KONO-S Anastomosis Is Not Superior to Conventional Anastomosis for the Reduction of Postoperative Endoscopic Recurrence in Crohn's Disease.

Postoperative Crohn's Disease Recurrence: Time to Adapt Endoscopic Recurrence Scores to the Leading Surgical Techniques

Background Recently, a new antimesenteric, functional, end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence (ER) and surgical recurrence (SR) rate in Crohn’s disease (CD). This trial aimed to provide randomized controlled data comparing Kono-S anastomosis and conventional stapled ileocolic side-to-side anastomosis. Methods Randomized controlled trial (RCT) at a tertiary referral centre. The primary endpoint is ER rate (Rutgeerts score ≥ i2) after 6 months and surgical recurrence at 60 months. Secondary endpoints are clinical recurrence (CR) rate after 24 and 36 months, and SR after 24 and 36 months. Statistics was performed by using standard analyses. Furthermore, a sample size able to consent the detection of a reduction >30% in total endoscopic recurrence (when assuming a 60% to 65% ER expected rate in the control group and a 30% in the case group) was calculated; to allow a 10% drop-out of patients, 36 patients per group were needed (72 patients in the entire population). Results A total of 119 CD patients were included in the study. In all, 51 ileocolic CD patients were randomized in the Kono group and 68 in the conventional side-to-side group. At 6 months, 17 (33.3%) patients in the Kono group and 51 (75%) patients in the conventional group presented an ER (Rutgeerts score≥i2) at colonoscopy (p<0.001). A severe post-operative ER (Rutgeerts score≥i3) was found in 8 (15.7%) patients in the Kono group versus 23 (33.8%) patients in the conventional group (p=0.03). At 24 months, CR rate was 19.6% in the Kono group versus 30.9% in the conventional group (p=0.2), while SR rate was 0% in the Kono group versus 4.4% (3 patients) in the standard group (p=0.2). At 36 months, CR rate was 19.6% in the Kono-s group versus 33.8% in the conventional group (p=0.1). At 36 months, no patients (0%) in the Kono group experienced SR, while 6 patients (8.8%) in the conventional group did (p=0.03). Furthermore, when considering a median follow-up of 54 (42-60) months at interim analysis of SR, the difference between the two groups was confirmed to be significant (0% vs 8.8%; p=0.02). Conclusion This is the first RCT comparing Kono-S anastomosis and conventional side-to-side anastomosis in CD. The results demonstrate a significant reduction in postoperative endoscopic and surgical recurrence rates, no safety issues, and a favourable trend for lower clinical recurrence rate in patients who underwent Kono-S anastomosis compared to the conventional side-to-side anastomosis.

Infliximab treatment of postoperative ulcers in Crohn's disease: to inject or not to inject—that is the question

Early endoscopic evaluation is recommended for assessment of postoperative recurrence (POR) of Crohn's disease (CD) but no further monitoring recommendations are available. To evaluate the long-term outcome of patients without endoscopic POR at first endoscopic assessment. Retrospective four-centre study including consecutive CD patients with ileocolonic resection (ICR) without endoscopic POR (Rutgeerts score i0-i1) at first endoscopic assessment performed within 18 months from ICR. All patients had a clinical follow-up ≥24 months and at least one further endoscopic assessment. Main outcomes were endoscopic, clinical and surgical POR, need for rescue therapy and "delayed POR" (any need for rescue therapy or clinical or surgical POR) during follow-up. Overall, 183 patients were included (79% with risk factors for POR, 44% without postoperative prophylaxis). Endoscopic POR was observed in 42% of patients. Clinical POR-free survival was 89.4% and 81.5% at 3 and 5 years, and delayed POR-free survival was 76.9% and 63.4% at 5 and 10 years, respectively. In multivariate analysis, postoperative prophylaxis (HR .55; 95% CI .325-.942) and active smoking (HR 1.72; 95%CI 1.003-2.962) were independent risk factors for clinical POR, whereas presence of mild endoscopic lesions at index ileocolonoscopy (i1) was the only risk factor for delayed POR (HR 1.824; 95% CI 1.108-3.002). Long-term risk of POR among patients with no or mild endoscopic lesions at first ileocolonoscopy after surgery is steadily low, being higher among smokers, in the absence of postoperative prophylaxis and when mild endoscopic lesions are observed in the first endoscopic assessment.

