Results of the Eighth Scientific Workshop of ECCO: Diagnosing Postoperative Recurrence of Crohn’s Disease After an Ileocolonic Resection With Ileocolonic Anastomosis

Abstract

Despite the introduction of potent biologic therapies, many patients with Crohn’s disease [CD] still require an ileocolonic resection [ICR] during the course of their disease. Furthermore, the need of redo ICR has not decreased over the past few decades, highlighting the need for better strategies to prevent and treat postoperative recurrence [POR]. The first step to develop such a strategy would be to define and standardise the description of POR with adequate diagnostic instruments. In this article, we will describe the different methodologies used to report POR [endoscopic, histological, radiological, biochemical, clinical, and surgical], and review their potential benefits and limitations, as well as the optimal timing of evaluation.

1. Introduction

Since the first description of Crohn’s disease [CD], surgical therapy has been a cornerstone of the treatment of ileocaecal CD.¹ Subsequent advances in drug development have increasingly restricted indications for surgery in ileocolonic CD to disease complications such as strictures, fistulas, and abscesses.² However, both short-term [1 year] and long-term [median 63.5 months] data from the LIR!C trial suggest that a laparoscopic ileocolonic resection [ICR] is a reasonable alternative to infliximab therapy as a first approach in patients with inflammatory ileocaecal CD with less than 40 cm of involved terminal ileum, who have failed conventional treatments [considering either corticosteroids, thiopurines, or methotrexate].^3,4 Despite these data about surgery, it is clear that the management of CD has dramatically evolved over the past three decades with the introduction of biologic therapies, non-invasive monitoring with biomarkers, and the development of both diagnostic and therapeutic endoscopy. A decrease in ICR rates of 8% per year was observed in a population-based study including Canadian patients diagnosed between 1996 and 2013, coincident with an increase of disease duration at surgery.⁵ Similarly, recent, national, registry-based data from Sweden have shown a progressive drop in the 5-year cumulative ICR rate from 36.8% in 1990–1995 to 29.0% in 1996–2000 and 13.3% in 2002–2008, levelling out at 12.4% in 2009–2014.⁶ However, although the incidence of first ICR has reduced over time, it is debated whether this is linked to the introduction of biologic therapy or an earlier detection of the disease.⁷

Redo surgery is often described as surgical recurrence of CD, but there is no clear definition for recurrent CD after an ICR. As early as the mid-1980s, Rutgeerts et al. showed that 72% of patients undergoing an ICR with ileocolonic anastomosis developed endoscopic recurrence within 1 year, and 88% of those had their recurrence at the ileocolonic anastomosis.⁸ Another modality of describing postoperative recurrence [POR] has been the recurrence of symptoms, with or without the use of clinical indices. As many as 22% and 31% of patients have been reported to suffer from CD-related symptoms within 1 and 5 years, respectively.^9–11 Other more objective modalities for describing POR are biomarkers such as faecal calprotectin [FC] and C-reactive protein [CRP],^12–14 and imaging modalities such as intestinal ultrasound [IUS], capsule endoscopy, and magnetic resonance enterography [MRE].^15–17

Regardless of which methodology is used, it is crucial that physicians and investigators remain consistent when describing POR after an ICR with ileocolonic anastomosis. This will help not only to describe POR, but also to estimate and compare the risk of POR. Ultimately, this will enable selection of patients prone to early POR and in need of a more intensive postoperative follow-up or prophylactic approach. The latter may influence the natural course of the disease, with less disease burden and less need for redo surgery.

In this article, we will describe the different methodologies to report POR and provide definitions for each setting [Table 1]. We will also review their potential benefits and limitations, as well as the best timing for their evaluation.

2. Endoscopic recurrence

2.1. Defining endoscopic recurrence

International guidelines recommend performing an ileocolonoscopy 6 to 12 months after surgery, as the gold standard to assess the presence of POR in adult CD patients who undergo an ICR with ileocolonic anastomosis.^18–20 In 1990, Rutgeerts et al. demonstrated that the severity of endoscopic lesions identified at the neoterminal ileum and at the ileocolonic anastomosis within 1 year after surgery is able to predict the subsequent occurrence of clinical activity.⁹ In their work, endoscopic lesions [including isolated aphthous ulcers] were observed in 73% and 83% of patients at 1 and 3 years after surgery, respectively. In subsequent studies, the interpretation of the prevalence of endoscopic recurrence has been hampered by heterogeneity of disease characteristics and variable postoperative management of patients. Although not formally validated, the postoperative endoscopic recurrence score, also known as the Rutgeerts score, has been widely adopted in clinical practice and is routinely used in clinical trials. This score consists of five progressive levels of severity: i0, no lesions; i1 ≤5 aphthous lesions in the neoterminal ileum; i2, >5 aphthous lesions in the neoterminal ileum with normal mucosa between the lesions, or skip areas of larger lesions, or lesions confined to the ileocolonic anastomosis [ie, <1cm in length]; i3, diffuse aphthous ileitis with diffusely inflamed mucosa; i4, diffuse inflammation of the neoterminal ileum with already larger ulcers, nodules, and/or narrowing [Figure 1].⁹ Conventionally, endoscopic recurrence is defined as a Rutgeerts score ≥i2, because recurrence of symptoms was rarely seen in patients with i0–i1.⁹ A prospective study on 40 operated CD patients undergoing ileocolonoscopy 6 months after ICR, and then clinically followed for 5 years, confirmed these initial findings, showing that clinical recurrence occurred in 11% of patients with i0–i1 compared with 57%, 75%, and 100% of i2, i3, and i4, respectively.²¹

