Efficacy and safety of ustekinumab in the induction therapy of TNF-α-refractory Crohn's disease patients: a systematic review and meta-analysis
Abstract
Aim: The aim of the systematic review and meta-analysis was to assess the efficacy and safety of ustekinumab in the induction therapy of anti-TNF-α failure patients with Crohn's disease. Methods: A systematic literature search was conducted in Medline (PubMed), EMBASE, Cochrane Library until 30 December 2016. We included randomized controlled trials that compared efficacy (clinical response and remission) and safety profile of ustekinumab in TNF-α failure Crohn's disease patients; primary and secondary TNF-α nonresponders or intolerant patients were also assessed. Included studies were critically appraised according to the PRISMA statement protocol; data aggregation with a RevMan® software was performed. Results: Three randomized controlled trials were revealed in the systematic review but only two of them (CERTIFI and UNITI-1) were homogenous to be included in the meta-analysis; aggregation of data only for induction phase of therapy was possible. Clinical response was significantly higher for patients who received ustekinumab compared with placebo patients in a group of TNF-α antagonist failure patients (relative benefit [RB] = 1.62; 95% CI: 1.28–2.04) and in the following subgroups: secondary nonresponders (RB = 1.98; 95% CI: 1.49–2.63), intolerant patients (RB = 1.47; 95% CI: 1.01–2.13) and patients who failed at least two TNF-α antagonists (RB = 2.19; 95% CI: 1.53–3.14) but in case of primary nonresponders it occurred insignificant (RB = 1.22; 95% CI: 0.76–1.98). The clinical remission in TNF-α antagonist failure population was significantly higher for patients who received ustekinumab compared with placebo (RB = 1.72; 95% CI: 1.17–2.53). Pooled analysis revealed that risk of adverse events in induction phase of therapy was not significantly different (risk ratio = 0.96; 95% CI: 0.86–1.06) between ustekinumab and placebo groups. Conclusion: The clinical response was significantly higher for TNF-α antagonist failure patients who received ustekinumab as well as in subgroups of secondary nonresponders or intolerant patients but not in case of primary nonresponders. Ustekinumab occurred as safe as placebo in the induction as well as in a maintenance phase of therapy.
Formats available
You can view the full content in the following formats:
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
1.
The Crohn's & Colitis Foundation of America. The Facts About Inflammatory Bowel Diseases. www.ccfa.org/assets/pdfs/updatedibdfactbook.pdf.
2.
Burisch J, Tine J, Martinato M. The burden of inflammatory bowel disease in Europe. J. Crohn's Colitis 7(4), 322–337 (2013).
3.
Floyd DN, Langham S. The economic and quality-of-life burden of Crohn's disease in Europe and the United States, 2000 to 2013: a systematic review. Dig. Dis. Sci. 60, 299–312 (2015).
4.
Roda G, Jharap B, Neeraj N et al. Loss of response to Anti-TNF-As: definition, epidemiology, and management. Clin. Transl. Gastroenterol. 7(1), e135 (2016).
5.
Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 132, 52–65 (2007).
• Summary of product characteristics for Stelara® (ustekinumab).
6.
Moher D, Liberati A, Tetzlaff J, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 6, e1000097 (2009).
7.
Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, NJ, USA (2008).
8.
Sandborn W, Gasink C, Long-Long G et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N. Engl. J. Med. 367, 1519–1528 (2012).
• Pivotal clinical trial in ustekinumab assessment.
9.
Feagan BG, Sandborn WJ, Gasink C et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 375, 1946–1960 (2016).
• Pivotal clinical trial in ustekinumab assessment.
10.
Sandborn WJ, Feagan BG, Fedorak RN et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate to severe Crohn's disease. Gastroenterology 135(4), 1130–1141 (2008).
•• Additional clinical trial in ustekinumab efficacy in Crohn's disease (CD) assessment.
11.
Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann. Intern. Med. 146, 829–838 (2007).
12.
Sandborn WJ. Clinical perspectives in Crohn's disease. Moving forward with anti-TNF-A-alpha therapy: current needs and future treatments. Rev. Gastroenterol. Disord. 7(Suppl. 2), S23–S35 (2007).
13.
Harris KA, Horst S, Gadani A et al. Patients with refractory Crohn's disease successfully treated with ustekinumab. Inflamm. Bowel Dis. 22(2), 397–401 (2016).
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. 14(2), 242–250 (2016).
•• Additional clinical trial in ustekinumab efficacy in CD assessment.
15.
Khorrami S, Ginard D, Marín-Jiménezet 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. 22(7), 1662–1669 (2016).
•• Additional clinical trial in ustekinumab efficacy in CD assessment.
16.
Singh S, Garg SK, Pardi D et al. Comparative efficacy of biologic therapy in biologic-naïve patients with Crohn disease: a systematic review and network meta-analysis. Mayo Clin. Proc. 89(12), 1621–1635 (2014).
17.
Singh S, Garg SK, Pardi D et al. Comparativeefficacy of biologic therapy in biologic-naïve patients with Crohn disease: asystematic review and network meta-analysis. Mayo Clin. Proc. 89(12), 1621–1635 (2014).
Information & Authors
Information
Published In
Copyright
© Future Medicine Ltd.
