Issue 04

Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editor at the annual national meeting, Mentoring in IBD XVII: The Master Class, held November 4, 2016 in Toronto, Ontario.

Introduction

A central feature of inflammatory bowel disease (IBD) is repeated intestinal epithelial injury with disruption of intestinal barrier function. This allows entry of commensal bacteria into the bowel wall, which activates an adaptive immune response and produces chronic inflammation. As the inflammation of ulcerative colitis (UC) is limited to the mucosa, mucosal healing should be a treatment target. Growing evidence links endoscopic healing with improved outcomes, such as sustained clinical remission; steroid-free remission; and reduced rates of hospitalization, surgery, and colorectal neoplasia. Mucosal healing should be considered a minimum therapeutic goal in the management of transmural Crohn’s disease (CD). Nevertheless, randomized trials have not yet proven the hypothesis that treating to this target leads to better outcomes than treating to resolution of clinical symptoms alone.

Mucosal healing in UC

Improved clinical outcomes

An investigation of the impact of early endoscopic improvement on subsequent clinical outcomes in the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) found that patients treated with infliximab, who had lower endoscopy subscores at 8 weeks, had a reduced risk of colectomy by 54 weeks (P=0.0004) (Figure 1).(1)

A study of 157 patients with newly diagnosed UC was conducted to determine whether early clinical and endoscopic responses to initial corticosteroid therapy predicted later outcomes.(2) Multivariate analysis found lack of mucosal healing at 3 months to be correlated with increased 5-year rates of hospitalization (P=0.0029) and colectomy (P=0.0268).

A case-control study of patients with long-standing extensive UC assessed risk factors for neoplasia in cases (n=68) compared with controls from the same surveillance population (n=136).(3) Multivariate analysis found increased histologic inflammation scores to be an independent predictor of neoplasia (P<0.001).

Despite these suggestive data, none of these studies provides causal proof that treating to a target of mucosal healing is better than treating to clinical remission.(1–3)

Clinical vs. endoscopic or histologic remission

A study to determine the association between patient-reported symptoms and endoscopic and histologic inflammation used patient data (N=103) from a multicentre observational study in UC.(4) Fecal calprotectin (FCP) was also measured. Lack of inflammation on endoscopy was associated with the absence of rectal bleeding and with lower FCP levels but not with complete normalization of stool frequency. Furthermore, histologic remission was not associated with symptom reduction. These data suggest non-inflammatory pathways may contribute to residual symptoms in UC.

Mucosal healing in CD

Improved clinical outcomes

A randomized, double-blind, placebo-controlled trial, Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing (EXTEND), evaluated maintenance of mucosal healing in endoscopically documented moderate-to-severe ileocolonic CD (N=135) after adalimumab induction.(5) Rates of mucosal healing were 24% for adalimumab and 0% for placebo (P<0.001) at 52 weeks.

A study to determine whether mucosal healing predicts a better outcome enrolled 133 treatment-naïve patients with CD.(6) Patients were randomized to either 3 infusions of infliximab plus azathioprine or conventional corticosteroid therapy. The azathioprine group received infliximab for relapses. The corticosteroid group received azathioprine for corticosteroid dependency and infliximab only in the event of azathioprine failure. At 2 years, ileocolonoscopy assessed disease in a representative subset of 49 patients. Complete mucosal healing at 2 years predicted sustained, corticosteroid-free remission at 3 and 4 years, with 15 of 17 patients who demonstrated mucosal healing at 2 years continuing in remission without additional infliximab therapy at 3 and 4 years (P=0.032).

The Inflammatory Bowel Disease in Southeastern Norway (IBSEN) study, a prospective population-based cohort, followed 843 patients with newly diagnosed IBD at 1, 5, and 10 years to identify potential prognostic factors for the development of complications.(7) For the 237 patients diagnosed with CD, the cumulative relapse rate over 10 years was 90% (95% confidence interval [CI] 86–94%), and the cumulative probability of surgery was 37.9% (95% CI 31.4–44.4%). Independent risk factors for surgery were terminal ileal disease (P<0.001), strictures (P=0.004), penetrating disease (P<0.001), and age <40 years (P=0.03) at diagnosis.

