Systematic Review

Efficacy of Escalated Maintenance Anti-tumour Necrosis Factor Therapy in Crohn's Disease

Vandita Y. Mattoo; Chamara Basnayake; William R. Connell; Nik Ding; Michael A. Kamm; Mark Lust; Ola Niewiadomski; Alexander Thompson; Emily K. Wright


Aliment Pharmacol Ther. 2021;54(3):249-266. 

In This Article

Materials and Methods

This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[17] (Table S1) using an a priori established protocol. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, registration ID: CRD42020206069).

Data Sources and Search Strategy

We performed a systematic search of English language articles from inception through to 26 August 2020 using six electronic databases: EMBASE + EMBASE Classic (Ovid), MEDLINE, MEDLINE In-Process, Epub Ahead of Print, Web of Science and, the Central Cochrane Register of Controlled Trials (CENTRAL). The search was then updated on 25 April 2021. The search strategy used a combination of free-text and medical subject heading (MeSH) terms to capture the following concepts: (a) Population: adult patients with CD (e.g., "Crohn's disease" [MeSH]); (b) Intervention: anti-TNF drugs (e.g., "infliximab" or "adalimumab"); (c) Anti-TNF dose optimisation (e.g., "dose escalation" or "dose intensification" or "empiric dose escalation" or "therapeutic drug monitoring")

The full search strategy for each database is shown in Tables S2-S5. We also manually searched reference lists of key publications and the proceedings from Digestive Disease Week, United European Gastroenterology Week and European Crohn's and Colitis Organisation for the past 5 years to identify additional studies and emerging data. The and databases were searched for ongoing trials. All search results were imported into a reference management software (Endnote X8, Clarivate Analytics) and duplicates were removed. Two authors (VYM and EKW) independently screened records by title and abstract, followed by full text, using predefined eligibility criteria, on Covidence (Covidence systematic review software, Veritas Health Innovation). Any disagreements between the authors were resolved by discussion, with third-party input as required.

Selection Criteria

Studies were eligible for inclusion if they met all of the following criteria: (a) full text publications; (b) study design: interventional (randomised or nonrandomised) or observational (prospective, retrospective or case-control); (c) adult population (age ≥18 years); (d) patients with luminal and/or perianal CD on maintenance anti-TNF therapy (infliximab or adalimumab); (e) at least 10 patients on escalated dosing (regular maintenance doses exceeding 40 mg every other week for adalimumab and 5 mg/kg every 8 weeks for infliximab); (f) reporting on at least one of the following outcomes of interest defined as per authors in individual studies:

  • Primary outcome: clinical response and clinical remission after dose escalation.

  • Secondary outcomes: biochemical response, biochemical remission, endoscopic response, endoscopic remission, radiologic response, radiologic remission, fistula healing, fistula closure, change in anti-TNF drug level, change in antidrug antibody titre.

Exclusion criteria were as follows: (a) studies only available in abstract form; (b) case reports, case series, reviews and meta-analyses; (c) studies that only provided pooled analyses for patients with CD and UC.

Data Extraction

Data from included studies were extracted in duplicate into a standardised data table in Excel (Microsoft software) by two independent authors (VYM and EKW). Any disagreements were resolved by consensus and reference to the original paper. The following predefined data were extracted: first author, year of publication, country where study was conducted, study design, single or multicentre, study duration, sample size, duration of follow up, population characteristics (disease phenotype, disease duration, prior anti-TNF exposure, concomitant therapy). The following data about the study intervention were extracted: biologic agent(s) used, anti-TNF optimisation strategy (empiric or TDM guided), escalated dosing schedule(s), time to dose escalation, proportion of patients on escalated dosing. Data on clinical, biochemical, endoscopic and/or radiologic outcomes after anti-TNF dose escalation were extracted. If available, pharmacokinetic data including anti-TNF drug levels, antidrug antibody titres and type of assay used were also recorded.

Risk of Bias Assessment

Two authors (VYM and EKW) independently evaluated the RCTs using the Cochrane Collaboration's tool for assessing risk of bias in randomised studies.[18] Bias was assessed across six domains: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias using Review Manager (RevMan version 5.4, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020). The RCTs were considered at low risk of bias if all domains were rated low risk of bias, at high risk of bias if one or more domains were rated high risk of bias, and at unclear risk of bias if one or more domains were rated unclear risk of bias with no high-risk domains. Observational studies and post hoc analyses of RCTs were assessed using the Newcastle-Ottawa scale (NOS).[19] Bias was evaluated across three domains: selection of study groups, comparability of groups and, ascertainment of exposure and outcomes. Studies were considered at low risk of bias if rated 7–9 stars on the NOS (out of a total maximum of 9 stars), at moderate risk of bias if rated 4–6 stars, and at high risk of bias if rated 0–3 stars. Any discrepancies in the risk of bias assessment were resolved by discussion and reference to the original paper.

Data Synthesis

Data from included studies were summarised in a qualitative synthesis. We did not perform a meta-analysis due to substantive heterogeneity in study design, therapeutic strategy and protocol for anti-TNF optimisation, and duration of follow-up in the included studies.