RARE DISEASE
Limited systemic sclerosis
Limited systemic sclerosis
Limited systemic sclerosis
Synonyms: Systemic sclerosis sine scleroderma
Synonyms: Systemic sclerosis sine scleroderma
Synonyms: Systemic sclerosis sine scleroderma
Drug discovery
19
drugs
With orphan designations
Overview
Limited Systemic Sclerosis (SSc) is a subtype of systemic sclerosis characterized by skin fibrosis restricted to distal extremities and face, often presenting as CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia). It features slow progression but is frequently complicated by pulmonary hypertension, with preserved survival compared to diffuse SSc [1][6][16][19].
Burden
Economic: Annual healthcare costs exceed controls by ~$12,820, driven by frequent hospitalizations and specialty care [4][9].
Morbidity: Skin fibrosis, digital ulcers, and pulmonary hypertension impair quality of life; 30% develop interstitial lung disease [5][14][16].
Survival: 10-year survival is 84–92%, but pulmonary hypertension reduces 3-year survival to 50% [1][6][19].
Therapies
Vasodilation: Calcium channel blockers (e.g., nifedipine) for Raynaud’s; endothelin receptor antagonists (e.g., bosentan) or PDE5 inhibitors (e.g., sildenafil) for pulmonary hypertension [1][3][18].
Symptom management: PPIs for gastroesophageal reflux, immunosuppressants (e.g., methotrexate) for early skin involvement, and annual echocardiography/pulmonary function tests for complication monitoring [1][6][16].
Emerging therapies: Rituximab (anti-CD20) and tocilizumab (anti-IL6) show promise in early trials for fibrosis and lung dysfunction [3][13].
Categories: rare cardiac diseases, rare renal diseases, rare respiratory diseases, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
768 drug discovery papers about Limited systemic sclerosis, with 2 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
768 drug discovery papers about Limited systemic sclerosis, with 2 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-24 | Why Men Fare Worse: Understanding Gender Disparities in Systemic Sclerosis-Associated Pulmonary Hypertension.
This study investigates gender disparities in clinical outcomes among patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH), focusing on cardiovascular events, right ventricular function, and survival. PAH is a severe and life-threatening complication of SSc, with male patients often experiencing worse outcomes despite its higher prevalence in women. Comparative data on gender differences in this population remain limited. We conducted a retrospective, single-center study including 61 patients with SSc-associated PAH (52 women, 9 men), confirmed by right heart catheterization. Clinical, serological, pulmonary, and echocardiographic data were analyzed. Differences between sexes in cardiovascular events, right ventricular dilation, and survival were evaluated using appropriate statistical methods. Male patients had a significantly higher incidence of cardiovascular events (median: 2.00 vs 1.00 in women; P = .031) and a greater prevalence of right ventricular dilation (100.00% vs 44.23%; P = .002). Kaplan-Meier analysis demonstrated reduced cardiovascular event-free survival (P = .001) and overall survival (P = .014) in men. Although mortality was higher in men (88.89%) than in women (57.69%), the difference was not statistically significant (P = .134). Men with SSc-associated PAH experience worse clinical outcomes, including more frequent cardiovascular events and reduced survival. The absence of estrogen's protective effects and the adverse influence of testosterone on cardiac remodeling may contribute to these disparities. These findings highlight the importance of early gender-specific risk stratification and the need for tailored therapeutic strategies to improve outcomes in this high-risk group.
2026-07-16 | Expression Profile and Clinical Significance of Ferroptosis-Related Genes in Peripheral Blood Mononuclear Cells of Patients with Systemic Sclerosis.
Systemic sclerosis (SSc) is a severe autoimmune disease marked by immune dysregulation and progressive fibrosis, yet reliable blood biomarkers remain limited. Ferroptosis, an iron‑dependent lipid peroxidation-driven cell death pathway, links iron/redox imbalance to inflammation and fibrotic remodeling, but its role in SSc is poorly defined. To profile Ferroptosis‑Related Genes (FRGs) in Peripheral Blood Mononuclear Cells (PBMCs) from SSc patients and assess their clinical significance. Transcriptional profiles from four SSc patients and six Healthy Controls (HCs) were analyzed using the Arraystar Human LncRNA Microarray to identify Differentially Expressed Genes (DEGs). Ferroptosis-related DEGs in SSc (Ferr-DEGs) were obtained by intersecting DEGs with a ferroptosis database, and key Ferr-DEGs were prioritized using bioinformatic analyses. Immune cell infiltration was estimated using single-sample gene set enrichment analysis (ssGSEA). The expression of selected genes was validated by quantitative real-time polymerase chain reaction (RT-qPCR) in an expanded cohort (SSc = 36, HC = 36), and correlations with clinical indicators were assessed. Diagnostic performance was evaluated using ROC curves. Microarray analysis revealed 397 upregulated and 637 downregulated DEGs in the SSc group. Bioinformatic analyses identified eight ferroptosis-associated key genes in SSc: MAPK14, SRC, ATF3, CYBB, ACSL1, STK11, PLIN2, and NCF2. MAPK14, SRC, ATF3, and CYBB were significantly upregulated in SSc compared with HCs, whereas ACSL1 was downregulated. Notably, SRC showed good diagnostic performance for SSc, with an AUC of 0.891 (95% CI, 0.819-0.964). Given the emerging link between ferroptosis and autoimmune diseases, exploring its role in the pathogenesis of Systemic Sclerosis (SSc) could open new avenues for improving diagnostic and therapeutic strategies. Our findings indicate significant dysregulation of FRGs in PBMCs from SSc patients, suggesting their potential involvement in inflammation, immune cell infiltration, and fibrosis; notably, SRC may serve as a candidate diagnostic marker for SSc.
2026-07-14 | Itaconate Ameliorates Skin Fibrosis Through Inhibition of HIF-1α/LDHA-Driven Aerobic Glycolysis.
Skin fibrosis is a hallmark of scleroderma and other fibrotic skin disorders, yet effective therapies remain limited. Immune-derived metabolites have emerged as regulators of inflammation and tissue remodeling, but whether metabolic reprogramming within dermal fibroblasts contributes to skin fibrosis remains unclear. Human fibrotic skin samples, a bleomycin-induced mouse model, and primary dermal fibroblasts were used to investigate the role of immune-responsive gene 1 (Irg1) and its metabolic product itaconate. Transcriptomic analyses, metabolic profiling, pharmacologic modulation, and genetic perturbation were employed to define downstream signaling mechanisms. Irg1 expression and endogenous itaconate levels were reduced in fibrotic human and murine skin. Restoration of itaconate significantly attenuated dermal thickening, collagen deposition, and fibroblast activation. Mechanistically, itaconate suppressed glycolytic reprogramming in activated fibroblasts, as evidenced by reduced glucose uptake, lactate production, and glycolytic enzyme expression. This metabolic effect was associated with inhibition of the Akt/GSK-3β pathway, destabilization of hypoxia-inducible factor 1α (HIF-1α), and subsequent downregulation of lactate dehydrogenase A (LDHA) transcription. Genetic or pharmacologic interference with HIF-1α or LDHA partially phenocopied itaconate's antifibrotic effects, supporting a functional link between itaconate signaling, fibroblast metabolism, and fibrotic progression. This study identifies loss of Irg1-itaconate signaling as a previously unrecognized driver of fibroblast metabolic reprogramming in skin fibrosis. By revealing a fibroblast-intrinsic, metabolism-centered mechanism linking immunometabolite deficiency to extracellular matrix overproduction, these findings extend itaconate's scope beyond immune regulation and highlight metabolic targeting of fibroblasts as a promising therapeutic strategy for fibrotic skin disease. Antioxid. Redox Signal. 45, 512-533.
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.
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.
cell therapies
2026-07-28 | CAR-based cellular therapies for autoimmune diseases: immune reset, clinical evidence, and translational boundaries.
