With data demonstrating the association between drug levels and antibody concentrations with response to medical therapy, several studies have assessed the impact of therapeutic drug monitoring (TDM) on clinical outcomes in IBD. In general, there are two potential approaches to employing these laboratory tests [42]. “Reactive TDM” refers to the utilization of drug levels and antibodies in response to changes in the clinical status of the patient receiving biologic therapy. When a patient has an increase in symptoms or non-response, these assays are then employed to determine if the patient would potentially benefit from modification of the current biologic dose, changing to another anti-TNF, or switching to an alternative class of medication. “Proactive TDM” refers to the use of these assays at specific time points in therapy to ensure that the dose is optimized, prior to loss of response or non-response, with the goal of achieving “therapeutic” trough drug levels to possibly prevent flares of disease. Several studies have assessed these two approaches and will be reviewed.

A standardized algorithm has been developed to guide clinicians in the interpretation of anti-TNF drug level and antibody results (Fig. 8.1). In this example of reactive monitoring, the initial step is determining that active mucosal inflammation is present, ensuring that the symptoms being treated are not related to other etiologies, such as overlapping irritable bowel syndrome, infection, bile salt diarrhea, bacterial overgrowth, or other causes. Once inflammation/active disease has been confirmed, a trough sample is collected as data on TDM using trough samples is more robust than at other time points. Trough samples are typically drawn on the day of infusion or injection, before the dose of the anti-TNF is received. If drug levels are low, without detectable antibodies, one could increase the dose of the medication or reduce the dosing frequency. If drug levels are within therapeutic range with un detectable antibodies, one should consider switching to another class of medication with a different mechanism of action, such as vedolizumab. If a ntibodies are present, the concentration of the antibodies may influence the decision-making process as follows: if antibody concentrations are high, most experts would argue that switching to either another anti-TNF would be appropriate; if the antibody levels are low, there are some data suggesting that antibodies can be suppressed with the addition of immunomodulators and/or increase in anti-TNF dosing, with subsequent improved clinical response and increased drug levels [43]. While promising that this may be a useful approach in patients developing anti-drug antibodies, further research is required to confirm these results in larger cohorts.

Several studies have assessed the clinical utility of reactive TDM, using a similar algorithm as above. An initial retrospective cohort study by Afif and colleagues evaluated the clinical impact of this approach in a cohort comprised of 121 patients with CD, 31 patients with UC, and 3 patients with indeterminate colitis, who were receiving infliximab [44]. Seventy-six patients (49%) underwent TDM evaluation for loss of response, thirty-four (22%) underwent testing for partial response, and eight (5%) underwent testing for primary non-response. The remaining 37 patients were tested for several other indications. Thirty-five of the 155 patients were positive for ATIs. Consistent with the proposed algorithm, 12 patients with ATIs were transitioned to another anti-TNF, with 11 of 12 noting an improved clinical response. Dose optimization of the anti-TNF was performed for 6 of 35 patients with ATIs, of which only 2 had an improved clinical response (p < 0.016). Sixty-three patients had subtherapeutic infliximab levels; in this subgroup, 29 underwent dose optimization, with 86% noting a clinical improvement. Six patients changed to another anti-TNF, of which 33% had a clinical response (p < 0.016). Collectively, these data support the proposed approach to the interpretation of drug levels and anti-drug antibodies. However, this was a retrospective cohort study and the sample size was small. These results have been supported in several recent additional studies. Vande Casteele and colleagues employed an HMSA-based assay and were able to distinguish between trans ient antibody formation and persistent antibodies [45]. In those with transient antibodies, the rate of clinical response to dose modification was 69%. However, in those with persistent antibodies measured by HMSA, response to dose modification was only 16% (p = 0.0028). Another retrospective study by Pariente and colleagues also suggests that there may be a subset of patients with ATIs who will respond to dose intensification [46]. In a cohort of 76 patients with IBD who had lost response, 16 (22.4%) had ATIs. Ten of these 16 patients underwent dose intensification of IFX, with a 60% response rate, in which there was a 50% response rate among patients with high-titer antibodies.

