Advertisement

Mucosal Healing As a Target of Therapy for Colonic Inflammatory Bowel Disease and Methods to Score Disease Activity

Open AccessPublished:May 06, 2014DOI:https://doi.org/10.1016/j.giec.2014.03.005

      Keywords

      Key points

      • Mucosal healing is an important end point in clinical trials.
      • Mucosal healing predicts the following:
        • Less corticosteroid use
        • Lower hospitalization rates
        • Increased sustained clinical remission
        • Lower colectomy and bowel resection rates
      • Mucosal healing decreases the risk of colorectal cancer in ulcerative colitis (UC).
      • 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.
      Figure thumbnail gr1
      Fig. 1Assessment of mucosal healing using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) with descriptors of vascular pattern (V), bleeding (B), and erosions/ulcers (E). (A) UCEIS 0 (V0 B0 E0), (B) UCEIS 5 (V2 B1 E0), and (C) UCEIS 8 (V2 B3 E3).

      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.
      • Sandborn W.J.
      • Feagan B.G.
      • Hanauer S.B.
      • et al.
      A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with Crohn's disease.
      • D'Haens G.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.
      • Neurath M.F.
      • Travis S.P.
      Mucosal healing in inflammatory bowel diseases: a systematic review.

      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.
      • D'Haens G.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.
      However, some studies allow erythema and friability in the definition of mucosal healing.
      • Dave M.
      • Loftus E.V.
      Mucosal healing in inflammatory bowel disease - a true paradigm of success?.
      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.
      • Walsh A.J.
      • Ghosh A.
      • Brain A.O.
      • et al.
      Comparing disease activity indices in ulcerative colitis.

      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.
      • D'Haens G.R.
      • Fedorak R.
      • Lémann M.
      • et al.
      End points for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease.
      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.
      • De Cruz P.
      • Kamm M.A.
      • Prideaux L.
      • et al.
      Mucosal healing in Crohn’s disease: a systematic review.
      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:
      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.
      • Rutter M.D.
      • Saunders B.P.
      • Wilkinson K.H.
      • et al.
      Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk.
      The presence of persisting histologic inflammation was, however, a determinant of risk for colorectal cancer.
      • Rutter M.
      • Saunders B.
      • Wilkinson K.
      • et al.
      Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.
      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.
      • Frøslie K.F.
      • Jahnsen J.
      • Moum B.A.
      • et al.
      Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort.
      • Rutgeerts P.
      • Diamond R.H.
      • Bala M.
      • et al.
      Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with 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.
      • Rutgeerts P.
      • Van Assche G.
      • Sandborn W.J.
      • et al.
      Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial.
      • De Cruz P.
      • Bernardi M.P.
      • Kamm M.A.
      • et al.
      Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.
      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.
      • Schoepfer A.M.
      • Vavricka S.
      • Zahnd-straumann N.
      • et al.
      Monitoring inflammatory bowel disease activity: clinical activity is judged to be more relevant than endoscopic severity or biomarkers.
      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,
      • Riley S.A.
      • Mani V.
      • Goodman M.J.
      • et al.
      Microscopic activity in ulcerative colitis: what does it mean?.
      • Burger D.C.
      • Thomas S.J.
      • Walsh A.J.
      • et al.
      Depth of remission may not predict outcome of UC over 2 years.
      so endoscopic mucosal healing alone may be an insufficient therapeutic goal.
      • Peyrin-Biroulet L.
      • Bressenot A.
      • Kampman W.
      Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.
      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.
      • Schoepfer A.M.
      • Vavricka S.
      • Zahnd-straumann N.
      • et al.
      Monitoring inflammatory bowel disease activity: clinical activity is judged to be more relevant than endoscopic severity or biomarkers.

