Disease Penetrance Research Articles

P146 Initial response to induction treatment more important than type of induction treatment for achieving sustained steroid free remission at 1 year in new-onset paediatric Crohn’s disease

Abstract Background For paediatric patients with high risk of complicated Crohn’s disease (CD) [stricturing or penetrating disease], paediatric guidelines recommend upfront anti-tumor necrosis factor-alpha (ATA). Early ATA therapy has been demonstrated to result in higher steroid- and surgery-free remission rates at 1 year than induction with conventional treatment (CONV) [Exclusive Enteral Nutrition (EEN) or corticosteroids followed by immunomodulatory therapy]. However, it is unknown whether either type of induction treatment or achieving steroid free remission (SFR) at 3 months is a more important predictor of sustained SFR (SSFR) at 1 year. Therefore, we aimed to evaluate the independent effect of early ATA use after achieving induction of remission on sustained SFR (SSFR) rates at 1 year in an international prospective observational study. Methods Since January 2017, children (0–18 years) with newly-diagnosed CD were prospectively enrolled in 28 European and Asian paediatric IBD centers. Extensive demographic and clinical data were collected at baseline, and at 1, 3, 6 and 12 months. The primary outcome was SSFR at 1 year, defined as a weighted Paediatric CD Activity Index (wPCDAI) <12.5 without steroids at 3, 6, and 12 months. Secondary outcomes included SFR at 3 and 12 months, and treatment escalation to ATA. Outcomes were compared between the early ATA induction treatment group (defined as ATA within 3 months after diagnosis) and the CONV induction treatment group (EEN or corticosteroids), using χ 2 tests. Results Up to July 2021, 235 children with new-onset CD were included and completed at least 1 year of follow-up (61.7% male, median age 13.7 [IQR 11.4–15.0]). At 1 year, 62/203 (30.5%) achieved SSFR. Patients that received early ATA were more likely to achieve SSFR compared to patients with CONV (35/79 [44%] vs. 27/110 [25%], p=0.004). After induction treatment, 99/213 [47%] achieved SFR at 3 months. Patients with early ATA had higher rates of SFR at 3 months (48/84 [57%]) than those with CONV (51/129 [40%], p=0.012), and higher rates of low faecal calprotectin (67% vs. 17%, p<0.001) or low CRP (< 5 mg/l) (82% vs. 53%, p<0.001). Of those patients in SFR at 3 months, 71% achieved SSFR, which was not significantly different between those in SFR at 3 months with early ATA vs. with CONV (35/45 [78%] vs. 27/43 [63%], p=0.12). Conclusion While only one-third of paediatric CD patients achieve SSFR at 1 year, 71% of patients achieve SSFR after having achieved SFR at 3 months. Patients with early ATA had higher rates of SFR at 3 months and SSFR at 1 year than those without early ATA. Remission at 3 months was found to be more important for SSFR than type of induction treatment, highlighting the importance of initial response to induction treatment.

P416 Addition of oral antibiotics to mechanical bowel preparation significantly improves anastomotic healing after ileocolic resection for Crohn’s disease

Abstract Background Addition of oral antibiotics (OA) to mechanical bowel preparation (MBP) is thought to reduce postoperative morbidity compared to MBP alone. However, data supporting this concept in Crohn’s disease patients undergoing ileocolic resection do not exist. Methods Starting, 2016, all ileocolic resections were performed after preoperative MBP combined with OA consisting of two separate dosages of Metronidazole/Neomycine or Metronidazol/Paramomycine. These patients were compared to previous controls undergoing ileocolic resection after mere MBP (1992–2005). Between, 2005 and, 2016, surgeries were performed without preoperative MBP. Patients undergoing an ileocolic resection without construction of anastomosis (i.e., two staged resection) and patients not receiving MBP were excluded from the study. „Anastomotic complications“ were defined as anastomotic leakage, presence of abscess or peritonitis in direct proximity to anastomosis. Results 312 patients underwent ileocolic resections with construction of an anastomosis:, 159 after MBP only and, 153 after preoperative MBP+OA. Patients in MBP+OA group were older (39 y. vs., 35 y., p=0.001), had penetrating disease less frequently (50% vs., 69%, p=0.001), were on biologicals more frequently (31% vs., 1%, p<0.001), on steroids less frequently (12% vs., 59%, p<0.001), underwent laparoscopic surgery more often (80% vs., 15%, p<0.001), and received preoperative parenteral nutrition more often (16% vs., 7%, p=0.033). Patients receiving OA were not able to complete MBP more often (19% vs., 9%, p=0.009). By the multivariate analysis, addition of OA to MBP was associated with a significant reduction of anastomotic complication rate (3% vs., 11%, Hazard ratio, 0.24, p=0.036). Weight loss and steroids were associated with an increased anastomotic morbidity. Conclusion Oral antibiotics added to MBP further improve the anastomotic healing in Crohn’s disease patients undergoing ileocolic resection, although the study has demonstrated an apparent time bias. Further research is needed to clarify whether OA without MBP are as protective as MBP+OA.

