Predictors of Complicated Disease Course in Adults and Children With Crohn's Disease: A Nationwide Study from the epi-IIRN.

BACKGROUND: Since data on predictors of complicated Crohn's disease (CD) from unselected populations are scarce, we aimed to utilize a large nationwide cohort, the epi-IIRN, to explore predictors of disease course in children and adults with CD. METHODS: Data of patients with CD were retrieved from Israel's 4 health maintenance organizations, whose records cover 98% of the population (2005-2020). Time-to-event modeled a complicated disease course, defined as CD-related surgery, steroid-dependency, or the need for >1 class of biologics. Hierarchical clustering categorized disease severity at diagnosis based on available laboratory results. RESULTS: A total of 16 659 patients (2999 [18%] pediatric-onset) with 121 695 person-years of follow-up were included; 3761 (23%) had a complicated course (750 [4.5%] switched to a second biologic class, 1547 [9.3%] steroid-dependency, 1463 [8.8%] CD-related surgery). Complicated disease was more common in pediatric- than adult-onset disease (26% vs 22%, odds ratio, 1.3; 95% confidence interval [CI], 1.2-1.4). In a Cox multivariate model, complicated disease was predicted by induction therapy with biologics (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6) and severity of laboratory tests at diagnosis (HR, 1.7; 95% CI, 1.2-2.2), while high socioeconomic status was protective (HR, 0.94; 95% CI, 0.91-0.96). In children, laboratory tests predicted disease course (HR, 1.8; 95% CI, 1.2-2.5), as well as malnutrition (median BMI Z score -0.41; 95% CI, -1.42 to 0.43 in complicated disease vs -0.24; 95% CI, -1.23 to 0.63] in favorable disease; P < .001). CONCLUSIONS: In this nationwide cohort, CD course was complicated in one-fourth of patients, predicted by laboratory tests, type of induction therapy, socioeconomic status, in addition to malnutrition in children.

Prognostic factors of complicated disease course are vital for considering early escalation to biologics. In this nationwide cohort, complicated disease course was apparent in approximately one-fourth of patients and was predicted particularly by routinely collected laboratory tests, age, and type of induction therapy at diagnosis.

High red meat consumption among PNPLA3 polymorphism carriers is associated with NAFLD in a multi-center cross-sectional study.

BACKGROUND & AIM: Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphism has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD), with evidence for potential interaction with nutrition. However, the combination of meat consumption with genetic polymorphism has not been tested. Therefore, this study aims to test the association between the joint presence of PNPLA3 rs738409 G-allele with high meat consumption and NAFLD in populations with diverse meat consumption. METHODS: A cross-sectional study among Israeli screening and Brazilian primary healthcare populations. Food consumption was assessed by a food-frequency questionnaire. PNPLA3 polymorphism was defined as homozygous (GG) or heterozygous (GC). Inconclusive/probable NAFLD was defined as a fatty liver index (FLI) ≥ 30 and probable NAFLD as FLI ≥ 60. RESULTS: The sample included 511 subjects from the screening and primary healthcare populations (n = 213 and n = 298, respectively). Genetic polymorphism (homozygous GG or heterozygous GC) combined with high consumption of total meat, red and/or processed meat, unprocessed red meat, and processed meat was associated with the highest odds for inconclusive/probable NAFLD (OR = 2.75, 95%CI 1.27-5.97, p = 0.011; OR = 3.24, 1.43-7.34, p = 0.005; OR = 2.92, 1.32-6.47, p = 0.008; OR = 3.16, 1.46-6.83, p = 0.003, respectively), adjusting for age, gender, BMI, alcohol consumption, carbohydrate, and saturated fat intake. In addition, genetic polymorphism combined with high processed meat consumption was associated with the highest odds for probable NAFLD (OR = 2.40, 95%CI 1.04-5.56, p = 0.040). CONCLUSIONS: High red meat intake may confer a greater risk for NAFLD among PNPLA3 polymorphism carriers. Prospective studies are needed to confirm these findings and consider minimizing red and processed meat consumption among PNPLA3 polymorphism carriers.

Ultra-processed food consumption and non-alcoholic fatty liver disease, metabolic syndrome and insulin resistance: A systematic review.