      Methods to score disease activity

      Ulcerative Colitis

      Truelove and Witts
      • Truelove S.C.
      • Witts L.J.
      Cortisone in ulcerative colitis; final report on a therapeutic trial.
      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.
      • Truelove S.C.
      • Richards W.C.
      Biopsy studies in ulcerative colitis.
      Endoscopic indices evolved from the Baron score,
      • Baron J.H.
      • Connell A.M.
      • Lennard-Jones J.E.
      Variation between observers in describing mucosal appearances in proctocolitis.
      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.
      • Travis S.P.
      • Schnell D.
      • Krzeski P.
      • et al.
      Developing an instrument to assess the endoscopic severity of ulcerative colitis: the ulcerative colitis endoscopic index of severity (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.
      • Travis S.P.
      • Higgins P.D.
      • Orchard T.
      • et al.
      Review article: defining remission in ulcerative colitis.
      Table 1Endoscopic disease activity indices
      The word index is best used for an instrument designed to assess activity and score for the level of activity assigned by the index.31
      for ulcerative colitis
      Index
      The word index is best used for an instrument designed to assess activity and score for the level of activity assigned by the index.31
      ValidatedVariablesStrengthsWeaknesses
      Truelove and Witts Endoscopy Index
      • Truelove S.C.
      • Witts L.J.
      Cortisone in ulcerative colitis; final report on a therapeutic trial.
      NoGranularity, hyperemiaPrecedence (first reported index), but no other meritNo description of endoscopic lesions, so interobserver variability is high
      Baron Index
      • Baron J.H.
      • Connell A.M.
      • Lennard-Jones J.E.
      Variation between observers in describing mucosal appearances in proctocolitis.
      NoBleeding, vascular pattern, friabilityEasy to useUlcerations not included in score, no definition of mucosal healing
      Powell-Tuck Index
      • Powell-Tuck J.
      • Day D.W.
      • Buckell N.A.
      • et al.
      Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis.
      NoBleedingEasy to useUlceration not included, no definition of mucosal healing
      Sutherland Index
      • Sutherland L.R.
      • Martin F.
      • Greer S.
      • et al.
      5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.
      NoFriability, bleeding, exudationEasy to use; overlap in descriptive terms used for different levels of activitySubjective, no definition of mucosal healing
      Mayo Clinic Index: endoscopic subscore
      • Schroeder K.W.
      • Tremaine W.J.
      • Ilstrup D.M.
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.
      NoVascular pattern, erythema, friability, erosions and ulcerations, bleedingEasy to use, commonly used in clinical trials; overlap in descriptive terms used for different levels of activityNo validated definition of mucosal healing

