Key messages
• Ustekinumab is more effective than placebo (dummy treatment) in treating Crohn's disease (an inflammatory disorder of the large bowel) when used in the short term.
• Ustekinumab probably does not cause increased severe unwanted effects when compared to placebo.
• There is not enough evidence to draw any conclusions on the effect of ustekinumab compared to other medications.
What is Crohn's disease?
Crohn's disease is a long-term (chronic) inflammatory bowel disease that can affect any part of the gastrointestinal (digestive) tract, from the mouth to the anus. Symptoms include abdominal pain, non-bloody diarrhea, fatigue (tiredness), and weight loss.
What is ustekinumab, and how is it used to treat Crohn's disease?
Ustekinumab is a biologic (a medication that comes from living organisms). It can be injected under the skin using a syringe or directly infused into a vein (intravenous). Biologic therapies suppress the immune system and reduce the inflammation that occurs in Crohn's disease. When people with Crohn's disease are experiencing symptoms, the disease is said to be 'active'; periods when the symptoms stop are called 'remission.'
Briakinumab is another medication that works in a similar way and was considered in previous versions of this review. However, briakinumab is no longer used for the treatment of Crohn's disease, and the manufacturer stopped production in 2011, so we decided to exclude it in this review update.
What did we want to find out?
We wanted to find out whether ustekinumab is more effective than a placebo (dummy treatment) or other drugs in producing remission in people with active Crohn's disease, and whether these medications cause any unwanted effects.
What did we do?
We searched the medical literature for studies comparing ustekinumab to placebo or other medications, such as adalimumab or guselkumab. We also included trials examining different doses of medications. We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We found eight studies including a total of 3224 people. Five studies compared ustekinumab to placebo; one study compared different doses of ustekinumab in children; and two studies compared ustekinumab to other biologic medications. All studies lasted for at least eight weeks.
Main results
Ustekinumab reduces the number of people failing to achieve remission after eight weeks of treatment. It is an effective therapy for improving symptoms in people with Crohn's disease. Compared to placebo, ustekinumab probably does not cause an increase in severe unwanted effects at eight weeks. Worsening of Crohn's disease and infections were the most common unwanted effects in people receiving ustekinumab.
Different doses of ustekinumab in children were investigated. The evidence for which is the better dose is very uncertain. Separate information on serious unwanted effects at eight weeks in children was not available.
The evidence for the effects of ustekinumab compared to other biologics is also very uncertain. No studies reported the rate of serious unwanted effects at eight weeks for this comparison.
What are the limitations of the evidence?
We are confident in the evidence for the benefit of ustekinumab over placebo. We are only moderately confident in the evidence for severe unwanted effects due to the low number of severe unwanted effects reported.
Our confidence in the evidence comparing different doses of ustekinumab and comparing ustekinumab to other biologics is very low because there were not enough studies to be certain about the results, and the studies did not cover all the people we were interested in.
How up-to-date is this evidence?
The evidence is current to February 2024.
Ustekinumab reduces the risk of people with CD failing to enter clinical remission at eight weeks. It probably does not lead to more serious adverse events when compared to placebo.
There were inadequate data to conclude the more effective induction dose of ustekinumab in children. No studies evaluated adverse events at eight weeks for this comparison.
There may be little to no difference between ustekinumab and other biologics, such as adalimumab or guselkumab, in inducing clinical remission at week 8, but the evidence is very uncertain, and separate data on adverse events at eight weeks were not available.
Crohn's disease (CD) is a chronic inflammatory bowel disease leading to symptoms such as abdominal pain, diarrhea, weight loss, fatigue, and complications such as strictures and fistulas. Ustekinumab (CNTO 1275) and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of CD. Briakinumab has been withdrawn for the treatment of CD, making ustekinumab the only available antibody against the p40 subunit of interleukin-12 and interleukin-23 approved for this purpose.
To assess the benefits and harms of anti-IL-12/23p40 antibodies for induction of remission in CD, as compared to no treatment, placebo, other drug treatment, or varying dosing schedules.
We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and MEDLINE (from inception to 2 February 2024) and Embase (from inception until 12 August 2022). We also searched ClinicalTrials.gov, WHO ICTRP, references, and conference abstracts to identify additional studies.
We included randomized controlled trials (RCTs) of at least four weeks' duration in which monoclonal antibodies against IL-12/23p40 were compared to placebo, no treatment, or another active comparator in people with active CD. We also included trials examining different doses of antibodies against IL-12/23p40.
Two review authors independently screened studies for inclusion and extracted data. We assessed the methodological quality of the included studies using Cochrane's RoB 2 tool. The primary outcome was failure to induce clinical remission by week 8, or 6 to 12 as available. Secondary outcomes included failure to induce clinical improvement (clinical response), induction of endoscopic remission, quality of life, and adverse events, serious adverse events, and withdrawals due to adverse events. We calculated the risk ratio (RR) or risk difference (RD) and 95% confidence intervals (95% CI) for each outcome unless substantial heterogeneity was detected. We analyzed data on an intention-to-treat basis. We assessed the certainty of the evidence using the GRADE approach.
Eight RCTs involving a total of 3224 participants with CD met the inclusion criteria. All studies were double-blinded. We assessed the risk of bias for most outcomes as either low risk of bias or some concerns.
Based on a pooled analysis of three trials, ustekinumab decreased the number of participants failing to achieve clinical remission at eight weeks when compared to placebo. Seventy-four per cent (693/938) of participants in the ustekinumab group and 87% (421/483) of those in the placebo group did not enter clinical remission (RR 0.85, 95% CI 0.81 to 0.89; 3 studies; 1421 participants; high-certainty evidence).
Treatment with ustekinumab likely did not lead to more serious adverse events when compared to placebo, with 5% (48/966) and 6% (30/505) of participants affected in the ustekinumab and placebo groups, respectively (RD −0.01, 95% CI −0.03 to 0.01; 3 studies; 1471 participants; moderate-certainty evidence).
A single small study in children compared two different induction doses of ustekinumab. The evidence for this outcome is very uncertain due to wide CIs. Eighty-one per cent (17/21) of participants receiving the higher induction dose (9 mg/kg or 390 mg) did not enter clinical remission at eight weeks, compared to 78% (18/23) of participants receiving the lower induction dose of 3 mg/kg or 130 mg (RR 1.03, 95% CI 0.77 to 1.39; 1 study; 44 participants; very low-certainty evidence). Separate safety data for the eight-week time point were not available for this comparison.
Based on one trial comparing ustekinumab to adalimumab, the evidence is very uncertain about which is the more beneficial drug. Fifty per cent (95/191) of participants receiving ustekinumab did not enter remission compared to 52% (101/195) of participants receiving adalimumab (RR 0.96, 95% CI 0.79 to 1.17; 1 study; 386 participants; very low-certainty evidence). Separate results on adverse events at eight weeks were not reported for this comparison.