Diagnostics and Prognostics in IBD Dig Dis 2013;31:351–356 DOI: 10.1159/000354691
Endoscopy as a Prognostic Marker in Inflammatory Bowel Disease Marine Camus a, b Benjamin Pariente a, c Xavier Dray a, b Matthieu Allez a, c Philippe Marteau a, b c
University Paris Diderot, Sorbonne Paris Cité, b APHP, Gastroenterology Unit, Hôpital Lariboisière, and APHP, Gastroenterology Unit, Hôpital Saint Louis, Paris, France
Key Words Inflammatory bowel disease · Crohn’s disease · Ulcerative colitis · Prognosis · Endoscopy
Abstract In patients suffering from reflux esophagitis, the severity of the lesions helps to predict the prognosis and adapt treatment. We herein review the data which suggest that endoscopy also has a prognostic value in inflammatory bowel disease. In the 1990s, the general opinion, based on a few studies, was that assessing endoscopic lesions was not critical for the management of inflammatory bowel disease. The more recent therapeutic strategies using less steroids but purine analogs and anti-TNF antibodies have led to a higher chance of mucosal healing (MH), and there is growing evidence that reaching healing of lesions is of good prognostic value both in ulcerative colitis and Crohn’s disease. There is a lower risk of hospitalization and of surgery in patients with MH than in those without healing. There is also a (moderately) lower risk of relapse after stopping treatments in patients with MH than in those with persistent lesions. The risk of cancer (on a long-term basis) also seems be lower in patients with controlled inflammatory lesions than in subjects with persistent
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0351$38.00/0 E-Mail [email protected] www.karger.com/ddi
inflammation. There are still many unanswered questions, the major one being what is the best treatment choice when MH is not reached? © 2013 S. Karger AG, Basel
Introduction
In patients suffering from duodenal ulcers or reflux esophagitis, the type and persistence of mucosal lesions help in predicting the prognosis. The guidelines of management of reflux esophagitis recommend taking into account the type of lesions to adjust the dose and duration of proton pump inhibitors and the need or not for a control of their healing [1]. We herein critically review the data which suggest that endoscopic lesions, their extent and their fate also have a prognostic value in inflammatory bowel disease (IBD). Studies have established elementary lesions observed in subjects with Crohn’s disease (CD) and ulcerative colitis (UC), which of them are recognized with a reasonable interobserver agreement and which are associated with overall severity evaluated by experts [2–5]. At the present time, severity of CD takes into account the extent of lesions in the gastrointestinal Philippe Marteau, MD, PhD Gastroenterology Unit, Lariboisière Hospital 2, rue A.-Paré FR–75010 Paris (France) E-Mail philippe.marteau @ lrb.aphp.fr
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a
Extent of Lesions
Endoscopy allows assessing the extent of disease more precisely than clinical examination and radiological techniques. Histology may show persistent inflammation in some cases considered as in clinical and endoscopic remission. The question whether the clinician should consider macro- or microscopy when deciding to adapt treatment should be answered in future prospective trials. Endoscopic scores of severity take into account the extent of the lesions in CD [2, 3] but not in UC [4, 5]. Ulcerative Colitis Extensive colitis carries a higher risk of severe episodes and colon cancer than distal colitis or proctitis [12, 13]. In the IBSEN cohort, extensive colitis at diagnosis was significantly associated with a higher chance of mucosal 352
Dig Dis 2013;31:351–356 DOI: 10.1159/000354691
healing (MH) at 1 year (in comparison to more distal UC). This may be due to a different disease behavior (with more resistant forms in cases of distal colitis) and/or to a different treatment strategy (with a more aggressive treatment in extensive disease) [14]. Periappendiceal lesions sometimes observed in subjects with distal UC may be associated with a more responsive course of disease and a higher risk of pouchitis after ileal pouch anastomosis, but this needs to be confirmed [15]. The presence of backwash ileitis had in some studies a prognostic value for a higher risk of colon cancer, and further development of pouchitis in case of pouch-anal anastomosis [12]. Crohn’s Disease The extent of the lesions and ulcerations are taken into account in the calculation of the CDEIS and in the SESCD. They are evaluated in the ileum and 4 colonic segments and the total score considers the sum of 5 subscores obtained in and in each of those segments. In the CDEIS, evaluation uses a visual analog scale graduated in centimeters (continuous variable from 0 to 10), while in the SES-CD, evaluation is made in 4 groups (for lesions: no lesion give 0 point, lesions affecting less than 50% of the surface of the evaluated segment give 1 point, lesions extending between 50 and 75% of the surface of the segment give 2 points, and more extensive lesions give 3 points) [2, 3]. Results obtained with those scoring systems are well correlated [3, 16].