Unfortunately, the Rutgeerts score has its limitations. As mentioned, it has never been formally validated. In addition, it has shown only moderate reproducibility in interobserver variability studies [kappa estimates ranging from 0.43 to 0.53],^22–24 leading to potentially inappropriate treatment decisions in inaccurately scored patients. Moreover, the Rutgeerts score was originally developed for the evaluation of an ileocolonic end-to-end anastomosis. However, due to the imminent risk of anastomotic strictures, this classical end-to-end ileocolonic anastomosis has been replaced by a range of new techniques [side-to-end, end-to-side, isoperistaltic side-to-side, antiperistaltic side-to-side, Kono-S] that are accompanied by the presence of novel anatomical landmarks.²⁵ The clinical relevance of active inflammation at these locations, such as the ileal inlet, the ileal body, and the ileal blind loop, is currently unclear. Only one study has provided data on the natural history of ileal blind loop lesions.²⁶ Among 125 endoscopies in which the ileal blind loop was described, isolated lesions in this area were found in 43/125 [34%] patients with side-to-side anastomosis. These lesions tended to be associated with clinical, endoscopic, and surgical POR within a short period of follow-up.²⁶ Therefore, it is no longer sufficient to limit the endoscopic report to the Rutgeerts score, but it is important to visualise and describe the presence or absence of lesions at the anastomotic line, the neoterminal ileum and, whenever present, the ileal inlet, the ileal body, and the ileal blind loop.

The original Rutgeerts score fails to distinguish between mild lesions at the anastomosis and multiple but isolated lesions in the neoterminal ileum. In this regard, lesions confined to the anastomosis have been shown to be associated with lower FC.²⁷ Consequently, a separation of i2 findings into i2a [anastomotic lesions] and i2b [>5 aphthous ulcers or larger areas of skip lesions in the neoterminal ileum with normal intervening mucosa] has been suggested.²⁸ Subsequently, several papers have been published to investigate the possibility of different prognostic outcomes between these i2a and i2b lesions. Rivière et al. included 365 patients who were diagnosed with an i2 score within 1 year after surgery, and found no difference in clinical recurrence rates or need for an intervention [either balloon dilation or ICR] after a median follow-up of 79 months, even after excluding patients receiving an immediate change of therapy following endoscopy.²⁹ Similar conclusions were reported in a multicentre French study, in which 23 patients with i2a and 27 with i2b were observed to have an equivalent median time to clinical recurrence.³⁰ Conversely, Ollech et al. reported that patients with i2b [n = 25] had a higher risk of endoscopic progression towards i3-i4 and redo ICR, compared with patients with i2a [n = 40] (hazard ratio 6.22; 95% confidence interval [95% CI] 2.38–16.2, p = 0.0008].³¹ This observation was later supported by the Cleveland Clinic and the French REMIND groups.^32,33 Therefore, it is still unclear whether i2a and i2b findings should be treated and monitored differently.

It is currently debated whether the development of anastomotic lesions following an ICR can be considered a unique feature of CD or a common consequence of stapling after ICR for several indications.^34,35 Three recent studies reported that anastomotic ulcers are associated with CD recurrence and significantly influence the natural history of the disease.^36–38 In contrast for lesions located in the neoterminal ileum, investigators of the postoperative Crohn’s endoscopic recurrence [POCER] trial suggested that these were not predictive of long-term outcome. They developed a new POCER index ranging from 0 to 4, based on the anastomotic ulcer depth [<2 mm or ≥2 mm] and circumferential extent [<25% or ≥25%] of anastomotic lesions. A POCER index ≥2 [presence of deep ulcerations or a circumferential extent of ≥25%] was superior to a Rutgeerts score ≥i2 at 6 months in predicting endoscopic recurrence at 18 months [Rutgeerts score ≥i2].³⁸ This new score seems promising due to its ease of use and is associated with high reproducibility. However, a POCER index ≥2 was not predictive of severe endoscopic recurrence [Rutgeerts score ≥i3] or clinical recurrence at 18 months. Similar conclusions were reached by the REMIND group, where patients with recurrent lesions exclusively in the neoterminal ileum were associated with poorer clinical long-term outcomes than those with lesions confined to the anastomosis.³²