P473 Real world experience with the Crohn’s Disease Exclusion Diet (CDED) in a tertiary IBD clinic

Abstract Background The Crohn’s Disease Exclusion Diet (CDED) is a whole-food diet designed to reduce exposure to dietary components, hypothesized to negatively affect the microbiome, intestinal barrier, and immune response. In a clinical study in adults with mild-moderate CD (<5 years duration), an inflammatory phenotype involving the terminal ileum, it induced clinical, biochemical and endoscopic disease remission. We aimed to describe our real-world experience with the CDED, in a clinically diverse CD population. Methods A retrospective cohort study of CD patients prescribed with the CDED, between 1.2018 and 11.21. Patients’ medical background, medical therapy, nutritional status and clinical disease activity as well as adherence and clinical outcomes were documented from patients’ medical files. Results The CDED was recommended to 218 CD patients. Of these, 62 were excluded from the analysis due to lack of medical information (n=11), prior personal experience with the CDED (n=23), patient’s refusal (n=24), and stoma patients (n=4). The CDED was initiated in 155 patients (age 37.7±16.3, 66% men, disease duration 7.8±9.6), 35.3% had colonic/ileo-colonic disease, 23.7% and 25% had a stricturing and penetrating disease respectively, 27.5% had a history of intestinal resection, 19.9% had extra-intestinal involvement, and 7.7% had a severe endoscopic disease at diet initiation. Indications for therapy included patient’s will (44.7%), adjunctive therapy (23.7%), bridge with biologic induction (20.4%), rescue therapy (3.9%), exhaustion/contraindication of other advanced therapy options (1.4%), de-escalation of biologics (0.7%), preparation for surgery (0.7%), and others (3.9%). Upon initiation, 67.3% (n=105) had an active disease [Harvey Bradshaw index (HBI) ≥5 / Calprotectin ≥250 g/l] and 32.7% were in remission. Physician and dietician follow-up at the end of phase 1 was documented in 89 (57.4%) and 74 (47.7%) of patients with an active disease (mean follow-up period 14.6±9.3 weeks). Fifty-eight percent of patients with dietary follow-up (n=43) were fairly-fully compliant to the CDED. Clinical response (drop in HBI>2 points) and remission (HBI<5) at the end of phase 1, were achieved by 58.9% (n=62) and 57.5% (n=60) of patients who were treated for an active disease (n=105). Clinical remission rate at the end of phase 1 was lower among patients with higher baseline HBI score (P for trend=0.028), lower dietary adherence (P for trend<0.001) and a surgical history (P=0.033). Conclusion The CDED may have efficacy across different clinical scenarios. Adherence is reasonable, and is associated with higher remission rates among patients treated for an active disease.

P627 Variables associated with evolution to moderate to severe Crohn’s disease at two reference centers in Salvador, Bahia, Brazil