Severity of Lesions
Ulcerative Colitis Severe lesions are inconstantly observed in patients with severe UC (diagnosis classically made on the basis of Truelove and Witts’ clinical and biological signs [10, 12]. Those which proved to be well correlated with pathology findings on the colectomy specimen include deep and extensive ulcers appearing as deeps ulcers, mucosal detachment or well-like ulcerations [10]. In a retrospective study of 85 patients, such lesions were associated with a higher failure of intensive intravenous treatment (RR 2.32, 95% CI 1.23 ± 4.39) [17]. This was also observed in a series of 118 patients treated with cyclosporine [18] in which the presence of severe endoscopic lesions was an independent predictive factor of colectomy (2.38, 1.80–3.14), 71% of the patients with severe endoscopic lesions requiring colectomy versus 17% of the patients without severe endoscopic lesions (p < 0.001).
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tract, while for UC only the most severe lesions are considered and the extent of the disease is not part of the endoscopy severity indices [2–5]. In CD, lesions with an acceptable interobserver agreement include ulcerated and non-ulcerated stenosis, deep ulceration, superficial ulceration, aphthoid ulceration, frankly swollen mucosa, frank erythema, healed ulceration and pseudopolyp [6]. The Crohn’s Disease Endoscopic Index of Severity (CDEIS) was built taking into account deep and superficial ulcers, the extent of ulceration, the extent of any lesions and stenosis [2]. It was further validated on an independent series of endoscopies [2] and used in clinical trials as secondary or primary endpoint [7]. Assessment of the extent of lesions and ulceration using a visual analog scale is considered difficult by some clinicians and this led to build another index, the SES-CD, which does not precisely measure surfaces but quotes them in groups [3]. In UC, lesions with a good interobserver agreement include changes in the mucosal vascular pattern, hemorrhage and erosion-ulceration [4, 5]. Interestingly, mucosal friability which was previously and since the Baron score considered a major sign of UC was recently shown to be insufficiently reproducible even after attempts to standardize it [4, 5]. Several scores were proposed and used in clinical trials. The most used at the present time is the Mayo score [8], but the most precisely studied concerning interobserver variability is the recently developed UCEIS [4, 9]. Severe lesions of UC and CD that correlated with lesions seen on surgical specimens were the presence of deep and extensive ulcers which could appear as deeps ulcers, mucosal detachment or well-like ulcerations [10, 11].