History
Published online: 29 June 2017
Keywords:
Topics
Authors
Metrics & Citations
Metrics
Article Usage
Article usage data only available from February 2023. Historical article usage data, showing the number of article downloads, is available upon request.
Citations
How to Cite
Efficacy and safety of ustekinumab in the induction therapy of TNF-α-refractory Crohn's disease patients: a systematic review and meta-analysis. (2017) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer-2017-0022
Export citation
Select the citation format you wish to export for this article or chapter.
Citing Literature
- Mahmoud H. Mosli, Badr Al-Bawardy, Turki AlAmeel, Nahla A. Azzam, Shakir A. Bakkari, Othman R. Alharbi, Abdulelah Almutairdi, Yaser K. Meeralam, Omar I. Saadah, Majid A. Almadi, Waleed Alhazzani, Haifa F. Alotaibi, Khalidah A. Alenzi, Bedor A. Al-Omari, Hajer Y. Almudaiheem, Ahmed H. Al-Jedai, Practical guidelines on medical management of adults with moderate-to-severe inflammatory bowel disease, Saudi Journal of Gastroenterology, 10.4103/sjg.sjg_277_25, (2025).
- Ahmed G. Alghamdi, Hadeel S. Aldofaian, Mohammed S. Alahmari, Bashaar K. Alibrahim, Mishal A. Alshowair, Hussam A. Alhamidi, Abdullah H. Bawazir, Amal M. Aseri, Alaa A. Aldeibani, Mohanned M. AlRaddadi, Reem O. Almutairi, Sultan S. Alshahrani, Abdullah D. Alenezi, Rakan H. Alshala, Abeer M. Alhuraibi, Renad M. Alharbi, Patterns and predictors of biologic therapy switching in inflammatory bowel disease at a tertiary care center: A retrospective observational study, Saudi Journal of Gastroenterology, 10.4103/sjg.sjg_169_25, (2025).
- Hongkun Li, Yuyue Zhang, Simin Du, Jinghan Shen, Xingyan Liu, Jie Jing, “Remodeling the intestinal immune microenvironment”: immune regulation and tissue regeneration by mesenchymal stem/stromal cells in the repair microenvironment of inflammatory bowel disease, Frontiers in Immunology, 10.3389/fimmu.2025.1543702, 16, (2025).
- Jildou van der Werf, Nicholas Ian Fleming, Are single nucleotide polymorphisms underutilized for guiding treatment of inflammatory bowel disease?, Immunology & Cell Biology, 10.1111/imcb.70029, 103, 6, (551-562), (2025).
- Richard Silva, José Nunes de Azevedo, Jorge Pereira Machado, Jorge Magalhães Rodrigues, Placebo-Controlled Trials in the Management of Crohn’s Disease: An Umbrella Review of Meta-Analyses, Medical Sciences, 10.3390/medsci13010012, 13, 1, (12), (2025).
- Mahesh Krishna, Ellen J. Spartz, Laura Maas, Vivy Cusumano, Sowmya Sharma, Berkeley Limketkai, Alyssa Parian, Retrospective Cohort Study on the Predictive Value of Primary Non-response to Initial Biologic for Future Biologic Use in Patients with Inflammatory Bowel Disease, Digestive Diseases and Sciences, 10.1007/s10620-024-08816-9, 70, 2, (746-753), (2025).
- Sunil Samnani, Emily C L Wong, Hasan Hamam, Parambir S Dulai, John K Marshall, Vipul Jairath, Walter Reinisch, Neeraj Narula, Outcomes of Patients With Prior Biologic Intolerance Are Better Than Those With Biologic Failure in Clinical Trials of Inflammatory Bowel Disease, Journal of Crohn's and Colitis, 10.1093/ecco-jcc/jjae151, 19, 3, (2024).
- Omar I. Saadah, Turki AlAmeel, Ahmed Al Sarkhy, Mohammed Hasosah, Abdulrahman Al-Hussaini, Majid A. Almadi, Badr Al-Bawardy, Talal A. Altuwaijri, Mohammed AlEdreesi, Shakir A. Bakkari, Othman R. Alharbi, Nahla A. Azzam, Abdulelah Almutairdi, Khalidah A. Alenzi, Bedor A. Al-Omari, Hajer Y. Almudaiheem, Ahmed H. Al-Jedai, Mahmoud H. Mosli, Saudi consensus guidance for the diagnosis and management of inflammatory bowel disease in children and adolescents, Saudi Journal of Gastroenterology, 10.4103/sjg.sjg_171_24, 31, 3, (107-136), (2024).
- Yaqing Bai, Yinghao Sun, Qi He, Xiaoyin Bai, Hong Yang, Comparative effectiveness and safety of ustekinumab at different intervals of maintenance phase in inflammatory bowel disease: a systematic review and meta-analysis, European Journal of Gastroenterology & Hepatology, 10.1097/MEG.0000000000002718, 36, 4, (359-370), (2024).
- Yago González-Lama, Elena Ricart, Daniel Carpio, Guillermo Bastida, Daniel Ceballos, Daniel Ginard, Ignacio Marin-Jimenez, Luis Menchen, Fernando Muñoz, Controversies in the management of anti-TNF therapy in patients with Crohn’s disease: a Delphi consensus, BMJ Open Gastroenterology, 10.1136/bmjgast-2023-001246, 11, 1, (e001246), (2024).
- See more