Subcutaneous Infliximab (CT-P13) as Maintenance Therapy for Inflammatory Bowel Disease: 2 Randomized Phase 3 Trials.

BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. We aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. Co-primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).

Curcumin-QingDai Combination for Patients With Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND & AIMS: We evaluated the efficacy of herbal combination of curcumin-QingDai (CurQD) in active ulcerative colitis (UC). METHODS: Part I was an open-label trial of CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index score of 5 or higher and a Mayo endoscopic subscore of 2 or higher. Part II was a placebo-controlled trial conducted in Israel and Greece, randomizing active UC patients at a 2:1 ratio to enteric-coated CurQD 3 g/d or placebo for 8 weeks. The co-primary outcome was clinical response (reduction in the Simple Clinical Colitis Activity Index of ≥3 points) and an objective response (Mayo endoscopic subscore improvement of ≥1 or a 50% fecal calprotectin reduction). Responding patients continued either maintenance curcumin or placebo alone for an additional 8 weeks. Aryl-hydrocarbon receptor activation was assessed by cytochrome P450 1A1 (CYP1A1) mucosal expression. RESULTS: In part I, 7 of 10 patients responded and 3 of 10 achieved clinical remission. Of 42 patients in part II, the week 8 co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (P = .033). Clinical response was observed in 85.7% vs 30.7% (P < .001), clinical remission in 14 of 28 (50%) vs 1 of 13 (8%; P = .01), a 50% calprotectin reduction in 46.4% vs 15.4% (P = .08), and endoscopic improvement in 75% vs 20% (P = .036) in the CurQD and placebo groups, respectively. Adverse events were comparable between groups. By week 16, curcumin-maintained clinical response, clinical remission, and clinical biomarker response rates were 93%, 80%, and 40%, respectively. CurQD uniquely up-regulated mucosal CYP1A1 expression, which was not observed among patients receiving placebo, mesalamine, or biologics. CONCLUSIONS: In this placebo-controlled trial, CurQD was effective for inducing response and remission in active UC patients. The aryl-hydrocarbon receptor pathway may merit further study as a potential UC treatment target. CLINICALTRIALS: gov ID: NCT03720002.

Unsedated colonoscopy utilizing virtual reality distraction: a pilot-controlled study.

BACKGROUND: Sedation increases colonoscopy risks and prolongs recovery time. We examined whether virtual reality (VR) can substitute for sedation. The primary outcome was the overall satisfaction of patients who underwent colonoscopy with VR headset compared with patients who underwent standard sedation. Pain during the procedure, polyp detection rate (PDR), colonoscopy duration, post-colonoscopy adverse events, post-colonoscopy recovery, time-to-return to daily functions, and turnaround time at the endoscopy unit were secondary outcomes. METHODS: The study was approved by Sheba Medical Center's ethics committee IRB number 21-8177-SMC. Sixty patients were sequentially enrolled in a 1:1 ratio to either standard sedated colonoscopy or VR-unsedated procedure, and all patients signed a written informed consent. 28/30 patients successfully completed the colonoscopy using VR headset. Overall satisfaction score was comparable between the groups. RESULTS: There was no difference between VR and controls in colonoscopy duration, or PDR. VR patients had numerically lower rate of post-colonoscopy adverse events than controls. The proportion of VR patients who reported resuming daily activities on the day of the procedure was significantly higher than in the control group. The VR group patients spent significantly less time in the hospital compared to the control group. CONCLUSIONS: VR technology can provide adequate substitution for sedation for most patients undergoing colonoscopy and offers comparable patient satisfaction and faster return to daily activities.

Assessing Generative Pretrained Transformers (GPT) in Clinical Decision-Making: Comparative Analysis of GPT-3.5 and GPT-4.