The above-mentioned scores do not include possible lesions in the colon and in the more proximal part of the small bowel. An attempt to investigate the impact of colonic disease recurrence has recently been undertaken, with the use of the Simple Endoscopic Score-Crohn’s Disease [SES-CD] and its Modified Multiplied version [MM-SES-CD].³⁹ A subgroup analysis of the PREVENT trial, on 208 CD patients after ICR, demonstrated that SES-CD and MM-SES-CD at Week 76, performed in the same way as the Rutgeerts score, predicts subsequent clinical recurrence at Week 104. When adjusting for covariates, an MM-SES-CD cut-off score ≥26 was associated with higher odds ratio for clinical recurrence by Week 104 compared with a Rutgeerts score ≥i2.³⁹ Consequently, authors suggested implementation of postoperative endoscopic assessment by combining information on colonic activity.

Finally, since a wide variation of endoscopic recurrence rates has been reported in the real-life cohorts mentioned above, central review of endoscopic videos, using common language and scoring system, should be encouraged in prospective studies to increase the strength of their findings.

For a more informative evaluation of proximal CD, capsule endoscopy [CE] could be used.⁴⁰ This is a non-invasive and well-tolerated tool, able to visualise the full length of the small bowel and to detect endoscopic recurrences missed by ileocolonoscopy. However, larger prospective studies are necessary to assess its clinical impact.⁴¹ The pooled sensitivity and specificity of CE for the diagnosis of POR, using ileocolonoscopy and the Rutgeerts score as reference standard, were 100% [95% CI, 91%–100%] and 69% [95% CI, 52%–83%] respectively (area under the curve [AUC] 0.94).⁴² Three small studies, without a control group having ileocolonoscopy, have used the Lewis score⁴⁰ to quantify inflammatory lesions.^43–45 The Lewis score evaluated three CE findings: villous oedema, ulcers, and stenosis. The small bowel transit time was divided into three equal parts [proximal, middle, and distal tertiles] and every tertile scored individually. The total Lewis score was defined by the highest tertile of oedema and ulcer scores plus the stenosis score. A Lewis score >135 identified the presence of endoscopic activity and was found in more than 80% of the patients within 3 months of surgery.^43–45 It was also correlated with clinical recurrence.⁴⁴ In addition, inflammatory lesions have been found by CE within 4 weeks of surgery.^17,43 However, these may represent residual lesions rather than novel postoperative lesions. Moreover, it is sometimes difficult to evaluate the extent of the lesions, as CE could stop in the same area for a prolonged time. Finally, the risk of capsule retention should be considered, and cross-sectional imaging and/or patency capsule should be performed beforehand [Table 2].

2.2. Optimal timing of postoperative endoscopic assessment

In the POCER trial, 174 patients received a 3-month course of metronidazole, with the addition of prophylactic treatment with a thiopurine or adalimumab [if thiopurine intolerant] in high-risk patients. Patients were then randomly assigned to either an endoscopy 6 months after surgery [‘active care’] or clinical follow-up only [‘standard care’].⁴⁶ Treatment decision based on postoperative ileocolonoscopy was superior to standard of care, as 49% of endoscopic recurrences [Rutgeerts score ≥i2] were reported at 18-month ileocolonoscopy in the ‘active care’ group vs. 67% in the ‘standard care’ group [p = 0.03].⁴⁶ This study provides convincing evidence that an early endoscopic assessment is crucial for a timely step-up of therapy in case of recurrence, to improve the long-term outcomes, regardless of the use of immediate postoperative prophylactic therapy. A subsequent Cochrane review has reinforced this recommendation.⁴⁷

Despite the results of the POCER trial, there is currently insufficient evidence on when to perform the second endoscopic evaluation, particularly in patients with endoscopic remission [Rutgeerts score <i2] at the first ileocolonoscopy, or if it can even be avoided in this group. In a multicentre study aiming to assess late POR rates in patients with initial endoscopic remission, it was found that 40.8% experienced a relapse [defined as either clinical recurrence, hospitalisation due to CD complications, occurrence of bowel damage, need for balloon dilation of the anastomosis, or redo resection] after a median of 3.5 years.⁴⁸ Accordingly, the Global Interventional IBD Group advises continuing endoscopic follow-up every 1–3 years, at the judgment of the treating clinician based on the need for dysplasia surveillance, treatment monitoring, and potential endoscopic therapy.⁴⁹ Therefore, timing for additional endoscopic follow-up should be flexible and individualised to patient symptoms, as suggested by Spanish guidelines that recommend non-invasive monitoring after first negative endoscopy unless symptoms occur.⁵⁰ In a recent European survey, 90% of participating gastroenterologists reported using FC as a marker for follow-up of patients with endoscopic remission at first assessment; repeat ileocolonoscopy was favoured by only 46% of physicians.⁵¹

A non-passable stenosis could be detected at the anastomotic line or at the ileal inlet at first postoperative endoscopy. An endoscopic balloon dilation of the stricture may be suggested in these cases, even in asymptomatic patients, to allow a more thorough assessment of POR in the neoterminal ileum, to overcome potential progression of POR due to faecal stasis,⁵² and to lower the risk of bowel obstruction. Therefore, an informative discussion with the patient regarding this possibility and the associated risks [cumulative perforation and bleeding rate <3%]⁵³ should always be carried out, prior to performing the first endoscopic evaluation in centres with adequate expertise.

