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Background There is a growing need for biomarkers of inflammation to monitor and predict therapeutic outcome in Crohn’s disease (CD) patients. We aimed to evaluate whether the level of circulating blood cells, expressed as ratios (NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; ELR, eosinophil-to-lymphocyte ratio and ENLR, eosinophil*neutrophil-to-lymphocyte ratio), could be used as early prognostic biomarker of endoscopic response (ER) in patients starting biological therapy with infliximab, adalimumab, vedolizumab and ustekinumab. Association with steroid-free clinical remission at week 54 and endoscopic disease activity at baseline, as well as other variables related with ER were also evaluated as secondary outcomes. Methods Consecutive patients with CD who started biological therapy between June 2016 and July 2019 in two Italian tertiary centers were enrolled. We used multivariate analysis to evaluate whether NLR, PLR, ELR and ENLR at baseline and after 12 weeks of treatment could predict ER (SES-CD ≤ 2 or SES-CD ≤ 2 and Rutgeerts score i0-i1) after 54 weeks of treatment. Receiver operating characteristic (ROC) curves were generated to identify the area under the curve (AUC) and find the best cut-off values of NLR, PLR, ELR and ENLR for the prediction of ER. To enhance the diagnostic performance, these ratios were combined with baseline Harvey Bradshaw Index (HBI) in a prognostic model. Results 107 patients were included. Patients who achieved ER had significantly lower baseline NLR (p = 0.025), ELR (p = 0.013) and ENLR (p = 0.021) compared with those without ER; similar results were confirmed after 12 weeks of treatment for ELR (p = 0.006) and ENLR (p = 0.026). AUC was 0.64 (p = 0.003), 0.67 (p = 0.006) and 0.65 (p = 0.014) for NLR, ELR and ENLR, respectively. The best cut-offs values were included in the HBI-based prognostic model: 81.8% of patients with HBI ≥ 5 and higher ratios did not achieve ER, while all patients with HBI < 5 and lower ratios reached ER. Interestingly, ENLR was found to be linearly associated with SES-CD at baseline (p = 0.035). Conclusion To the best of our knowledge, this is the first study assessing NLR, ELR and ENLR as predictive markers of therapeutic response in CD patients. Low levels of these ratios can predict endoscopic response and could be used in clinical practice for a better management of CD patients needing biological therapy. Further prospective studies are needed to confirm these results in larger cohorts.

Background The role of Vedolizumab (VDZ) as therapeutic option for the postoperative recurrence of Crohn’s disease (CD) following ileocolonic resection is currently unknown. We aimed to assess the effectiveness of VDZ in this setting. Methods All consecutive CD patients with an available baseline colonoscopy at 6-12 months from the ileocolonic resection and treated with VDZ for the postoperative recurrence after the baseline colonoscopy were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). The primary outcome was endoscopic success, assessed at the first colonoscopy following initiation of VDZ. In patients with Rutgeerts score i0 or i1 at baseline, endoscopic success was defined by maintenance of Rutgeerts score i0 or i1; in patients with Rutgeerts score ≥ i2 at baseline, it was defined as reduction of at least one point of Rutgeerts score. The secondary outcome was clinical failure, assessed at one year and at the end of follow-up. Results Seventy patients were included (median follow-up: 23.5 months). All 9 patients without endoscopic recurrence at baseline (Rutgeerts score i0 or i1) and available post-treatment colonoscopy maintained a Rutgeerts score i0 or i1 (treatment success: 100%). In patients with endoscopic recurrence (Rutgeerts score ≥ i2 at baseline), a reduction of at least one point in the Rutgeerts score was obtained in 20 out of 42 patients (47.6%). By combining the two subgroups, the overall endoscopic success was achieved in 29 out of 51 patients (56.9%). Furthermore, 14 out of 42 patients (33.3%) with endoscopic recurrence at baseline achieved a Rutgeerts score i0 or i1 at the subsequent colonoscopy. Clinical failure was reported in 13/70 patients (18.6%) at one year, and in 23/70 patients (32.9%) at the end of follow-up. A new resection was required in 7/70 patients (10.0%). Conclusion VDZ may be a therapeutic option for the management of postoperative recurrence of CD. Further studies are needed to confirm these results.

