Ileal Crohn's Disease Research Articles

Diagnostic accuracy of different cross-sectional imaging techniques for disease location and activity in Crohn's disease and external validation and comparison of MARIAs and IBUS-SAS.

The comparative accuracy of cross-sectional imaging techniques for evaluating Crohn's disease (CD) remains uncertain. This study aimed to assess diagnostic accuracy of disease location and activity in different cross-sectional images and validate and compare International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) and Simplified Magnetic Resonance Index of Activity (MARIAs). CD patients were retrospectively included from August 2018 to May 2021. We compared accuracy of B-mode intestinal ultrasound (B-IUS), computed tomography enterography (CTE), and magnetic resonance enterography (MRE) for the identification of disease location. Meanwhile, disease activity was compared on B-IUS, color Doppler imaging, CTE, and MRE. ROC analyses were used to validate MARIAs and IBUS-SAS. Spearman rank correlation was performed to evaluate the relationships between MARIAs/IBUS-SAS and CDAI, SES-CD, and inflammatory indicators. A total of 115 CD patients were evaluated. The diagnostic accuracy of MRE in detecting small bowel disease was superior to that of B-IUS/CTE, showing sensitivity (89.3%), specificity (71.4%), and AUC (0.820). B-IUS had the highest sensitivity (81.2%), specificity (84.8%), and AUC (0.830) for detecting terminal ileal lesions. The diagnostic accuracy for colonic disease and disease activity was not significantly different among these techniques. In the validation of IBUS-SAS, the AUC was 0.860, with an optimal cutoff value to predict active disease of 46.7. MARIAs and IBUS-SAS showed no significant differences in the correlations of CDAI, SES-CD, and inflammatory indicators. MRE and B-IUS are more sensitive for detecting small bowel CD and terminal ileal CD, respectively. IBUS-SAS has potential for precisely defining CD activity.

S41 Unusual Case of Tongue Deviation

Case: Background: Anti-tumor necrosis factor-α (TNFα) therapy is the mainstay of treatment for inflammatory bowel disease such as Crohn’s Disease (CD) and ulcerative colitis (UC). Despite its widespread use, anti-TNFα leads to significantly altered inflammatory response and increased risk of severe skin and soft tissue infections. Here, we highlight an uncommon presentation of severe soft tissue infection in a patient with ileal CD maintained on anti-TNFα therapy. Case Presentation: A 50-year-old female with a 25-year history of Crohn's ileitis maintained on certolizumab for 3 years presented to the emergency department (ED) with an expanding left, lateral neck mass resulting in decreased cervical range of motion. This was accompanied by a left-sided tongue deviation. She first presented to our ED 8 weeks earlier with severe throbbing headaches without focal neurologic symptoms. A head MRI only showed non-specific T2/FLAIR hyperintensities. Her vital signs and labs were normal, and these headaches were presumed to be complex migraines. Three weeks after her first presentation, she came back to the ED with worsening headaches, neck pain and a new left-sided tongue deviation. Again, her vital signs and laboratory evaluation were normal apart from an ESR of 68 mm/hr (nl: 0-30 mm/hr) and CRP of 10.34 mg/dL (nl<0.5 mg/dL). Her repeat imaging studies did not show any evidence of stroke; however, opacification of the paranasal sinuses and left mastoid air cells were observed. Nonetheless, given her lack of systemic inflammatory symptoms, she was discharged home with close outpatient otolaryngology (ENT) referral. As an outpatient, she was diagnosed with bacterial sinusitis which was treated with a 15-day course of cefdinir and dexamethasone. Her symptoms initially improved; however, she eventually experienced dysphagia with pus drainage from her sinuses. Another antibiotic and steroid course was prescribed. Despite this, approximately 8 weeks after her initial presentation, she developed a rapidly expanding neck mass which prompted her return to the ED. Physical examination revealed a tender neck mass limiting her cervical range of motion and a more pronounced tongue deviation. She was afebrile, non-tachycardiac, and normotensive. Laboratory testing again revealed elevated inflammatory markers (ESR 83 mm/hr, CRP 8.59 mg/dL) but otherwise her WBC was normal (8310 cells/ µL, nl: 10400 cells/µL) with no evidence of sepsis-related end-organ dysfunction (Cr 0.89 mg/dL, AST 20, ALT 55 mg/dL, T-bili 0.3 mg/dL, platelets 348000 platelets/µL). Neck imaging showed multifocal ring-enhancing collections within the left paravertebral soft tissue with left hypoglossal nerve involvement. Intravenous vancomycin, cefepime, and metronidazole were started. Surgical debridement of the left posterior paraspinal abscess was performed. Intraoperative cultures were positive for Streptococcus anginosus. She completed a 6-week course of ceftriaxone but follow up imaging 2 weeks later showed recurrence of her neck abscesses. This again required surgical debridement. Her infections finally cleared with 24 weeks of piperacillin/tazobactam. Her certolizumab remains permanently discontinued. Conclusions: Hallmark symptoms of severe infection may not be present in patients on anti-TNF therapy. A high index of suspicion for an underlying infectious etiology must be maintained when treating this population.

