Ulcerative Colitis Activity Index Research Articles

P178 Evaluation of the Ulcerative Colitis Intestinal Ultrasound (UC-IUS) Index in Pediatric patients with newly diagnosed ulcerative colitis

Abstract Background Transabdominal bowel ultrasound (TABUS) is a non-invasive tool that can be used to assess bowel inflammation in ulcerative colitis (UC). It is particularly attractive for use in children, given the need for general anesthesia when undergoing endoscopic assessment of bowel inflammation. A standardized TABUS scoring system in UC has only been developed in adults (the UC Intestinal Ultrasound (UC-IUS) Index). Our aim was to evaluate the UC-IUS Index in Pediatric patients. Methods Pediatric patients (<18 years old) with suspected UC were prospectively enrolled. TABUS was performed for the right side colon, transverse, descending, and sigmoid colons. UC-IUS Index scores were calculated: bowel wall thickness (BWT) (>2mm=1, >3mm=2, >4mm=3), Doppler signal (spots=1, stretches=2), haustrations (abnormal=1), and fat wrapping (present=1). Mayo endoscopic subscore (for each segment), Pediatric Ulcerative Colitis Activity Index (PUCAI), and inflammatory biomarkers were collected. Non-parametric tests were used to correlate UC-IUS and BWT with Mayo endoscopic subscores. Receiver operating characteristic (ROC) analyses evaluated the UC-IUS Index BWT cut-offs. Results Fifty-two patients (56% male) were included (Table 1). Data for 206 colonic segments were analyzed (2 segments missing due to 1 incomplete colonoscopy). Total UC-IUS scores significantly correlated with CRP (rho=0.61), albumin (rho=-0.49), PUCAI (rho=0.54), FCP (rho=0.41). UC-IUS Index scores and mean BWT for each segment showed significant moderate correlations with Mayo sub-scores of that segment (rho=0.60 and rho=0.58, respectively) (p<0.001) (Fig 1). These correlations were strong in the right colon (rho=0.77, rho=0.69), and moderate in the transverse (rho=0.52, rho=0.56), descending (rho=0.43, rho=0.50), and sigmoid (rho=0.50, rho=0.46) colons (p<0.01). The adult UC-IUS 2mm cut-off (Mayo 0 vs. Mayo 1-3) performed similarly in our Pediatric patients (sensitivity 80%, specificity 96%, area under the curve (AUC) 0.92). The 3mm (Mayo 0-1 vs. Mayo 2-3) and 4mm (Mayo 0-2 vs. Mayo 3) cut-offs had lower sensitivity (sensitivity 44%, specificity 98%, AUC 0.87; sensitivity 59%, specificity 92%, AUC 0.80) (Fig 2). Thinner BWT cut-offs performed better: 2.5mm (sensitivity 65%; specificity 89%) and 3.5mm (sensitivity 71%; specificity 86%). Fig 1: Fig 2: Conclusion In Pediatric patients with newly diagnosed UC, TABUS was a useful tool, with the UC-IUS and BWT correlating well with their endoscopic, clinical, and biochemical disease activity. Compared to the adult UC-IUS Index, Pediatric patients need a thinner BWT cut-off to better discriminate between mild vs. moderate/severe disease (2.5mm instead of 3mm) and mild/moderate vs. severe disease (3.5mm instead of 4mm).

P735 Real-life experience with the use of Tofacitinib in Colombian patients with moderate to severe Ulcerative Colitis: a descriptive study