Background In a 6-year, multicenter, prospective nested case–control study, we aimed to evaluate risk factors for incident cancer in inflammatory bowel disease (IBD), when considering clinical characteristics of IBD and immunomodulator use. The secondary end point was to provide characterization of incident cancer types. Methods All incident cases of cancer occurring in IBD patients from December 2011–2017 were prospectively recorded in 16 Italian Group for the Study of Inflammatory Bowel Disease units. Each of the IBD patients with a new diagnosis of cancer was matched with 2 IBD patients without cancer, according to IBD phenotype (ulcerative colitis [UC] vs Crohn’s disease [CD]), age (±5 years), sex. Risk factors were assessed by multivariate logistic regression analysis. Results Cancer occurred in 403 IBD patients: 204 CD (CD cases), 199 UC (UC cases). The study population included 1209 patients (403 IBD cases, 806 IBD controls). Cancer (n = 403) more frequently involved the digestive system (DS; 32%), followed by skin (14.9%), urinary tract (9.7%), lung (6.9%), genital tract (6.5%), breast (5.5%), thyroid (1.9%), lymphoma (2.7%, only in CD), adenocarcinoma of the small bowel (SBA; 3.9%, 15 CD, 1 pouch in UC), other cancers (15.9%). Among cancers of the DS, colorectal cancer (CRC) more frequently occurred in UC (29% vs 17%; P < 0.005), whereas SBA more frequently occurred in CD (13% vs 6.3% P = 0.039). In CD, perforating (B3) vs non-stricturing non-perforating (B1) behavior represented the only risk factor for any cancer (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.33–4.11). In CD, risk factors for extracolonic cancer (ECC) were a B3 vs B1 and a stricturing (B2) vs B1 behavior (OR, 2.95; 95% CI, 1.62–5.43; OR, 1.79; 95% CI, 1.09–2.98). In UC, risk factors for ECC and for overall cancer were abdominal surgery for UC (OR, 4.63; 95% CI, 2.62–8.42; OR, 3.34; 95% CI, 1.88–5.92) and extensive vs distal UC (OR, 1.73; 95% CI, 1.10–2.75; OR, 1.99; 95% CI, 1.16–3.47). Another risk factor for ECC was left-sided vs distal UC (OR, 1.68; 95% CI, 1.00–2.86). Inflammatory bowel disease duration was a risk factor for skin and urinary tract cancers. Conclusions Perforating CD, extensive UC, and abdominal surgery for UC were identified as risk factors for overall incident cancer and for ECC. The clinical characteristics associated with severe IBD may increase cancer risk.

Background No real-life study aiming at comparing at the same time the effectiveness of vedolizumab (VDZ), adalimumab (ADA), and golimumab (GOL) in Ulcerative colitis (UC) is currently available. Methods Data of consecutive patients with UC treated with VDZ, ADA, and GOL from June 2015 to December 2018 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). A three-arms propensity score-adjusted analysis was performed to reduce bias caused by imbalanced covariates at baseline, including the proportion of TNF-α inhibitor naïve and non-naïve patients, using the Inverse Probability of Treatment Weighting (IPTW) method. The effectiveness was evaluated at 8 weeks, 52 weeks, and as treatment persistence at the end of follow-up. The clinical endpoints were steroid-free clinical remission (partial Mayo score Results A total of 463 treatments (VDZ: n = 187; ADA: n = 168; GOL: n = 108) were included, with a median follow-up of 47.6 weeks (IQR 20.0–85.9). At 8 weeks, a clinical benefit was achieved in 70.6% patients treated with VDZ, in 68.5% patients treated with ADA, and in 67.6% patients treated with GOL (p = n.s. for all comparisons). After 52 weeks, VDZ showed better rates of clinical benefit compared with both ADA (71.6% vs. 47.5; OR: 2.79, 95% CI 1.63–4.79, p < 0.001) and GOL (71.6% vs. 40.2%; OR: 3.77, 95% CI 2.08–6.80, p < 0.001), while the difference between ADA and GOL was not significant. Cox survival analysis demonstrated that patients treated with VDZ had a reduced probability of treatment discontinuation compared with those treated with ADA (HR: 0.42, 95% CI 0.28–0.64, p < 0.001) and GOL (HR: 0.30, 95% CI 0.19–0.46, p < 0.001), while patients treated with ADA had a reduced risk of treatment discontinuation compared with those treated with GOL (HR: 0.71, 95% CI 0.50–1.00, p = 0.048). Post-treatment mucosal healing rates showed a numerical but non-significant difference in favour of VDZ (48.1%) compared with ADA and GOL (38.0% and 34.6%, respectively). Conclusion In the first study comparing at the same time the clinical effectiveness of VDZ, ADA, and GOL in UC patients via propensity score-adjusted analysis, VDZ was superior to both subcutaneous agents at 52 weeks and as treatment persistence, while ADA showed a superior treatment persistence compared with GOL.

