Long-Acting Muscarinic Antagonists for the Treatment of Difficult-to-Treat and Severe Asthma: A Narrative Review Focusing on Inflammation from Bench to Bedside.

Asthma is a heterogeneous disorder characterized by chronic airway inflammation and airway hyperresponsiveness (AHR). Inhaled corticosteroids (ICS) combined with long-acting β2-agonists (LABA) remain the mainstay of therapy, yet a subset of patients with difficult-to-treat or severe disease remains uncontrolled and requires high-intensity treatment. Recommendations support adding a long-acting muscarinic antagonist (LAMA) (i.e., tiotropium, glycopyrronium, umeclidinium) as part of triple therapy for these patients. Robust clinical evidence from randomized controlled trials and meta-analyses indicates that open and fixed-dose triple combinations improve lung function and reduce exacerbation risk vs. ICS/LABA, although effects on moderate exacerbations are inconsistent. The established mechanism of action of LAMA is bronchodilation through antagonism of M3 muscarinic acetylcholine (ACh) receptors (mAChR) on airway smooth muscle. However, evidence for anti-inflammatory effects derives mainly from preclinical investigations. These studies suggest that mAChR expressed on airway epithelial and immune cells may contribute to inflammation and remodeling via non-neuronal ACh signaling. In experimental models, LAMA reduce pro-inflammatory mediator release, limit neutrophil recruitment, and modulate tissue remodeling pathways, with potential synergistic effects when combined with ICS and LABA. Additional indirect anti-inflammatory mechanisms, including reduced airway stretch and potential antiviral activity, have been described. Overall, while clinical benefits of adding a LAMA in difficult-to-treat and severe asthma are well established, the evidence of anti-inflammatory effect of LAMA remains preliminary and requires confirmation in targeted ex vivo studies and further clinical trials.