Preferential phosphodiesterase inhibition as a novel strategy to modulate key pathways in systemic sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease marked by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. The high disease burden and impact on quality of life highlight the need for therapies that target underlying pathogenic mechanisms rather than merely treating organ-specific symptoms. Phosphodiesterases, including phosphodiesterase 4B (PDE4B), are key regulators of cellular function and inflammatory responses of several cell types central to SSc pathogenesis. Given PDE4B's broad effects, targeting it may provide benefits beyond organ-specific manifestations and improve current care. Selective PDE4B inhibition represents a novel therapeutic approach for SSc, with improved subtype selectivity compared with earlier pan-PDE4 inhibitors. Nerandomilast preferentially inhibits PDE4B (ninefold over PDE4D), potentially improving tolerability versus oral pan-PDE4 inhibitors by avoiding adverse events such as gastrointestinal intolerance. Preclinical findings in SSc-relevant mouse and cell models show that PDE4B inhibition modulates inflammatory cytokine secretion, smooth muscle cell tension, endothelial and epithelial barrier integrity, and extracellular matrix synthesis under oxidative stress; this suggests nerandomilast could attenuate immune dysregulation, fibrosis, and potentially impact vasculopathy. Two pivotal Phase III trials evaluated nerandomilast in patients with idiopathic pulmonary fibrosis (FIBRONEER™-IPF; NCT05321069) and progressive pulmonary fibrosis (FIBRONEER™-ILD; NCT05321082), the latter of which included patients with SSc-associated interstitial lung disease (SSc-ILD). The ongoing CONQUEST trial (NCT06195072) is investigating the efficacy and safety of various drugs, including nerandomilast, in patients with early active SSc-ILD. This perspective highlights the rationale for targeting PDE4B in SSc therapy and explores preclinical findings in SSc and clinical findings in SSc-ILD to date.