Copyright
©The Author(s) 2021.
World J Gastroenterol. Oct 7, 2021; 27(37): 6231-6247
Published online Oct 7, 2021. doi: 10.3748/wjg.v27.i37.6231
Published online Oct 7, 2021. doi: 10.3748/wjg.v27.i37.6231
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] |
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 |
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 |
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 | - |
- Citation: Albader F, Golovics PA, Gonczi L, Bessissow T, Afif W, Lakatos PL. Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring. World J Gastroenterol 2021; 27(37): 6231-6247
- URL: https://www.wjgnet.com/1007-9327/full/v27/i37/6231.htm
- DOI: https://dx.doi.org/10.3748/wjg.v27.i37.6231