Mucosal healing is an important therapeutic end point in clinical trials and clinical practice. There is no validated definition of mucosal healing in patients with inflammatory bowel disease, although the benefits of achieving mucosal healing include decreased need for corticosteroids, sustained clinical remission, decreased colectomy, and bowel resection. The Ulcerative Colitis Endoscopic Index of Severity is the only validated endoscopic index in ulcerative colitis. The Crohn’s Disease Endoscopic Index of Severity and the Simple Endoscopic Score for Crohn’s Disease are validated for Crohn disease, and the Rutgeerts Postoperative Endoscopic Index is used to predict recurrence after an ileocolic resection.
Key points
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Mucosal healing is an important end point in clinical trials.
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Mucosal healing predicts the following:
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Less corticosteroid use
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Lower hospitalization rates
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Increased sustained clinical remission
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Lower colectomy and bowel resection rates
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Mucosal healing decreases the risk of colorectal cancer in ulcerative colitis (UC).
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Mucosal healing should be recognized by clinicians and health care providers as a goal for inflammatory bowel disease (IBD) therapy.
Introduction
UC and Crohn’s disease are characterized by the presence of gut inflammation accompanied by areas of ulceration ( Fig. 1 ). Mucosal healing is becoming increasingly important in the clinical management of UC and Crohn’s disease, as well as being used as an end point in clinical trials. Achieving mucosal healing has unequivocally been associated with better outcomes, and for these reasons, it has become an important treatment goal. There are, however, multiple methods to score endoscopic disease activity in both UC and Crohn’s disease. This article therefore focuses on those used most frequently or that have been validated: the Mayo endoscopic score and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for UC and the Crohn’s Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for Crohn’s Disease (SES-CD), and the Rutgeerts Postoperative Endoscopic Index for Crohn’s disease. Because indices are complex and potentially confusing, the article follows a standard approach describing the indices in this order.
Introduction
UC and Crohn’s disease are characterized by the presence of gut inflammation accompanied by areas of ulceration ( Fig. 1 ). Mucosal healing is becoming increasingly important in the clinical management of UC and Crohn’s disease, as well as being used as an end point in clinical trials. Achieving mucosal healing has unequivocally been associated with better outcomes, and for these reasons, it has become an important treatment goal. There are, however, multiple methods to score endoscopic disease activity in both UC and Crohn’s disease. This article therefore focuses on those used most frequently or that have been validated: the Mayo endoscopic score and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for UC and the Crohn’s Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for Crohn’s Disease (SES-CD), and the Rutgeerts Postoperative Endoscopic Index for Crohn’s disease. Because indices are complex and potentially confusing, the article follows a standard approach describing the indices in this order.
Definition of mucosal healing
Mucosal healing in the context of IBD refers to the endoscopic assessment of disease activity. Simply stated, mucosal healing should imply the absence of ulceration and erosions. Nevertheless, there is currently no validated definition of mucosal healing in IBD.
Ulcerative Colitis
In patients with UC, mucosal healing may represent the ultimate therapeutic goal, because the disease is limited to the mucosa. The pattern of inflammation in UC is associated with several mucosal changes, initially vascular congestion, erythema, and granularity. As inflammation becomes more severe, friability (bleeding to light touch), spontaneous bleeding, and erosions and ulcers develop. An International Organization of Inflammatory Bowel Disease (IOIBD) task force defined mucosal healing in UC as the absence of friability, blood, erosions, and ulcers in all visualized segments of the colonic mucosa. However, some studies allow erythema and friability in the definition of mucosal healing. Many different endoscopic indices for UC have been used in clinical trials, although none have been fully validated in prospective studies; this creates problems when comparing trials.