Another retrospective study examined 199 CD and 42 UC patients, of which 140 were receiving infliximab and 107 were receiving adalimumab, who had lost response underwent drug level and antibody monitoring [47]. In those with loss of response while receiving adalimumab, the presence of trough levels >4.5 μg/mL had a 100% positive predictive value (PPV) of response to switching to an alternative therapy and a 90% PPV for failure to respond to dose intensification. In addition, titers of anti-adalimumab drug antibodies >4 μg/mL had a PPV of 76% for failure to dose intensification. In this retrospective study, the predictive characteristics for infliximab were not as robust as those appreciated by Afif and colleagues, with a PPV of 72% for responding to switching to another class of medication with adequate drug levels and a 56% PPV for failure to respond to dose intensification. Interestingly, the authors did appreciate some evidence of being able to continue anti-TNFs in the setting of low-level antibodies. Specifically, patients with low-level antibodies who had increases in their anti-TNF dose also had si gnificant increases in drug concentration and also had significantly higher clinical response rates when combining both infliximab and adalimumab users. These data suggest that when anti-drug antibodies are present but in low concentration, further anti-TNF titration may be effective, consistent with the findings of Pariente and colleagues [46].

Reactive TDM has also recently been demonstrated to be cost-effective, both in simulation modeling and in clinical practice. Velayos and colleagues constructed a Markov model to simulate those individuals undergoing dose escalation guided by drug level measurement, compared to a strategy of dose escalation based only on symptoms. While clinical outcomes were the same for both cohorts, a significant cost saving was realized, likely secondary to reductions in unnecessary dose escalation [48]. Interestingly, the model was not sensitive to variations in test cost up to $5700 per level measurement [48, 49]. Similar findings were appreciated in a prospective randomized controlled trial of dose escalation versus reactive monitoring in 69 patients wi th secondary loss of response to infliximab [50]. Comparable clinical response rates were appreciated in each cohort, with significant savings i n costs for those undergoing therapeutic drug level monitoring.

As opposed to reactive TDM , an alternative approach is to assess drug levels and antibody formation in a proactive manner to ensure that drug levels are within the appropriate proposed therapeutic range during both induction and maintenance therapy. This approach, also known as “proactive TDM,” is designed to maximize the clinical benefit of anti-TNF therapies with the goal of preventing flares of disease by maintaining adequate trough concentrations. In proactive TDM, trough levels and anti-drug antibodies are typically assessed at the end of induction and then at least every 6–12 months, with dose modification or immunomodulator addition when appropriate to optimize levels within a desired therapeutic range.

Several recent studies have attempted to assess the clinical efficacy of proactive TDM, all with infliximab. Cheifetz and colleagues evaluated 48 patients who had undergone proactive TDM [51]. Twelve of these 48 required escalation therapy, whereas 15% required dose reduction. Compared to a control cohort of 78 patients, the monitored group had a significantly lower rate of infliximab discontinuation (HR 0.3, 95% CI 0.1–0.6). The likelihood of remaining on infliximab was highest for those with a trough IFX concentration >5 μg/mL, but similar results were seen with a cutoff level of 3 μg/mL.

Proactive TDM has also been assessed by two randomized controlled trials. In the TAXIT trial, patients with IBD in stable clinical response on infliximab (95% of whom were on infliximab monotherapy) received initial dose optimization to attain infliximab levels of 3–7 μg/mL [52]. After dose modification (if necessary), patients were then randomized to either proactive TDM with target infliximab level 3–7 μg/mL (which also allowed for dose de-escalation) or drug dosing based on increased clinical symptoms or CRP. Although remission rates at 1 year were nearly identical between the two groups, it is important to note that rates of remission were significantly higher in patients with CD after initial dose intensification than prior to dose intensification, thus implying that TDM had a beneficial effect. Also, all patients were initially optimized with TDM and followed subsequently for up to only 1 year, which may not be long enough to appreciate a difference. In addition, the proactive TDM group was significantly less likely to have flared than their counterparts (7% vs. 17%, p = 0.018). Costs of therapy were also significantly reduced in the proactive TDM arm.

The other randomized controlled trial, TAILORIX, which is currently published only in abstract form, included 122 patients with active CD who were randomized to one of three strategies after standard IFX induction at 5 mg/kg: (1) a dose increase by 2.5 mg/kg based on drug levels, clinical symptoms, or biomarkers, (2) similar monitoring with a dose increase to 10 mg/kg, or (3) dose intensification to 10 mg/kg [53]. There was no significant difference in individuals without ulceration (47% vs. 38% vs. 40%, respectively) or mucosal healing (51% vs. 65% vs. 40%, respectively) at 54 weeks. However, when examining the percentage of individuals who had sustained IFX levels >3 μg/mL at each time point during the 54 weeks of follow-up, the third group undergoing reactive monitoring had the highest persistently therapeutic drug levels (60%) compared to either the first proactively monitored group (47%) or the second group (46%). As such, these results are somewhat difficult to interpret.