Baseline exposure to an immunomodulator did not improve the odds of clinical response or remission when starting anti–tumor necrosis factor (anti-TNF) therapy for Crohn’s disease (CD), said authors of a meta-analysis of 11 randomized, controlled trials. Pending better trials, patients with CD and their clinicians will need to carefully weigh the risks and benefits of continuing an immunomodulator when starting anti-TNF therapy, Dr. Jennifer Jones of Dalhousie University in Halifax, Canada and her associates wrote in the December issue of Clinical Gastroenterology and Hepatology.
Intense debate persists about whether patients with CD who have already been exposed to immunomodulators such as azathioprine, 6-mercaptopurine, and methotrexate should stay on them when starting anti-TNF agents. The landmark 2010 SONIC trial could not answer this question because it only enrolled patients who had never received an immunomodulator, and more recent studies (Clin Gastroenterol Hepatol. 2011;9:36-41) have raised concerns about the safety of immunomodulators, the researchers noted. To compare combination immunomodulators and anti-TNF treatment with anti-TNF monotherapy in luminal and fistulizing CD, they analyzed original datasets from 11 randomized, controlled trials published between 1980 and 2008. A total of 625 patients with CD had received an immunomodulator, while 976 patients had not. The investigators excluded trials in which patients were naive to both immunomodulators and anti-TNF agents (Clin Gastroenterol Hepatol. 2015 [doi: 10.1016/j.cgh.2015.06.034]).
Nephron/Wikimedia Commons/CC BY-SA 3.0/
High magnification micrograph of Crohn's disease. Biopsy of colon. H&E stain.
In the overall analysis, combination therapy was no better than anti-TNF monotherapy in terms of 6-month remission, maintenance of response, or partial or full fistula closure, Dr. Jones and her associates reported. The same was true for subgroup analyses, but the odds ratio for infliximab reached statistical significance in a sensitivity analysis that included data from the ACCENT 2 (Clin Gastroenterol Hepatol. 2004;2:912-20) trial. “For the infliximab-only analysis, adding ACCENT 2 resulted in minimal change in the point estimate but, as expected, increased the precision of the 95% CIs (the lower CI increased from 0.97 to 1.06), which led to a statistically significant difference in the comparison between infliximab monotherapy and combination therapy,” the researchers commented. While sensitivity analyses have limitations, the finding “does raise the question” of whether the benefits of staying on an immunomodulator depend on the anti-TNF agent, they said.
Combination therapy did not heighten the chances of infusion reactions, malignancies, serious infections, or death, said the investigators. In fact, baseline immunomodulator exposure was associated with fewer injection site reactions among infliximab patients (OR, 0.46; 95% CI, 0.26-0.79). The researchers did not uncover publication bias, and found significant heterogeneity among studies only for the 6-month clinical response endpoint, they added.
The findings “challenge the clinical importance of combination therapy” in the setting of baseline immunomodulator exposure, but “it is hard to ignore the preponderance of data” on anti-TNF pharmacokinetics that support combination therapy over monotherapy, the investigators emphasized. “Whether combination therapy has a greater protective effect against anti-drug antibody development and lower trough levels for all anti-TNF agents or for patients previously exposed to anti-TNF agents is still in question,” they added. They called for a well-designed, randomized, placebo-controlled trial that uses objective measures of disease activity and follow patients long enough to assess efficacy.
The investigators reported no funding sources for the study. Dr. Jones reported having been a speaker for Jansen, Merck, Schering-Plough, Abbott, and AbbVie, and having served on advisory boards for Janssen, Abbott, and Takeda. Nine co-authors reported financial and consulting relationships with Jansen, Merck, Schering-Plough, Abbott, and a number of other pharmaceutical companies.
Source: American Gastroenterological Association