Temporal and Sequential Relationships Between Perianal and Severe Ileal Crohn’s, Both as Strong Representations of Crohn’s Fistulizing Phenotypes

Abstract Introduction/Objective Most cases of inflammatory bowel disease can be categorized as ulcerative colitis(UC) or Crohn’s disease(CD) on the basis of clinical profile, disease distribution, imaging and endoscopic findings, and pathological abnormalities. Ileal CD with deep fissuring ulcers and imminent or overt fistulae represents a specific phenotype. A similar fistulizing phenotype is indicated by complex perianal CD which shows fistulous tracts between rectum and perineum. We followed CD patients with either disease to discover if both fistulizing phenotypes occurred concurrently or with any predictable sequence. Methods/Case Report From our databases, we collected 21 patients with complex perianal CD(M:F=7:14, ages 23-80) and 19 patients with fistulizing ileal CD(M:F=11:8, ages 10-67) and followed them for a period of up to 16 years(2005-2021). Our purpose was to discover if both fistulizing phenotypes occurred in the same patients, and if so, was it concurrent or in any sequence, and to find the strength of the clinical diagnosis of CD when one or both phenotypes presented in a patient. Results (if a Case Study enter NA) Concurrent occurrence of perianal and ileal CD was the most common(6/21 perianal &amp; 8/19 ileal cases: total 35%). When patients first presented with perianal CD, they had an equal chance of not manifesting ileal phenotype(5/21) or manifesting it earlier(5/21: average of 5 years earlier) or later(5/21: average of 2.5 years later). However, when patients first presented with ileal CD, they had a strong possibility of having manifested perianal disease in the past(10/21 or 48%: average of 5 years), when it was overlooked as a strong indicator of Crohn’s. Perianal CD was considered a strong clinical diagnosis of Crohn’s but only when it occurred concurrently or was preceded by ileal CD. Fistulizing Ileal CD was considered a strong clinical diagnosis of Crohn’s and most cases had prior perianal CD. Conclusion Both perianal and severe ileal CDs are fistulizing phenotypes that are strong indicators of Crohn’s and occur concurrently in 35% of cases. When followed for a long period, both phenotypes manifest in most patients when they have severe fistulizing disease. Perianal CD appears to precede ileal CD by an average of 5 years. While fistulizing ileal CD is clinically unequivocally diagnosed as Crohn’s, perianal CD may be overlooked as Crohn’s, unless there is concurrent or prior ileal CD.

Preoperative cross-sectional imaging findings in patients with surgically complex ileocolic Crohn's disease.

The aim of this study was to evaluate the diagnostic performance of preoperative cross-sectional imaging findings using the SAR-AGA definitions in Crohn's disease (CD) patients who underwent ileocolic resection (ICR) with and without surgically complex ileocolic CD (CIC-CD). 69 CD patients [38 men; mean (± SD) age: 40.6 (16.2) years] who underwent ICR were retrospectively classified by surgical complexity by a colorectal surgeon using operative findings. CIC-CD was defined as ileal CD, not confined to the distal ileum. Two radiologists retrospectively evaluated the preoperative imaging for the presence and type of penetrating disease, stricture, or probable stricture using the SAR-AGA consensus definitions. The diagnostic performance of preoperative imaging findings was compared for patients with and without CIC-CD. Estimated blood loss (EBL), operative time (OT), conversion to open surgery, diversion, and length of hospital stay (LOS) were compared. 60.9% had CIC-CD and 79.7% underwent primary ICR. Penetrating disease was more common in patients with than without CIC-CD (76.2% vs. 40.7%, p = 0.0048) and similar among primary versus redo ICR (p = 0.12). Patients with CIC-CD had more complex fistulas (59.5% vs. 11.1%; p < 0.0001) and fewer simple fistulas (2.4% vs. 18.5%; p = 0.03) than those without. Mesenteric findings (abscess, inflammatory mass) were more frequent in patients with (35.7%) than without (0%) (p = 0.0002) CIC-CD. Stricture and probable stricture were similar (p = 0.59). CIC-CD patients had greater EBL (178cc vs. 57cc, p = 0.006), conversion rates (30% vs. 0%, p = 0.0026), and diversion (80% vs. 52%, p = 0.04). Complex fistula, mesenteric abscess, or inflammatory mass defined by the SAR-AGA guidelines suggests CIC-CD. ICR for CIC-CD had greater EBL, conversion to open surgery, and diversion.