Mucosal Healing and Its Prognostic Value
Several drug regimens have been shown to induce significant MH, especially when prescribed early in the course of the disease [20]. This is why some studies are focusing on early disease and why mixing patients with early disease and advanced disease probably leads to heterogeneity. Ulcerative Colitis In UC, MH has been considered a relevant therapeutic goal for a long time, but it was not chosen as a primary endpoint of randomized trials until recently. It was also often not well defined and indices were validated only in the last years. Microscopic changes, especially basal plasmacytosis, can persist despite apparent resolution of symptoms and MH [21, 22] so that the question remains open whether endoscopic remission or histologic remission should be chosen as target for clinical trials and daily practice. In the IBSEN cohort of 513 patients with incidental cases of UC who were followed in Norway in the early 1990s (before the immunosuppressant era), MH 1 year after diagnosis was significantly associated with a lower risk of colectomy over the next 5 years (2 vs. 7%) [14]. In the study by Ardizzone et al. [23], who considered the first course of corticosteroids for newly diagnosed UC, lack of early MH was associated with negative outcomes Endoscopy as Prognostic Marker
at 5 years. In a post hoc analysis of the ACT1/2 trials [24] which compared infliximab to placebo, infliximab-treated patients with a Mayo endoscopy subscore of 0 or 1 at week 8 had a significantly lower risk of colectomy over the next year, compared to patients with a Mayo score of 3 or 4, as well as a better chance of clinical remission and a lower rate of steroid use. Noticeably, a difference was observed between Mayo Clinic endoscopy subscores of 0 and 1 with regard to symptoms and steroid dependency (not colectomy): an endoscopy subscore of 0 at week 8 predicted symptom relief at weeks 30 and 54 in 71 and 74%, respectively, compared to 51 and 47% for a score of 1 at week 8. Laharie et al. [25] recently analyzed retrospectively the outcome of 63 adult patients with refractory UC receiving maintenance treatment with infliximab in five French referral centers. Colectomy-free survival rates at 12, 24 and 36 months were respectively 100, 96 and 96% in the 30 patients with MH versus 80, 65 and 65% in patients without MH (p = 0.004). By multivariate analysis, MH was the only factor associated with colectomy-free survival, with an odds ratio of 18 (95% CI 1.6– 205) [25]. There seems to be a correlation between the absence of MH and the colon cancer risk. Persistent pseudopolyps or inflammatory lesions were independently associated with the risk of colorectal neoplasia during surveillance in the St Mark’s cohort [26]. In the CESAME cohort, the risk of colorectal cancer was lower among patients receiving thiopurines than in those who never received this treatment [13]. This suggests that a good anti-inflammatory therapy might reduce the risk of neoplasia. This has not been studied in prospective randomized clinical trials, but these are probably impossible to perform as they would need very large numbers of subjects and as the control group without treatment is not ethical. Crohn’s Disease MH in CD seems to have an inconstant prognostic value to predict relapse or complications in literature. A GETAID study reported no correlation between MH and clinical relapse rates in the following 18 months in corticosteroid-treated CD patients, and this argued in favor of a purely symptom-oriented approach to CD in the 1990s [27]. In the IBSEN cohort, 227 subjects with incident cases of CD were followed [14]. At 1 year, MH was observed in 38% of cases and there was a lower chance of MH when patients were treated with steroids than with other drugs (which at that time did not include anti-TNF). In this study, MH at 1 year was associated with a lower chance of Dig Dis 2013;31:351–356 DOI: 10.1159/000354691
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Crohn’s Disease Nahon et al. [11] showed that the depth and extent of ulcerations at colonoscopy for CD were in agreement with pathological findings at colectomy specimen examination. Allez et al. [19] followed for a median time of 52 months a series of 102 patients with colonic CD who were retrospectively stratified as having severe endoscopic lesions or moderate endoscopic lesions. Severe lesions were defined as large coalescent and deep ulcerations covering more than 10% of the mucosal area of at least one segment of the rectocolon. Such severe lesions were observed in half of the study population. During follow-up, 37 patients underwent colonic resection and the risk of colectomy was significantly and independently affected by the presence of severe lesions (RR 5.42, 95% CI 22.64–11.18), a high clinical disease activity index (CDAI) and the absence of immunosuppressants. The probabilities of colectomy at 1, 3 and 8 years were respectively 31, 42 and 62% in the severe lesion group versus 6, 8 and 18% for the moderate lesion group.
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Dig Dis 2013;31:351–356 DOI: 10.1159/000354691
a complete but complex multivariable predictive model and not retained in a simplified model which also discarded infliximab trough levels [33].
