small molecules

2026-09-04 | Methotrexate Versus Mycophenolate Mofetil as First-Line Therapy in Systemic Sclerosis: Evidence from Clinical Trials and Real-World Studies—A Narrative Review

Systemic sclerosis (SSc) is a heterogeneous autoimmune connective tissue disease characterized by immune activation, vasculopathy and progressive fibrosis of the skin and internal organs. Immunosuppressive treatment is commonly used in early inflammatory disease and in SSc-associated interstitial lung disease (SSc-ILD), yet the optimal first-line agent depends on the dominant clinical phenotype. Methotrexate (MTX) and mycophenolate mofetil (MMF) are two widely used conventional immunomodulatory options. This review summarizes the clinical trial evidence from the last four decades and places it into the context of contemporary guideline recommendations and real-world comparative effectiveness data. Two randomized placebo-controlled trials support a modest role for MTX in early diffuse cutaneous SSc, particularly for skin and musculoskeletal manifestations, but evidence for lung benefit is limited. MMF has stronger evidence for SSc-ILD, principally from the Scleroderma Lung Study II, a randomized double-blind trial showing comparable efficacy to oral cyclophosphamide with better tolerability, and from subsequent pilot, open-label, and real-world studies. Overall, the current evidence supports a phenotype-driven approach: MTX may be considered when skin or joint disease predominates without clinically relevant ILD, whereas MMF is generally preferred for SSc-ILD and systemic inflammatory disease. Direct head-to-head MTX versus MMF trials are lacking and remain an important research priority.

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2026-09-03 | A compact five-gene immuno-fibrotic profile distinguishing systemic sclerosis subtypes with PXDN validated as a fibrosis-associated target.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by a paucity of reliable biomarkers for accurate diagnosis and subtype stratification. The considerable clinical variability between diffuse and limited cutaneous subtypes underscores an urgent need for molecular tools that can dissect this heterogeneity and guide therapeutic strategies. To address this, we employed a multi-step computational approach. Initially, Weighted Gene Co-expression Network Analysis (WGCNA) was applied to the GSE130955 dataset to identify disease-associated modules. This was followed by the application of three machine-learning algorithms-LASSO regression, random forest, and SVM-RFE-to the GSE181549 dataset for hub gene selection. Immune cell infiltration was estimated using CIBERSORT, and the expression of candidate genes was validated at single-cell resolution using the GSE138669 dataset. Experimental validation was performed for the top candidate, PXDN, assessing its protein expression in human fibroblasts, SSc patient skin, and a bleomycin-induced murine fibrosis model. Finally, molecular docking with AutoDock Vina was conducted to evaluate the binding affinity of small molecules to PXDN. WGCNA identified a module strongly correlated with SSc status (r = 0.73, p < 2e-16), which was enriched in immune chemotaxis and extracellular matrix organization pathways. The convergence of the three machine-learning algorithms nominated a five-gene signature (CPXM1, ELN, GSTM5, PXDN, PDE7B), which demonstrated high diagnostic accuracy (AUC = 0.985, 95% CI: 0.965-1) and effectively distinguished diffuse from limited cutaneous SSc. Single-cell analysis confirmed predominant expression of these genes in fibroblast and macrophage populations within SSc lesional skin. Experimentally, PXDN was found to be upregulated by TGF-β1 in human fibroblasts and was significantly elevated in skin and lung tissues from SSc and IPF patients, as well as in the bleomycin-induced mouse model. Although molecular docking nominated Protokylol hydrochloride as a compound satisfying distal-cavity geometric criteria, this serves as a hypothesis-generating finding rather than a confirmed inhibitor. Our integrative analysis identifies a concise immunofibrotic gene signature that robustly distinguishes SSc and its major subtypes. This signature highlights a potential nexus of immune-stromal interactions that may underlie disease heterogeneity, offering candidate biomarkers for molecular stratification and therapeutic targeting. Notably, PXDN emerges as a particularly promising target, warranting further experimental investigation to validate its functional role and therapeutic potential in SSc.

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2026-08-01 | Systemic Sclerosis Induced by Immune Checkpoint Inhibitors from the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO): A Case Series

Objectives Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, improving outcomes in multiple advanced malignancies. Their use is often limited by immune-related adverse events (irAEs), including rare rheumatic irAEs, such as ICI-induced systemic sclerosis (ICI-SSc). Compared to idiopathic SSc, ICI-SSc typically presents with fewer extra-cutaneous manifestations and negative serologies, but data remains limited.[1] This case series describes the clinical presentation, management, and outcomes of patients with ICI-SSc to guide clinicians in balancing autoimmune toxicities with cancer control. Methods A retrospective chart review was conducted on 7 adults diagnosed with systemic sclerosis following ICI exposure between March 2021 and August 2025. All patients were referred to a Canadian academic rheumatology clinic specializing in Immuno-Oncology during ICI therapy. Clinical data was abstracted from medical records, including patient demographics, malignancy type and stage, ICI type and duration, clinical features, serologies, treatment, and outcomes. Results Of the 7 patients identified, 5 (71.4%) were female and 2 (28.6%) were male, with a mean age (SD) of 63 (10.9) years. Malignancies included: metastatic melanoma (n=4), metastatic squamous cell carcinoma (n=1), breast cancer Stage IIA/IIB (n=1), and metastatic endometrial adenocarcinoma (n=1). ICIs used included: pembrolizumab (n=2), nivolumab (n=1), cemiplimab (n=1), and ipilimumab/nivolumab combination followed by nivolumab monotherapy (n=2), which were discontinued due to SSc symptoms within 1-13 months of initiation. Serologies showed ANA positivity in 4 patients (57.1%), with SSc-specific antibodies (anti-Scl-70) detected in 1 patient. Other antibodies detected included anti-RP-11, anti-RP-155, anti-Ro-52, anti-chromatin, and anti-OJ. 2 patients had negative serologies, 1 with elevated inflammatory markers. All patients had scleordactyl (diffuse 57.1%, limited 42.9%) and extra-cutaneous features, most commonly Raynaud’s phenomenon (71.4%). Other manifestations included inflammatory arthritis (42.9%), nailfold capillary changes (42.9%), esophageal dysmotility (28.6%), telangiectasia (14.3%), and sicca symptoms (14.3%). No patients developed interstitial lung disease, pulmonary arterial hypertension, or scleroderma renal crisis. Management included ICI cessation for all patients, prednisone (85.7%), disease-modifying antirheumatic drugs (mycophenolate mofetil 57.1%, methotrexate 28.6%, hydroxychloroquine 28.6%), infliximab and intravenous immunoglobulins, and vasodilatory therapies. All malignancies were stable at 6 months post-ICI therapy. Conclusion ICI-SSc is a significant irAE primarily characterized by cutaneous manifestations but, in contrast to previous reports, this case series demonstrates that extra-cutaneous manifestations and seropositivity can occur. Along with ICI-cessation, immunosuppressive therapy was effective in symptom control without compromising cancer stability. This work may assist those involved in caring of patients with ICI-SSc to initiate immunosuppressive therapy and minimize the risk of end-organ complications. References [1.] Cho LK. Rheum Dis Clin North Am 2024;50:301-12.

