Am J Gastroenterol. Published online March 15, 2011
A meta-analysis of randomized controlled trials (RCTs) supports the use of FDA-approved biological therapies in patients with active Crohn's disease (CD) or ulcerative colitis (UC) who have failed first- and second-line therapy or who are dependent on corticosteroids, researchers report.
Lead author Dr. Alexander C. Ford, from Leeds Gastroenterology Institute in the UK, told Reuters Health that this meta-analysis is the first one to pool data for all RCTs of FDA-approved biological therapies in inflammatory bowel disease (IBD). Also, he said, it contains data from unpublished studies and more data for fistulizing CD than has previously been available.
The research, funded by the American College of Gastroenterology, was published online March 15 in the American Journal of Gastroenterology.
The researchers searched MEDLINE, EMBASE, and the Cochrane central register through December 2010, netting 3,061 relevant studies. They evaluated 66 of them and included 27 in their analysis. These studies enrolled adults with active or quiescent CD or UC; they compared placebo to the anti-TNF-alpha agents infliximab, adalimumab or certolizumab, or the alpha-4-integrin inhibitor natalizumab.
Dr. Ford emphasized to Reuters Health that they used "very conservative" methods in this analysis in order to "minimize the likelihood that the efficacy of biological therapies has been overestimated."
Overall, the results indicate that these drugs are "more efficacious than placebo in inducing remission in moderate to severely active luminal CD, preventing relapse of quiescent luminal CD once remission has been achieved and, in the case of infliximab, in inducing remission in moderate to severely active UC," the researchers reported.
Both the anti-TNF therapies and natalizumab were superior to placebo in inducing remission of luminal CD; the relative risks of no remission were 0.87 and 0.88, respectively. The number needed to treat (NNT) to achieve remission in one patient with active CD was 8 for anti-TNF agents and 11 for natalizumab.
There was heterogeneity between the three different anti-TNF agents studied, the investigators note, and they say infliximab, natalizumab and adalimumab appear to have the most evidence for inducing remission of active luminal CD. "Certolizumab did not appear to be of benefit in inducing remission of Crohn's disease, which was surprising," Dr. Ford told Reuters Health.
Once remission of CD was achieved, all of the biological therapies were better than placebo in preventing relapse, with an NNT of 4.
The "major benefit" of biological therapies in CD, Dr. Ford said, seems to be in preventing relapse of disease activity once remission has been achieved, rather than inducing remission itself, although they were still superior to placebo in the latter situation as well.
In terms of active UC, infliximab proved "highly effective" for remission induction, with an NNT of only 4. The researchers say they didn't find any trials adequately designed to answer the question of whether biological agents are effective in preventing relapse of UC.
There was no overall benefit for anti-TNF therapies in promoting the healing of fistulizing CD compared with placebo; however, a statistically significant difference was detected when the analysis was restricted only to studies with longer follow-up, the researchers say.
The single trial that made fistula healing its primary end point showed a "clear benefit" of infliximab over placebo. "There was also a significant reduction in fistula recrudescence in CD, although only one RCT examined this issue," the authors report.
In general, serious adverse effects events were no more common with biological therapies than with placebo, at least in the studies they reviewed. They caution, however, that the safety data "may not be particularly robust" given that the trials had relatively small numbers of subjects who were on the medications for a relatively short period of time.
They also remind clinicians that the serious safety concerns with these drugs include opportunistic infection, reactivation of latent tuberculosis, development of hematologic malignancies including hepatosplenic T-cell lymphoma, and in the case of natalizumab, progressive multifocal leukoencephalopathy.
Published simultaneously in the American Journal of Gastroenterology are two related papers on IBD. One is a single-center retrospective cohort study looking at the tolerability of accelerated infliximab infusion times in IBD patients.
In a nutshell, Dr. Gert Van Assche of Leuven University Hospitals, Belgium, and colleagues report that in selected patients who can tolerate two-hour infusions of infliximab 5 mg/kg scheduled maintenance therapy, the infusion time can be shortened to one hour with "good tolerability."
The other paper focuses on the loss of response to adalimumab and the need for adalimumab dose intensification in patients with CD.
In a systematic review of 39 studies looking at this specific issue, Dr. Laurent Peyrin-Biroulet from Universite Henri Poincare in Nancy, France, and colleagues found that about one-fifth of patients will lose their response to adalimumab and will need higher doses. Most patients who increase the dose will regain their response to the drug, the researchers say.
