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Zeroing in on endoscopic and histologic mucosal healing to reduce the risk of colorectal neoplasia in inflammatory bowel disease

      Abbreviations:

      CRC (colorectal cancer), CRN (colorectal neoplasia), IBD (inflammatory bowel disease), PSC (primary sclerosing cholangitis), UC (ulcerative colitis)
      The past 2 decades have witnessed unprecedented advances in our understanding of the causes and pathogenesis of inflammatory bowel disease (IBD). Taken together with an expanding therapeutic armamentarium, this has emboldened the definitions of disease control, placing greater emphasis on achieving mucosal healing than on clinical remission alone. What can now be achieved through abrogation of immunoinflammatory events such as reduction in disease relapse, hospitalization, surgery, and colorectal neoplasia (CRN) has redefined our perceptions of meaningful disease control.
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
      The disconnect between symptoms and objective measures of disease activity stemmed from post-hoc analyses of clinical trials,
      • Colombel J.-F.
      • Narula N.
      • Peyrin-Biroulet L.
      Management strategies to improve outcomes of patients with inflammatory bowel diseases.
      but resurgent interest in histologic healing suggests that histologic remission may be our new goal in the treat-to-target paradigm.
      • Bryant R.V.
      • Burger D.C.
      • Delo J.
      • et al.
      Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up.
      Adding to our understanding of histologic remission, Flores and colleagues
      • Flores B.M.
      • OʼConnor A.
      • Moss A.C.
      Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis.
      present a timely meta-analysis to reaffirm our suspicions that ongoing colonic inflammation increases the risk of CRN, encompassing dysplasia and cancer in patients with ulcerative colitis (UC).
      Among the well-established risk factors for the development of CRN in IBD, including duration and extent of disease, family history of sporadic colorectal cancer (CRC) and primary sclerosing cholangitis (PSC), colitis-related dysplasia appears to confer the greatest risk. Inflammation is another risk factor and arguably the only potentially modifiable variable.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      Colonic strictures and pseudopolyps, endoscopic findings that reflect prior mucosal inflammation in patients with UC, are also associated with an increased risk of CRN. The risk of CRC is considerable: 2% after 10 years, 8% after 20 years, and 18% after 30 years of colitis,
      • Eaden J.A.
      • Abrams K.R.
      • Mayberry J.F.
      The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
      leading GI societies to advocate for colonoscopic surveillance aimed at the detection of CRN in high-risk patients.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      More unsettling is that CRN in IBD has been identified in areas that appear endoscopically normal but not histologically normal.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      Recent studies, however, suggest a decrease in the risk of CRC: a temporal reduction that may be attributed to aggressive control of inflammation through medications, greater uptake of surveillance colonoscopies allowing detection and resection of dysplastic lesions before the development of CRC, and indeed appropriate timing of colectomy.
      • Choi C.H.
      • Rutter M.D.
      • Askari A.
      • et al.
      Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview.
      • Jess T.
      • Rungoe C.
      • Peyrin-Biroulet L.
      Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies.
      Thus, the risks of persistent inflammation and the benefits of mucosal healing provide an added impetus toward achieving deep remission and optimizing subsequent surveillance strategies for CRN.
      The timing of the first surveillance colonoscopy based on disease duration ranges from 8 to 10 years according to most GI societies.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      • Magro F.
      • Gionchetti P.
      • Eliakim R.
      • et al.
      Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders.
      The guidelines for interval colonoscopies are also quite varied and do not necessarily account for ongoing colitis. The American Society for Gastrointestinal Endoscopy acknowledges that certain risk factors merit annual surveillance, active inflammation being one of them.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      Similarly, the American Gastroenterological Association postulates that patients with active inflammation may benefit from more frequent surveillance but does not offer further guidance.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      The European societies are slightly more nuanced in their risk-stratified approach, recommending interval surveillance based on the degree of inflammation present (a maximum interval of 5 years in low-risk patients vs 3 years in American society guidelines).
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      • Magro F.
      • Gionchetti P.
      • Eliakim R.
      • et al.
      Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders.
      • Cairns S.R.
      • Scholefield J.H.
      • Steele R.J.
      • et al.
      Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).
      • Shergill A.K.
      • Lightdale J.R.
      • Bruining D.H.
      • et al.
      American Society for Gastrointestinal Endoscopy Standards of Practice Committee
      The role of endoscopy in inflammatory bowel disease.
      Nonetheless, in the absence of standardized histologic scoring and reporting, much is left open to interpretation.
      The meta-analysis by Flores and colleagues
      • Flores B.M.
      • OʼConnor A.
      • Moss A.C.
      Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis.
      identified 6 retrospective studies involving 1025 patients with disease for 7 to 20 years; documented histologic inflammation, endoscopic inflammation, or both; and examined the development of CRN. Four studies examined the development of CRN in patients with mucosal inflammation (either endoscopic or histologic) versus patients without inflammation, yielding an odds ratio (OR) of 3.5 (95% confidence interval [CI], 2.6-4.8; P <.001) with little heterogeneity. Because the studies differed in their interpretation of the degree of inflammation, it was considered a dichotomous variable for the purposes of this analysis. Odds ratios were extracted from 5 studies that reported on patients with histologic inflammation only, yielding a pooled OR of 2.6 (95% CI, 1.5-4.5; P < .01). Considering the available literature on the overall risk of CRC across the full spectrum of IBD patients (OR of 1.5 to 2 for CRC in IBD vs the general population
      • Eaden J.A.
      • Abrams K.R.
      • Mayberry J.F.