Background: High ultra-processed food (UPF) consumption is associated with the development of various diet-related non-communicable diseases, especially obesity and type 2 diabetes. The present study aimed to systematically review the association between UPF consumption and non-alcoholic fatty liver disease (NAFLD) and its leading risk factors; metabolic syndrome (MetS) and insulin resistance (IR). Methods: A comprehensive search was conducted in PubMed, Scopus, Embase, Web of Science, CINAHL, and Cochrane (March 2023), and references of the identified articles were checked. The search keywords were defined through an exploratory investigation in addition to MeSH and similarly controlled vocabulary thesauruses. Observational and interventional studies were included. Studies that focused only on specific groups of processed foods or overlapping dietary patterns were excluded. The quality assessment was conducted using the Joanna Briggs Institute's critical appraisal tools for observational studies and Cochrane's risk of bias 2 tool for randomized-control trials. A narrative synthesis was employed to report the results. Results: Fifteen studies were included, with a total of 52,885 participants, one randomized-controlled trial, and fourteen observational studies (nine cross-sectional and five prospective). The review has shown a significant association between UPF consumption and NAFLD in three studies out of six, MetS in five out of eight, and IR in one out of three. All large-scale prospective cohorts that studied NAFLD or MetS outcomes demonstrated a positive association. In contrast, studies that did not demonstrate significant associations were mostly cross-sectional and small. The evidence for an association with IR was insufficient and conflicting. Conclusion: The included studies are few, observational, and based upon self-reported dietary assessment tools. However, current evidence indicates that UPF is not only associated with obesity and type 2 diabetes but may also be a risk factor for NAFLD and MetS. UPF is a worldwide concern deserving further longitudinal research. Impact and implications: Overconsumption of ultra-processed food (UPF) may lead to the development of obesity and type 2 diabetes, but the association with non-alcoholic fatty liver disease (NAFLD) is not well established. The present systematic review shows that UPF may be associated with NAFLD, although more large prospective studies are needed. These findings emphasize the importance of minimizing the consumption of UPF to prevent NAFLD and other metabolic diseases among the general adult population. This systematic review and further prospective studies, epidemiological or interventional, can help physicians provide patients with evidence-based nutritional recommendations and will support policymakers in restricting the marketing of UPF as well as promoting affordable, healthy, and minimally processed foods.

Residence in Peripheral Regions and Low Socioeconomic Status Are Associated With Worse Outcomes of Inflammatory Bowel Diseases: A Nationwide Study From the epi-IIRN.

BACKGROUND: Timely access to quality medical care impacts patient outcomes in inflammatory bowel disease (IBD). In a nationwide study from the epidemiology group of the Israeli IBD research nucleus we aimed to assess the impact of residence and socioeconomic status (SES) on disease outcomes. METHODS: We utilized data from the 4 health maintenance organizations in Israel, representing 98% of the population. Regions were defined as central, northern and southern; SES was graded from lowest to highest (from 1 to 4) as per Israel Central Bureau of Statistics. The primary outcome was steroid dependency, with secondary outcomes of surgeries and biologic therapy use. RESULTS: A total of 28 216 IBD patients were included: 15 818 (56%) Crohn's disease (CD) and 12 398 (44%) ulcerative colitis; 74%, 12% and 14% resided in central, southern, and northern Israel, respectively (SES 1: 21%, SES 4: 12%). Lower SES was associated with steroid dependency (20% in SES 1 vs 12% in SES 4 in CD; P < .001; and 18% vs 12% in ulcerative colitis; P < .001), and higher surgery rates (12% vs 7%; P < .001, and 1.4% vs 0.7%; P = .115, respectively). There were higher steroid dependency and CD surgery rates in peripheral vs central regions. In multivariable models, both SES and peripheral region were independently associated with poorer outcomes. CONCLUSIONS: We found that lower SES and peripheral residence were associated with deleterious outcomes in IBD. This should be considered by policymakers and should encourage strategies for improving outcomes in populations at risk.

In a novel nationwide population study, we found that patients with inflammatory bowel disease living in peripheral regions and those with lower socioeconomic status had significantly worse inflammatory bowel disease outcomes, notably higher corticosteroid dependency, higher surgery rate, and higher repeat surgery rate.

Prevalence and Outcomes of No Treatment Versus 5-ASA in Ulcerative Colitis: A Nationwide Analysis From the epi-IIRN.

