Is Transmural Healing an Achievable Goal in Inflammatory Bowel Disease?
Abstract
1. Introduction
2. Methods
3. Results
3.1. Definitions and Heterogeneity in Assessing Transmural Healing
3.1.1. Variability in TH Definitions Across Studies and Guidelines
3.1.2. Challenges and Implications for Research and Clinical Practice
3.2. Modalities for Assessing Transmural Healing
3.2.1. Intestinal Ultrasonography
Sonographic Parameters of TH
- Bowel wall thickness (BWT): A BWT >3 mm has been shown to be more accurate than a 4 mm cut-off (88% sensitivity, 93% specificity vs. 75% sensitivity, 97% specificity, respectively) [40]. Notably, BWT measurement has a good interobserver agreement both in CD and UC (κ = 0.96 and κ = 0.63, respectively) [38,41].
- Bowel wall stratification (BWS): In active disease, BWS is often disrupted, with focal or extensive bowel wall alterations up to complete loss of stratification [42].
- Lymph node enlargement: Lymph nodes with a short-axis diameter >10 mm are more likely to be pathological. Interobserver reproducibility is good (κ = 0.61) [42].
Accuracy, Reproducibility, and Clinical Evidence
Score Name | Key Parameters Included | Formula |
---|---|---|
Intestinal Ultrasound (IUS) Scores | ||
IBUS-SAS (International Bowel Ultrasound Segmental Activity Score) [38] | BWT, CDS, BWS, inflammatory mesenteric fat | 4 × BWT + 15 × i-fat + 7 × CDS + 4 × BWS |
BUSS (Bowel Ultrasound Score) [39] | BWT, CDS | 0.75 × BWT + 1.65 × BWF, where BWF = 1 if present, or BWF = 0 if absent |
MUC (Milan Ultrasound Criteria) [48] | BWT, CDS | 1.4 × BWT + 2 × BWF, where BWF = 1 if present, or BWF = 0 if absent |
Magnetic Resonance Imaging (MRI) Scores | ||
MaRIA (Magnetic Resonance Index of Activity) [49] | BWT, RCE, edema, ulcers | = 1.5 × wall thickness + 0.02 × RCE + 5 × edema + 10 × ulceration |
Simplified MaRIA [50] | BWT, edema, fat stranding, ulcers | (1 × thickness > 3 mm) + (1 × edema) + (1 × fat stranding) + (1 × ulcers) |
3.2.2. Magnetic Resonance Imaging (MRI)
MRI Markers of TH
- Edema: High signal intensity on T2-weighted or STIR images due to increased water content in inflamed bowel walls. Qualitative assessment with no standard quantitative threshold but often graded based on signal intensity relative to nearby muscle or unaffected bowel.
- Bowel Wall Thickening: The cut-off of >3 mm is commonly used as abnormal; can also be evaluated as a continuous variable with higher values indicating more severe disease.
- Increased Contrast Enhancement: Detected post-gadolinium contrast administration on T1-weighted sequences. A relative enhancement >50% compared to pre-contrast images is often indicative of active inflammation, though exact thresholds may vary.
- Diffusion-Weighted Hyperintensity: High signal on DWI images (especially at high b-values like b800–1000 s/mm2). It is a qualitative evaluation of the presence of hyperintensity and supports active inflammation.
- Apparent Diffusion Coefficient (ADC): Quantitative measure of water molecule diffusion and inversely related to disease activity. ADC < 1.3 × 10−3 mm2/s has been proposed in some studies to differentiate active from inactive disease, but cut-offs vary.
- Injected Sequences (RCE): Quantifies the degree of bowel wall enhancement after contrast administration. The formula used to assess it is RCE = [(Signal intensity post-contrast – pre-contrast)/pre-contrast signal] × 100%. RCE > 100% is often considered indicative of active inflammation in Crohn’s disease, though this threshold can vary between institutions.
