The relationship between endoscopic and clinical recurrence in postoperative Crohn’s disease: a systematic review and meta-analysis

Background and Aims We aimed to quantify the magnitude of the association between endoscopic recurrence and clinical recurrence [symptom relapse] in patients with postoperative Crohn’s disease. Methods Databases were searched to October 2, 2020 for randomised controlled trials [RCTs] and cohort studies of adult patients with Crohn’s disease with ileocolonic resection and anastomosis. Summary effect estimates for the association between clinical recurrence and endoscopic recurrence were quantified by risk ratios [RR] and 95% confidence intervals [95% CI]. Mixed-effects meta-regression evaluated the role of confounders. Spearman correlation coefficients were calculated to assess the relationship between these outcomes as endpoints in RCTs. An exploratory mixed-effects meta-regression model with the logit of the rate of clinical recurrence as the outcome and the rate of endoscopic recurrence as a predictor was also evaluated. Results Thirty-seven studies [N=4053] were included. For 8 RCTs with available data, the RR for clinical recurrence for patients who experienced endoscopic recurrence was 10.77 [95% CI 4.08-28.40; GRADE moderate certainty evidence]; the corresponding estimate from 11 cohort studies was 21.33 [95% CI 9.55-47.66; GRADE low certainty evidence]. A single cohort study showed a linear relationship between Rutgeerts score and clinical recurrence risk. There was a strong correlation between endoscopic recurrence and clinical recurrence treatment effect estimates as trial outcomes [weighted Spearman correlation coefficient 0.51]. Conclusions The associations between endoscopic recurrence and subsequent clinical recurrence lend support to the choice of endoscopic recurrence to monitor postoperative disease activity and as a primary endpoint in clinical trials of postoperative Crohn’s disease.

Endoscopic Prediction of Crohn’s Disease Postoperative Recurrence

Background The presence and severity of endoscopic recurrence after Crohn's disease intestinal resection predicts subsequent disease course. The Rutgeerts postoperative endoscopic recurrence score is unvalidated but has proven prognostically useful in many clinical studies. This study aimed to investigate the association between specific early endoscopic findings and subsequent disease course. Methods In the setting of a randomized controlled trial (the POCER study), 85 patients underwent colonoscopy at 6 and 18 months after intestinal resection. Patients received 3 months of metronidazole, and high-risk patients received a thiopurine (or adalimumab if they were thiopurine intolerant). For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped up to a thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. Central readers confirmed Rutgeerts, Simple Endoscopic Score for Crohn’s Disease, Crohn’s Disease Endoscopic Index of Severity scores, and 5 newly tested endoscopic parameters: anastomotic ulcer depth (superficial vs deep), number of ulcers (0, ≤2, >2), ulcer size (1-5 mm, ≥6 mm), circumferential extent of ulceration (<25%, ≥25%), and the presence or absence of stenosis. The POCER index, based on the 6-month postoperative findings, was then developed in relation to predicting the endoscopic outcome at 18 months. Results Of the 5 parameters, the combination of ulcer depth and circumference at the anastomosis at 6 months was associated with endoscopic recurrence at 18 months (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.03-2.50; P = 0.035) with an area under the receiver operating characteristic curve of 0.62 (95% CI, 0.5-0.75). The combination of these 2 parameters formed the basis of the POCER index (range, 0-4 with 0 denoting no ulcers and 4 denoting deep ulceration with >25% circumferential involvement). The new index had a strong correlation with the Rutgeerts score measured at the same time points: Spearmans’ r = .80 at 6 months and r = .77 at 18 months (P < 0.001 at both time points). A POCER index of ≥2 and a Rutgeerts score of ≥i2 both had a sensitivity of 0.41 for recurrence; however, the POCER index had a higher specificity (0.8 and 0.67, respectively). The POCER index at 6 months was associated with endoscopic recurrence at 18 months (OR, 1.5; 95% CI, 1.2-2.0; P = 0.002; area under the receiver operating characteristic curve of 0.70; 95% CI, 0.57-0.82), but the Rutgeerts score was not (OR, 1.2; 95% CI, 0.8-1.8; P = 0.402). Conclusions The POCER postoperative index comprises 2 key endoscopic factors related to the anastomosis that are associated with subsequent disease progression. A higher score, comprising the adverse prognostic factors of deep or circumferentially extensive anastomotic ulceration, may help identify patients who require more intensive therapy.

Wireless Capsule Endoscopy for Diagnosis and Management of Post-Operative Recurrence of Crohn’s Disease

Despite aggressive medical therapy, many patients with Crohn’s disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score ‘per se’ bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn’s disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy.