CAR-based cellular therapy is emerging as a time-limited strategy for severe autoimmune disease, but its clinical value depends on more than early response. We conducted a structured narrative review with a targeted update of PubMed/MEDLINE and ClinicalTrials.gov through July 11, 2026, with study-level extraction and explicit handling of overlapping cohorts. Autologous CD19 CAR-T has the most mature evidence, particularly in systemic lupus erythematosus and other systemic rheumatic diseases, while one randomized phase 2b trial has evaluated transient mRNA BCMA-directed CAR-T in myasthenia gravis. Early studies also support disease-specific development in systemic sclerosis, idiopathic inflammatory myopathy, rheumatoid arthritis, autoimmune cytopenias, and selected neurologic disorders. However, cohorts remain small and heterogeneous, and severe cytokine release syndrome, neurotoxicity, hematotoxicity, infection, viral reactivation, hypogammaglobulinemia, and prolonged organ dysfunction have been reported. Immune reset should therefore be treated as a testable multidomain state: durable disease control after the acute treatment phase, withdrawal of conventional immunosuppression, evolution or recovery of the targeted immune compartment without immediate pathogenic recurrence, and preservation of clinically acceptable immune competence. It is not synonymous with cure, continued aplasia, complete autoantibody eradication, or reversal of fixed organ damage. Future development requires disease-specific comparative trials, biomarker-guided platform selection, standardized clinical and immune-reconstitution endpoints, transparent reporting of manufacturing attrition and cohort overlap, experienced multidisciplinary delivery, and long-term registries capturing infection, fertility, neurologic outcomes, secondary malignancy, relapse, retreatment, and patient-centered value. Until these data mature, autoimmune CAR therapy should remain investigational and restricted to highly selected patients in prospective programs.
2026-06-15 | CAR-T cell therapy for autoimmune diseases: current clinical trial landscape and the next wave of development.
Chimeric antigen receptor T-cell (CAR-T) therapy has expanded beyond oncology and is emerging as a promising strategy for autoimmune diseases. Early clinical experience, particularly with CD19-directed CAR-T cells, has shown that deep remission can occur in refractory disorders such as systemic lupus erythematosus, inflammatory myopathies, and systemic sclerosis. These observations are consistent with an immune-reset-like process, although its durability, cellular basis, and disease-specific mechanisms remain incompletely defined. However, the clinical development landscape remains uneven. Based on an April 2026 Trialtrove snapshot, the field is growing rapidly but remains concentrated in a limited number of countries, diseases, and target classes, with most studies in early-phase development. These features suggest that autoimmune CAR-T therapy has moved beyond proof of concept, but has not yet reached a mature, indication-optimized stage of clinical translation. In this Perspective, we argue that the next phase of progress will depend less on increasing trial numbers than on improving biological precision, platform diversity, and trial design. The current pipeline is dominated by CD19-centered programs and diseases in which B-cell depletion appears biologically plausible, but this approach is unlikely to be equally informative across autoimmune disease. Key questions remain regarding remission durability, relapse after B-cell reconstitution, patient selection, toxicity management, and scalability. Looking ahead, major opportunities include plasma cell-directed approaches, dual-target strategies, chimeric autoantigen receptor platforms, tolerance-oriented cell therapies, off-the-shelf products, and in vivo engineering. The near-term readout window will be critical in determining whether autoimmune CAR-T therapy becomes broadly deployable or remains limited to selected indications and settings.
2026-05-26 | Immunomodulatory Mechanisms of Mesenchymal Stromal Cells: Cytokine Networks and Therapeutic Potential Across Immune-Mediated, Inflammatory, and Regenerative Disorders.
Mesenchymal stromal cells (MSCs) are multipotent cells characterized by their regenerative capacity and strong immunomodulatory properties. In recent years, MSC-based therapy has attracted significant attention as a potential treatment for a wide range of immune-mediated and degenerative diseases. The therapeutic effects of MSCs are primarily mediated through paracrine signaling and secretion of cytokines that regulate immune responses and promote tissue repair. This review focuses on five key cytokines involved in MSC immunomodulation: interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). These cytokines interact within a complex signaling network that allows MSCs to suppress excessive inflammation and restore immune balance. The role of MSC therapy is examined in several clinically relevant conditions, including systemic lupus erythematosus, systemic sclerosis, ischemic stroke, spinal cord injury, diabetes mellitus, and female infertility. Across these diseases, MSCs demonstrate the ability to inhibit pro-inflammatory immune cell activity, promote regulatory immune phenotypes, reduce oxidative stress, and stimulate regeneration through the secretion of growth factors and extracellular vesicles. Despite promising experimental and early clinical findings, several limitations remain, including variability in MSC sources, limited cell survival after transplantation, and the need for optimized dosing strategies. Overall, MSC therapy represents a multifunctional therapeutic approach combining immunomodulation, anti-inflammatory activity, and regenerative support. Further research is required to better understand cytokine interactions, improve standardization of MSC-based treatments, and enhance clinical efficacy across diverse pathological conditions.
2026-04-08 | Chimeric antigen receptor macrophage (CAR-M) immunotherapy in autoimmune inflammatory rheumatic diseases.
Chronic autoimmune inflammatory rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, systemic sclerosis (SSc), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), are characterized by the dysregulation of the immune system and that of the neuroendocrine immune networks, leading to chronic inflammation and tissue damage. Perturbations of T, B, and macrophage cells result in uncontrolled inflammation. Traditional therapeutic approaches have focused on immunosuppressive drugs but more recently the use of biologics targeting specific cytokines or receptors on immune cells, and intracellular JAK pathways has been employed. However, these therapies often have limited efficacy and significant side effects. Moreover, they are not globally accessible due to high drug costs especially in poor as well as low- to middle-income countries. Cell immunotherapy, such as CAR-T and CAR-M cell therapy based on chimeric antigen receptor (CAR) technology, is opening up novel potential avenues for a precision approach to managing AIRD. This area is still experimental and in the research phase. This paper reviews the potential of CAR-M immunotherapy in AIRDs, highlighting its mechanisms of action and therapeutic applications.
2026-03-31 | Time-Controlled Refrigerated Stem Cell Therapy Mitigates Scleroderma Fibrosis via Modulation of Mitochondrial Autophagy and Gut Metabolism.
Scleroderma is a chronic autoimmune disease characterized by progressive fibrosis, associated with high morbidity and mortality, limited therapeutic efficacy, and significant systemic side effects. Therefore, there is an urgent need to develop novel treatment strategies with improved tissue targeting and safety profiles. In this study, a refrigerated-treated mesenchymal stem cell (RT-MSCs) system was established by culturing human umbilical cord-derived MSCs under controlled low-temperature conditions. The antifibrotic effects of RT-MSCs were evaluated through both in vivo and in vitro experiments, together with an assessment of their regulatory role in mitochondrial autophagy. Their lesion-targeting capacity was also investigated. Furthermore, the effects of RT-MSCs on gut microbiota composition and metabolic pathways in model mice were comprehensively analyzed using 16S rRNA sequencing and intestinal content metabolomics, and the safety of RT-MSCs was systematically evaluated. The results demonstrated that RT-MSCs effectively attenuated fibrosis progression by modulating mitochondrial autophagy. Within 30 min after administration, RT-MSCs accumulated at lesion sites and persisted for up to 7 days. RT-MSCs significantly improved intestinal microbiota dysbiosis in scleroderma mice and regulated the expression of associated intestinal metabolites. In summary, as an optimized stem cell-based therapeutic strategy, RT-MSCs offer new insights and potential avenues for treating scleroderma.
proteins
2025-02-26 | Hyaluronic Acid Binding Peptide Regulates Extracellular Matrix Deposition and Diminishes Fibroblast Contractility.