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2026-06-30 | Rethinking immunosuppression in limited cutaneous systemic sclerosis. The lcSSc conundrum; pros and cons for a timely immunosuppressive treatment.

The use of immunosuppressants (IS) has dramatically changed the management of autoimmune diseases. In systemic sclerosis (SSc), randomized controlled trials and international recommendations support IS use in patients with rapidly progressive diffuse disease or interstitial lung disease (ILD). However, their role in the limited cutaneous systemic sclerosis (lcSSc) subset remains controversial. This article discusses arguments both in favor of and against the use of IS in lcSSc, integrating clinical evidence, pathophysiological insights, and registry data, while acknowledging the limitations inherent to observational findings. Overall, the available evidence suggests that reliance on skin subset classification alone may be insufficient to guide treatment decisions, and highlights the potential value of more refined, biology-informed approaches. However, further prospective validation is required before such strategies can be translated into clinical practice.

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2026-06-22 | Pruritus associated with systemic sclerosis: a systematic review of treatment-based clinical trials.

This paper aims to examine the latest research on treatments for itch (pruritus) in people with systemic sclerosis (SSc), identify areas where information is lacking, and propose suggestions for future studies.A comprehensive literature search was performed in PubMed and Scopus in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies evaluating therapeutic interventions for pruritus in SSc. Eligible studies included randomized controlled trials, cohort studies, and case series comprising a minimum of three patients. Data extraction encompassed study design, patient demographics, pruritus assessment instruments including validated and non-validated measures, and clinical outcomes. Studies were excluded if they concerned localized scleroderma, irrelevant populations, case reports, systematic reviews, lacking relevant outcome data, or incomplete trials. Ten studies met criteria, evaluating immunomodulatory agents, mast cell stabilizers, opioid receptor antagonist, and lysophosphatidic acid receptor antagonists. Pruritus assessment varied and was often secondary to fibrosis outcomes. Oral lenabasum improved pruritus in a phase II trial; low-dose opioid receptor modulators and rituximab also showed qualitative improvement. Pruritus is a frequently overlooked yet clinically significant symptom in systemic sclerosis (SSc) that negatively impacts patients' quality of life. Existing evidence regarding effective therapeutic options remains limited. Future research should prioritize pruritus as a predefined outcome and utilize validated assessment instruments to inform treatment strategies and enhance patient quality of life.

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proteins

2024-09-08 | Role of intravenous immunoglobulins in systemic sclerosis (SSc): A systematic literature review.

Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity and mortality. Intravenous Immunoglobulin (IVIG) is a therapeutic option for SSc; however, reports of its efficacy have been variable, and its use across multiple organ manifestations of SSc has not been comprehensively reviewed. The aim of this study was to systematically assess the existing literature on the role of IVIG use across a range of SSc manifestations. Medline, Embase, Cochrane, Web of Science and Scopus were searched from 01/01/2003-15/04/2024 using terms related to SSc and IVIG. Included studies were English-language full texts, where ≥5 adults with SSc received IVIG, and where a reportable outcome was documented. Of 418 potentially relevant records, 12 were included in this review, comprising 266 patients across one randomised control trial, two pilot studies, one open label study, seven retrospective studies and one case control study. Eighteen outcomes were documented across five different organ systems: cutaneous, respiratory, musculoskeletal, gastrointestinal, and other (clinical improvement and corticosteroid sparing benefit). Results showed a favourable effect of IVIG in reducing the extent of skin thickening, muscle and joint pain, gastrointestinal symptoms, steroid dosing and improving patient/physician reported quality of life. Whilst IVIG may appear to be less beneficial for respiratory disease, the stabilisation in pulmonary function tests and radiological features may be considered a positive outcome in itself. Limitations included a lack of high-quality studies, and the use of concomitant therapies in many studies, rendering the efficacy of IVIG alone difficult to ascertain. IVIG showed benefit in treating some manifestations of SSc, however there was a lack of convincing evidence for the efficacy in others. The lack of high-quality data highlights the need for further well-designed clinical trials to confirm these findings and inform guidelines for IVIG use.

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2024-04-25 | TANGO1 inhibitors reduce collagen secretion and limit tissue scarring.

Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.