BACKGROUND: Data regarding patients with ulcerative colitis (UC) not receiving maintenance treatment are scarce. In this nationwide study, we aimed to explore the frequency and long-term outcomes of untreated patients with UC vs treated patients. METHODS: We retrieved data from Israel's Health Maintenance Organizations, covering 98% of the population. No maintenance treatment (NMT) was defined as lack of treatment during the period from 3 to 6 months from diagnosis, allowing at most 3 months for induction treatment. RESULTS: A total of 15 111 patients have been diagnosed with UC since 2005, of whom 4410 (29%) have had NMT, with 36 794 person-years of follow-up. NMT was more likely in adults (31%) and in elderly-onset UC (29%) than in pediatric-onset UC (20%; P < .001) and decreased from 38% in 2005 to 18% in 2019 (P < .001). The probability of remaining without treatment was 78%, 49%, and 37% after 1, 3, and 5 years from diagnosis, respectively. In propensity score-matched analysis of 1080 pairs of treated (93% with 5-aminosalicylic acid) and untreated patients, outcomes were comparable for time to biologics (P = .6), surgery (P = .8), steroid dependency (P = .09), and hospitalizations (P = .2). Multivariable modeling indicated that failing NMT was less likely in adults or elderly-onset patients who received at most rectal therapy or antibiotics as induction therapy. CONCLUSIONS: Nowadays, 18% of patients with UC do not receive maintenance therapy, of whom half remain without treatment after 3 years. Matched pairs of patients on NMT and 5-aminosalicylic acid, representing the mildest patients of the latter, had similar outcomes. Prospective studies are needed to further explore the role of NMT in UC.

The rate of no maintenance treatment (NMT) decreased in the last years, but in a propensity score­matched analysis, 5-aminosalicylic acid monotherapy did not demonstrate any therapeutic advantage over NMT. NMT seems to be a viable option in a subset of patients with mild ulcerative colitis.

Medical concept embedding of real-valued electronic health records with application to inflammatory bowel disease.

Deep learning approaches are gradually being applied to electronic health record (EHR) data, but they fail to incorporate medical diagnosis codes and real-valued laboratory tests into a single input sequence for temporal modeling. Therefore, the modeling misses the existing medical interrelations among codes and lab test results that should be exploited to promote early disease detection. To find connections between past diagnoses, represented by medical codes, and real-valued laboratory tests, in order to exploit the full potential of the EHR in medical diagnosis, we present a novel method to embed the two sources of data into a recurrent neural network. Experimenting with a database of Crohn's disease (CD), a type of inflammatory bowel disease, patients and their controls (~1:2.2), we show that the introduction of lab test results improves the network's predictive performance more than the introduction of past diagnoses but also, surprisingly, more than when both are combined. In addition, using bootstrapping, we generalize the analysis of the imbalanced database to a medical condition that simulates real-life prevalence of a high-risk CD group of first-degree relatives with results that make our embedding method ready to screen this group in the population.

Surveillance and Management of Pouch Neoplasia in Familial Adenomatous Polyposis: A Systematic Review.

BACKGROUND: Patients with familial adenomatous polyposis often require prophylactic colectomy with ileal pouch-anal anastomosis to treat and/or reduce to risk of colorectal neoplasia. However, after surgery, patients are still at some risk of developing pouch polyps and even cancer in both handsewn or stapled anastomoses. Management relies mainly on endoscopic or surgical interventions, while chemopreventive agents have a limited role in the management and prevention of pouch neoplasia. Novel endoscopic techniques are evolving and may gradually overtake surgical intervention in selected cases. Since familial adenomatous polyposis is relatively rare, there is scarcity of data regarding the natural history of pouch polyps and cancer in this population. OBJECTIVE: This systematic literature review aims to describe the evolution, characteristics, various treatment modalities and their outcomes as well as recommended surveillance strategies of pouch neoplasia. DATA SOURCES: PubMed and Cochrane databases, the international pouch consortium (for expert opinion). STUDY SELECTION: Studies between 1990 and 2023, in English were included. Studies reporting neoplastic outcomes of inflammatory bowel disease pouch patients only were excluded. MAIN OUTCOME MEASURES: Incidence of pouch neoplasia and its outcomes (successful resections, surgical complications, mortality). RESULTS: Thirty-five studies were included. LIMITATIONS: Most studies focus on inflammatory bowel diseases pouch patients, there is scarce data regarding polyposis patients only. Most cohorts are small and retrospective. Data on interventions is mainly descriptive and no randomized controlled trials are available. CONCLUSIONS: Pouch adenoma are common and well managed by endoscopic resections, as advanced-endoscopic techniques are becoming more available. Additional data are required for defining updated recommendations for either endoscopic or surgical intervention. Pouch cancer is a very rare event and may arise despite surveillance. Continued endoscopic surveillance is key in cancer prevention and early detection. Outcome of cancer cases is poor and management in a referral center should be advised with tumor board discussions.

BNT162b2 mRNA COVID-19 Vaccine Effectiveness in Patients with Coeliac Disease Autoimmunity: Real-World Data from Mass Vaccination Campaign.

