Disease monitoring strategies in inflammatory bowel diseases: What do we mean by “tight control”?

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

Study	Study type	Treatment targets evaluated	Patient population	Compared patient groups	Outcomes
Colombel et al[13] (CALM)	Randomized clinical trial	Combined clinical and biomarker	CD– 244 patients	Incremental therapy escalation based on “tight control”with biomarker (CRP and FCAL) and clinical assessment every 12 wk vs “clinical management” with only clinical assessment	Outcomes 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 trial	Endoscopy	CD – 122 patients	Endoscopic 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 NOT	Composite 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-analysis	Endoscopy	CD – 673 patients (12 studies included)	Achieving MH at first endoscopic assessment after therapy initiation vs NOT	Outcomes 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-analysis	Endoscopy	UC – 2073 patients (13 studies included)	Achieving MH at first endoscopic assessment after therapy initiation vs NOT	Outcomes 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-analysis	Histology	UC – 13 studies included	Histological remission vs NO histological remission at baseline Histological remission vs NO histological remission at baseline among patients in combined clinical and endoscopic remission	Outcomes 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]	Prospective	Histology	UC – 91 patients	Histological remission vs NO histological remission at baseline	Outcomes 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, Randomized	Biomarker	UC – 91 patients	Monthly FCAL measurement: Dose-escalation of 5-ASA in patients with FCAL > 300 μg/g vs NO intervention	18 mo follow-up: Fewer clinical relapses observed in intervention group, 28.6% vs 57.1%; P < 0.05
Zhulina et al[52]	Prospective	Biomarker	CD – 49 patients; UC – 55 patients	First clinical relapse vs NO relapse in patients with clinical remission at baseline	2 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]	Prospective	Combined clinical and biomarker	CD – 40 patients	Clinical and biomarker remission at 12 wk (CDAI < 150 and CRP ≤ 2.9 mg/L and FCAL < 300 μg/g) vs NOT	Predictive 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)

CD: Crohn’s disease; UC: Ulverative colitis; CRP: C-reactive protein; FCAL: Fecal calprotectin; CDAI: Crohn’s Disease Activity Index; CDEIS: Crohn’s Disease Endoscopic Index of Severity; 5-ASA: 5-aminosalicylic acid; RR: Relative risk; HR: Hazard ratio; OR: Odds ratio; CI: Confidence interval; NPV: Negative predictive value; PPV: Positive predictive value; aHR: Adjusted hazard ratio.

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 evaluation	6-9 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 evaluation	3-6 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]

¹Using C-reactive protein alone has only moderate predictive value in identifying relapse in patients with clinical remission. PRO: Patient reported outcome; CDAI: Crohn’s Disease Activity Index; HBI: Harvey Bradshaw Index; CRP: C-reactive protein; FCAL: Fecal calprotectin; STRIDE: Selecting therapeutic targets in inflammatory bowel disease.

Table 3 Therapeutic drug monitoring-based algorithm for handling patients with treatment failure on biologic therapy[59-61]

	Detectable anti-drug antibodies	Undetectable anti-drug sntibodies
Sub-therapeutic anti-TNF drug levels	Change 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.

TNF: Tumor necrosis factor.