Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring

Table 1 Association between various thresholds for serum drug concentrations and clinical outcomes

Drug	Serum drug level	Clinical outcome
Infliximab (IFX)
IFX	< 2 μg/mL for CD/UC at week 14	Increased incidence of IFX antibodies[52]
IFX	> 2.1 μg/mL at week 14 in UC	Associated with mucosal healing[53]
IFX	≥ 3 μg/mL during maintenance	Clinical remission[48]
IFX	> 3 μg/mL at week 14 or 22 in CD	Sustained response[54]
IFX	3-7 μg/mL during maintenance	Remission[16]
IFX	≥ 7 μg/mL during maintenance	Mucosal healing[48]
IFX	< 7 μg/mL at week 14 in luminal CD	Absence of primary response[53]
IFX	> 9.2 μg/mL at induction week 2 in CD	Fistula response at weeks 14 and 30[56]
IFX	≥ 10 μg/mL at induction week 6	Clinical response[48]
IFX	> 15 μg/mL at week 6 in UC	Associated with mucosal healing[53]
IFX	≥ 20 μg/mL at induction week 2	Clinical response[48]
IFX	≥ 22 μg/mL at week 6 in UC	Clinical response at week 8[55]
IFX	≥ 25 μg/mL at induction week 2	Mucosal healing[48]
Adalimumab (Ada.)
Ada.	≥ 3 μg/mL during maintenance	Clinical response[48]
Ada.	≥ 5 μg/mL post induction (week 14)	Clinical response[48]
Ada.	≥ 7 μg/mL post induction (week 14)	Mucosal healing[48]
Ada.	≥ 8 μg/mL during maintenance	Mucosal healing[48]
Ada.	< 12 μg/mL at week 14 in luminal CD	Absence of primary response[53]
Ustekinumab (UST)
UST	≥ 1 μg/mL during maintenance	Clinical response[48]
UST	≥ 3.5 μg/mL post induction (week 8)	Clinical response[48]
UST	≥ 4.5 μg/mL during maintenance	Mucosal healing[48]
Vedolizumab (VDZ)
VDZ	≥ 12 μg/mL during maintenance	Clinical response[48]
VDZ	≥ 14 μg/mL during maintenance	Mucosal healing[48]
VDZ	≥ 15 μg/mL post induction (week 14)	Clinical response[48]
VDZ	≥ 17 μg/mL post induction (week 14)	Mucosal healing[48]
VDZ	≥ 24 μg/mL at induction (week 6)	Clinical response[48]
VDZ	≥ 28 μg/mL at induction (week 2)	Clinical response[48]

Many studies that looked at exposure response relationship studies of anti-tumor necrosis factor drugs have demonstrated that specific drug concentration thresholds are associated with certain clinical outcomes, such as clinical response, improvement in biochemical markers, endoscopic remission, and mucosal healing.

Table 2 A list of the main trials looking at both reactive and proactive therapeutic drug monitoring