Postoperative Recurrence of Lesions in CD and Fortuitous Discovery of Asymptomatic Lesions of CD and Their Prognostic Value
Rutgeerts et al. [34] showed that the postoperative recurrence of symptoms of ileal CD differed between groups of patients depending on the nature of lesions seen on the anastomosis and above some months after ileal resection. A strategy of treatment escalation based on the lesions has recently been shown to be superior to optimal drug therapy alone in preventing postoperative recurrence [35]. Along with this, Baudry et al. [36] have recently reported that tailored treatment according to the lesions significantly reduced clinical recurrence after surgery. Performing ileocolonoscopy during the year following ileal resection for CD is recommended in order to approach prognosis and adapt treatment to the lesions [37]. A recent study showed that subjects with a fortuitous diagnosis of CD during endoscopy performed for other purposes (screening for example) have a high risk of developing clinical symptoms [38]. This risk was shown to be equal in this series of 40 patients to the risk of patients who develop lesions after surgery. If confirmed, this would argue for treating asymptomatic patients and this should now be studied prospectively in larger groups.
Conclusion
There is a tendency to now consider endoscopy endpoints to adapt treatment in various situations of IBD. However, the supporting evidence remains limited. Unanswered questions and unmet needs for the clinician include more universal and strict definitions of MH, agreement on the diagnosis of elementary lesions and teaching how to use scores to decrease interobserver variation. In this aspect, central reading of endoscopies is being more and more used in clinical trials [39] but may change the result of studies from what they would have been in reallife conditions (i.e. with standard clinician evaluating lesions and taking decisions on their observations). In addition, if strategies to manage situations of IBD were only established on the basis of results from such studies, there would be a risk that the therapeutic decisions made by the usual specialist may significantly differ with the opinion Camus /Pariente /Dray /Allez /Marteau
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being still on steroids at 5 years but was not predictive of (associated with) clinical relapse in the next 5 years, disease extension, and disease complications [14]. A type 2 error is possible considering the relatively low number of subjects in the study; however, one must keep in mind that this is still the best evidence in literature before antiTNF agents and that this study did not disclose a prognostic value of MH. Several studies suggested that when an anti-TNF treatment achieves MH, this is associated with a better prognosis. In a retrospective study of 183 patients, Schnitzler et al. [28] found that MH during maintenance infliximab treatment was associated with a lower risk of surgery. In the ACCENT I endoscopic substudy, none of the patients with MH at weeks 10 and 54 needed hospitalization, compared to 4/16 (25%) patients with MH at only one of these time points and 34/74 (46%) of the subjects without MH at both time points [29]. The follow-up of a subset of 49 patients in the ‘step-up/top-down’ study showed that those patients who achieved complete MH at 2 years (absence of ulcers, SES-CD = 0) had significantly higher rates of clinical remission, steroid-free remission, and steroidfree remission without flare through years 3 and 4 [30]. MH also predicted a higher chance of long-term clinical benefits in adalimumab-treated patients [31]. The persistence of endoscopic lesions versus MH has also been studied as a prognostic variable to predict relapse in patients stopping treatments while in remission. Lémann et al. [32] performed a double-blind, withdrawal study in 83 patients in clinical remission on azathioprine for ≥42 months and who were randomized to continue azathioprine or to receive a placebo for 18 months. CDEIS level was low in the 45 patients who had a colonoscopy at baseline and 36% of them had CDEIS 0 (absence of any lesion). The presence of endoscopic lesions or of ulcerations was not predictive of relapse. In their prospective STORI trial, Louis et al. [33] looked for factors predicting the risk of relapse in patients who stopped long-term scheduled infliximab therapy. To be included, subjects had to be treated for at least 1 year with scheduled infliximab and azathioprine, and be in corticosteroid-free remission for at least 6 months. After a median follow-up of 28 months following infliximab cessation, half of them had experienced a relapse, and multivariate analysis showed that absence of MH was one of the risk factors for relapse. The hazard ratio estimate of an association between time of relapse and a CDEIS >0 was 2.3 (95% CI 1.1–4.9; p = 0.04). This suggests that patients with persistent endoscopic lesions should probably not stop antiTNF treatments. Endoscopy assessment was included in
of the central reader. We and others are currently trying to develop more objective measures of some lesions using optoelectronic tools. Prospective studies evaluating decision-making based on endoscopic assessment started in the postoperative period of CD should now be performed in all IBD situations.
Disclosure Statement M. Allez: consultancies or honorarium for lectures from Abbvie, MSD, Ferring, Novo Nordisk, GSK, and P. Marteau: consultancies or honorarium for lectures from Abbvie, Ferring, MSD. The other authors have no conflicts of interest to disclose.