Background/AimsWe assessed the effectiveness of anti-TNF agents and its associated factors to prevent endoscopic and clinical postoperative recurrence (POR) in Crohn’s disease (CD). MethodsFrom a prospectively-maintained database, we retrieved 316 CD patients who underwent intestinal resection (2011–2017). Endoscopic (Rutgeerts index ≥ i2 at 6 months) and clinical (recurrence of symptoms leading to hospitalization or therapeutic escalation) POR were assessed. ResultsIn 117 anti-TNF-naïve patients, anti-TNF therapy was more effective than immunosuppressive agents (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.8–43.9; P=0.008) and no medication/5-aminosalicylates (OR, 5.2; 95% CI, 1.0–27.9; P=0.05) to prevent endoscopic POR. In 199 patients exposed to anti-TNF prior to the surgery, combination with anti-TNF and immunosuppressive agents was more effective than anti-TNF monotherapy (OR, 2.32; 95% CI, 1.02–5.31; P=0.046) to prevent endoscopic POR. Primary failure to anti-TNF agent prior to surgery was predictive of anti-TNF failure to prevent endoscopic POR (OR, 2.41; 95% CI, 1.10–5.32; P=0.03). When endoscopic POR despite anti-TNF prophylactic medication (n=55), optimizing anti-TNF and adding an immunosuppressive drug was the most effective option to prevent clinical POR (hazard ratio, 7.38; 95% CI, 1.54–35.30; P=0.012). Anti-TNF therapy was the best option to prevent clinical POR (hazard ratio, 3.10; 95% CI, 1.09–8.83; P=0.034) in patients with endoscopic POR who did not receive any biologic to prevent endoscopic POR (n=55). ConclusionsAnti-TNF was the most effective medication to prevent endoscopic and clinical POR. Combination with anti-TNF and immunosuppressive agents should be considered in patients previously exposed to anti-TNF.

Mesenteric hypertrophy has been recognized as an indicator of the complicated course of Crohn's disease. The aim of this study was to investigate whether the visceral fat area (VFA) is associated with postoperative clinical and endoscopic recurrence. Computed tomography was used to measure the subcutaneous fat area and VFA, and the mesenteric fat index (MFI) was defined as the ratio of the VFA to the subcutaneous fat area. Associations between body mass index, subcutaneous fat area, VFA and MFI and postoperative clinical and endoscopic recurrence were investigated. The factors associated with postoperative endoscopic recurrence at 6months after surgery were a high VFA value (P=0.019) and MFI values above the median (P=0.008). VFA values were significantly correlated with endoscopic recurrence (r=0.895, P= 0.040) and endoscopic lesions (r=0.617, P<0.0001). Additionally, MFI values correlated well with endoscopic recurrence (r=0.918, P=0.02) and endoscopic scores (r=0.584, P<0.0001). Multivariate analysis indicated that VFA values above the median (hazard ratio 2.63, 95% CI 1.03-6.74) were predictive of postoperative clinical recurrence in Crohn's disease. A high VFA value is associated with postoperative recurrence of Crohn's disease and has clinical implications with respect to optimizing prophylaxis for each individual. However, further studies are needed to confirm the predictive role of this biomarker in a different data set.

This trial aimed to provide randomized controlled data comparing Kono-S anastomosis and stapled ileocolic side-to-side anastomosis. Recently, a new antimesenteric, functional, end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence score and surgical recurrence rate in Crohn disease (CD). Randomized controlled trial (RCT) at a tertiary referral institution. Primary endpoint: endoscopic recurrence (ER) (Rutgeerts score ≥i2) after 6 months. Secondary endpoints: clinical recurrence (CR) after 12 and 24 months, ER after 18 months, and surgical recurrence (SR) after 24 months. In all, 79 ileocolic CD patients were randomized in Kono group (36) and Conventional group (43). After 6 months, 22.2% in the Kono group and 62.8% in the Conventional group presented an ER [P < 0.001, odds ratio (OR) 5.91]. A severe postoperative ER (Rutgeerts score ≥i3) was found in 13.8% of Kono versus 34.8% of Conventional group patients (P = 0.03, OR 3.32). CR rate was 8% in the Kono group versus 18% in the Conventional group after 12 months (P = 0.2), and 18% versus 30.2% after 24 months (P = 0.04, OR 3.47). SR rate after 24 months was 0% in the Kono group versus 4.6% in the Conventional group (P = 0.3). Patients with Kono-S anastomosis presented a longer time until CR than patients with side-to-side anastomosis (hazard ratio 0.36, P = 0.037). On binary logistic regression analysis, the Kono-S anastomosis was the only variable significantly associated with a reduced risk of ER (OR 0.19, P < 0.001). There were no differences in postoperative outcomes. This is the first RCT comparing Kono-S anastomosis and standard anastomosis in CD. The results demonstrate a significant reduction in postoperative endoscopic and clinical recurrence rate for patients who underwent Kono-S anastomosis, and no safety issues.ClinicalTrials.gov ID NCT02631967.