Sensitivity and Specificity Compared to Other Techniques
3.2.3. Computed Tomography Enterography (CTE)
3.3. Is Transmural Healing Achievable with Current IBD Therapies?
3.3.1. Evidence from Biologics and Small Molecules in CD
3.3.2. Evidence from Biologics and Small Molecules in UC
Therapy | Author, Ref. | Study Design | Imaging | Definition of TH | N | Intervention | Results |
---|---|---|---|---|---|---|---|
Anti-TNFα | Paredes, 2010 [64] | Prospective, longitudinal | IUS | BWT: 3 mm, absence of a color Doppler signal, absence of intestinal complications (fistula, abscess) | 24 | 1 year of treatment with IFX or ADA | TH: 5/17 (29.0%) |
Castiglione, 2013 [15] | Prospective, longitudinal | IUS | BWT ≤ 3 mm | 133 | 2 years of treatment with IFX or ADA | TH: 17/66 (25.0%) MH: 25/66 (38.0%) | |
Moreno, 2014 [17] | Prospective, longitudinal | IUS | BWT: 3 mm, color Doppler signal (using Limberg score 0–1), % of parietal enhancement increase less than 46% | 30 | 1 year of treatment with IFX or ADA (±ISS) | TH: 15 (83.3%) MH: 18 (60%) | |
Ripollés, 2016 [18] | Prospective, multicenter | IUS | BWT: 3 mm, color Doppler signal (using Limberg score 0), absence of intestinal complications (fissures, fistulas, inflammatory masses) | 51 | 1 year of treatment with IFX or ADA | TH week 12: 7/51 (14.0%) TH week 52: 15/51 (29.5%) | |
Castiglione, 2017 [16] | Prospective, longitudinal | IUS, MRI | BWT ≤ 3 mm | 40 | 2 years of treatment with IFX or ADA | TH (IUS): 10/40 (25.0%) TH (MRI): 9/40 (23.0%) MH: 14/40 (35.0%) | |
Orlando, 2018 [65] | Prospective, longitudinal | IUS | BWT ≤ 3 mm | 30 | 52 weeks of treatment with IFX or ADA | TH week 14: 8/30 (27.0%) TH week 52: 9/30 (30.0%) | |
Castiglione, 2019 [38] | Prospective, single center, longitudinal | IUS | Normalization of BWT of all inflamed segments involved in CD; BWT ≤ 3 | 218 | 2 years of treatment with IFX or ADA | TH: 68 (31.2%) MH: 60 (27.5%) NH: 90 (41.3%) | |
Paredes, 2019 [66] | Prospective, single center | IUS | Normalization of BWT (<3), Limberg 0 or 1 | 33 | 1 year of treatment with IFX or ADA | TH: 14 (42.2%) NH: 19 (57.6%) | |
Bossuyt, 2021 [67] | Prospective | MRI | MaRIA score < 7 in all segments | 36 | 52 weeks of treatment with IFX | TH: 30.3% MH: 71.0% | |
Lafeuille, 2021 [35] | Retrospective, database review | MRI | TH: MH+ MRI healing MRI healing: no MRI signs of inflammation and no complication (stricture, abscess, or fistula) | 154 | IFX | TH: 5/28 (17.9%) MRI healing: 6/30 (20.0%) NH: 14/80 (17.5%) | |
ADA | TH: 4/28 (14.3%) MRI healing: 2/30 (6.7%) NH: 16/80 (20.0%) | ||||||
Calabrese, 2022 [12] | Prospective, multicenter | IUS | Normalization of all parameters | 188 | 1 year of treatment with IFX, 31 patients (16%) | TH: 37.0% NH: 23.0% | |
1 year of treatment with ADA, 103 patients (55%) | TH: 26.5% NH: 33.0% | ||||||
Oh, 2022 [68] | Retrospective, single center | MRI, CTE | BWT < 3 mm, absence of mural hyperenhancement, normal mural signal, no perienteric infiltration, absence of newly developed or worsening preexisting stricturing or penetrating complications | 392 | Anti-TNF therapy for more than one year | MH+TH: 114/392 (29.1%) TH: 41/392 (10.4%) MH: 59/392 (15.0%) NH: 178/392 (45.4%) | |
Revés, 2025 [25] | Multicenter, retrospective | MRI | Normalization of all MRI parameters | 154 | IFX | TH: 20/85 (23.5%) NH: 65/85 (76.5%) | |
ADA | TH: 8/55 (14.5%) NH: 47/55 (85.5%) | ||||||
Vedolizumab | Lafeuille, 2021 [35] | Retrospective, database review | MRI | TH: MH+ MRI healing MRI healing: no MRI signs of inflammation and no complication (stricture, abscess or fistula) | 154 | VDZ | TH: 0/28 (0.0%) MRI healing: 1/30 (3.3%) NH: 3/80 (3.7%) |