      The term minimal or slight friability is subjective and leads to inconsistent results
      Rachmilewitz Index
      • Rachmilewitz D.
      Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.
      NoGranulation, mucosal damage, vascular pattern, vulnerability of mucosa (bleeding)None reportedComplex and subjective descriptive terms
      Modified Baron Index
      • Feagan B.G.
      • Greenberg G.R.
      • Wild G.
      • et al.
      Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
      NoVascular pattern, granularity, friability, bleeding, ulcerationEasy to useNo validated definition of mucosal healing
      Endoscopic Activity Index
      • Naganuma M.
      • Ichikawa H.
      • Inoue N.
      • et al.
      Novel endoscopic activity index is useful for choosing treatment in severe active ulcerative colitis patients.
      NoSize 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
      • Matts S.G.
      The value of rectal biopsy in the diagnosis of ulcerative colitis.
      NoGranularity, bleeding, edema, ulcerationEasy to use
      Ulcerative Colitis Endoscopic Index or Severity
      • Travis S.P.
      • Schnell D.
      • Krzeski P.
      • et al.
      Developing an instrument to assess the endoscopic severity of ulcerative colitis: the ulcerative colitis endoscopic index of severity (UCEIS).
      Preliminary
      • Travis S.P.
      • Schnell D.
      • Krzeski P.
      • et al.
      Reliability and initial validation of the ulcerative colitis endoscopic index of severity.
      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.
      • Travis S.P.
      • Schnell D.
      • Krzeski P.
      • et al.
      Developing an instrument to assess the endoscopic severity of ulcerative colitis: the ulcerative colitis endoscopic index of severity (UCEIS).
      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).
      • Schroeder K.W.
      • Tremaine W.J.
      • Ilstrup D.M.
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.
      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.
      • D'Haens G.
      • Feagan B.
      • Colombel J.F.
      • et al.
      Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease.
      This inconsistency has lead to an adaptation of the index to remove friability from level 1.
      • Kamm M.A.
      • Sandborn W.J.
      • Gassull M.
      • et al.
      Once-daily, high-concentration MMX mesalamine in active ulcerative colitis.
      Table 2Mayo endoscopic score
      Adapted from Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625–9; with permission.
      ScoreDisease ActivityEndoscopic Features (Descriptors)
      0Normal or inactiveNone
      1MildErythema, decreased vascular pattern, mild friability
      Endoscopic assessment in the mesalamine MMX trials removed friability from level 1 (see text).
      2ModerateMarked erythema, absent vascular pattern, friability, erosions
      3SevereSpontaneous bleeding, ulceration
      a Endoscopic assessment in the mesalamine MMX trials removed friability from level 1 (see text).
      The value of this index lies with its widespread use in clinical trials. In trials of infliximab and adalimumab, mucosal healing was defined as a Mayo subscore of 0 or 1 or a decrease from the baseline subscores of 2 or 3. In Active Ulcerative Colitis Trials, patients with a posttreatment Mayo score of grade 1 were no more likely to undergo a colectomy than those with a score of 0.
      • Rutgeerts P.
      • Sandborn W.J.
      • Feagan B.G.
      • et al.
      Infliximab for induction and maintenance therapy for ulcerative colitis.
      The UCEIS (Table 3) was developed because of wide interobserver variation in endoscopic assessment of disease activity.
      • Travis S.P.
      • Schnell D.
      • Krzeski P.
      • et al.
      Developing an instrument to assess the endoscopic severity of ulcerative colitis: the ulcerative colitis endoscopic index of severity (UCEIS).
