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Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease

Overview of attention for article published in Cochrane database of systematic reviews, November 2016
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  • Good Attention Score compared to outputs of the same age (66th percentile)

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Title
Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease
Published in
Cochrane database of systematic reviews, November 2016
DOI 10.1002/14651858.cd007572.pub3
Pubmed ID
Authors

John K MacDonald, Tran M Nguyen, Reena Khanna, Antje Timmer

Abstract

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 Crohn's disease. The objectives of this review were to assess the efficacy and safety of anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. We searched the following databases from inception to 12 September 2016: PubMed, MEDLINE, EMBASE, and the Cochrane Library (CENTRAL). References and conference abstracts were searched to identify additional studies. Randomized controlled trials (RCTs) trials in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in patients with active Crohn's disease were included.  DATA COLLECTION AND ANALYSIS: Two authors independently screened  studies for inclusion and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to induce clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to induce clinical improvement, adverse events, serious adverse events, and withdrawals due to adverse events. Clinical improvement was defined as decreases of > 70 or > 100 points in the CDAI from baseline. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. Six RCTs (n = 2324 patients) met the inclusion criteria. A low risk of bias was assigned to all studies. The two briakinumab trials were not pooled due to differences in doses and time points for analysis. In both studies there was no statistically significant difference in remission rates. One study (n = 79) compared doses of 1 mg/kg and 3 mg/kg to placebo. In the briakinumab group 70% (44/63) of patients failed to enter clinical remission at 6 or 9 weeks compared to 81% (13/16) of placebo patients (RR 0.86, 95% CI 0.65 to 1.14). Subgroup analysis revealed no significant differences by dose. The other briakinumab study (n = 230) compared intravenous doses of 200 mg, 400 mg and 700 mg with placebo. Eighty-four per cent (154/184) of briakinumab patients failed to enter clinical remission at six weeks compared to 91% (42/46) of placebo patients (RR 0.92, 95% CI 0.83 to 1.03). Subgroup analysis revealed no significant differences by dose. GRADE analyses of the briakinumab studies rated the overall quality of the evidence for the outcome clinical remission as low. Based on the results of these two studies the manufacturers of briakinumab stopped production of this medication. The ustekinumab studies were pooled despite differences in intravenous doses (i.e. 1mg/kg, 3 mg/kg, 4.5 mg/kg, and 6 mg/kg), however the subcutaneous dose group was not included in the analysis, as it was unclear if subcutaneous was equivalent to intravenous dosing. There was a statistically significant difference in remission rates. At week six, 84% (764/914) of ustekinumab patients failed to enter remission compared to 90% (367/406) of placebo patients (RR 0.92, 95% CI 0.88 to 0.96; 3 studies; high-quality evidence). Subgroup analysis showed a statistically significant difference for the 6.0 mg/kg dose group (moderate-quality evidence). There were statistically significant differences in clinical improvement between ustekinumab and placebo-treated patients. In the ustekinumab group, 55% (502/914) of patients failed to improve clinically (i.e. 70-point decline in CDAI score), compared to 71% (287/406) of placebo patients (RR 0.78, 95% CI 0.71 to 0.85; 3 studies). Subgroup analysis revealed significant differences compared to placebo for the 1 mg/kg, 4.5 mg/kg and 6 mg/kg dosage subgroups. Similarly for a 100-point decline in CDAI, 64% (588/914) of patients in the ustekinumab group failed to improve clinically compared to 78% (318/406) of placebo patients (RR 0.82, 95% CI 0.77 to 0.88; 3 studies; high-quality evidence). Subgroup analysis showed a significant difference compared to placebo for the 4.5 mg/kg and 6.0 mg/kg (high-quality evidence) dose groups. There were no statistically significant differences in the incidence of adverse events, serious adverse events or withdrawal due to adverse events. Sixty-two per cent (860/1386) of ustekinumab patients developed at least one adverse event compared to 64% (407/637) of placebo patients (RR 0.97, 95% CI 0.90 to 1.04; 4 studies; high-quality evidence). Five per cent (75/1386) of ustekinumab patients had a serious adverse event compared to 6% (41/637) of placebo patients (RR 0.83, 95% CI 0.58 to 1.20; 4 studies; moderate-quality evidence). The most common adverse events in briakinumab patients were injection site reactions and infections. Infections were the most common adverse event in ustekinumab patients. Worsening of Crohn's disease and serious infections were the most common serious adverse events. High quality evidence suggests that ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's disease. Moderate to high quality evidence suggests that the optimal dosage of ustekinumab is 6 mg/kg. Briakinumab and ustekinumab appear to be safe. Moderate quality evidence suggests no increased risk of serious adverse events. Future studies are required to determine the long-term efficacy and safety of ustekinumab in patients with moderate to severe Crohn's disease.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 102 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 102 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 16 16%
Student > Bachelor 16 16%
Researcher 14 14%
Student > Ph. D. Student 11 11%
Other 9 9%
Other 21 21%
Unknown 15 15%
Readers by discipline Count As %
Medicine and Dentistry 42 41%
Pharmacology, Toxicology and Pharmaceutical Science 9 9%
Nursing and Health Professions 8 8%
Biochemistry, Genetics and Molecular Biology 5 5%
Agricultural and Biological Sciences 4 4%
Other 12 12%
Unknown 22 22%

Attention Score in Context

This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 April 2018.
All research outputs
#4,078,973
of 13,999,449 outputs
Outputs from Cochrane database of systematic reviews
#7,030
of 10,793 outputs
Outputs of similar age
#123,626
of 380,269 outputs
Outputs of similar age from Cochrane database of systematic reviews
#114
of 162 outputs
Altmetric has tracked 13,999,449 research outputs across all sources so far. This one has received more attention than most of these and is in the 70th percentile.
So far Altmetric has tracked 10,793 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 21.5. This one is in the 33rd percentile – i.e., 33% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 380,269 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 66% of its contemporaries.
We're also able to compare this research output to 162 others from the same source and published within six weeks on either side of this one. This one is in the 29th percentile – i.e., 29% of its contemporaries scored the same or lower than it.