Sclérose systémique

Overview

Sclérose systémique (SSc), aussi appelée sclérodermie systémique, est une maladie auto-immune rare dans laquelle une dysfonction immunitaire, des dommages aux petits vaisseaux sanguins et une production excessive de collagène provoquent la cicatrisation (fibrose) de la peau et potentiellement des poumons, du cœur, des reins et du tractus digestif. Elle débute généralement à l’âge adulte et affecte les femmes de manière bien plus fréquente que les hommes; la gravité de la maladie varie considérablement, allant de symptômes principalement cutanés et circulatoires à une maladie d’organes internes potentiellement mortelle. Il n’existe actuellement aucun remède établi. NIAMS overview Global epidemiology meta-analysis

Current care is individualized and focuses on preventing irreversible organ damage: immune-suppressing medicines such as mycophenolate or cyclophosphamide for inflammatory lung or skin disease; targeted therapies including rituximab or tocilizumab in selected patients; nintedanib to slow decline in lung function in SSc-associated interstitial lung disease (ILD); vasodilators for Raynaud phenomenon, digital ulcers, and pulmonary arterial hypertension; and physical, occupational, gastrointestinal, and cardiopulmonary care. For carefully selected people with rapidly progressive diffuse SSc, high-dose immune therapy followed by autologous hematopoietic stem-cell transplantation (HSCT) is an intensive disease-modifying option. EULAR treatment recommendations NIAMS diagnosis and treatment

Scope of Recent Research (2020–present)

Recent research has become more ambitious: rather than only slowing fibrosis or treating individual organs, investigators are testing whether the autoimmune system can be durably “reset,” especially by HSCT and CD19-directed chimeric antigen receptor (CAR) T cells that eliminate antibody-producing B-cell lineages. Parallel work is seeking medicines that interrupt fibroblast activation, vascular injury, and inflammatory signaling, while platform trials and detailed biological profiling aim to match treatments to the patients most likely to benefit. The field has credible early signals of deep remission, but no therapy has yet demonstrated that it reliably cures SSc across patients or reverses established organ scarring. CD19 CAR-T case series CONQUEST platform-trial design

Major Breakthroughs and Emerging Therapies

Immune reset with autologous HSCT. HSCT remains the strongest established example of a treatment that can produce prolonged, treatment-free disease control in severe diffuse SSc. It uses chemotherapy and immune-depleting treatment to remove much of the malfunctioning immune system, then reinfuses the patient’s own blood-forming stem cells to rebuild it. A prospective European real-world study of 80 transplanted patients reinforced the effectiveness observed in earlier randomized trials, while also underscoring that this procedure is reserved for specialized centers and patients without advanced, high-risk heart or lung disease. European HSCT prospective study EULAR treatment recommendations

Autologous CD19 CAR-T cells. CAR-T therapy genetically equips a patient’s T cells to recognize CD19, a marker on B cells. The goal is a deeper, more sustained B-cell depletion than standard antibody therapies, potentially allowing the re-emerging immune system to become tolerant rather than autoreactive. In a 2024–2025 Erlangen case series, six people with severe diffuse SSc that had not responded to at least two prior treatments received CD19 CAR-T cells; during a median 487 days of follow-up, no prespecified progression or treatment-intensification events occurred, and composite response scores, skin disease, imaging, laboratory, and patient-reported measures improved. This is an important proof of concept, not proof of cure, because it was an uncontrolled series of six patients. Erlangen CD19 CAR-T case series

Off-the-shelf, gene-edited CAR-T cells. A 2024 Cell report tested donor-derived CD19 CAR-T cells edited with CRISPR-Cas9 to reduce immune rejection in two people with diffuse cutaneous SSc. The cells persisted for more than three months, depleted B cells within two weeks, and the two SSc participants had deep clinical remission with improvement in inflammatory and fibrotic findings through six months, without cytokine-release syndrome or other serious adverse events in that very small report. If confirmed, donor-derived products could make CAR-T treatment faster and more scalable than individually manufactured autologous products. Allogeneic gene-edited CAR-T study

