2025 Systemic Sclerosis Therapies: CAR-T Cells, Bispecifics and Precision Medicine

Systemic sclerosis remains one of the most treatment-resistant autoimmune diseases, combining immune dysregulation, progressive fibrosis and vasculopathy that together drive severe organ damage and premature death. Pulmonary complications—interstitial lung disease (ILD) in up to 80% of patients and pulmonary arterial hypertension (PAH)—are the leading causes of SSc-related mortality. Gastrointestinal involvement affects nearly 90% of patients, and digital ulcers occur in roughly half, underscoring the multisystem burden of the disease. This review by Sieiro Santos and Del Galdo, published in RMD Open in July 2025, provides a comprehensive update on both standard organ-based care and an accelerating wave of novel therapies.

Established immunosuppressive regimens—mycophenolate mofetil, cyclophosphamide and rituximab—continue to anchor management of skin and lung disease, while autologous haematopoietic stem cell transplantation (HSCT) remains the only proven disease-modifying option for carefully selected high-risk patients. Tocilizumab and nintedanib have secured roles in slowing SSc-ILD progression, and PAH management has improved substantially through early combination therapy with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, selexipag and riociguat. Despite these advances, no approved therapy reliably reverses the underlying disease process.

The most striking emerging data involve CD19-targeted CAR-T cell therapy. In patients with diffuse cutaneous SSc, CAR-T19 achieved a 100% probability of ACR-CRISS improvement at 6 months, a 31% median reduction in modified Rodnan skin scores within 100 days, a 4% reduction in CT-quantified lung disease extent, and a median 195 mL gain in forced vital capacity—remarkable outcomes in a disease where FVC typically declines. A Novartis Phase 2 randomised trial (NCT06655896) comparing rapcabtagene autoleucel with rituximab, with up to 15 years of long-term follow-up, is now underway. Bispecific antibodies targeting CD3/CD19, CD3/CD20 or fibroblast activation protein represent a complementary frontier still in preclinical development.

Several phase 2b trials are evaluating precision biologics across SSc manifestations. Anifrolumab, already approved in lupus, targets the type I interferon receptor upstream of both autoimmunity and fibrosis (NCT05925803). Belimumab is being trialled in SSc-ILD through BAFF inhibition (NCT05878717). The CONQUEST platform trial (NCT06195072) is simultaneously assessing nerandomilast (PDE4B inhibitor, previously effective in idiopathic pulmonary fibrosis) and amlitelimab (anti-OX40 ligand, effective in atopic dermatitis) in early active SSc-ILD. MT-7117, a melanocortin receptor agonist, targets both inflammatory and fibrotic pathways. FcRn inhibitors, which reduce pathogenic IgG autoantibodies, and avenciguat, a soluble guanylate cyclase activator evaluated in the VITALISScE study, further broaden the pipeline. Telitacicept, a dual BLyS/APRIL inhibitor, is under investigation in early diffuse SSc.

Biomarker integration is increasingly enabling personalised risk stratification. Serum markers KL-6, SP-D and CCL18 correlate with ILD severity; CXCL4 and endostatin flag vascular risk including PAH and digital ulcers; skin biopsy gene-expression signatures identify inflammatory versus fibroproliferative endotypes that may predict biologic response; and novel autoantibodies such as anti-ETAR and anti-AT1R refine prediction of renal crisis and PAH. These tools, combined with precision therapeutic targeting, represent a foundational shift from symptom management toward early, mechanism-driven disease modification in SSc.