The Value of Myenteric Plexitis to Predict Early Postoperative Crohn’s Disease Recurrence

Background An ileocolonic resection with ileocolonic anastomosis is often required in patients with Crohn’s disease (CD). Postoperative recurrence (POR) is common, with host-luminal interactions being implicated. However, these interactions are poorly understood. We aimed to obtain insights in the early mechanisms of POR CD focusing on sequencing-based gene networks in the mucosa. Methods We included 36 CD patients who underwent ileocolonic resection with ileocolonic anastomosis, and collected mucosal biopsies from the neoterminal ileum 6 months after surgery (Table 1). We defined POR by a Rutgeerts score ≥i2b at month 6, and compared this to complete absence of endoscopic activity (i0). All biopsies underwent single-end RNA sequencing (Illumina TruSeq Stranded mRNA). Gene co-expression network clusters were identified using weighted gene co-expression network analysis (R\WGCNA), were tested for correlation with the primary outcome POR and clinical factors, and multiple testing correction was applied (FDR&amp;lt;0.05). Cellular deconvolution was performed using xCell; and top enriched pathways and upstream regulators were analysed using IPA (p&amp;lt;0.05). Results WGCNA analysis identified 25 co-expression clusters, of which five correlated with the postoperative outcome (clusters V, VI, IX, XV, XXV) (Fig.1). All but cluster XXV were upregulated in POR, with a profound immune-related enrichment in cluster V and VI (eg. (a)granulocyte adhesion and diapedesis, and IL17 signalling); microRNA biogenesis (cluster IX) and wound healing and fibrosis signalling (cluster XV). Interestingly, one cluster (XXV) was inversely correlated with POR, and genes within this cluster were mainly involved in autophagy, ferroptosis and oxidative stress response. The main hub gene (r=0.95, FDR=8.17E-19) within this cluster XXV was GPX4 (Glutathione peroxidase 4), a negative regulator of ferroptosis. Moreover, after cellular deconvolution, we found a positive correlation between the epithelial gene enrichment signature and the expression of GPX4 (r=0.52, p=0.0011). Finally, the main upstream regulator of the genes within this cluster XXV was HNF4A, a transcription factor known to regulate ferroptotic response. Conclusion We identified a mucosal transcriptomic signature associated with postoperative CD recurrence. Both autophagy and ferroptosis were found to be key protective pathways for recurrence with GPX4 as central hub. Our results complement recent findings of impaired epithelial GPX4 activity in ileal CD lesions evoking an inflammatory response to dietary lipids (Mayr et al Nat Comm 2020).

Is stapled Kono-S anastomosis a protective factor against postoperative endoscopic recurrence in Crohn disease? A single-center, retrospective cohort study.