BACKGROUND: Data on COVID-19 vaccine effectiveness among patients with coeliac disease are currently lacking because patients with immune conditions were excluded from clinical trials. We used our coeliac disease autoimmunity (CDA) cohort to explore the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing SARS-CoV-2 infection among patients with CDA. METHODS: This retrospective cohort study included patients with positive autoantibodies against tissue transglutaminase (tTG-IgA). In the primary analysis, the cohort included CDA patients who received two vaccine doses against COVID-19 and matched patients in a 1:3 ratio. Patients were divided into subgroups based on their positive tTG-IgA level at diagnosis and their current serology status. RESULTS: The cohort included 5381 vaccinated patients with CDA and 14,939 matched vaccinated patients. The risk for breakthrough SARS-CoV-2 infection evaluated with Kaplan-Meier survival analysis via log-rank tests was similar between groups (p = 0.71). In a Cox regression survival analysis, the hazard ratio for breakthrough infection among patients with CDA compared to matched patients was 0.91 (95% confidence interval = 0.77-1.09). CONCLUSIONS: COVID-19 vaccination is effective in patients with coeliac disease autoimmunity. Vaccine effectiveness was comparable to the reference population.

Thiopurines Have Longer Treatment Durability than Methotrexate in Adults and Children with Crohn's Disease: A Nationwide Analysis from the epi-IIRN Cohort.

BACKGROUND: Thiopurines and methotrexate have long been used to maintain remission in Crohn's disease [CD]. In this nationwide study, we aimed to compare the effectiveness and safety of these drugs in CD. METHODS: We used data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel. Outcomes were compared by propensity-score matching and included therapeutic failure, hospitalisations, surgeries, steroid dependency, and adverse events. RESULTS: Of the 19264 patients diagnosed with CD since 2005, 3885 [20%] ever received thiopurines as monotherapy and 553 [2.9%] received methotrexate. Whereas the use of thiopurines declined from 22% in 2012-2015 to 12% in 2017-2020, the use of methotrexate remained stable. The probability of sustaining therapy at 1, 3, and 5 years was 64%, 51%, and 44% for thiopurines and 56%, 30%, and 23% for methotrexate, respectively [p <0.001]. Propensity-score matching, including 303 patients [202 with thiopurines, 101 with methotrexate], demonstrated a higher rate of 5-year durability for thiopurines [40%] than methotrexate [18%; p <0.001]. Time to steroid dependency [p = 0.9], hospitalisation [p = 0.8], and surgery [p = 0.1] were comparable between groups. These outcomes reflect also shorter median time to biologics with methotrexate (2.2 [IQR 1.6-3.1 years) versus thiopurines (6.6 [2.4-8.5]; p = 0.02). The overall adverse events rate was higher with thiopurines [20%] than methotrexate [12%; p <0.001], including three lymphoma cases in males, although the difference was not significant [4.8 vs 0 cases/10 000 treatment-years, respectively; p = 0.6]. CONCLUSION: Thiopurines demonstrated higher treatment durability than methotrexate but more frequent adverse events. However, disease outcomes were similar, partly due to more frequent escalation to biologics with methotrexate.

Association of Antibiotic Use with Durability of Biologic Agents in Inflammatory Bowel Disease: a Report from the epi-IIRN.

BACKGROUND: Different antibiotic classes were reported to have variable effects on immunogenicity towards anti-tumour necrosis factor [TNF] agents. However, the impact of antibiotic administration on biologic treatment durability was not investigated. We aimed to assess the association between antibiotic treatment and persistence of different classes of biologic therapy in inflammatory bowel disease [IBD] patients. METHODS: Data from the epi-IIRN, a nationwide registry of all Israeli IBD patients were analysed. All patients who filled a prescription of either infliximab, adalimumab, vedolizumab, or ustekinumab, were included. Treatment cessation was defined as drug discontinuation of at least 6 months. Macrolides, cephalosporins, fluoroquinolones, and penicillins with beta-lactamase inhibitors were selected as primary exposure variables. Survival analysis was performed using marginal structural models for each drug separately. RESULTS: In all 13 513 IBD patients, with a total of 39 600 patient-years, were included. Significant differences of overall treatment persistence were demonstrated, with highest persistence rates for ustekinumab and the lowest for infliximab treatment. Macrolides were found to be significantly associated with reduced risk of infliximab cessation (adjusted hazard ratio [aHR] 0.72, 95% CI 0.62-0.89]. Fluoroquinolones and cephalosporins were associated with an elevated risk of adalimumab treatment cessation [aHR 1.33, 95% CI 1.22-1.46; and aHR 1.20, 95% CI 1.08-1.34, respectively]. No significant effects of the studied antibiotics were observed in ustekinumab and vedolizumab users. CONCLUSIONS: Specific antibiotic classes are associated with duration of anti-TNF treatment, but not with durability of vedolizumab or ustekinumab treatments. Further research is required to study the effect of specific antibiotics on response to biologics.