      There was only 76% agreement for severe and 27% agreement for normal endoscopic mucosal appearances between 10 experienced investigators and a central reader. Thirty different investigators then rated 25/60 different videos for 10 descriptors and assessed overall severity on a 0 to 100 visual analog scale. Kappa statistics tested interobserver and intraobserver variability for each descriptor. Different models to predict the overall assessment of severity as judged by a visual analog scale were developed using general linear mixed regression. The final model incorporated just 3 descriptors, each with precise definitions. A third validation phase used another 25 different investigators from North America and Europe, who assessed in a randomly selected subset of 28/60 videos, including 2 duplicated videos to assess test-retest reliability. Intraobserver kappa values were 0.82, 0.72, and 0.78 for vascular pattern, bleeding, and erosion and ulcer descriptors, and interobserver kappa values were 0.83, 0.56, and 0.77, respectively. The correlation coefficient (r2) between UCEIS and overall severity evaluation was 0.94 (P<.0001), meaning that it accounted for 88% (0.942) of the variation between observers in the overall assessment of endoscopic activity.
      • Travis S.P.
      • Schnell D.
      • Krzeski P.
      • et al.
      Reliability and initial validation of the ulcerative colitis endoscopic index of severity.
      Table 3The Ulcerative Colitis Endoscopic Index of Severity
      Adapted from Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 2012;61:1619–35.
      Descriptor (Score Most Severe Lesions)Likert Scale Anchor PointsDefinition
      Vascular patternNormal (0)Normal vascular pattern with arborization of capillaries clearly defined, or with blurring or patchy loss of capillary margins
      Patchy obliteration (1)Patchy obliteration of vascular pattern
      Obliterated (2)Complete obliteration of vascular pattern
      BleedingNone (0)No visible blood
      Mucosal (1)Some spots or streaks of coagulated blood on the surface of the mucosa ahead of the scope, which can be washed away
      Luminal mild (2)Some free liquid blood in the lumen
      Luminal moderate or severe (3)Frank blood in the lumen ahead of endoscope or visible oozing from mucosa after washing intraluminal blood, or visible oozing from a hemorrhagic mucosa
      Erosions and ulcersNone (0)Normal mucosa, no visible erosions or ulcers
      Erosions (1)Tiny (≤5 mm) defects in the mucosa, of a white or yellow color with a flat edge
      Superficial ulcer (2)Larger (>5 mm) defects in the mucosa, which are discrete fibrin-covered ulcers when compared with erosions, but remain superficial
      Deep ulcer (3)Deeper excavated defects in the mucosa, with a slightly raised edge
      Copyright Warner Chilcott Pharmaceuticals, although the index is freely available for use by investigators.
      The term friability invariably needs explanation. The UCEIS dispensed with the term mucosal friability, because the model including friability as a descriptor did not perform significantly better than one including bleeding. In practical terms, the most severely affected part of the mucosa is scored. There are, however, still limitations; thresholds for remission and mild, moderate, and severe disease have yet to be set. The extent to which full colonoscopy may influence the score compared with the flexible sigmoidoscopy on which it was based, has only started to be evaluated.
      • Thia K.T.
      • Loftus E.V.
      • Pardi D.S.
      • et al.
      Measurement of disease activity in ulcerative colitis: interobserver agreement and predictors of severity.
      Knowledge of symptoms does not materially influence the score, and a comparison with the Mayo Clinic endoscopy subscore shows that the UCEIS is less subject to variation by a central reader.
      • Pola S.
      • Feagan B.G.
      • Fahmy M.
      • et al.
      Observer agreement and construct validity in central endoscopic assessment of disease activity in ulcerative colitis.
      Nevertheless, the UCEIS is simple enough to use in clinical practice and should achieve its goal of reducing variation in endoscopic assessment of activity between observers. Clinicians are beginning to use the UCEIS in clinical practice, and a preliminary study in patients admitted with acute severe colitis shows that a score of 7 or 8 (out of 8) on admission predicted an inadequate response to intravenous steroids and the need for rescue therapy with cyclosporine or infliximab.
      • Corte C.J.
      • Fernandopulle A.N.
      • Catuneanu A.
      • et al.
      Correlation between the ulcerative colitis endoscopic index of severity (UCEIS) and outcomes in acute severe ulcerative colitis.
      The UCEIS is now being used in clinical trials of UC that are in progress.