Anti-fibrotic and immune-targeted medicines. Drug development continues to test ways to suppress the immune signals that drive fibroblasts—the cells that produce scar tissue—and to directly inhibit fibrosis. Romilkimab, an antibody blocking interleukin-4 and interleukin-13 signaling, produced a statistically significant reduction in skin fibrosis in a 24-week phase 2 trial, but needs confirmatory development. In contrast, a small phase 2 study of the ROCK2 inhibitor belumosudil was stopped early and did not show a placebo-adjusted signal on its primary composite response endpoint, illustrating the difficulty of translating biologically plausible anti-fibrotic mechanisms into clear patient benefit. Romilkimab phase 2 trial Belumosudil phase 2 trial

Clinical Trials and Experimental Approaches

The most cure-oriented clinical programs are now CAR-T trials. Cabaletta Bio’s recruiting RESET-SSc study, NCT06328777, is an open-label phase 1/2 trial of autologous CD19 CAR-T therapy CABA-201, also called rese-cel, in adults with severe skin or organ involvement from SSc. Fate Therapeutics’ recruiting NCT06308978 is a phase 1 basket trial of FT819, an induced-pluripotent-stem-cell-derived, donor-origin CD19 CAR-T product, in systemic sclerosis and other B-cell-mediated autoimmune diseases. These studies are principally designed to establish safety, cell persistence, B-cell depletion, and preliminary activity; neither has yet established durable cure-level outcomes. RESET-SSc trial FT819 phase 1 trial

The Scleroderma Research Foundation-sponsored CONQUEST study, NCT06195072, is a multicenter phase 2b adaptive platform trial for early active SSc-ILD. It began recruitment in April 2024 across more than 150 centers in over 25 countries and initially evaluates amlitelimab and nerandomilast against placebo, using change in forced vital capacity—the amount of air a person can forcibly exhale—as its main outcome. Platform design allows multiple therapies to be compared using shared infrastructure, potentially speeding decisions about which candidates should advance to larger trials. CONQUEST platform-trial design

Recent completed trials also provide necessary negative results. In Scleroderma Lung Study III, adding pirfenidone to mycophenolate for 18 months did not significantly improve lung-function change compared with mycophenolate alone; the trial enrolled only 51 of its intended 150 participants, and discontinuations and adverse events were numerically more frequent with the combination. Scleroderma Lung Study III A phase 1/2 study of allogeneic bone-marrow-derived mesenchymal stromal cells in 20 people with severe diffuse SSc found a single infusion feasible and without treatment-related serious adverse events, but a randomized trial is still needed to determine efficacy. Mesenchymal stromal-cell phase 1/2 study

Methodologies and Scientific Approaches

SSc research increasingly combines clinical outcomes with molecular measurements. Trials track skin thickness using the modified Rodnan skin score, lung function using forced vital capacity and gas-transfer testing, high-resolution CT imaging, autoantibodies, B-cell recovery, and composite response indices such as ACR-CRISS. CAR-T studies additionally measure expansion and persistence of engineered cells, depletion and return of B cells, immunoglobulin levels, infections, cytokine-release syndrome, and neurologic toxicity. Erlangen CD19 CAR-T case series CAR-T in HSCT-ineligible patients

Researchers are also building patient-derived disease models that better reflect the interaction of immunity, blood vessels, and fibrosis. In one 2022 study, induced pluripotent stem cells from people with SSc were converted into skin cells and three-dimensional skin organoids, enabling screening of 770 approved drugs; raloxifene reduced fibrosis-related measures in those models and in mice, but has not been proven clinically effective for SSc. A 2026 blood-vessel-organoid study combined RNA sequencing, epigenetic analysis, and spatial protein profiling; removing immunoglobulin G from SSc serum restored vascular structure in the model, supporting a role for pathogenic antibodies and identifying Notch/γ-secretase signaling as a possible experimental target. iPSC skin-organoid drug screen SSc blood-vessel organoids

Leading Institutions and Funding

University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg have led influential autologous CD19 CAR-T work in severe diffuse SSc, while Shanghai Changzheng Hospital, East China Normal University, and BRL Medicine have advanced gene-edited allogeneic CAR-T approaches. Major multicenter trial infrastructure includes Cabaletta Bio’s RESET-SSc program, Fate Therapeutics’ FT819 program, and the Scleroderma Research Foundation’s CONQUEST platform trial. Erlangen CD19 CAR-T case series Allogeneic gene-edited CAR-T study RESET-SSc trial FT819 phase 1 trial CONQUEST platform-trial design

