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 β 2 -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 M 3 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.