Background Recently, a new antimesenteric, functional end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence score and surgical recurrence rate in Crohn’s disease (CD).This trial aimed to provide randomised controlled data comparing Kono-S anastomosis and stapled ileocolic side-to-side anastomosis. Methods Randomised controlled trial at a tertiary referral institution, enrolling and randomising to undergo either the ‘Kono group’ or the ‘Conventional group’, all CD subjects needing surgery. Primary endpoint: endoscopic recurrence (ER) (Rutgeerts score ≥i2) after 6 months. Secondary endpoints: clinical recurrence (CR) after 12 and 24 months, ER after 18 months and surgical recurrence (SR) after 24 months. Also, short-term outcomes and postoperative complications were recorded. A sample size of 70 patients (35 in each group) was considered necessary to demonstrate a reduction &amp;gt;30% in endoscopic recurrence at 6 months follow-up in the Kono group when assuming a 60% endoscopic recurrence expected rate in the control group. Results 79 CD patients were enrolled and randomised in the Kono group (36) or Conventional group (43) (Table 1). After 6 months, 22.2% in the Kono group and 62.8% in the Conventional group presented an ER (p &amp;lt; 0.001; OR 5.91). A severe postoperative ER (Rutgeerts score ≥i3) was found in 13.8% of Kono vs. 34.8% of Conventional group (p = 0.03; OR 3.32). CR rate was 8% in the Kono group vs. 18% in the Conventional group after 12 months (p = 0.2) and 18% vs. 30.2% after 24 months (p = 0.04, OR 3.47). SR rate after 24 months was 0% in the Kono group vs. 4.6% in the Conventional group (p = 0.3). Patients with Kono-S anastomosis presented a longer time until CR than patients with side-to-side anastomosis (HR 0.36, p = 0.037). On binary logistic regression analysis, the Kono-S anastomosis was the only variable significantly associated with a reduced risk of ER (OR 0.19, p &amp;lt; 0.001). About postoperative outcomes, there were no differences between Kono and Conventional groups in terms of surgery duration (p = 0.8), days to gas (p = 0.4) or stool canalisation (p = 0.8) and postoperative stay (p = 0.3). Infections (included wound infection) were found in 4 subjects in the Kono group (13.7%) vs. 6 patients (16.6%) in the Conventional group (p = 0.749). Conclusion This is the first RCT comparing Kono-S anastomosis vs. standard anastomosis in CD, which found a significant reduction of postoperative endoscopic recurrence rate by using the novel technique, without concerns about safety. The Kono-S anastomosis could be considered the new recommended surgical technique in CD. ClinicalTrial.gov NCT02631967.

Background As no direct comparison between IBD drugs to prevent endoscopic postoperative recurrence (POR) In Crohn’s disease (CD) are available, hierarchizing these therapeutic options remains challenging. The objective of this network meta-analysis was to compare the effectiveness of treatments to prevent endoscopic POR of CD. Methods We performed a systematic review and network meta-analysis of comparative studies conducted in adults, evaluating a treatment to prevent endoscopic POR after ileocecal resection. The selection of studies was made according to PRISMA guidelines. The primary endpoint was endoscopic POR at 6 months defined as Rutgeerts score ≥ i2. The network meta-analysis was carried out according to a random effects model. The results are presented as odds ratio (OR) with 95% confidence interval, adjusted for risk factors of POR. The risk of bias of the studies was assessed according to the Cochrane risk-of-bias tool for randomized trials and overall statistical heterogeneity between studies was assessed using τ². The SUCRA ranking method (surface under the cumulative ranking) was used to rank the treatments. Results Twenty studies were included in this network meta-analysis, including a total of 2414 patients. Overall heterogeneity was moderate (τ²=0.34). After adjustment for POR risk factors, ustekinumab (OR = 0.23 [0.07-0.70]), vedolizumab (OR = 0.17 [0.05 -0.59]), infliximab (OR = (0.18 [0.36-0.88]) and adalimumab (OR = 0.17 [0.07-0.42]) were superior to placebo to prevent endoscopic POR, contrary to 5-ASA (OR = 0.79 [0.42 -1.48]) and thiopurines (RR = 0.52 [0.22-1.24]) (Table 1). Ustekinumab (OR = 0.29 [0.08-0.99]), vedolizumab (OR = 0.22 [0.06-0.85]), infliximab (OR = (0.23 [0.09-0.54]) and adalimumab (OR = 0.22 [0.08-0.59]) were more effective than 5-ASA in preventing endoscopic POR. Adalimumab (OR = 0.33 [0.15-0.74]) and infliximab (OR = 0.34 [0.13-0.87]) were also more effective than thiopurines. We observed no difference in efficacy between the 4 biologics (infliximab, adalimumab, ustekinumab and vedolizumab) (Table 1). The SUCRA ranking identified adalimumab (SUCRA=0.81), infliximab (SUCRA=0.80), vedolizumab (SUCRA=0.79) and ustekinumab (SUCRA=0.72) as the most effective treatments. The likelihood that thiopurines (SUCRA=0.41), 5-ASA (SUCRA=0.24), placebo (SUCRA = 0.16) and antibiotics (SUCRA=0.08) was the best option is very low. Conclusion This network meta-analysis confirms the efficacy of anti-TNF agents, vedolizumab and ustekinumab in preventing endoscopic CD POR without any difference between them. When prophylactic therapy is necessary, biologics appear as the best therapeutic option to prevent of endoscopic POR. Due to lower efficacy, the use of 5-ASA and thiopurines should be limited in this situation.