3. Histological recurrence

Histological evidence of activity may be present in areas of the neoterminal ileum that appear macroscopically normal.⁸ As these microscopic findings are associated with subsequent overt clinical activity,^54–56 there is growing interest in assessing the mucosa at the microscopic level using real-time imaging, such as confocal laser endomicroscopy [CLE]. This method consists of the intravenous administration of a contrast agent, such as fluorescein, and further assessment of the mucosal barrier with a magnificator, to identify functional and structural defects that are encapsulated in the Watson score. The score ranges on a scale of 1 to 3 points: Watson 1 is normal mucosa; Watson 2 is functional mucosal defects with fluorescein leakage; and Watson 3 refers to structural mucosal defects with associated micro-erosions. CLE has been tested in 25 CD patients, enabling the identification of patients in endoscopic remission [i0-i1] but with a Watson score ≥2, who were at higher risk of endoscopic recurrence after a median follow-up of 35 months.⁵⁷ Although derived from a small cohort, these results suggest that adjunctive methods may help clinicians identify at-risk patients.

4. Radiological recurrence

Although ileocolonoscopy is considered the gold standard for detecting POR, it is invasive and therefore unappealing to the patient. In the ‘treat-to-target’ era, a non-invasive approach for monitoring patients has become increasingly necessary. In recent years, radiological techniques, including intestinal ultrasound [IUS] and magnetic resonance imaging [MRE], have been proposed as both alternative and complementary tools for assessing the small bowel.⁵⁸ Similarly, computed tomography enterography has shown high sensitivity in POR setting,^59,60 but its use should be avoided in the elective setting due to radiation exposure and the availability of safer alternatives.

A meta-analysis found that IUS and MRE provided accurate and comparable assessment of POR in CD, using ileocolonoscopy and the Rutgeerts score as reference standard: for MRE, sensitivity of 97% [95% CI, 89%–100%], specificity of 84% [95% CI, 62%–96%], and AUC of 0.98; for IUS, sensitivity of 89% [95% CI, 85%–92%], specificity of 86% [95% CI, 78%–93%], and AUC of 0.93.⁴²

Schaefer et al. recently validated the MONITOR index, by using MRE to assess POR in CD.¹⁶ This score was built based on MRE items considered as accurate and relevant in the diagnosis of ileal disease. Presence of ulcers was scored as 2.5 points, whereas other items, including presence of wall thickening, contrast enhancement, diffusion-weighted signal or T2 signal increase, oedema, and length of affected segment ≥20 mm were scored as 1 point each. Using this score, an index ≥1 was shown to be a reliable indicator of endoscopic recurrence [Rutgeerts score ≥i2] with a sensitivity of 79%, a specificity of 55%, a positive predictive value of 68%, and a negative predictive value of 68%. From the literature, this is the second magnetic resonance index developed for this particular clinical setting. The previous score used enteroclysis to achieve adequate luminal distension instead of oral solution. Despite a good agreement with the Rutgeerts score [kappa 0.78]⁶¹ and correlation with clinical POR,⁶² this method has not been adopted because of low tolerability for patients and the lack of informative diffusion-weighted sequences.

The benefit of using MRE or IUS is the additional available assessment beyond the mucosa, extending to transmural and extramural evaluation [Figures 2 and 3]. A submucosal involvement with thickening of the bowel wall may occur in the absence of any mucosal inflammatory activity. Such assessments would be impossible with the Rutgeerts score. However, there are inherent disadvantages of MRE. It is time-consuming, requires oral and intravenous contrast agents, and is expensive and not compatible with some metallic implants. Furthermore, not all patients are able to tolerate it for various reasons: claustrophobia or inability to hold their breath or lie still. In contrast, IUS is a patient-friendly and inexpensive modality that does not need specific preparation and contrast media.^63,64 Moreover, it can be performed in real time, augmenting the clinical decision making process.⁶⁵ A meta-analysis of 10 prospective studies by Rispo et al. confirmed the accuracy of IUS in detecting POR: a bowel wall thickness [BWT] >3 mm had a pooled sensitivity of 82% [95% CI 76%–88%] and a pooled specificity of 88% [95% CI 74%–95%], with an overall accuracy of 87.5% for diagnosing endoscopic recurrence [Rutgeerts score ≥i1]. Specifically, a BWT ≥5.5 mm appeared to be the best cut-off for detecting a severe endoscopic POR [Rutgeerts i3-i4] (sensitivity 83.8% [95% CI, 73.6%–90.6%] and specificity 97.7% [95% CI, 93%–99%]).¹⁵ Of note, an increased BWT was shown to predict both clinical and surgical recurrence.^66–68