BACKGROUND: Artificial intelligence, particularly chatbot systems, is becoming an instrumental tool in health care, aiding clinical decision-making and patient engagement. OBJECTIVE: This study aims to analyze the performance of ChatGPT-3.5 and ChatGPT-4 in addressing complex clinical and ethical dilemmas, and to illustrate their potential role in health care decision-making while comparing seniors' and residents' ratings, and specific question types. METHODS: A total of 4 specialized physicians formulated 176 real-world clinical questions. A total of 8 senior physicians and residents assessed responses from GPT-3.5 and GPT-4 on a 1-5 scale across 5 categories: accuracy, relevance, clarity, utility, and comprehensiveness. Evaluations were conducted within internal medicine, emergency medicine, and ethics. Comparisons were made globally, between seniors and residents, and across classifications. RESULTS: Both GPT models received high mean scores (4.4, SD 0.8 for GPT-4 and 4.1, SD 1.0 for GPT-3.5). GPT-4 outperformed GPT-3.5 across all rating dimensions, with seniors consistently rating responses higher than residents for both models. Specifically, seniors rated GPT-4 as more beneficial and complete (mean 4.6 vs 4.0 and 4.6 vs 4.1, respectively; P<.001), and GPT-3.5 similarly (mean 4.1 vs 3.7 and 3.9 vs 3.5, respectively; P<.001). Ethical queries received the highest ratings for both models, with mean scores reflecting consistency across accuracy and completeness criteria. Distinctions among question types were significant, particularly for the GPT-4 mean scores in completeness across emergency, internal, and ethical questions (4.2, SD 1.0; 4.3, SD 0.8; and 4.5, SD 0.7, respectively; P<.001), and for GPT-3.5's accuracy, beneficial, and completeness dimensions. CONCLUSIONS: ChatGPT's potential to assist physicians with medical issues is promising, with prospects to enhance diagnostics, treatments, and ethics. While integration into clinical workflows may be valuable, it must complement, not replace, human expertise. Continued research is essential to ensure safe and effective implementation in clinical environments.

Exploring the Link Between Ankylosing Spondylitis and Inflammatory Bowel Disease: A Retrospective Cohort Study.

BACKGROUND: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are chronic conditions with overlapping pathogenic mechanisms. The genetic predisposition and inflammatory pathways common to both diseases suggest a syndemic relationship. While some evidence points to a connection between the two conditions, other reports do not support this link. OBJECTIVES: To investigate the association between AS and the subsequent incidence of IBD. To identify potential risk factors and effect modifiers that contribute to this relationship. METHODS: Utilizing the Chronic Disease Registry of Clalit Health Services, we conducted a retrospective cohort study of individuals diagnosed with AS between January 2002 and December 2018. We compared these patients with age- and sex-matched controls, excluding those with a prior diagnosis of IBD. Statistical analyses included chi-square and t-tests for demographic comparisons, and Cox proportional hazards models for evaluating the risk of IBD development, with adjustments for various co-morbidities and demographic factors. RESULTS: The study included 5825 AS patients and 28,356 controls. AS patients demonstrated a significantly higher incidence of IBD with hazard ratios of 6.09 for Crohn's disease and 2.31 for ulcerative colitis, after multivariate adjustment. The overall incidence of IBD in the AS cohort was significantly higher compared to controls. CONCLUSIONS: AS patients exhibit a markedly increased risk of developing IBD. These findings advocate for heightened clinical vigilance for IBD symptoms in AS patients and suggest the need for a multidisciplinary approach to patient care. Further research into the shared pathogenic pathways is needed to develop personalized treatment strategies and improve patient management.

Patency Capsule: A Novel Independent Predictor for Long-Term Outcomes Among Patients With Quiescent Crohn's Disease.

INTRODUCTION: Patency capsule (PC) is a recommended procedure to rule out small bowel stenosis before video capsule endoscopy (VCE). We examined future clinical outcomes among patients with a failed PC vs patients in whom the PC had passed (passed PC). METHODS: A post hoc analysis of 2 prospective cohort studies of adult patients with quiescent small bowel Crohn's disease (CD) who underwent PC between 2013 and 2020. The primary composite outcome was the need for intestinal surgery or endoscopic dilation during follow-up in patients with or without a failed PC. RESULTS: A total of 190 patients were included (47: failed PC and 143: passed PC, median follow-up 34.12 months). Patients with a failed PC had higher rates of the primary composite outcome (21.3% vs 1.4%, hazard ratio [HR] 20.3, 95% confidence interval [CI] 4.4-93.7, P < 0.001) and also secondary outcomes including intestinal surgery (14.9% vs 0.70%, P < 0.001), endoscopic dilation (14.9% vs 0.70%, P < 0.001), admissions (23.3% vs 5.7%, P < 0.001), and clinical flares (43.9% vs 27.7%, P = 0.005) during follow-up compared with controls. Failed PC was the only statistically significant factor for surgery and/or endoscopic dilation, regardless of a B2/B3 phenotype at baseline. In sensitivity analyses restricted only to patients with a stricturing phenotype (n = 73), a failed PC still predicted the long-term composite outcome (HR 8.68, 95% CI 1.72-43.68, P = 0.002). Of the 190 patients ingesting a PC, only 1 patient with a failed PC had 48 hours of self-limiting mild symptoms. DISCUSSION: Patients with clinically stable CD with a failed PC have worse long-term clinical outcomes than those without, independently of the CD phenotype. Standalone PC may serve as a novel, safe, and affordable prognostic examination to identify patients with quiescent CD who have a higher risk for future worse clinical outcomes.

