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.

Mesenchymal stem cell therapy for Crohn's perianal fistula-a real-world experience.

AIM: Remission rates of medically and surgically treated complex perianal fistulas in Crohn's disease are low. Recently, trials have demonstrated the potential for long-term remission with local injection of allogeneic adipose-derived mesenchymal stem cells (darvadstrocel). Our aim was to analyse outcomes from our real-world experience with this new treatment. METHODS: All patients with Crohn's disease suffering complex perianal fistulas who consecutively underwent administration of darvadstrocel at two centres were followed up and evaluated. Patients were assessed for clinical remission, response, failure, and any complications during follow-up. The results of all patients with a minimum of 3 months' follow-up are presented. RESULTS: Thirty-three patients with Crohn's disease and complex perianal fistulas were included. Of these, 20 (61%) experienced clinical remission that was maintained for a mean follow-up of 14 (3-32) months. A total of 24 of 33 (73%) experienced at least 3 months of clinical remission, with four later having recurrence (3-12 months). Among the remaining nine patients who did not experience clinical remission, two (6%) had partial remission (such as one of two fistulas closing), two (6%) showed signs of response but not remission, and five (15%) showed no signs of healing. The mean time to maintained clinical remission was 6 weeks (range 2 weeks to 6 months), and there were no severe adverse events. CONCLUSION: In this real-world experience, treatment of Crohn's disease complex perianal fistulas with darvadstrocel had a 61% success rate for maintained clinical remission.

I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators. METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia. CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Lower Serologic Response to COVID-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFα.

BACKGROUND & AIM: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)α biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). METHODS: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinally. RESULTS: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. CONCLUSIONS: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

Fecal Calprotectin and Quality of Life Questionnaires Are Responsive to Change in Pouch Disease Activity After Antibiotic Therapy: Results From a Prospective Clinical Trial.

INTRODUCTION: Whether fecal calprotectin (FC) and quality of life (QoL) questionnaires reflect change in disease activity in patients with a J-pouch is unknown. METHODS: Patients with acute pouchitis were prospectively treated with a 2-week course of antibiotics. The full Pouchitis Disease Activity Index, FC, and QoL questionnaires were measured at baseline and after antibiotic therapy. RESULTS: Twenty patients were prospectively enrolled. After 2 weeks of antibiotic treatment, the Pouchitis Disease Activity Index decreased from a median of 9 to 5 ( P = 0.007). FC decreased from a median of 661 ug/g to 294 ug/g ( P = 0.02), and QoL questionnaires improved significantly. DISCUSSION: FC and QoL questionnaires reflect real-time changes in inflammatory pouch activity.

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.

Video Capsule Endoscopy after Bariatric Surgery: A Tertiary Referral Center Experience.

BACKGROUND AND AIM: Minimal data are available regarding the performance of video capsule endoscopy (VCE) in patients who underwent bariatric surgery. We aimed to report indications, feasibility, and safety of VCE performed after bariatric surgery, specifically focusing on diagnosis rates of Crohn's disease (CD) in this population. METHODS: A retrospective analysis of all VCE procedures was performed between January 2015 and December 2019. All patients who underwent bariatric surgery prior to VCE were included. Indication for VCE, ingestion methods, completion rates, retention rates, and endoscopic findings were recorded. RESULTS: A total of 1,255 patients underwent VCE examination during the study period, of which 31 (2.5%) underwent bariatric surgery prior to VCE. The most common bariatric surgery was laparoscopic sleeve gastrectomy (16 patients, 51.6%), and the most common indication for VCE was evaluation of iron deficiency anemia (14 patients, 45.1%). The majority of patients ingested the capsule independently, without endoscopic assistance (20, 64.5%). Although a patency capsule was not used in our cohort, no events of capsule retention were documented. Mean transit time was 4.32 h. Only 4 events of incomplete examination were recorded. Over a median follow-up of 27.5 months (IQR 13.0-34.2), 10 patients (31.2%) had a final diagnosis of CD with a median Lewis score of 225 (IQR 135-900). CONCLUSION: VCE is a feasible and safe procedure after bariatric surgery. Oral ingestion does not carry risk of retention. It is an effective means of diagnosis of small-bowel CD in this population.

Fecal Calprotectin Is Increased in Pouchitis and Progressively Increases With More Severe Endoscopic and Histologic Disease.