Pre-procedure administration of contrast agents has been suggested to increase the diagnostic accuracy of IUS. However, the observed modest gain in terms of sensitivity with the use of contrast-enhanced ultrasound [CEUS] or hyperosmolar luminal contrast [small intestine contrast ultrasonography, SICUS] needs to be balanced against the additional invasiveness and time requirements.^69,70

Whereas cross-sectional imaging techniques are considered accurate for the detection of transmural inflammation, early lesions limited to the mucosal surface may be missed.^70,71 Therefore, a combination of an IUS-based assessment tool and FC monitoring could represent a useful way of predicting endoscopic POR, particularly in the early phases after ICR.⁷² A similar strategy may be suggested in asymptomatic patients with anastomotic stenosis that precludes the endoscopic assessment of the neoterminal ileum, particularly if a balloon dilation is not performed. A common caveat is reporting of normal FC levels in some patients with mild endoscopic POR. However, subjects with a BWT ≥5.5 mm, highly indicative of severe endoscopic recurrence [Rutgeerts score i3-i4], may avoid ileocolonoscopy [negative likelihood ratio of 0.165, positive likelihood ratio of 36.4].¹⁵ The main concern pertaining to the use of IUS is the operator dependence and the need for training. However, studies specifically addressing observer variability have reported a fair to good agreement⁷³ and interrater reliability for BWT was very high [interclass correlation coefficient, ICC 0.96].^74,75 Larger prospective studies of both IUS and FC measurement are necessary. Table 2 summarises advantages and limitations of IUS and MRE for the diagnosis of POR.

5. Biochemical recurrence

5.1. Defining biochemical POR

In part due to the practical challenges of performing early and repeated endoscopies, biochemical measures to diagnose and monitor POR have received increasing attention. Although there have been isolated reports that raised serum CRP levels may be able to predict subsequent endoscopic POR,⁷⁶ the majority of studies have demonstrated that CRP is neither sensitive nor specific enough to be used as a single diagnostic or monitoring tool in the postoperative setting.^77,78 Therefore, most of the current data on biochemical POR relate to elevated levels being detected on stool testing, particularly with the calcium-binding protein calprotectin, and to a lesser extent with the iron-binding glycoprotein lactoferrin.

5.2. Correlation of biochemical markers with endoscopic POR

In a Spanish cohort including 119 patients who underwent an ileocolonoscopy to assess endoscopic POR [Rutgeerts score ≥i2b], FC correlated closely with endoscopy (AUC 0.75 [95% CI, 0.66–0.84]).¹² Both higher sensitivity and negative predictive value were observed when combining FC >100 µg/g and serum CRP level >5 mg/L, with sensitivity of 82%, specificity of 53%, positive predictive value of 54%, and negative predictive value of 81% to detect endoscopic POR.¹² In a prospective pilot study of 20 Japanese patients with CD who remained in clinical remission 6 to 12 months after ICR, FC and FL both correlated with the Rutgeerts score. Furthermore, an FC cut-off value of 170 µg/g [sensitivity 83%, specificity 93%], and an FL cut-off value of 140 µg/g [sensitivity 67%, specificity 71%] were predictive of clinical POR (Crohn’s Disease Activity Index [CDAI] >150) during the following year.⁷⁹ Nevertheless, it is clear that a single cut-off value will never be optimal to accurately distinguish endoscopic POR for individual patients.

Further work from a French cohort of 55 patients confirmed that a very low FC cut-off value of <65 µg/g at 3 months could effectively identify patients in endoscopic remission 1 year after their resection [negative predictive value of 91%, but positive predictive value of 50%].⁸⁰ In the seminal POCER randomised, controlled trial, the mean FC level at 6 months for patients in endoscopic remission was 72 µg/g, whereas it was 275 µg/g for patients with endoscopic POR [Rutgeerts score ≥i2].⁸¹ High negative predictive values have been demonstrated from other prospective cohorts, and conclusions reached that using a cut-off value of 100 µg/g FC might be clinically useful to determine likelihood of endoscopic remission.⁸² However, it is important to acknowledge that several other studies have not fully supported the use of FC for biochemical monitoring in the postoperative setting.^83,84 As in the preoperative setting, some patients with clear endoscopic POR in the neoterminal ileum may have FC levels below selected cut-off values. Data therefore suggest that no single cut-off value is suitable for all patients. Instead, the greatest use of FC appears to be in assessing variation and trend over time, when used as a monitoring tool in postoperative follow-up.