Lesion severity and prognosis

A study to determine whether greater lesion severity predicted increased rates of penetrating complications and colectomy enrolled 102 patients with CD, of whom 53 had severe endoscopic lesions (extensive and deep ulcerations, >10% of the mucosal area, ≥1 colonic segment) at index colonoscopy.(8) The risk of resection (n=37) during a median 52-month follow-up was independently predicted by severe endoscopic lesions at index colonoscopy (relative risk [RR] 5.43, 95% CI 2.64–11.18), Crohn’s Disease Activity Index >288 (RR 2.21; 95% CI 1.09–4.47), and no immunosuppressive therapy during the follow-up (RR 2.44; 95% CI 1.20 –5.00). All patients (n=6) with penetrating complications had severe endoscopic lesions at index colonoscopy.

A prospective cohort study of 89 patients, who had undergone ileal resection for CD, assessed the natural history of early postoperative recurrence.(9) Within 1 year, the endoscopic recurrence rate was 73% in the neoterminal ileum, and the symptomatic recurrence rate was 20%. At 3 years, the endoscopic recurrence rate was 85%, and the symptomatic recurrence rate was 34%. Endoscopic severity of early postoperative lesions best predicted the disease course. Even when patients were stratified by preoperative disease activity, postoperative endoscopic lesion severity remained a strong predictor of symptomatic recurrence.

Relapse prediction after TNF-α inhibitor withdrawal

Stop Infliximab in Patients with Crohn’s Disease (STORI) prospectively studied infliximab discontinuation in 115 patients treated with infliximab plus an immunosuppressant for ≥1 year, who were in stable corticosteroid-free remission for >6 months.(10) The 1-year relapse rate was 43.9% ± 5.0%. Multivariate analysis found risk factors for relapse were male sex, absence of surgical resection, leukocyte counts >6.0×10⁹/L, hemoglobin ≤145 g/L, C-reactive protein (CRP) ≥5.0 mg/L, and FCP ≥300 μg/g. Patients with ≤2 risk factors has a 15% risk of relapse within 1 year.

These studies indicate that the presence of mucosal healing is associated with better outcomes in CD and that increasing severity of inflammation is associated with worse outcomes.

Treat-to-target recommendations

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program developed consensus recommendations for composite treatment targets for UC and CD.(11) The objective targets are endoscopic remission, although no consensus yet exists on the precise definition of this target.

UC treatment target

STRIDE defined the treatment target for UC as follows:(11)

• Clinical and patient-reported remission: resolution of rectal bleeding and diarrhea or altered bowel habit (assessed at least every 3 months until resolution, then every 6 to 12 months), plus
• Endoscopic remission: Mayo endoscopic subscore of 0 or 1 (assessed 3 to 6 months after starting therapy in symptomatic patients and then at least every 3 months during active disease).

CD treatment target

STRIDE defined the treatment target for CD as follows:(11)

• Clinical and patient-reported remission: resolution of abdominal pain and diarrhea or altered bowel habit (assessed at least every 3 months until resolution, then every 6 to 12 months), plus
• Endoscopic remission: resolution of ulceration at ileocolonoscopy, or resolution of inflammation on cross-sectional imaging, in patients who could not be assessed adequately by ileocolonoscopy (assessed at least every 6 to 9 months during active disease).

Endoscopic scoring systems

Routine use of an appropriate endoscopic scoring system improves assessment and standardization of disease extent and severity. If scoring systems are not used, then it is important to describe the following for each endoscopy, including details for each bowel segment:

• Perineum
• Inflammation: location, extent (% surface area)
• Bowel involvement: continuous or patchy
• Erythema
• Loss of vascularity
• Bleeding: spontaneous or contact
• Erosions or ulcerations: superficial or deep
• Strictures or fistulas
• Overall impression

Mayo endoscopic subscore

The Mayo endoscopic subscore can differentiate between superficial and deep ulcers, which can have prognostic value, but it does not quantify the extent of disease.(12)

Ulcerative Colitis Endoscopic Index of Severity

The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores the vascular pattern, bleeding, and erosions and ulcers.(13) The UCEIS has been validated and found to show satisfactory intra-investigator and inter-investigator reliability. The presence of bleeding discriminates between levels of disease severity.