Validation of stricture length, duration and obstructive symptoms as predictors for intervention in ileal stricturing Crohn's disease.

Risk factors for intervention in terminal ileal (TI) stricturing Crohn's disease (CD) are poorly defined. Novel and rigorous definitions for TI strictures recently became available. We aimed to describe the rates of symptoms or need for endoscopic balloon dilation (EBD) or surgery as well as risk factors of progression in a well-defined stricturing CD cohort. Consecutive adult patients with non-penetrating stricturing TI CD, as defined by centrally-read magnetic resonance enterography CONSTRICT criteria, were separated into a derivation and validation cohort. Clinical and imaging characteristics were collected following prespecified scoring conventions. Primary outcome was a composite endpoint of EBD or surgery ("intervention"). Multivariable analysis was performed. Eighty-six patients (48.8% female, median age 36years) met selection criteria, 17.4% had prior EBD, 59.3% previously received biologics and 58.1% of strictures were anastomotic. Median follow-up was 63.4 [95% CI: 57, 68.9] months. In the derivation cohort, at 12 and 48months, 26% and 45% of patients had intervention, respectively. Multivariable analysis showed obstructive symptoms (Hazard ratio [HR] 1.444; 95% CI 1.126-1.852), stricture duration (HR 0.974; 95% CI, 0.954-0.995) and length (HR 1.039; 95% CI, 1.011-1.069) predicted intervention. The concordance index for split-sample validation was 0.74 and 0.67, respectively. Biologics were not associated with intervention. An online risk calculator was constructed. In patients with TI stricturing CD, 26% and 45% required intervention at 1 and 4years. Obstructive symptoms, stricture duration and length were independent and validated predictors of the need for intervention. These findings are important for clinical practice and aid in the design of future trials for CD strictures.

Development of a multimodal machine-learning fusion model to non-invasively assess ileal Crohn’s disease endoscopic activity

Background and Objective: Recurrent attentive non-invasive observation of intestinal inflammation is essential for the proper management of Crohn’s disease (CD). The goal of this study was to develop and evaluate a multi-modal machine-learning (ML) model to assess ileal CD endoscopic activity by integrating information from Magnetic Resonance Enterography (MRE) and biochemical biomarkers. Methods: We obtained MRE, biochemical and ileocolonoscopy data from the multi-center ImageKids study database. We developed an optimized multimodal fusion ML model to non-invasively assess terminal ileum (TI) endoscopic disease activity in CD from MRE data. We determined the most informative features for model development using a permutation feature importance technique. We assessed model performance in comparison to the clinically recommended linear-regression MRE model in an experimental setup that consisted of stratified 2-fold validation, repeated 50 times, with the ileocolonoscopy-based Simple Endoscopic Score for CD at the TI (TI SES-CD) as a reference. We used the predictions’ mean-squared-error (MSE) and the receiver operation characteristics (ROC) area under curve (AUC) for active disease classification (TI SEC-CD≥3) as performance metrics. Results: 121 subjects out of the 240 subjects in the ImageKids study cohort had all required information (Non-active CD: 62 [51%], active CD: 59 [49%]). Length of disease segment and normalized biochemical biomarkers were the most informative features. The optimized fusion model performed better than the clinically recommended model determined by both a better median test MSE distribution (7.73 vs. 8.8, Wilcoxon test, p<1e-5) and a better aggregated AUC over the folds (0.84 vs. 0.8, DeLong’s test, p<1e-9). Conclusions: Optimized ML models for ileal CD endoscopic activity assessment have the potential to enable accurate and non-invasive attentive observation of intestinal inflammation in CD patients. The presented model is available at https://tcml-bme.github.io/ML_SESCD.html.

The Simplified MR Index of Activity Score in Pediatric Small-Bowel Crohn Disease: An Interreader Agreement and Responsiveness Study.