Abstract Background In Latin America the experience in clinical practice with tofacitinib for moderate to severe Ulcerative Colitis (UC), in terms of both effectiveness and safety, is still limited. In Colombia, the incidence of UC as well as the availability of these new therapeutic options has been increasing, also, patients are frequently more refractory to treatments with higher rates of hospitalizations and surgeries. The aim of this study is to describe the real-life experience in Colombian patients with UC treated with Tofacitinib. Methods descriptive observational study, patients with moderate-severe UC as defined by the American College of Gastroenterology Ulcerative Colitis Activity Index (ACG score) treated with tofacitinib in induction phase (10mg every 12 hours) and maintenance (5mg every 12 hours), in different reference centers nationwide. Therapeutic response was evaluated in endoscopic (Mayo score), paraclinical (CRP, ESR, fecal calprotectin, hemoglobin) and clinical (absence of abdominal pain, diarrhea and rectorrhagia) terms. Additionally, the frequency of adverse events, steroid use and extraintestinal manifestations were measured. Results 51 patients, 55% women, the average age was 37,14 years (range14-72). All patients had moderate to severe UC; 73% patients with pancolitis, and 21,6% with left colitis. The mean age at UC diagnosis was 29,77 (SD17,8) years (range 12.77-66,4). And the mean time between disease onset and tofacitininb initiation was 7,33 (SD17,1) years (range 0.001-22.72). 42/51(82,4%) patients had previously failed tumor necrosis factor inhibitors and 15/51(29,4%) had failed alpha4 beta7 integrin inhibitor (Vedolizumab). Six patients were naïve to any biologic drug. Ten patients had extraintestinal manifestations. During the induction phase, 68,6% achieved clinical remission, 58,8% endoscopic remission, and 60,8% paraclinical remission. During maintenance phases, information was obtained from 18 patients during the first 6 months, 16 of whom reported clinical, paraclinical and endoscopic remission, while information was obtained from 7 patients at 12 months, 5 of whom showed clinical remission, and 6/7 endoscopic and paraclinical remission. Four patients reported adverse events No thromboembolic or cardiovascular events were reported. Conclusion Tofacitinib is an effective and safe therapeutic alternative in the management of moderate-severe UC in our population. It is safe in patients with previous use of anti-TNF and anti-integrin, without presenting thrombotic or cardiovascular events. Also, it is a promising alternative in the bio-naïve patient. Its use in pediatric patients is off-label, the patients included presented clinical and paraclinical remission.

GROWTH OUTCOMES OF IV ANTI-TNF BIOSIMILARS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Biosimilars are biologic products similar in safety and efficacy to the originator product. Tumor necrosis factor-alpha inhibitors (anti-TNFs) are used in the treatment of inflammatory bowel diseases (IBD). There are limited studies evaluating the long-term outcomes of anti-TNF biosimilars in children with IBD. Growth is an important clinical outcome, especially in childhood-onset IBD. However, no study to date has compared growth outcomes in patients initiated on the IV anti-TNF originator as compared to a biosimilar. METHODS This was a single-center retrospective review of patients with IBD, younger than 16 years old, and initiated on the IV anti-TNF originator or a biosimilar between April 2016 and February 2021 at Nationwide Children’s Hospital. To be eligible for the study and evaluate the primary outcome, patients must remain on the IV anti-TNF therapy for at least 12-months. We used propensity score methodology to identify 37 pairs of matched patients based on baseline characteristics (age of anti-TNF initiation, disease (CD vs UC/IC), behavior, location, perianal type, race). Demographic data, laboratory values, disease activity scores, and growth values (z-scores were recorded for weight, height, and BMI) were collected at baseline (prior to anti-TNF initiation) and 6-months and 12-months post initiation. Linear mixed models with random intercepts accounting for within patient correlation of measurements were fit to test differences in measures over time and between study groups. Hypothesis testing was conducted at an alpha of 0.05 to be used for all statistical analyses. RESULTS There were 113 patients on the originator and 39 patients on a biosimilar who met our eligibility criteria. Nineteen percent of patients on the originator and 16% of patients on a biosimilar were excluded from analysis due to discontinuing the IV anti-TNF agent prior to 12 months. Weight, height, and BMI z-scores increased over time (from baseline to 12-months) for both groups (p<0.05). There was not a significant difference in the rate of change for weight, height, or BMI z-scores between study groups. Clinical outcomes of lab values (albumin, c-reactive protein, and hemoglobin) were not statistically different in the rate of change from baseline to 12-months between patients initiated on the originator or biosimilar. There also was not a significant difference in the pediatric Crohn’s disease activity index, pediatric ulcerative colitis activity index, or the physician global assessment between patients initiated on the biosimilar or originator from baseline to 12-months. CONCLUSIONS There were similar improvements in growth and clinical outcomes in patients initiated on the IV anti-TNF originator compared to a biosimilar agent. This is the first study to evaluate whether anti-TNF biosimilars have similar growth outcomes in children with IBD.

Validation of red dichromatic imaging score (RDI score) to evaluate the severity of ulcerative colitis.

