Systematic Review With Meta-analysis

Loss of Response and Requirement of Ustekinumab Dose Escalation in Inflammatory Bowel Diseases

Hongsheng Yang; Bingyang Li; Qin Guo; Jian Tang; Bo Peng; Ni Ding; Miao Li; Qingfang Yang; Zicheng Huang; Na Diao; Xia Zhu; Jun Deng; Huili Guo; Pinjin Hu; Kang Chao; Xiang Gao


Aliment Pharmacol Ther. 2022;55(7):764-777. 

In This Article

Abstract and Introduction


Background: Ustekinumab is effective in treating Crohn's disease (CD) and ulcerative colitis (UC). However, the loss of response (LOR) to ustekinumab and the efficacy of dose escalation have not been systematically explored.

Methods: Databases were searched for eligible studies from inception through July 2021. Summary estimates were pooled, and subgroup analyses were performed to explore heterogeneity.

Results: We included 14 studies (CD: 13; UC: 1). In CD patients, the annual risk of LOR to ustekinumab and dose escalation among primary responders was 21% (95% confidence interval [CI] 12–31%, 1530 person-years, n = 9) per person-year and 25% (95% CI 12–32%, 657 person-years, n = 5) per person-year respectively. Clinical response was regained in 58% (95% CI 49–67%, 279 patients, n = 8) of secondary non-responders after dose escalation (interval reduction or intravenous reinduction). In UC patients, no studies provided data on LOR, but only one study showed that 35% (100/284) of patients underwent dose escalation (or sham dose adjustment), leading to an annual risk of dose escalation of 18% per person-year. After dose escalation, 58% (14/24) of the patients regained symptomatic remission.

Conclusions: Primary responders with CD experienced LOR to ustekinumab at a risk of 21% per person-year and required dose escalation at a risk of 25% per person-year. Fifty-eight per cent of secondary non-responders with CD may benefit from dose escalation. LOR has not been well characterized in patients with UC.


Over the last two decades, biologics have revolutionised the treatment paradigm for inflammatory bowel disease (IBD). Biologics, with varied mechanisms of action, are used to treat IBD that is not optimally controlled by traditional drugs. These biologics include anti-tumour necrosis factor (anti-TNF) inhibitors (infliximab, adalimumab, golimumab and certolizumab-pegol), anti-integrin inhibitors (vedolizumab) and anti-interleukin 12/23 inhibitors (ustekinumab).[1,2]

Patients with IBD who do not respond to initial treatment with biological agents are known as primary non-responders. In addition, a proportion of primary responders, known as secondary non-responders, subsequently lose response over time. The loss of response (LOR) poses a difficult clinical problem for gastroenterologists. Once patients lose response to biologics, a dose escalation, a switch to other drugs, or surgery should be considered.[2,3]

Ustekinumab is a fully human IgG monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23. It inhibits the receptors for these two cytokines on T cells, natural killer cells and antigen-presenting cells.[4] Ustekinumab has been demonstrated to be efficacious and safe for treating adult patients with moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC).[5,6] A single intravenous infusion of ustekinumab using a weight-range-based dose, at approximately 6 mg/kg of body weight, is recommended in adults with CD and UC at week 0, followed by a 90 mg dose administered subcutaneously every 8 weeks (q8w), or alternatively, every 12 weeks (q12w) in some countries or regions.

To date, neither the rate of loss of response (LOR) to ustekinumab nor the efficacy of ustekinumab dose escalation in patients with IBD has been systematically explored. Therefore, we performed a systematic review and meta-analysis of clinical trials and observational studies to investigate (a) LOR to ustekinumab and dose escalation requirements in patients with IBD, (b) the efficacy of dose escalation to regain therapeutic benefit in this population and (c) predictors of LOR or dose escalation.