Risk of colorectal advanced neoplasia in patients with acute diverticulitis with and without previous colonoscopy.

BACKGROUND AND AIM: Guidelines recommend a colonoscopy after an episode of complicated diverticulitis and after a first episode of uncomplicated diverticulitis. The influence of a previous colonoscopy on postdiverticulitis colonoscopic findings has not been studied. The aim of this work was to examine the incidence of adenoma detection rate (ADR), advanced adenoma (AA) and colorectal cancer (CRC) in patients with diverticulitis with and without previous colonoscopy. METHOD: This was a retrospective case-control study of subjects with acute diverticulitis. Subsequent and previous colonoscopies were abstracted for ADR, AA and CRC diagnoses. The incidence of neoplasia was compared between patients with and without previous colonoscopy and also with that of a screening population. RESULTS: Compared with a healthy control group (n = 975), diverticulitis patients without prior colonoscopy (n = 325) had a significantly higher ADR (26.8% vs. 20.5%, p = 0.019) and invasive CRC rate (0.9% vs. 0%, p = 0.016). Risk factors for advanced neoplasia included age ≥ 70 years and complicated diverticulitis. Among subjects with diverticulitis and previous colonoscopy (n = 124), only one patient developed AA and there were no cancer cases. CONCLUSIONS: A previous normal colonoscopy within 5 years before diverticulitis probably overshadows other risk factors for findings of advanced neoplasia and should be considered in the decision to repeat a colonoscopy.

Cardiovascular Risk Factors and Physical Fitness Among Subjects with Asymptomatic Colonic Diverticulosis.

BACKGROUND: The association between diverticular disease and atherosclerotic cardiovascular disease (ASCVD) has been demonstrated previously, mainly in symptomatic subjects. AIMS: To evaluate 10 years cardiovascular risk, exercise performance and association to ASCVD among subjects with asymptomatic diverticulosis. METHODS: A retrospective cross-sectional cohort of self-referred participants in a medical screening program, who underwent a screening colonoscopy. Demographics, clinical and laboratory variables, ASCVD score, and metabolic equivalents (METs) during treadmill stress test were compared between subjects with and without diverticulosis as diagnosed on screening colonoscopy. RESULTS: 4586 participants underwent screening colonoscopy; 799 (17.4%) had diverticulosis. Among 50-69 yo participants, diverticulosis subjects had a higher ASCVD score compared to non-diverticulosis subjects. Exercise performance was comparable between the groups, across all age groups. Using logistic regression analysis, advanced age group (50-59 yo Adjusted odds ratio (AOR) [95% confidence interval (CI)] 2.57 (1.52-4.34), p < 0.001; 60-69 yo, AOR 2.87 (2.09-3.95), p < 0.001; ≥ 70 yo AOR 4.81 (3.23-7.15), p < 0.001; compared to < 50 yo age group), smoking [AOR 1.27 (1.05-1.55), p = 0.016], HTN [AOR 1.27 (1.03-1.56), p = 0.022], obesity [AOR 1.36 (1.06-1.74), p = 0.014] and male sex [AOR 1.29 (1.02-1.64), p = 0.036] were associated with diverticular detection during screening colonoscopy. Among males, achieving METs score ≥ 10 was inversely associated with diverticular detection during screening colonoscopy [AOR 0.64 (0.43-0.95), p = 0.027]. CONCLUSIONS: Ten years probability for ASCVD estimated by the ASCVD score is higher among subjects with asymptomatic diverticulosis compared to subjects without diverticulosis. Improved exercise performance is demonstrated for the first time to correlate with decreased probability for diverticular disease in screening colonoscopy.