      Crohn's Disease

      There are validated endoscopic indices for the assessment of Crohn's disease activity (Table 4). The CDEIS is the standard, whereas the SES-CD is a simplified version. The Rutgeerts Postoperative Endoscopic Index is used for estimating the risk of recurrence after ileocolic resection for Crohn's disease.
      Table 4Endoscopic indices for Crohn's disease
      IndexValidatedVariablesStrengthsWeaknesses
      Crohn’s Disease Endoscopic Index of Severity (CDEIS)
      • Mary J.Y.
      • Modigliani R.
      Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).
      YesSuperficial and deep ulceration, ulcerated and nonulcerated stenosis, surface area of ulcerated and disease segmentsStandard, reproducible, gold standardComplex, need experience/training, difficult for beginners and daily routine, no validated definition of mucosal healing
      Simple Endoscopic Score for Crohn’s Disease (SES-CD)
      • Daperno M.
      • D'Haens G.
      • Van Assche G.
      • et al.
      Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.
      YesUlcer size, ulcerated surface, affected surface, presence of stenosisSimplified index; performance correlates with CDEISValidated against CDEIS in only one study, less frequently used than CDEIS, no validated definition of mucosal healing
      Rutgeerts Postoperative Endoscopic Index
      • Rutgeerts P.
      • Geboes K.
      • Vantrappen G.
      • et al.
      Predictability of the postoperative course of Crohn's disease.
      NoAphthous ulcerations, inflammation, ulcers, nodules, narrowingStandard for evaluating postoperative recurrence, validated levels for predicting relapseOnly for use after ileocolic resection
      The CDEIS
      • Mary J.Y.
      • Modigliani R.
      Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).
      is a prospectively developed instrument constructed to detect changes in disease activity and examines 4 endoscopic variables (deep ulceration, superficial ulceration, length of ulcerated mucosa, and length of diseased mucosa) in each of the following locations: rectum, sigmoid and left colon, transverse colon, and right colon and ileum (Table 5). The total score is then divided by the number of locations explored (1–5). An additional 3 points is given if an ulcerated stenosis is present, and a further 3 points if a nonulcerated stenosis is present. CDEIS scores range from 0 to 44.
      • Deep ulcerations: score 0 if absent or 12 if present
      • Superficial ulcerations: score 0 if absent or 6 if present
      • Length of ulcerated mucosa (0–10 cm): score 0 to 10 according to length in centimeters
      • Length of diseased mucosa (0–10 cm): score 0 to 10 according to length in centimeters
      Table 5Example of the CDEIS scoring form
      Adapted from Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989;30:983–9; with permission.
      RectumSigmoid & Left ColonTransverse ColonRight ColonIleumTotal
      Deep ulcerations (12 present, 0 absent)012012N/A24Total 1
      Superficial ulceration (6 present, 0 absent)6666N/A24Total 2
      Surface involved by the disease (per 10 cm)
      Analog scales to be converted to numeric values.
      5.64.93.45.6N/A19.5Total 3
      Ulcerated surface (per 10 cm)
      Analog scales to be converted to numeric values.
      0.70.50.90.4N/A22Total 4
      Total 1 + Total 2 + Total 3 + Total 489.5Total A
      Number (n) of segments totally or partially examined (1–5)4n
      Total A divided by n22.4Total B
      Quote 3 if ulcerated stenosis anywhere, 0 if not3C
      Quote 3 if nonulcerated stenosis anywhere, 0 if not0D
      Total B + C + D25.4CDEIS
      a Analog scales to be converted to numeric values.
      Although CDEIS is the standard index and is reproducible, it is also complex. It requires training and experience, especially for estimating ulcerated or diseased mucosal surfaces and distinguishing between superficial and deep ulceration. It is cumbersome to use in clinical practice. The CDEIS has appropriate sensitivity to measure changes in the mucosal appearance. Endoscopic remission (minor or no lesions) is defined as a CDEIS score less than or equal to 6 or less than or equal to 7, and complete endoscopic remission (mucosal healing, ie, no lesions at all or scarred lesions only) is defined as a CDEIS score less than or equal to 3 or less than or equal to 4. An endoscopic response is a decrease from baseline CDEIS score of at least 4 or 5 points. The CDEIS has been used in trials of corticosteroids, thiopurines, and TNF antagonists.
