In the presence of loss of response, what should I do if my patient has a high infliximab level?

By Simon PL. Travis, MD Volume 1 - Issue 9

Runs 1:19

Relation between drug levels and loss of response

Evidence concerning the appropriate clinical strategy in patients with adequate drug levels and loss of response is somewhat limited, as prospective randomized trials are lacking in the area of therapeutic drug monitoring (TDM). To determine the clinical strategy for a patient with therapeutic drug levels and loss of response, in many cases, inferences must be drawn from available data generated by retrospective and observational studies.

An observational study analyzed 1487 trough samples from 483 patients with Crohn’s disease who had participated in 4 infliximab maintenance clinical studies.(1) The analysis found an association between active disease and antidrug antibodies (ADAs), even in the presence of adequate drug levels and even at low ADA titres. ADAs may block the binding of infliximab to tumour necrosis factor-α (TNF-α) and directly neutralize drug efficacy.

A retrospective chart review was performed of 155 patients with inflammatory bowel disease (IBD) who had ADA and infliximab concentrations measured to determine whether this information changed the clinical strategy.(2) The chart review found that among patients with apparent loss of response and therapeutic infliximab levels, 62% had no endoscopic or radiographic evidence of inflammation and 76% were maintained at the same infliximab dose. These results make the important point that patients with secondary loss of response should first be assessed to confirm that their symptoms reflect active IBD. If not, they should be investigated for another etiology.

A retrospective study of 76 patients with IBD who had lost response to infliximab evaluated their clinical response to various treatment strategies and correlated this with trough drug and ADA levels.(3) Intensification of infliximab therapy restored response in 69% of patients in whom it was implemented, including those with therapeutic infliximab levels. This suggests that “adequate” trough levels may actually be higher than those currently accepted as therapeutic.

A prospective study of 82 patients with IBD with a disease flare during adalimumab treatment measured trough drug and ADA levels.(4) The study found that adalimumab trough levels >4.9 μg/mL were associated with failure of both intensification of adalimumab therapy and subsequent conversion to infliximab therapy in 90% of cases. In this situation, where a different pathway may be operative, a switch to another drug class would be a consideration.

A review of tailoring TNF-α therapy in IBD discussed possible interpretations of TDM results in patients with secondary loss of response.(5) If drug levels were undetectable and ADAs were present, a likely interpretation is accelerated drug clearance due to neutralizing ADAs. If ADAs were not present with undetectable drug levels, loss of response could result from symptoms from a noninflammatory IBD disease process, non-IBD causes, a shift to a non-TNF-α disease mechanism, paradoxical inflammation, or assay limitations. In practice, when confronted with loss of response in a patient with adequate drug levels, it is critical to first determine whether IBD inflammation is present and whether it is the cause of the symptoms, and to consider the mechanisms behind the loss of response.

Despite the relative lack of data about managing loss of response in patients with IBD, use of TDM in an algorithm-based approach may be both useful and cost effective. A randomized, controlled, single-blind, multicentre study investigated the cost effectiveness of algorithm-based interventions after loss of response to infliximab in 69 patients with IBD.(6) The algorithm was designed to identify reasons for therapeutic failure, and the study found that using an algorithm that was based on both trough and ADA levels significantly reduced treatment costs (34% in the intention-to-treat population) compared with empiric dose intensification, without negatively affecting efficacy. A 1-year follow-up study determined that the financial benefit of the algorithm-based approach was maintained.(7)


  1. Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut. 2014 Oct 21. pii: gutjnl-2014-307883. doi: 10.1136/gutjnl-2014-307883. [Epub ahead of print].
  2. Afif W, Loftus Jr EV, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133–9.
  3. Pariente B, Pineton de Chambrun G, Krzysiek R, et al. Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:1199–1206.
  4. Roblin X, MD, Rinaudo M, Del Tedesco E, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.Am J Gastroenterol. 2014;109:1250–6.
  5. Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014;11:243–55.
  6. Steenholdt C, Brynskov J, Thomsen JO, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919–27.
  7. Steenholdt C, Brynskov J, Thomsen JO, et al. Individualized therapy is a long-term cost-effective method compared to dose intensification in Crohn’s disease patients failing infliximab. Dig Dis Sci. DOI 10.1007/s10620-015-3581-4.

Special Edition IBD Dialogue: Therapeutic Drug Monitoring in Clinical Practice 2014·Volume 01 is made possible by an unrestricted educational grant from…