Article

Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials.

Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Lille, France.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association (Impact Factor: 6.53). 06/2008; 6(6):644-53. DOI: 10.1016/j.cgh.2008.03.014
Source: PubMed

ABSTRACT We performed a meta-analysis of placebo-controlled trials to evaluate safety and efficacy of tumor necrosis factor (TNF) antagonists for Crohn's disease.
We searched MEDLINE, Cochrane Library, and EMBASE. The primary end points were clinical remission for luminal Crohn's disease and fistula closure at > or =2 consecutive visits. Deaths, serious infections, and malignancies were also analyzed by the methods of Peto and Der Simonian and Laird.
Fourteen luminal Crohn's disease trials enrolled 3995 patients. In overall analysis, anti-TNF therapy was effective for induction of remission at week 4 (mean difference, 11%; 95% confidence interval [CI], 6%-16%; P < .001) and maintenance of remission at weeks 20-30 in patients who responded to induction therapy and in patients randomized before induction (mean difference, 23%; 95% CI, 18%-28% and mean difference, 8%; 95% CI, 3%-12%, respectively; P < .001 for all comparisons). Ten studies evaluated anti-TNF for treatment of fistulizing Crohn's disease, involving 776 patients. In overall analysis, anti-TNF therapy was effective for fistula closure only in maintenance trials after open-label induction (mean difference, 16%; 95% CI, 8%-25%; P < .001). In 21 studies enrolling 5356 individuals, anti-TNF therapy did not increase the risk of death, malignancy, or serious infection.
Infliximab, adalimumab, and certolizumab are effective in luminal Crohn's disease. Efficacy of anti-TNF agents other than infliximab in treating fistulizing Crohn's disease requires additional investigations. A longer duration of follow-up and a larger number of patients are required to better assess the safety profile of TNF antagonists in Crohn's disease.

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    ABSTRACT: Abstract Background. Some patients with inflammatory bowel disease (IBD) never respond or lose their response to a second anti-TNF. Aim. To review the efficacy and safety of a third anti-TNF after failure of two previous anti-TNFs. Methods. Bibliographical searches in PubMed for studies evaluating infliximab, adalimumab, or certolizumab as the third anti-TNF in IBD patients whose two previous anti-TNF treatments had failed. Results. Two retrospective studies with a small sample size and limited follow up evaluated the effectiveness of a third anti-TNF patients whose two previous anti-TNFs had failed. The arguments for this switching strategy are as follows: a)favorable-albeit limited-efficacy (in the study by Allez et al., clinical response was observed in 51% of patients at week 20; and in the study by de Silva et al., over 50% of patients remained on the third anti-TNF at 1 year); b)the eventual response to the third anti-TNF is relatively quick; c) no other medical options have been approved for IBD treatment; d)the only alternative options are surgery, compassionate use with non-anti-TNFs, and clinical trials. However, there are also arguments against the prescription of a third anti-TNF: a)lack of experience, since the few available studies are limited by their small sample size; b)the relatively low response in the long term (mainly due to loss of response); c) and finally, and most importantly, the risk of severe adverse events. Conclusion. The delicate balance between pros and cons means the use of a third anti-TNF after failure of two previous agents should be considered only in patients with no other therapeutic options. Decisions should be taken on an individual basis.
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    ABSTRACT: One-third of patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving anti-TNFs do not respond to treatment, and a relevant proportion experience loss of response or intolerance. To investigate the efficacy and safety of a second anti-TNF agent after primary/secondary failure or intolerance to a first drug. Inclusion criteria: studies evaluating the efficacy of infliximab (IFX), adalimumab (ADA) and certolizumab-pegol (CZP) as the second anti-TNF in CD or UC. Search strategy: Bibliographical searches (PubMed/Embase). Data synthesis: percentage of response/remission; the meta-analysis was performed using the inverse variance method. We included 46 studies (37 CD, 8 UC, 1 pouchitis). The CD studies comprised 32 switching IFX→ADA, 4 IFX→CZP and 1 ADA→IFX. Overall, the second anti-TNF after the failure of IFX in CD induced remission in 43% and response in 63% of patients. The remission rate was higher when the reason to withdraw the first anti-TNF was intolerance (61%) than after secondary (45%) or primary failure (30%); response rates were, respectively, 72%, 62% and 53%. All UC studies switched IFX→ADA, six of them reporting remission rates ranging from 0% to 50%. Adverse events rate ranged from 0% to 81% in CD, most of them mild (serious adverse event 0-21%, discontinuation rate <20%). The efficacy of a second anti-TNF in CD patients largely depends on the cause for switching. The remission rate is higher when the reason to withdraw the first anti-TNF is intolerance (61%), compared with secondary (45%) or primary failure (30%). Further studies of switch ADA→IFX are needed to evaluate this strategy. PROSPERO-registry-number: CRD42014012943. © 2015 John Wiley & Sons Ltd.
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