Nerandomilast in Autoimmune-Associated Interstitial Lung Diseases: Translating Evidence from Progressive Pulmonary...

Systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD) comprises a heterogeneous group of fibrosing lung disorders frequently complicated by progressive pulmonary fibrosis, a phenotype associated with accelerated lung function decline and increased mortality. Although antifibrotic therapies have improved clinical outcomes, significant unmet needs remain, particularly regarding treatment tolerability and integration with background immunosuppressive strategies. Preferential phosphodiesterase-4B (PDE4B) inhibition has emerged as a novel therapeutic approach targeting both inflammatory and fibrotic pathways through modulation of intracellular cyclic adenosine monophosphate signaling. This narrative review summarizes the biological rationale and emerging clinical evidence supporting nerandomilast, an oral preferential PDE4B inhibitor, in autoimmune-associated interstitial lung diseases. Preclinical data indicate that PDE4B inhibition may attenuate fibroblast activation, inflammatory signaling, and extracellular matrix deposition. Clinical trials conducted in progressive pulmonary fibrosis populations have demonstrated a reduction in lung function decline, with subgroup analyses suggesting potential benefit in autoimmune-related diseases, although evidence remains limited. The safety profile appears mainly characterized by gastrointestinal adverse events, with ongoing evaluation of neuropsychiatric safety and drug interactions in complex autoimmune populations. Overall, nerandomilast represents a promising investigational strategy bridging antifibrotic and immunomodulatory mechanisms, warranting further dedicated studies in SARD-ILD.