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2024-04-01 | Reliability, validity, and sensitivity of the Japanese version of the University of California Los Angeles scleroderma clinical trial consortium gastrointestinal tract instrument: Application to efficacy assessment of intravenous immunoglobulin administration

This study aimed to develop and assess the reliability, validity, and sensitivity of the Japanese version of the University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract (GIT) Instrument 2.0 (the GIT score), as an evaluation tool for GIT symptoms in systemic sclerosis (SSc). The Japanese version of the GIT score was constructed using the forward-backward method. The reliability and validity of this instrument were evaluated in a cohort of 38 SSc patients. Correlation analysis was conducted to assess the relationship between the GIT score and existing patient-reported outcome measures. Additionally, the sensitivity of the GIT score was examined by comparing GIT scores before and after intravenous immunoglobulin (IVIG) administration in 10 SSc-myositis overlap patients, as IVIG has recently demonstrated effectiveness in alleviating GIT symptoms of SSc. As a result, the Japanese version of the GIT score exhibited internal consistency and a significant association with the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease. Furthermore, the total GIT score, as well as the reflux and distention/bloating subscales, displayed moderate correlations with the EuroQol 5 dimensions (EQ-5D) pain/discomfort subscale and the Short Form-36 body pain subscale. Notably, following IVIG treatment, there was a statistically significant reduction in the total GIT score and multiple subscales. We first validated the Japanese version of the GIT score in Japanese SSc patients in real-world clinical settings. This instrument holds promise for application in future clinical trials involving this patient population.

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2024-04-01 | P135 Association of Serum Anti-Muscarinic 3 Antibodies with Gastrointestinal Disease in Systemic Sclerosis

Abstract Background/Aims Gastrointestinal (GI) complications of systemic sclerosis (SSc) are frequent and debilitating with symptoms ranging from reflux to faecal soilage. The pathogenesis of GI disease in SSc is poorly understood. Circulating antibodies against Muscarinic type 3 Receptors (anti-M3R) have been implicated in GI smooth muscle dysfunction and neural activation impairment. We examine whether anti-M3R antibodies associate with objective measures of gastrointestinal symptoms. Methods Sera were collected from SSc patients fulfilling the American College of Rheumatology (ACR) classification criteria for SSc. Healthy control (HC) sera were obtained from age-matched volunteers. SSc patients completed the UCLA GIT 2.0 (UCLA GIT) questionnaire. Serum anti-M3R antibodies were measured using specific enzyme-linked immunosorbent assay (ELISA)(CellTrend GmbH, Germany). SSc sera had elevated anti-M3R antibodies if the concentration exceeded two standard deviations above the mean of HC sera. Statistical comparisons were made using Fisher’s exact test and two sample t-test. Results Sera from 40 SSc patients and five HC were assayed for anti-M3R antibodies. Anti-M3R antibody was higher in SSc patients in comparison to HC (1547 vs 1183U/ml, p = 0.33). Anti-M3R antibody levels were significantly elevated in nine (23%) SSc patients. Cohort characteristics were compared based on anti-M3R antibody levels for SSc patients (Table 1). Group demographics were similar in gender, age and disease duration. There was a trend for higher anti-M3R antibodies in limited compared with diffuse cutaneous SSc subset (66.7 vs 32.2, p = 0.12). Although there was no significant association between Anti-M3R antibody level and GIT score (r = 0.014 p = 0.51), SSc patients with elevated anti-M3R antibody did report numerically more severe reflux symptoms (1.24 vs 0.8, p = 0.23) and fewer lower GI domains of severe soilage (0.56 vs 0.87, p = 0.37) and constipation (0.28 vs 0.52, p = 0.2). Conclusion These results show that there is a subset of SSc patients with elevated anti-M3R antibodies which could be pathogenic by perturbing cholinergic neurotransmission in the GI tract. The trend observed of elevated anti-M3R antibodies with more severe GI symptoms warrants further exploration in a larger cohort of SSc. If confirmed, our findings provide mechanistic rationale for reported benefit from intravenous immunoglobulin on symptom severity in SSc GI disease. Disclosure E. Roblin: None. C. Beesley: None. R. Maclean: None. F. Ahmed: None. C. Murray: None. V.H. Ong: None. C. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.

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2024-03-06 | Imbalance of TH17/TREG cells in Tunisian patients with systemic sclerosis.

Fibrosis is a pathological manifestation in which connective tissue replaces normal one. It can affect many tissues from the skin to internal organs such as the lungs. Manifestations of pulmonary involvement can be pulmonary arterial hypertension or pulmonary fibrosis. The latter one is currently the leading cause of death in various autoimmune diseases, including systemic sclerosis. Our study group consists of 50 patients with systemic sclerosis: 24 with limited cutaneous form and 26 with diffuse cutaneous form. This cohort was compared to 50 healthy controls (age and sex matched); our aim is to explore the distribution of TH17 cells (TH17) as well as regulatory T cells (TREG) and study their correlation with the disease's progress. Our results show an increase for IL17A in patients compared to controls and that this increase is correlated with a specific clinical involvement: Pulmonary fibrosis. This correlation suggests a crucial role of IL17A in fibrosis especially in systemic sclerosis. In addition, we have shown that the percentages of TH17 cells are higher in patients; however, the percentages of TREG cells are similar between patients and controls. A study of TREG cell activity showed that TREG lost suppressive activity by inactivating the FOXP3 transcription factor. This proves that despite their presence, TREG does not adequately carry out their regulatory activity. Finally, we analyzed the correlation between TH17/TREG and clinical damage; the results show a positive correlation with pulmonary involvement proving the role of TH17/TREG balance in induced fibrosis in systemic sclerosis. No significative difference was observed, for all the parameters, between the two different forms of the disease. In conclusion, the results associated with the TH17/TREG scale and their correlations with fibrosis in systemic sclerosis open a way for new tools to manage this autoimmune disease, which up to today has neither treatment nor accurate diagnosis.

