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:
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 | 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.
2026-07-28 | 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.
2026-07-24 | 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.
2026-07-21 | 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.
2026-07-29 | [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 | 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.
2026-07-28 | 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.
2026-07-24 | 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.
2026-07-21 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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