Systemic sclerosis (SSc) is a multi-system autoimmune disease of fibrosis and vasculopathy, in which interstitial lung disease (SSc-ILD) is a leading cause of death. Recent trials have moved the field from broad immunosuppression toward targeted antifibrotic and B-cell strategies — and, most recently, toward cellular therapy.
Antifibrotic and biologic therapy for lung disease
Nintedanib, a tyrosine kinase inhibitor targeting fibrotic pathways, was the first antifibrotic approved for SSc-ILD: in the SENSCIS trial it significantly slowed the annual decline in forced vital capacity (−52.4 vs −93.3 mL/year), with diarrhea the most common side effect. Tocilizumab, an IL-6 receptor antibody, preserved lung function in early diffuse SSc-ILD in the focuSSced trial (FVC change −0.1% vs −6.3% predicted at 48 weeks) without a clear skin benefit, and is used, sometimes off-label, in early progressive disease. Rituximab improved both skin thickening and FVC in the DESIRES trial and is generally better tolerated than cyclophosphamide.
First-line immunosuppression
The Scleroderma Lung Study II established that mycophenolate mofetil and cyclophosphamide have comparable efficacy in SSc-ILD, but mycophenolate is better tolerated, making it the preferred first-line agent; cyclophosphamide is reserved for rapidly progressive, severe disease. These positions are reflected in the 2023 ACR/CHEST guideline for ILD in autoimmune disease.
Cell therapy: an emerging frontier
The most exciting new development is CD19-targeted CAR-T cell therapy. In a case series of patients with diffuse systemic sclerosis, CD19 CAR-T produced meaningful improvement in skin score (a mean reduction of around 9 points on the modified Rodnan skin score) and drug-free remission by deeply resetting B-cell-driven autoimmunity. As across other autoimmune diseases, the data are early and uncontrolled — and relapse rates in SSc appear higher than in lupus — but the approach may address a disease that has long resisted immunomodulation.
Beyond these, management of pulmonary arterial hypertension (with PDE-5 inhibitors, endothelin-receptor antagonists, and prostacyclins) and of Raynaud's and digital ulcers remains central to comprehensive care.
| Therapy | Indication | Key result | Role |
|---|---|---|---|
| Nintedanib | SSc-ILD | Slowed FVC decline (SENSCIS) | Antifibrotic, first/second-line |
| Tocilizumab | Early SSc-ILD | FVC preserved (focuSSced) | Early progressive disease |
| Rituximab | Progressive SSc/ILD | Improved skin and FVC (DESIRES) | Refractory / skin + lung |
| Mycophenolate | SSc-ILD | Comparable to cyclophosphamide, better tolerated | First-line |
| CD19 CAR-T | Diffuse SSc | Skin improvement, drug-free remission | Experimental |
Further reading: SENSCIS nintedanib (Distler et al., NEJM 2019); focuSSced tocilizumab (Roofeh et al., 2021); DESIRES rituximab (2021–2023); Scleroderma Lung Study II; CD19 CAR-T in diffuse SSc (Lancet Rheumatology 2025).