title: Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti-Tumor Necrosis Factor Therapy for Crohn's Disease: A Meta-analysis of Placebo-controlled Trials.
abstract: OBJECTIVE
  There is debate over whether patients with Crohn's disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy.
  
  
  METHODS
  We performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohn's disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents.
  
  
  RESULTS
  Overall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.)
  
  
  CONCLUSIONS
  On the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.
authors.affiliation: Dalhousie University, Halifax, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Jones
authors.affiliation: University of Calgary, Calgary, Canada.
authors.forename: Gilaad G
authors.initials: GG
authors.lastname: Kaplan
authors.affiliation: Inserum U954 and Université de Lorraine, Nancy, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Baidoo
authors.affiliation: University of Calgary, Calgary, Canada.
authors.forename: Shane
authors.initials: S
authors.lastname: Devlin
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Gil Y
authors.initials: GY
authors.lastname: Melmed
authors.affiliation: University of Calgary, Calgary, Canada.
authors.forename: Divine
authors.initials: D
authors.lastname: Tanyingoh
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Laura
authors.initials: L
authors.lastname: Raffals
authors.affiliation: Guy's and St Thomas' Hospitals, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Irving
authors.affiliation: Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kozuch
authors.affiliation: The Alfred Hospital, Melbourne, Australia.
authors.forename: Miles
authors.initials: M
authors.lastname: Sparrow
authors.affiliation: University of California San Francisco, San Francisco, California.
authors.forename: Fernando
authors.initials: F
authors.lastname: Velayos
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Bressler
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Adam
authors.initials: A
authors.lastname: Cheifetz
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jean-Frederic
authors.initials: JF
authors.lastname: Colombel
authors.affiliation: Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Electronic address: corey.a.siegel@hitchcock.org.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Siegel
mesh_terms: D003424:Crohn Disease / Q000188:drug therapy*; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects*; D010919:Placebos / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D007155:Immunologic Factors; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha
keywords: Clinical Trial; IBD; Immune Suppression; Inflammatory Bowel Disease