BACKGROUND. The simplified MR index of activity (MaRIA) score is used to assess the severity of small-bowel inflammation without use of IV contrast material. OBJECTIVE. The purposes of this study were to assess interreader agreement on the use of simplified MaRIA scores for evaluation of the inflammatory activity of terminal ileal Crohn disease in children and young adults and to assess whether simplified MaRIA scores change after biologic medical therapy. METHODS. This analysis was ancillary to a previously reported primary prospective research investigation. The study included 20 children and young adults with newly diagnosed ileal Crohn disease and 15 healthy control participants who underwent research small-bowel MRI examinations between December 2018 and October 2021. The participants with Crohn disease underwent baseline MRI and MRI 6 weeks and 6 months after beginning anti-tumor necrosis factor α-treatment as well as weighted pediatric Crohn disease activity index (wPCDAI) and C-reactive protein (CRP) assessment on the day of each examination. Control participants underwent one MRI examination. Four pediatric radiologists independently assigned simplified MaRIA scores using axial and coronal T2-weighted SSFSE images. Median simplified MaRIA score among readers was computed. Interreader agreement was assessed with Fleiss kappa coefficients and intra-class correlation coefficient (ICC). Analysis included the Mann-Whitney U test, Friedman test, and Spearman rank correlation. RESULTS. Simplified MaRIA scores (across time points and study groups) had substantial interreader agreement (κ = 0.65 [95% CI, 0.56-0.74]; ICC, 0.71 [95% CI, 0.63-0.78]). Median scores were higher in participants with Crohn disease at baseline than in healthy control participants (3.5 [IQR, 2.5-4.9] vs 0.5 [IQR, 0-2.0]; p < .001). Scores decreased after medical treatment in participants with Crohn disease (p = .005). The median score was 3.5 (IQR, 2.5-4.9) at baseline, 2.3 (IQR, 1.6-3.9) at 6 weeks, and 2.0 (IQR, 0.5-2.5) at 6 months. In participants with Crohn disease, median scores had significant correlations with wPCDAI (ρ = 0.46 [95% CI, 0.18-0.64]; p < .001) and CRP level (ρ = 0.48 [95% CI, 0.27-0.65]; p < .001). CONCLUSION. Radiologists had substantial agreement in use of simplified MaRIA scores to assess intestinal inflammation in ileal Crohn disease. Scores changed over time after medical therapy. CLINICAL IMPACT. The results support the simplified MaRIA score as an objective MRI-based clinical measure of intestinal inflammation in children and young adults with Crohn disease.

Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity.

Objective: Ulcerative colitis (UC) and Crohn's disease (CD) are two subtypes of chronic inflammatory bowel disease (IBD). Differential diagnosis remains a challenge. Anti-TNFα treatment is an important treatment for IBD, yet resistance frequently occurs and cannot be predicted. Consequently, many patients receive ineffective therapy with potentially adverse effects. Novel assays are needed to improve diagnosis, and predict and monitor response to anti-TNF-α compounds. Design: Signal transduction pathway (STP) technology was used to quantify activity of STPs (androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, Hedgehog, Wnt, NFκB, JAK-STAT1/2, and JAK-STAT3 pathways) in colon mucosa samples of CD and UC patients, based on transcriptome analysis. Previously described STP assay technology is based on computational inference of STP activity from mRNA levels of target genes of the STP transcription factor. Results: Results show that NFκB, JAK-STAT3, Wnt, MAPK, and androgen receptor pathways were abnormally active in CD and UC. Colon and ileum-localized CD differed with respect to STP activity, the JAK-STAT1/2 pathway being abnormally active in ileal CD. High activity of NFκB, JAK-STAT3, and TGFβ pathways was associated with resistance to anti-TNFα treatment in UC and colon-located CD, but not in ileal CD. Abnormal STP activity decreased with successful treatment. Conclusion: We believe that measuring mucosal STP activity provides clinically relevant information to improve differential diagnosis of IBD and prediction of resistance to anti-TNFα treatment in patients with colon-localized IBD, and provides new targets for treatment and overcoming anti-TNFα resistance.

Correlation between magnetic resonance enterography and ileo-colonoscopy for assessment of disease activity in terminal ileal Crohn's disease.

