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

Abstract and Introduction


Background: Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD).

Aims: To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD.

Methods: EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included.

Results: A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes.

Conclusions: Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.


Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract which causes progressive intestinal damage and disability.[1] Anti-tumour necrosis factor alpha (anti-TNF) monoclonal antibodies are the mainstay of treatment for moderate to severe CD when conventional treatments have failed.[2] The introduction of these agents (infliximab, adalimumab and certolizumab pegol) has revolutionised the treatment of CD, making control of inflammation and mucosal healing attainable therapeutic targets.[3,4]

However, despite robust efficacy data, not all patients respond to anti-TNF therapy, and many lose response over time.[5] Rates of primary nonresponse range from 10% to 30%, with secondary loss of response by 12 months as high as 23%-46% (dose escalation rates) or 5%-13% (drug discontinuation rates).[5] Immunogenicity is an established mechanism of treatment failure,[6] with antidrug antibodies developing within the first 12 months of treatment in most cases.[7] The implications of treatment failure are significant, including the risks of disease progression, complications and surgery,[1,5] as well as the economic consequences.[8]

With each subsequent biologic therapy, clinical response rates fall.[6] Therefore, it is important that each anti-TNF agent be optimised prior to switching to an alternative. Standard dosing of infliximab (5 mg/kg every eight weeks) and adalimumab (40 mg every other week), as defined in registration studies,[9–11] is efficacious for maintaining remission in CD. However, emerging strategies for optimising anti-TNF therapy support dose escalation in certain clinical scenarios.[3,4,6,7,12] Such strategies may achieve early control of disease activity and longer term remission,[12] with the potential to limit disease progression and alter the natural history of this condition.[4]

Therapeutic drug monitoring (TDM) may be used to guide clinical decision-making in response to treatment failure, often referred to as 'reactive' TDM.[6,7] 'Proactive' TDM, or dose adjustments to meet drug level targets in the absence of clinical or biochemical loss of response, remains a controversial strategy.[6,7] Various treatment algorithms based on serum drug levels and the presence or absence of antidrug antibodies have been described.[5–7] Subtherapeutic drug levels are associated with an increased risk of antibody formation.[13] In turn, the development of antibodies is associated with lower drug levels and an increase in disease activity.[14–16]

Loss of response to anti-TNF therapy and the subsequent need for dose intensification have been well described;[5] however, the evidence for dose escalation in CD (with or without guidance from TDM) remains controversial. In this systematic review, we aimed to assess the clinical efficacy of dose escalation in CD patients receiving maintenance infliximab or adalimumab therapy. We also aimed to compare the efficacy of dose escalation strategies and evaluate the role of TDM based dosing. Finally, we sought to identify predictors of response to dose-escalated therapy.