Red dichromatic imaging (RDI) is a new imaging technology that has been closely correlated with the activity index of ulcerative colitis (UC). Although the RDI score has been developed no study has validated a correlation between the RDI score and the activity index of UC. Therefore, this study aims to validate the RDI score prospectively. A total of 34 patients with UC in whom colonoscopy was scheduled between May 2019 and October 2021 at our hospital were enrolled prospectively. MES, UCEIS, RDI scores, and Nancy index were evaluated in a blinded fashion. We evaluated the correlation between RDI and WLI scores using still images with histology. We analyzed 191 sites of colorectum. RDI score showed the positive correlation with UCEIS (r = 0.74 P < 0.0001) and MES (r = 0.78 P < 0.0001). RDI score also showed the positive correlation with Nancy index (r = 0.63 P < 0.0001). RDI score was more strongly correlated with Nancy index than UCEIS (r = 0.51) and MES (r = 0.48). When comparing still images of RDI and WLI scores, we showed RDI had a higher correlation to histology than WLI. The University Hospital Medical Information Network (UMIN000041750).

Gut metabolomic profiles in paediatric ulcerative colitis patients prior to and after receiving faecal microbiota transplants.

Ulcerative colitis (UC) is an immune-mediated inflammation of the colonic mucosa. Gut microbiota dysbiosis may play a significant role in disease pathogenesis by causing shifts in metabolomic profiles within the gut. To identify differences and trends in the metabolomic profile of paediatric UC patients pre- and post-faecal microbiota transplants (FMT). Forty-six paediatric patients with mild-to-moderate UC and 30 healthy paediatric patients were enrolled in this study. Baseline stool samples were collected prior to FMT initiation and at months 1, 3, 6, and 12 post-FMT. Pediatric Ulcerative Colitis Activity Index (PUCAI) scores were calculated at baseline and months 1, 3, 6, and 12 after FMT. The average Bray-Curtis dissimilarities to healthy subjects decreased after FMT. In principal coordinate analysis plots, UC patients' centroids drew nearer to healthy individuals. The variance explained by phenotype (Healthy versus UC) reduced and remained significant. From 1 to 3 months after FMT, PUCAI trends were statistically significant and decreasing. PUCAI scores remain flat starting 6 months after FMT. This study concludes that paediatric UC patients have a significantly different baseline metabolite profile than healthy controls. Although being time limited, FMT significantly altered these metabolite profiles and shifted them towards that of healthy controls.

Risk factors for intolerance of oral 5-aminosalicylic acid preparations in pediatric ulcerative colitis.

No previous study of Japanese children with ulcerative colitis (UC) has reported the risk factors for intolerance of 5-aminosalicylic acid (5-ASA). We aimed to identify risk factors for intolerance of oral 5-ASA preparations in pediatric UC. Patients with childhood-onset UC who were seen at our hospital between November 2003 and March 2020 were investigated. Intolerance of 5-ASA was defined as having clinical symptoms (pyrexia, abdominal pain, diarrhea, bloody stool) that worsened after starting oral administration of 5-ASA and improved after discontinuation of 5-ASA. Patient sex, age, body size, laboratory data, pediatric UC activity index scores, and colonoscopy-based determinations of the extent and severity of the affected lesion at initiation of 5-ASA of intolerant and tolerant groups were compared. Fifteen patients were in the intolerant group, and 37 were in the tolerant group. The leukocyte count, C-reactive protein level, and erythrocyte sedimentation rate were significantly higher in the intolerant group than the tolerant group; the albumin level in the intolerant group was significantly lower. All intolerant patients and 68% of tolerant patients had pancolitis (Paris classification E4). Patients with a large, affected area (Paris classifications E3 and E4) more frequently had intolerance to 5-ASA than patients with a small lesion. The cumulative Mayo endoscopic subscore (cMES), which is the sum of MES scores for six regions of the large intestine, was significantly higher in the intolerant group. Pediatric UC patients with more intense inflammation and a large lesion could have an increased risk of intolerance for 5-ASA.

Development and Validation of the TUMMY-UC: A Patient-Reported Outcome for Pediatric Ulcerative Colitis

