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


Implementing a 'treat-to-target' strategy in Crohn's disease, which may have the potential to prevent disease progression, requires the optimal use of anti-TNF therapies. Loss of response to anti-TNF agents is a common therapeutic challenge,[5] but dose escalation can recapture response in a majority of patients without an increased risk of toxicity,[9–11] and is likely to be an important strategy in prolonging the life of these treatments.

We considered a number of factors that may affect patient response to intensified therapy. Prior anti-TNF exposure predicts the need for dose escalation in population based cohorts,[24] however, outcomes following treatment escalation were generally comparable between anti-TNF naïve and anti-TNF experienced patients.[16,25,27,45,47,57] This likely reflects the efficacy of dose escalation in overcoming low levels of immunogenicity.[54] Thiopurine cotherapy reduces immunogenicity and the risk of loss of response in anti-TNF treated patients,[80–82] but did not appear to improve the clinical response to dose escalation, with only one retrospective study[57] showing an additional therapeutic benefit of combination therapy compared to escalated monotherapy.

Anti-TNF treatment failure is predicted by low serum drug levels.[80] A significant increase in drug level after dose escalation was an important predictor of clinical, biochemical and endoscopic response in observational studies.[29,69,71] However, antidrug antibody titre remains important with dose escalation restoring therapeutic drug levels most reliably when antibodies are absent or present in low-titres.[54,71] Therapeutic drug monitoring may prevent futile treatment escalation by identifying patients with high-titre antidrug antibodies, and has been found to be a cost-effective strategy in the 'reactive' setting.[20,21]

However, the clinical utility and longitudinal benefits of regular or proactive TDM remain uncertain. Randomised controlled trials comparing TDM-based strategies to empiric escalation for infliximab have failed to reach their primary end-points.[58,59] Similarly, preliminary data from the recent Serene-CD Maintenance Study showed comparable clinical and endoscopic outcomes in adalimumab-treated patients who underwent proactive TDM compared to clinically adjusted dosing.[83] One reason for this may be the lack of long-term follow-up in many of these studies. In the TAXIT trial,[58] all patients were initially optimised to achieve therapeutic trough levels prior to randomisation, which may have obscured potential benefits of proactive dosing in comparison to standard treatment. However, some recent data do indicate that proactively dosed patients have fewer flares and lower rates of treatment discontinuation compared to those receiving standard care.[58,63,64]

The pharmacokinetics of anti-TNF agents have significant inter-individual variability.[84] Moreover, optimal drug levels may vary according to therapeutic target, disease phenotype or complexity.[85] In perianal fistulising disease, for instance, the need for more aggressive drug level targets, to achieve endpoints such as fistula healing, is well established.[78,79] Intensified maintenance doses are likely required to achieve adequate drug levels in this group of patients.[78] In most studies, patients with complex disease phenotypes, including those with perianal involvement, had similar clinical and biochemical response rates to treatment escalation compared to patients with predominantly inflammatory luminal disease.[25,27,30,39,45,47,51,57,60] In an era moving increasingly towards personalised treatments, dashboard systems that incorporate individual patient data,[12] including disease severity and phenotype, to determine the optimal anti-TNF dose are a novel therapeutic strategy, requiring further validation in 'real world' settings.

The control of biomarkers, such as faecal calprotectin and C-reactive protein, may be an alternative therapeutic target to guide the escalation of maintenance treatment in CD. The CALM trial[3] provides compelling evidence for this 'tight-control' approach. Early treatment escalation in response to biomarker elevation, which may indicate residual intestinal inflammation, was associated with superior clinical and endoscopic outcomes in this study.[3] However, further data are required to determine the efficacy of such tight control algorithms in clinical practice, where it may be more challenging to apply stringent clinical and biochemical treatment escalation criteria.

The potential for bias in the included literature must be considered. While rates of clinical and biomarker response to dose escalation were high in randomised trials, patients were generally dose escalated on an 'open-label' basis and assessments of response to escalated therapy were subject to investigator bias.[3,9–11] In addition, much of the evidence to support anti-TNF escalation in the setting of treatment failure comes from nonrandomised uncontrolled assessments, with largely retrospective data. The majority of these studies did not follow a standardised protocol for treatment optimisation and, definitions of secondary loss of response and dose escalation were often applied retrospectively.

Moreover, this review has several limitations. We have qualitatively summarised the relevant literature, but did not perform a meta-analysis of the evidence supporting each dose escalation strategy. Our focus was on anti-TNF maintenance therapy, emerging data comparing standard and high induction dosing regimens were not reviewed.[86] The pharmacoeconomic implications of each therapeutic strategy were not evaluated in this review, although optimising the cost efficacy of anti-TNF agents remains an important consideration.

We have identified some knowledge gaps. In clinical practice, treatment de-escalation is often unsuccessful,[24,87] however, data evaluating effective step-down strategies for anti-TNF therapy are lacking. Moreover, the optimal duration of intensified anti-TNF treatment following secondary loss of response is not yet established. While empiric escalation may be adequate initially to re-establish clinical response, further prospective data are needed to determine the utility of regular TDM for maintaining remission in patients receiving intensified therapy.

In this systematic review, we have summarised the controlled trial and 'real world' experience with escalated maintenance anti-TNF dosing. We have examined the exposure-response relationship following dose escalation, and the comparative efficacy of intensification strategies, including for perianal fistulising disease, which has not been done elsewhere. Our findings have implications for clinical practice. In the setting of secondary anti-TNF loss of response, empiric dose escalation was found to be an effective therapeutic strategy. The evidence to support the use of proactive TDM in guiding treatment escalation is limited. Biomarker normalisation may be a helpful target in driving anti-TNF dose escalation, however, the efficacy of such tight-control strategies in prospective 'real world' settings remains to be seen.