Background Currently, there are no randomised controlled trials focussing on direct comparisons between biologics in Crohn’s disease (CD), while there is an unmet need to better understand and compare the effectiveness of these drugs. We performed a multicentre, real-life, comparison of the effectiveness of vedolizumab (VDZ) and adalimumab (ADA) in CD. Methods Data of consecutive patients with CD treated with VDZ and ADA from January 2016 to April 2019 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). A propensity score analysis was performed using the Inverse Probability of Treatment Weighting (IPTW) method. The effectiveness was evaluated at 12 weeks, 52 weeks, and as treatment persistence at the end of follow-up. The clinical endpoints were steroid-free clinical remission (Harvey–Bradshaw Index < 5 without steroid use) and clinical response (reduction of the Harvey–Bradshaw Index ≥ 3 points with a concomitant decrease of steroid dosage compared with baseline). The sum of the two outcomes was defined as a clinical benefit. The achievement of endoscopic response (a reduction of Simple Endoscopic Score for CD ≥ 50% compared with baseline) or mucosal healing (Simple Endoscopic Score for CD ≤ 2) was assessed after at least 6 months of treatment. Results A total of 585 treatments (VDZ: n = 277; ADA: n = 308) were included, with a median follow-up of 56.0 weeks (IQR 24.0–104.0). After 12 weeks, a clinical benefit was achieved in 64.3% patients treated with VDZ and in 83.1% patients treated with ADA (p = 0.11 in propensity score analysis), while at 52 weeks a clinical benefit was observed in 54.0% patients treated with VDZ and in 69.1% patients treated with ADA (p = 0.33 in propensity score analysis). The median treatment persistences for VDZ and ADA were 52 weeks and 64 weeks, respectively. Cox survival analysis weighted for IPTW showed no significant difference in the probability of treatment discontinuation between the two drugs (HR for VDZ=1.20; p = 0.34). Post-treatment endoscopic response and mucosal healing rates were similar between the two drugs (endoscopic response: 35.3% for VDZ and 25.5% for ADA, p = 0.15; mucosal healing: 31.8% for VDZ and 33.8% for ADA, p = 0.85). Conclusion This is the first real-life study comparing VDZ and ADA in CD patients via propensity score-adjusted analysis. Even if crude rates of all clinical outcomes were higher for ADA compared with VDZ, such differences were not significant when patients’ characteristics at baseline were weighted by propensity score.

Background. Almost 20% of patients with active Crohn's disease are refractory to conventional therapy. Infliximab is a treatment of proven efficacy in this group of patients and it is not clear which variables predict a good response. Aims. To evaluate the role of infliximab looking at the predictors of response in a large series of patients with Crohn's disease. Patients and methods. Five hundred and seventy-three patients with luminal refractory Crohn's disease (Crohn's Disease Activity Index (CDAI) > 220–400) (312 patients) or with fistulising disease (190 patients) or both of them (71 patients) were treated with a dose of 5 mg/kg in 12 Italian referral centres. The primary endpoints of the study were clinical response and clinical remission for luminal refractory and fistulising disease. We evaluated at univariable and multivariable analysis the following variables: number of infusions, sex, age at diagnosis, smoking habit, site of disease, previous surgery, extraintestinal manifestations and concomitant therapies, and type of fistulas. Results. Patients with luminal refractory disease: 322 patients (84.1%) had a clinical response and 228 (59.5%) reached clinical remission. Patients with fistulising disease: 187 patients (72%) had a reduction of 50% of the number of fistulas and in 107 (41%) a total closure of fistulas was observed. For luminal disease, single infusion (OR 0.49, 95% CI 0.28–0.86) and previous surgery (OR 0.53, 95% CI 0.30–0.93) predicted a worse response for fistulising disease. Other fistulas responded worse than perianal fistulas (OR 0.57, 95% CI 0.303–1.097). Conclusion. In Crohn's disease infliximab is effective in luminal refractory and in fistulising disease. A single infusion and previous surgery predicted a worse response in luminal disease whereas perianal fistulas predicted a better response than other type of fistulas.

