Combined immunosuppressive therapy in systemic sclerosis-associated interstitial lung disease: Phenotypes matter

Current evidence suggests that combined immunosuppressive therapy with mycophenolate mofetil (MMF)-or less frequently cyclophosphamide (CYC)- plus a biologic agent-such as rituximab (RTX) or tocilizumab (TCZ)-is a rational and effective strategy in inflammatory, progressive systemic sclerosis (SSc)-associated interstitial lung disease (ILD), particularly when ILD coexists with other SSc domains encompassing skin involvement, arthritis, and myositis. Although recommendations agree on the importance of early treatment and close monitoring, the optimal strategy for treatment escalation in extensive or progressive SSc-ILD remains undefined. In clinical practice, switching, sequential add-on, or upfront combination therapies are therefore frequently individualized according to the disease trajectory, radiological phenotype, inflammatory activity, and patient-specific risk factors, while a universal algorithm is lacking. The path forward is therefore to embed them in phenotype-driven, treatable trait-based algorithms. While awaiting dedicated phenotype-based studies, treatment decisions should aim to reflect disease biology: in mild inflammatory and mild fibrotic SSc-ILD, MMF can be started as backbone therapy; if ILD worsening occurs or the target MMF dosage cannot be achieved, patients with the inflammatory phenotype could benefit from a sequential add-on therapy with a biologic agent, while for the fibrotic phenotype, nintedanib should be added. An upfront combination therapy is advisable for severe inflammatory and fibrotic SSc-ILD, i.e. MMF plus a biologic agent or nintedanib, respectively. In case of worsening, switching MMF with CYC should be considered. The optimal positioning of newer therapies, including emerging B-cell-targeting agents, such as ianalumab, and novel antifibrotics, such as nerandomilast, remains to be defined within this evolving therapeutic landscape.