Tumor necrosis factor-alpha antagonists for treatment of pediatric Crohn's disease.

Rationale: The incidence of pediatric Crohn's disease has been steadily increasing. In this population, the disease often presents with more extensive inflammation, a tendency toward a more aggressive course, and frequently requires early immunomodulation. Anti-tumor necrosis factor (TNF) antibodies work by neutralizing pro-inflammatory effectors, thus interrupting the inflammatory cascade. There is broad consensus that biologics are effective in achieving mucosal healing in Crohn's disease. Despite this, several important questions about anti-TNF therapy in children and adolescents remain unanswered. These include determining the optimal dosing regimen for both safety and durability, identifying the ideal timing for initiating anti-TNF treatment before irreversible bowel damage occurs, and deciding whether to use a top-down or step-up approach tailored to the individual patient's disease location, behavior, and other predictors of complicated outcomes.

Objectives: To assess the efficacy and safety of TNF-alpha antagonists for induction of remission in children and adolescents with active Crohn's disease.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, Embase (Elsevier), LILACS (Latin American and Caribbean Health Science Information database) (BIREME), and Science Citation Index Expanded and Conference Proceedings Citation Index-Science (Web of Science). We applied no language or document type restrictions. The last update of evidence was on 1 June 2024.

Eligibility criteria: We included randomized controlled trials (RCTs), irrespective of publication type, publication status, and language, assessing the benefits and harms of TNF-alpha antagonist for induction of remission treatment for pediatric Crohn's disease.

Outcomes: Our critical outcomes were induction of clinical remission and incidence of serious adverse effects. Important outcomes were all-cause mortality and morbidity related to Crohn's disease, endoscopic remission, incidence of steroid withdrawal, proportion of participants in need of surgical intervention, loss of response to anti-TNF, and incidence of mild adverse events.

Risk of bias: We assessed risk of bias using Cochrane's RoB 1 tool. The only included trial was at overall high risk of bias.

Synthesis methods: We used standard Cochrane methodology to perform this systematic review. We used the GRADE approach to assess the certainty of evidence per outcome.

Included studies: Only one study fulfilled the inclusion criteria. The study was an open-label, multicenter RCT conducted in 12 hospitals in three European countries, and included 100 children (51 boys and 49 girls) newly diagnosed with moderate-to-severe Crohn's disease with a 52-week follow-up. Children were randomly assigned to first-line infiximab (FL-IFX) (n = 50) or conventional treatment (n = 50). The trial was at overall high risk of bias.

Synthesis of results: Clinical remission was achieved by 59% (24/41) in the FL-IFX group versus 34% (15/44) in the conventional-treatment group, therefore favoring FL-IFX (risk ratio [RR] 1.72, 95% confidence interval [CI] 1.06 to 2.79; low certainty evidence). Endoscopic remission was achieved by 59% (16/27) in the FL-IFX group versus 17% (5/30) in the conventional-treatment group, therefore favoring FL-IFX (RR 3.56, 95% CI 1.51 to 8.39; low certainty evidence). The included study did not assess all-cause morbidity or mortality related to Crohn's disease or incidence of serious or mild adverse events. No funding information was provided. This study is part of the TISKid study, which is in development and includes the same population with a planned follow-up of five years.

Authors' conclusions: There is limited evidence to support the use of anti-TNF therapy for induction of remission in pediatric Crohn's disease. Only one randomized clinical trial at high risk of bias suggests that FL-IFX may result in a slight increase in induction of clinical remission and endoscopic remission when compared to conventional treatment. The results of this trial need to be interpreted with caution. Several important questions remain regarding the optimal timing of anti-TNF therapy, the preference between step-up versus top-down strategies, and other related issues. Further RCTs are needed to achieve stronger evidence, address these questions, and provide clearer guidance. There is a need for larger randomized clinical trials following the SPIRIT and CONSORT statements, assessing the benefits and harms of using anti-TNF versus conventional therapy for pediatric Crohn's disease induction treatment.

Funding: This Cochrane review had no dedicated funding.

Registration: The intervention protocol was published on Cochrane Database of Systematic Reviews 2022, DOI: 10.1002/14651858.CD014497.