Calabrese, 2022 [12] | Prospective, multicenter | IUS | Normalization of all parameters | 188 | 1 year of treatment with VDZ, 24 patients (13%) | TH: 27.2% NH: 41.0% | |
Rimola, 2024 [31] | Prospective, multicenter | MRI | MaRIA score of <7 in all bowel segments | 59 | 26 and 52 weeks of treatment with VDZ | TH week 26: 8/37 (21.9%) TH week 52: 4/22 (38.1%) | |
Carter, 2025 [69] | Prospective, multicenter | IUS | 70 | 6 months of treatment with VDZ | TH: 9/28 (32.1%) | ||
Revés, 2025 [25] | Multicenter, retrospective | MRI | Normalization of all MRI parameters | 154 | VDZ | TH: 0/1 (0.0%) NH: 1/1 (100%) | |
Ustekinumab | Lafeuille, 2021 [35] | Retrospective, database review | MRI | TH: MH+ MRI healing MRI healing: no MRI signs of inflammation and no complication (stricture, abscess, or fistula) | 154 | ustekinumab | TH: 0/28 (0.0%) MRI healing: 0/30 (0.0%%) NH: 3/80 (3.7%) |
Miranda, 2021 [70] | Prospective | MRI/IUS | MRI: complete healing of all layers of the bowel wall IUS: TH ≤ BWT 3 mm and normal IUS examination | 92 | ustekinumab | TH: 15/75 (20.0%) TH: 11/75 (14.7%) MH: 26/75 (34.0%) | |
Calabrese, 2022 [12] | Prospective, multicenter | IUS | Normalization of all parameters | 188 | 1 year of treatment with ustekinumab, 30 patients (16%) | TH: 20.0% NH: 48.0% | |
Kucharzik, 2023 [59] | RCT phase 3b | IUS | Normalization of BWT, CDS, BWS, and i-fat | 77 | 24 weeks of treatment with ustekinumab | TH: (13/54) 24.1% | |
Revés, 2025 [25] | Multicenter, retrospective | MRI | Normalization of all MRI parameters | 154 | VDZ | TH: 4/13 (30.8%) NH: 9/13 (69.2%) | |
Upadacitinib | Bezzio, 2024 [71] | Observational, cohort | IUS | BWT < 3 mm | 64 | upadacitibib | TH: 15/52 (28.8%) |
Filgotinib | D’Haens, 2023 [23] | Randomized control trial, phase 2 | MRI | MaRIA < 7 in all segments | 78 | filgotinib for 24 weeks | TH filgotinib 100 mg: 2/32 (6.3%) TH filgotinib 200 mg: 2/25 (8.0%) |
Author | Study Design | Imaging | Definition of TH | N | Intervention | Results |
---|---|---|---|---|---|---|
Maaser, 2019 [72] | Sub-analysis of TRUST&UC, a prospective, observational, multicenter study | IUS | BWT < 4 mm for sigmoid colon and <3 mm for the descending colon | 224 | ADA, IFX, or golimumab | TH week 6: 21/44 (47.7%) |
Helwig, 2022 [32] | Post-hoc analysis of TRUST studies | IUS | Complete TH: BWT, CDS, i-fat normalized | 171 | - | TH: 45.0% |
Saleh, 2023 [73] | Retrospective study | IUS | BWT < 3 mm + normalization of all parameters (CDS ≤ 1, i-fat, BWS) | 39 | Mesalamine, biologics, small molecules | TH: 14/39 (35.9%) |
Gilmore, 2023 [74] | Case series | IUS | BWT < 3 mm in the most affected segment with a modified Limberg score of 0 | 6 | ASUC treated with upadacitinib | TH week 8: 4/6 (66.7%) |
Lim, 2024 [63] | Prospective, single center, IBD registry study | MRI, CTE | Absence of inflammation on either CT or MR enterography | 51 | ustekinumab | TH: 16.7% |
Madsen, 2025 [62] | Prospective, multicenter, population-based, inception, cohort study | IUS | If no inflammation was present (normal BWT, CDS, BWS, i-fat) | 193 | - | TH week 3: 82/140 (59.0%) TH 12 months: 95/126 (75.0%) |
3.3.3. Factors Influencing the Likelihood of Achieving TH
3.3.4. Ongoing Clinical Trials Evaluating TH as an Endpoint
- TRENCH 1 (TRansmural hEaliNg Definition in Crohn’s Disease; NCT05903066): This is a multicenter, prospective, observational, cross-sectional study involving patients with CD with an indication for MRE based on routine clinical practice. The primary objective is to define the depth or grading of TH based on specific radiologic features observed during MRE. The study aims to standardize the radiologic interpretation of TH in CD, providing a more structured and reproducible definition for future clinical applications and research.
