Targeting autoimmune pulmonary alveolar proteinosis with GM-CSF: insights from clinical trials and emerging therapies

Pulmonary alveolar proteinosis (PAP) is a rare lung disease caused by impaired surfactant clearance resulting in lipoproteinaceous material accumulation in the alveoli often causing progressive dyspnea and respiratory failure. Autoimmune PAP (aPAP), accounting for ~90% of cases with a prevalence of 6.7-6.9 per million, disrupts granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via neutralizing autoantibodies.

This article explores the role of GM-CSF in the pathogenesis and treatment of PAP. GM-CSF autoantibodies block signaling essential for alveolar macrophage function. Therapeutic whole lung lavage (WLL) remains the gold standard of treatment for PAP. While WLL is an effective and safe treatment, and can indeed complement GM-CSF therapy, it is labor intensive and often requires repeated procedures. GM-CSF augmentation represents a new era of therapeutic advancement targeting the pathogenesis of PAP to ensure sustained, efficacious results. Inhaled GM-CSF shows superior efficacy over subcutaneous treatment. Trials through recent decades including IMPALA-2 show improvements in symptoms, physiology, and radiology with a favorable safety profile. These studies have helped inform the much-needed European Respiratory Society guidelines for the diagnosis and management of PAP in 2024.

Despite our greater understanding of this ultra-rare disease, further studies are required to explore the mechanistic and logistical aspects of treatment with GM-CSF. We explore some of these aspects in our expert opinion section.