Mucosal healing as a treatment for IBD?

Abstract

In the last years mucosal healing has emerged as an important therapeutic goal for patients with inflammatory bowel disease. Growing evidence suggests that mucosal healing can improve patient outcomes and, potentially, can alter the natural course of the disease by inducing sustained clinical remission and reducing hospitalizations and surgery. However several questions remain to be answered. A validated definition of mucosal healing is still lacking and the effect size of different drugs is difficult to assess because of different definitions, different study design, and different timing of endoscopic evaluation. The evidence that mucosal healing has a high positive predictive value for long-term good clinical outcome is still limited and, therefore, mucosal healing remains a weak surrogate end point of disease course. Future studies are needed to develop a standardized definition of mucosal healing and to prospectively assess the impact of mucosal healing on long-term clinical outcomes.

Keywords::

• Crohn’s disease
• endoscopy
• inflammatory bowel disease
• mucosal healing
• ulcerative colitis

The management of inflammatory bowel disease (IBD) has traditionally been aimed at improving symptoms and little attention has been focused on healing of mucosal lesions. Nevertheless, mucosal healing (MH) has been always considered important in ulcerative colitis (UC), but not in Crohn’s disease (CD). Since the 60s, in fact, clinical studies suggested that the long-term outcome after a steroid course was more favorable in UC patients who achieved both clinical and endoscopic remission compared with those who achieved only clinical remission [1]. Conversely, observational studies failed to report a clear impact of healing of mucosal lesions on relapse rate in CD patients with corticosteroid-induced remission [2]. These observations led clinicians to limit their CD treatment only on symptomatic remission.

Since the entry of anti-TNF-α drugs in the clinical scenario of IBD, clinicians’ attitude toward MH has drastically changed because of the possibility to achieve a rapid and sustained healing of mucosal lesions also in CD. Since then, the interest on MH in IBD grew so much up to the current consideration that MH is a relevant end point in clinical trials and a desirable goal in clinical practice in the conviction that MH could improve patient’s outcome in terms of reduction of relapses, recurrences, complications and surgery. Future studies that focus on MH and disease course as primary outcome measures have been advocated by some authors [3].

A good outcome measure should be simple to calculate, objective, reproducible and it should be an accurate predictor of the course of the disease. Does MH fulfill all these criteria? Several questions may arise from this issue.

The first question concerns the definition of MH. IBD encompasses a wide range of endoscopic lesions, but there is no current standardized definition of MH and several criteria have been arbitrarily used. In CD, MH has been defined either in a simple and pragmatic manner as ‘absence of ulcerations at follow-up endoscopy in patients who had ulcerations at baseline’ [4] or using endoscopic scores, such as the CD endoscopic index of severity or the simple endoscopic score for CD (SES-CD) [5]. Unfortunately, these scores were initially conceived as continuous-variable systems and no agreement on cut-off values to define MH exist. Different cut-off values have been used in various studies: 0, below 3 or below 6 for the CD endoscopic index of severity, and 0 or below 5 for the simple endoscopic score for CD [5]. In UC, there is plenty of endoscopic scores, but none of them has been properly validated [6]. One of the most used is the Mayo Endoscopic Subscore, and the International Organization of IBD has proposed a definition of MH as “absence of friability, blood, erosions, ulcers in all visualized segments” corresponding to a Mayo score between 0 and 1 [6].

A precise definition of MH would be of critical importance. Any definition should carry a prognostic value, in order to be useful in clinical terms. Whether the definition of MH should be reserved for those cases of complete healing or, less strictly, it could be defined as a clear improvement, but without complete restitutio ad integrum, it is current matter of discussion. In this regard, we learned an important lesson from the use of the Rutgeerts’ score of postoperative recurrence in CD [7]. In this pivotal study, Rutgeerts et al. found that the severity of endoscopic recurrence 1 year after surgery strongly correlated with the risk of developing symptomatic recurrence in the following years. However, no difference was observed, in prognostic terms, between patients with no recurrence and patients with mild endoscopic recurrence. The distinction between these two grades is, therefore, not clinically relevant and current postoperative therapeutic strategies are aimed at aggressively treating only severe endoscopic recurrence. Similarly, in a retrospective study on a large cohort of CD patients treated with infliximab, no difference in the long-term need of major abdominal surgery was observed in patients who achieved complete MH (absence of ulcerations) or partial MH (clear improvement of mucosal lesions, but still with ulcerations) [4]. In UC, a substudy of the ACT 1 and ACT 2 trials showed that early MH with infliximab was associated with a reduced risk of colectomy within 1 year, but the colectomy-free survival was similar in patients who achieved complete MH (Mayo score = 0) or partial MH (Mayo score = 1) [8]. Taken together, these observations suggest that a distinction between complete and partial MH may not be relevant in clinical terms.