Fibroblasts are central to a variety of homeostatic events such as wound healing and tissue regeneration. However, their pathologic activation is thought to play roles in a variety of diseases not only limited to fibrosis, foreign body reaction, scleroderma but also cancer metastasis. Biophysical properties of the extracellular matrix (ECM) deposited by an activated fibroblast determine whether there is a pro-regenerative or scarring response. Compared to aged fibroblasts, embryonic fibroblasts were shown to deposit a pro-regenerative ECM characterized by early hyaluronic acid (HA) deposition and increased levels of pro-regenerative collagens such as type III collagen. Since HA is also a regulator of collagen organization, we propose that early accumulation of HA by fibroblasts can facilitate pro-regenerative matrix formation. Given that the molecular weights of HA present in pro-regenerative matrix are higher than synthetic HA, we strategize attracting HA synthesized by fibroblasts. In this study, we used a synthetic peptide sequence known to have affinity to HA as a strategy to instruct fibroblasts to retain HA on the surface. We hypothesized that hyaluronic acid binding peptide (HABP) may instruct fibroblast endogenous HA deposition onto functionalized surfaces. We functionalized silica glass surfaces with HABP using aminoorganosilane mediated chemisorption and screened primary human dermal fibroblasts (HDFs) for cell morphology, cytoskeletal arrangement, and alpha-smooth muscle actin (α-SMA) expression. Our results show HABP treated surfaces retain higher levels of HA on silica glass compared to control surfaces on fibroblast-derived matrices. Analysis of α-SMA shows increased α-SMA expression on hDFs and increased stress fiber formation. HABP treated surfaces were found to have reduced α-SMA expression. The physical features of collagen fibers deposited by fibroblasts were also organized differently in the presence of HABP. Due to their ability to diminish fibroblast contractility and promote regenerative ECM production, HABPs are a potentially viable strategy to instruct pro-regenerative fibroblasts and can be used therapeutically to treat fibrotic diseases.
2024-03-29 | Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis.
Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19, an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin34-76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.
2023-07-17 | Impaired Regulation by IL-35 in Systemic Sclerosis.
This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β (p < 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β (p < 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.
2021-09-29 | Safety and effectiveness of abatacept in systemic sclerosis: The EUSTAR experience.
To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc). Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests. Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p<0.03 and p<0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p<0.05) and on morning stiffness at 6 and 12 months (p<0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p<0.05). No changes in lung or gastrointestinal involvement were found. ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.
2021-07-13 | Abatacept in the treatment of localized scleroderma: A pediatric case series and systematic literature review.
Localized scleroderma (LS) is a rare chronic immune-mediated skin condition of unknown etiology characterized by an inflammatory response in the skin and subcutaneous tissues resulting in collagen deposition and subsequent fibrosis. There is no cure for LS. No therapies have been licensed specifically for the treatment of LS and the clinical management of the disease remains largely empirical. Abatacept, a recombinant fusion protein interfering with the T-cell costimulatory pathway, has been reported to be effective in adult cases of LS. We report the successful use of abatacept in a juvenile localized scleroderma (jLS) cohort and conduct a systematic literature review to evaluate the evidence supporting the use of abatacept in the treatment of LS. We compiled retrospectively the clinical data on 8 cases of jLS that were treated with abatacept in our academic center. A systematic review protocol was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines and has been registered with the international prospective register of systematic reviews (PROSPERO). Standardized searches of MEDLINE/PubMed and EMBASE were undertaken to identify studies reporting the use of abatacept in the treatment of LS. Heterogeneity in study design, interventions and reported outcomes necessitated a qualitative data synthesis. The use of abatacept was effective and safe in our cohort of jLS patients. Our standardized searches identified 30 articles, of which 3 deemed eligible for full data extraction. All 3 studies were small (total of 18 patients; mean 6 subjects per study), single center, open-label, uncontrolled and non-randomized. The Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS) identified high risk-of bias for confounding variables and blinding of assessors in each of the 3 studies evaluated and in our pediatric case series. The evidence-base to support the use of abatacept in the treatment of LS is currently limited and clinical practice guidelines should take a measured approach to such recommended therapy. Nonetheless, as the empirical evidence on the clinical effectiveness of abatacept in the treatment of LS accumulates, a double-blind placebo-controlled randomized clinical trial is necessary to formally evaluate the observations documented by case-based reports.
antibodies
2026-07-29 | [From CAR-T to T-cell engagers : New T-cell-based treatment in rheumatology].
Cellular forms of treatment mark a paradigm shift in the treatment of autoimmune diseases. While conventional and targeted antirheumatic treatment controls disease activity mostly by continued immunomodulation, innovative cellular approaches, especially chimeric antigen receptor (CAR) T‑cells targeting CD19, target a deep elimination of disease-relevant immune cell compartments with subsequent immunological reconstitution. This concept of an immune reset is particularly attractive for those diseases in which autoreactive B‑cells, plasmablasts, autoantibodies and misdirected lymphocyte networks are pathogenetically central. In addition, T‑cell engagers or bispecific T‑cell engagers (TCE) are now becoming of interest, which as off the shelf strategies without cellular production also enable a deep B‑cell or plasma cell depletion via T cell-mediated cytotoxicity. The most impressive clinical data so far are available for systemic lupus erythematosus (SLE), likewise accumulating indications for the efficacy in systemic sclerosis (SSc) and idiopathic inflammatory myositis (IIM). The concept is highly plausible for rheumatoid arthritis (RA) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) but is clinically still in an early developmental stage. Initial clinical experiences are available for TCE, especially for refractory RA and for severe connective tissue diseases, including SSc and antisynthetase syndrome. The evidence for other rheumatological indications is so far much more limited. This article discusses the biological principles, production and mechanisms of action, the revolutionary potential of these strategies, current evidence in selected rheumatological indications and open questions on safety, patient selection and future perspectives.
2026-07-28 | Imaging Modalities Related to Cardiac Involvement in Systemic Sclerosis.
Systemic sclerosis (SSc) is a chronic rheumatic disease characterized by the unique pathogenetic triad of microvasculopathy, autoimmunity, and fibrosis leading to significant morbidity/mortality. SSc has an annual incidence of 0.6 to 5.6/100 000, affects predominantly women and remains the most lethal of rheumatic diseases being the direct cause of death in >50% of patients. SSc with diffuse cutaneous involvement is defined as skin thickening proximal to the elbows/knees, whereas the limited form denotes cutaneous involvement limited to the distal extremities. Pulmonary fibrosis, pulmonary hypertension, and cardiac inflammation/fibrosis, although varying widely among patients in terms of severity, represent the main causes of death. Primary heart involvement occurs in the majority of patients at some disease stage but is overlooked. It may precede SSc diagnosis and should be carefully monitored using laboratory and imaging biomarkers. Among imaging biomarkers, echocardiography and cardiac magnetic resonance are the most commonly used. Echocardiography can provide functional information of both ventricles and assessment of pulmonary artery pressure. Additionally, strain echocardiography and cardiac magnetic resonance feature tracking can detect early systolic dysfunction before ejection fraction alterations take place. However, cardiac magnetic resonance, by providing functional assessment in parallel with tissue characterization, is the only imaging modality that has the potential to reveal early myocardial inflammation/replacement/diffuse fibrosis and coronary microvascular disease before any systolic alteration takes place. Prospective, multicenter studies that are currently under way will clarify the role of cardiac magnetic resonance in diagnosis, prognosis, and treatment decisions and will facilitate the conception of new imaging-based guidelines for cardiac involvement in SSc.
2026-07-21 | Beyond immune checkpoint blockade: T cell engagers and antibody-drug conjugates in cancer and autoimmune disease.
Immune checkpoint inhibitors have transformed cancer treatment; however, resistance, on-target toxicity, and limited efficacy in autoimmune disorders have motivated next-generation immunotherapies. T cell engagers (TCEs) redirect cytotoxic T cells to kill pathogenic cells independently of MHC restriction, whereas antibody-drug conjugates (ADCs) deliver potent payloads directly into target cells via receptor-mediated internalization. This review synthesizes preclinical and clinical data on TCEs and ADCs in oncology and immune-mediated inflammatory disorders (IMIDs). The CD47/SIRPα innate immune checkpoint is briefly examined as a case study in next-generation immunopharmacology, with agents like evorpacept and BYON4228 showing encouraging objective response rates (50% ORR) in non-hodgkin lymphoma when combined with rituximab, with next-generation designs reducing hematologic toxicity. Recent compassionate use findings in autoimmunity demonstrate that CD19 × CD3 TCE (blinatumomab) and (B-cell maturation antigen) BCMA × CD3 TCE (teclistamab) elicit rapid clinical improvement in refractory antisynthetase syndrome and systemic sclerosis, accompanied by cytokine release syndrome (CRS) (grade 3 in 40% and 100% of patients, respectively) and no neurotoxicity. In engineered TCEs with attenuated CD3 affinity, grade 1-2 CRS occurs in < 20% of patients. Beyond cell-depleting strategies, bispecific antibodies targeting OX40L/TNFα and anti-TL1A antibodies are advancing in hidradenitis suppurativa and rheumatic diseases. Conversely, ADC strategies have yielded mixed results; an anti-TNF-glucocorticoid receptor modulator ADC failed to outperform adalimumab in a phase 2b trial. Safety profiles differ: TCEs predominantly cause cytokine release syndrome, whereas ADCs pose off-target payload toxicity risks. Emerging dual-targeting TCEs, half-life-extended formats, and rational combinations illustrate key immunopharmacological principles that may broaden the therapeutic landscape for cancer and autoimmune diseases.
