Not All Transmural Healing is Equal in Crohn’s Disease: Magnetic Resonance Enterography and Intestinal Ultrasound for Stricture Assessment in the STRIDENT Trial

The concept of transmural healing (TH) in Crohn’s disease (CD), reflecting the true resolution of the inflammation throughout the bowel wall, has gained recognition in recent years.¹ Achieving TH compared to other parameters such as endoscopic healing has been associated with long-term benefits including higher rates of clinical remission, lower probability of disease relapse, treatment escalation, hospitalization, and surgery.^1,2 However, TH remains a complex target because there is no current validated definition, and the reported rates vary widely between studies (14%-42%) depending on the criteria used.¹ Currently, in the era of treat-to-target management, TH is considered an adjunct objective rather than a formal one for clinicians and patients to aim for. Although endoscopic healing has remained the cornerstone treat-to-target, it is important to note that endoscopic outcomes might not capture involvement beyond the bowel lumen.³

Cross-sectional imaging modalities, particularly intestinal ultrasound (IUS) and magnetic resonance enterography (MRE) have been proposed to evaluate TH.⁴ However, not all transmural involvement is equivalent, and specific disease manifestations, such as intestinal strictures, represent a distinct phenotype with unique structural and functional characteristics. Unlike inflammatory lesions, strictures often involve a mix of inflammation and fibrosis, and their response to treatment requires more tailored evaluation criteria.⁵

In the current issue of Inflammatory Bowel Disease, Lovett et al.⁶ present secondary results from the STRIDENT randomized trial that assessed the efficacy of an intensive high-dose of adalimumab plus azathioprine vs standard dose monotherapy of adalimumab for patients with symptomatic stricturing CD. An important and unique aspect of STRIDENT was that participants had endoscopy and MRE assessment at baseline and 12 months and IUS at baseline, 4, 8, and 12 months.

Inclusion in STRIDENT required patients to have a CD stricture defined by MRE (bowel segment with ≥ 80% lumen diameter reduction compared to adjacent proximal intestine, and bowel wall thickness [BWT] > 3 mm, and narrowing present). Although not used for inclusion into the study, a stricture was also identified with IUS as a segment with a BWT > 3 mm and luminal narrowing, with or without prestenotic dilatation (> 2.5 cm).

At 12 months, 29% (17/59) of patients had stricture resolution on IUS (BWT < 3 mm, resolution of hyperemia [Limberg score ≤ 1], and normalization of prestenotic dilatation). In addition, 39% (23/59) had stricture improvement on IUS, defined as a reduction of the BWT ≥ 25% from baseline, hyperemia resolution, and normalization of prestenotic dilatation. While on MRE, stricture resolution (normal BWT, normal lumen diameter, and resolution of prestenotic dilatation [< 3cm]) was seen in 22% (16/72) of patients. Stricture improvement (normalization of prestenotic dilatation, improvement ≥ 25% from the baseline MaRIA score, and reduction in the stricture simplified MaRIA score ≥ 1 point) was observed in 24/72 (33%) patients at 12 months. These findings showed a strong association for stricture resolution between both IUS and MRE modalities.

Interestingly, patients with clinical response to therapy had greater rates of IUS stricture resolution (37% vs 6%, P = .02) and lower IUS BWT. This lower BWT was seen on both imaging techniques in patients with adalimumab trough levels > 9.7 µg/L at 4 months. Moreover, the ROC analysis identified an adalimumab trough level of 11.0 µg/dL (sensitivity 100%, specificity 59%, AUC 0.72) as the cutoff to identify patients with and without stricture resolution at 4 months. Other factors associated with stricture resolution at 12 months included the BWT and stricture length < 5 cm on the baseline IUS and multiple strictures on the baseline MRE.

The CREOLE study,⁷ a prospective non-randomized cohort, had previously demonstrated that patients with symptomatic small bowel strictures could benefit from medical therapy with adalimumab and had therapy persistence of 64% at 12 months and 29% at 4 years of follow-up. The findings from STRIDENT further support these findings and suggest that there is a role for medical therapy not just to improve symptoms, but also to reduce stricturing on cross-sectional imaging.⁸ Early initiation of medical therapy in patients with stricturing CD may also help earlier identification of responders and non-responders and help plan timely surgical or endoscopic interventions for medication non-responders.

These data highlight the importance of frequent monitoring, especially for stricturing CD, using cross-sectional imaging.⁹ Indeed, frequent monitoring of patients with stricturing disease would allow objective information to be acted upon rather than waiting for obstructive symptoms to recur or worsen. An important aspect for future work will be to demonstrate whether a proactive imaging strategy translates to reduced hospitalizations and urgent abdominal surgeries and increased longer-term bowel preservation. It seems likely that, given the higher practicality and levels of patient acceptance with IUS,¹⁰ this will be used more frequently in comparison to MRE (particularly given the comparable sensitivity between both modalities).¹¹

A major challenge that has hindered the implementation of cross-sectional monitoring strategies to date in stricturing CD has been the absence of standardized definitions for strictures and their response to treatment. In this regard, the STAR (Stenosis Therapy and Anti-Fibrotic Research) international expert guidance¹² has sought to address this gap by proposing consensus-based definitions for identifying and monitoring strictures using IUS. According to STAR, a small bowel stricture on IUS is defined by the presence of BWT > 3 mm, luminal narrowing (< 1cm or < 50% relative to normal adjacent bowel loop), and prestenotic dilatation defined as > 2.5 cm in diameter or > 50% increase in bowel diameter or unequivocal increase in bowel diameter relative to normal adjacent bowel loops, with or without impaired motility. These parameters help differentiate strictures from segments of non-strictured inflammation and provide a framework for tracking changes over time.

Even though STRIDENT did not use the exact definitions as outlined by STAR, this was the first prospective randomized trial to assess cross-sectional imaging response to therapy in stricturing CD. It is also the first trial to do so using ileocolonoscopy, MRE, and IUS. The results from this study frame TH as a tangible target in stricturing CD beyond symptom control and endoscopic healing, offering hope that the natural history of the disease can be altered and cumulative bowel damage can be reduced over time. STRIDENT further emphasizes the role of IUS not only as a diagnostic tool but also as a feasible and reliable method for treat-to-target monitoring in patients with stricturing CD.

Acknowledgments

None.

Author Contributions

K.E.S. and N.M.N. wrote and approved the final version of the manuscript.

Funding

There was no specific funding for this article. N.M.N. is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Conflicts of Interest

K.E.S. discloses education/travel grants and/or speaker fees from AbbVie, AstraZeneca, Ferring, J&J, Pfizer, Satisfai, and Takeda. N.M.N. discloses educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma AG.

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