The TUMMY-UC is a patient-reported outcome measure for pediatric ulcerative colitis (UC) with an observer-reported outcome version for children aged <8 years. It includes eight items selected by concept elicitation interviews. We aimed to finalize the TUMMY-UC by cognitive interviews (stage 2) and to evaluate the index for its psychometric properties (stage 3). The TUMMY-UC items were first finalized during 129 cognitive debriefing interviews. Then, in a prospective, multicenter validation study, 84 children who underwent colonoscopy or provided stool for calprotectin completed the TUMMY-UC and various measures of disease activity. Assessments were repeated after 7 and 21 days for evaluating reliability and responsiveness. During stage 2, the items were formatted with identical structure to ensure conceptual equivalence and weighted based on ranking of importance. In stage 3, the TUMMY-UC total score had excellent reliability in repeated assessments (intraclass correlation coefficient, 0.90; 95% confidence interval, 0.84-0.94). It also had moderate to strong correlations with all constructs of disease activity: r= 0.70 with UC endoscopic index of severity, r= 0.63 with the IMPACT-III questionnaire, r= 0.43 with calprotectin, r= 0.80 with the Pediatric Ulcerative Colitis Activity Index, r= 0.75 with global assessment of disease activity, and r= 0.46 with C-reactive protein (all P < .015). The index had excellent discrimination of disease activity, with a score of <9 defining remission (area under the receiver operating characteristic curve, 0.95; 95% confidence interval, 0.93-0.99). The ΔTUMMY-UC showed high responsiveness and differentiated well between children who experienced changed from those with no change. The TUMMY-UC, constructed from patient-reported outcome and observer-reported outcome versions, is a reliable, valid and responsive index that can be now used in practice and clinical trials.

PERFUSE: Non-Interventional Cohort Study of Patients Receiving Infliximab Biosimilar SB2: Results in Pediatric Patients.

PERFUSE is a non-interventional study of 1233 patients [inflammatory rheumatic disease, n = 496; inflammatory bowel disease (IBD), n = 737] receiving infliximab (IFX) biosimilar SB2 therapy. This analysis describes response to treatment and persistence on SB2 for up to 12 months in pediatric IBD patients (n = 126). Pediatric IBD patients with Crohn disease (CD) or ulcerative colitis (UC), either naïve or switched from originator IFX, who started SB2 in routine practice after September 2017 were eligible. Data were captured for 12 months following SB2 initiation. Disease activity was measured using C-reactive protein (CRP) levels and the Harvey-Bradshaw Index or Pediatric Ulcerative Colitis Activity Index for CD and UC patients, respectively. Body mass index and height z scores were used to assess patient growth between initiation (M0) and month 12 (M12). One hundred twenty-six pediatric IBD patients were included (102 CD patients, 51 naïve and 51 switched; 24 UC patients, 9 naïve and 15 switched). Naive patients' disease scores decreased between M0 and M12. CRP measurements also decreased in naïve CD patients. Switched patients' disease scores and CRP levels remained stable between M0 and M12. Height z scores improved significantly over the course of the treatment for all groups except for naïve UC patients. SB2 provides effective disease control for naïve and switched pediatric patients. Clinical remission rates improved in naïve patients and no loss of control was observed in switched patients after 1 year. Growth failure is not observed in IBD patients under SB2 treatment.

Quality of Life Among Children with Inflammatory Bowel Disease in Saudi Arabia: A Cross-Sectional Study.

The aim of this study was to investigate the quality of life in children and adolescents aged 7-18 years with inflammatory bowel disease and identify the factors that influence it. A multi-center cross-sectional study in which participants were recruited from 3 governmental hospitals in the Eastern Province of Saudi Arabia. A total of 61 children with inflammatory bowel disease were approached, 44 participants were included according to their age (7-18 years), disease duration of at least 6 months, and without any other co-morbidities. A translated Arabic version of the IMPACT-III questionnaire was used to assess the quality of life of the participants with inflammatory bowel disease. In addition, disease-specific indices were used to measure their disease activity; Harvey Bradshaw for patients with Crohn's disease and Pediatric Ulcerative Colitis Activity Index for ulcerative colitis patients. The mean age of the 44 participants was 13.36 ± 2.85. Crohn's disease accounted for 56.8% of the sample, while 36.4% had ulcerative colitis and 6.8% had unclassified type. The majority were males and in disease remission. The mean total score of the questionnaire was 74.10 ± 12.21, where the domain of social functioning scored the highest and the domain of emotional functioning scored the lowest. Children who are 11 years or older scored significantly higher in emotional functioning and total mean scores. Statistical significance was also observed between the well-being domain and not having flare-ups in the past year, as well as disease severity with emotional functioning, body image, and total mean scores. It was found that corticosteroid utilization is a predictor of poorer quality of life and was statistically significant with the body image domain. Measuring the quality of life in children with inflammatory bowel disease can aid in reducing its burden and help address its factors.

Aberrant Mucin Expression Profiles Associate With Pediatric Inflammatory Bowel Disease Presentation and Activity.

