Treat-to-target in Crohn’s disease: Will transmural healing become a therapeutic endpoint?

Table 1 Characteristics of the included studies

First author, year, country	Study type	CD population, disease location, behavior, surgery	Duration of CD in yr	MD	Aim of study	Methods used to assess CD activity, timing	Follow-up time
Eder, 2016, Czech Republic[42]	RS	26 adults, responsive to induction doses of anti-TNF, median age (IQR) 27 yr (IQR: 21-36), 61% F, L3, B1 62%, B2 7%, B3 31%	Median (IQR): 4 (2-6)	Study MD: IFX or ADA, 1 yr Concomitant MD: CS 88%, AZA 88%, 5ASA 100%, AB 54%	Predictive role of MH, TH and IH healing on long-term CR	Clinical, endoscopic, and MRE activity: before starting anti-TNF and after induction (week 12-14 for ADA and week 9-12 for IFX)	Median 29 mo (IQR: 14-46) after finishing 1 yr of anti-TNF
Sauer, 2016, United States[43]	RS	101 children, 41.6% F, L1 28%, L2 24%, L3 54.5%, L4a 17.8%, L4b 24.7%, B1 76%, B2 18%, B3 2%, B2B3 4%, perianal 14%	Median (range): 4.7 (1.65-11.5)	IMD 33%, Biologic 67%	Predictive role of MRE remission on long-term CR, MD change and surgery	MRE, at median of 1.3 yr from diagnosis	Median 2.8 yr after MRE
Deepak, 2016, United States[14]	RS	150 adults, 66% treatment-naïve, median age (IQR) at diagnosis 23 yr (IQR: 19-33), 50% F, L1 48.7%, L3 40.7%, L4 10.6%, B1 45%, B2 35.3%, B3 19.3%, perianal 19.3%, prior CD-related surgery 61.3%	Median (IQR): 9 (3-21)	At second CTE/MRE: Anti-TNF alone: 20%, THIO alone 36%, MTX alone 5.3%, Anti-TNF + THIO 24%, Anti-TNF + MTX 5.3%, Budesonide 8%, Natalizumab 1.4%	Predictive role of radiologic response on long-term outcomes: CS use, hospitalization, and surgery	Serial CTE/MRE: first and follow-up (705 CTE/MREs): pre-therapy and after 6 mo or 2 CTE/MREs ≥ 6 mo apart (during maintenance therapy)	Median 4.6 yr (IQR: 1.6-7)
Fernandes, 2017, Spain[13]	RS	214 adults, 49.5% F, median age (IQR) 36.8 (16–77) yr, L1 76.6%, L3 23.4%, L4 10.3%, B1 44.4%, B2 26.2%, B3 29.4%, perianal 29.9%, prior intestinal resection 40.7%	Median (IQR): 7.4 (0-40.8)	THIO 54.7%, MTX 0.5%, Anti-TNF 18.7%	Predictive roles of MH and TH for hospital admission, surgery and MD escalation (start an IMD or biologic, escalate anti-TNF or switch to a different biologic)	MRE and IC performed within a 6-mo interval (median: 2.3 mo)	Median (IQR): 3.5 (1-7.9) yr Evaluation after 12 mo
Ripollés, 2016, Spain[41]	PS multicenter	51 adults, active disease, 47% F, median age (IQR) 35 yr (27-46), L1 57%, L2 21.5%, L3 21.5%, B1 57%, B2 10%, B3 33%, perianal 27.5%, history of surgery 33%	Median (IQR): 5 (2-10.3)	Active MD: Anti -TNF (IFX or ADA) 100% (63% combined with IMD)	Predictive role of TH on clinical outcome, change in MD, surgery	Clinical and US / CEUS at baseline, 12 wk and 1 yr after treatment	Median (IQR): 16 mo (12.2-32)
Orlando, 2018, Italy[44]	PS	30 adults, 33.3% F, mean age (± SD) 38.8 (± 14.5) yr, L1 40%, L3 60%, B1 53.3%, B2 40%, B3 6.7%, prior intestinal resection 40%	Mean ± SD: 9.8 ± 7.7	Active MD: Anti-TNF (IFX 53.3%, ADA 46.7%) Concomitant MD: 5ASA 10%, CS 10%, THIO 16.7%	Predictive role of TH and intestinal fibrosis on clinical outcome (hospitalization and surgery)	US and UEI at baseline, 14 and 52 wk after therapy	Median (range): 20 mo (10-38)
Laterza, 2018, Italy[15]	PS	57 adults, mean age (± SD) 45.3 (± 17) yr, 42.2% F, L1 38.6%, L2 8.7%, L3 52.6%, B1 31.6%, B2 54.4%, B3 14%, perianal 7%, previous surgery 22.8%	Mean ± SD: 7.4 ± 1	No therapy 10.5%, CS 26.3%, Anti-TNF 10.5%, CS + IMD 15.8%, CS + anti-TNF 8.8%, IMD + anti-TNF 8.8%, CS + IMD + anti-TNF 19.2%	Predictive role of a single and/or combined (CR, MH and TH) remission on outcomes (surgery, hospitalizations, MD changes - introduction of IMD or anti-TNF, anti-TNF escalation, switch to another anti-TNF, need for CS and deaths)	Clinical, endoscopic and CTE at baseline	Up to 36 mo

5ASA: 5-Amino salicylates; AB: Antibiotics; ADA; Adalimumab; Anti-TNF agents: Anti-tumoral necrosis alpha agents; AZA: Azathioprine; B: Behavior according to Montreal or Paris classification, with B1 inflammatory, B2 stricturing, B3 perforating, B2B3 both stricturing and perforating; CD: Crohn’s disease; CEUS: Contrast-enhanced ultrasound; CR: Clinical remission; CS: Corticosteroids; CTE: Computed tomography enterography; F: Female; IC: Ileocolonoscopy; IFX: Infliximab; IH: Intestinal healing; IMD: Immunomodulators; IQR: Interquartile range; L: Location according to Montreal or Paris classification, with L1 distal 1/3 ileum ± limited cecal disease, L2 colonic, L3 ileocolonic, L4 upper proximal disease with L4a upper disease proximal to the ligament of Treitz, L4b upper disease distal to the ligament of Treitz and proximal to distal 1/3 ileum; MD: Medication; MH: Mucosal healing; MRE: Magnetic resonance enterography; MTX: Methotrexate; N/A: Not available; PS: Prospective; RS: Retrospective; SD: Standard deviation; TH: Transmural healing; THIO: Thiopurines; UEI: Ultrasound elasticity imaging; US: Ultrasonography.