Abstract Background The identification of variables associated with evolution to moderate to severe disease is essential for the therapeutic management of patients with Crohn’s disease (CD). However, studies on this topic are scarce in developing countries. The main objective of this study is to determine the variables associated with hospitalization in patients with CD. The secondary objective is to identify variables associated with surgery, intestinal resection, rehospitalization, surgical recurrence and use of immunobiological therapy. Methods Cross-sectional study with a retrospective component that involved two reference centers for inflammatory bowel diseases in the public health system. Data were collected through a specific questionnaire and review of medical records in the period 2019 to 2021. The association between variables was evaluated through Chi-Square test and multivariate binary logistic regression. Results Were included 220 patients, 50.9% female. The most common findings were: age at diagnosis between 17 and 40 years (67.7%), colonic location (45.0%) and no stricturing no penetrating behavior (75.9%). Perianal disease was observed in 27.7% and involvement of the upper gastrointestinal (GI) in 16.1% (Table 1). 174 (79.1%) patients were hospitalized, 109 (49.5%) underwent surgery, being 50 (22.7%) bowel resection. 106 (60.9%) were readmitted, 13 (26.0%) presented surgical recurrence and 128 (58.2%) used immunobiologicals. Perianal disease was the only variable associated with hospitalization (p=0.012). Stricturing or penetrating behavior (p<0.001) and perianal disease (p<0.001) were associated with surgery. Regarding intestinal resection, ileal or ileocolon location (p=0.044) and stricturing or penetrating behavior (p<0.001) were variables associated. The use of corticosteroids in the first flare (p<0.001) was associated with rehospitalization, and postoperative complications (p=0.029) with surgical recurrence. Age at diagnosis below 40 years (p=0.004), upper GI involvement (p=0.040) and perianal disease (p<0.001) were associated with the use of immunobiologicals (Table 2). Conclusion This is a pioneer study in Brazil on variables associated with evolution to moderate to severe CD. Perianal disease and stricturing or penetrating behavior were associated with more than one outcome. Age at diagnosis below 40 years, ileal and ileo-colic location, upper GI involvement, use of corticosteroids in the first flare and postoperative complications were also variables found. These data are similar to those found in countries with a high prevalence of the disease1. Reference 1. Torres J et al. Predicting Outcomes to Optimize Disease Management in Inflammatory Bowel Diseases. J Crohns Colitis. 2016;10(12):1385–1394.

P640 Incidence, prevalence, disease phenotype and maximal therapeutic step in Crohn’s disease patients in Western Hungary – a population-based study between 2007–2018, data from the Veszprem county cohort

Abstract Background The number of epidemiological population-based studies are still limited from Eastern Europe. The present study is a continuation of the Veszprem IBD population based cohort with a follow-up of the incidence and disease course of IBD since 1977. Our aim was to analyze the incidence and disease phenotype at diagnosis, and the maximal therapeutic step distributions during follow-up in a prospective population-based database from Veszprem Province, including incident Crohn’s disease (CD) patients diagnosed between January 1, 2007 and December 31, 2018. Methods Data of 421 incident CD patients were analyzed (male/female: 237/184; median age at diagnosis: 29 years(y) [IQR: 21–42]). Both in-hospital and outpatient records were collected and comprehensively reviewed at diagnosis and during clinical follow-up. The source of age- and gender-specific demographic data was derived from the national population census in 2011. Results Adjusted mean incidence rate was 9.94(CI95%: 9.0–10.9)/105 person-years in this 12 year period[males:11.5(CI95%:10.2–13.2)/105; females:8.4(CI95%:7.3–9.7)/105]. Prevalence rate was 191.18(CI95%:177.0–205.7)/105 persons in 2011 and 236.78(CI95%:220.8–252.8) in 2015. For detailed annual incidence rates and age-specific mean incidence rates see Figure1 and 2. Peak onset age in CD was 20–29 years of age. Diagnostic delay from symptom onset was ≥1year in 26.6%, and ≥3 years in 10% of the patients. Disease location was ileal(L1) in 29.7%, colonic(L2) in 24.5%, and ileo-colonic(L3) in 45.8% at diagnosis. Upper gastrointestinal manifestation or perianal disease were present in 7.6% and 13.5%. Disease behavior at diagnosis was luminal(B1) in 62.5%, stenosing(B2) in 17.6%, penetrating(B3) in 16.4%, and B2+B3 in 3.6%. Patients with ileocolonic disease were younger (29.2y,SD:14.6) at diagnosis compared to patients with ileal(35.7y,SD:15.5;p<0.001) or colonic disease(37.7y;SD:18.1;p<0.001). Extraintestinal manifestations were as follows: hepatic5.0%(PSC 1.9%), arthritis13.8%, ocular1.7%, cutan4.3%. Active smokers at diagnosis were 35.4%. Distribution of maximal therapeutic steps during the course of follow-up (8.53y,SD: 3.3) were 5-ASA in 15.7%, systemic corticosteroids in 14.3%, immunosuppressive therapy in 42.5%; anti-TNF biologic therapy in 23.3% and other biologic therapy in 2.9%. Conclusion The incidence of CD in this 12 year period was high, comparable to high-incidence areas in Western European countries, and comparable to previous data from the Veszprem cohort, while prevalence rates continue to rise.(Lakatos 2011, IBD). Ileocolonic location and penetrating disease behavior were somewhat higher compared to previous population-based data from Western Europe.(Burisch 2018, JCC).