BACKGROUND & AIMS: Data regarding fecal calprotectin (FC), commonly used for noninvasive monitoring in inflammatory bowel diseases, are scarce in patients with ileal pouch-anal anastomosis (IPAA). We aimed to assess the association between FC levels and pouch inflammation in patients with ulcerative colitis who underwent IPAA. METHODS: A cross-sectional study of adults with ulcerative colitis who underwent IPAA with J-pouch formation prospectively followed in a dedicated pouch clinic. Patients had clinical, endoscopic, and histologic assessments within 90 days of FC sampling. Each patient encounter was evaluated separately. Pouchitis was defined as a Pouchitis Disease Activity Score of ≥7 (maximum score: 18). RESULTS: Overall, 156 patients had 296 encounters that met inclusion criteria. A total of 52% of patients were male, median age at evaluation was 43 (IQR, 35-58) years, and median pouch age was 10 (interquartile range [IQR], 2.5-15) years. Median FC values were significantly lower in patients without compared with those with pouchitis (208 [IQR, 96-478] µg/g vs 550 [IQR, 250-1051] µg/g; P < .0001). Mean FC values increased among patients with higher endoscopic and histologic scores. FC performed better than C-reactive protein as a predictor of pouchitis. FC of >460 µg/g had >80% specificity for predicting significant endoscopic disease (Pouchitis Disease Activity Score endoscopic subscore ≥5), while an FC of <125 µg/g had over 80% specificity in predicting endoscopic remission. CONCLUSIONS: FC levels are increased in patients with endoscopic and histologic inflammation of the pouch. FC may be a useful tool in the management of patients following IPAA.

Venous Thromboembolism Among Patients With Inflammatory Bowel Diseases is Not Related to Increased Thrombophilia: A Case-Control Study.

GOAL: The aim was to assess whether thrombophilia significantly contributes to the risk of venous thromboembolic events (VTEs) in patients with inflammatory bowel disease (IBD). BACKGROUND: Patients with IBD have a high risk of VTE. The underlying mechanism has been only partially defined. METHODS: A case-control study in adults with IBD and an episode of VTE (IBD-VTE) were matched and compared with non-IBD patients with a VTE (non-IBD-VTE). The study population was comprised of patients seen in 2 tertiary medical centers in Israel between 2000 and 2013. Characteristics of IBD and risk factors for VTE were retrieved from medical charts, and a comprehensive thrombophilia panel was completed in all patients. RESULTS: Forty-four IBD-VTE cases (27 Crohn's disease) were matched with 127 non-IBD-VTE controls. The majority of VTE had a clear etiology and were considered provoked events. Provoked and unprovoked VTE rates were not different between the 2 groups. Likewise, thrombophilia rates were similar among patients with IBD-VTE and controls (40.9% vs. 53.5%, respectively, P=0.14). However, among patients with unprovoked VTE, thrombophilia rates were significantly lower in the IBD-VTE group compared with controls (42.1% vs. 70.7%, respectively, P=0.03). Among patients with IBD-VTE, an unprovoked event, and negative thrombophilia, 77% had active inflammation at the time of VTE. CONCLUSION: Thrombophilia rates are similar among patients with IBD-VTE and controls but are less common among patients with unprovoked IBD-VTE. This finding suggests that either inflammation or other novel pathways drive VTE in patients with IBD.

Exploring Popular Social Media Networks for Patients With Inflammatory Bowel Diseases: Insights for Better Care.

GOAL: The aim was to assess topics of interest and concerns among patients with inflammatory bowel diseases (IBD) who are active online. BACKGROUND: Social media (SM) networks are a major communication tool for patients with IBD and health care professionals. PATIENTS AND METHODS: We performed an anonymized investigation of SM networks for IBD patients; I-a thematic analysis of patients' posts, II-an online survey advertised through Facebook and other popular SM networks throughout November 2019. RESULTS: Analyzing 2133 posts (2014 to 2019) revealed 18 topics of interest. The online survey was completed by 534 respondents [63%-Crohn's disease, 56%-female, median age-38 years (interquartile range: 28.7 to 51.0)]. Most respondents (70%) were followed in referral centers, and 45% were receiving biological therapy. Respondents reported high satisfaction with IBD care and health care provider professionalism. The top 5 topics of interest were diet, lifestyle, complementary and alternative medicine, diagnostic test interpretation, and specialist referrals and reviews. Cluster analysis demonstrated that gender, income, and education level were associated with specific interest and concerns. CONCLUSION: Patients' activity on SM is independent of their satisfaction with formal IBD care and rather reflects an ongoing need for information and support. These needs may be addressed both in clinical settings and through online tools.

