Methods: We conducted a randomized, double-blind, placebo-controlled, multi-center 24 week proof-of-principle trial of imatinib in severe asthmatics with persistent airway hyperresponsiveness (AHR) and poor asthma control despite maximal inhaled corticosteroid and long-acting beta-agonist therapy. The effect of imatinib on mast cells was evaluated through tryptase measurement and MC enumeration in endobronchial biopsies.
Results: 62 subjects were randomized per protocol. Baseline serum tryptase correlated with baseline smooth muscle and total airway mast cell numbers (r2=0.319, 0.403; P<0.01, respectively) and intact, non-degranulating, smooth muscle mast cells (r2=0.567, P<0.001). Imatinib reduced serum tryptase compared with placebo (-2.02±2.32 ng/ml vs. -0.56±1.39 ng/ml; p=0.015) while airway mast cell numbers decreased in both groups with a trend toward greater decrease on imatinib (p=0.06). Imatinib reduced AHR (p=0.04) and improved FEV1 (P=0.04) compared to placebo. The decrease in total airway MC numbers correlated with improvement in FEV1% of predicted in subjects on imatinib (r2=0.163, p=0.056) but not change in AHR.
Conclusions: In poorly-controlled patients with severe asthma, serum tryptase correlates with airway mast cells. Use of imatinib inhibited MCs and changes in mast cell numbers on imatinib correlated with physiological improvements. These data suggest a role for mast cells in airway obstruction in this severe population.