Systematic Review With Network Meta-analysis

The Efficacy of Anti-TNF Agents for the Treatment of Crohn's Disease

R. W. Stidham; T. C. H. Lee; P. D. R. Higgins; A. R. Deshpande; D. A. Sussman; A. G. Singal; B. J. Elmunzer; S. D. Saini; S. Vijan; A. K. Waljee


Aliment Pharmacol Ther. 2014;39(12):1349-1362. 

In This Article

Abstract and Introduction


Background. Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown.

Aim. To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD.

Methods. After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated.

Results. Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17–2.36 and RR: 1.43, 95% CI: 1.17–1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51–2.09 and RR: 1.68, 95% CI: 1.46–1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21–7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients.

Conclusions. All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.


Anti-tumour necrosis factor alpha (anti-TNF) therapies are established treatments for moderate to severe Crohn's disease (CD). Randomised controlled trials of three anti-TNF agents, infliximab (IFX), adalimumab (ADA), and certolizumab pegol (CZP), have demonstrated efficacy over placebo and are FDA approved for the induction and maintenance of clinical response and remission in moderate to severe CD.[1–10] However, while these anti-TNF agents are each effective against placebo, whether they share comparable efficacy remains questioned and has not been well studied.

Biological differences among anti-TNF agents allow for potential variability in therapeutic properties and efficacy. IFX is a monoclonal IgG1 antibody with a partially murine anti-TNF Fab region, ADA is an IgG1 antibody containing a humanised Fab region, and CZP is pegylated without an Fc region. Despite these molecular differences, in vitro studies have not demonstrated significant variability in neutralisation of soluble and membrane-bound TNF or modulation of lymphocyte apoptosis between these anti-TNF agents.[11,12] Retrospective and nonrandomised studies have demonstrated IFX and ADA to have similar clinical outcomes in avoidance of corticosteroids, surgery, hospitalisation and improvement in quality of life in patients with CD.[13–17] In summary, biologic and retrospective clinical data suggest similar therapeutic activity of these agents in CD.

Head-to-head direct comparative efficacy trials among anti-TNF agents for CD have not been performed. Network meta-analysis (NMA) allows indirect comparisons of individual anti-TNF agents relative to a common comparator (placebo), yielding an estimate of comparative efficacy. We performed both traditional and network meta-analyses of IFX, ADA and CZP clinical trials to assess comparative efficacy for induction and maintenance among anti-TNF agents for CD.