      In the MUSIC (Endoscopic Mucosal Improvement in Patients With Active Crohn’s Disease Treated With Certolizumab Pegol) study of certolizumab pegol in Crohn's disease, maintenance of improvement between weeks 10 and 54, based on individual patient data, was found in 70% of those who responded (decline in CDEIS >5) and those with complete remission (CDEIS<3), and in more than 40% of those with remission (CDEIS<6).
      • Hébuterne X.
      • Lémann M.
      • Bouhnik Y.
      • et al.
      Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.
      The SES-CD (Table 6) correlates well with the CDEIS, with a correlation coefficient r = 0.920 and excellent interobserver reliability (k coefficients 0.791–1.000). This score was developed to meet the need for a reliable, easy-to-use endoscopic scoring instrument for Crohn's disease, one that by contrast would be less complex than the CDEIS. Selected endoscopic parameters (ulcer size, ulcerated and affected surfaces, stenosis) were scored from 0 to 3, whereby SES-CD = 0 equates to absence of ulcers.
      • Daperno M.
      • D'Haens G.
      • Van Assche G.
      • et al.
      Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.
      No cutoff values have been determined for the SES-CD, and there is no definition of mucosal healing.
      Table 6Simple Endoscopic Score for Crohn’s Disease
      Adapted from Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004;60:505–12; with permission.
      Variable0123
      Size of ulcers (cm)NoneAphthous ulcers (diameter 0.1–0.5 cm)Large ulcers (diameter 0.5–2 cm)Very large ulcers (diameter >2 cm)
      Ulcerated surface (%)None<1010–30>30
      Affected surface (%)Unaffected segment<5050–75>75
      Presence of narrowingsNoneSingle, can be passedMultiple, can be passedCannot be passed
      Total SES-CD: sum of the values of the 4 variables for the 5 bowel segments. Values are given to each variable and for every examined bowel segment.
      The Rutgeerts Postoperative Endoscopic Index (Table 7) determines the severity of endoscopic disease recurrence at the anastomosis and in the neoterminal ileum after ileocolic resection.
      • Rutgeerts P.
      • Geboes K.
      • Vantrappen G.
      • et al.
      Predictability of the postoperative course of Crohn's disease.
      • Rutgeerts P.
      • Geboes K.
      • Vantrappen G.
      • et al.
      Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery.
      The severity of endoscopic recurrence predicts clinical recurrence, so it has gained popularity.
      • Rutgeerts P.
      • Geboes K.
      • Vantrappen G.
      • et al.
      Predictability of the postoperative course of Crohn's disease.
      In the year after ileocolic resection, patients with a Rutgeerts score of 0 or 1 have a low risk of clinical recurrence (20% at 3 years follow-up) compared with those patients who have a score of grade 3 or 4 (92% at 3 years follow-up). Level 2 is associated with an intermediate risk of clinical recurrence, but the definition of grade 2 is more subjective and is exposed to variability.
      Table 7Rutgeerts Postoperative Endoscopic Index
      Adapted from Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956–63; with permission.
      Distal Ileum
      Grade 0Nil
      Grade 1≤5 Aphthous ulcers
      Grade 2>5 Aphthous ulcers with normal intervening mucosa, or skip areas of larger lesions or lesions confined to the ileocolic anastomosis (ie, <1 cm in length)
      Grade 3Diffuse aphthous ulceration with diffusely inflamed mucosa
      Grade 4Diffuse inflammation with large ulcers, nodules, and/or narrowing
      An endoscopic scoring system for postoperative disease recurrence in Crohn's disease. The original paper uses the term grade rather than level, and as with other tables, the descriptions are precisely those used in the original paper.
      This index has also been incorporated into a randomized clinical trial. In the Post Operative Crohn’s Endoscopic Recurrence study, it was shown that treating according to the risk of recurrence with a 6-month postoperative colonoscopy and treatment step up for those who had a Rutgeerts score ≥i2, is significantly superior to drug therapy alone in preventing postoperative recurrence.
      • De Cruz P.
      • Kamm M.A.
      • Hamilton A.L.
      • et al.
      Optimising post-operative Crohn’s disease management: best drug therapy alone versus colonoscopic monitoring with treatment step-up. The POCER study.