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Endoscopy as Prognostic Marker
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Endoscopy as a Prognostic Marker in Inflammatory Bowel Disease Marine Camus a, b Benjamin Pariente a, c Xavier Dray a, b Matthieu Allez a, c Philippe Marteau a, b c
University Paris Diderot, Sorbonne Paris Cité, b APHP, Gastroenterology Unit, Hôpital Lariboisière, and APHP, Gastroenterology Unit, Hôpital Saint Louis, Paris, France
Key Words Inflammatory bowel disease · Crohn’s disease · Ulcerative colitis · Prognosis · Endoscopy
Abstract In patients suffering from reflux esophagitis, the severity of the lesions helps to predict the prognosis and adapt treatment. We herein review the data which suggest that endoscopy also has a prognostic value in inflammatory bowel disease. In the 1990s, the general opinion, based on a few studies, was that assessing endoscopic lesions was not critical for the management of inflammatory bowel disease. The more recent therapeutic strategies using less steroids but purine analogs and anti-TNF antibodies have led to a higher chance of mucosal healing (MH), and there is growing evidence that reaching healing of lesions is of good prognostic value both in ulcerative colitis and Crohn’s disease. There is a lower risk of hospitalization and of surgery in patients with MH than in those without healing. There is also a (moderately) lower risk of relapse after stopping treatments in patients with MH than in those with persistent lesions. The risk of cancer (on a long-term basis) also seems be lower in patients with controlled inflammatory lesions than in subjects with persistent
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0351$38.00/0 E-Mail [email protected] www.karger.com/ddi
inflammation. There are still many unanswered questions, the major one being what is the best treatment choice when MH is not reached? © 2013 S. Karger AG, Basel
Introduction
In patients suffering from duodenal ulcers or reflux esophagitis, the type and persistence of mucosal lesions help in predicting the prognosis. The guidelines of management of reflux esophagitis recommend taking into account the type of lesions to adjust the dose and duration of proton pump inhibitors and the need or not for a control of their healing [1]. We herein critically review the data which suggest that endoscopic lesions, their extent and their fate also have a prognostic value in inflammatory bowel disease (IBD). Studies have established elementary lesions observed in subjects with Crohn’s disease (CD) and ulcerative colitis (UC), which of them are recognized with a reasonable interobserver agreement and which are associated with overall severity evaluated by experts [2–5]. At the present time, severity of CD takes into account the extent of lesions in the gastrointestinal Philippe Marteau, MD, PhD Gastroenterology Unit, Lariboisière Hospital 2, rue A.-Paré FR–75010 Paris (France) E-Mail philippe.marteau @ lrb.aphp.fr
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a
Extent of Lesions
Endoscopy allows assessing the extent of disease more precisely than clinical examination and radiological techniques. Histology may show persistent inflammation in some cases considered as in clinical and endoscopic remission. The question whether the clinician should consider macro- or microscopy when deciding to adapt treatment should be answered in future prospective trials. Endoscopic scores of severity take into account the extent of the lesions in CD [2, 3] but not in UC [4, 5]. Ulcerative Colitis Extensive colitis carries a higher risk of severe episodes and colon cancer than distal colitis or proctitis [12, 13]. In the IBSEN cohort, extensive colitis at diagnosis was significantly associated with a higher chance of mucosal 352
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healing (MH) at 1 year (in comparison to more distal UC). This may be due to a different disease behavior (with more resistant forms in cases of distal colitis) and/or to a different treatment strategy (with a more aggressive treatment in extensive disease) [14]. Periappendiceal lesions sometimes observed in subjects with distal UC may be associated with a more responsive course of disease and a higher risk of pouchitis after ileal pouch anastomosis, but this needs to be confirmed [15]. The presence of backwash ileitis had in some studies a prognostic value for a higher risk of colon cancer, and further development of pouchitis in case of pouch-anal anastomosis [12]. Crohn’s Disease The extent of the lesions and ulcerations are taken into account in the calculation of the CDEIS and in the SESCD. They are evaluated in the ileum and 4 colonic segments and the total score considers the sum of 5 subscores obtained in and in each of those segments. In the CDEIS, evaluation uses a visual analog scale graduated in centimeters (continuous variable from 0 to 10), while in the SES-CD, evaluation is made in 4 groups (for lesions: no lesion give 0 point, lesions affecting less than 50% of the surface of the evaluated segment give 1 point, lesions extending between 50 and 75% of the surface of the segment give 2 points, and more extensive lesions give 3 points) [2, 3]. Results obtained with those scoring systems are well correlated [3, 16].