Intestinal mucosal healing is nowadays preferred as the therapeutic endpoint in inflammatory bowel disease (IBD), but objective measurements at the molecular level are lacking. Because dysregulated mucin expression is suggested to be involved in mucosal barrier dysfunction in IBD, we investigated mucin expression in association with barrier mediators and clinical characteristics in colonic tissue of a pediatric IBD population. In this cross-sectional monocentric study, we quantified messenger RNA (mRNA) expression of mucins, intercellular junctions, and cell polarity complexes in inflamed and noninflamed colonic biopsies from pediatric IBD (n = 29) and non-IBD (n = 15) patients. We then validated mucin expression at protein level and correlated mucin mRNA expression with expression of barrier mediators and clinical data. The expression of MUC1, MUC3A, MUC4, and MUC13 was increased in the inflamed colon of pediatric IBD patients compared with the noninflamed colon of non-IBD control subjects. Especially MUC13 mRNA expression associated with the expression of barrier mediators, including CDH1, OCLN, and TJP2. MUC1 and MUC3B mRNA expression in combination with calprotectin levels most accurately discriminated IBD patients from non-IBD control subjects (90.6% area under the receiver-operating characteristic curve [AUCROC], 92.0% sensitivity, 73.7% specificity), whereas aberrant mRNA expression of MUC1, MUC3A, MUC4, and MUC13 was distinctive for ulcerative colitis and of MUC3B for Crohn's disease. Furthermore, expression of MUC3A, MUC3B, and MUC4 correlated with clinical disease activity (ie, Pediatric Ulcerative Colitis Activity Index and Pediatric Crohn's Disease Activity Index), and of MUC1, MUC2, MUC4, and MUC13 with endoscopic colitis severity in ulcerative colitis patients. Colonic mucin expression is disturbed in pediatric IBD patients and associates with disease activity and presentation, suggesting its use as molecular marker to aid in disease diagnosis and management.

Mucosal and Plasma Metabolomes in New-onset Paediatric Inflammatory Bowel Disease: Correlations with Disease Characteristics and Plasma Inflammation Protein Markers.

To advance the understanding of inflammatory bowel disease [IBD] pathophysiology, we compared the mucosal and plasma metabolomes between new-onset paediatric IBD patients and symptomatic non-IBD controls, and correlated plasma inflammation markers and disease characteristics with the altered metabolites. Paired colonic and ileal biopsies and plasma from 67 treatment-naïve children with incident Crohn's disease [CD; n = 47], ulcerative colitis [UC; n = 9], and non-IBD controls [n = 11] were analysed using ultra-performance liquid chromatography-mass spectrometry [UPLC-MS/MS]. Inflammatory plasma proteins [n = 92] were assessed. The metabolomes in inflamed mucosal biopsies differed between IBD patients and controls. In CD, mucosal levels of several lysophospholipids [lysophosphatidylcholines, lysophosphatidyletanolamines, lysophosphatidylinositols, and lysophosphatidylserines] were decreased, correlating with various plasma metabolites including amino acid analogues and N-acetylated compounds. In both CD and UC, mucosal sphingolipids, including ceramide [d18:2/24:1, d18:1/24:2], lactosyl-N-palmitoyl-sphingosine [d18:1/16:0], behenoyl sphingomyelin [d18:1/22:0], lignoceroyl sphingomyelin [d18:1/24:0], and/or sphingomyelin [d18:1/24:1, d18:2/24:0] were increased, correlating with sphingolipids, bile acids, and/or N-acetylated metabolites in plasma. Among proteins associated with CD, interleukin-24 correlated with plasma metabolites, including lactosyl-N-palmitoyl sphingosine [d18:1/16:0] and phosphatidyletanolamine [18:1/18:1], haemoglobin, and faecal calprotectin. In UC, interleukin-24, interleukin-17A, and C-C motif chemokine 11 correlated with several plasma metabolites, including N-acetyltryptophan, tryptophan, glycerate, and threonate, and with the Paediatric Ulcerative Colitis Activity Index, C-reactive protein, and faecal calprotectin. Mucosal perturbations of lysophospholipids and sphingolipids characterised the metabolome in new-onset paediatric IBD and correlated with plasma metabolites. By integrating plasma metabolomics data with inflammatory proteins and clinical data, we identified clinical and inflammatory markers associated with metabolomic signatures for IBD.