2026-06-01 | P.362 A rare presentation in limited cutaneous systemic sclerosis –’like in looks, so in the eyes’
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. 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. 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. 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?
2026-04-10 | Anti-CD52 therapy of rheumatic diseases: Revisited in the era of immune reset.
Alemtuzumab is a humanized monoclonal antibody targeting CD52, a glycosylphosphatidylinositol-anchored surface antigen broadly expressed on lymphocytes and other immune cells. Although currently approved for multiple sclerosis and used in selected transplantation settings, alemtuzumab was among the earliest lymphocyte-depleting biologics explored across a wide spectrum of autoimmune rheumatic diseases. With renewed interest in deep immune-depleting strategies, including CAR-T cells and bispecific T-cell engagers, revisiting the immunobiology and clinical experience of alemtuzumab is timely. This review summarizes current knowledge of CD52 structure, expression, and immunological function, highlighting its dual role as both a co-stimulatory and immunoregulatory molecule. We examine the mechanisms underlying alemtuzumab-induced lymphocyte depletion, subsequent immune reconstitution, and the paradoxical development of secondary autoimmunity. Clinical evidence for alemtuzumab use in rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, idiopathic inflammatory myopathies, ocular inflammatory disease, and Behçet's syndrome, is reviewed, with emphasis on efficacy, durability of response, and safety outcomes. Across multiple refractory disease settings, alemtuzumab has demonstrated the capacity to induce rapid clinical improvement and, in some cases, prolonged drug-free remission. However, treatment is limited by risks of infection, delayed immune reconstitution, and immune dysregulation. We conclude that alemtuzumab remains a potent immunomodulatory option in selected refractory rheumatic diseases, provided that careful patient selection, cautious monitoring, and long-term follow-up are implemented.
other
2024-06-03 | Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis.
Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited treatment strategies. This is in part due to our fragmented understanding of how dermal white adipose tissue (DWAT) contributes to skin fibrosis. We identified elevated sine oculis homeobox homolog 1 (SIX1) expression in SSc skin samples from the GENISOS and PRESS cohorts, the expression of which correlated with adipose-associated genes and molecular pathways. SIX1 localization studies identified increased signals in the DWAT area in SSc and in experimental models of skin fibrosis. Global and adipocyte specific Six1 deletion abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage induced by SQ bleomycin treatment. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. However, SIX1 deletion did not appear to affect cellular trans differentiation. Taken together these results point at SIX1 as a potential target for dermal fibrosis in SSc.
2023-05-30 | Differentially expressed genes in systemic sclerosis: Towards predictive medicine with new molecular tools for clinicians.
Systemic sclerosis (SSc) is a rare and chronic autoimmune disease characterized by a pathogenic triad of immune dysregulation, vasculopathy, and progressive fibrosis. Clinical tools commonly used to assess patients, including the modified Rodnan skin score, difference between limited or diffuse forms of skin involvement, presence of lung, heart or kidney involvement, or of various autoantibodies, are important prognostic factors, but still fail to reflect the large heterogeneity of the disease. SSc treatment options are diverse, ranging from conventional drugs to autologous hematopoietic stem cell transplantation, and predicting response is challenging. Genome-wide technologies, such as high throughput microarray analyses and RNA sequencing, allow accurate, unbiased, and broad assessment of alterations in expression levels of multiple genes. In recent years, many studies have shown robust changes in the gene expression profiles of SSc patients compared to healthy controls, mainly in skin tissues and peripheral blood cells. The objective analysis of molecular patterns in SSc is a powerful tool that can further classify SSc patients with similar clinical phenotypes and help predict response to therapy. In this review, we describe the journey from the first discovery of differentially expressed genes to the identification of enriched pathways and intrinsic subsets identified in SSc, using machine learning algorithms. Finally, we discuss the use of these new tools to predict the efficacy of various treatments, including stem cell transplantation. We suggest that the use of RNA gene expression-based classifications according to molecular subsets may bring us one step closer to precision medicine in Systemic Sclerosis.
2022-11-07 | MiR-27a as a diagnostic biomarker and potential therapeutic target in systemic sclerosis
Systemic sclerosis (SSc) or scleroderma is a multiorgan rheumatoid disease characterized by skin tightening or organ dysfunction due to fibrosis, vascular damage, and autoimmunity. No specific cause has been discovered for this illness, and hence no effective treatment exists for it. On the other hand, due to the lack of diagnostic biomarkers capable of effectively and specifically differentiating the patients, early diagnosis has not been possible. Due to their potent regulatory roles in molecular pathways, microRNAs are among the novel candidates for the diagnosis and treatment of diseases like SSc. MiR-27a is a microRNA known for its role in the pathogenesis of fibrosis and cancer, both of which employ similar signaling pathways; hence we hypothesized that Mir-27a could be dysregulated in the blood of individuals affected by SSc and it might be useful in the diagnosis or treatment of this disease. Blood was collected from 60 SSc patients (30 limited and 30 diffuse) diagnosed by a rheumatologist according to ACR/AULAR criteria; following RNA isolation and cDNA synthesis; real-time qPCR was performed on the samples using Taq-Man probes and data were analyzed by the ΔΔCT method. Also, potential targets of miR-27a were evaluated using bioinformatics. It was revealed that miR-27a was significantly down-regulated in SSc patients in comparison to healthy individuals, but there was no difference in miR-27 expression between limited and diffused SSc patients. Besides, miR-27a was found to target several contributing factors to SSc. It seems that miR-27a has a protective role in SSc, and its downregulation could result in the disease's onset. Based on bioinformatics analyses, it is speculated that miR-27a likely targets factors contributing to the pathogenesis of SSc, which are elevated upon the downregulation of miR-27a; hence, miR-27a mimics could be considered as potential therapeutic agents for the treatment of SSc in future studies. Since no difference was observed between limited and diffuse patient groups, it is unlikely that this microRNA has a role in disease progression. According to ROC analysis of qPCR data, miR-27a could be employed as a valuable diagnostic biomarker for SSc.
2022-05-27 | Localized scleroderma: actual insights and new biomarkers.
Localized scleroderma (LS, morphea, limited scleroderma, focal scleroderma) is a chronic autoimmune disease characterized by a progressive damage to the connective tissue with a predominance of fibrosclerotic disorders in the skin and the subcutaneous tissue. In addition surrounding structures may be affected: fascia, muscle, and bone tissues. This review reflects the current understanding about limited scleroderma, its pathogenesis, diagnosis, new biomarkers, and information about the possibilities of its transition to systemic scleroderma. The following new biomarkers have been identified: galactosylated IgG (Ig-Gal), progranulin (PGRN), chemokine CCXL 18, various types of microRNA (miRNA-let-7a, miRNA-7, miRNA-196a, miRNA-155, miRNA-483-5p), periostin, and myelin basic protein (MBP). Knowledge about new biomarkers of LS will help us to explore the patients' predisposition to the development of systemic scleroderma. In addition, by acting on these biomarkers, it is possible to prevent the progression of LS in the early stages and its transition to systemic scleroderma. The review also presents the current understanding of autoantibodies in LS and their correlation with clinical signs of the disease.
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.
small molecules
2026-07-24 | Why Men Fare Worse: Understanding Gender Disparities in Systemic Sclerosis-Associated Pulmonary Hypertension.