Severity of Lesions
Ulcerative Colitis Severe lesions are inconstantly observed in patients with severe UC (diagnosis classically made on the basis of Truelove and Witts’ clinical and biological signs [10, 12]. Those which proved to be well correlated with pathology findings on the colectomy specimen include deep and extensive ulcers appearing as deeps ulcers, mucosal detachment or well-like ulcerations [10]. In a retrospective study of 85 patients, such lesions were associated with a higher failure of intensive intravenous treatment (RR 2.32, 95% CI 1.23 ± 4.39) [17]. This was also observed in a series of 118 patients treated with cyclosporine [18] in which the presence of severe endoscopic lesions was an independent predictive factor of colectomy (2.38, 1.80–3.14), 71% of the patients with severe endoscopic lesions requiring colectomy versus 17% of the patients without severe endoscopic lesions (p < 0.001).
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tract, while for UC only the most severe lesions are considered and the extent of the disease is not part of the endoscopy severity indices [2–5]. In CD, lesions with an acceptable interobserver agreement include ulcerated and non-ulcerated stenosis, deep ulceration, superficial ulceration, aphthoid ulceration, frankly swollen mucosa, frank erythema, healed ulceration and pseudopolyp [6]. The Crohn’s Disease Endoscopic Index of Severity (CDEIS) was built taking into account deep and superficial ulcers, the extent of ulceration, the extent of any lesions and stenosis [2]. It was further validated on an independent series of endoscopies [2] and used in clinical trials as secondary or primary endpoint [7]. Assessment of the extent of lesions and ulceration using a visual analog scale is considered difficult by some clinicians and this led to build another index, the SES-CD, which does not precisely measure surfaces but quotes them in groups [3]. In UC, lesions with a good interobserver agreement include changes in the mucosal vascular pattern, hemorrhage and erosion-ulceration [4, 5]. Interestingly, mucosal friability which was previously and since the Baron score considered a major sign of UC was recently shown to be insufficiently reproducible even after attempts to standardize it [4, 5]. Several scores were proposed and used in clinical trials. The most used at the present time is the Mayo score [8], but the most precisely studied concerning interobserver variability is the recently developed UCEIS [4, 9]. Severe lesions of UC and CD that correlated with lesions seen on surgical specimens were the presence of deep and extensive ulcers which could appear as deeps ulcers, mucosal detachment or well-like ulcerations [10, 11].