Jejunal Inflammation in Crohn's Disease: Comparison between Diffusion Weighted Magnetic Resonance Imaging and Video Capsule Endoscopy.

BACKGROUND: Jejunal disease is associated with worse prognosis in Crohn's disease. The added value of diffusion weighted imaging for evaluating jejunal inflammation related to Crohn's Disease is scarce. OBJECTIVES: To compare diffusion weighted imaging, video capsule endoscopy, and inflammatory biomarkers in the assessment of Crohn's disease involving the jejunum. METHODS: Crohn's disease patients in clinical remission were prospectively recruited and underwent magnetic resonance (MR)-enterography and video capsule endoscopy. C-reactive protein and fecal-calprotectin levels were obtained. MR-enterography images were evaluated for restricted diffusion, and apparent diffusion coefficient values were measured. The video capsule endoscopy-based Lewis score was calculated. Associations between diffusion weighted imaging, apparent diffusion coefficient, Lewis score, and inflammatory biomarkers were evaluated. RESULTS: The study included 51 patients, and 27/51 (52.9%) with video capsule endoscopies showed jejunal mucosal inflammation. Sensitivity and specificity of restricted diffusion for video capsule endoscopy mucosal inflammation were 59.3% and 37.5% for the first reader, and 66.7% and 37.5% for the second reader, respectively. Diffusion weighted imaging was not statistically associated with jejunal video capsule endoscopy inflammation (P = 0.813). CONCLUSIONS: Diffusion weighted imaging was not an effective test for evaluation of jejunal inflammation as seen by video capsule endoscopy in patients with quiescent Crohn's disease.

Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review.

Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.

BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

[UPPER GASTROINTESTINAL BLEEDING CAUSED BY BREAST ANGIOSARCOMA METASTASIS LOCATED IN THE GASTRO-ESOPHAGEAL JUNCTION].

INTRODUCTION: Angiosarcomas are rare and aggressive tumors that originate from endothelial cells and make up roughly 2-3% of all soft-tissue sarcomas. Breast angiosarcomas may be idiopathic or secondary to radiation therapy or chronic lymphatic edema. Primary angiosarcoma of the gastrointestinal (GI) tract is rare and usually causes abdominal pain or GI bleeding. In this case report, we present a patient who appeared with upper gastrointestinal bleeding due to a radiation-induced breast angiosarcoma metastatic lesion in the gastroesophageal junction (GEJ). To the best of our knowledge, breast angiosarcoma metastases to the GEJ were not previously described, and moreover, GI bleeding secondary to breast angiosarcoma GI metastases was not previously reported.

European Registry on Helicobacter pylori management (Hp-EuReg): First-line Therapy in Israel.

BACKGROUND: The antibiotic resistance profile of Helicobacter pylori (H. pylori) is constantly changing. Up-to-date and reliable data for the effectiveness of first-line H. pylori treatment protocols are necessary to provide evidence-based best-practice guidelines. OBJECTIVES: To determine the effectiveness, compliance and safety of first-line treatment for H. pylori in Israel. METHODS: An observational, prospective, multicenter study was conducted in tertiary referral centers in Israel, as part of the European registry on H. pylori management (Hp-EuReg). H. pylori-infected patients were included from 2013 to March 2020. Data collected included demographics, clinical data, diagnostic tests, previous eradication attempts, current treatment, compliance, adverse events, and treatment outcome result. RESULTS: In total, 242 patients were registered, including 121 (50%) who received first-line therapy, 41% of these individuals received clarithromycin based triple therapy and 58.9% received a four-drug regimen. The overall effectiveness of first-line therapy was 85% and 86% by modified intention-to-treat and per protocol analyses, respectively. The effectiveness of both sequential and concomitant therapies was 100% while clarithromycin-based triple therapy achieved an eradication rate of 79%. Treatment eradication was higher among patients who received high dose proton pump inhibitor (PPI) compared to those treated with low dose PPI (100% vs. 81.5% respectively, P < 0.01). No difference in treatment effectiveness was found between 7-, 10-, and 14-day treatment. CONCLUSIONS: The effectiveness of clarithromycin-based triple therapy is suboptimal. First-line treatment of H. pylori infection should consist of four drugs, including high dose PPI, according to international guidelines.