5-aminosalicylate maintenance is not superior to no maintenance in patients with newly diagnosed Crohn's disease-A nationwide cohort study.

BACKGROUND: 5-aminosalicylates (5-ASA) are widely used in Crohn's disease (CD) despite guidelines advising otherwise. We aimed to assess in nationwide study the outcomes of first-line 5-ASA maintenance therapy (5-ASA-MT) compared with no maintenance treatment (no-MT) in patients with newly diagnosed CD. METHODS: We utilised data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel between 2005 and 2020. Propensity score (PS) matching was utilised to compare outcomes in the 5-ASA-MT versus no-MT groups. RESULTS: Of the 19,264 patients diagnosed with CD, 8610 (45%) fulfilled the eligibility criteria (3027 [16%] received 5-ASA-MT and 5583 [29%] received no-MT). Both strategies declined over the years; 5-ASA-MT from 21% of CD patients diagnosed in 2005 to 11% in 2019 (p < 0.001) and no-MT from 36% to 23% (p < 0.001). The probability of maintaining therapy at 1, 3 and 5 years from diagnosis: 5-ASA-MT-78%, 57% and 47% and no-MT-76%, 49% and 38% respectively (p < 0.001). PS analysis successfully matched 1993 pairs of treated and untreated patients and demonstrated comparable outcomes of time to: biologic (p = 0.2), steroid dependency (p = 0.9), hospitalisation (p = 0.5) and CD-related surgery (p = 0.1). Rates of acute kidney injury (5.2% vs. 3.3%; p < 0.001) and pancreatitis (2.4% vs. 1.8%; p = 0.03) were higher in the 5-ASA-MT group compared with the no-MT group but after PS matching the rates of adverse events were similar. CONCLUSION: First-line 5-ASA monotherapy was not superior to no-MT but associated with a slightly higher rates of adverse events, while both strategies have declined over the years. These findings suggest that a subset of patients with mild CD may be offered a watchful waiting approach.

The epidemiology and burden of gastroparesis: Real-world data from a large healthcare provider in Israel.

BACKGROUND: Gastroparesis is a gastrointestinal motility dysfunction characterized by delayed gastric emptying in the absence of gastric mechanical obstruction. Data on the epidemiology of gastroparesis are sparse even though the condition substantially impairs patients' quality of life. The aim of this study was to describe the epidemiology and estimate the short-term healthcare resource use burden of gastroparesis in a large population. METHODS: This cross-sectional study utilized computerized data from Maccabi Healthcare Services, a 2.5-million member state-mandated health organization in Israel. Data were collected between 2003 and 2018 to assess the prevalence of gastroparesis. Definite gastroparesis was defined by gastroparesis diagnosis and gastric emptying test. Probable gastroparesis was defined by gastroparesis diagnosis only. To compare the healthcare resource utilization (HCRU), data were also collected on controls that were individually matched (1:2) for age, sex, and comorbidities. KEY RESULTS: A total of 522 patients with gastroparesis were identified (21.1 per 100,000 WHO age-standardized), including 204 with definite gastroparesis (8.6 per 100,000 WHO). Male to female ratio was 1:2 and mean ± SD age of 54.7 ± 17.1 years. Diabetes accounted for 25.9% of gastroparesis cases and the rest were idiopathic. Gastroparesis patients were more likely to have cardiovascular diseases (10% vs. 6.9% for controls, p = 0.034) and lower prevalence of obesity (17% vs. 24.4%, p < 0.001). HCRU within the 2 years after index date were higher with more hospitalizations than controls (26.4% vs. 15.4%, p < 0.001), and more emergency room visits (31.6% vs. 24.1%, p = 0.002). CONCLUSIONS & INFERENCES: Gastroparesis is uncommon or under-documented in community care settings. Gastroparesis in general is associated with cardiovascular morbidities, lower BMI, and elevated utilization of healthcare services.

Implementing electronic patient reported outcomes in inflammatory bowel disease: patient participation, score reliability and validity.