- REASON (Transmural Healing and Disease-Modifying Effect of Guselkumab in Crohn’s Disease Patients; NCT06408935): This is a phase 3b, open-label, multicenter Study. Participants receive guselkumab high dose (200 mg subcutaneous (SC) every 4 weeks or low dose (100 mg SC every 8 weeks). The study aims to evaluate the efficacy of guselkumab in achieving TH using MaRIA score with an evaluation at week 48.
- VECTORS—A Study to Evaluate Transmural Healing as a Treatment Target in Crohn’s Disease (NCT06257706): This phase 4 trial aims to evaluate whether a treat-to-target strategy that includes corticosteroid-free (CS-free) IUS outcomes in addition to clinical symptoms and biomarkers is superior to a strategy based solely on clinical symptoms and biomarkers in achieving CS-free endoscopic remission, as measured by the SES-CD.
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADA | adalimuamab |
BWT | bowel wall thickness |
BWS | bowel wall stratification |
CD | Crohn’s disease |
CDS | color Doppler signal |
CS-free | corticosteroid-free |
CTE | computed tomography enterography |
DH | deep healing |
EH | endoscopic healing |
HR | hazard ratio |
IBD | inflammatory bowel disease |
IFX | infliximab |
IUS | intestinal ultrasound |
MaRIA | Magnetic Resonance Index of Activity |
MH | mucosal healing |
MRI | magnetic resonance imaging |
NH | non-healing |
OR | odds ratio |
RCT | randomized controlled trial |
RH | radiologic healing |
SES-CD | Simple Endoscopic Score for Crohn’s Disease |
TH | transmural healing |
PICMI | Pediatric Inflammatory Crohn’s MRE Index |
UC | ulcerative colitis |
VDZ | vedolizumab |
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Faggiani, I.; Solitano, V.; D’Amico, F.; Parigi, T.L.; Zilli, A.; Furfaro, F.; Peyrin-Biroulet, L.; Danese, S.; Allocca, M. Is Transmural Healing an Achievable Goal in Inflammatory Bowel Disease? Pharmaceuticals 2025, 18, 1126. https://doi.org/10.3390/ph18081126
Faggiani I, Solitano V, D’Amico F, Parigi TL, Zilli A, Furfaro F, Peyrin-Biroulet L, Danese S, Allocca M. Is Transmural Healing an Achievable Goal in Inflammatory Bowel Disease? Pharmaceuticals. 2025; 18(8):1126. https://doi.org/10.3390/ph18081126
Chicago/Turabian StyleFaggiani, Ilaria, Virginia Solitano, Ferdinando D’Amico, Tommaso Lorenzo Parigi, Alessandra Zilli, Federica Furfaro, Laurent Peyrin-Biroulet, Silvio Danese, and Mariangela Allocca. 2025. "Is Transmural Healing an Achievable Goal in Inflammatory Bowel Disease?" Pharmaceuticals 18, no. 8: 1126. https://doi.org/10.3390/ph18081126
APA StyleFaggiani, I., Solitano, V., D’Amico, F., Parigi, T. L., Zilli, A., Furfaro, F., Peyrin-Biroulet, L., Danese, S., & Allocca, M. (2025). Is Transmural Healing an Achievable Goal in Inflammatory Bowel Disease? Pharmaceuticals, 18(8), 1126. https://doi.org/10.3390/ph18081126