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cell therapies

2026-06-01 | P.013 The stromal vascular fraction mitigates bleomycin-induced fibrosis in mice

Introduction

Systemic sclerosis (SSc), or scleroderma, is a refractory autoimmune disorder marked by microvascular dysfunction and progressive fibrosis affecting the skin and multiple internal organs. Currently, treatment options for scleroderma-related fibrosis remain limited. The stromal vascular fraction (SVF), derived from adipose tissue, contains multiple regenerative cell components, including adipose-derived stem cells, has demonstrated promising therapeutic potential in various fibrotic diseases.

Material and Methods

SVF was obtained from the subcutaneous adipose tissue of C57BL/6 mice and delivered via different administration routes to evaluate its efficacy against skin and pulmonary fibrosis. Dermal thickness and collagen deposition were assessed through histological examination. SVF retention within fibrotic subcutaneous tissue was monitored longitudinally using in vivo imaging and immunofluorescence. Cutaneous vascular architecture and the production of antifibrotic factors—including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF-2)—were analyzed via flow cytometry and immunofluorescence. Additionally, the functional roles and mechanistic contributions of key SVF subpopulations in attenuating fibrosis were investigated.

Results

SVF effectively alleviates skin and pulmonary fibrosis in mice through distinct mechanisms at different disease stages. In the early phase of skin fibrosis, SVF modulates vascular lesions and inflammation via endothelial cells, while in the late stage, stromal cells mediate antifibrotic effects by secreting reparative cytokines. The CD45- subpopulation is identified as the primary effector cell group responsible for these therapeutic effects. Additionally, tracheal delivery of SVF demonstrates superior efficacy compared to tail-vein injection in alleviating pulmonary fibrosis, with prolonged retention of SVF in the lungs under this administration route. These findings provide mechanistic insights into the therapeutic potential of SVF and support its clinical application in treating SSc-related fibrosis.

Conclusions

The CD45- negative subset of SVF exhibits strong therapeutic potential for mitigating skin fibrosis in systemic sclerosis. Intratracheal administration significantly potentiates the efficacy of SVF in treating pulmonary fibrosis. Collectively, these findings underscore the utility of SVF-based therapies for fibrotic diseases and provide a robust rationale for future clinical translation.

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2026-05-27 | Beyond Hematology-Current Insights into Chimeric Antigen Receptor (CAR) T-Cell Therapy for Skin and Connective Tissue Disorders.

Chimeric antigen receptor (CAR) T-cell therapy represents a major advance in modern immunotherapy. This narrative review summarizes evidence from the past five years, including case reports, case series, and clinical trials, on its application beyond hematologic malignancies, focusing on autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), as well as solid tumors including melanoma and primary cutaneous lymphomas. CD19-directed CAR T-cells have demonstrated clinical benefits in SLE and SSc, with sustained immune reset, reduced autoreactive antibody levels, and clinical improvement. In melanoma, CAR T-cells targeting GD2, cMET, and CD20 have shown in vivo expansion and tumor infiltration; however, clinical efficacy remains limited, with transient stabilization or disease progression in most patients. In primary cutaneous lymphomas, early-phase studies with anti-CD70 and anti-CCR4.30 CAR T-cells indicate partial tumor regression and disease stabilization, often requiring additional therapy. Key challenges include limited durability of immune reset due to persistent plasma cells in autoimmune disorders, tumor heterogeneity, antigen loss or overlap, infiltration barriers, resistance mechanisms, and T-cell depletion in solid tumors, collectively reducing response durability and safety. The main toxicities include grade 1-2 cytokine release syndrome and rare hematologic complications, while immune effector cell-associated neurotoxicity syndrome is uncommon. Clinical translation remains limited and requires larger studies to improve efficacy and define safety profiles.

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2026-04-13 | Beyond Hematology—Current Insights into Chimeric Antigen Receptor (CAR) T Cell Therapy for Skin and Connective Tissue Disorders

Chimeric antigen receptor (CAR) T cell therapy represents one of the greatest breakthroughs in modern immunotherapies. To date, it has been approved by the Food and Drug Administration (FDA) for the treatment of several hematological malignancies, including different subtypes of leukemia, lymphoma, and multiple myeloma. However, recent reports suggest that CAR T therapy may also be effective in the treatment of severe systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Case reports and small case series have demonstrated the efficacy of anti-CD19 CAR T cell therapy while maintaining a favorable safety profile. The most frequently reported adverse events include grade 1 or 2 cytokine release syndrome (CRS), hypogammaglobulinemia, and mild infectious complications. Moreover, CAR T therapy may also have potential in the treatment of advanced metastatic solid tumors, including melanoma. Early clinical studies have demonstrated the feasibility and safety of CAR T cell therapy in metastatic melanoma; however, several challenges remain. These include limited tumor trafficking and infiltration of CAR T cells, due to the presence of an immunosuppressive tumor microenvironment. Additionally, following the remarkable success of CAR T therapy in lymphomas, this approach may also be applied to the treatment of cutaneous lymphomas, including cutaneous T-cell and B-cell lymphomas. Key challenges include tumor heterogeneity, optimal target antigen selection, fratricidal activity of CAR T cells, and potential contamination of the CAR T product with lymphoma cells.

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2026-01-09 | Clinical Applications of Autologous Fat Grafting in Pathological Hand Conditions.