In recent years, self-expandable metallic stents (SEMSs) have emerged as a promising treatment alternative for the bridging and sealing of esophageal perforations and extensive anastomotic leaks after esophageal resection or total gastrectomy. A 56-year-old woman underwent a total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy for a gastric signet ring cell carcinoma. Ten days later, esophagogastroduodenoscopy showed a 2 cm fistula in the distal end of the Roux limb of the anastomosis. This was confirmed by gastrografin esophagography. The patient was started on total parenteral nutrition. Having deemed clipping treatment for this fistula unfeasible, we decided to insert a partially silicone-coated SEMS (Evolution Controlled Release Esophageal Stent System, Cook Medical, Winston-Salem, N.C., USA). The stent was removed after ten days. Gastrografin esophagography showed no further contrast extravasation, and esophagogastroduodenoscopy showed closure of the fistula. No clinical complications were observed, and the patient was able to start normal per os nutrition. In conclusion, the treatment of symptomatic leaks in patients who have undergone esophagojejunostomy is challenging, and leakage from the jejunal stump can be a potentially serious complication. In the treatment of leakage after total gastrectomy, plastic stents (which are either too light or exercise too little radial force) and totally covered metallic stents may not adhere sufficiently to the esophagojeujunal walls and, as a result, migrate beyond the anastomosis. The promising results of this report suggest that early stenting, using a partially silicone-coated SEMS, is a feasible alternative to surgical treatment in this category of patients.

Summary Background Remission and response are the main outcomes to evaluate the efficacy of new treatments for Crohn’s disease (CD). Aim To explain variation of remission and response rates in active luminal CD. Methods We studied control patients from trials of biological therapies through articles retrieved by MEDLINE search (from 1997 to 2007) and by bibliography review. Thousand nine hundred and thirteen control patients from 28 trials were identified; data were extracted by three independent observers and pooled by DerSimonian and Laird random effect model; factors influencing remission and clinical response were explored by metaregression for aggregated data. Results The pooled control rates of remission and response were 17% and 33%, respectively, both with significant heterogeneity among studies (P

BACKGROUND AND AIMS: The widespread use of anti-tumour necrosis factor alpha antibody (Infliximab) in Crohn's disease (CD) raises concerns about a possible cancer risk in the long term. In a matched pair study, we assessed whether Infliximab is associated with an increased risk of neoplasia. METHODS: In a multicentre matched pair study, 404 CD patients treated with Infliximab (CD-IFX) were matched with 404 CD patients who had never received Infliximab (CD-C). Cases and controls were matched for sex, age (+/-5 years), site of CD, age at diagnosis (+/-5 years), immunosuppressant use, and follow up. New diagnoses of neoplasia from April 1999 to October 2004 were recorded. RESULTS: Among the 404 CD-IFX, neoplasia was diagnosed in nine patients (2.22%) while among the 404 CD-C, seven patients developed neoplasia (1.73%) (odds ratio 1.33 (95% confidence interval 0.46-3.84); p=0.40). The survival curve adjusted for patient year of follow up showed no differences between CD-IFX and CD-C (p=0.90; log rank test). In the CD-IFX group, there was one cholangiocarcinoma, three breast cancers, one skin cancer, one leukaemia, one laryngeal cancer, and two anal carcinomas. Among the 7/404 (1.73%) CD-C, there were three intestinal adenocarcinomas (two caecum, one rectum), one basalioma, one spinalioma, one non-Hodgkin's lymphoma, and one breast cancer. Age at diagnosis of neoplasia did not differ between groups (CD-IFX v CD-C: median 50 (range 40-70 years) v 45 (27-72); p=0.50). CONCLUSION: In our multicentre matched pair study, the frequency of a new diagnosis of neoplasia in CD patients treated with Infliximab was comparable with CD patients who had never received Infliximab.