BACKGROUND: Patient-reported outcome measures (PROMs) are recommended for assessing patient-centered outcomes in inflammatory bowel disease (IBD). The main aims were to assess the level of participation in an electronic PROM (ePROM) data collection system among patients with IBD, and evaluate reliability and validity of the resulting scores. METHODS: Patients included in the IBD registry of Maccabi Healthcare Services, a state-mandated healthcare provider for over 2.6 million people in Israel, were invited to complete the IBD-Control measure and a general health item, with follow-up ePROMs at 3 and 6 months including a global rating of change item. Descriptive statistics were used to compare patient characteristics by participation rate, and assess survey completion time. Initial scores were assessed for internal consistency reliability using Cronbach's alpha. Test-retest reliability was assessed using the intraclass correlation coefficient from paired scores of patients identified as unchanged between the initial and first follow-up. Construct validity was assessed by the ability of IBD-control scores to discriminate between patient sub-groups in expected ways. Empirical validity was assessed using ePROM score correlations with laboratory markers of disease activity. Score coverage was also assessed. RESULTS: A total of 13,588 patients were invited to participate [Mean age = 49 years (SD = 17); females = 51%]. Participation rate was 31.5%. Participants compared to non-participants were slightly older, were more likely to be female, to have a history of biologic treatment, to have higher socio-economic status, and to be more experienced in the usage of the digital patient portal. Median survey completion time was approximately 1:30 min. Internal consistency and test-retest reliability were 0.86 and 0.98, respectively. Scores discriminated between patient sub-groups in clinically expected ways, with expected correlations to laboratory markers of disease activity. A notable ceiling effect was observed (> 15%) for IBD-Control scores. CONCLUSIONS: Feasibility, reliability, and validity of the ePROM system was supported for measuring the level of perceived disease control in patients diagnosed with IBD in Israel. Additional research is needed to identify ways to increase patient participation, assess clinical implications of the identified measurement ceiling of the IBD-control, and evaluate the added value of the derived scores in support of clinical decision making.

Trends in Biochemical Parameters, Healthcare Resource and Medication Use in the 5 Years Preceding IBD Diagnosis: A Health Maintenance Organization Cohort Study.

BACKGROUND: Few data describing pre-diagnosis changes in patients with inflammatory bowel disease (IBD) exist. We aimed to determine if there is a pattern of change in use of health resources, medications and laboratory results in the years preceding diagnosis. METHODS: This retrospective study used electronic medical records of Maccabi Health Services (MHS). Patients with IBD ≥ 16 years of age and minimum of 5-years follow-up were identified by entry into the MHS IBD registry and included in the analysis. Demographic, clinical, medication and laboratory data were collected. Generalized estimating equation model was applied to study trends and compare between years. RESULTS: This study included 5643 patients with IBD. Of these, 3039 (53.8%) had Crohn's disease (CD), 2322 (41.1%) had ulcerative colitis (UC) and 282 (5%) had indeterminate colitis (IC). Laboratory parameters including white blood cells, platelets and C-reactive protein showed significant increases while haemoglobin and mean cell volume showed significant decreases in mean values in the 2 years prior to diagnosis with stable values prior to that (p < 0.0001). Parameters such as creatinine, total protein and albumin showed significant, progressive decreases in mean values starting 5 years prior to diagnosis (p < 0.0001). Patients with CD had distinct laboratory trends when compared with patients with UC. CONCLUSIONS: Changes in laboratory parameters, healthcare service and medication use occur during the 5-year period before IBD diagnosis. These data can have future clinical applicability by developing a composite score and referral algorithm introducing red flags into primary care visits and appropriate referral for specialist care.

The Association of Inflammatory Bowel Disease with Coeliac Disease and Coeliac Autoimmunity in Children and Adults: A Nationwide Study from the epi-IIRN.

BACKGROUND AND AIMS: Given the paucity of population-based data on the association between inflammatory bowel diseases [IBD], coeliac disease [CeD], and coeliac autoimmunity [CeA] we aimed to study the associations in a nationwide study. METHODS: Using health administrative data for all four health maintenance organisations in Israel, covering 98% of the population, we explored the prevalence of CeD in children and adults with IBD versus non-IBD matched controls. CeD was defined by three ICD-9 codes and CeA by positivity for tissue transglutaminase antibodies. RESULTS: In total, 34 375 IBD patients (56% Crohn's disease [CD] and 44% ulcerative colitis [UC]) were compared with 93 603 non-IBD controls. Among IBD patients, 319 [0.93%] had CeD versus 294 [0.31%] non-IBD controls (odds ratio [OR] = 2.97, 95% confidence interval [CI] 2.54-3.48; p <0.001). CeA was identified in 575 [1.67%] IBD patients vs 158 [0.17%] controls [OR = 10.06, 95% CI 8.43-12; p <0.001]. The prevalence of CeD was higher in paediatric-onset IBD (87/5243 [1.66%]) than adult-onset IBD (232/29 132 [0.79%]; p <0.001). CD patients had a higher prevalence of CeD (229/19 264 [1.19%]) than UC patients (90/15 111 [0.56%]; OR = 2.01, 95% CI 1.57-2.56; p <0.001). The diagnosis of CeD preceded the diagnosis of IBD in 241/319 cases [76%]. The time to treatment escalation was shorter in patients with both IBD and CeD than in patients with IBD without CeD [p = 0.017]. CONCLUSION: CeD and CeA are more prevalent in IBD patients, especially in paediatric-onset IBD and in CD. The diagnosis of CeD usually precedes that of IBD. Having CeD is associated with more intensified treatment for IBD.