Crohn’s Disease Endoscopic Index of Severity

The Crohn’s Disease Endoscopic Index of Severity (CDEIS) is a numerical grading system (0–44) that scores CD activity (including specific lesion types and disease extent) in each of the terminal ileum, right colon, transverse colon, left colon and sigmoid, and rectum).(14) As this complicated and time-consuming scoring system requires training and expertise in estimating the extent of disease and depth of ulcers, the CDEIS is used mainly in clinical trials.

Simple Endoscopic Score for Crohn’s Disease

The Simple Endoscopic Score for Crohn’s Disease (SES-CD) is a numerical grading system (0–56) that scores ulcer size, ulcerated surface, affected surface, and presence of narrowing in each of the ileum, right colon, transverse colon, left colon, and rectum on a scale of 0 to 3.(15) The SES-CD is a simple, reproducible, and easy-to-use scoring system that has been validated and found to have excellent inter-observer agreement and a strong correlation with the CDEIS.

Rutgeerts Postoperative Endoscopic Index for Crohn’s disease

Endoscopic severity of early postoperative disease recurrence best predicts the postoperative disease course. The Rutgeerts index scores postoperative lesions from i0 (no lesions) to i4 (diffuse inflammation with large ulcers, nodules, and/or narrowing).(9)

Histologic remission

Endoscopy allows visualization of the mucosa, but histology adds information about the submucosa, muscularis propria, subserosa, and serosa. Ultrasound and cross-sectional imaging can provide additional information about inflammation in the entire bowel wall.

A prospective study to determine predictors of clinical relapse followed 74 patients with clinically and endoscopically inactive UC for 1 year or until relapse.(16) Rectal biopsies were obtained at baseline, 6 and 12 months, and/or at relapse. Among the 27 patients who relapsed, multivariate analysis found younger age (P=0.003) female sex with >5 prior relapses (P <0.001) and basal plasmacytosis on rectal biopsy specimens (P=0.003) predicted shorter time to clinical relapse.

A study to determine the impact of endoscopic and histologic remission in UC followed 91 patients for a median 72 months.(17) Concordance between endoscopic and histological remission was only moderate (κ=0.56, 95% CI 0.36 to 0.77), and 24% of patients with endoscopic remission had persistent inflammation. Histologic remission better predicted a decreased need for corticosteroids (P=0.02) and acute severe colitis requiring hospitalization (P=0.02) than did endoscopic remission.

These results indicate that histologic remission and mucosal healing in UC are distinct treatment targets and that histologic remission may better identify complete remission.

Ability to achieve mucosal healing

In clinical practice today, the ability to achieve mucosal healing varies with the disease and with the agent used.(18–27)

Surrogates for endoscopic disease activity

A database review of 19 eligible studies evaluating the diagnostic accuracy of CRP, FCP, and lactoferrin compared with endoscopy in patients with clinically active IBD found that these biomarkers, although useful, have limitations as surrogates for endoscopic disease activity.(28) The utility of CRP varies between CD and UC, and about 20% of patients do not have increased CRP with inflammation. In addition, results are confounded by age, sex, and body mass index. The utility of FCP is limited by unclear cut-off values, intra-individual variation, and lack of assay standardization. In addition, higher levels are normally seen in the colon compared with the ileum. CRP and FCP are most useful when baseline levels are correlated with endoscopy and serial measurements are used. The use of lactoferrin is limited by unclear cut-off values and the instability of lactoferrin at room temperature.

Conclusion

Mucosal healing is an important treatment target, as it is linked to lower rates of hospitalization and relapse in IBD, lower risk of colorectal cancer in UC, and lower rates of bowel damage in CD. Mucosal healing can be achieved by stratifying patients by risk level, initiating appropriate therapy, and monitoring routinely (Figure 3). Histologic remission is an emerging treatment target. Prospective trials validating these treatment targets are awaited.

