Different levels of healing in inflammatory bowel diseases: mucosal, histological, transmural, barrier and complete healing

Correspondence to Professor Markus F Neurath, First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, D-91054, Germany; [email protected]

Key messages

• Mucosal healing on endoscopy has emerged as a key prognostic parameter in the management of patients with IBD.

• Mucosal healing predicts sustained clinical remission, steroid-free remission and resection-free survival in IBD.

• In UC, a second, deeper type of mucosal healing, denoted histological healing, has been defined which requires the absence of active inflammation in mucosal biopsies.

• Mucosal healing on endoscopy (IBD) and histological healing (UC) are important endpoints for clinical trials and may be considered for treatment of patients with IBD in clinical routine.

• New techniques for the analysis of mucosal healing comprise artificial intelligence-based analysis of endoscopic or histological images as well as endocytoscopy and endomicroscopy.

• Transmural healing and functional barrier healing of the mucosa emerge as potentially deeper layers of healing in IBD.

Introduction

The first papers on the term mucosal healing were published in the 1980s. It should be emphasised that these manuscripts did not deal with inflammatory intestinal diseases.^1–3 After the year 2000, however, this term received increasing attention in the context of studies on experimental wound healing and IBD.^{2 4–11} These studies highlighted the concept that mucosal healing in the intestine is a complex process involving specific signalling pathways. Here, mucosal healing requires the extensive absence or resolution of intestinal inflammation with an associated reduction of inflammatory immune cells such as neutrophils. Moreover, it requires the healing of mucosal ulcers via epithelial cell proliferation and regeneration, which is regulated by soluble autocrine and paracrine factors as well as by cell surface receptors.^12–14 Finally, mucosal healing is associated with matrix remodelling which is controlled by activated fibroblasts, soluble factors and enzymes such as matrix metalloproteinases.¹⁵

In 2007, a landmark study by Frøslie et al¹⁶ studied the clinical significance of mucosal healing on endoscopy in 740 patients with IBD over a period of 5 years. In UC, mucosal healing was significantly associated with a low risk of future colectomy, while in Crohn’s disease (CD) mucosal healing correlated with less inflammation after 5 years and decreased future steroid treatment. Subsequent studies indicated that mucosal healing on endoscopy is a surrogate marker for more effective disease control with associated symptom...