Types of TNF Antagonist Drug Failure
Our understanding of the causes of biologic treatment failure are evolving but are typically classified as due to mechanistic failure, non-immune-mediated pharmacokinetic failure, or immune-mediated pharmacokinetic failure [9]. Differentiating between these classes of treatment failure requires therapeutic drug monitoring (TDM), which will be discussed in more detail below.
Mechanistic failure is encountered when the underlying biology does not favor a response to a particular therapy. Studies indicate a strong association between particular genetic phenotypes and the probability of a response to induction with anti-TNF agents [10]. This suggests that some individuals have IBD driven by a biochemical inflammatory cascade in which TNF features prominently, while others have alternative mechanistic drivers of inflammation without significantly elevated TNF levels. Mechanistic failure will typically present as primary nonresponse, but can also be seen in patients with secondary loss of response. Mechanistic failure can be elucidated clinically by the use of TDM. In the case of mechanistic failure, active disease is seen in the presence of adequate drug level, without the presence of anti-drug antibodies. The AGA recommends considering switching to a biologic with a different mechanism of action when mechanistic failure is identified [8].
Non-immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to a drug at adequate drug levels experiences suboptimal drug levels because of pharmacokinetic factors. In the case of anti-TNF therapy, this can be conceptualized as either an increased clearance of anti-TNF from the body (eg, in patients with significant hypoalbuminemia or severe colitis), a reduction in the average serum anti-TNF level because of the redistribution of drug in patients with a large body mass index, or inadequate saturation of the total body burden of TNF-alpha in subjects with a high baseline level of inflammation [11]. Non-immune-mediated pharmacokinetic failure can also be identified clinically through TDM. In this case, active disease is seen in the presence of a suboptimal drug level, without the presence of anti-drug antibodies. The AGA recommends considering dose-escalation of the current TNF antagonist when non-immune-mediated pharmacokinetic failure is identified [8], as this can improve clinical response in an estimated 82% of patients [9].
Finally, immune-mediated pharmacokinetic failure is encountered when a patient who would otherwise respond to the current biologic therapy when at adequate drug concentration levels experiences suboptimal drug levels because of increased drug clearance mediated by anti-drug antibodies [9]. Because anti-TNF agents are monoclonal antibodies, they are inherently immunogenic, and it is well established that episodic dosing and lower serum drug concentrations are strong risk factors for the development of anti-drug antibodies [12]. When anti-drug antibodies are present, and are associated with both a decreased serum drug concentration and active inflammatory bowel disease, immune-mediate pharmacokinetic failure can be invoked. When anti-drug antibodies are present, but at a low level, the AGA recommends dose escalation of current TNF antagonist. When anti-drug antibodies are present at a high level, the AGA recommends considering either the addition of an immunomodulator (if not already being used), or changing to a different class of biologic therapy [8]. This recommendation is based in part on data showing that the proportion of patients with sustained anti-drug antibodies during the first year of therapy with an TNF antagonist is likely between 14% and 20% for those on monotherapy, but between 1% and 5% for those on concomitant immunomodulatory therapy [13,14].
Therapeutic Drug Monitoring of Anti-TNF Agents
As described above, TDM, which is the process of testing the patient’s serum for both the concentration of the TNF antagonist and for the presence and concentration of anti-drug antibodies, can help differentiate between mechanistic failure, non-immune-mediated pharmacokinetic failure, and immune-mediated pharmacokinetic failure (Table 1).
Therapeutic drug monitoring can be classified as either proactive or reactive. Proactive TDM is performed during induction or maintenance therapy when the patient does not have signs or symptoms of active disease to suggest a loss of response. Theoretically, this would allow dose modification and optimization, including dose de-escalation in certain circumstances, and could thus provide cost savings with minimal impact on clinical outcomes. The TAXIT trial provides the most robust evaluation of proactive TDM in TNF antagonist therapy. In this study, patients with Crohn’s disease or ulcerative colitis who had a stable clinical response while on maintenance infliximab were first dose optimized proactively to a target trough concentration of 3–7 μg/mL, then randomized to having dose modifications made based on clinical factors alone, defined as reactive monitoring, or dose modifications based on proactive monitoring, performed by checking the drug concentration and antibody levels before each infusion. At 1 year there was no statistically significant difference in the proportion of patients in remission. In addition, some patients in the proactive TDM group were able to have a dose reduction without a subsequent flare of disease, thus providing cost savings [15]. This study suggests that proactive TDM may have a role in drug optimization, particularly with respect to cost-effectiveness, but provides only indirect evidence of a clinical benefit, since all subjects enrolled in the study were proactively dose optimized prior to randomization. This study had a limited follow-up time of 1 year so was not able to assess for longer-term benefits and risks associated with proactive TDM.
More recently, a large, multicenter, retrospective cohort study provided additional evidence that proactive TDM may provide a clinical benefit in addition to cost savings. This study retrospectively evaluated consecutive patients receiving maintenance infliximab for Crohn’s disease between 2006 and 2015, with a median follow-up time of 2.4 years. They were classified as having had either proactive TDM or reactive TDM. Proactive TDM was associated with statistically significant reductions in the risk of treatment failure (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.09–0.27), the need for surgery (HR 0.30, 95% CI 0.11–0.80), hospitalization (HR 0.16, 95% CI 0.07–0.33), and anti-drug antibody formation (HR 0.25, 95% CI 0.07–0.84) [16].
To date, however, no randomized controlled trials have been published comparing proactive TDM to reactive TDM in treatment-naive patients. Because of the paucity of prospective studies, the AGA currently makes no recommendation regarding the use of proactive TDM in clinical practice. However, the current AGA guidelines do recommend reactive TDM in the setting of secondary loss of response based on the results of one randomized controlled trial (RCT) and several observational studies. The RCT was small (n = 69), and enrolled patients with Crohn’s disease on maintenance therapy with infliximab. Similar to the TAXIT trial, the study did not show a statistically significant difference in rates of clinical remission when subjects were randomized to either empiric dose escalation (to 5 mg/kg every 4 weeks) based on symptoms, or to dose escalations based on the results of reactive TDM. Also similar to the TAXIT trial, it showed an estimated cost savings of about 34% based on local prices in Denmark for reactive TDM over empiric dose escalation [17].
Meanwhile, the observational studies for reactive TDM provided additional support to the clinical benefit of reactive TDM, but also to the underlying hypotheses that drive reactive TDM, namely that subjects with mechanistic failure benefit from a change in drug class, those with non-immune-mediated pharmacokinetic failure benefit from dose escalation, and that those with immune-mediated pharmacokinetic failure may benefit from either dose escalation or a change in mechanism of action, depending on antibody titers. Specifically, on pooled analysis of 2 of these studies, 82% of subjects who were found to have non-immune-mediated pharmacokinetic failure responded to empiric dose escalation, whereas only 8% of subjects who were found to have immune-mediated pharmacokinetic failure with high anti-drug antibody titers responded to dose escalation [9]. Likewise, in a retrospective study involving subjects who were being treated with infliximab and then had reactive TDM performed, when non-immune-mediated pharmacokinetic failure was identified, a clinical response was seen in 86% of subjects who underwent dose escalation, and only 33% among those who were switched to a different anti-TNF (P < 0.016). Conversely, dose escalation resulted in a clinical response only 17% of the time when anti-drug antibodies were detectable, compared to a 92% response rate when the subject was switched to a different anti-TNF (P < 0.004) [18].