      The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
      ), the results of this meta-analysis, which predict a higher OR of 2.6 to 3.5 in patients with uncontrolled disease, seem plausible.
      In the absence of previous (and likely future) randomized controlled trials on the risk of CRN in patients with ongoing colonic inflammation, this timely investigation by Flores and colleagues
      • Flores B.M.
      • OʼConnor A.
      • Moss A.C.
      Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis.
      is to be welcomed for its standing in the evidentiary chain. However, the strength of meta-analyses is heavily underscored by the availability of high-quality studies, and such analyses are therefore limited to retrospective cohort and case-control studies, as emphasized by the authors. Disparate use of endoscopic scoring systems and limited availability of histologic information in the era before deep remission, led to the exclusion of most studies. In the opportune instance when such information was documented, variable definitions of histologic inflammation across studies prevented standardization and limited study of a severity-to-risk association. The definition of neoplasia also differed, in addition to ongoing disparity among pathologists, especially in the interpretation of low-grade dysplasia. Other limitations included differing statistical analyses, unadjusted odds ratios for key covariates, and incongruous subjects (for instance, the Nieminen study included both UC and Crohn’s disease patients vs only UC patients in other included studies). The limitations of this meta-analysis primarily reflect a scarcity of available literature on this topic and highlight the need for further research, meanwhile making a compelling case for clinicians and researchers to pause and consider our current paradigms with treating-to-target and its practice-changing implications.
      Although we have indirect data with respect to improved mortality,
      • Choi C.H.
      • Rutter M.D.
      • Askari A.
      • et al.
      Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview.
      • Ananthakrishnan A.N.
      • Cagan A.
      • Cai T.
      • et al.
      Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases.
      endoscopic mucosal healing has been shown to correlate with sustained clinical response and reduces morbidity from meaningful surrogates such as hospitalization, corticosteroid use, surgery, and CRC. Studies are under way to assess the effects of early mucosal healing on disease course in IBD.
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
      Despite the lack of randomized controlled trials, the invasive nature of CRC, and the use of of societal resources, surveillance colonoscopy has been shown to detect CRC at earlier stages and to be cost effective; consequently, it is endorsed by multiple societies.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      • Magro F.
      • Gionchetti P.
      • Eliakim R.
      • et al.
      Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders.
      • Cairns S.R.
      • Scholefield J.H.
      • Steele R.J.
      • et al.
      Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).
      In spite of variance in recommendations of surveillance intervals after a screening colonoscopy, societies universally recommend annual surveillance for patients with the highest risk of IBD-associated CRN, which includes patients with extensive colitis and active endoscopic or histologic inflammation.
      • Farraye F.A.
      • Odze R.D.
      • Eaden J.
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      • Magro F.
      • Gionchetti P.
      • Eliakim R.
      • et al.
      Third European evidence-based consensus on diagnosis and management of ulcerative colitis. part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders.
      • Cairns S.R.
      • Scholefield J.H.
      • Steele R.J.
      • et al.
      Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).
      Colonic inflammation can make pathologic discrimination of dysplasia difficult; thus, surveillance should ideally take place after optimal treatment of underlying inflammation followed by endoscopic re-evaluation, preferably with chromoendoscopy when the patient is in clinical remission.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      Despite the challenges of achieving deep remission and of detecting dysplasia in the presence of inflammation, newer optical techniques will continue to refine (and perhaps even extend) surveillance intervals for colonoscopy. Future studies will also need to adjust for key covariates such as family history of CRC, PSC, smoking status, and perhaps even use of chemopreventive medications.
      The pivotal role played by mucosal healing in driving favorable outcomes in UC is universally acknowledged, but whether this bar should unequivocally be set at histologic healing and if so, at what level, remains to be established. Arguably, the first step is to better define histologic remission and healing in UC. Permeation of disease activity scores into current treatment and surveillance guidelines has real clinical significance for both patients and providers. Modern and evolving definitions of disease control have adopted the treat-to-target approach, involving a composite assessment of clinical symptoms, biomarkers of disease activity, endoscopic activity, and patient-reported outcomes, which are now well integrated in the clinical trial setting but need wider adoption in clinical practice. The use of validated endoscopic scoring systems should provide objectivity, uniformity, and standardization in reporting mucosal appearances, augmenting clinical decision making and ultimately affecting appropriate treatment targets and desirable patient outcomes.
      • Peyrin-Biroulet L.
      • Sandborn W.
      • Sands B.E.
      • et al.
      Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target.
      • Colombel J.-F.
      • Narula N.
      • Peyrin-Biroulet L.
      Management strategies to improve outcomes of patients with inflammatory bowel diseases.
      The meta-analysis by Flores and colleagues
      • Flores B.M.
      • OʼConnor A.
      • Moss A.C.
      Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis.
      raises several important questions, challenging our perceptions regarding mucosal healing and highlighting the need for universal adoption of validated scoring systems internationally. As we “zero in” on endoscopic healing, bolder definitions of disease control along with improved surrogate outcomes (including CRN) will hinge on robust data from well-designed prospective trials using rigorous endpoints. We are now poised to witness the dawn of a new era of collaborative efforts, and as we aim higher, zero may well be the goal.

      Disclosure

      All authors disclosed no financial relationships relevant to this publication.

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