5.3. Optimal timing of biochemical testing to detect POR

In a study from the UK, a group of 114 patients provided a single stool sample at various time points in the postoperative period, and an additional small cohort of 13 patients was followed prospectively for 1 year with regular FC and FL measurements.⁸⁵ In those with an uncomplicated ICR, both stool markers normalised by 2 months. However, even in these patients with good clinical outcomes, elevated FC or FL levels were observed within the first 2 months. The authors concluded that early elevated FC or FL levels within 2 months of an ICR may simply be indicative of normal postoperative healing and immune response.

Further data about optimal timing for faecal samples were provided by the POPCUR randomised, placebo-controlled, postoperative prevention trial, assessing azathioprine with or without curcumin. Faecal samples were taken at baseline, 1 month, and 3 months postoperatively. In this cohort, >10% increase in level of FC at 3 months compared with baseline could predict endoscopic POR at 6 months with moderate levels of accuracy (sensitivity of 65% [95% CI, 41%–83%) and specificity of 88% [95% CI, 68%–96%].⁸⁶ Therefore, it might be suggested to start FC measurement at Month 3 after surgery and to anticipate endoscopic assessment in case of elevated levels.

5.4. Novel biochemical tests to detect endoscopic POR

Despite the widespread use of FC, there remain practical limitations of stool-based testing, including low sample return rates in real-world practice and an increasing recognition that many patients prefer blood-based monitoring.⁶³ This has resulted in significant focus on developing blood-based biomarkers, including discovery and validation of the Endoscopic Healing Index [EHI]-a test measuring a panel of 13 proteins, including CRP.^87,88 The EHI has since been assessed for postoperative CD, using paired serum samples and endoscopic assessments from 131 patients in the POCER trial.⁸⁹ The EHI showed comparable performance to FC at 6 months for predicting endoscopic POR. However, at 18 months FC had superior accuracy to the EHI for detecting endoscopic POR.⁹⁰ Therefore, whereas the EHI and other novel tools are welcome, there are key questions that will need answering for any novel biochemical test, including optimal timing for assessment, relative cost-effectiveness compared with FC or other non-invasive tests, and validation in diverse patient cohorts.⁹¹

6. Clinical recurrence

Despite the desirable target for treating CD focusing on the achievement and maintenance of endoscopic remission, clinical wellbeing is undoubtedly an important goal for both patients and clinicians. Patient-reported outcomes [PROs] have been recently introduced in the comprehensive evaluation of the disease.⁹² In the context of postoperative assessment of CD, recurrence of clinical symptoms is observed in 22% of patients 1 year after surgery,¹¹ whereas endoscopic activity has been reported in up to 85% of cases within the same period.⁹³ Accordingly, many studies have reported poor correlation between clinical and endoscopic POR, particularly when symptoms are assessed with the Crohn’s Disease Activity Index [CDAI].^77,94,95 A recent systematic review with meta-analysis reported a risk of clinical recurrence that was 12.89 times higher [95% CI, 6.56–25.34] for patients with endoscopic POR than for patients without.⁹⁶

In an attempt to improve the correlation of clinical symptoms with endoscopic activity in CD, the use of composite biomarkers consisting of clinical score and laboratory tests has been evaluated.⁹⁷ For example, in a prospective study of 86 postoperative CD patients, the combination of Harvey-Bradshaw Index [HBI] ≥2 and a CRP ≥0.32 mg/dL provided a positive predictive value of 95.7 [95% CI, 79.0–99.2] in discriminating between endoscopic remission and endoscopic recurrence [Rutgeerts ≥i2b], and this was not inferior to the use of FC.⁹⁸ In contrast, the concomitant assessment of PROs with HBI and CRP resulted in poor agreement with endoscopic activity in a group of 40 patients with previous ICR.⁹⁹

In addition, patients with prior bowel resection due to complicated CD may present with clinical symptoms mimicking recurrence of disease, but those symptoms may be due to altered anatomy, bacterial overgrowth, irritable bowel syndrome, adhesion partial obstruction, bile salt malabsorption, or functional disorders. As a result, the definition of clinical POR remains debated, since relying solely on clinical symptoms to define CD recurrence and to guide disease-specific treatment places patients at risk of under- or over-treatment.¹⁰⁰ We suggest defining clinical postoperative recurrence as the combination of CD-related symptoms and morphological [endoscopic or radiological] evidence of POR at the site of the ileocolonic anastomosis or the neoterminal ileum.