Specialized Emergency Department Assessment and Multidisciplinary Intervention After Discharge Improve Management of Patients With Inflammatory Bowel Diseases.

GOAL: The aim was to assess proactive specialized inflammatory bowel diseases (IBD) emergency department (ED) consultation and multidisciplinary IBD team (IBD-MDT) intervention on IBD-related patient outcomes after discharge. BACKGROUND: Despite advances in patient care, IBD-related ED visits have increased and substantially contribute to the IBD burden. METHODS: Consecutive patients with IBD (below 50 y) who visited the ED during November 2017 to April 2018 (intervention group) were compared with patients with IBD that visited the same ED during 2014 to 2017 (standard-care group). The primary outcomes were hospitalization and ED revisits at 30, 90, and 180 days. RESULTS: The intervention group (45 patients, mean age 32.43±8.6 y, 57.8% male) and the standard-care group (237 patients) had comparable baseline characteristics, including age, sex, and IBD type, and similar rates of hospital admissions from the ED (46.7% vs. 38.8%, P=0.32). The intervention group more frequently underwent computed tomography (40% vs. 8%, P<0.001) and surgical interventions (13.3% vs. 0.8%, P<0.001) within the same hospital admission, compared with the standard-care group. In the intervention group, 24 patients were discharged from the ED, of whom 17 patients visited the IBD clinic (median 5 d postdischarge) and the majority were referred to ambulatory IBD-MDT services (dietitian: 46.7%, psychologist: 6.7%, advanced endoscopist: 8.9%, and proctology services: 6.7%). The intervention group had significantly fewer ED revisits than the standard-care group (30 d: 4.4% vs. 19.8%, P=0.013; 90 d: 4.4% vs. 35.9%, P<0.001; 180 d: 6.7% vs. 43%, P<0.001). CONCLUSION: Proactive specialized ED assessments and IBD-MDT interventions after a hospital discharge were preferable; they significantly reduced the ED revisit rate for at least 6 months.

Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics: A Population-based Study From The epidemiology group of the Israeli IBD Research Nucleus (epiIIRN).

BACKGROUND AND OBJECTIVES: Both perianal and pediatric-onset Crohn disease (CD) disease are associated with complicated disease course and higher drug utilization. we aimed to explore the differences between pediatric and adult-onset perianal CD and their disease course. METHODS: We included all patients with newly diagnosed CD from 2005 to 2019 at two Israeli Health Maintenance Organizations, covering 78% of the population. A combination of ICD-9 codes, radiology and procedures was used to define fistulizing perianal CD (PCD) and its severity according to the association with simple and complex perianal disease. RESULTS: A total of 12,905 patients were included (2186 [17%] pediatric-onset, 10,719 [83%] adults), with a median follow-up of 7.8 years. PCD was diagnosed in 1530 (12%) patients, with higher incidence in children (308 [14%] children vs 1222 adults [11%]; P  < 0.001). Children had higher incidence of severe PCD (141/308 [47%] vs 433/1222 [35%]; P < 0.001). At 5 years, children with PCD were more likely than adults to be treated with biologics (212 [69%] vs 515 [42%]; odds ratio [OR] 2.6 [95% confidence interval (CI) 1.6-4.0]; P < 0.001) and immunomodulators (238 [74%] vs 643 [53%]; OR 2.8 [95% CI 2.1-3.6]; P < 0.001). PCD in children was still associated with poorer disease outcomes as shown for surgeries (36 [12%] vs 93 [8%]; P = 0.02) and steroid-dependency (52 [17%] vs 156 [13%]; P < 0.001). Multivariable modeling indicated that the severity of PCD is a stronger predictor of disease course than age. CONCLUSION: PCD is more common in pediatric-onset CD and is associated with higher drug utilization and worse disease outcomes, in large due to higher rate of severe PCD in children.

[CUFFING PRISONERS AND DETAINEES IN ISRAELI HOSPITALS - A MULTI-CENTER STUDY].