S1031 Association Between Nutritional Profile and Disease Activity in a Sample of Lebanese Patients With Inflammatory Bowel Disease (IBD): A Case Control Study

Introduction: Many studies have evaluated dietary habits of patients with inflammatory bowel disease (IBD) and their impact on disease activity. This study aims to evaluate this association in Lebanese patients with IBD, as no investigation of this kind has been done in Lebanon. Methods: In this prospective study, patients with IBD were identified by their treating physicians while controls were recruited via emails sent to staff and students at the affiliated university. Both groups were gender and age matched. Baseline characteristics and nutritional profile, as assessed using a validated food frequency questionnaire (FFQ) adapted to the Lebanese diet were compared between cases and controls. Cases were divided into 2 groups, those in remission and those with active disease according to the Harvey-Bradshaw Index for Crohn’s disease (HBCD) and Ulcerative Colitis Activity Index (UCAI). Results: A total of 47 patients with IBD and 101 controls were included. There was no difference in mean age between cases and controls. Patients with IBD consumed significantly less % of lipids, saturated fatty acids (SFAs), fiber, and sucrose compared to controls (p=0.0001). The multivariate analysis comparing cases to controls showed higher odds of consuming more % carbohydrates of total energy intake (TEI) at 1.31 (95%CI; 1.15-1.51) and more % proteins of TEI at 1.25 (95%CI;1.09-1.43), and lower odds of consuming fiber at 0.934 (95%CI;0.89-0.99). There was no difference in odds of fat consumption between cases and controls. Of 47 IBD patients, 25 UC and 22 CD, 28 were in clinical remission (HBCD ≤ 4 or UCAI ≤ 2) and 19 had active disease. IBD patients in remission consumed more % protein than controls (p=0.032). The % intake of poly-unsaturated fatty acids (PUFAs) was higher among IBD patients with active disease than those in remission, specifically among those with UC (p=0.032). Conclusion: Although there was a difference in protein consumption between cases and controls, it was only significant between controls and IBD patients in remission. It is possible that differences in diet between patients with IBD and controls were associated with nutritional restrictions patients impose on themselves. In contrast, consumption of PUFAs was associated with active disease in IBD patients, which concords with the available literature. This study could serve as a steppingstone for future prospective and experimental studies that could inform nutritional rehabilitation for IBD patients (Table). Table 1. - Energy Intake, Macronutrients and Micronutrients Per Day in Controls, IBD Patients in Remission and IBD Patients with Active Disease Controls (n=101) IBD patients in Remission (n=28) IBD patients with active disease (n=19) p-value DRI Energy Intake (kcals/day) for men 2622.4 ± 0.21 1923.53 ± 0.16 1644.37 ± 0.03 0.015 2300-2900 Energy Intake (kcals/day) for women 2597.2 ± 0.17 1563.15 ± 0.05 1897.14 ± 0.13 0.0001 1900-2200 BMI (kg/m2) 23.29 ± 0.06 25.87 ± 0.06 24.03 ± 0.08 0.007 N/A Average (%) of Protein of TEI 16.06 ± 0.09 18.62 ± 0.05 16.48 ± 0.08 0.004 10-35 Average (%) of Lipids of TEI 38.33 ± 0.08 30.28 ± 0.06 33.02 ± 0.07 0.0001 20-35 MUFAs (%) 12.33 ± 0.11 11.52 ± 0.06 11.04 ± 0.12 0.119 15-20 PUFAs (%) 6.05 ± 0.15 5.14 ± 0.10 6.58 ± 0.12 0.032 5-10 SFAs (%) 11.95 ± 0.12 6.50 ± 0.14 6.84 ± 0.14 0.0001 < 10 Average (%) of carbohydrates of TEI 45.15 ± 0.05 50.68 ± 0.03 49.30 ± 0.05 0.0001 45-65 Average Sucrose (g) 89.16 ± 0.21 43.89 ± 0.22 52.70 ± 0.21 0.0001 50 Average Lactose (g) 5.60 ± 0.59 5.17 ± 0.44 5.17 ± 0.44 0.942 N/A Average Fibers (g) 28.09 ± 0.18 18.02 ± 0.10 21.52 ± 0.20 0.0001 20-38 Alcohol (yes), n (%) 22 (23.9%) 4 (14.3%) 6 (31.6) 0.918 N/A Vitamin D supplementation (yes), n (%) 15 (14.9%) 13 (46.4%) 5 (26.3%) 0.006 N/A Categorical variables were reported as numbers and percentages, test used: chi-square test. Continuous variables were reported as geometric means ± Standard deviation, test used: independent t-test. p<0.05. IBD= Inflammatory Bowel Diseases, DRI= Daily Recommended Intake, BMI= Body Mass Index, TEI= Total Energy Intake, MUFAs= Mono-unsaturated Fatty Acids, PUFAs= Poly-unsaturated Fatty Acids, SFAs= Saturated Fatty Acids, N/A= Not applicable.