P340 Risankizumab in Inflammatory Bowel Disease: Real World Experience from a Pre-Approval Access Program

Abstract Background Risankizumab is a new generation monoclonal antibody which inhibits interleukin-23A. It has applications in several immune mediated inflammatory diseases including moderate-to-severe CD. Pre-approval access was granted for a cohort of patients who had active disease and prior use of all European licenced biologic therapies for CD. We aimed to define the effectiveness and tolerability of risankizumab in this real-world, treatment refractory cohort. Methods We performed a retrospective cohort analysis of prospectively maintained data for patients starting risankizumab between January and September, 2021. All patients received doses at four weekly intervals (IV, 600mg doses for CD and SC, 300mg doses for IBD-U). Clinical disease activity, biochemical activity and quality of life were measured using HBI, CRP and IBD-C scores, respectively. Study evaluations were made at baseline, weeks, 4 and, 12. Data were analysed in GraphPad prism and are described as median (range). Results Since January, 2021, 16 patients have started risankizumab. We included, 13 patients who had completed the, 12 week induction period at the time of submission;, 12 with CD and, 1 with IBD-U. Demographics are shown in Table, 1. The characteristics are consistent with a more aggressive phenotype with the majority of patients (9 (75%)) having perianal involvement as well as having either stricturing (5(42%)) or internal penetrating disease (3(25%)). Nine (75%) patients had undergone prior luminal surgery, 7 of whom still had stomas, therefore were not included in the analysis for HBI. Median HBI at baseline was, 5 (0–10) vs, 2 (0–8) at week, 4 and, 1.5 (0–2) at week, 12 and due to small patient numbers was not statistically significant. There was an improvement in IBD-C scores. Median IBD-C score at baseline was, 5 (0–14) vs, 11 (4–16) at week, 4 (p=0.034) and, 12 (2–16) at week, 12 (p=0.067). CRP decreased from, 12 mg/L (1–48) at baseline to, 8 mg/L (1–20) at week, 4 (p=0.23) and to, 6 mg/L (1–34) at week, 12 (p=0.022). Results are represented in Figure, 1. Two patients experienced mild headaches, no other side effects were reported. At initiation two patients were being treated with steroids; one has since discontinued and one has remained on steroids. No other patients initiated steroids. No patients discontinued risankizumab during the study period. Conclusion We present a heterogeneous cohort of patients with refractory CD despite multiple biologic mechanisms. Overall, there was a positive impact of risankizumab induction over a, 12 week period with respect to symptoms, quality of life and CRP, showing the effectiveness of risankizumab in this refractory cohort. We will follow up, and at week, 24 will objectively assess disease activity with cross sectional imaging and/or endoscopy.

X-linked dystonia-parkinsonism: over and above a repeat disorder.

X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder, caused by a founder retrotransposon insertion in an intron of the TAF1 gene. This insertion contains a polymorphic hexanucleotide repeat (CCCTCT)n, the length of which inversely correlates with the age at disease onset (AAO) and other clinical parameters, aligning XDP with repeat expansion disorders. Nevertheless, many other pathogenic mechanisms are conceivably at play in XDP, indicating that in contrast to other repeat disorders, the (CCCTCT)n repeat may not be the actual (or only) disease cause. Here, we summarize and discuss genetic and molecular aspects of XDP, highlighting the role of the hexanucleotide repeat in age-related disease penetrance and expressivity.

Existing Prediction Models of Disease Course in Paediatric Crohn's Disease Are Poorly Replicated in a Prospective Inception Cohort.

