Review
Copyright ©The Author(s) 2019.
World J Gastroenterol. Nov 7, 2019; 25(41): 6172-6189
Published online Nov 7, 2019. doi: 10.3748/wjg.v25.i41.6172
Table 1 Selected studies supporting the use of clinical, biochemical, endoscopic, histological and combined targets since the publication of selecting therapeutic targets in inflammatory bowel disease consensus
StudyStudy typeTreatment targets evaluatedPatient populationCompared patient groupsOutcomes
Colombel et al[13] (CALM)Randomized clinical trialCombined clinical and biomarkerCD– 244 patientsIncremental therapy escalation based on “tight control”with biomarker (CRP and FCAL) and clinical assessment every 12 wk vs “clinical management” with only clinical assessmentOutcomes at 48 wk: Mucosal healing (CDEIS < 4 and no deep ulcerations), 45.9% vs 30.3%; P = 0.010 steroid free remission, 59.8% vs 39.3%; P < 0.001 deep remission (CDAI < 150, CDEIS < 4 and no deep ulcers), 36.9% vs 23.0%; P = 0.014 biological remission (FCAL < 250 μg/g, CRP < 5 mg/L, and CDEIS < 4), 29.5% vs 15.6; P = 0.006
Ungaro et al [55] (CALM – long term extension)Randomized clinical trialEndoscopyCD – 122 patientsEndoscopic remission (CDEIS < 4 and no deep ulcerations) at 1 yr vs NOT Deep remission (CDAI < 150, CDEIS < 4 and no deep ulcers) at 1 yr vs NOTComposite of major adverse outcomes reflecting CD progression: New internal fistula/abscess, stricture, perianal fistula/abscess, CD hospitalization, or CD surgery (median 3 yr follow-up after end of CALM): aHR = 0.44, 95%CI: 0.20-0.96, P = 0.038 aHR = 0.25, 95%CI: 0.09-0.72, P = 0.01
Shah et al[38]Meta-analysisEndoscopyCD – 673 patients (12 studies included)Achieving MH at first endoscopic assessment after therapy initiation vs NOTOutcomes reported at ≥ 50 wk: Clinical remission [OR] 2.80, 95%CI: 1.91-4.10 maintenance of mucosal healing [OR] 14.30, 95%CI: 5.57-36.74 resective surgery [OR] 2.22, 95%CI: 0.86-5.69
Shah et al[39]Meta-analysisEndoscopyUC – 2073 patients (13 studies included)Achieving MH at first endoscopic assessment after therapy initiation vs NOTOutcomes reported at ≥ 50 wk: clinical remission [OR] 4.50, 95%CI: 2.12-9.52 avoiding colectomy [OR] 4.15, 95%CI: 2.53-6.81 maintenance of mucosal healing [OR] 8.40, 95%CI: 3.13-22.53 long-term corticosteroid-free clinical remission [OR] 9.70, 95%CI: 0.94-99.67
Park et al[70]Meta-analysisHistologyUC – 13 studies includedHistological remission vs NO histological remission at baseline Histological remission vs NO histological remission at baseline among patients in combined clinical and endoscopic remissionOutcomes up to 12 mo follow-up: Clinical relapse/ exacerbation [RR] 0.48, 95%CI: 0.39–0.60 Clinical relapse/ exacerbation [RR] 0.81, 95%CI: 0.70–0.94
Bryant et al[68]ProspectiveHistologyUC – 91 patientsHistological remission vs NO histological remission at baselineOutcomes reported over a median 72 mo follow-up: corticosteroid use [HR] 0.42, 95%CI: 0.2-0.9; P = 0.02 acute severe colitis requiring hospitalization [HR] 0.21, 95%CI: 0.1-0.7; P = 0.02
Lasson et al[93]Prospective, RandomizedBiomarkerUC – 91 patientsMonthly FCAL measurement: Dose-escalation of 5-ASA in patients with FCAL > 300 μg/g vs NO intervention18 mo follow-up: Fewer clinical relapses observed in intervention group, 28.6% vs 57.1%; P < 0.05
Zhulina et al[52]ProspectiveBiomarkerCD – 49 patients; UC – 55 patientsFirst clinical relapse vs NO relapse in patients with clinical remission at baseline2 yr of follow-up: Doubling of faecal calprotectin level between two consecutively samples 3 mo apart predicted relapse [HR] 2.01, 95%CI: 1.53-2.65
Sollelis et al[94]ProspectiveCombined clinical and biomarkerCD – 40 patientsClinical and biomarker remission at 12 wk (CDAI < 150 and CRP ≤ 2.9 mg/L and FCAL < 300 μg/g) vs NOTPredictive power for corticosteroid-free clinical remission at 52 wk: Sensitivity = 69.2% (42.0-87.4) specificity = 100.0% (84.9-100.0) PPV = 100.0% (100.0-100.0) NPV = 87.1% (75.3-98.9)
Table 2 Intervals of clinical, biomarker, and endoscopic assessment in the treat-to-target and tight control framework
Active disease/at flare
Clinical remission
Crohn’s disease
Clinical evaluation (PRO, CDAI, HBI indices)3 mo [STRIDE and CALM protocol][28,13]6-12 mo [STRIDE][28] 3 mo [CALM protocol][13]
Endoscopic evaluation6-9 mo after therapy initiation [STRIDE][28]Based on screening recommendations in deep remission Prompted by clinical symptoms or (consecutive) biomarker positivity – FCAL[52,53]
Biomarker evaluation (CRP and FCAL)3 mo (FCAL + CRP) [CALM protocol][13,94] Approximately 12-14 wk after therapy initiation (CRP)[95,96] Approximately 14 wk after therapy initiation (FCAL)[94,97,98]3 mo (FCAL + CRP) [CALM protocol][13] (2)-3 mo (FCAL)[52,53] 3 mo (CRP1)[99]
Ulcerative colitis
Clinical evaluation (PRO, CDAI, HBI indices)3 mo [STRIDE][28]6-12 mo [STRIDE][28]
Endoscopic evaluation3-6 mo after therapy initiation [STRIDE][28]Based on screening recommendations in deep remission Prompted by clinical symptoms or (consecutive) biomarker positivity – FCAL[52,53]
Biomarker evaluation (CRP and FCAL)Approximately 10 wk after therapy initiation (FCAL)[100](2)-3 mo[51-53,101]
Table 3 Therapeutic drug monitoring-based algorithm for handling patients with treatment failure on biologic therapy[59-61]
Detectable anti-drug antibodiesUndetectable anti-drug sntibodies
Sub-therapeutic anti-TNF drug levelsChange to different TNF-inhibitor.Intensify the treatment regimen of the currently used TNF-inhibitor.
Therapeutic anti-TNF drug levels(Repeat assessments of anti-TNF drug and anti-drug antibodies over time) Switch to another biological agent with a different mechanism of action.Switch to another biological agent with a different mechanism of action.