Incidence, Management, and Outcomes of Very Early Onset Inflammatory Bowel Diseases and Infantile-Onset Disease: An Epi-IIRN Study.

BACKGROUND & AIMS: In this nationwide study from the Israeli Inflammatory Bowel Disease Research Nucleus, we aimed to describe the incidence of very early onset inflammatory bowel diseases (VEOIBDs) with a focus on infantile-onset disease and to compare management and disease course with older children. METHODS: Data were retrieved from the 4 Israeli Health Maintenance Organizations covering 98% of the population. Pediatric-onset IBD was categorized as follows: adolescent onset (10 to <18 y), early onset (6 to <10 y), VEOIBD (0 to <6 y), toddler onset (2 to <6 y), and infantile onset (<2 y). RESULTS: A total of 5243 children with 35,469 person-years of follow-up evaluation, were diagnosed with IBD during 2005 to 2020: 4444 (85%) with adolescent onset, 548 (10%) with early onset, and 251 (4.8%) with VEOIBD, of whom 81 (1.5%) had infantile onset. The incidence of pediatric-onset IBD increased from 10.8 per 100,000 in 2005 to 15.3 per 100,000 in 2019 (average annual percentage change, 2.8%; 95% CI, 2.2%-3.4%), but that of VEOIBD remained stable (average annual percentage change, 0%; 95% CI, -2.5% to 2.6%). The infantile-onset and toddler-onset groups were treated less often with biologics (36% and 35%, respectively) vs the early onset (57%) and adolescent-onset groups (53%; P < .001). The time to steroid dependency was shorter in infantile-onset (hazard ratio [HR], 2.1; 95% CI, 1.5-2.9) and toddler-onset disease (HR, 1.6; 95% CI, 1.2-2.0) vs early onset and adolescent-onset disease, but time to hospitalizations, time to surgery, and growth delay were worse only in infantile-onset disease. In a multivariable model, infantile-onset patients had a higher risk for surgery (HR, 1.4; 95% CI, 1.1-1.9) and hospitalization (HR, 1.7; 95% CI, 1.2-2.4) than the toddler-onset group. CONCLUSIONS: The incidence of VEOIBD remained stable. Infantile-onset IBD had worse outcomes than older children, while toddler onset had mostly similar outcomes, despite less frequent use of biologics.

Wide-area transepithelial sampling with computer-assisted analysis to detect high grade dysplasia and cancer in Barrett's esophagus: a multicenter randomized study.

BACKGROUND: Current surveillance for Barrett's esophagus (BE), consisting of four-quadrant random forceps biopsies (FBs), has an inherent risk of sampling error. Wide-area transepithelial sampling (WATS) may increase detection of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). In this multicenter randomized trial, we aimed to evaluate WATS as a substitute for FB. METHODS: Patients with known BE and a recent history of dysplasia, without visible lesions, at 17 hospitals were randomized to receive either WATS followed by FB or vice versa. All WATS samples were examined, with computer assistance, by at least two experienced pathologists at the CDx Diagnostics laboratory. Similarly, all FBs were examined by two expert pathologists. The primary end point was concordance/discordance for detection of HGD/EAC between the two techniques. RESULTS: 172 patients were included, of whom 21 had HGD/EAC detected by both modalities, 18 had HGD/EAC detected by WATS but missed by FB, and 12 were detected by FB but missed by WATS. The detection rate of HGD/EAC did not differ between WATS and FB (P = 0.36). Using WATS as an adjunct to FB significantly increased the detection of HGD/EAC vs. FB alone (absolute increase 10 % [95 %CI 6 % to 16 %]). Mean procedural times in minutes for FB alone, WATS alone, and the combination were 6.6 (95 %CI 5.9 to 7.1), 4.9 (95 %CI 4.1 to 5.4), and 11.2 (95 %CI 10.5 to 14.0), respectively. CONCLUSIONS: Although the combination of WATS and FB increases dysplasia detection in a population of BE patients enriched for dysplasia, we did not find a statistically significant difference between WATS and FB for the detection of HGD/EAC as single modality.