7. Surgical recurrence

Surgery in ileocaecal CD is mostly restricted to resections of the ileocaecal region, but strictureplasties over the ileocaecal valve have been recently suggested in selected cases with long ileal segments with inflammation.¹⁰¹ Such strictureplasties are a potential alternative in small bowel disease, especially in the presence of multiple strictured segments and/or inherent risk of developing short bowel syndrome.^101,102 Recurrence of CD leading to redo surgery after an ICR is mostly located at the anastomosis itself or in the pre-anastomotic ileum [83–87%],^103,104 whereas after strictureplasties, recurrent strictures occur more commonly distal to the index strictureplasty.^105,106 It has also been reported that there is an increased risk of surgical recurrence if the POR is located in the ileum, proximal to the anastomosis, rather than in the anastomosis itself.³²

Surgical recurrence is generally defined as the need for redo surgery or strictureplasty at the site of ileocolonic anastomosis due to POR. It is, however, important to bear in mind that not all surgical re-interventions are due to recurrent CD, as missed strictures at the time of index surgery or technical errors may account for up to 20% of early re-interventions.¹⁰⁷ As already stated, other indications for redo surgery in CD may be secondary to small bowel obstruction due to adhesions after previous surgery rather than the underlying disease, or to development of CD strictures elsewhere in the gastrointestinal tract. A meta-analysis of eight studies did not find a significant decline in the risk of redo surgery in CD, using time-trend, mixed-effect meta-regression [5- and 10-year risk, p = 0.21 and p = 0.16, respectively].⁷ Accordingly, data from the Swedish national registry reported that the need of redo ICR has remained stable despite the introduction of biologics [mild drop from 5.5% to 4.4% at 5 years and 13.0% to 8.8% at 10 years, without any significant decrease thereafter].⁶

On the other hand, the need for either an endoscopic balloon dilation or a redo ICR at the ileocolonic anastomosis is currently regarded as ‘modified surgical POR’.¹⁰⁸ Therefore, a suggestion is to limit the term ‘surgical recurrence’ after ICR to the need for a new ICR or a strictureplasty at the site of the ileocolonic anastomosis due to endoscopic or radiological POR. There are also conflicting data as to whether endoscopic recurrences can be used to predict surgical recurrences.¹⁰⁹ Further, there might be a risk of over-estimating endoscopic recurrences in stapled anastomoses, as some ulcerations may be associated with ischaemia or a reaction against the stapler rather than an aphthous ulcer and a recurrent CD.^27,34 Nowadays, postoperative medications and selection of patients in need of such prophylaxis is of prime importance, particularly as the cumulative need of redo surgery in patients diagnosed with CD in the 21st century has been reported as high as 14.8% [95% CI, 11.0–19.7] and 25.5% [95% CI, 11.9–46.6], at 5 and 10 years respectively.⁷

8. Unmet needs and future horizons of POR diagnosis

In patients with CD, a diagnosis of active disease based only on clinical symptoms is not reliable. Instead, a postoperative ileocolonoscopy remains the gold standard to diagnose POR. Although the Rutgeerts score is commonly used in the postoperative setting, the available literature provides conflicting evidence on the need to distinguish patients with lesions confined to the ileocolonic anastomosis [i2a] from patients with more than five isolated aphthous lesions in the neoterminal ileum [i2b]. In the ongoing, prospective, randomised, controlled POMEROL study, endoscopic remission rates [modified Rutgeerts score i0-i1] at 12 months will be evaluated in patients with an i2a or i2b endoscopic POR 6 to 12 months after surgery, who either escalated to subcutaneous infliximab or did not [Clinicaltrials.gov NCT05072782]. Furthermore, the commonly used [modified] Rutgeerts score has not been formally validated and does not consider surgical techniques different from end-to-end anastomosis.²⁵ Although studies evaluating the natural history of postoperative endoscopic recurrence will be hampered by the introduction of medical therapy in case of more severe endoscopic lesions, a more granular scoring of endoscopic POR will be required to evaluate the predictive value of lesions at the ileal inlet, the ileal body, and the ileal blind loop. Furthermore, it is very likely that CLE and other advanced techniques, including artificial intelligence, will be tested in the near future to explore additional features other than endoscopic appearance to diagnose and predict the course of POR.⁵⁸ However, the adjunctive value of these instruments is difficult to predict.

As ileocolonoscopy is often onerous for patients, particularly in the postoperative setting, less invasive imaging techniques have been investigated. CE is highly sensitive in early endoscopic POR, but concerns related to capsule retention and costs limit its use.⁵⁸ Both MRE and IUS significantly correlate with the Rutgeerts score. In addition, they have the advantage of visibility extending to the bowel wall and surrounding space. The accuracy of IUS for detecting severe endoscopic recurrence may ultimately decrease the reliance on ileocolonoscopy in this particular scenario.¹⁵ In cases of milder endoscopic POR that is difficult to detect with radiological tools, the combination of IUS or MRE with FC may increase sensitivity and eventually make ileocolonoscopy redundant.¹¹⁰ In fact, in the past decade, point-of-care FC testing showed accurate prediction of endoscopic POR.⁷⁷ Nevertheless, single cut-off value for FC applicable for all patients remains evasive.

