Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease

Aliment Pharmacol Ther. 2018 Aug;48(4):394-409. doi: 10.1111/apt.14852. Epub 2018 Jun 19.


Background: There are limited data to inform positioning of agents for treating moderate-severe Crohn's disease (CD).

Aim: We assessed comparative efficacy and safety of first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor [TNF]-α) agents) biologic therapy for moderate-severe CD, through a systematic review and network meta-analysis, and appraised quality of evidence (QoE) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Methods: We identified randomised controlled trials (RCTs) in adults with moderate-severe CD treated with approved anti-TNF agents, anti-integrin agents and anti-IL12/23 agents, first-line or second-line, and compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of clinical remission; safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.

Results: No head-to-head trials were identified. In biologic-naïve patients, infliximab (SUCRA,0.93) and adalimumab (SUCRA,0.75) were ranked highest for induction of clinical remission (moderate QoE). In patients with prior anti-TNF exposure, adalimumab (SUCRA, 0.91; low QoE, in patients with prior response or intolerance to anti-TNF agents) and ustekinumab (SUCRA, 0.71) were ranked highest for induction of clinical remission. In patients with response to induction therapy, adalimumab (SUCRA, 0.97) and infliximab (SUCRA, 0.68) were ranked highest for maintenance of remission. Ustekinumab had lowest risk of serious adverse events (SUCRA, 0.72) and infection (SUCRA, 0.71; along with infliximab, SUCRA, 0.83) in maintenance trials.

Conclusion: Indirect comparisons suggest that infliximab or adalimumab may be preferred first-line agents, and ustekinumab a preferred second-line agent, for induction of remission in patients with moderate-severe CD. Head-to-head trials are warranted.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adalimumab / therapeutic use
  • Adult
  • Antibodies, Monoclonal / therapeutic use
  • Biological Factors / therapeutic use*
  • Crohn Disease / diagnosis
  • Crohn Disease / drug therapy*
  • Crohn Disease / epidemiology
  • Crohn Disease / pathology
  • Data Accuracy
  • Humans
  • Induction Chemotherapy / methods
  • Induction Chemotherapy / standards
  • Induction Chemotherapy / statistics & numerical data
  • Infliximab / therapeutic use
  • Maintenance Chemotherapy / methods
  • Maintenance Chemotherapy / standards
  • Network Meta-Analysis
  • Prognosis
  • Severity of Illness Index
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology
  • Ustekinumab / therapeutic use


  • Antibodies, Monoclonal
  • Biological Factors
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Ustekinumab
  • Adalimumab