In the presence of loss of response, can you help me interpret TDM results?

By Shomron Ben-Horin, MD Volume 1 - Issue 7

Runs 1:33

Relation between infliximab levels and response

A comparison of infliximab levels with outcomes in moderate-to-severe ulcerative colitis used data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2). Infliximab levels at Weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission.(1) Infliximab levels of 41 μg/mL at week 8 of induction and trough levels of 3.7 μg/mL during maintenance were linked to optimal outcomes. Patients in the lowest serum level quartile had lower treatment efficacy, lower albumin levels, and an increased incidence of antidrug antibodies (ADAs).

An infliximab reinitiation study was performed in patients who had received only episodic therapy, who had lost response, or who had experienced infusion reactions.(2) The study assessed factors related to the success and safety of restarting infliximab, including ADAs and drug trough levels, as restarting infliximab is associated with a high risk of developing ADAs. An infliximab trough level >2 μg/mL and undetectable ADAs soon after reinitiation predicted response. Measuring early trough levels allows early optimization if low infliximab levels are found. Among patients who had failed immunomodulator therapy, combination therapy was superior to monotherapy only in patients with lowest-quartile trough levels.

A radioimmunoassay study found infliximab levels of 0.5 μg/ml can discriminate between loss of response and maintenance of remission.(3) In addition, an ADA level of 10 U/mL can discriminate between patients with loss of response and those who maintain remission, as ADA levels were significantly higher in patients with loss of response (median 35 U/mL). A combined assessment using both trough levels and ADA titres can further increase accuracy.

Detection of ADAs in the presence of drug

In the double-antigen enzyme-linked immunosorbent assay (ELISA), the most common test used for infliximab ADAs, the presence of infliximab interferes with ADA detection. An alternative ELISA that uses antihuman lambda chain antibody to detect ADAs overcomes this interference.(4) The presence of both drug and ADA may have clinical significance, as subsequent loss of response has been seen in some patients with this double positivity. Trough and ADA levels, however, inconsistently predict response. Only half of patients with loss of response had low infliximab levels. In the remainder of patients, loss of response may have been linked to another mechanism or to ADAs that do not affect drug levels. In addition, almost half of patients with loss of response have no detectable ADAs. Furthermore, patients with detectable ADAs may remain in clinical remission. Thus, the finding of simultaneous drug and ADA levels may have important clinical implications, but a comprehensive patient assessment is still needed.

Approach to dose optimization

An analysis of the association between trough drug levels and ADAs evaluated outcomes of interventions implemented in patients with loss of response to infliximab or adalimumab.(5) Patients with undetectable or low ADA titres responded to dose intensification. Patients with adequate trough levels (>4.5 μg/mL adalimumab and >3.8 μg/mL infliximab) did not respond to dose intensification or a switch to another TNF-α antagonist but did respond to expectant management or out-of-class interventions. Patients with >4 μg/mL-equivalent adalimumab ADA or >9 μg/mL-eq infliximab ADA did not respond to an increased drug dosage but did respond to switching tumour necrosis factor-α (TNF-α) antagonists.

Dose optimization can often restore clinical response, and although pharmacokinetic models suggest that shortening the dosing interval is superior to increasing the dose, there do not seem to be significant differences between the strategies clinically.(3) Patients who do not benefit from dose optimization may respond to a switch to a second TNF-α antagonist, but efficacy tends to be lower than with the first agent.

A review of the use of TNF-α antagonists in inflammatory bowel disease proposed a management algorithm for patients with loss of response, based on therapeutic drug monitoring.(6) Among patients with adequate trough drug levels and low or undetectable ADA levels, dose intensification, possibly with the addition of an immunomodulator is an option, as is switching to a medication with a different mechanism of action. If antibody levels are high, there are three options: add an immunosuppressant, change the TNF-α antagonist, or switch to a medication with a different mechanism of action. If trough drug levels are low or undetectable and antibody levels are high, possible options are dose intensification with the addition of an immunomodulator, change to another TNF-α antagonist, or change to a drug with a different mechanism of action. If both trough drug and ADA levels are low, dose intensification, possibly with the addition of an immunomodulator, is the therapeutic decision.


  1. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis.Gastroenterology. 2014;147(6):1296-1307.
  2. Baert F, Drobne D, Gils A, et al. Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy. Clin Gastroenterol Hepatol. 2014;12(9):1474–81.e2; quiz e91.
  3. Steenholdt C. Use of infliximab and anti-infliximab antibody measurements to evaluate and optimize efficacy and safety of infliximab maintenance therapy in Crohn’s disease. Dan Med J. 2013;60(4):B4616.
  4. Kopylov U, Mazor Y, Yavzori M, et al. Clinical utility of antihuman lambda chain-based enzyme-linked immunosorbent assay (elisa) versus double antigen elisa for the detection of anti-infliximab antibodies. Inflamm Bowel Dis. 2012;18(9):1628–33.
  5. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13(3):522–30.
  6. Eser A, Primas C, Reinisch W. Drug monitoring of biologics in inflammatory bowel disease. Curr Opin Gastroenterol. 2013;29(4):391–6.

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