This study investigates gender disparities in clinical outcomes among patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH), focusing on cardiovascular events, right ventricular function, and survival. PAH is a severe and life-threatening complication of SSc, with male patients often experiencing worse outcomes despite its higher prevalence in women. Comparative data on gender differences in this population remain limited. We conducted a retrospective, single-center study including 61 patients with SSc-associated PAH (52 women, 9 men), confirmed by right heart catheterization. Clinical, serological, pulmonary, and echocardiographic data were analyzed. Differences between sexes in cardiovascular events, right ventricular dilation, and survival were evaluated using appropriate statistical methods. Male patients had a significantly higher incidence of cardiovascular events (median: 2.00 vs 1.00 in women; P = .031) and a greater prevalence of right ventricular dilation (100.00% vs 44.23%; P = .002). Kaplan-Meier analysis demonstrated reduced cardiovascular event-free survival (P = .001) and overall survival (P = .014) in men. Although mortality was higher in men (88.89%) than in women (57.69%), the difference was not statistically significant (P = .134). Men with SSc-associated PAH experience worse clinical outcomes, including more frequent cardiovascular events and reduced survival. The absence of estrogen's protective effects and the adverse influence of testosterone on cardiac remodeling may contribute to these disparities. These findings highlight the importance of early gender-specific risk stratification and the need for tailored therapeutic strategies to improve outcomes in this high-risk group.
2026-07-16 | Expression Profile and Clinical Significance of Ferroptosis-Related Genes in Peripheral Blood Mononuclear Cells of Patients with Systemic Sclerosis.
Systemic sclerosis (SSc) is a severe autoimmune disease marked by immune dysregulation and progressive fibrosis, yet reliable blood biomarkers remain limited. Ferroptosis, an iron‑dependent lipid peroxidation-driven cell death pathway, links iron/redox imbalance to inflammation and fibrotic remodeling, but its role in SSc is poorly defined. To profile Ferroptosis‑Related Genes (FRGs) in Peripheral Blood Mononuclear Cells (PBMCs) from SSc patients and assess their clinical significance. Transcriptional profiles from four SSc patients and six Healthy Controls (HCs) were analyzed using the Arraystar Human LncRNA Microarray to identify Differentially Expressed Genes (DEGs). Ferroptosis-related DEGs in SSc (Ferr-DEGs) were obtained by intersecting DEGs with a ferroptosis database, and key Ferr-DEGs were prioritized using bioinformatic analyses. Immune cell infiltration was estimated using single-sample gene set enrichment analysis (ssGSEA). The expression of selected genes was validated by quantitative real-time polymerase chain reaction (RT-qPCR) in an expanded cohort (SSc = 36, HC = 36), and correlations with clinical indicators were assessed. Diagnostic performance was evaluated using ROC curves. Microarray analysis revealed 397 upregulated and 637 downregulated DEGs in the SSc group. Bioinformatic analyses identified eight ferroptosis-associated key genes in SSc: MAPK14, SRC, ATF3, CYBB, ACSL1, STK11, PLIN2, and NCF2. MAPK14, SRC, ATF3, and CYBB were significantly upregulated in SSc compared with HCs, whereas ACSL1 was downregulated. Notably, SRC showed good diagnostic performance for SSc, with an AUC of 0.891 (95% CI, 0.819-0.964). Given the emerging link between ferroptosis and autoimmune diseases, exploring its role in the pathogenesis of Systemic Sclerosis (SSc) could open new avenues for improving diagnostic and therapeutic strategies. Our findings indicate significant dysregulation of FRGs in PBMCs from SSc patients, suggesting their potential involvement in inflammation, immune cell infiltration, and fibrosis; notably, SRC may serve as a candidate diagnostic marker for SSc.
2026-07-14 | Itaconate Ameliorates Skin Fibrosis Through Inhibition of HIF-1α/LDHA-Driven Aerobic Glycolysis.
Skin fibrosis is a hallmark of scleroderma and other fibrotic skin disorders, yet effective therapies remain limited. Immune-derived metabolites have emerged as regulators of inflammation and tissue remodeling, but whether metabolic reprogramming within dermal fibroblasts contributes to skin fibrosis remains unclear. Human fibrotic skin samples, a bleomycin-induced mouse model, and primary dermal fibroblasts were used to investigate the role of immune-responsive gene 1 (Irg1) and its metabolic product itaconate. Transcriptomic analyses, metabolic profiling, pharmacologic modulation, and genetic perturbation were employed to define downstream signaling mechanisms. Irg1 expression and endogenous itaconate levels were reduced in fibrotic human and murine skin. Restoration of itaconate significantly attenuated dermal thickening, collagen deposition, and fibroblast activation. Mechanistically, itaconate suppressed glycolytic reprogramming in activated fibroblasts, as evidenced by reduced glucose uptake, lactate production, and glycolytic enzyme expression. This metabolic effect was associated with inhibition of the Akt/GSK-3β pathway, destabilization of hypoxia-inducible factor 1α (HIF-1α), and subsequent downregulation of lactate dehydrogenase A (LDHA) transcription. Genetic or pharmacologic interference with HIF-1α or LDHA partially phenocopied itaconate's antifibrotic effects, supporting a functional link between itaconate signaling, fibroblast metabolism, and fibrotic progression. This study identifies loss of Irg1-itaconate signaling as a previously unrecognized driver of fibroblast metabolic reprogramming in skin fibrosis. By revealing a fibroblast-intrinsic, metabolism-centered mechanism linking immunometabolite deficiency to extracellular matrix overproduction, these findings extend itaconate's scope beyond immune regulation and highlight metabolic targeting of fibroblasts as a promising therapeutic strategy for fibrotic skin disease. Antioxid. Redox Signal. 45, 512-533.
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.
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.
cell therapies
2026-07-28 | CAR-based cellular therapies for autoimmune diseases: immune reset, clinical evidence, and translational boundaries.
CAR-based cellular therapy is emerging as a time-limited strategy for severe autoimmune disease, but its clinical value depends on more than early response. We conducted a structured narrative review with a targeted update of PubMed/MEDLINE and ClinicalTrials.gov through July 11, 2026, with study-level extraction and explicit handling of overlapping cohorts. Autologous CD19 CAR-T has the most mature evidence, particularly in systemic lupus erythematosus and other systemic rheumatic diseases, while one randomized phase 2b trial has evaluated transient mRNA BCMA-directed CAR-T in myasthenia gravis. Early studies also support disease-specific development in systemic sclerosis, idiopathic inflammatory myopathy, rheumatoid arthritis, autoimmune cytopenias, and selected neurologic disorders. However, cohorts remain small and heterogeneous, and severe cytokine release syndrome, neurotoxicity, hematotoxicity, infection, viral reactivation, hypogammaglobulinemia, and prolonged organ dysfunction have been reported. Immune reset should therefore be treated as a testable multidomain state: durable disease control after the acute treatment phase, withdrawal of conventional immunosuppression, evolution or recovery of the targeted immune compartment without immediate pathogenic recurrence, and preservation of clinically acceptable immune competence. It is not synonymous with cure, continued aplasia, complete autoantibody eradication, or reversal of fixed organ damage. Future development requires disease-specific comparative trials, biomarker-guided platform selection, standardized clinical and immune-reconstitution endpoints, transparent reporting of manufacturing attrition and cohort overlap, experienced multidisciplinary delivery, and long-term registries capturing infection, fertility, neurologic outcomes, secondary malignancy, relapse, retreatment, and patient-centered value. Until these data mature, autoimmune CAR therapy should remain investigational and restricted to highly selected patients in prospective programs.
2026-06-15 | CAR-T cell therapy for autoimmune diseases: current clinical trial landscape and the next wave of development.