Pseudoamaolides A-O, anti-inflammatory triterpene spiroketal lactones from seeds of Pseudolarix amabilis

Fifteen new triterpenoids (1–15), along with twenty known ones (16–35), were isolated from Pseudolarix amabilis. The triterpenoid structures include multiple skeleton types, such as 2,3-seco-cycloartane, 3,4-seco-cycloartane, 3,4:9,10-diseco-cycloartane, and 3,4:8,9:9,10-triseco-cycloartane, as elucidated by extensive spectroscopy (1D NMR, 2D NMR, HRESIMS, and IR) and single-crystal X-ray diffraction. The anti-inflammatory activities of compounds 1–35 were evaluated. Compounds 3, 11, 16, 24, 25, and 26 suppressed the transcription of the NF-κB-dependent reporter gene in LPS-induced 293T/NF-κB-Luc cells with IC50 values of 0.12, 0.10, 0.30, 0.09, 0.49, and 0.35 μM, respectively. In addition, compound 16 showed anti-inflammatory activity against xylene-induced ear swelling in vivo with an inhibition rate of 44.7 % (30 mg/kg). Compound 16 significantly improved the disease activity index (DAI) of ulcerative colitis at a dose of 400 mg/kg in a dextran sodium sulfate (DSS)-induced mouse model of experimental ulcerative colitis (P < 0.01).

Tofacitinib Salvage Therapy for Children Hospitalized for Corticosteroid- and Biologic-Refractory Ulcerative Colitis.

Colectomy rates following acute severe ulcerative colitis have plateaued around 20% despite intravenous corticosteroid and intensified anti-tumor necrosis factor (TNF) biologic dosing. Recent studies have shown tofacitinib to provide additional benefit in further decreasing colectomy rates among hospitalized adult patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Pediatric data describing the effectiveness of tofacitinib for this indication does not yet exist. We aimed to describe the treatment courses and colectomy-free survival among pediatric patients treated with tofacitinib while hospitalized for refractory ulcerative colitis. We performed a retrospective single-center cohort study of consecutive hospitalized pediatric patients initiating tofacitinib for refractory ulcerative colitis from 2018 to 2021. The primary outcome was 90-day colectomy-free survival. Secondary outcomes included colectomy-free clinical remission, corticosteroid independence, colectomy-free tofacitinib drug-persistence, tofacitinib-related adverse events, and postoperative complications. Baseline characteristics and details of the timing and positioning of therapies utilized during hospitalization were described. Outcomes were described using counts, percentages, and Kaplan-Meier curves. Eleven patients met inclusion criteria. All patients demonstrated nonresponse to both intravenous corticosteroids and anti-TNF therapy prior to tofacitinib initiation. Median hospitalization length was 22 days and mean maximum pediatric ulcerative colitis activity index during hospitalization was 68. Eight of 11 patients remained colectomy-free at 90 days following hospital admission and 6 remained colectomy-free over median 182-day follow-up, including 4 of whom remained on tofacitinib. Tofacitinib may represent a new treatment option for hospitalized pediatric patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Future research is essential in determining the optimal positioning of these therapies.

Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis.

Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 (P2) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was −0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1–E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.

Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis

We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index), and colectomy-free survival. Thirty-eight participants received IFX (median initial dose, 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P= .013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and 4 (10.8%) participants underwent colectomy by week 26 and 2 years, respectively. Day 3 IFX clearance >0.02 L/h was associated with colectomy (hazard ratio, 58.2; 95% confidence interval, 6.0-568.6; P < .001). At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and at week 26 with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine whether sustained intensification can overcome rapid clearance and improve later outcomes. gov identifier: NCT02799615.

How has the disease course of pediatric ulcerative colitis changed throughout the biologics era? A comparison with the IBSEN study.

