Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial

Abstract

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E₄ overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E₄ concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E₄ concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E₄ overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Keywords: aspirin hypersensitivity; aspirin tolerance; aspirin-exacerbated respiratory disease; leukotriene E4; omalizumab.

Figure 1.

(A) Study design. (B) Flow diagram. AERD = aspirin-exacerbated respiratory disease; Fe_NO = fractional exhaled nitric oxide.

Figure 2.

Difference in the area under the logarithm level of urinary biomarker concentration versus time curve (AUC_{(Before-24 h)}) and levels of urinary LTE₄ and tetranor-PGDM concentrations during oral aspirin challenge between the placebo and omalizumab phases. (A) AUC_{[Before-24 h]} of LTE₄. (B) AUC_{[Before-24 h]} of tetranor-PGDM. (C and D) Time course of log-transformed levels of urinary LTE₄ (C) and tetranor-PGDM (D) concentrations. Wilcoxon signed-rank test. *P < 0.05 and **P < 0.01. The log-transformed urinary LTE₄ and tetranor-PGDM concentrations are expressed as medians and interquartile ranges. LTE₄ = leukotriene E₄; tetranor-PGDM = 11,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid.

Figure 3.

(A and B) Cumulative response rate according to the Global Evaluation of Treatment Effectiveness scale in the omalizumab (A) and placebo (B) phases. (C–E) Scores from the Asthma Control Test (ACT) (C), Asthma Control Questionnaire-6 (ACQ-6) (D), and Sino-Nasal Outcome Test-22 (SNOT-22) (E) in the omalizumab and placebo phases. McNemar test; *P < 0.05 and **P < 0.01 compared with the placebo phase. Global Evaluation of Treatment Effectiveness was used to classify responders and nonresponders. Wilcoxon signed-rank test; ^†P < 0.05 and ^††P < 0.01 compared with the placebo phase. Circles (placebo phase) and squares (omalizumab phase) indicate median values, and bars indicate interquartile ranges.

Figure 4.

(A and B) Difference in the levels of urinary LTE₄ (A) and tetranor-PGDM (B) concentrations between the placebo and omalizumab phases. Wilcoxon signed-rank test; *P < 0.05. Circles (placebo phase) and squares (omalizumab phase) indicate median values, and bars indicate interquartile ranges. LTE₄ = leukotriene E₄; tetranor-PGDM = 11,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid.