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Mucosal IL23A expression predicts the response to Ustekinumab in inflammatory bowel disease

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Abstract

Background

Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction.

Methods

We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction.

Results

There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance.

Conclusions

The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.

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Change history

  • 20 October 2021

    This article has been updated to add the missing supplementary figure.

References

  1. 1.

    Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369:1641–57.

    CAS  Article  Google Scholar 

  2. 2.

    Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361:2066–78.

    CAS  Article  Google Scholar 

  3. 3.

    Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014;11:243–55.

    CAS  Article  Google Scholar 

  4. 4.

    Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011;3:535–45.

    Article  Google Scholar 

  5. 5.

    Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.

    CAS  Article  Google Scholar 

  6. 6.

    Pouillon L, Travis S, Bossuyt P, et al. Head-to-head trials in inflammatory bowel disease: past, present and future. Nat Rev Gastroenterol Hepatol. 2020;17:365–76.

    Article  Google Scholar 

  7. 7.

    Singh S, George J, Boland BS, et al. Primary non-response to tumor necrosis factor antagonists is associated with inferior response to second-line biologics in patients with inflammatory bowel diseases: a systematic review and meta-analysis. J Crohns Colitis. 2018;12:635–43.

    Article  Google Scholar 

  8. 8.

    Gisbert JP, Chaparro M. Ustekinumab to treat Crohn’s disease. Gastroenterol Hepatol. 2017;40:688–98.

    Article  Google Scholar 

  9. 9.

    West NR, Hegazy AN, Owens BMJ, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23:579–89.

    CAS  Article  Google Scholar 

  10. 10.

    Bertani L, Fornai M, Fornili M, et al. Serum oncostatin M at baseline predicts mucosal healing in Crohn’s disease patients treated with infliximab. Aliment Pharmacol Ther. 2020;52:284–91.

    CAS  Article  Google Scholar 

  11. 11.

    Gisbert JP, Chaparro M. Predictors of primary response to biologic treatment (anti-tnf, Vedolizumab, and Ustekinumab) in patients with inflammatory bowel disease: from basic science to clinical practice. J Crohns Colitis. 2020;14:694–709.

    Article  Google Scholar 

  12. 12.

    Barre A, Colombel JF, Ungaro R. Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease. Aliment Pharmacol Ther. 2018;47:896–905.

    CAS  Article  Google Scholar 

  13. 13.

    Iboshi Y, Nakamura K, Fukaura K, et al. Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis. J Gastroenterol. 2017;52:315–26.

    CAS  Article  Google Scholar 

  14. 14.

    Wils P, Bouhnik Y, Michetti P, et al. Subcutaneous Ustekinumab provides clinical benefit for two-thirds of patients with Crohn’s disease refractory to anti-tumor necrosis factor agents. Clin Gastroenterol Hepatol. 2016;14(242–50):e1-2.

    Google Scholar 

  15. 15.

    Harris KA, Horst S, Gadani A, et al. Patients with refractory Crohn’s disease successfully treated with Ustekinumab. Inflamm Bowel Dis. 2016;22:397–401.

    Article  Google Scholar 

  16. 16.

    Khorrami S, Ginard D, Marin-Jimenez I, et al. Ustekinumab for the treatment of refractory Crohn’s disease: the Spanish experience in a large multicentre open-label cohort. Inflamm Bowel Dis. 2016;22:1662–9.

    Article  Google Scholar 

  17. 17.

    Kopylov U, Afif W, Cohen A, et al. Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn’s disease–the McGill experience. J Crohns Colitis. 2014;8:1516–22.

    CAS  Article  Google Scholar 

  18. 18.

    Greenup AJ, Rosenfeld G, Bressler B. Ustekinumab use in Crohn’s disease: a Canadian tertiary care centre experience. Scand J Gastroenterol. 2017;52:1354–9.

    CAS  Article  Google Scholar 

  19. 19.

    Yamamoto T, Umegae S, Kitagawa T, et al. Systemic and local cytokine production in quiescent ulcerative colitis and its relationship to future relapse: a prospective pilot study. Inflamm Bowel Dis. 2005;11:589–96.

    Article  Google Scholar 

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Acknowledgements

The authors thank the staffs of endoscopy units at Kyushu Medical Center, Fukuoka Higashi Medical Center, Kitakyushu Municipal Medical Center, Saiseikai Fukuoka General Hospital, and Harasanshin Hospital for helpful discussions, and Dr. Junji Kishimoto (Center for Clinical and Translational Research, Kyushu University) for assistance with statistical analysis.

Funding

This study was supported in part by the Japan Society for the Promotion of Science KAKENHI (20K08389).

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Authors

Contributions

KN: designed and performed experiments, analyzed and interpreted data, performed statistical analyses, and wrote the manuscript; HO: study concept and design, patient recruitment, and interpreted data, funding and study supervision; TC: interpreted data and edited the manuscript; EI: interpreted data and study supervision; YT: interpreted data and study supervision; KN: interpreted data and study supervision; YO: interpreted data and study supervision. All authors contributed to critical revision of the manuscript and gave their final approval of the version submitted.

Corresponding author

Correspondence to Eikichi Ihara.

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Conflict of interest

EI belongs to an endowed course supported by companies Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Terumo Corporation, Fancl FANCL Corporation, and Ohga Pharmacy. No other authors have any conflict of interest to report.

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Nishioka, K., Ogino, H., Chinen, T. et al. Mucosal IL23A expression predicts the response to Ustekinumab in inflammatory bowel disease. J Gastroenterol 56, 976–987 (2021). https://doi.org/10.1007/s00535-021-01819-7

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Keywords

  • Ustekinumab
  • Inflammatory bowel disease
  • Drug response prediction