Notably, the concept of MH had already started approximately 50 years ago. In 1966, Wright et al. reported a higher relapse rate in patients who did not achieve MH after oral and rectal steroids when compared with patients who did achieve MH (40% vs 18%). [3] Courtney et al. also reported that flares during a 12-month period following an episode of active colitis were observed in only 4% of the patients with clinical remission and mucosal healing, and in 30% of those whose clinical remission was accompanied by persistent mucosal lesions [4]. In 2001, Bitton et al. reported on clinical, biological, and histologic parameters that would predict time to clinical relapse. Surprisingly, they had already reported that one of the factors related to clinical relapse was basal plasmacytosis on rectal biopsy. The hazard ratio (HR) for predicting clinical relapse was 4.5, and the authors concluded that this factor may help identify patients with inactive UC who will require optimal maintenance therapy [5]. Although MH endpoints have not been focused on in clinical trials, the relevance of the endoscopic activity of UC has been translated into the new concept of “mucosal healing (MH)” as the therapeutic goal to achieve, because considerable scientific evidence indicated the favorable prognostic value of a healed mucosa in the clinical outcome of UC. Thus, MH assessed by endoscopy seems almost like the “gold standard” for evaluating UC activity. However, there are a number of questions to address before granting MH in assessing UC activity. These include: (1) what is the exact definition of MH—is there a uniformly accepted standard? and (2) does MH change the clinical outcome and reduce dysplasia and colorectal cancer in UC patients?

Despite no standardized definition of MH, a practical currently accepted definition of MH is “the complete resolution of the visible alterations or lesions, irrespective of their severity and/or type at baseline colonoscopy” [6]. Although there have been 50 years of clinical trials and differently designed endoscopic scoring systems, (Baron score, Mayo score, Sutherland, Powell-Tuck and Rachmilewitz indices, among others) [7–14], the definitions and the scoring methods of these instruments have never been prospectively validated. However, having no validated endoscopic score for UC activity evaluation might reflect the complexity in measuring its disease activity [15].

For example, in recent clinical trials, the Mayo endoscopy subscore has been the most commonly used, defining MH as a score of ≤1 (normal mucosa or loss of vascular pattern, but no mucosal friability), when the endoscopy subscore was 2 or 3 at baseline. The Mayo score is not theoretical but might be easily applicable in clinical practice. The main issues on the majority of several indices such as Mayo score include the overlap of mucosal features (such as vascularity, granularity, erythema, friability, bleeding, and ulceration), which could result in inter-observer variation in endoscopic evaluation, and the lack of clear and standardized thresholds for endoscopic remission. In fact, judging from data that a recent RCT on the use of mesalamine in UC patients showed different results after a revision of the endoscopic examination findings by a blinded central reader [16], issues with regard to definition of MH might greatly influence results of clinical trials.

Recently, two new scoring systems have been developed and prospectively validated, the Ulcerative Colitis Endoscopic Index of Severity and the Ulcerative Colitis Colonoscopic Index of Severity [17, 18]. However, data regarding the applicability of these new scoring systems in clinical trials and in clinical practice should be awaited, and accumulation of further clinical trials data with these systems might support the move toward a standardized definition of MH.

Moreover, regarding microscopic mucosal healing, “the authors do not recommend that histologic remission be used as the primary end point for a therapeutic trial in patients with UC.” [19]. Nevertheless, there have been several reports concerning the necessity of histological evaluation in colonic mucosa of UC. Also, it should be noted that the term “mucosal healing” was initially proposed only for the disappearance of the inflammatory infiltrate in the histological examination [20]. Currently, recent interest on mucosal healing skews toward not only endoscopic remission but also histological improvement. Bessissow et al. reported that the presence of basal plasmacytosis predicts UC clinical relapse in patients with complete mucosal healing, although this was a retrospective study [21]. In addition, Peyrin-Biroulet et al. described that data indicating a prognostically relevant role for histologic activity in the mucosa of UC patients, in addition to the macroscopic activity, have opened the door to the concept of “histological MH”, with the complete absence of clinical, laboratory, endoscopic, and histological features of active inflammation [22]. However, questions regarding histological MH should be addressed; [1] how many biopsy specimens should be taken? [2] where should biopsy specimens be taken? and [3] can histological results of rectal biopsy reflect inflammatory condition in the entire colonic mucosa of patients with extensive UC who have endoscopic remission? Possibly, deciding the exact definition of histological MH seems to be more difficult than that of endoscopic MH.

Do you know the reason why many IBD experts been interested in achievement of MH? Clinical trial data with various IBD treatments might account for this question. During the last decade, anti-TNF alpha antibodies have launched a “Copernican resolution” in the clinical approach to IBD patients. These drugs have resulted in rapid and dramatic improvement of clinical symptoms and intestinal mucosal lesions. Since emergence of anti-TNF alpha antibodies in the field of IBD treatment, the relevance of the endoscopic activity of IBD has been definitely stated, and MH has been proposed with increasing strength as a fundamental therapeutic goal of IBD treatment. In this regard, the significance of MH as a treatment goal in IBD is of increasing interest, and has become a common endpoint in clinical trials. For example, in the recent trials of infliximab for moderate to severe UC, assessed by the Mayo score, those patients with documented mucosal healing at week 8 and 30 were more likely to be in remission than those who did not [23]. The ACT1 and ACT2 trials showed that UC patients treated with infliximab who achieved MH at week 8 had a higher rate of clinical remission at week 30 than patients without MH (48.3% vs 9.5%) [23]. Moreover, a post-hoc analysis of the ACT1/ACT2 trials conducted by Colombel et al. demonstrated that a Mayo endoscopy subscore of 0–1 in infliximab-treated patients was related to a lower probability of colectomy than a score of 2–3 through a follow-up period of 54 weeks. [24]. Thus, data in ACT trial suggested that MH could affect clinical outcome of UC. It has been reported that UC patients who achieved clinical remission together with MH after leukocytapheresis had a higher rate of sustained clinical response than those with a clinical response alone (88% vs 41%) [25]. With regard to corticosteroid treatment, it has been reported that the lack of mucosal healing at 3 months after the first administration of corticosteroid was the only factor associated with negative outcomes at 5 years (use of immunosuppressants, hospitalization, and colectomy) [26]. An observational study of the IBSEN cohort showed that in 513 UC patients, the colectomy rate was lower in patients with MH [defined by a simple endoscopic score of 0–1 (0, normal; 1, light erythema or granularity)] at a 5-year follow-up (2% vs 8%, P < 0.05) [27]. Similar results were observed by Solberg et al., who reported a decrease in the colectomy rate in UC patients with MH at 1 year after diagnosis, regardless of the therapy used to achieve it [28].