Mucosal Healing and Its Prognostic Value
Several drug regimens have been shown to induce significant MH, especially when prescribed early in the course of the disease [20]. This is why some studies are focusing on early disease and why mixing patients with early disease and advanced disease probably leads to heterogeneity. Ulcerative Colitis In UC, MH has been considered a relevant therapeutic goal for a long time, but it was not chosen as a primary endpoint of randomized trials until recently. It was also often not well defined and indices were validated only in the last years. Microscopic changes, especially basal plasmacytosis, can persist despite apparent resolution of symptoms and MH [21, 22] so that the question remains open whether endoscopic remission or histologic remission should be chosen as target for clinical trials and daily practice. In the IBSEN cohort of 513 patients with incidental cases of UC who were followed in Norway in the early 1990s (before the immunosuppressant era), MH 1 year after diagnosis was significantly associated with a lower risk of colectomy over the next 5 years (2 vs. 7%) [14]. In the study by Ardizzone et al. [23], who considered the first course of corticosteroids for newly diagnosed UC, lack of early MH was associated with negative outcomes Endoscopy as Prognostic Marker
at 5 years. In a post hoc analysis of the ACT1/2 trials [24] which compared infliximab to placebo, infliximab-treated patients with a Mayo endoscopy subscore of 0 or 1 at week 8 had a significantly lower risk of colectomy over the next year, compared to patients with a Mayo score of 3 or 4, as well as a better chance of clinical remission and a lower rate of steroid use. Noticeably, a difference was observed between Mayo Clinic endoscopy subscores of 0 and 1 with regard to symptoms and steroid dependency (not colectomy): an endoscopy subscore of 0 at week 8 predicted symptom relief at weeks 30 and 54 in 71 and 74%, respectively, compared to 51 and 47% for a score of 1 at week 8. Laharie et al. [25] recently analyzed retrospectively the outcome of 63 adult patients with refractory UC receiving maintenance treatment with infliximab in five French referral centers. Colectomy-free survival rates at 12, 24 and 36 months were respectively 100, 96 and 96% in the 30 patients with MH versus 80, 65 and 65% in patients without MH (p = 0.004). By multivariate analysis, MH was the only factor associated with colectomy-free survival, with an odds ratio of 18 (95% CI 1.6– 205) [25]. There seems to be a correlation between the absence of MH and the colon cancer risk. Persistent pseudopolyps or inflammatory lesions were independently associated with the risk of colorectal neoplasia during surveillance in the St Mark’s cohort [26]. In the CESAME cohort, the risk of colorectal cancer was lower among patients receiving thiopurines than in those who never received this treatment [13]. This suggests that a good anti-inflammatory therapy might reduce the risk of neoplasia. This has not been studied in prospective randomized clinical trials, but these are probably impossible to perform as they would need very large numbers of subjects and as the control group without treatment is not ethical. Crohn’s Disease MH in CD seems to have an inconstant prognostic value to predict relapse or complications in literature. A GETAID study reported no correlation between MH and clinical relapse rates in the following 18 months in corticosteroid-treated CD patients, and this argued in favor of a purely symptom-oriented approach to CD in the 1990s [27]. In the IBSEN cohort, 227 subjects with incident cases of CD were followed [14]. At 1 year, MH was observed in 38% of cases and there was a lower chance of MH when patients were treated with steroids than with other drugs (which at that time did not include anti-TNF). In this study, MH at 1 year was associated with a lower chance of Dig Dis 2013;31:351–356 DOI: 10.1159/000354691
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Crohn’s Disease Nahon et al. [11] showed that the depth and extent of ulcerations at colonoscopy for CD were in agreement with pathological findings at colectomy specimen examination. Allez et al. [19] followed for a median time of 52 months a series of 102 patients with colonic CD who were retrospectively stratified as having severe endoscopic lesions or moderate endoscopic lesions. Severe lesions were defined as large coalescent and deep ulcerations covering more than 10% of the mucosal area of at least one segment of the rectocolon. Such severe lesions were observed in half of the study population. During follow-up, 37 patients underwent colonic resection and the risk of colectomy was significantly and independently affected by the presence of severe lesions (RR 5.42, 95% CI 22.64–11.18), a high clinical disease activity index (CDAI) and the absence of immunosuppressants. The probabilities of colectomy at 1, 3 and 8 years were respectively 31, 42 and 62% in the severe lesion group versus 6, 8 and 18% for the moderate lesion group.
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a complete but complex multivariable predictive model and not retained in a simplified model which also discarded infliximab trough levels [33].
Postoperative Recurrence of Lesions in CD and Fortuitous Discovery of Asymptomatic Lesions of CD and Their Prognostic Value
Rutgeerts et al. [34] showed that the postoperative recurrence of symptoms of ileal CD differed between groups of patients depending on the nature of lesions seen on the anastomosis and above some months after ileal resection. A strategy of treatment escalation based on the lesions has recently been shown to be superior to optimal drug therapy alone in preventing postoperative recurrence [35]. Along with this, Baudry et al. [36] have recently reported that tailored treatment according to the lesions significantly reduced clinical recurrence after surgery. Performing ileocolonoscopy during the year following ileal resection for CD is recommended in order to approach prognosis and adapt treatment to the lesions [37]. A recent study showed that subjects with a fortuitous diagnosis of CD during endoscopy performed for other purposes (screening for example) have a high risk of developing clinical symptoms [38]. This risk was shown to be equal in this series of 40 patients to the risk of patients who develop lesions after surgery. If confirmed, this would argue for treating asymptomatic patients and this should now be studied prospectively in larger groups.
