High serum free IL-18 is associated with decreased omalizumab efficacy: findings from a 2-year omalizumab treatment study

Abstract

Objective

Omalizumab is more effective in severe allergic patients with eosinophilic asthma than those with non-eosinophilic asthma. IL-18, a unique cytokine involved in allergic but non-eosinophilic inflammation, might be associated with the latter condition. We aimed to clarify the roles of IL-18 related pathways in insufficient response to omalizumab treatment.

Methods

Patients with severe allergic asthma who completed 2-year omalizumab treatments at Kyoto University Hospital were included in this study (UMIN000002389). Associations between pretreatment levels of serum free IL-18 in addition to other mediators and asthma phenotypes including responses to omalizumab treatment were analyzed. Changes in serum free IL-18, periostin and total IgE levels during the treatment were also examined.

Results

Twenty-seven patients (19 females, average age of 55.7 years) were examined. Fifteen incomplete responders who experienced exacerbations in the second year, were significantly and more frequently obese and showed significantly earlier asthma onset, lower blood eosinophils and more exacerbations before omalizumab treatment than complete responders. Significantly more patients showed high baseline serum free IL-18 levels (≥141 pg/mL, a threshold for the highest tertile) among the incomplete responders than complete responders. Patients with high serum free IL-18 levels shared similar characteristics with incomplete responders, showing significant reductions in serum total IgE levels during omalizumab treatment. Finally, serum free IL-18 levels negatively correlated with serum periostin levels at baseline and in change ratios.

Conclusions

High baseline serum free IL-18 levels may predict reduced omalizumab efficacy in severe allergic patients with type-2 low asthma, regarding reduction of exacerbations.

Keywords:

• IgE
• IL-18
• omalizumab
• periostin
• treatment efficacy

Disclosure statement

H. M. reports receipt of lecture fees from Novartis, AstraZeneca, GlaxoSmithKline, Astellas Pharma, Boehringer Ingelheim, KYORIN Pharmaceutical Co., outside the submitted work. Y.G. reports receipt of honoraria from Novartis, AstraZeneca, GlaxoSmithKline, Astellas Pharma, Boehringer Ingelheim, outside the submitted work. K. I. reports grants from Japan Science and Technology Agency (JST), grants from the Japan Society for the promotion of Science, during the conduct of the study, grants from Shino-Test Corporation, advisor fees from Chugai Pharmaceutical Co. Ltd, advisor fees from Aqua Therapeutics Co. Ltd., lecture fees from AstraZeneca, outside the submitted work. In addition, K.I. has a patent application of serum periostin for treatment of bronchial asthma issued. I. I. reports receipt of grants from GlaxoSmithKline, outside the submitted work. The other authors have nothing to disclose.

Additional information

Funding

This study was funded by the Adaptable and Seamless Technology Transfer Program through target-driven R&D, Japan Science and Technology Agency; Grants-in-Aid for Scientific Research; the Japan Society for the Promotion of Science; the Strategic Foundational Technology Improvement Support Operation of the Japanese Government and the Nihon University Joint Research Grant; and Japan Research Foundation for Clinical Pharmacology.

Notes on contributors

Chie Morimoto

C. M. involved in performance of free IL-18 level measurements; analyses and interpretation of data; drafting the manuscript. H. M. contributed to conception of the study; involved in patient recruitment, diagnosis and management; performed data acquisition and interpretation; and wrote and revised the manuscript. T. T. involved in patient management; performed data acquisition and blood tests. Y. G., R I. and S. H. involved in the performance of free serum IgE level measurements. K. I., J. O. and S. O. involved in the performance of serum periostin level measurements. M. S. and K. O. involved in the performance of blood tests. I. I. and T. O. involved in patient diagnosis and management. T. N. and Y. I. involved in the performance of data acquisition. A. N. contributed to conception of the study and involved in patient recruitment, patient diagnosis and management. T. H. supervised the study.