SERPINB9 is associated with clinical improvement during aspirin therapy in aspirin-exacerbated respiratory disease.

RATIONALE: Aspirin therapy after desensitization (ATAD) is a unique treatment option for patients with aspirin-exacerbated respiratory disease (AERD). However, biomarkers predicting response are lacking, and the effects of high-dose aspirin remain unclear. OBJECTIVES: To determine clinical response to ATAD, identify predictive biomarkers, and compare aspirin-related molecular effects between AERD patients and healthy controls. METHODS: We conducted an 18-week, randomized, double-blind, placebo-controlled crossover trial of aspirin (600 mg/day) in patients with AERD (n=14) and controls (n=13). Each treatment arm lasted 8 weeks with a 2-week washout. Blood, induced sputum, nasal lavage [NL] and urine samples were collected at four time points. Clinical outcomes, transcriptional profiles, cytology and levels of eicosanoids, cytokines and chemokines were assessed. RESULTS: At baseline, AERD patients had higher blood eosinophils and elevated leukotriene E4 in plasma, NL, and urine, with reduced eoxin C4 in sputum supernatant and lower prostaglandin E2 and 12-hydroxyeicosatetraenoic acid in NL compared with controls. No differences in sputum gene expression were observed. SERPINB9 expression correlated with IL4RA in both groups and with PTGS2 in AERD. Eight patients (57.1%) responded to aspirin; however, the same number responded to placebo, with substantial overlap between treatments. Higher baseline SERPINB9 expression predicted response (OR, 62.3; padj=0.03). After aspirin, SERPINB9 correlations with IL4RA and PTGS2 were lost in AERD but persisted in controls. No consistent molecular changes were observed after either treatment. CONCLUSION: Clinical improvement during ATAD was comparable to placebo. However, elevated baseline sputum SERPINB9 was associated with clinical improvement, highlighting potential as a candidate biomarker.