Background: Autologous fat grafting (AFG) is increasingly explored beyond cosmetic applications, with interest in its regenerative potential for hand conditions such as cutaneous systemic sclerosis, thumb base osteoarthritis, Dupuytren contracture, burn scars, trauma and congenital hand deformities. This systematic review evaluates the therapeutic efficacy, techniques and outcomes associated with AFG across pathological hand conditions. Methods: A systematic literature search was conducted in July 2023 using PubMed, Ovid MEDLINE, Embase and Web of Science. Studies were included if they involved autologous fat or stromal vascular fraction (SVF) grafting for therapeutic purposes in hand conditions. Risk of bias (RoB) was assessed using RoB 2.0 for randomised controlled trials (RCTs) and the MINORS tool for non-RCTs. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed throughout. Results: Twenty-five studies were included (8 RCTs, 17 non-RCTs), involving a total of 909 patients. Conditions studied included systemic sclerosis (n = 7 studies), thumb base osteoarthritis (n = 7), Dupuytren contracture (n = 6), burn-related scars (n = 2), hand trauma (n = 2) and congenital deformities (n = 2). AFG was most consistently associated with improvements in pain (visual analogue scale [VAS]), joint mobility (range of motion) and functional scores such as the Cochin Hand Function Scale (CHFS), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) and Michigan Hand Questionnaire (MHQ), particularly in systemic sclerosis and thumb base osteoarthritis. Findings in Dupuytren's contracture were mixed, with observational studies reporting early improvements but RCTs showing higher recurrence rates. Outcomes for burn scars, trauma and congenital deformities were less consistent. Techniques for fat harvesting, processing and injection varied widely. Conclusions: AFG shows therapeutic potential across several hand conditions, with the strongest current evidence supporting its use in systemic sclerosis and thumb base osteoarthritis. However, significant methodological heterogeneity and limited high-level evidence remain. Further robust, standardised RCTs are needed to clarify indications, optimise techniques and assess long-term outcomes. Level of Evidence: Level III (Therapeutic).

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2025-08-27 | Definition of relapse criteria in patients with rapidly progressive systemic sclerosis treated with autologous haemopoietic stem cell transplantation

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by the accumulation of extracellular collagen matrix in tissues and target organs, such as skin, lung, gut, and heart [ 1 ]. The clinical spectrum of SSc is largely heterogeneous, but usually two distinct forms are recognized., i.e., the limited cutaneous (lc) and the diffuse cutaneous (dc) SSc. The two variants strongly differ in the terms of skin extension, type and severity of internal organ involvement, and expected survival. Among patients with dcSSc, a subset may be characterized by a rapidly progressive course with early appearance and quick worsening of skin and internal organ involvement, and consequently a high mortality rate within the first five years after first non-Raynaud phenomenom symptoms [ 2 ]. In these cases of rapidly progressive dcSSc, autologous haematopoietic stem cell transplantation (AHSCT) has been recognized as a standard-of-care therapy option since 2017 [ 3 , 4 , 5 , 6 ]. This statement was the direct consequence of the consistent results obtained in three randomized controlled trials where this procedure had been shown to be superior to traditional immunosuppressive therapy in improving skin involvement, preserving lung function, and reducing mortality rates [ 6 ]. These results have been further confirmed in a recent retrospective study where AHSCT was shown to be superior to rituximab in improving all the above-mentioned outcomes [ 7 ]. Nevertheless, several aspects of AHSCT warrant further consideration. First, transplantation related mortality still exists, although it has been significantly reduced thanks to the important progress made, with better pretransplant evaluation of cardiac and pulmonary involvement and improved selection of patients at lower risk of complications [ 8 ]. Another question to be answered is how long the effects of AHSCT will last. Preliminary data indicate that the incidence of disease progression could happen between 4 and 6 years after transplantation and that disease response varied according to patients [ 9 ]. However, although the observed clinical response after AHSCT has been defined since the early pivotal trials (ASSIT, ASTIS, SCOT) and the absence of response or disease progression after AHSCT is easy to define as its counterpart, no dedicated and validated tools are currently available to precisely define the disease relapse after AHSCT. Acquiring the moment of relapse after prior response to AHSCT may make it easier to adopt therapeutic interventions that may allow to maintain the disease remission induced by AHSCT.

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antibodies

2026-07-10 | Phenotype-specific associations of mosaic chromosomal alterations in systemic sclerosis.

Mosaic chromosomal alterations (mCAs) increase with age and are associated with many diseases, including autoimmune diseases. The associations between mCAs and systemic sclerosis (SSc) and its clinical subtypes have not been explored. We recruited study subjects from 2 independent datasets (set 1: 635 SSc, 4401 controls; set 2: 347 SSc, 2170 controls) and detected mCAs (loss, loss of heterozygosity [LOH], gain, and mosaic loss of the X chromosome [mLOX]) from their peripheral blood samples. Logistic regression analyses were conducted with covariates in each cohort, and the results were meta-analysed. We also conducted stratified analyses by age groups, the age at disease onset, clinical phenotypes based on the skin lesions, autoantibody profiles, and the presence of complications. We observed a trend of increased loss in SSc, especially in old age (P = .0063). The association of loss was strengthened in certain subtypes of SSc, including lcSSc (odds ratio [OR] = 2.22, P = .019) and SSc with vascular complications (digital ulcers, pulmonary hypertension, or renal crisis; OR = 3.30, P = .0054). The effect sizes of Loss increased in patients with high cell fractions (CFs). We also observed that mLOX was significantly associated with SSc, limited cutaneous systemic sclerosis (lcSSc), and anticentromere antibody-positive systemic sclerosis (ACA-SSc) only for subjects with high CFs. mLOX was significantly associated with lcSSc and ACA-SSc even compared with dcSSc and ATA-SSc, respectively. These associations were consistently observed in each of the 2 datasets. Finally, we identified majority of the associations of Loss were mainly driven by SSc with late age at onset. Loss and mLOX were significantly and differentially associated with SSc and its subtypes, underscoring potential phenotype-specific contributions of mCAs.

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2026-06-01 | P.314 Determinants of functional disability in systemic sclerosis: insights from the scleroderma health assessment questionnaire (SHAQ

Introduction

Systemic sclerosis (SSc) is a multisystemic disease that significantly impacts quality of life and function. The SSc-specific Scleroderma Health Assessment Questionnaire (SHAQ) measures functional disability and incorporates five visual analogue scales (VAS) assessing patient-reported impairment due to Raynaud’s phenomenon (RP), digital ulcers (DU), gastrointestinal (GI) symptoms, respiratory symptoms, and overall disease severity. We aim to evaluate the relationship between SHAQ and objective disease measures and identify potential factors associated with disability in SSc.