Several groups have proposed models to predict disease outcomes in paediatric Crohn's disease [CD], notably the RISK, GROWTH, and the Porto group, but none were externally validated. We aimed to explore these predictive models and individual predictors summarised by the PIBD-ahead project in a prospective inception cohort of paediatric CD. We included children who were diagnosed with CD at two medical centres and followed them at 3 and 12 months thereafter as well as at the last follow-up. Outcomes included steroid-free remission [SFR], surgery, and stricturing/fistulising disease. In all 155 children were included (median follow-up of 31 [16-48] months, 107 [71%] had moderate-to-severe disease). Stricturing and penetrating disease at diagnosis were noted in 34 [22%] and two [1.3%] children, respectively, and these were excluded from the relevant analyses. At 1 year, 10 [8.3%] developed new stricturing disease, two [1.7%] developed penetrating disease, seven [5%] required intestinal surgery, and 15 [10%] required perianal surgery. The sensitivity/specificity/positive predictive value [PPV]/negative predictive value [NPV] of the GROWTH criteria for predicting SFR at 12 months [occurring in 70% of children] were 20%/85%/76%/31% and for surgery at 2 years were 96%/20%/16%/96%, respectively. Strictures were predicted by the RISK model with sensitivity/specificity/PPV/NPV of 33%/73%/18%/86%, respectively. The sensitivity/specificity/PPV/NPV of the Porto criteria to predict surgery were 86%/10%/4%/94%, respectively. None of the Pediatric Inflammatory Bowel Disease-ahead [PIBD-ahead] predictors were associated with surgery or stricturing disease. None of the three main predictive models in paediatric CD achieved sufficient accuracy, far from that reported in the original cohorts. This highlights the necessity of external validation in any prediction model prior to its implementation in clinical practice.

Sex Disaggregated Analysis of Risk Factors for Adverse Outcomes in Hypertrophic Cardiomyopathy

Patient sex has been associated with differences in disease penetrance and clinical expression in hypertrophic cardiomyopathy (HCM). We sought to investigate sex-disaggregated differences in risk factors for adverse outcomes in a large international HCM registry.

Risk Factors for Surgery in Pediatric Patients with Crohn’s Disease

Objective: Pediatric Crohn’s disease (CD) has a more aggressive phenotype and course than in adults. Many patients develop complications that require surgery. The aim of this study was to identify the factors associated with increased risk for surgical intervention in pediatric patients with CD. Subjects and Methods: This study is a retrospective review of medical records. We analyzed the following variables: sex, age at diagnosis, presenting symptoms, duration of symptoms before diagnosis, disease location and severity, the presence of extraintestinal manifestations, and the presence of anti-Saccharomyces cerevisiae antibodies. Univariate analysis using the Mann-Whitney test and Fisher’s exact test was performed to detect the factors associated with surgery. Potential risk factors with p < 0.05 were further analyzed using a multivariate binary logistic regression model. Results: Fifty-seven patients (27 girls and 30 boys) were included in the analysis. More than one-fourth of them (28.1%) required surgical management. Female sex (p = 0.043), disease behavior (p = 0.012), and the presence of perianal disease at diagnosis (p < 0.001) were the variables associated with surgical intervention. Stricturing disease (B2) (odds ratio [OR], 24.944; p = 0.016), stricturing and penetrating disease (B2B3) (OR, 28.276; p = 0.011), and the presence of perianal disease at diagnosis (OR, 95.802; p = 0.001) were independent risk factors for surgery. Female sex was associated with surgery without being an independent risk factor. Conclusion: Females with B2 or B2B3 or the presence of perianal disease at diagnosis are at a higher risk for surgery and should be considered for more aggressive medical treatments.

CT or MR Enterography to Assess Response During Vedolizumab Therapy for Small Bowel Crohn's Disease.

To describe response to therapy of small bowel (SB) Crohn's disease (CD) at CT or MR enterography (CTE/MRE) in patients on vedolizumab. Patients with SB CD who underwent CTE/MRE exams greater than 12 months apart on vedolizumab therapy were included. Length (in cm) and inflammation severity (EMBARK score) of inflamed SB segments were assessed. Changes in inflammation length of 3.4cm or greater or inflammation severity of 2 EMBARK points or greater was categorized as response or progression, as appropriate, with development of newly inflamed segments, strictures, or penetrating complications also indicating progression. Patients not meeting the criteria for response or progression were categorized as having stable disease. Of 36 SB CD patients, the large majority had prior surgery (86%; 31), anti-TNF use (92%; 33), and internal penetrating (78%; 28) disease. Thirty-two patients had paired baseline and follow-up CTE/MRE exams without interval surgery, with clinical response observed in 24/32 (75%). Based on imaging response criteria, 22% (7/32; 95% CI: 9%-40%) had response, 50% (16/32; 95% CI: 32%-68%) were stable, and 28% (9/32; 95% CI: 14%-47%) had disease progression. Fifty-six percent of (18/32; 95% CI: 38%-74%) patients had clinical improvement with response or stable disease by imaging. Patients with stable disease had shorter median baseline lengths of SB inflammation (P = .012). Proportion of patients with colonic inflammation, perianal disease, or penetrating complications did not change. Most patients on vedolizumab for over 12 months demonstrated response or stable SB disease when using objective cross-sectional radiologic imaging criteria using CTE/MRE.