      Summary

      The colonoscopic assessment of mucosal healing has proved increasingly important in the management of both UC and Crohn's disease. All clinicians should strive for this goal. There is evidence for a decrease in corticosteroid use, decreased hospitalization, an increase in sustained remission, and a decrease in the need for surgery. Further advancements with surrogate noninvasive markers for mucosal healing may help to overcome existing limitations and need for colonoscopy. Multiple endoscopic indices exist for UC; however, the only validated index is the UCEIS, and its use in both clinical practice and clinical trials is encouraged. The CDEIS and the SES-CD are both validated for Crohn's disease. The Rutgeerts Postoperative Endoscopic Index is useful for the prediction of postoperative recurrence in those patients who have had an ileocolic resection.

      References

        • Sandborn W.J.
        • Feagan B.G.
        • Hanauer S.B.
        • et al.
        A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with Crohn's disease.
        Gastroenterology. 2002; 122: 512-530
        • D'Haens G.
        • Sandborn W.J.
        • Feagan B.G.
        • et al.
        A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.
        Gastroenterology. 2007; 132: 763-786
        • Neurath M.F.
        • Travis S.P.
        Mucosal healing in inflammatory bowel diseases: a systematic review.
        Gut. 2012; 61: 1619-1635
        • Dave M.
        • Loftus E.V.
        Mucosal healing in inflammatory bowel disease - a true paradigm of success?.
        Gastroenterol Hepatol. 2012; 8: 29-38
        • Walsh A.J.
        • Ghosh A.
        • Brain A.O.
        • et al.
        Comparing disease activity indices in ulcerative colitis.
        J Crohns Colitis. 2014; 8: 318-325
        • D'Haens G.R.
        • Fedorak R.
        • Lémann M.
        • et al.
        End points for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease.
        Inflamm Bowel Dis. 2009; 15: 1599-1604
        • De Cruz P.
        • Kamm M.A.
        • Prideaux L.
        • et al.
        Mucosal healing in Crohn’s disease: a systematic review.
        Inflamm Bowel Dis. 2013; 19: 429-444
        • Frøslie K.F.
        • Jahnsen J.
        • Moum B.A.
        • et al.
        Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort.
        Gastroenterology. 2007; 133: 412-422
        • Ardizzone S.
        • Maconi G.
        • Russo A.
        • et al.
        Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis.
        Gut. 2006; 55: 47-53
        • Rutgeerts P.
        • Diamond R.H.
        • Bala M.
        • et al.
        Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease.
        Gastrointest Endosc. 2006; 63: 433-442
        • Schnitzler F.
        • Fidder H.
        • Ferrante M.
        • et al.
        Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn's disease.
        Inflamm Bowel Dis. 2009; 15: 1295-1301
        • Colombel J.F.
        • Rutgeerts P.
        • Reinisch W.
        • et al.
        Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.
        Gastroenterology. 2011; 141: 1194-1201
        • Rutter M.D.
        • Saunders B.P.
        • Wilkinson K.H.
        • et al.
        Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk.
        Gut. 2004; 53: 1813-1816
        • Rutter M.
        • Saunders B.
        • Wilkinson K.
        • et al.
        Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.
        Gastroenterology. 2004; 126: 451-459
        • Rutgeerts P.
        • Van Assche G.
        • Sandborn W.J.
        • et al.
        Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial.
        Gastroenterology. 2012; 142: 1102-1111.e2
        • De Cruz P.
        • Bernardi M.P.
        • Kamm M.A.
        • et al.
        Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.
        Colorectal Dis. 2013; 15: 187-197
        • Schoepfer A.M.
        • Vavricka S.
        • Zahnd-straumann N.
        • et al.
        Monitoring inflammatory bowel disease activity: clinical activity is judged to be more relevant than endoscopic severity or biomarkers.
        J Crohns Colitis. 2012; 6: 412-418
        • Riley S.A.
        • Mani V.
        • Goodman M.J.
        • et al.
        Microscopic activity in ulcerative colitis: what does it mean?.
        Gut. 1991; 32: 174-178
        • Burger D.C.
        • Thomas S.J.
        • Walsh A.J.
        • et al.
        Depth of remission may not predict outcome of UC over 2 years.
        Gut. 2011; 60: A133
        • Peyrin-Biroulet L.
        • Bressenot A.
        • Kampman W.
        Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.
        Clin Gastroenterol Hepatol. 2013; ([Epub ahead of print])
        • Truelove S.C.
        • Witts L.J.
