A 2020 Delphi consensus of Swiss inflammatory bowel disease (IBD) experts (Greuter et al., Digestion) endorsed therapeutic drug monitoring (TDM) — measurement of biologic drug trough concentrations and anti-drug antibodies — for guiding management of secondary loss of response (LoR) to anti-TNF agents, concluding that optimal cutoff levels depend on the type of anti-TNF and that more studies are needed to address the value of such measurements for non-anti-TNF biologics. Across the consensus and the subsequent literature, what remains unresolved is: optimal trough targets rest on heterogeneous, mostly retrospective evidence and lack prospective outcome-driven validation; anti-drug-antibody assays are heterogeneous, with transient kinetics and no harmonized quantitative units, so no universally applicable antibody cutoffs exist; data are sparse or absent for the other biologic agents named by the panel (vedolizumab, ustekinumab, golimumab); assay turnaround of up to two weeks and limited point-of-care availability prevent real-time TDM-guided decisions; and there is no validated, standardized prospective definition of LoR combining symptoms, biomarkers, imaging, and pharmacokinetics. The literature through August 2026 leaves each thread only partially advanced — the sole randomized trial of algorithm-guided reactive TDM at LoR showed cost savings but not superiority, prospective cohort data still cannot identify a trough threshold predicting failure of dose escalation, a WHO reference panel for infliximab anti-drug antibodies was only established in 2022, point-of-care assays have shown analytical but not clinical-outcome value, and non-anti-TNF TDM evidence remains retrospective — leaving the core problem open: establishing prospectively validated, outcome-driven, assay-harmonized TDM decision rules for managing loss of response to biologic therapy, anchored to a standardized definition of LoR.

Background

Inflammatory bowel disease (IBD) comprises Crohn's disease and ulcerative colitis, chronic relapsing inflammatory disorders of the gastrointestinal tract that are commonly treated with biologic drugs. The most established biologics are antibodies against tumor necrosis factor (anti-TNF agents: infliximab, adalimumab, certolizumab pegol). A frequent complication is secondary loss of response (LoR): a patient who initially responded to maintenance anti-TNF therapy relapses, most often because drug clearance rises — frequently driven by anti-drug antibodies (antibodies the patient's immune system develops against the biologic, which accelerate drug elimination) — leaving trough concentrations (the drug level in serum immediately before the next dose) too low to suppress inflammation.

Therapeutic drug monitoring (TDM) is the measurement of these drug trough concentrations and anti-drug antibodies to rationalize management: a low trough with high antibody titers suggests switching drug class or adding an immunomodulator, whereas a low trough without antibodies suggests dose intensification, and a normal-to-high trough suggests that inflammation is not TNF-driven and therapy should be changed. Evidence for this strategy is largely observational and retrospective: exposure–response studies and post-hoc analyses of trials show that higher drug concentrations correlate with better outcomes. The only randomized trial of algorithm-guided reactive TDM at secondary infliximab failure (Steenholdt et al., Gut 2014) found response rates similar to routine dose intensification but 34% lower cost, and the TAXIT trial (Vande Casteele et al., Gastroenterology 2015) showed that after dose optimization to a trough of 3–7 µg/mL, continued concentration-based dosing did not improve one-year remission versus clinically based dosing. A 2021 systematic review of escalated anti-TNF maintenance therapy (Mattoo et al.) concluded that randomized trials comparing TDM to empiric treatment intensification have failed to reach their primary endpoints, even though empiric escalation recaptures response in a majority of LoR patients.

Against this background, Greuter et al. (Digestion 2020) conducted a Delphi-style consensus (an iterative voting procedure among a panel of 8 IBD specialists) on TDM use specifically at LoR to anti-TNFs. The panel agreed that LoR is associated with inadequate drug levels, that trough is the best sampling timepoint, with thresholds of 5 µg/mL (infliximab), 8 µg/mL (adalimumab), and 10 µg/mL (certolizumab pegol), and that antibody titers and trough levels are key determinants of the treatment algorithm. Crucially, the panel judged data on biologic agents beyond the established anti-TNFs too limited for any recommendation — the agents it named being vedolizumab (an antibody blocking gut-homing integrins, a non-anti-TNF biologic), ustekinumab (an antibody blocking the cytokines interleukin-12 and interleukin-23, a non-anti-TNF biologic), and golimumab (an anti-TNF antibody used mainly in ulcerative colitis, grouped with them by the panel) — and its published conclusion calls for more studies to address the value of such measurements for these agents. Five unresolved issues frame future research in this area: (1) the numeric trough targets are imprecise and require validation in prospective, outcome-driven studies; (2) assay heterogeneity for anti-drug-antibody measurement, transient antibody kinetics, and the lack of harmonized quantitative units prevent universally applicable antibody cutoff values beyond manufacturers' qualitative positive/negative calls; (3) data for vedolizumab, ustekinumab, and golimumab are sparse or absent, so the value of TDM and antibody testing for these agents, and appropriate thresholds or interpretive rules, are unknown; (4) assay turnaround times of up to two weeks and limited point-of-care availability hamper real-time TDM-guided decisions, requiring development and testing of rapid assays; and (5) there is no universally accepted, prospective definition of LoR that combines symptoms, biomarkers, imaging, and pharmacokinetics in a validated, standardized way. Reviews of LoR definition and epidemiology (e.g., Roda et al., 2016) confirm that definitions vary across studies, which has hindered the interpretation of every TDM study since.

Problem Statement

The open problem left by the 2020 Delphi consensus (Greuter et al., Digestion 2020) is to convert therapeutic drug monitoring (TDM — the measurement of biologic drug trough concentrations, i.e., drug levels in serum immediately before the next dose, and of anti-drug antibodies) from an expert-opinion-based heuristic into a prospectively validated, outcome-driven guide for clinical decision making in IBD patients with secondary loss of response (LoR — relapse of disease activity after an initial response to maintenance biologic therapy). The common scientific objective is a TDM-based decision strategy — specifying when to intensify the current biologic, when to add or switch immunomodulatory co-therapy, and when to change drug class — whose every input is validated against patient outcomes. Concretely, the following linked open questions frame this objective: (1) what are the optimal drug trough concentration targets for dose-escalation and switch decisions at loss of response, validated in prospective, outcome-driven studies rather than heterogeneous retrospective datasets? (2) can anti-drug-antibody measurements, currently assay-heterogeneous and reported in non-harmonized units with transient kinetics, support universally applicable quantitative clinical cutoffs rather than only qualitative positive/negative calls? (3) what is the value of TDM and antibody testing for the biologic agents beyond the established anti-TNFs — vedolizumab (an integrin-blocking antibody), ustekinumab (an interleukin-12/23 blocker), and golimumab (an anti-TNF used mainly in ulcerative colitis) — and what thresholds or interpretive rules, if any, apply to these agents? (4) can rapid or point-of-care assays with short turnaround make TDM-guided decisions feasible in real time, and does their use improve outcomes? and (5) what is a validated, standardized, prospective definition of secondary loss of response that combines symptoms, biomarkers (e.g., C-reactive protein and fecal calprotectin, blood and stool markers of intestinal inflammation), imaging/endoscopy, and pharmacokinetics — the definition on which the endpoints of all the preceding studies depend?

References

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