Conclusion
There is a tendency to now consider endoscopy endpoints to adapt treatment in various situations of IBD. However, the supporting evidence remains limited. Unanswered questions and unmet needs for the clinician include more universal and strict definitions of MH, agreement on the diagnosis of elementary lesions and teaching how to use scores to decrease interobserver variation. In this aspect, central reading of endoscopies is being more and more used in clinical trials [39] but may change the result of studies from what they would have been in reallife conditions (i.e. with standard clinician evaluating lesions and taking decisions on their observations). In addition, if strategies to manage situations of IBD were only established on the basis of results from such studies, there would be a risk that the therapeutic decisions made by the usual specialist may significantly differ with the opinion Camus /Pariente /Dray /Allez /Marteau
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being still on steroids at 5 years but was not predictive of (associated with) clinical relapse in the next 5 years, disease extension, and disease complications [14]. A type 2 error is possible considering the relatively low number of subjects in the study; however, one must keep in mind that this is still the best evidence in literature before antiTNF agents and that this study did not disclose a prognostic value of MH. Several studies suggested that when an anti-TNF treatment achieves MH, this is associated with a better prognosis. In a retrospective study of 183 patients, Schnitzler et al. [28] found that MH during maintenance infliximab treatment was associated with a lower risk of surgery. In the ACCENT I endoscopic substudy, none of the patients with MH at weeks 10 and 54 needed hospitalization, compared to 4/16 (25%) patients with MH at only one of these time points and 34/74 (46%) of the subjects without MH at both time points [29]. The follow-up of a subset of 49 patients in the ‘step-up/top-down’ study showed that those patients who achieved complete MH at 2 years (absence of ulcers, SES-CD = 0) had significantly higher rates of clinical remission, steroid-free remission, and steroidfree remission without flare through years 3 and 4 [30]. MH also predicted a higher chance of long-term clinical benefits in adalimumab-treated patients [31]. The persistence of endoscopic lesions versus MH has also been studied as a prognostic variable to predict relapse in patients stopping treatments while in remission. Lémann et al. [32] performed a double-blind, withdrawal study in 83 patients in clinical remission on azathioprine for ≥42 months and who were randomized to continue azathioprine or to receive a placebo for 18 months. CDEIS level was low in the 45 patients who had a colonoscopy at baseline and 36% of them had CDEIS 0 (absence of any lesion). The presence of endoscopic lesions or of ulcerations was not predictive of relapse. In their prospective STORI trial, Louis et al. [33] looked for factors predicting the risk of relapse in patients who stopped long-term scheduled infliximab therapy. To be included, subjects had to be treated for at least 1 year with scheduled infliximab and azathioprine, and be in corticosteroid-free remission for at least 6 months. After a median follow-up of 28 months following infliximab cessation, half of them had experienced a relapse, and multivariate analysis showed that absence of MH was one of the risk factors for relapse. The hazard ratio estimate of an association between time of relapse and a CDEIS >0 was 2.3 (95% CI 1.1–4.9; p = 0.04). This suggests that patients with persistent endoscopic lesions should probably not stop antiTNF treatments. Endoscopy assessment was included in
of the central reader. We and others are currently trying to develop more objective measures of some lesions using optoelectronic tools. Prospective studies evaluating decision-making based on endoscopic assessment started in the postoperative period of CD should now be performed in all IBD situations.
Disclosure Statement M. Allez: consultancies or honorarium for lectures from Abbvie, MSD, Ferring, Novo Nordisk, GSK, and P. Marteau: consultancies or honorarium for lectures from Abbvie, Ferring, MSD. The other authors have no conflicts of interest to disclose.
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