AIMS: To describe the extent of prisoner/detainee cuffing and characterize cuffing methods. BACKGROUND: Thousands of prisoners and detainees receive medical treatment in Israeli hospitals every year. According to the Israeli law, cuffing during hospital stay should be an exceptional measure, to be considered only in cases of real threat of violence or escape, based on individual assessment. There is no documentation of cuffing rates in hospitals. METHODS: A multi-center study in 12 hospitals was performed during 2020-2021. Data were collected prospectively or retrieved retrospectively from security records, when available. RESULTS: A total of 1857 prisoners/detainees were documented, of whom 1794 (96.6%) were cuffed. Of the 241 hospitalized patients, 230 (95.4%) were cuffed. Details regarding cuffing methods were available for 185 hospitalized patients, revealing that at least 63 patients (68% of patients for whom details regarding cuffing to bed were available) were cuffed to the bed with opposite arm and leg in a cross position. Cuffing rates of prisoners under custody of the Prisons Authority, police and the Israeli Defense Forces, were 98.5%, 96.6%, and 83%, respectively. Impaired mobility for medical reasons was documented in 64 cases, of whom 85.9% were cuffed regardless. CONCLUSIONS: Cuffing of prisoners/detainees in Israeli hospitals is performed non-selectively, in violation of the law. During hospitalization, cuffing is usually performed in a cross position, severely impairing mobility. Our findings highlight the need for routine documentation of cuffing due to its medical consequences and the responsibility of medical staff towards patients according to rules of ethics and regulations.

Effective Treatment of Acute Severe Ulcerative Colitis in Pregnancy Is Associated With Good Maternal and Fetal Outcomes.

Data regarding the management and outcomes of acute severe ulcerative colitis (ASUC) in pregnant patients is sparse, consisting mainly of case reports.1-3 We report on the largest cohort of pregnant patients hospitalized with ASUC and performed a systematic review of the medical literature.

Early Indolent Course of Crohn's Disease in Newly Diagnosed Patients Is Not Rare and Possibly Predictable.

BACKGROUND & AIMS: The early stages of Crohn's disease (CD) course are heterogeneous, and it is a challenge to predict the course of disease in patients with new diagnosis. METHODS: We performed an observational longitudinal study of 156 adults (79 male; median age, 27.7 years; 57 treatment naïve) with newly diagnosed CD (within 6 months of enrollment), referred from medical centers and community clinics in Israel from 2013 through 2017. Study participants each received semi-annual scheduled evaluations. Indolent disease was defined as a disease course without need for strict interventions to control complicated course of CD (hospitalization or surgery, or decision to start steroid, immunomodulator, or biologic therapy). Cox regression and receiver operating characteristic analyses were used to identify factors associated with early indolent or complicated course of CD. We validated our findings in an independent cohort of patients with CD from a separate medical center in Israel in 2018. RESULTS: Over a median follow-up period of 17.2 months (interquartile range, 8.8-23.8 months), 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. The median time to first intervention was 3.4 months (95% CI, 2.4-4.4). We developed a model based on clinical factors that identified 4 factors associated with complicated course in treatment-naïve patients: body mass index <25 kg/m2 (hazard ratio [HR], 2.45; 95% CI, 1.07-5.43; P = .033), serum level of vitamin B12 <350 pg/mL (HR, 2.78; 95% CI, 1.21-6.41; P = .016), white blood cells ≥7 × 103/µL (HR, 2.419; 95% CI, 1.026-5.703; P = .044), and serum level of ALT ≥25 IU/L (HR, 2.680; 95% CI, 1.186-6.058; P = .018). This model discriminated between patients with vs without a complicated course of disease with 90% and 89% accuracy at 6 and 12 months after diagnosis, respectively. A validation cohort demonstrated a discriminatory ability of 79% at 3 months after diagnosis, and a nomogram was constructed. CONCLUSIONS: In an observational longitudinal study of 156 patients with newly diagnosed CD, we found that one third have an early indolent course of disease. We identified factors that can be measured at diagnosis to identify patients at risk for an early complicated course-these might be used in patient management and selection of treatment.

Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD.

OBJECTIVE: Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. DESIGN: We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. RESULTS: We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. CONCLUSIONS: Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.

Crohn's Disease Behavior and Location is Altered when Associated with Primary Sclerosing Cholangitis.