        Cortisone in ulcerative colitis; final report on a therapeutic trial.
        Br Med J. 1955; 2: 1041-1048
        • Truelove S.C.
        • Richards W.C.
        Biopsy studies in ulcerative colitis.
        Br Med J. 1956; 1: 1315-1318
        • Baron J.H.
        • Connell A.M.
        • Lennard-Jones J.E.
        Variation between observers in describing mucosal appearances in proctocolitis.
        Br Med J. 1964; 1: 89-92
        • Powell-Tuck J.
        • Day D.W.
        • Buckell N.A.
        • et al.
        Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis.
        Dig Dis Sci. 1982; 27: 533-537
        • Sutherland L.R.
        • Martin F.
        • Greer S.
        • et al.
        5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.
        Gastroenterology. 1987; 92: 1894-1898
        • Schroeder K.W.
        • Tremaine W.J.
        • Ilstrup D.M.
        Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.
        N Engl J Med. 1987; 317: 1625-1629
        • Rachmilewitz D.
        Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.
        BMJ. 1989; 298: 82-86
        • Feagan B.G.
        • Greenberg G.R.
        • Wild G.
        • et al.
        Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
        N Engl J Med. 2005; 352: 2499-2507
        • Naganuma M.
        • Ichikawa H.
        • Inoue N.
        • et al.
        Novel endoscopic activity index is useful for choosing treatment in severe active ulcerative colitis patients.
        J Gastroenterol. 2010; 45: 936-943
        • Matts S.G.
        The value of rectal biopsy in the diagnosis of ulcerative colitis.
        Q J Med. 1961; 30: 393-407
        • Travis S.P.
        • Schnell D.
        • Krzeski P.
        • et al.
        Developing an instrument to assess the endoscopic severity of ulcerative colitis: the ulcerative colitis endoscopic index of severity (UCEIS).
        Gut. 2012; 61: 535-542
        • Travis S.P.
        • Schnell D.
        • Krzeski P.
        • et al.
        Reliability and initial validation of the ulcerative colitis endoscopic index of severity.
        Gastroenterology. 2013; 145: 987-995
        • Travis S.P.
        • Higgins P.D.
        • Orchard T.
        • et al.
        Review article: defining remission in ulcerative colitis.
        Aliment Pharmacol Ther. 2011; 34: 113-124
        • D'Haens G.
        • Feagan B.
        • Colombel J.F.
        • et al.
        Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease.
        Gastroenterology. 2012; 143: 1461-1469
        • Kamm M.A.
        • Sandborn W.J.
        • Gassull M.
        • et al.
        Once-daily, high-concentration MMX mesalamine in active ulcerative colitis.
        Gastroenterology. 2007; 132: 66-75
        • Rutgeerts P.
        • Sandborn W.J.
        • Feagan B.G.
        • et al.
        Infliximab for induction and maintenance therapy for ulcerative colitis.
        N Engl J Med. 2005; 353: 2462-2476
        • Thia K.T.
        • Loftus E.V.
        • Pardi D.S.
        • et al.
        Measurement of disease activity in ulcerative colitis: interobserver agreement and predictors of severity.
        Inflamm Bowel Dis. 2011; 17: 1257-1264
        • Pola S.
        • Feagan B.G.
        • Fahmy M.
        • et al.
        Observer agreement and construct validity in central endoscopic assessment of disease activity in ulcerative colitis.
        Gastroenterology. 2013; 144: S-763
        • Corte C.J.
        • Fernandopulle A.N.
        • Catuneanu A.
        • et al.
        Correlation between the ulcerative colitis endoscopic index of severity (UCEIS) and outcomes in acute severe ulcerative colitis.
        Gastroenterology. 2013; 144: S-102
        • Mary J.Y.
        • Modigliani R.
        Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).
        Gut. 1989; 30: 983-989
        • Daperno M.
        • D'Haens G.
        • Van Assche G.
        • et al.
        Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.
        Gastrointest Endosc. 2004; 60: 505-512
        • Rutgeerts P.
        • Geboes K.
        • Vantrappen G.
        • et al.
        Predictability of the postoperative course of Crohn's disease.
        Gastroenterology. 1990; 99: 956-963
        • Hébuterne X.
        • Lémann M.
        • Bouhnik Y.
        • et al.
        Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.
        Gut. 2013; 62: 201-208
        • Rutgeerts P.
        • Geboes K.
        • Vantrappen G.
        • et al.
        Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery.
        Gut. 1984; 25: 665-672
        • De Cruz P.
        • Kamm M.A.
        • Hamilton A.L.
        • et al.
        Optimising post-operative Crohn’s disease management: best drug therapy alone versus colonoscopic monitoring with treatment step-up. The POCER study.
        Gastroenterology. 2013; 144: S-164