Material and Methods

A retrospective observational study of adult SSc patients from our center was conducted. Continuous variables are reported as mean±SD, and categorical variables as frequencies. Comparisons used chi-squared and Mann-Whitney U tests. Correlations used Spearman’s coefficient. Factors possibly associated with SHAQ were analysed using separate multiple linear regression models. Significance was set at p<0.05.

Results

We included 106 patients, 96(90.6%) were female. Mean age was 59.1±12.5years and disease duration 11.1±10.7years. Limited cutaneous SSc was the most common SSc form (73.6%). RP occurred in 98.1% and DU in 34%. Pulmonary involvement was present in 18.9%, GI in 35.8%, articular in 38.5%, and cardiac in 1.9%. Mean SHAQ was 1.6±0.8: 21.7% of patients reporting mild (SHAQ<1), 45.3% moderate (1<=SHAQ<2), and 33% severe (SHAQ>=2). SHAQ was higher in diffuse SSc [2.13±0.9;p=0,03], patients with pulmonary involvement [2.05±0.6;p=0.006], GI involvement [1.78±0.7;p=0.02], and those on bDMARD therapy [2.80±0.2; p=0.002]. A correlation was also found with Medsger disease severity scale: general [r=0.251; p=0.020] and joint/tendon [r=0.231;p=0.035] domain scores. Among the VAS domains, the highest values were reported for the overall disease severity VAS (52.5±26.6). Mean VAS impairment for RP was 25.6±32.4, for DU was 2.3±11.5 and, for GI symptoms was 20.1±29.6. VAS respiratory impairment was 19.8±29.4, patients with pulmonary involvement reported higher values [44±34;p<0.001] and presented correlation with Medsger’s pulmonary severity [r=0.241; p=0.029]. In separate multivariable models, higher SHAQ scores were associated with modified Rodnan skin score [B=0.026; p=0.043], C-reactive protein (CRP)[B=0.028; p=0.029], presence of pulmonary involvement [B=0.563; p=0.005], use of csDMARD [B=0.366; p=0.018], and bDMARD [B=0.754; p=0.005].

Conclusions

SHAQ revealed a predominantly moderate functional impact, with overall disease severity and pulmonary symptoms emerging as the most burdensome domains. Higher SHAQ scores are significantly associated with skin and pulmonary involvement, CRP levels, and DMARD use, confirming its validity as a patient-reported measure of multisystem impact in SSc. These findings suggest that patients have a real perception of their disease severity, further supported by the association between SHAQ and pulmonary involvement, a major determinant of vital prognosis.

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2026-06-01 | P.409 Phenotypic variations and clinical pathways in scleroderma renal crisis

Introduction

Scleroderma renal crisis (SRC) is a rare but life-threatening complication of systemic sclerosis (SSc), occurring in 2.4-10% of patients, predominantly those with the diffuse cutaneous subtype. It is characterized by the abrupt onset of acute renal failure and malignant hypertension, historically associated with high mortality. Key risk factors include rapidly progressive diffuse skin involvement and the presence of RNA polymerase III antibodies. Although the introduction of ACE inhibitors has significantly improved patient outcomes, the role of immunosuppressive therapies in the management of SRC remains poorly understood. The aims of this study were to characterize the clinical profiles of scleroderma renal crisis (SRC) patients, evaluate the use of immunosuppressive therapies, and assess the association between these treatments and patient outcomes.

Material and Methods

We conducted a retrospective review of a prospectively maintained database containing data from 460 SSC patients. The analysis involved descriptive statistical methods.

Results

From 2003 to 2025, 22 patients were diagnosed with scleroderma renal crisis (SRC) and treated with ACE inhibitors. Of these, 20 had at least 24 months of follow-up and were divided into three outcome groups. Group A (n=6): Patients with a rapidly progressive course who died within four months. All had diffuse SSc and severe organ involvement. Five received intensive immunosuppression but did not improve. Group B (n=4): Patients who survived the initial episode but died within four years, mainly from sepsis or sudden cardiac death. Two patients with limited SSc required permanent dialysis and did not receive immunosuppression. Two patients with diffuse SSc treated with rituximab and/or mycophenolate mofetil had mixed renal outcomes. Group C (n=10): Patients who achieved long-term survival with renal function recovery. Most received continuous immunosuppressive therapy. Three patients with poor prognostic factors treated with rituximab had a surprisingly good outcome. Interestingly, three patients developed SRC more than six years after their SSc diagnosis, with two cases occurring after stopping immunosuppressive therapy.

Conclusions

Clinical vigilance for scleroderma renal crisis (SRC) should be maintained for more than five years after SSc diagnosis, as approximately 15% of cases may occur later, especially in patients with comorbidities. The use of immunosuppressive therapy appears to be associated with improved survival and better clinical outcomes in SRC.

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2026-06-01 | P.006 S100A4 regulated genes are differentially activated in systemic sclerosis skin across limited and diffuse cutaneous subsets

Introduction

S100A4 is one of a family of damage-associated molecular peptide proteins causing downstream intracellular and extracellular fibrotic effects. Pre-clinical animal and functional studies have shown that S100A4 is implicated in skin and lung fibrosis in systemic sclerosis (SSc). Previous work [Denton et al, 2023] demonstrated that recombinant S100A4 protein promotes a fibrotic phenotype in normal fibroblasts whilst anti-S100A4 neutralising monoclonal antibody (AX-202) attenuated the profibrotic phenotype of SSc fibroblasts (SScF). Integrated analysis determined a set of 475 genes (the ‘’S100A4 signature’’) that are differentially expressed between normal (NDF) and SScF, induced in NDF by recombinant S100A4, and significantly attenuated in SScF by AX-202.