Crohn’s Disease
In contrast to UC, mucosal healing in Crohn’s disease might reasonably be considered a minimum (rather than the ultimate) therapeutic goal, because the disease is transmural. Even this therapeutic goal, however, is not routine clinical practice in most centers. The pattern of inflammation in Crohn’s disease is characterized by several mucosal features that include patchy erythema, nodularity, aphthoid, and then deeper, serpiginous ulceration, strictures, and, in severe cases, penetrating ulcers. The complete resolution of all visible ulcers is a simple definition of mucosal healing for clinical practice, and this is what has been suggested by IOIBD task force. Nevertheless, this binomial definition (presence or absence of ulcers) is currently unvalidated, is difficult to achieve, and is rather crude for use in therapeutic trials because it does not allow quantification of improvement of mucosal inflammation. The largest trials that have used mucosal healing as a primary or major secondary end point have used the definition of absence of ulcers rather than the prespecified cut-off values on the CDEIS or SES-CD. Studies have yet to determine the minimum degree of endoscopic improvement associated with improved clinical outcomes.
Benefits of mucosal healing
Mucosal healing in IBD has been associated with the following:
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Decreased need for corticosteroids
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Decreased hospitalization rates
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Sustained clinical remission
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Decreased colectomy and bowel resection
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Decreased risk of colorectal cancer
Multivariate analysis of data from a case-controlled study of patients with long-standing, extensive UC showed that those with endoscopically normal mucosa at surveillance colonoscopy had the same 5-year cancer risk as the general population. The presence of persisting histologic inflammation was, however, a determinant of risk for colorectal cancer. In the same surveillance population, evidence of postinflammatory polyps or strictures was associated with a significantly increased colorectal cancer risk. For Crohn’s disease, there has been no demonstrable reduction in colorectal cancer in those with mucosal healing.
Before monoclonal antibodies against tumor necrosis factor (anti-TNF) were introduced for Crohn’s disease, a symptom-oriented management approach was common. This approach was largely used because of the failure to demonstrate a correlation between endoscopic remission (mucosal healing) and decrease in relapse rates in patients treated with steroids compared with clinical remission (symptom control). Steroids, however, do not heal the ileal or colonic mucosa. In contrast, both azathioprine and anti-TNF therapy have now been shown to achieve and then maintain mucosal healing, thereby influencing the course of Crohn’s disease.
For these reasons, mucosal healing has emerged since 2012 as an important therapeutic goal for both UC and Crohn’s disease. Moreover, because trials in IBD have traditionally had a high placebo response rate, there is a move to include mucosal healing as an end point in trials to drive down placebo rates. For most patients, mucosal healing is only maintained with continued therapy. Current treatments do not cure the disease, and therefore, cessation of therapy almost invariably leads to disease recurrence. If mucosal healing influences the subsequent course of disease, logic suggests that its presence should be confirmed or therapy augmented if it has not been achieved. For these reasons, endoscopic assessment is increasingly used in clinical practice to guide decision making in the management of IBD, but augmenting treatment in the absence of symptoms just because endoscopic lesions are present remains a challenge to many clinicians. On the other hand, most are persuaded that mucosal healing is an appropriate therapeutic goal when starting, stepping up, switching, or stopping expensive biologic therapy.
Limitations of mucosal healing
Although colonoscopy is considered to be a low-risk invasive procedure, it still carries a risk of perforation, bleeding, or sedation. Furthermore, colonoscopy is an investment of time and resources both for the patient and the community.
Even when using validated indices such as the UCEIS and CDEIS, further research is needed to determine what degree of improvement, measured by endoscopy, is clinically meaningful. In addition, although disease may seem inactive at endoscopy, microscopic disease activity may persist. Persistent histologic activity is associated with a shorter time to relapse in UC, so endoscopic mucosal healing alone may be an insufficient therapeutic goal. Surrogate, noninvasive markers of mucosal healing are therefore needed, but biomarkers such as fecal calprotectin have yet to demonstrate sufficient specificity for mucosal healing to replace endoscopic assessment.