P190 Ileo-caecal Crohn’s Disease; medical or surgical management. Cost and outcomes

Background An ileo-caecectomy is known to be an effective treatment for Crohn’s disease limited to the terminal ileum that can lead to a long term remission. ECCO guidelines recommend that patients with active inflammation should be treated medically. However the LIR!C trial suggested there are QOL benefits and reduced costs to performing primary surgery. Methods We aimed to compare the outcomes of patients treated with primary medical treatment to primary surgery for patients with Crohn’s disease limited to the terminal ileum. We reviewed our database to identify all these patients and analysed outcome data. Results 49 patients were identified: Mean age was 50 yrs (range 22 - 93). 23 were male. Mean length of follow-up was 96 months (range 3 - 404). 1st line treatment was: medical; 33 (67.3%), surgery; 16 (32.6%). Outcomes after medical treatment: 27 of 33 patients failed primary medical treatment, they required surgery at a mean of 38 months (range 1–900) after initiating medical treatment. Colonoscopy after surgery to assess for disease recurrence: Colonoscopic assessment or calprotectin post was undertaken ileo-caecectomy in 4 of 16 patients at a mean of 6.2 months (range 1–10) who underwent primary surgery; and in 25 of 27 patients who underwent surgery following failure of medical treatment. Outcomes after surgery: 4 of 16 patients who had primary surgical treatment had endoscopic recurrence, requiring medical treatment after a mean of 4.4 months (range 0–10). 8 of 27 patients who had surgery post-failure of medical treatment developed disease recurrence, requiring medical treatment after a mean of 40 months (range 7–136) Bile acid malabsorption (BAM): BAM occurred after surgery in 10 of 43 patients. No medically managed patient developed BAM. Conclusion These data suggest that in our population the vast majority of patients with ileo-caecal Crohn’s disease will fail medical treatment and require surgery. 25% of those who undergo surgery will develop BAM (requiring medication), and 40% of those treated surgically will require immunosuppressant treatment in the medium term. These outcomes should be discussed with patients so that they appreciate that ileo-caecectomy is unlikely to lead to long term drug free treatment, and medical treatment is unlikely to lead to the avoidance of surgery. From a health-economics point of view it could be argued there is little point in offering primary medical therapy and ileo-caecectomy should be the initial treatment of choice for patients with limited ileo-caecal Crohn’s disease. Unfortunately endoscopic/calprotectin assessment following primary surgery was often not performed in the majority of patients, and changes in our local practice need to be undertaken to correct this.

DOP36 Non-invasive assessment of postoperative disease recurrence in Crohn’s Disease: A multicenter, prospective cohort study

Background Prevention of postoperative recurrence is a critical goal in Crohn’s disease (CD) management. Currently, postsurgical CD management and treatment are based on endoscopic monitoring performed within the first year after surgery. However, colonoscopy (CS) is an invasive and expensive procedure, unpleasant to patients. A non-invasive and patient friendly approach is required. Methods Consecutive CD patients who underwent ileo-cecal resection from July 2017 to January 2020 were prospectively enrolled in three Italian Centers and performed CS and bowel ultrasound (US) after six months from the surgery, in a blinded fashion. The patients also underwent complete clinical assessment and blood and stool samples were obtained for C-reactive protein (CRP), and fecal calprotectin (FC) measurements. The disease was considered clinically active if the Harvey–Bradshaw Index (HBI) was higher than 4. Uni- and multivariable analyses were used to assess the correlation between non-invasive parameters, including bowel US findings and FC values and endoscopic recurrence, defined by a Rutgeerts’s score (RS) > 2. Sensitivity, specificity, accuracy, PPV and NPV of bowel US parameters alone and in combination with FC in assessing endoscopic recurrence were calculated. Results Seventy patients were enrolled, 45 patients (64%) had an endoscopic recurrence (RS > 2) at 6 months. Thirteen out of 45 (29%) were symptomatic (HBI > 4). Bowel wall thickness (BWT), bowel wall flow (BWF, presence of vascular signals at color Doppler), the presence of mesenteric hypertrophy, the presence of limph-nodes and FC values significantly correlated with the endoscopic recurrence (p < 0.005). Independent predictors for endoscopic recurrence were BWT (for 1-mm increase: OR 2.63; 95% CI 1.136.12; p= 0.024), presence of lymph-nodes (OR 23.24; 95% CI 1.85291.15; p= 0.014) and FC > 50 µg/g (OR 11.86; 95% CI 2.60–54.09; p= 0.001). Sensitivity, specificity, accuracy, PPV and NPV of bowel US and/or FC are showed in Table 1. Table 1: Diagnostic accuracy of Bowel US and/or FC compared to CS in assessing endoscopic activity (CI 95%): per-patient analysis Conclusion Combined use of bowel US and FC is accurate in assessing endoscopic recurrence at 6 months in CD patients and represent a valid alternative to endoscopic assessment after surgery