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study.

BACKGROUND: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. METHODS: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than -20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. FINDINGS: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13-CT-P13 group and 55 to the CT-P13-infliximab group) and 109 to initiate infliximab (54 to the infliximab-infliximab group and 55 to the infliximab-CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference -4·9% [95% CI -16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13-CT-P13 group, 34 [62%] in the CT-P13-infliximab group, 37 [69%] in the infliximab-infliximab group, and 40 [73%] in the infliximab-CT-P13 group). INTERPRETATION: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. FUNDING: Celltrion, Pfizer.

Exposure to Vedolizumab in IBD Pregnant Women Appears of Low Risk for Mother and Neonate: A First Prospective Comparison Study.

OBJECTIVES: Despite encouraging data gathered in inflammatory bowel diseases (IBD) patients, Vedolizumabs' (VDZ) safety profile in pregnancy is not established. DESIGN: Data of 330 consecutive pregnancies with IBD was prospectively collected. RESULTS: Women with IBD were treated with: VDZ (n = 24), anti-tumor necrosis factors (n = 82) or conventional therapy (n = 224). Gravidity and parity were similar among the 3 groups. The VDZ group was comprised mostly of Crohn's disease patients who were all not naïve to biological treatment. They had significantly higher conception rates during active disease (P < 0.05), with fewer flares during pregnancy. DISCUSSION: Although further study is needed, VDZ appears of low risk during pregnancy.

Individualized Dynamics in the Gut Microbiota Precede Crohn's Disease Flares.

OBJECTIVES: Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined. METHODS: We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase. RESULTS: Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3-42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers. DISCUSSION: Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.

Prolonged Recurrent Abdominal Pain is Associated With Ongoing Underlying Mucosal Inflammation in Patients who had an Episode of Acute Complicated Diverticulitis.

BACKGROUND: Recent data suggest continuous chronic inflammation in patients after an acute diverticulitis (AD) episode. GOALS: The aim of this article was to compare clinical parameters, inflammatory cytokine expression, and immune-cell infiltrates between patients after severe versus nonsevere AD, as defined by radiology examination during the acute episode. STUDY: Sixteen patients, after suffering an episode of AD, were included, and, of them, 8 had severe disease. Demographic data, disease characteristics, and inflammatory markers were collected. Tissue samples from diverticular and unaffected tissue were obtained during colonoscopy. Mucosal inflammation was assessed histologically and by measuring inflammatory cytokine mRNA expression. RESULTS: Clinically, continued nonspecific abdominal symptoms were significantly more prevalent among patients after severe AD compared with patients after nonsevere AD (P=0.0002). Patients after severe AD also had significantly higher C reactive protein levels (9.85±7.5 vs. 3±2.1 mg/dL; P=0.027) and tendency for higher calprotectin levels (115.7±85 vs. 35±8.7 mg/g; P=0.08). Reverse transcription polymerase chain reaction-determined cytokines levels were 5.4±4.4, 5.14±10, and 0.8±0.82 for tumor necrosis factor alpha, interleukin-6, and interleukin-1ß, respectively, in affected mucosa compared with 1.06±1.57, 1.56±2.1, and 0.35±0.5, respectively, in nonaffected mucosa (P=0.01, 0.05, 0.14, respectively). Cytokine expression in patients after nonsevere AD did not differ significantly between affected and nonaffected mucosa. Histologic scores for crypt distortion, lymphoid aggregates, and lymphocyte infiltration were all significantly higher in patients after severe AD compared with patients after nonsevere AD (P<0.05 for all comparisons). CONCLUSIONS: Patients after severe AD have more prolonged chronic symptoms, higher inflammatory markers, higher tissue inflammatory cytokine levels, and more inflammatory infiltrates in diverticular colonic tissue than patients after nonsevere AD. These results may contribute to patients' risk stratification and guide therapeutic decisions.