BACKGROUND: Up to 3.4% of Crohn's disease (CD) patients will be diagnosed with concomitant primary sclerosing cholangitis (PSC). Despite the worldwide increase incidence of CD, data on the clinical characteristics of PSC-CD patients are scarce. OBJECTIVES: To clinically characterize CD in patients who have concomitant PSC. METHODS: A retrospective case-control analysis was conducted with 18 CD patients with concomitant PSC who attended the Inflammatory Bowel Disease Center at the Tel Aviv Sourasky Medical Center between 2011-2014 (PSC-CD patients). They were matched by age, gender, and disease duration to 90 control patients (those with CD who did not have concomitant PSC). Disease phenotype (according to the Montreal classification), demographics, and clinical data were compared in the two groups. RESULTS: PSC-CD patients were characterized by a disease that was more frequently limited to the colon (L2) (50% vs. 16%, P = 0.004) and by a non-stricturing and non-penetrating inflammatory phenotype (83% vs. 33%, P = 0.0001) compared to controls who had an increased prevalence of the penetrating phenotype (B3) (6% vs. 33% P < 0.05). Use of 5-aminosalicylic acid agents as a single therapy was significantly more prevalent among PSC-CD patients than in controls (39% vs. 7%, P < 0.005). In contrast, biologic therapy was significantly less common among PSC-CD patients compared to controls (17% vs. 52%, P = 0.0086). CONCLUSIONS: Patients with PSC-CD are clinically distinct from patients with isolated CD, and are characterized by predominant colonic involvement and an inflammatory, non-stricturing and non-penetrating phenotype.

Prevention of Antidrug Antibody Formation to Infliximab in Crohn's Patients With Prior Failure of Thiopurines.

BACKGROUND & AIMS: Combination thiopurine-infliximab (IFX) therapy is associated with reduced generation of antidrug antibodies (ADA) compared with IFX monotherapy. Whether past clinical response to thiopurine therapy bears an effect on ADA prevention is unknown. METHODS: This was a retrospective observational multicenter study of patients with Crohn's disease (CD) treated by IFX and thiopurines who had serial ADA measurements. Therapy was classified into past thiopurine response or its lack of, de novo combination, or IFX monotherapy. The primary endpoint was risk of ADA appearance. RESULTS: Out of 494 patients with serial ADA measurements 207 eligible patients were included in the final analysis. The 1-year cumulative risk of ADA development was similar in past thiopurine responders (19.3%) compared with past thiopurine failures (16.1%) (log rank P = .54). ADA was found in 46.6% of the monotherapy group and was significantly different compared with past thiopurine responders (P = .007) and past thiopurine failures (P = .007). The adjusted hazards for ADA development were significantly lower in past responders and past failures compared with the monotherapy group (hazard ratio, 0.47 [95% CI, 0.22-1.00] and 0.32 [95% CI, 0.11-0.93], respectively). CONCLUSIONS: Thiopurines-IFX cotherapy in patients with Crohn's disease is associated with reduced ADA formation compared with IFX monotherapy. This is probably regardless of initial thiopurine therapeutic effect.

Comparative Study of Two Cohorts of Newly Diagnosed Crohn's Disease Demonstrates Change in Therapeutic Strategies.

BACKGROUND: There has been a paradigm shift in the treatment of Crohn's disease (CD) involving the rapid introduction of biologics and/or immunomodulators after diagnosis. We wished to assess whether this was applied to patients with newly diagnosed CD in a tertiary inflammatory bowel disease referral centre in Israel. METHODS: Newly diagnosed CD patients were stratified into 2 groups: the early group was diagnosed between 2005 and 2007 and the late group was diagnosed between 2010 and 2012. Baseline demographics, medical and surgical treatments, disease course and complications during those 2 periods were analyzed. RESULTS: Each group included 60 patients. Significantly higher rates of immunomodulators and biologics were administered to patients in the late group compared to the early group (81.7 and 36.7% compared to 56.7 and 18.3%, p = 0.004 and p = 0.021, respectively). On the other hand, steroid therapy was less prevalent in the late (36.7%) group compared to that of the early group (56.7%), p = 0.059. Medical and surgical CD outcomes, including exacerbations/hospitalizations and surgeries, were comparable for both groups. CONCLUSIONS: There was a change in treatment strategy between 2005-2007 and 2010-2012, as reflected in higher proportions of biologics/immunomodulators for patients with newly diagnosed CD. This was associated with a steroid-sparing effect.