At this stage, we continue to recommend an ileocolonoscopy within 6 to 12 months of surgery to diagnose endoscopic POR [Figure 4], particularly in centres with limited experience in IUS. In absence of prospective studies evaluating a more granular scoring of postoperative endoscopic lesions, endoscopic POR can be defined as a Rutgeerts score ≥i2. Furthermore, this invasive investigation should be combined with a baseline measurement of FC [at the time of endoscopy] to facilitate patient follow-up and with adopting serial testing of this biochemical marker. Systematic evaluation of FC may be helpful also to follow the effect of a treatment that was initiated in case of endoscopic disease activity. In centres with sufficient IUS expertise, the first [and subsequent] ileocolonoscopy may eventually be replaced by serial testing of both IUS and FC. However, a prospective, randomised trial should evaluate if this less invasive approach is as valuable on the long-term. As an alternative to routine prophylactic treatment, in patients with one or more risk factors for recurrence a more intense instrumental follow-up may be proposed [eg, starting at Month 3 after surgery]. Finally, such long-term studies should evaluate surgical POR robustly, and we suggest defining surgical POR after ICR as the need for a new ICR or strictureplasty at the site of the ileocolonic anastomosis due to endoscopic or radiological POR.

Based on this expert review, 12 research priorities for the diagnosis and follow-up of POR have been identified [Table 3].

Scientific Workshop Steering Committee

Pauline Rivière,^a Marc Ferrante,^b,c Yves Panis^d

^aDepartment of Gastroenterology and Hepatology, Centre Médico-chirurgical Magellan, Hôpital Haut-Lévêque, CHU de Bordeaux; Université de Bordeaux; INSERM CIC 1401; Bordeaux, France

^bDepartment of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium

^cTranslational Research in Gastrointestinal Disorders [TARGID], Department of Chronic Diseases and Metabolism [CHROMETA], KU Leuven, Leuven, Belgium

^dParis IBD Center, Groupe Hospitalier Privé Ambroise Paré-Hartmann, Neuilly/Seine, France

Disclaimer

ECCO Scientific Workshop Papers are targeted at health care professionals only and are based on a standardised drafting procedure. Any treatment decisions are a matter for the individual clinician and may not be based exclusively on the content of the ECCO Scientific Workshop Papers. The European Crohn’s and Colitis Organisation and/or any of its staff members and/or any paper contributor may not be held liable for any information published in good faith in the ECCO Scientific Workshop Papers.

In conclusion, despite the limitations of all current diagnostic modalities, consistency in describing and reporting POR is crucial. With the current manuscript, the Eighth Scientific Workshop of the European Crohn’s and Colitis Organisation [ECCO] highlights an overarching need for prospective studies on newer diagnostic modalities other than ileocolonoscopy.

Other collaborators in the 8th Scientific Workshop of the European Crohn’s and Colitis Organisation:

a] Lieven Pouillon, Imelda GI Clinical Research Center, Imelda General Hospital, Bonheiden, Belgium

b] Míriam Mañosa, Department of Gastroenterology and Hepatology, Hospital Universitari Germans Trias i Pujol, Badalona; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], Spain

c] Edoardo Savarino, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; and Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy

d] Matthieu Allez, Gastroenterology Department, Hôpital Saint-Louis - APHP, Université Paris Cité, INSERM U1160, Paris, France

e] Christina Kapizioni, Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

f] Naila Arebi, Department of Inflammatory Bowel Disease, St Mark’s Hospital, Harrow, London, UK

g] Michele Carvello, Department of Biomedical Sciences, Humanitas University, Milan, Italy

h] Annemarie C. De Vries, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands

i] Eugeni Domènech, Department of Gastroenterology and Hepatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], Madrid

j] Gabriele Bislenghi, Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium

k] Bram Verstockt, Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium; and Translational Research in Gastrointestinal Disorders [TARGID], Department of Chronic Diseases and Metabolism [CHROMETA], KU Leuven, Leuven, Belgium

l] Steven Brown, Department of Surgery, Sheffield Teaching Hospitals, Sheffield, UK

m] Melissa Give family name tag. Department of Colorectal Surgery, University Hospitals of Birmingham NHS Trust, Birmingham, UK

n] Willem Bemelman, Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands; and Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy

o] Gianluca Pellino, Department of Advanced Medical and Surgical Science, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy

p] Paulo Gustavo Kotze, IBD Outpatient Clinics, Colorectal Surgery Unit, Pontifícia Universidade Católica do Paraná [PUCPR], Curitiba, Brazil

Conflict of Interest

ECCO has diligently maintained a disclosure policy of potential conflicts of interests [CoI]. The conflict of interest declaration is based on a form used by the International Committee of Medical Journal Editors [ICMJE]. The CoI disclosures are not only stored at the ECCO Office and the editorial office of JCC, but are also open to public scrutiny on the ECCO website [https://www.ecco-ibd.eu/about-ecco/ecco-disclosures.html], providing a comprehensive overview of potential conflicts of interest of the authors. None of the authors declared a conflict of interest.

References