Association of Vedolizumab Level, Anti-Drug Antibodies, and α4ß7 Occupancy With Response in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: There are few data available on the real-life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin α4ß7. We performed a prospective study of patients with inflammatory bowel diseases (IBDs) treated with vedolizumab to determine serum drug concentrations, formation of antivedolizumab antibodies (AVAs), and integrin α4ß7 saturation. METHODS: We performed a prospective study of 106 patients with IBD (67 with Crohn's disease and 39 with ulcerative colitis) treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel. Clinical data and serum samples were collected before and during induction and maintenance therapy. Clinical remission was defined as Harvey-Bradshaw index scores below 5 or as Simple Clinical Colitis Activity Index scores of 3 or less. We measured serum levels of vedolizumab, AVAs, and markers of inflammation. Peripheral blood mononuclear cells were obtained from some patients at designated trough time points and CD3+ CD45RO+ T cells were isolated from 36 samples. Cells were incubated with fluorescent-conjugated vedolizumab and flow cytometry was used to quantify α4ß7 integrin saturation. We also performed flow cytometry analyses of CD3+ CD45RO+ lamina propria T cells isolated from intestinal mucosa of patients without IBD (non-IBD controls, n = 6), patients with IBD not treated with vedolizumab (untreated IBD controls, n = 8), and patients with IBD treated with vedolizumab (n = 15). RESULTS: Clinical remission was achieved by 48 of 106 patients (45%) by week 6 and 50 of 106 patients (48%) by week 14 of treatment. The median level of vedolizumab at week 6 was higher in patients in clinical remission (40.2 µg/mL) than in patients with active disease (29.7 µg/mL; P = .05). The median serum level of vedolizumab was significantly higher in patients with a normal level of C-reactive protein (21.8 µg/mL vedolizumab) vs the level in those with a high level of C-reactive protein (11.9 µg/mL vedolizumab) during maintenance treatment (P = .0006). The other clinical outcomes measured were not associated with median serum level of vedolizumab at any time point examined. AVAs were detected in 17% of patients during induction therapy and 3% of patients during maintenance therapy, but did not correlate with clinical outcomes. Flow-cytometry analysis of peripheral blood memory T cells (n = 36) showed near-complete occupancy of α4ß7 integrin at weeks 2 and 14 and during the maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+ memory T cells of healthy and IBD controls expressed α4ß7 (72%; interquartile range, 56%-81%). In contrast, free α4ß7 was detectable on only 5.6% of intestinal memory cells (interquartile range, 4.4%-11.2%) (P < .0001) from vedolizumab-treated patients, regardless of response. CONCLUSIONS: In a prospective study of real-life patients with IBD, we associated vedolizumab drug levels with remission and inflammatory marker level. Integrin α4ß7 was blocked in almost all T cells from patients treated with vedolizumab, regardless of serum level of the drug or response to treatment. These findings indicate a need to explore alternative mechanisms that prevent response to vedolizumab.

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The POETIC Study.

OBJECTIVES: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific-85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.

Comparing diagnostic yield of a novel pan-enteric video capsule endoscope with ileocolonoscopy in patients with active Crohn's disease: a feasibility study.

BACKGROUND AND AIMS: Crohn's disease (CD) is typically diagnosed with ileocolonoscopy (IC); however, when inflammation is localized solely in the small bowel, visualization of the entire small-bowel mucosa can be challenging. The aim of this study was to compare the diagnostic yield of a pan-enteric video capsule endoscope (small-bowel colon [SBC] capsule) versus IC in patients with active CD. METHODS: This was a prospective, multicenter study. Patients with known active CD and proven bowel luminal patency underwent a standardized colon cleansing protocol followed by ingestion of the capsule. After passage of the capsule, IC was performed and recorded. Lesions indicative of active CD were assessed. RESULTS: One hundred fourteen subjects were screened; 66 subjects completed both endoscopic procedures. The per-subject diagnostic yield rate for active CD lesions was 83.3% for SBC and 69.7% for IC (yield difference, 13.6%; 95% confidence interval [CI], 2.6%-24.7%); 65% of subjects had active CD lesions identified by both modalities. Of the 12 subjects who were positive for active CD by SBC only, 5 subjects were found to have active CD lesions in the terminal ileum. Three subjects were positive for active CD by IC only. Three hundred fifty-five classifying bowel segments were analyzed; the per-segment diagnostic yield rate was 40.6% for SBC and 32.7% for IC (yield difference 7.9%; 95% CI, 3.3%-12.4%). CONCLUSION: This preliminary study shows that the diagnostic yields for SBC might be higher than IC; however, the magnitude of difference between the two is difficult to estimate. Further study is needed to confirm these findings.