The second question concerns the real impact of MH on the clinical course of IBD. Over the last years, accumulating evidence suggest that MH is prognostically relevant. In a Norwegian population-based cohort, MH was found to have a significant impact on the long-term outcome of both CD and UC [9]. Observational studies and subgroup analyses of randomized controlled trials in CD indicate that MH is associated with lower relapse rates, corticosteroid-free remission, reduced hospitalizations and reduced need for surgery at least in the medium term [4,10,11]. MH has been associated with a more favorable outcome such as reduced risk of relapse, fewer hospitalizations and lower colectomy rates also in UC [8,12,13]. Finally, MH could potentially prevent the development of colorectal cancer in UC [11]. However, when considering the impact of MH on the clinical course of IBD, an important point for discussion is to establish if MH is a valid surrogate end point of disease outcome. A surrogate end point is an outcome measure that per se has not a direct clinical importance, but it reflects a clinically relevant outcome. The greatest potential for the validity of a surrogate end point is when the surrogate is in the only causal pathway of the disease process and the therapeutic effect on the true clinical outcome is mediated through its effect on the surrogate [14]. It is difficult to find this ideal setting in a complex and multifactorial disease such IBD and, therefore, surrogate end points could yield misleading conclusions. This is the case for MH: although several drugs are capable of inducing MH in different clinical settings of disease location and severity, the effect size of different treatments and the duration of the effect (short-term or sustained MH) are difficult to assess because of different definitions, different study designs and different timing of endoscopic evaluation [15]. Moreover, current evidence that MH has a high positive predictive value for long-term good clinical outcome is still limited.

Apart from difficulties in defining MH and in establishing its validity as a surrogate end point of disease outcome, there are other debated issues. How can we assess mucosal lesions in CD of the upper gastrointestinal tract? Should wireless capsule endoscopy or other device-assisted enteroscopy be routinely used in the assessment of MH? Moreover, it is debated whether histology should be included in the evaluation of MH. Although the prognostic relevance of histological healing has not been studied in CD, microscopic inflammation has been shown to be predictive of relapse in UC patients in clinical remission [16] and some studies indicate that persistence of microscopic inflammation is an independent risk factor for colorectal cancer in UC [17]. In this setting, advanced endoscopic imaging techniques, such as confocal laser endomicroscopy, are emerging as promising tools to improve diagnostic accuracy [18].

Finally, the issue of the appropriateness of MH as a relevant end point in the treatment of a transmural disease like CD is argument of discussion. A lesson about the inadequateness of superficial healing in a transmural condition, we learnt from fistulizing CD, where it has clearly emerged how the closure of fistulas’ external orifices can be achieved despite the persistence of the fistulous tracks [19].

The concept of MH in CD is currently evolving toward a more complex model of intestinal healing, with the elaboration of an instrument, the Lemann score, which should enable an assessment of the cumulative structural bowel damage [20]. The score includes not only endoscopy, but also cross-sectional imaging techniques and, in the near future, it could be used in clinical trials and observational studies to measure the progression of bowel damage over time and to assess the effects of treatment on the progression of bowel damage [20].

In conclusion, in the last years, the therapeutic goals of IBD have changed from mere control of symptoms toward long-term strategies aimed at affecting the natural course of the disease. MH is an emerging end point in this setting. Although compelling arguments suggest that MH is associated with improved disease outcome, it remains a weak surrogate end point of disease course. Future studies are needed to develop a standardized definition of MH, to prospectively assess the impact of MH on long-term clinical outcomes, and finally to answer the most important question for clinical practice: should we systematically assess MH and target our treatment strategies to achieve MH in IBD patients?

Financial & competing interests disclosure

C Papi has received consultancy fees from Abbvie and MSD and educational grants from Abbvie, Chiesi and Sofar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.