Methods to score disease activity
Ulcerative Colitis
Truelove and Witts were the first to comment on mucosal appearance as a measure of disease activity, using rigid sigmoidoscopy in the first placebo-controlled trial of cortisone for UC in 1955. Since 1956, it has been recognized that endoscopic and histologic microscopic changes can persist despite symptom resolution. Endoscopic indices evolved from the Baron score, initially developed for rigid proctoscopy in ambulatory patients with mild to moderate disease, which rated vascular pattern, mucosal bleeding, and friability. Subsequent endoscopic indices of increasing complexity incorporated the presence of ulcers, mucopus, granularity, and appearance of light scattering, in addition to bleeding and friability. Such modifications were intended to improve the capture of disease activity, but they invariably increased the subjectivity of the scoring system. Table 1 summarizes commonly used endoscopic indices for UC, none of which have been validated with the exception of the UCEIS. Nonetheless, there is no agreed threshold for defining either mucosal healing or endoscopic remission, which makes it almost impossible to compare mucosal healing rates between studies.
| Index a | Validated | Variables | Strengths | Weaknesses |
|---|---|---|---|---|
| Truelove and Witts Endoscopy Index | No | Granularity, hyperemia | Precedence (first reported index), but no other merit | No description of endoscopic lesions, so interobserver variability is high |
| Baron Index | No | Bleeding, vascular pattern, friability | Easy to use | Ulcerations not included in score, no definition of mucosal healing |
| Powell-Tuck Index | No | Bleeding | Easy to use | Ulceration not included, no definition of mucosal healing |
| Sutherland Index | No | Friability, bleeding, exudation | Easy to use; overlap in descriptive terms used for different levels of activity | Subjective, no definition of mucosal healing |
| Mayo Clinic Index: endoscopic subscore | No | Vascular pattern, erythema, friability, erosions and ulcerations, bleeding | Easy to use, commonly used in clinical trials; overlap in descriptive terms used for different levels of activity | No validated definition of mucosal healing The term minimal or slight friability is subjective and leads to inconsistent results |
| Rachmilewitz Index | No | Granulation, mucosal damage, vascular pattern, vulnerability of mucosa (bleeding) | None reported | Complex and subjective descriptive terms |
| Modified Baron Index | No | Vascular pattern, granularity, friability, bleeding, ulceration | Easy to use | No validated definition of mucosal healing |
| Endoscopic Activity Index | No | Size of ulcers (4 levels), depth of ulcers (4 levels), redness (3 levels), Bleeding (4 levels), mucosal edema (4 levels), mucosal exudate (3 levels) | Closely correlated with clinical activity. Comparable to other indices. Useful in severe disease | |
| Matts Index | No | Granularity, bleeding, edema, ulceration | Easy to use | |
| Ulcerative Colitis Endoscopic Index or Severity | Preliminary | Vascular pattern (3 levels), bleeding (4 levels), ulceration (4 levels) | Easy to use Independent of clinical symptoms, accounts for 88% of variation between observers | Sensitivity to change, and mucosal healing remain undefined |
a The word index is best used for an instrument designed to assess activity and score for the level of activity assigned by the index.
Space does not allow a review of all indices, so this article focuses on the Mayo Clinic endoscopy subscore, because this is commonly used in clinical trials, and the UCEIS, which has been validated.
The Mayo Clinic endoscopy subscore has 4 components, with a maximum total score of 3 ( Table 2 ). There is overlap in the features of the different levels of this endoscopic index, which causes high interobserver variation. The most troublesome component of this index is friability, as this is subjective and leads to inconsistent results. This inconsistency has lead to an adaptation of the index to remove friability from level 1.
Related posts:
Learning to Detect Flat Neoplastic Lesions in Inflammatory Bowel Disease
Quality Bowel Preparation for Surveillance Colonoscopy in Patients with Inflammatory Bowel Disease Is a Must
Image-Enhanced Endoscopy Is Critical in the Surveillance of Patients with Colonic IBD
The Unique Pathology of Nonpolypoid Colorectal Neoplasia in IBD
Toward a Consensus on Endoscopic Surveillance of Patients with Colonic Inflammatory Bowel Disease
Surgical Management of Nonpolypoid Colorectal Lesions and Strictures in Colonic Inflammatory Bowel Disease
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