Material and Methods

Gene set enrichment analysis interrogated the S100A4 signature gene expression in whole skin in 68 well characterised SSc patients or healthy controls prospectively from a large tertiary centre over the course of 24 months (BIOPSY cohort). These included early diffuse cutaneous (dc)SSc (n=21), limited cutaneous (lc)SSc (n=15) and established dcSSc (n=14) with 16 matched healthy controls. Bulk RNA sequencing assessed genome-wide gene expression of whole skin samples to obtain normalised gene expression values for each sample.

Results

Of the 475 S100A4 signature genes, 460 genes were also identified in the BIOPSY cohort. 191 of the 460 genes showed statistically significant expression (p value <0.01) across all subsets of SSc compared to healthy controls. Principal component analysis shows the variability of expression of the top 50 differentially expressed genes with the tightest expression profile in the healthy control samples. The early diffuse subset scatter more widely and overlap with the established subset suggesting transitional heterogeneity. Supervised hierarchical clustering by samples and genes (figure 1) revealed distinct genetic signatures as illustrated by the dendrograms. Expression values of each gene are calculated using normalised z scores to highlight relative over and under expression of the gene in each sample. The relative expression by fold change of each of the top 20 differentially expressed genes by subset (early diffuse, all SSc and established diffuse SSc) compared to healthy controls is shown in the bar plot (figure 2).

Conclusions

Our findings confirm differential activation of S100A4 regulated genes across the spectrum of SSc subsets that is not present in healthy skin. Since S100A4 is a potential molecular marker and target in different SSc subgroups our findings may inform future clinical study design to help understand differential treatment response.

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2026-06-01 | P.362 A rare presentation in limited cutaneous systemic sclerosis –’like in looks, so in the eyes’

Introduction

Systemic Sclerosis (SSc) is an autoimmune disease comprising of autoimmune activation, inflammation leading to vasculopathy and fibrosis resulting in organ damage. It is very heterogenous in its pattern and extent of clinical manifestations. To date, very little is known about eye manifestations. We present such a case.

Material and Methods

A 44-year lady with mild stable limited cutaneous systemic sclerosis diagnosed in 2022 upon reviews over time showed only mild progression at last review in August 2024. Her clinical features and laboratory test details are as in table 1a and 1b. She also had baseline PFTs, ECHO and CXR (which were all normal). Her medications were omeprazole only. Calcium channel blocker had been advised but her preference was for physical therapy for her infrequent raynauds. In February 2025 she developed sudden blurring of vision in her left eye.

Results

She was seen promptly in the Eye clinic and was diagnosed with left eye central retinal vein occlusion (CRVO). The results of her examinations before and after the therapy are as in figure 1 & 2.

Conclusions

Eye manifestations, the appropriate guidelines for screening and their treatment of SSc remains an unmet need. Literature review by K. Paczwa et al have illustrated the various ocular manifestations of SSc in their review based on case reports or short small studies only. Our patient is a very young lady with stable lcSSc with minimal mRSS score, as well as had infrequent raynauds, nevertheless still developed CRVO with its inherent morbidity of diminished vision. She received Bevacizumab (an anti-angiogenic agent; an anti-VEGF-A agent) with which she apparently seems to have stabilized temporarily. However, there is scant data on the role of calcium channel blockers, immunosuppressive agents (ISA), endothelin receptor blockers, or even on anti-fibrotic agents in prevention or treatment of retinal complication secondary to SSc, which remains an unmet need. We would suggest further larger studies are needed to see if there is any significant association, as well as any role of various agents currently used in SSc with vasculopathy or fibrosis as well as to confirm the findings of fewer smaller studies done earlier having shown possibility of association with the NVC, mRSS and disease activity. We also, wonder if there ought to be screening guidelines in SSc patients regarding eye involvement?

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other

2023-06-20 | Regulation of MicroRNA Expression in Scleroderma and Idiopathic Pulmonary Fibrosis: A Research Study

Introduction: Scleroderma (SSc) is an autoimmune disorder with the hallmark of fibrosis of the skin, vasculature and internal organs. Patients with SSc and undifferentiated connective tissue disease (UCTD) are susceptible to interstitial lung disease (ILD), leading to decreased lung function and death. Idiopathic pulmonary fibrosis (IPF) is a form of ILD that is not associated with extrapulmonary manifestations. In this study, lung involvement of SSc was studied by observing how disease progression and pathogenesis differ among patients with SSc, UCTD, and ILD compared to healthy controls and patients with IPF. Our group has previously identified disease targets through microRNA sequencing, including the DICER enzyme, which works closely with the protein DGCR8 and the enzyme DROSHA in the RNA interference pathway. The canonical pathway stipulates that DICER processes microRNAs in the cytosol while DGCR8 and DROSHA process microRNAs in the nucleus. DICER, DROSHA, and DGCR8 are hypothesized to contribute to ILD progression. Methods: Human peripheral blood mononuclear cells (PBMCs) were isolated from voluntary participants, including healthy controls. PBMCs were subsequently lysed with subcellular fractionation buffer. Western blotting was done on the resulting cytosolic and nucleic fractions for DICER, DROSHA, and DGCR8 protein expression. The cytosolic fractions were normalized to GAPDH, while the nucleic fractions were normalized to B2M. Nonparametric Kruskal‐Wallis tests were used for statistical analysis. Results: The medians were significantly higher for healthy controls for DICER in the nucleus with a p-value of 0.0302, and DROSHA in the cytosol with a p-value of 0.0406 compared to patients with SSc, UCTD, and IPF. Discussion: Differences in expression were found for DROSHA in the cytosol and DICER in the nucleus, suggesting dysregulation of the non-canonical RNA interference pathways in SSc, UCTD, and IPF patients. Variability of disease progression within the groups could lead to variable enzyme and protein levels within the same disease status. With larger sample sizes, statistically insignificant differences would become significant. Lipid nanoparticle technology could be used to deliver deficient microRNAs to silence mRNA in patients. Conclusion: Due to dysregulation of the RNA interference pathway, microRNAs may be inadequately processed in the patient groups.