Ref.	Study design; n	Population studied	Type of intervention	Primary outcome	Results
Vande Casteele et al[16], 2015 (Proactive)	Prospective single center study RCT, n = 263	Adults with mod to severe UC responders to infliximab (IFX)	IFX. Target 3-7 μg/mL during maintenance phase. Clinical vs concentration-based dose escalation	Clinical and biochemical remission	Fewer flares in concentration-based group. No difference in remission rates at 1 yr
Papamichael et al[73], 2017 (Proactive)	Retrospective multi-center RCT, n = 264	Adults with CD + UC	IFX 5-10 μg/mL	Treatment failureNeed for IBD related hospitalization or surgery. Adverse events	Proactive was associated with better clinical outcomes, including greater drug durability, less need for IBD-related surgery or hospitalization
Perinbasekar et al[74], 2017 (Proactive)	Retrospective single center study, n = 127	Adult IBD patients initiating treatment with either IFX or adalimumab (Ada)	IFX target ≥ 3 μg/mL; Ada target ≥ 5 μg/mL	Clinical response at 1 yr. Endoscopic response. Persistence with anti-TNF at 1 yr	Persistence with therapy and clinical and endoscopic response were superior for proactive compared to control patients treated with infliximab
Bernardo et al[75], 2017 (Proactive)	Retrospective single center study, n = 117	Adult IBD patients on treatment with infliximab	Clinical based vs proactive TDM. (1) Target IFX CD 3-7 μg/mL; (2) Target IFX UC 5-10 μg/mL; (3) Target Ada CD 5-7 μg/mL; and (4) Target Ada UC 7-9 μg/mL	At 48 wk (1) Clinical remission; (2) Rates of hospitalizations; (3) Rates of surgery; and (4) Therapeutic failure	No difference noted in relation to outcomes. Higher rates of drug escalation in proactive group. Longer period of remission in proactive group
D’Haens et al[12], 2018 (Proactive)	Prospective multi-center RCT, n = 122	Adults with mod to severe luminal CD biologic naïve on infliximab maintenance	Dose escalation using combined approach of clinical + TDM vs symptom-based approach. IFX target > 3 μg/mL during maintenance phase	Sustained steroid-free clinical remission at weeks 22-54 and mucosal healing at week 54	No difference in terms of rates of steroid-free remission
Papamichael et al[10], 2018 (Proactive vs reactive)	Retrospective multicenter study, n = 102	Adult IBD patients on infliximab	Reactive TDM followed by subsequent proactive TDM vs reactive testing IFX target 5-10 μg/mL	Treatment failure. IBD related hospitalization and surgery	Proactive monitoring after reactive testing associated with greater drug persistence and fever IBD related hospitalizations
Papamichael et al[11], 2019 (Proactive)	Retrospective multicenter study, n = 382	IBD patients on maintenance therapy with adalimumab	Proactive vs reactive TDM. Ada > 10 μg/mL	Treatment failure	Proactive associated with lower risk of treatment failure
Assa et al[14], 2019 (Proactive)	Prospective multi-center RCT, n = 78	Ages 6-17 yr with CD with response to adalimumab	Ada target trough levels ≥ 5 μg/mL	Sustained steroid-free clinical remission (weeks 8-72)	Higher rates of steroid free clinical remission in proactive group
Strik et al[76], 2019 (Proactive)	Retrospective multi-center RCT, n = 80	UC + CD in clinical remission on infliximab maintenance therapy	Dashboard driven dose escalation with TDM vs non TDM. IFX level > 3 μg/mL	Clinical remission	Dashboard-guided dosing resulted in a significant higher proportion of patients who maintained clinical remission during 1 yr of treatment
Danese et al[70], 2020 (Proactive)	Prospective multi-center RCT, n = 184	Clinical responders from induction phase of SERENE-CD	Clinical based group vs proactive TDM (TL 5-10 μg/mL) adalimumab every week or every other week	Clinical remission and endoscopic response and remission at 1 yr	No difference in terms of clinical end points
Fernandes et al[15], 2020 (Proactive)	Prospective study, n = 205	IBD patients completing infliximab induction therapy	Prospective arm (TDM-based dose escalation) vs retrospective arm (non-TDM). IFX levels 3-7 μg/mL CD; IFX levels 5-10 μg/mL UC	Need for surgery, hospital admission, treatment endrates of mucosal healing at 2 yr of treatment	Proactive TDM associated with fewer surgeries and higher rates of mucosal healing
Bossuyt et al[71], 2020 (Proactive vs reactive)	Prospective multi-center RCT	All IBD patients on infliximab therapy > week 14	Using point of care testing at the time of infusion > proactive vs reactive TDM	Clinical remissionDiscontinuation of infliximab. Composite end points of IBD related hospitalizations and surgeries, change of treatment	No difference in terms of rate of clinical remission or treatment discontinuationUltra-proactive not superior to reactive
Afif et al[67], 2010 (Reactive)	Retrospective study, n =155	IBD patients who had infliximab	Measurements of human anti-chimeric antibodies (HACAs) and infliximab concentrations	Loss of response. Change in treatment	Measurement of both antibody and drug levels lead to improved response
Steenholdt et al[66], 2014 (Reactive)	Prospective RCT, n = 69	CD patients failing on infliximab therapy	Infliximab intensification vs algorithm defined using TDM	Clinical and economic outcomes at week 20	Lower healthcare costs in algorithm-based group. Similar rates of clinical response and remission
Kelly et al[63], 2017 (Reactive)	Retrospective study, n = 312	Primary responders on infliximab who underwent dose escalation	TDM vs clinical based dose escalation of infliximab	Endoscopic remissionClinical response	Higher rates of endoscopic remission with TDM
Pouillon et al[77], 2018 (Reactive)	Retrospective single center study, n = 226	IBD patients who completed maintenance phase of TAXIT	Clinical based vs trough concentration-based dosing of infliximab, infliximab level 3-7 μg/mL	IBD related hospitalization and surgery. Steroid use. Mucosal healing	Similar rates of mucosal healing in both groups. Higher rates of treatment discontinuation in clinic-based group

TDM: Therapeutic drug monitoring; TNF: Tumor necrosis factor; IBD: Inflammatory bowel disease; RCT: Randomized controlled study; IFX: Infliximab; Ada: Adalimumab.

Table 3 Recommendations and statements made by various gastroenterology guidelines and consensus groups

Guideline/Consensus group	Recommendation
AGA[18,19]	Active IBD with anti-TNF → suggest use of reactive TDM
	Quiescent IBD with anti-TNF → not recommended
Inflammatory bowel disease Sydney/Australian Inflammatory bowel disease consensus working group (2017)[20]	Use of TDM preferred in (1) Upon suspected treatment failure; (2) Following successful induction; and (3) When completed drug holiday
	For those in clinical remission, consider TDM periodically only if it will change management
British guidelines (2019)[21]	Good practice recommendation → ALL IBD patients should be reviewed 2-4 wk post loading dose to assess response and check drug levels and anti-drug antibodies
	Use of serum drug trough & anti-drug antibody concentrations to be incorporated when deciding in change of therapy (dose escalation vs switch to other anti-TNF drug or out of class change)
ECCO (2020)[22]	CD in remission on anti-TNF → insufficient evidence to recommend FOR or AGAINST TDM
	CD patients who have lost response → insufficient evidence

AGA: American Gastroenterology Association; ECCO: European Colitis & Crohn’s Organization; TDM: Therapeutic drug monitoring; TNF: Tumor necrosis factor; IBD: Inflammatory bowel disease.

Table 4 Therapeutic drug monitoring thresholds used in current practice (Using enzyme-linked immunoassay)

Drug	Cut-off for serum drug concentration	Cut-off for detectable ADA
Infliximab	> 3 μg/mL	Present if > 10 μg/mL
Adalimumab	> 5 μg/mL	Present if > 10 μg/mL
Certolizumab	> 15 μg/mL	-
Ustekinumab	Insufficient evidence to make a suggestion	-
Vedolizumab	Insufficient evidence to make a suggestion	-

ADA: Anti-drug antibody.