Efficacy of Wholistic Turmeric Supplement on Adenomatous Polyps in Patients with Familial Adenomatous Polyposis-A Randomized, Double-Blinded, Placebo-Controlled Study.

Several studies have demonstrated that curcumin can cause the regression of polyps in familial adenomatous polyposis (FAP), while others have shown negative results. Wholistic turmeric (WT) containing curcumin and additional bioactive compounds may contribute to this effect. We performed a double-blinded, randomized, controlled trial to assess the efficacy of WT in FAP patients. Ten FAP patients were randomly assigned to receive either WT or placebo for 6 months. Colonoscopies were performed at baseline and after 6 months. The polyp number and size, as well as the cumulative polyp burden, were assessed. No differences were noted between the groups in terms of changes from the baseline's polyp number, size, or burden. However, stratifying the data according to the right vs. left colon indicated a decrease in the median polyp number (from 5.5 to 1.5, p = 0.06) and polyp burden (from 24.25 mm to 11.5 mm, p = 0.028) in the left colon of the patients in the WT group. The adjusted left polyp number and burden in the WT arm were lower by 5.39 (p = 0.034) and 14.68 mm (p = 0.059), respectively. Whether WT can be used to reduce the polyp burden of patients with predominantly left-sided polyps remains to be seen; thus, further larger prospective trials are required.

High Meat Consumption Is Prospectively Associated with the Risk of Non-Alcoholic Fatty Liver Disease and Presumed Significant Fibrosis.

Non-alcoholic fatty liver disease (NAFLD) has been associated with meat consumption in cross-sectional studies. However, only a few prospective studies have been conducted, and they did not test for liver fibrosis. We aimed to assess the association between meat consumption changes and the incidence and remission of NAFLD and significant liver fibrosis. We used a prospective cohort study design, including 316 subjects aged 40-70 years, participating in baseline and follow-up evaluations at Tel-Aviv Medical Center. NAFLD was determined by liver ultrasound or controlled attenuation parameter (CAP), and liver fibrosis was determined by FibroScan. Meat consumption (g/day) was assessed by a food frequency questionnaire (FFQ). In multivariable-adjusted analyses, high consumption of red and/or processed meat (≥gender-specific median) was associated with a higher risk of NAFLD with elevated alanine aminotransferase (ALT) (OR = 3.75, 1.21-11.62, p = 0.022). Consistently high (in both baseline and follow-up evaluations) total meat consumption was associated with 2.55-fold (95% CI 1.27-5.12, p = 0.009) greater odds for new onset and/or persistence of NAFLD compared to consistently low meat consumption. A similar association was shown for consistently high consumption of red and/or processed meat (OR = 2.12, 95% CI 1.11-4.05, p = 0.022). Consistently high red and/or processed meat consumption was associated with 4.77-fold (95% CI 1.36-16.69, p = 0.014) greater odds for significant fibrosis compared to consistently low consumption. Minimizing the consumption of red and/or processed meat may help prevent NAFLD and significant fibrosis.

Adenomatous Polyposis Phenotype in BMPR1A and SMAD4 Variant Carriers.

INTRODUCTION: Variants in SMAD4 or BMPR1A cause juvenile polyposis syndrome, a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. A phenotype of attenuated adenomatous polyposis without hamartomatous polyps is rare. METHODS: We describe a retrospective cohort of individuals with SMAD4 or BMPR1A heterozygous germline variants, having ≥10 cumulative colorectal adenomas and/or colorectal cancer without hamartomatous polyps. All individuals had multigene panel and duplication/deletion analysis to exclude other genetic syndromes. RESULTS: The study cohort included 8 individuals. The pathogenic potential of the variants was analyzed. Variants detected included 4 missense variants, 1 nonsense variant, 1 splice site variant, and 2 genomic deletions. Features of pathogenicity were present in most variants, and cosegregation of the variant with polyposis or colorectal cancer was obtained in 7 of the 8 families. Three of 8 individuals had colorectal cancer (age less than 50 years) in addition to the polyposis phenotype. Two individuals had extraintestinal neoplasms (pancreas and ampulla of Vater). DISCUSSION: The clinical phenotype of SMAD4 and BMPR1A variants may infrequently extend beyond the classical juvenile polyposis syndrome phenotype. Applying multigene panel analysis of hereditary cancer-related genes in individuals with unexplained polyposis can provide syndrome-based clinical surveillance for carriers and their family members.