, NK, and mast cells decreased. The bioinformatics prediction results from the mRNA chip were in line with the expression levels of IL-6 and CYBB.Conclusions: Necroptosis and ferroptosis were upregulated in patients with SSc and involved in modulating cell proliferation, differentiation, and migration. IL-6 and CYBB are key ferroptosis-related genes in SSc. Ferroptosis and related genes might be promising targets in the treatment of SSc.

Traditional Chinese Medicine Integrated Responsive Microneedles for Systemic Sclerosis Treatment.

Traditional Chinese medicine, such as Tripterygium wilfordii and Paeonia lactiflora, has potential values in treating systemic sclerosis (SSc) and other autoimmune diseases, while their toxic side effect elimination and precise tropical drug delivery are still challenges. Here, we present multiple traditional Chinese medicine integrated photoresponsive black phosphorus (BP) microneedles (MNs) with the desired features for the SSc treatment. By employing a template-assisted layer-by-layer curing method, such MNs with triptolide (TP)/paeoniflorin (Pae) needle tips and BP-hydrogel needle bottoms could be well generated. The combined administration of TP and Pae can not only provide anti-inflammatory, detoxification, and immunomodulatory effects to treat skin lesions in the early stage of SSc but also remarkably reduce the toxicity of single drug delivery. Besides, the additive BPs possess good biocompatibility and near-infrared (NIR) responsiveness, imparting the MN photothermal-controlled drug release capability. Based on these features, we have demonstrated that the traditional Chinese medicine integrated responsive MNs could effectively improve skin fibrosis and telangiectasia, reduce collagen deposition, and reduce epidermal thickness in the SSc mouse models. These results indicated that the proposed Chinese medicine integrated responsive MNs had enormous potential in clinical therapy of SSc and other diseases.