A meta-analysis of randomized controlled trials (RCTs) supports the use of FDA-approved biological therapies in patients with active Crohn's disease (CD) or ulcerative colitis (UC) who have failed first- and second-line therapy or who are dependent on corticosteroids, researchers report.
Lead author Dr. Alexander C. Ford, from Leeds Gastroenterology Institute in the UK, told Reuters Health that this meta-analysis is the first one to pool data for all RCTs of FDA-approved biological therapies in inflammatory bowel disease (IBD). Also, he said, it contains data from unpublished studies and more data for fistulizing CD than has previously been available.
The research, funded by the American College of Gastroenterology, was published online March 15 in the American Journal of Gastroenterology.
The researchers searched MEDLINE, EMBASE, and the Cochrane central register through December 2010, netting 3,061 relevant studies. They evaluated 66 of them and included 27 in their analysis. These studies enrolled adults with active or quiescent CD or UC; they compared placebo to the anti-TNF-alpha agents infliximab, adalimumab or certolizumab, or the alpha-4-integrin inhibitor natalizumab.
Dr. Ford emphasized to Reuters Health that they used "very conservative" methods in this analysis in order to "minimize the likelihood that the efficacy of biological therapies has been overestimated."
Overall, the results indicate that these drugs are "more efficacious than placebo in inducing remission in moderate to severely active luminal CD, preventing relapse of quiescent luminal CD once remission has been achieved and, in the case of infliximab, in inducing remission in moderate to severely active UC," the researchers reported.
Both the anti-TNF therapies and natalizumab were superior to placebo in inducing remission of luminal CD; the relative risks of no remission were 0.87 and 0.88, respectively. The number needed to treat (NNT) to achieve remission in one patient with active CD was 8 for anti-TNF agents and 11 for natalizumab.
There was heterogeneity between the three different anti-TNF agents studied, the investigators note, and they say infliximab, natalizumab and adalimumab appear to have the most evidence for inducing remission of active luminal CD. "Certolizumab did not appear to be of benefit in inducing remission of Crohn's disease, which was surprising," Dr. Ford told Reuters Health.
Once remission of CD was achieved, all of the biological therapies were better than placebo in preventing relapse, with an NNT of 4.
The "major benefit" of biological therapies in CD, Dr. Ford said, seems to be in preventing relapse of disease activity once remission has been achieved, rather than inducing remission itself, although they were still superior to placebo in the latter situation as well.
In terms of active UC, infliximab proved "highly effective" for remission induction, with an NNT of only 4. The researchers say they didn't find any trials adequately designed to answer the question of whether biological agents are effective in preventing relapse of UC.
There was no overall benefit for anti-TNF therapies in promoting the healing of fistulizing CD compared with placebo; however, a statistically significant difference was detected when the analysis was restricted only to studies with longer follow-up, the researchers say.
The single trial that made fistula healing its primary end point showed a "clear benefit" of infliximab over placebo. "There was also a significant reduction in fistula recrudescence in CD, although only one RCT examined this issue," the authors report.
In general, serious adverse effects events were no more common with biological therapies than with placebo, at least in the studies they reviewed. They caution, however, that the safety data "may not be particularly robust" given that the trials had relatively small numbers of subjects who were on the medications for a relatively short period of time.
They also remind clinicians that the serious safety concerns with these drugs include opportunistic infection, reactivation of latent tuberculosis, development of hematologic malignancies including hepatosplenic T-cell lymphoma, and in the case of natalizumab, progressive multifocal leukoencephalopathy.
Published simultaneously in the American Journal of Gastroenterology are two related papers on IBD. One is a single-center retrospective cohort study looking at the tolerability of accelerated infliximab infusion times in IBD patients.
In a nutshell, Dr. Gert Van Assche of Leuven University Hospitals, Belgium, and colleagues report that in selected patients who can tolerate two-hour infusions of infliximab 5 mg/kg scheduled maintenance therapy, the infusion time can be shortened to one hour with "good tolerability."
The other paper focuses on the loss of response to adalimumab and the need for adalimumab dose intensification in patients with CD.
In a systematic review of 39 studies looking at this specific issue, Dr. Laurent Peyrin-Biroulet from Universite Henri Poincare in Nancy, France, and colleagues found that about one-fifth of patients will lose their response to adalimumab and will need higher doses. Most patients who increase the dose will regain their response to the drug, the researchers say.