An optimized protocol for evaluating pathogenicity of VHL germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants

The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and germline. Despite the progress made in the integrated analysis of somatic and germline findings, the assessment of pathogenicity of germline variants in high penetrance genes remains grossly underutilized. Indeed, standard ACMG/AMP guidelines for interpreting germline sequence variants do not address the evidence derived from tumor data in cancer. Previously, we have demonstrated the utility of somatic tumor data as supporting evidence to elucidate the role of germline variants in patients suspected with VHL syndrome and other cancers. We have leveraged the key elements of cancer genetics in these cases: genes with expected high disease penetrance and those with a known biallelic mechanism of tumorigenicity. Here we provide our optimized protocol for evaluating the pathogenicity of germline VHL variants using informative somatic profiling data. This protocol provides details of case selection, assessment of personal and family evidence, somatic tumor profiles, and loss of heterozygosity (LOH) as supporting evidence for the re-evaluation of germline variants.

Indications, Postoperative Management, and Long-term Prognosis of Crohn's Disease After Ileocecal Resection: A Multicenter Study Comparing the East and West.

The Crohn's disease (CD) phenotype differs between Asian and Western countries and may affect disease management, including decisions on surgery. This study aimed to compare the indications, postoperative management, and long-term prognosis after ileocecal resection (ICR) in Hong Kong (HK) and the Netherlands (NL). CD patients with primary ICR between 2000 and 2019 were included. The endpoints were endoscopic (Rutgeerts score ≥i2b and/or radiologic recurrence), clinical (start or switch of inflammatory bowel disease medication), and surgical recurrences. Cumulative incidences of recurrence were estimated with a Bayesian multivariable proportional hazards model. Eighty HK and 822 NL patients were included. The most common indication for ICR was penetrating disease (HK: 32.5%, NL: 22.5%) in HK vs stricturing disease (HK: 32.5%, NL: 48.8%) in the NL (P < .001). Postoperative prophylaxis was prescribed to 65 (81.3%) HK patients (28 [35.0%] aminosalicylates [5-aminosalicylic acid]; 30 [37.5%] immunomodulators; 0 biologicals) vs 388 (47.1%) NL patients (67 [8.2%] 5-aminosalicylic acid; 187 [22.8%] immunomodulators; 69 [8.4%] biologicals; 50 [6.1%] combination therapy) (P < .001). Endoscopic or radiologic evaluation within 18 months was performed in 36.3% HK vs 64.1% NL (P < .001) patients. No differences between both populations were observed for endoscopic (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.24-1.21), clinical (HR, 0.91; 95% CI, 0.62-1.32), or surgical (HR, 0.61; 95% CI, 0.31-1.13) recurrence risks. The main indication for ICR in CD patients is penetrating disease in HK patients and stricturing disease in NL patients. Although considerable pre- and postoperative management differences were observed between the two geographical areas, the long-term prognosis after ICR is similar.

Long-Term Follow-up and Predictors of Complicated Disease Behavior in Pediatric Crohn's Disease Patients.

Identifying predictors of inflammatory bowel disease (IBD) outcome in order to optimize individual patient management in has become an important goal. We aimed to describe the long-term outcome of pediatric Crohn disease (CD) patients and identify risk factors for complicated behavior. Pediatric CD patients diagnosed between 1998 and 2014, with long-term follow-up were included. Baseline data; age, gender, weight/height/BMI percentiles, and family history of IBD. Disease characteristics (Paris classification), laboratory testing, imaging and treatment were documented. Outcome data; evidence of stricturing or penetrating disease, hospitalizations, surgical intervention, malignancies, and mortality. Of 93 patients included, mean age at diagnosis 13.5 (±3.2), 51 (55%) male, median follow-up 10.3 years (±4 SD(. Disease location at diagnosis: 29 (31.2%) distal ileum, 17 (18.3%) colonic, 40 (43.0%) ileo-colonic. Seven (7.5%) had upper gastrointestinal and 36 (38.7%) perianal involvement. Behavior at diagnosis, 68 (73.1%) inflammatory (B1), and 25 (26.9%) complicated [(B2 (stricturing) and/or B3 (penetrating)]. Twenty (23.2%) of B1 evolved to B2 and/or B3, thus by the end of follow-up 45 (48.4%) had complicated behavior. Sixty-seven (72%) were hospitalized, 20 (21.5%) underwent surgery, two developed malignancy with no mortalities. In a logistic regression model, growth delay (hazard ratio [HR], 5.02 [1.10-22.85], P = 0.037) and low albumin levels (HR, 3.97 [1.32-11.97], P = 0.014) at diagnosis were predictors of complicated disease in adulthood. Over a quarter of pediatric Crohn disease patients present with complicated behavior. During follow-up another quarter progress to complicated disease behavior. Delayed growth and low albumin at diagnosis predict progression.