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2022-03-23 | MicroRNA-411-3p inhibits bleomycin-induced skin fibrosis by regulating transforming growth factor-β/Smad ubiquitin regulatory factor-2 signalling.

Skin fibrosis, which is characterized by fibroblast proliferation and increased extracellular matrix, has no effective treatment. An increasing number of studies have shown that microRNAs (miRNAs/miRs) participate in the mechanism of skin fibrosis, such as in limited cutaneous systemic sclerosis and pathological scarring. The objective of the present study was to determine the role of miR-411-3p in bleomycin (BLM)-induced skin fibrosis and skin fibroblast transformation. Using Western blot analysis and real-time quantitative polymerase chain reaction assess the expression levels of miR-411-3p, collagen (COLI) and transforming growth factor (TGF)-β/Smad ubiquitin regulatory factor (Smurf)-2/Smad signalling factors both in vitro and in vivo with or without BLM. To explore the regulatory relationship between miR-411-3p and Smurf2, we used the luciferase reporter assay. Furthermore, miR-411-3p overexpression was identified in vitro and in vivo via transfection with Lipofectamine 2000 reagent and injection. Finally, we tested the dermal layer of the skin using haematoxylin and eosin and Van Gieson's staining. We found that miR-411-3p expression was decreased in bleomycin (BLM)-induced skin fibrosis and fibroblasts. However, BLM accelerated transforming growth factor (TGF)-β signalling and collagen production. Overexpression of miR-411-3p inhibited the expression of collagen, F-actin and the TGF-β/Smad signalling pathway factors in BLM-induced skin fibrosis and fibroblasts. In addition, miR-411-3p inhibited the target Smad ubiquitin regulatory factor (Smurf)-2. Furthermore, Smurf2 was silenced, which attenuated the expression of collagen via suppression of the TGF-β/Smad signalling pathway. We demonstrated that miR-411-3p exerts antifibrotic effects by inhibiting the TGF-β/Smad signalling pathway via targeting of Smurf2 in skin fibrosis.

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2021-11-26 | The Contribution of LIGHT (TNFSF14) to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts

Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and T helper (Th)2/Th17 cytokines serve as critical disease drivers. LIGHT is a proinflammatory cytokine promoting IL-6 production in lung fibroblasts and Th1 chemokine expression in dermal fibroblasts (DFs) stimulated with IFN-γ. In this study, we investigated the potential contribution of LIGHT to SSc development using clinical samples and animal models. In SSc-involved skin, LIGHT was upregulated in inflammatory cells, whereas herpesvirus entry mediator (HVEM), a receptor of LIGHT, was downregulated in DFs. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter, and FLI1 small interfering RNA suppressed HVEM expression in normal DFs. In SSc DFs, LIGHT significantly increased IL-6 production, whereas IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with that in normal DFs. Importantly, LIGHT small interfering RNA significantly attenuated bleomycin-induced skin fibrosis, and serum LIGHT levels were elevated in patients with diffuse cutaneous SSc and positively correlated with clinical parameters reflecting skin and pulmonary fibrosis. Taken together, these results suggest that altered response of DFs to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.

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2021-06-24 | Endothelial CCR6 Expression Due to FLI1 Deficiency Contributes to Vasculopathy Associated with Systemic Sclerosis

Abstract Background: We have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the development of SSc vasculopathy. Therefore, we explored this hypothesis using clinical samples, cultured cells and murine SSc models. Methods: The expression levels of CCL20 and CCR6 in the skin, mRNA levels of target genes and the binding of transcription factor FLI1 to the target gene promoter were evaluated by immunostaining, quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Vascular permeability was evaluated by Evans blue dye injection in bleomycin-treated mice. Angiogenic activity of endothelial cells was assessed by in vitro angiogenesis assay. Results: CCL20 expression was significantly elevated in dermal fibroblasts of patients with early diffuse cutaneous SSc, while CCR6 was significantly up-regulated in dermal small vessels of SSc patients irrespective of disease subtypes and disease duration. In human dermal microvascular endothelial cells, FLI1 siRNA induced the expression of CCR6, but not CCL20, and FLI1 bound to the CCR6 promoter. Importantly, vascular permeability, a representative SSc-like vascular feature of bleomycin-treated mice, was attenuated by Ccr6 siRNA treatment, and CCR6 siRNA suppressed the angiogenic activity of human dermal microvascular endothelial cells assayed by in vitro tube formation. Conclusions: The increased expression of endothelial CCR6 due to FLI1 deficiency may contribute to the development of SSc vasculopathy.

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2019-07-26 | Gastrointestinal Involvement in Systemic Sclerosis: Overview, Neglected Aspects, Malnutrition, Body Composition and Management

Gastrointestinal tract (GIT) involvement is the most common internal organ manifestation and is present in up to 90% of patients with systemic sclerosis (SSc). Clinical manifestations can differ according to the part of the GIT affected, disease course and symptoms. A majority of the symptoms are caused by GIT dysmotility. Up to 8% of SSc patients develop several GIT symptoms, which increase the mortality. Although GIT involvement is rarely the direct cause of death, it can lead to several comorbidities including malnutrition and negative alterations of body composition. These factors have a negative impact on quality of life and increase the mortality. To date, the treatment is rather symptomatic. The pathogenesis of GIT involvement in SSc still remains to be clarified to improve the treatment approaches including intravenous immunoglobulins and microRNA interventions.

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