P678 Definition of a microbial signature as a predictor of post-surgical recurrence in patients with Crohn’s disease

Background Although there are several effective drugs for the treatment of Crohn’s disease (CD), almost 80% of patients will end up needing a surgical resection throughout their lives. This procedure is not always curative, as the disease often reappears in the intestine. Endoscopic recurrence occurs in 65%-90% of patients after one year from surgery. The aetiology of the recurrence is unknown; however, several studies have shown how the resident microbiota is modified after surgery. The aim of this study is to evaluate samples from patients with CD before and after an intestinal resection to determine if at baseline there are differences in the abundance of different microbial markers, which could be capable of predicting endoscopic recurrences. Methods In this observational study, a stool sample was obtained from 20 patients with CD before undergoing surgery, recruited at Hospital Universitari Dr. Josep Trueta, Hospital Universitari of Bellvitge, and the Hospital Universitari Germans Trias i Pujol. From each sample, DNA was purified and the relative abundance of the following microbial markers was quantified using qPCR: F. prausnitzii (Fpra) and its phylogroups (PHG-I and PHG-II), E. coli (Eco ), A. muciniphila (Akk), Ruminococcus sp. (Rum), Bacteroidetes (Bac), M. smithii (Msm), and total bacterial load (Eub). Results Individually, none of the biomarkers demonstrated the ability to differentiate patients who will develop post-surgical recurrence from those who will not. In contrast, the combination of 4 microbial markers (Eco, PHGI, Bac, and Eub) showed a high capacity of discrimination between the 2 groups. The algorithm that incorporates these three markers shows a sensitivity and specificity of 100% and 90.91%, respectively, and a positive and negative predictive value of 90.00% and 100%, respectively. Conclusion A microbial signature to determine patients who will have post-surgical recurrence has been identified. This tool can be very useful in daily clinical practice allowing to schedule a personalized therapy, enabling preventive treatment only in that subgroup of patients who really require it. A broader prospective study will be needed to validate these results.

DOP17 In high-risk Crohn’s Disease patients, anastomosis configuration types have similar rates of endoscopic recurrence

Background There is conflicting data on the influence of surgical anastomosis configuration on endoscopic postoperative recurrence (POR) of Crohn’s disease (CD) following ileocolonic resection (ICR). Furthermore, whether this relationship differs by preoperative risk factors for POR has not been studied. We aimed to assess the role of ileocolonic anastomosis type on the rate and time to POR by preoperative POR risk. Methods Retrospective cohort study of adult CD patients who underwent ICR between 2009–2020 at a quaternary IBD referral center. Patients with a primary or secondary anastomosis and ≥1 postoperative colonoscopy were included. Endoscopic activity was assessed by modified Rutgeerts’ scoring. POR was defined as Rutgeerts’ ≥ i2b. Patients were categorized by anastomosis type: end-to-end (ETE), end-to-side (ETS), or side-to-side (STS). High-risk CD patients were defined by ≥1: age ≤ 30 years, active smoker, or ≥2 ICR for penetrating disease. Results 548 CD patients (52.6% female, age 35 y, 15.5% > 1 prior ICR, 19.7% on biologic prophylaxis, 74.8% high-risk for POR) were included in the study (Figure 1). The majority received a STS (52.0%, N=285), 27.2% ETS, and 20.8% ETE. Patients with an ETE were diagnosed with CD at a younger age (p=0.04), had more penetrating disease (p=0.01), hand-sewn anastomoses (p <0.001), and diverting loop ileostomies (p=0.02). There were no differences in prior ICR, smoking, biologic prophylaxis, or in median time from ICR to first post-operative colonoscopy (388.5 days, p=0.41) or POR detection (905 days, p=0.8) by anastomosis type. ETS patients had a shorter median follow-up time (3.9 y, p=0.02). The majority (55.7%) of all patients experienced POR (57% ETS; 55.4% STS; 54.4% ETE). Overall, there was no significant association between anastomosis type and POR rate (p=0.91) or time to POR (p=0.32). However, in high-risk CD patients, ETS was significantly associated with more rapid time to POR on log-rank (p=0.03) and multivariable Cox modeling (HR=1.51; p=0.04). Postoperative prophylactic biologic therapy initiated within 3 months of ICR significantly delayed POR in the overall cohort (HR=0.64; p=0.012) and the high-risk CD subgroup (HR=0.67; p=0.047). High-risk CD patients on prophylactic biologics had no difference in time to POR by anastomosis type (p=0.66). Conclusion In post-operative CD patients, there is no difference in rates of endoscopic recurrence by anastomosis configuration regardless of risk stratification. In high-risk patients, ETS was associated with more rapid endoscopic recurrence compared to other configurations, however prophylactic postoperative biologics may protect against this effect. Figure 2: KM Survival analysis of time (days) to POR