Association between ABO blood group and risk of Crohn's disease: A case-control study in the Chinese Han population.

BackgroundBlood group O has been reported to be a potentially protective factor for Crohn's disease (CD) susceptibility in Caucasian and Korean populations, but a similar conclusion was not found in a Chinese study. The present study investigated the potential association in the Chinese Han population.MethodsWe included 275 CD patients, 132 ulcerative colitis (UC) patients and 1201 healthy individuals in this case‐control study. The demographic characteristics and ABO blood group were compared among the three groups. The clinical characteristics and treatment of CD were further investigated according to the blood group distribution.ResultsThe blood group distribution in CD patients was significantly different from healthy controls, and the frequency of O blood in CD patients was significantly lower compared to healthy controls. After adjusting for age and gender, the non‐O blood groups remained significantly associated with CD susceptibility in propensity score‐adjusted and propensity score‐matched analyses. Compared to CD patients with non‐O blood groups, patients with O blood were at a lower risk of developing penetrating disease, more likely to receive immunosuppressant treatment and less likely to receive biological treatment.ConclusionOur results confirmed that non‐O blood groups were significantly associated with an increased risk of CD in the Chinese Han population.

Serum exosomal microRNA-144-3p: a promising biomarker for monitoring Crohn's disease.

BackgroundCrohn’s disease (CD) has a tendency for recurrence and requires adequate monitoring and personalized treatment. Since endoscopy is considerably invasive, serum biomarkers are required as alternatives for CD monitoring. Toward this, exosomal microRNAs (miRNAs) may serve as promising candidates. In this study, we aimed to assess the role of serum exosomal microRNA-144-3p (miR-144-3p) as a biomarker for CD monitoring.MethodsWe prospectively recruited 154 patients without a history of surgery (Cohort 1) and 75 patients who were to undergo intestinal resection (Cohort 2). Serum samples were collected from Cohort 1 before colonoscopy and from Cohort 2 before surgery and during post-operative colonoscopic examination. The serum levels of exosomal miR-144-3p were measured using quantitative reverse-transcription polymerase chain reaction (PCR). Correlations between relative exosomal miR-144-3p levels, disease activity, and disease behavior were analysed. The area under the receiver-operating characteristic curve (AUC) was used to assess the predictive value of exosomal miR-144-3p regarding mucosal activity and post-operative recurrence.ResultsA 3.33-fold increase in serum exosomal miR-144-3p levels was recorded in patients with CD compared with those in healthy controls (P < 0.001). The exosomal miR-144-3p levels were positively correlated with the simple endoscopic score of CD (ρ = 0.547, P < 0.001) as well as the Rutgeerts score (ρ = 0.478, P < 0.001). Elevated exosomal miR-144-3p levels were correlated with the penetrating disease with high specificity (100% [95% confidence interval, 95.1%–100%]). The accuracy of exosomal miR-144-3p for identifying post-operative recurrence was higher than that of C-reactive protein (CRP) (AUC, 0.775 vs 0.639; P < 0.001).ConclusionsSerum exosomal miR-144-3p is a reliable biomarker of mucosal inflammation and penetrating CD. It may identify endoscopic CD recurrence after intestinal resection with higher accuracy than CRP testing.

Activation of Notch and Myc Signaling via B-cell-Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high-Myc-expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested (Sf3b1-Atm, Ikzf3, and MDR), and Dnmt3a-depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo. Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling. SIGNIFICANCE: Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition.

Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease.