Chimeric antigen receptor T-cell (CAR-T) therapy has expanded beyond oncology and is emerging as a promising strategy for autoimmune diseases. Early clinical experience, particularly with CD19-directed CAR-T cells, has shown that deep remission can occur in refractory disorders such as systemic lupus erythematosus, inflammatory myopathies, and systemic sclerosis. These observations are consistent with an immune-reset-like process, although its durability, cellular basis, and disease-specific mechanisms remain incompletely defined. However, the clinical development landscape remains uneven. Based on an April 2026 Trialtrove snapshot, the field is growing rapidly but remains concentrated in a limited number of countries, diseases, and target classes, with most studies in early-phase development. These features suggest that autoimmune CAR-T therapy has moved beyond proof of concept, but has not yet reached a mature, indication-optimized stage of clinical translation. In this Perspective, we argue that the next phase of progress will depend less on increasing trial numbers than on improving biological precision, platform diversity, and trial design. The current pipeline is dominated by CD19-centered programs and diseases in which B-cell depletion appears biologically plausible, but this approach is unlikely to be equally informative across autoimmune disease. Key questions remain regarding remission durability, relapse after B-cell reconstitution, patient selection, toxicity management, and scalability. Looking ahead, major opportunities include plasma cell-directed approaches, dual-target strategies, chimeric autoantigen receptor platforms, tolerance-oriented cell therapies, off-the-shelf products, and in vivo engineering. The near-term readout window will be critical in determining whether autoimmune CAR-T therapy becomes broadly deployable or remains limited to selected indications and settings.
2026-05-26 | Immunomodulatory Mechanisms of Mesenchymal Stromal Cells: Cytokine Networks and Therapeutic Potential Across Immune-Mediated, Inflammatory, and Regenerative Disorders.
Mesenchymal stromal cells (MSCs) are multipotent cells characterized by their regenerative capacity and strong immunomodulatory properties. In recent years, MSC-based therapy has attracted significant attention as a potential treatment for a wide range of immune-mediated and degenerative diseases. The therapeutic effects of MSCs are primarily mediated through paracrine signaling and secretion of cytokines that regulate immune responses and promote tissue repair. This review focuses on five key cytokines involved in MSC immunomodulation: interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). These cytokines interact within a complex signaling network that allows MSCs to suppress excessive inflammation and restore immune balance. The role of MSC therapy is examined in several clinically relevant conditions, including systemic lupus erythematosus, systemic sclerosis, ischemic stroke, spinal cord injury, diabetes mellitus, and female infertility. Across these diseases, MSCs demonstrate the ability to inhibit pro-inflammatory immune cell activity, promote regulatory immune phenotypes, reduce oxidative stress, and stimulate regeneration through the secretion of growth factors and extracellular vesicles. Despite promising experimental and early clinical findings, several limitations remain, including variability in MSC sources, limited cell survival after transplantation, and the need for optimized dosing strategies. Overall, MSC therapy represents a multifunctional therapeutic approach combining immunomodulation, anti-inflammatory activity, and regenerative support. Further research is required to better understand cytokine interactions, improve standardization of MSC-based treatments, and enhance clinical efficacy across diverse pathological conditions.
2026-04-08 | Chimeric antigen receptor macrophage (CAR-M) immunotherapy in autoimmune inflammatory rheumatic diseases.
Chronic autoimmune inflammatory rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, systemic sclerosis (SSc), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), are characterized by the dysregulation of the immune system and that of the neuroendocrine immune networks, leading to chronic inflammation and tissue damage. Perturbations of T, B, and macrophage cells result in uncontrolled inflammation. Traditional therapeutic approaches have focused on immunosuppressive drugs but more recently the use of biologics targeting specific cytokines or receptors on immune cells, and intracellular JAK pathways has been employed. However, these therapies often have limited efficacy and significant side effects. Moreover, they are not globally accessible due to high drug costs especially in poor as well as low- to middle-income countries. Cell immunotherapy, such as CAR-T and CAR-M cell therapy based on chimeric antigen receptor (CAR) technology, is opening up novel potential avenues for a precision approach to managing AIRD. This area is still experimental and in the research phase. This paper reviews the potential of CAR-M immunotherapy in AIRDs, highlighting its mechanisms of action and therapeutic applications.
2026-03-31 | Time-Controlled Refrigerated Stem Cell Therapy Mitigates Scleroderma Fibrosis via Modulation of Mitochondrial Autophagy and Gut Metabolism.
Scleroderma is a chronic autoimmune disease characterized by progressive fibrosis, associated with high morbidity and mortality, limited therapeutic efficacy, and significant systemic side effects. Therefore, there is an urgent need to develop novel treatment strategies with improved tissue targeting and safety profiles. In this study, a refrigerated-treated mesenchymal stem cell (RT-MSCs) system was established by culturing human umbilical cord-derived MSCs under controlled low-temperature conditions. The antifibrotic effects of RT-MSCs were evaluated through both in vivo and in vitro experiments, together with an assessment of their regulatory role in mitochondrial autophagy. Their lesion-targeting capacity was also investigated. Furthermore, the effects of RT-MSCs on gut microbiota composition and metabolic pathways in model mice were comprehensively analyzed using 16S rRNA sequencing and intestinal content metabolomics, and the safety of RT-MSCs was systematically evaluated. The results demonstrated that RT-MSCs effectively attenuated fibrosis progression by modulating mitochondrial autophagy. Within 30 min after administration, RT-MSCs accumulated at lesion sites and persisted for up to 7 days. RT-MSCs significantly improved intestinal microbiota dysbiosis in scleroderma mice and regulated the expression of associated intestinal metabolites. In summary, as an optimized stem cell-based therapeutic strategy, RT-MSCs offer new insights and potential avenues for treating scleroderma.
proteins
2025-02-26 | Hyaluronic Acid Binding Peptide Regulates Extracellular Matrix Deposition and Diminishes Fibroblast Contractility.
Fibroblasts are central to a variety of homeostatic events such as wound healing and tissue regeneration. However, their pathologic activation is thought to play roles in a variety of diseases not only limited to fibrosis, foreign body reaction, scleroderma but also cancer metastasis. Biophysical properties of the extracellular matrix (ECM) deposited by an activated fibroblast determine whether there is a pro-regenerative or scarring response. Compared to aged fibroblasts, embryonic fibroblasts were shown to deposit a pro-regenerative ECM characterized by early hyaluronic acid (HA) deposition and increased levels of pro-regenerative collagens such as type III collagen. Since HA is also a regulator of collagen organization, we propose that early accumulation of HA by fibroblasts can facilitate pro-regenerative matrix formation. Given that the molecular weights of HA present in pro-regenerative matrix are higher than synthetic HA, we strategize attracting HA synthesized by fibroblasts. In this study, we used a synthetic peptide sequence known to have affinity to HA as a strategy to instruct fibroblasts to retain HA on the surface. We hypothesized that hyaluronic acid binding peptide (HABP) may instruct fibroblast endogenous HA deposition onto functionalized surfaces. We functionalized silica glass surfaces with HABP using aminoorganosilane mediated chemisorption and screened primary human dermal fibroblasts (HDFs) for cell morphology, cytoskeletal arrangement, and alpha-smooth muscle actin (α-SMA) expression. Our results show HABP treated surfaces retain higher levels of HA on silica glass compared to control surfaces on fibroblast-derived matrices. Analysis of α-SMA shows increased α-SMA expression on hDFs and increased stress fiber formation. HABP treated surfaces were found to have reduced α-SMA expression. The physical features of collagen fibers deposited by fibroblasts were also organized differently in the presence of HABP. Due to their ability to diminish fibroblast contractility and promote regenerative ECM production, HABPs are a potentially viable strategy to instruct pro-regenerative fibroblasts and can be used therapeutically to treat fibrotic diseases.
2024-03-29 | Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis.
Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19, an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin34-76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.
2023-07-17 | Impaired Regulation by IL-35 in Systemic Sclerosis.
This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β (p < 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β (p < 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.
2021-09-29 | Safety and effectiveness of abatacept in systemic sclerosis: The EUSTAR experience.
To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc). Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests. Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p<0.03 and p<0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p<0.05) and on morning stiffness at 6 and 12 months (p<0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p<0.05). No changes in lung or gastrointestinal involvement were found. ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.
2021-07-13 | Abatacept in the treatment of localized scleroderma: A pediatric case series and systematic literature review.