Patient-focused foundations are important funders and organizers in this rare disease. The National Scleroderma Foundation reported $1.4 million in 2024 research grants and more than $33 million committed since 1998; its current research investment exceeds $1.5 million annually. The Scleroderma Research Foundation funds investigator-initiated and early-career work and supports the U.S. CONQUER registry, which had enrolled more than 1,400 patients across 20 major U.S. scleroderma centers by July 2026. National Scleroderma Foundation 2024 grants National Scleroderma Foundation research program CONQUER Registry SRF grant program

Strengths, Limitations, and Challenges

The central strength of the current field is that it now addresses a plausible root driver of disease: autoreactive B-cell immunity. HSCT has shown that deep immune reconstitution can produce long-lasting benefit, and the early CAR-T reports show simultaneous improvement in skin, lung, gastrointestinal, and inflammatory manifestations in some heavily pretreated patients. CAR-T may also be less toxic than myeloablative transplantation for some people, although that possibility remains unproven in comparative studies. European HSCT prospective study Erlangen CD19 CAR-T case series

The limitations are substantial. Published CAR-T evidence in SSc still consists primarily of case reports and small uncontrolled series, with limited follow-up and potential selection bias. Serious risk remains possible: in a five-patient report involving people ineligible for HSCT, one participant died after delayed, marked CAR-T expansion associated with herpes simplex virus infection and suspected underlying TET2-related vulnerability. Cell therapies also require specialized manufacturing, lymphodepleting chemotherapy, close infection monitoring, and high-cost hospital-based care. Meanwhile, conventional anti-fibrotic trials have often been small, underpowered, or negative, and it remains uncertain how much established fibrosis in lung, heart, kidney, or gut can truly reverse once present. CAR-T in HSCT-ineligible patients Belumosudil phase 2 trial Scleroderma Lung Study III

Outlook and Future Directions

À la date du 29 septembre 2026, la sclérose systémique n’est pas proche d’un remède largement validé, mais le domaine est plus proche qu’en 2020 d’évaluer des traitements à visée curative. Les jalons décisifs seront des études CAR-T contrôlées plus vastes montrant une rémission sans traitement sur plusieurs années; la preuve que les issues pulmonaires, cardiaques, gastro-intestinaux et vasculaires s’améliorent plutôt que de se stabiliser; une comparaison rigoureuse entre CAR-T, HSCT et les soins standard modernes; et des produits cellulaires prêts à l’emploi plus sûrs et plus accessibles. Parallèlement, les essais de plateforme, les registres et les organoïdes dérivés des patients devraient aider à identifier quel sous-type biologique de SSc est le plus susceptible de répondre avant le développement d’une fibrose irréversible. RESET-SSc trial CONQUEST platform-trial design SSc blood-vessel organoids

Références

• NIAMS overview — Institut national d’arthrite et des maladies musculo-squelettiques et cutanées, 2026.
• Global epidemiology meta-analysis — Bairkdar et al., 2021.
• EULAR treatment recommendations — Del Galdo et al., 2024.
• NIAMS diagnosis and treatment — National Institute of Arthritis and Musculoskeletal and Skin Diseases, 2026.
• Étude prospective européenne sur la greffe de cellules souches hématopoïétiques — Henes et al., 2021.
• Série de cas CD19 CAR-T d’Erlangen — Auteurs et al., 2025.
• Allogeneic gene-edited CAR-T study — Wang et al., 2024.
• Romilkimab phase 2 trial — Allanore et al., 2020.
• Belumosudil phase 2 trial — Chung et al., 2025.
• RESET-SSc trial — Mayo Clinic, 2026.
• FT819 phase 1 trial — Montefiore Einstein, 2026.
• CONQUEST platform-trial design — Khanna et al., 2024.
• Scleroderma Lung Study III — Khanna et al., 2025.
• Étude de phase 1/2 sur les cellules stromales mésenchymales — Farge et al., 2022.
• CAR-T in HSCT-ineligible patients — Pecher et al., 2025.
• iPSC skin-organoid drug screen — Kim et al., 2022.
• organoïdes vasculaires sanguins SSc — Matei et al., 2026.
• National Scleroderma Foundation 2024 grants — National Scleroderma Foundation, 2024.
• National Scleroderma Foundation research program — National Scleroderma Foundation, 2026.
• CONQUER Registry — Scleroderma Research Foundation, 2026.
• SRF grant program — Scleroderma Research Foundation, 2026.