Kono-S anastomosis has gained increasing interest although evaluation of its impact on reducing Crohn's recurrence shows conflicting results. This study aimed to evaluate the short- and long-term outcomes for patients with Crohn's disease requiring surgery with Kono-S compared to conventional anastomosis. A systematic review and meta-analysis included patients with Crohn's disease treated with bowel resection and Kono-S anastomosis reconstruction versus a comparator arm of conventional anastomosis technique. Recurrence outcomes examined were endoscopic recurrence rates, mean postoperative Rutgeerts score, surgical recurrence, clinical recurrence, and postoperative biologics use. Short-term postoperative outcomes include anastomotic leaks, surgical site infection, postoperative ileus, and mean operative time. A total of 873 studies were identified with 15 remaining after abstract review encompassing 1501 patients, 765 with Kono-S and 736 with conventional anastomosis. Recurrence was significantly lower in the Kono-S arm, with endoscopic recurrence rates of 41% vs 48% (RR 0.86, 95%CI 0.73-1.00, p = 0.05) and surgical recurrence rates of 2.7% vs 21.0% (RR 0.13, 95%CI 0.06-0.30, p < 0.001). There was a significantly lower anastomotic leak rate in the Kono-S arm when compared to conventional anastomosis, 1.7% vs 4.9% (RR 0.37, 95%CI 0.19-0.74, p = 0.005). Mean operative time was similar between both groups. Kono-S is a safe and feasible anastomotic technique with lower rates of endoscopic and surgical postoperative recurrence. While we await further trials to substantiate this benefit, Kono-S anastomosis should be considered as an important tool in the armamentarium of a surgeon in anastomotic construction to reduce recurrence.

Background We used the postoperative recurrence model to better understand the role of AIEC bacteria in Crohn’s disease (CD), taking advantage of a well-characterized postoperative cohort. Methods From the REMIND prospective, multicenter cohort of operated CD patients (ileocolonic resection), AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neo-terminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts’ index, which was interpreted, either from a clinical point of view (postoperative endoscopic recurrence ≥ i2b or severe ≥ i3), or from a pathophysiological point of view (reappearance of the first ileal lesions = i1 and more advanced postoperative ileal recurrence = i2b + i3). The mucosa-associated microbiota was analyzed by 16S sequencing at M0 and M6. Relative risks (RR) or odds ratios (OR) were adjusted on potential confounders ((gender, smoking, CD duration, CD phenotype, prior bowel resection, indication for surgery, granuloma, preventive treatment, antibiotics). Results Among the 228 patients included at the time of the analyzes, the search for AIEC was carried out in 181 patients at M0, and 119 patients at M6. Among these 181 patients included in our study, 46.3% did not receive any preventive treatment for endoscopic postoperative endoscopic recurrence while 24.3% have been treated with anti-TNF to prevent postoperative recurrence. AIEC prevalence was two-fold higher within the neo-terminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (p&amp;lt;0.001). AIEC within the neo-terminal ileum at M6 was associated with higher rate of early ileal lesions (i1) (41.6% vs 17.1%; aRR=3.49[1.01–12.04], p=0.048) or ileal lesions (i2b + i3) (38.2% vs 17.1%; aRR=3.45[1.06–11.30], p=0.040) compared to no lesion (i0). AIEC within the surgical specimen was predictive of higher risk of i2b-endoscopic POR (aOR=2.54[1.01–6.44], p=0.049) and severe endoscopic POR (aOR=3.36 [1.25–9.06], p=0.017). While only 5.0% (6/119) of the patients were AIEC-positive at both M0 and M6, 43.7% (52/119), patients with history of AIEC infection (M0 or M6) had higher risk of ileal endoscopic POR (aOR=2.32 [1.01–5.39], p=0.048]), i2b-endoscopic postoperative recurrence (aOR = 2.41[1.01–5.74]; p=0.048) and severe endoscopic postoperative (aOR = 3.84[1.32–11.18], p=0.013). AIEC colonization was associated with a specific microbiota signature including increased abundance of Ruminococcus gnavus. Conclusion Based on the postoperative recurrence model, our data support the role of AIEC in the early steps of ileal CD.

Tu1337 Anti-TNFα Treatment Efficacy in Prevention of Postoperative Recurrence in Crohn's Disease Depends on Previous Exposure to Anti-TNFα Agents