Localized scleroderma (LS) is a rare chronic immune-mediated skin condition of unknown etiology characterized by an inflammatory response in the skin and subcutaneous tissues resulting in collagen deposition and subsequent fibrosis. There is no cure for LS. No therapies have been licensed specifically for the treatment of LS and the clinical management of the disease remains largely empirical. Abatacept, a recombinant fusion protein interfering with the T-cell costimulatory pathway, has been reported to be effective in adult cases of LS. We report the successful use of abatacept in a juvenile localized scleroderma (jLS) cohort and conduct a systematic literature review to evaluate the evidence supporting the use of abatacept in the treatment of LS. We compiled retrospectively the clinical data on 8 cases of jLS that were treated with abatacept in our academic center. A systematic review protocol was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines and has been registered with the international prospective register of systematic reviews (PROSPERO). Standardized searches of MEDLINE/PubMed and EMBASE were undertaken to identify studies reporting the use of abatacept in the treatment of LS. Heterogeneity in study design, interventions and reported outcomes necessitated a qualitative data synthesis. The use of abatacept was effective and safe in our cohort of jLS patients. Our standardized searches identified 30 articles, of which 3 deemed eligible for full data extraction. All 3 studies were small (total of 18 patients; mean 6 subjects per study), single center, open-label, uncontrolled and non-randomized. The Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS) identified high risk-of bias for confounding variables and blinding of assessors in each of the 3 studies evaluated and in our pediatric case series. The evidence-base to support the use of abatacept in the treatment of LS is currently limited and clinical practice guidelines should take a measured approach to such recommended therapy. Nonetheless, as the empirical evidence on the clinical effectiveness of abatacept in the treatment of LS accumulates, a double-blind placebo-controlled randomized clinical trial is necessary to formally evaluate the observations documented by case-based reports.
antibodies
2026-07-29 | [From CAR-T to T-cell engagers : New T-cell-based treatment in rheumatology].
Cellular forms of treatment mark a paradigm shift in the treatment of autoimmune diseases. While conventional and targeted antirheumatic treatment controls disease activity mostly by continued immunomodulation, innovative cellular approaches, especially chimeric antigen receptor (CAR) T‑cells targeting CD19, target a deep elimination of disease-relevant immune cell compartments with subsequent immunological reconstitution. This concept of an immune reset is particularly attractive for those diseases in which autoreactive B‑cells, plasmablasts, autoantibodies and misdirected lymphocyte networks are pathogenetically central. In addition, T‑cell engagers or bispecific T‑cell engagers (TCE) are now becoming of interest, which as off the shelf strategies without cellular production also enable a deep B‑cell or plasma cell depletion via T cell-mediated cytotoxicity. The most impressive clinical data so far are available for systemic lupus erythematosus (SLE), likewise accumulating indications for the efficacy in systemic sclerosis (SSc) and idiopathic inflammatory myositis (IIM). The concept is highly plausible for rheumatoid arthritis (RA) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) but is clinically still in an early developmental stage. Initial clinical experiences are available for TCE, especially for refractory RA and for severe connective tissue diseases, including SSc and antisynthetase syndrome. The evidence for other rheumatological indications is so far much more limited. This article discusses the biological principles, production and mechanisms of action, the revolutionary potential of these strategies, current evidence in selected rheumatological indications and open questions on safety, patient selection and future perspectives.
2026-07-28 | Imaging Modalities Related to Cardiac Involvement in Systemic Sclerosis.
Systemic sclerosis (SSc) is a chronic rheumatic disease characterized by the unique pathogenetic triad of microvasculopathy, autoimmunity, and fibrosis leading to significant morbidity/mortality. SSc has an annual incidence of 0.6 to 5.6/100 000, affects predominantly women and remains the most lethal of rheumatic diseases being the direct cause of death in >50% of patients. SSc with diffuse cutaneous involvement is defined as skin thickening proximal to the elbows/knees, whereas the limited form denotes cutaneous involvement limited to the distal extremities. Pulmonary fibrosis, pulmonary hypertension, and cardiac inflammation/fibrosis, although varying widely among patients in terms of severity, represent the main causes of death. Primary heart involvement occurs in the majority of patients at some disease stage but is overlooked. It may precede SSc diagnosis and should be carefully monitored using laboratory and imaging biomarkers. Among imaging biomarkers, echocardiography and cardiac magnetic resonance are the most commonly used. Echocardiography can provide functional information of both ventricles and assessment of pulmonary artery pressure. Additionally, strain echocardiography and cardiac magnetic resonance feature tracking can detect early systolic dysfunction before ejection fraction alterations take place. However, cardiac magnetic resonance, by providing functional assessment in parallel with tissue characterization, is the only imaging modality that has the potential to reveal early myocardial inflammation/replacement/diffuse fibrosis and coronary microvascular disease before any systolic alteration takes place. Prospective, multicenter studies that are currently under way will clarify the role of cardiac magnetic resonance in diagnosis, prognosis, and treatment decisions and will facilitate the conception of new imaging-based guidelines for cardiac involvement in SSc.
2026-07-21 | Beyond immune checkpoint blockade: T cell engagers and antibody-drug conjugates in cancer and autoimmune disease.
Immune checkpoint inhibitors have transformed cancer treatment; however, resistance, on-target toxicity, and limited efficacy in autoimmune disorders have motivated next-generation immunotherapies. T cell engagers (TCEs) redirect cytotoxic T cells to kill pathogenic cells independently of MHC restriction, whereas antibody-drug conjugates (ADCs) deliver potent payloads directly into target cells via receptor-mediated internalization. This review synthesizes preclinical and clinical data on TCEs and ADCs in oncology and immune-mediated inflammatory disorders (IMIDs). The CD47/SIRPα innate immune checkpoint is briefly examined as a case study in next-generation immunopharmacology, with agents like evorpacept and BYON4228 showing encouraging objective response rates (50% ORR) in non-hodgkin lymphoma when combined with rituximab, with next-generation designs reducing hematologic toxicity. Recent compassionate use findings in autoimmunity demonstrate that CD19 × CD3 TCE (blinatumomab) and (B-cell maturation antigen) BCMA × CD3 TCE (teclistamab) elicit rapid clinical improvement in refractory antisynthetase syndrome and systemic sclerosis, accompanied by cytokine release syndrome (CRS) (grade 3 in 40% and 100% of patients, respectively) and no neurotoxicity. In engineered TCEs with attenuated CD3 affinity, grade 1-2 CRS occurs in < 20% of patients. Beyond cell-depleting strategies, bispecific antibodies targeting OX40L/TNFα and anti-TL1A antibodies are advancing in hidradenitis suppurativa and rheumatic diseases. Conversely, ADC strategies have yielded mixed results; an anti-TNF-glucocorticoid receptor modulator ADC failed to outperform adalimumab in a phase 2b trial. Safety profiles differ: TCEs predominantly cause cytokine release syndrome, whereas ADCs pose off-target payload toxicity risks. Emerging dual-targeting TCEs, half-life-extended formats, and rational combinations illustrate key immunopharmacological principles that may broaden the therapeutic landscape for cancer and autoimmune diseases.
2026-06-01 | P.362 A rare presentation in limited cutaneous systemic sclerosis –’like in looks, so in the eyes’
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. 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. 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. 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?
2026-04-10 | Anti-CD52 therapy of rheumatic diseases: Revisited in the era of immune reset.
Alemtuzumab is a humanized monoclonal antibody targeting CD52, a glycosylphosphatidylinositol-anchored surface antigen broadly expressed on lymphocytes and other immune cells. Although currently approved for multiple sclerosis and used in selected transplantation settings, alemtuzumab was among the earliest lymphocyte-depleting biologics explored across a wide spectrum of autoimmune rheumatic diseases. With renewed interest in deep immune-depleting strategies, including CAR-T cells and bispecific T-cell engagers, revisiting the immunobiology and clinical experience of alemtuzumab is timely. This review summarizes current knowledge of CD52 structure, expression, and immunological function, highlighting its dual role as both a co-stimulatory and immunoregulatory molecule. We examine the mechanisms underlying alemtuzumab-induced lymphocyte depletion, subsequent immune reconstitution, and the paradoxical development of secondary autoimmunity. Clinical evidence for alemtuzumab use in rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, idiopathic inflammatory myopathies, ocular inflammatory disease, and Behçet's syndrome, is reviewed, with emphasis on efficacy, durability of response, and safety outcomes. Across multiple refractory disease settings, alemtuzumab has demonstrated the capacity to induce rapid clinical improvement and, in some cases, prolonged drug-free remission. However, treatment is limited by risks of infection, delayed immune reconstitution, and immune dysregulation. We conclude that alemtuzumab remains a potent immunomodulatory option in selected refractory rheumatic diseases, provided that careful patient selection, cautious monitoring, and long-term follow-up are implemented.
other
2024-06-03 | Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis.
Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited treatment strategies. This is in part due to our fragmented understanding of how dermal white adipose tissue (DWAT) contributes to skin fibrosis. We identified elevated sine oculis homeobox homolog 1 (SIX1) expression in SSc skin samples from the GENISOS and PRESS cohorts, the expression of which correlated with adipose-associated genes and molecular pathways. SIX1 localization studies identified increased signals in the DWAT area in SSc and in experimental models of skin fibrosis. Global and adipocyte specific Six1 deletion abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage induced by SQ bleomycin treatment. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. However, SIX1 deletion did not appear to affect cellular trans differentiation. Taken together these results point at SIX1 as a potential target for dermal fibrosis in SSc.
2023-05-30 | Differentially expressed genes in systemic sclerosis: Towards predictive medicine with new molecular tools for clinicians.
Systemic sclerosis (SSc) is a rare and chronic autoimmune disease characterized by a pathogenic triad of immune dysregulation, vasculopathy, and progressive fibrosis. Clinical tools commonly used to assess patients, including the modified Rodnan skin score, difference between limited or diffuse forms of skin involvement, presence of lung, heart or kidney involvement, or of various autoantibodies, are important prognostic factors, but still fail to reflect the large heterogeneity of the disease. SSc treatment options are diverse, ranging from conventional drugs to autologous hematopoietic stem cell transplantation, and predicting response is challenging. Genome-wide technologies, such as high throughput microarray analyses and RNA sequencing, allow accurate, unbiased, and broad assessment of alterations in expression levels of multiple genes. In recent years, many studies have shown robust changes in the gene expression profiles of SSc patients compared to healthy controls, mainly in skin tissues and peripheral blood cells. The objective analysis of molecular patterns in SSc is a powerful tool that can further classify SSc patients with similar clinical phenotypes and help predict response to therapy. In this review, we describe the journey from the first discovery of differentially expressed genes to the identification of enriched pathways and intrinsic subsets identified in SSc, using machine learning algorithms. Finally, we discuss the use of these new tools to predict the efficacy of various treatments, including stem cell transplantation. We suggest that the use of RNA gene expression-based classifications according to molecular subsets may bring us one step closer to precision medicine in Systemic Sclerosis.
2022-11-07 | MiR-27a as a diagnostic biomarker and potential therapeutic target in systemic sclerosis
Systemic sclerosis (SSc) or scleroderma is a multiorgan rheumatoid disease characterized by skin tightening or organ dysfunction due to fibrosis, vascular damage, and autoimmunity. No specific cause has been discovered for this illness, and hence no effective treatment exists for it. On the other hand, due to the lack of diagnostic biomarkers capable of effectively and specifically differentiating the patients, early diagnosis has not been possible. Due to their potent regulatory roles in molecular pathways, microRNAs are among the novel candidates for the diagnosis and treatment of diseases like SSc. MiR-27a is a microRNA known for its role in the pathogenesis of fibrosis and cancer, both of which employ similar signaling pathways; hence we hypothesized that Mir-27a could be dysregulated in the blood of individuals affected by SSc and it might be useful in the diagnosis or treatment of this disease. Blood was collected from 60 SSc patients (30 limited and 30 diffuse) diagnosed by a rheumatologist according to ACR/AULAR criteria; following RNA isolation and cDNA synthesis; real-time qPCR was performed on the samples using Taq-Man probes and data were analyzed by the ΔΔCT method. Also, potential targets of miR-27a were evaluated using bioinformatics. It was revealed that miR-27a was significantly down-regulated in SSc patients in comparison to healthy individuals, but there was no difference in miR-27 expression between limited and diffused SSc patients. Besides, miR-27a was found to target several contributing factors to SSc. It seems that miR-27a has a protective role in SSc, and its downregulation could result in the disease's onset. Based on bioinformatics analyses, it is speculated that miR-27a likely targets factors contributing to the pathogenesis of SSc, which are elevated upon the downregulation of miR-27a; hence, miR-27a mimics could be considered as potential therapeutic agents for the treatment of SSc in future studies. Since no difference was observed between limited and diffuse patient groups, it is unlikely that this microRNA has a role in disease progression. According to ROC analysis of qPCR data, miR-27a could be employed as a valuable diagnostic biomarker for SSc.
2022-05-27 | Localized scleroderma: actual insights and new biomarkers.
Localized scleroderma (LS, morphea, limited scleroderma, focal scleroderma) is a chronic autoimmune disease characterized by a progressive damage to the connective tissue with a predominance of fibrosclerotic disorders in the skin and the subcutaneous tissue. In addition surrounding structures may be affected: fascia, muscle, and bone tissues. This review reflects the current understanding about limited scleroderma, its pathogenesis, diagnosis, new biomarkers, and information about the possibilities of its transition to systemic scleroderma. The following new biomarkers have been identified: galactosylated IgG (Ig-Gal), progranulin (PGRN), chemokine CCXL 18, various types of microRNA (miRNA-let-7a, miRNA-7, miRNA-196a, miRNA-155, miRNA-483-5p), periostin, and myelin basic protein (MBP). Knowledge about new biomarkers of LS will help us to explore the patients' predisposition to the development of systemic scleroderma. In addition, by acting on these biomarkers, it is possible to prevent the progression of LS in the early stages and its transition to systemic scleroderma. The review also presents the current understanding of autoantibodies in LS and their correlation with clinical signs of the disease.
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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Drug Discovery Landscape
19 orphan drug designations for Limited systemic sclerosis.
19 orphan drug designations for Limited systemic sclerosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Zolacabtagene autoleucel | cell therapies | EMA | 2026-08-20 | — | Bristol-Myers Squibb Pharma EEIG |
2-[1-(3-{6-[(1E)-(hydroxyimino)methyl]-5-methyl-4-oxo-7-propyl-3H,4H-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-4-propoxybenzenesulfonyl)piperidin-4-yl]ethyl nitrate | small molecules | FDA | 2025-08-11 | — | Topadur Pharma AG |
Iloprost | small molecules | EMA | 2025-06-20 | — | MWB Consulting |
artesunate | small molecules | FDA | 2025-01-31 | — | Artasome Therapeutics, LLC |
Avenciguat | small molecules | EMA | 2024-11-11 | — | Boehringer Ingelheim International GmbH |
anti-ephrinB2 humanized IgG1 monoclonal antibody | antibodies | FDA | 2024-10-18 | — | Mediar Therapeutics, Inc. |
autologous anti-CD19 CAR T cell immunotherapy | cell therapies | FDA | 2024-09-20 | — | Kyverna Therapeutics, Inc. |
Ziritaxestat | small molecules | EMA | 2020-01-09 | — | Lakefront Biotherapeutics |
Romilkimab | antibodies | EMA | 2020-01-09 | — | Sanofi-Aventis Groupe |
Lenabasum | small molecules | EMA | 2017-01-12 | — | Pharma Gateway AB |
Nintedanib esylate [Ofev] | small molecules | EMA | 2016-08-29 | — | Boehringer Ingelheim International GmbH |
Autologous adipose tissue-derived stromal vascular fraction | cell therapies | EMA | 2016-04-28 | — | Scendea (NL) B.V. |
Lanifibranor [IVA 337] | small molecules | EMA | 2014-11-19 | — | Inventiva S.A.S. |
Riociguat [Adempas] | small molecules | EMA | 2014-07-29 | — | Bayer AG |
Terguride | small molecules | EMA | 2013-02-08 | — | [INACTIVE] High Tech Participations GmbH |
TERGURIDE HYDROGENMALEATE | small molecules | EMA | 2013-01-24 | — | Medac Gesellschaft für klinische Spezialpräparate mbH |
Pomalidomide [Imnovid] | small molecules | EMA | 2012-04-26 | — | Celgene Europe Limited |
Metelimumab | antibodies | EMA | 2002-02-04 | — | [INACTIVE] Sanofi B.V. |
Halofuginone hydrobromide | small molecules | EMA | 2001-12-11 | — | PPD Global Limited |
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