Clinical case

Case presentation

After a consultation that included a panel of laboratory tests and a full colonoscopy with mapping biopsies, you start induction therapy in a 22-year-old female with UC.

Commentary

Appropriate baseline tests, at a minimum, are complete blood count, iron, ferritin, CRP, and FCP to define baseline inflammation and allow comparison at the induction therapy review at 12 to 16 weeks. An early drop in CRP is a positive indicator of response to a tumour necrosis factor-α (TNF-α) inhibitor. High pretreatment hemoglobin may also predict a better TNF-α inhibitor response. Adequate levels of albumin are necessary for optimal drug pharmacokinetics, and measurement of albumin at baseline may predict biologic pharmacokinetics. FCP is a reliable indicator of inflammation, and early reduction of this biomarker predicts clinical and endoscopic remission.

Use of biologics in UC is associated with high rates of primary (20–40%) nonresponse. Primary nonresponse to biologic therapy is rarely related to subtherapeutic drug levels, except in cases of acute severe colitis and fecal loss of drug or in cases with accelerated formation of antidrug antibodies. Predictors of response include greater disease severity, younger age, shorter disease duration, more extensive colitis, elevated CRP, normal hemoglobin and albumin, and elevated FCP. A determination of nonresponse at assessment requires adequate trough levels (>15 µg/mL), lack of improvement in inflammatory markers, and no evidence of infection.

Case evolution

Your patient goes into full clinical (as determined by the partial Mayo score you conduct at each visit) and biochemical (normal laboratory tests) remission on induction therapy. She now enters the maintenance phase of IBD therapy.

Commentary

Inflammatory markers should be measured and clinical assessment conducted at 6 and 12 months. Endoscopy should be performed between 6 and 12 months to confirm mucosal healing. In UC, FCP correlates well with response to induction and mucosal healing and predicts loss of response to maintenance. Failure of normalization with therapy should prompt additional endoscopic evaluation.

The primary goal in IBD treatment is to maximize long-term health-related quality of life through control of symptoms, prevention of structural damage, normalization of function, and participation in social and work-related activities. Symptoms affecting quality of life must be addressed and treatment goals tailored to the individual patient. Objective measures, such as endoscopic findings, are a critical part of comprehensive disease assessment and effective disease management in the treat-to-target strategy.

Case evolution

As part of your protocol for objective monitoring IBD therapy you perform a colonoscopy.

Commentary

Endoscopy should be performed within 12 months to confirm mucosal healing. Performing endoscopy too early can lead to false-positive results. When colonoscopy is not feasible due to stenosis or severe comorbidities, cross-sectional imaging can assess complications of UC and colonic disease.(29) Magnetic resonance imaging and bowel ultrasonography have good sensitivity for assessing luminal disease activity and are the most useful approaches in this situation. The treat-to-target concept rests on achieving mucosal healing. In UC, endoscopic remission is defined as a Mayo endoscopic subscore of 0 or 1.

References

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Editor-in-Chief

John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University, Hamilton, ON

Co-Editor-in-Chief

Richard N. Fedorak, MD FRCPC FRCP (London) FRCP (Edinburgh) FRCS, Dean, Faculty of Medicine and Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB

Contributing Editor

Vipul Jairath, BSc MBChB PhD MRCP (UK), Associate Professor of Medicine, Epidemiology and Biostatistics, Division of Gastroenterology, University of Western Ontario, London Health Sciences Centre, London, ON

Mentoring in IBD Curriculum Steering Committee

Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, ON
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON

IBD Dialogue 2017·Volume 13 is made possible by unrestricted educational grants from

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(c) Catrile & Associates Ltd., 2017. All rights reserved. None of the contents may be reproduced in any form without prior written permission from the publisher. The opinions expressed in this paper are those of the authors and do not necessarily reflect the opinions or recommendations of the sponsors, the grantor, or the publisher.