Hirschsprung disease is a congenital malformation where ganglia of the neural crest-derived enteric nervous system are missing over varying lengths of the distal gastrointestinal tract. This complex genetic condition involves both rare and common variants in dozens of genes, many of which have been functionally validated in animal models. Modifier loci present in the genetic background are also believed to influence disease penetrance and severity, but this has not been frequently tested in animal models. Here, we addressed this question using Holstein mice in which aganglionosis is due to excessive deposition of collagen VI around the developing enteric nervous system, thereby allowing us to model trisomy 21-associated Hirschsprung disease. We also asked whether the genetic background might influence the response of Holstein mice to GDNF enemas, which we recently showed to have regenerative properties for the missing enteric nervous system. Compared to Holstein mice in their original FVB/N genetic background, Holstein mice maintained in a C57BL/6N background were found to have a less severe enteric nervous system defect and to be more responsive to GDNF enemas. This change of genetic background had a positive impact on the enteric nervous system only, leaving the neural crest-related pigmentation phenotype of Holstein mice unaffected. Taken together with other similar studies, these results are thus consistent with the notion that the enteric nervous system is more sensitive to genetic background changes than other neural crest derivatives.

P045 Prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD) in a Brazilian public healthcare clinic.

Inflammatory Bowel Disease (IBD) is an inflammatory and chronic disease, as well as non-alcoholic fatty liver disease (NAFLD). Current literature has shown that IBD patients are at high risk for NAFLD. In those patients, the pathogenesis of NAFLD may be more complex and related to multifactor causes, such as gut dysbiosis, unhealthy nutritional behavior, body composition and systemic inflammation. There is an increase in NAFLD's incidence in the general population, otherwise, there are few studies evaluating NAFLD prevalence in IBD patients. So, this study aimed to evaluate prevalence of NAFLD and identify the clinical factors associated with the presence of NAFLD in patients with IBD. This cross-sectional, descriptive, observational study included 71 IBD patients from an IBD public outpatient in São Paulo State, Brazil. Laboratory evaluation and clinical data were collected. The presence of NAFLD was evaluated by ultrasonography. The exclusion criteria were as follows: pre-existing liver disease, history of alcohol intake >20g/day for women and >30g/day for men, and glucocorticoids treatment >20mg/day. Statistical analysis: descriptive statistics and association tests. 71 patients were included, of which 34 (47.89%) were Crohn´s disease (CD) and 37 (52.11%) ulcerative colitis (UC). Median age was 45.32±13.59 years, 63.38% were female, 69.1% Caucasian, 7.04% smokers. The time from diagnosis was 12.55 ± 8.01 years. Regarding the characteristics of the diseases, 42.42% of patients with CD have ileocolonic involvement, 50% penetrating disease and 39.4% perianal involvement. In relation to patients with UC, most patients have pancolitis (72.22%). Mostly, the patients were in clinical (63.89%) and endoscopic (52.86%) remission. Regarding medical treatment, the most used drugs were biological therapy (79.41%) and azathioprine (52.94%) in CD, and mesalazine (45.95%), azathioprine (40.54%) and biological therapy (40.54%) in UC. The NAFLD group consists of 32 (45.07%) patients: 40.63% had mild steatosis; 40.63% moderate and 18.65% intense NAFLD. Development of NAFLD vs no NAFLD was associated with body mass index (29.49 ± 3.93 vs 24.32 ± 3.85, p < 0.0001), and laboratory biomarkers, such as C-reactive protein (1.99 ± 4.39 vs 0.87 ± 0.52, p = 0.0061), AST (29.72 ± 16.64 vs 23.46 ± 5.31, p = 0.0226), ALT (24.92 ± 14.22 vs 17.92 ± 6.57, p = 0.0099), albumin (4.1 ± 0.37 vs 4.36 ± 0.32, p = 0.0415), fasting glucose (95.5 ± 14.01 vs 84.36 ± 13.01, p = 0.0251) and blood insulin (18.41 ± 11.88 vs 6.4 ± 4.26, p = 0.0054). Also, the NAFLD group had higher prevalence of systemic arterial hypertension (31.25% vs 10.26%, p = 0.0369). When comparing patients with the presence or absence of NAFLD, there was no difference between the groups regarding time since diagnosis (p = 0.9684), previous surgery (p = 0.5908), Montreal classification, clinical activity assessed by CDAI (p = 0.2258), clinical activity assessed by the Mayo score (p = 0.4935), endoscopic activity (p = 0.0599), histological activity (p = 1.0), or medical treatment. Development of NAFLD is a frequent occurrence in patients with IBD. NAFLD group had higher levels of body mass index, C-reactive protein, AST, ALT, fasting glucose and blood insulin, which are also associated with metabolic syndrome. Early diagnosis and appropriate nutritional orientation are necessary to prevent NAFLD related complications.

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States