BACKGROUNDIn Korea, infliximab was approved for use in children with ulcerative colitis (UC) in October 2012. AIMTo compare the clinical course of UC before and after the introduction of biological agents, and to compare with the IBSEN study. METHODSPatients under 18 years of age, who were diagnosed with UC and followed from January 2003 to October 2020, were included in the study. Group A (n = 48) was followed for at least 2 years between January 2003 and October 2012, and Group B (n = 62) was followed for at least 2 years between November 2012 and October 2020. We compared endoscopic remission, drug composition, relapse rate, steroid-free period, and the quality of life of each group. We plotted the clinical course of the included patients using the pediatric UC activity index score, and compared our patients with those in the IBSEN study. RESULTSAfter 2 years of treatment, colonoscopy evaluation revealed different outcomes in the two treatment groups. Remission was confirmed in 14 patients (29.2%) of Group A, and in 31 patients (50.0%) of Group B (P < 0.012). The median cumulative corticosteroid-free period was 3.0 years in Group A and 4.4 years in Group B. Steroid-free period of Group B was significantly longer than that of Group A (P < 0.001). There was a statistically significant difference between the two groups in evaluation of the relapse rate during the observation period (P < 0.001). The plotted clinical course graphs of Group A showed similar proportions to the graphs in the IBSEN study. However, in Group B, the proportion of patients corresponding to curve 1 (remission or mild severity after initial high activity) was high at 76% (47/62). CONCLUSIONThe incidence of relapse has decreased and the steroid-free period has increased after the introduction of the biological agent. The clinical course also showed a different pattern from that of IBSEN study. The active use of biological agents may change the long-term disease course in moderate to severe pediatric UC.

Vedolizumab as the First-Line of Biologicals for Pediatric Patients With Ulcerative Colitis

Vedolizumab (VDZ) was reported to be effective as a first-line biological in adult ulcerative colitis (UC). The aim of this study was to investigate the safety and effectiveness of VDZ as the first-line biological in pediatric refractory UC. We retrospectively extracted data from pediatric patients with UC who received first-line VDZ. The following were recorded: baseline characteristics; clinical activity of intestinal disease, levels of fecal calprotectin (FC), C-reactive protein, and serum amyloid A; and erythrocyte sedimentation rate. Clinical effectiveness, biochemical remission, and safety of VDZ were also investigated. Eight patients were identified (median age, 12 years). FC levels were abnormal in all cases and were remarkably elevated in 3 patients. C-reactive protein, serum amyloid A, and erythrocyte sedimentation rate values were abnormal in 2, 4, and 5 patients, respectively. According to the pediatric UC activity index score, 1, 5, and 2 patients had mild, moderate, and severe disease. Fourteen weeks after VDZ administration, 5 patients achieved remission, and 3 remained in remission until week 52. Of the 3 patients who did not reach remission in week 14, two achieved remission by week 52. In week 52, five of the eight patients continued receiving VDZ and maintained remission. All patients achieved clinical remission without corticosteroid use. No adverse events were observed in any patient. VDZ may serve as a safe and effective first-line biological option for treating pediatric patients with UC. FC levels before VDZ administration may be predictive of long-term remission.

Anti–Integrin αvβ6 Antibody as a Diagnostic Marker for Pediatric Patients With Ulcerative Colitis

Anti–Integrin αvβ6 Antibody as a Diagnostic Marker for Pediatric Patients With Ulcerative Colitis

Are Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Useful as Markers in Diagnostic Management of Children with Newly Diagnosed Ulcerative Colitis?

Matrix Metaloproteinase-9 (MMP-9) and Tissue Inhibitor of Metaloproteinase-1 (TIMP-1), enzymes involved in tissue remodelling, have been previously reported to be overexpressed in the colonic mucosa of patients with Ulcerative colitis (UC). The aim of this study was to determine the relation of MMP-9 and TIMP-1 with UC phenotypes, the disease activity index and routinely tested inflammatory markers in newly diagnosed paediatric patients. The study group comprised 35 children diagnosed with UC and 20 control groups. Serum and faecal concentrations of MMP-9 and TIMP-1 were estimated using enzyme-like immunosorbent assay kits and correlated to the disease activity index (Paediatric Ulcerative Colitis Activity Index, PUCAI), UC phenotype (Paris Classification), inflammatory markers and endoscopic score (Mayo score). Children with UC presented with significantly higher serum and faecal concentrations of studied markers compared to the control group. Both serums, MMP-9 and TIMP-1, were higher in children with more extended and severe lesions in the colon. Furthermore, serum MMP-9 correlated with the Mayo score, Paris classification and C-reactive protein (CRP) levels. Serum TIMP-1 showed correlation with PUCAI, Paris Classification, CRP levels and the erythrocyte sedimentation rate. Serum and faecal levels of MMP-9 and TIMP-1 are useful in discriminating UC patients and non-invasive assessments of disease phenotypes. It seemed that simultaneous measurement of these proteins in combination with other common markers of inflammation could be applied in clinical practice.