Magnetic resonance enterography (MRE) has emerged as a novel tool for the assessment of disease activity in Crohn's disease (CD). Real world data from Indian subcontinent on performance of MRE in terminal ileal CD are lacking. Retrospective analysis of patients with terminal ileal CD who underwent both ileo-colonoscopy and MRE was performed. Ileo-colonoscopy was considered the gold standard for assessment of disease activity. On ileo-colonoscopy, a simple endoscopic score for Crohn's disease (SES-CD) ≥2 was considered active disease; presence of ulcers indicated severe disease. MRE scoring of the disease activity was performed using magnetic resonance index of activity (MARIA) and simplified MARIA (MARIAs). The measure of agreement between ileo-colonoscopy and MRE and comparison of MARIA and MARIAs for assessment of disease activity and sensitivity of MRE to detect mucosal ulcerations were calculated. Seventy patients with terminal ileal CD (mean age 40.74±15.56 years; 71.4% males [n=50]) were evaluated. The sensitivities of MARIA and MARIAs scores to detect active disease were 0.76 and 0.84, respectively. The area under the receiver operating characteristic curve (AUROC) for detecting severe disease was 0.836 (p<0.0001) for MARIA and 0.861 (p<0.0001) for MARIAs. For mild active disease, there was no agreement between SES-CD and MARIA or MARIAs; however, for severe disease, the agreement was fair and moderate for MARIA and MARIAs, respectively. MARIA and MARIAs were comparable for identification of active and severe disease (κ 0.759, p<0.0001 and κ 0.840, p<0.0001, respectively). MRE was 68.18% sensitive to detect mucosal ulcers. MRE is a reliable and sensitive tool for detection of endoscopically severe, but not mild, terminal ileal CD.

S862 Rates and Outcomes of Histologic Healing in Crohn's Disease

Introduction: Histologic healing (HH) has been associated with favorable outcomes in patients with ulcerative colitis but its clinical significance in Crohn’s disease (CD) remains unclear. We aimed to determine the prevalence, predictors, and outcomes of HH in patients with CD. Methods: This is a single center, retrospective review of CD patients age ≥18 from 1/1/2012-12/1/2021. Patients with and without endoscopic healing (defined as the absence of ulcers or erosions) were included. HH was defined as either normal or chronic inactive/quiescent inflammation on review of pathology reports. The primary outcomes were the prevalence and predictors of HH in both distal ileal and colonic CD. Secondary outcomes included rates of corticosteroid use, CD-related ED visits, surgeries, and hospitalizations analyzed individually and as a composite outcome. Continuous variables were analyzed using an unpaired student’s t-test. Categorical variables were analyzed using a chi-square test. Results: A total of 90 CD patients were included. The median age was 47 years (range 18-85), 52.0% were female, 63.3% had ileocolonic disease, and 72.2% had endoscopic healing. The overall rate of HH was 30.0%. Among patients with endoscopic healing (n=65), 41.5% (n=27) achieved HH. Ileal HH rate was 63.2% and colonic HH rate was 47.6%. There were no significant differences between the HH and non-HH groups in terms of baseline and disease characteristics (Table). The percentage of patients on biologic medications was 70.4% in the HH group vs. 50% in the non-HH group (p=0.1). In the HH group, the rate of corticosteroid initiation was 42.9% vs. 57.1%, (p=0.89) and the rates of ED visits, hospitalizations, and IBD-related surgeries were not significantly different between the two groups (Figure). The composite outcome was noted in 40.7% of patients with HH vs. 59.3% of patients without HH (p=0.91). Conclusion: In this pilot study, 30% of CD patients achieved HH, with a higher rate of ileal compared to colonic HH. Among patients with endoscopic healing, HH was not associated with any further decrease in adverse clinical outcomes. This study is limited by small sample size and potentially sampling error of endoscopic biopsies due to the patchy nature of CD inflammation. Larger studies are needed to identify predictors and significance of HH in CD.Figure 1.: Comparison of outcomes between histologic healing vs. no histologic healing (*Composite outcome is defined by either discontinuation of therapy/dose escalation, steroid use, ED visits and/or hospitalizations related to active CD). Table 1. - Comparison of Characteristics Between Histologic Healing vs. No Histologic Healing Patient characteristics Histologic Healing (n=27) No Histologic Healing (n=38) P-value Baseline characteristics Age (years), mean (SD) 52.6 (16.0) 48.7 (17.8) 0.36 Female sex, n (%) 13 (48.2) 26 (68.4) 0.10 Smoking, n (%) 5 (18.5) 4 (10.5) 0.36 Disease duration (years), median (IQR) 16 (7-21) 11.5 (4-21.8) 0.38 Disease characteristics Prior bowel resection, n (%) 6 (22.2) 9 (23.7) 0.89 Presence of extraintestinal manifestations, n (%) 7 (25.9) 11 (28.9) 0.79 Perianal disease, n (%) 8 (29.6) 11 (28.9) 0.95 Medication factors On biologic, n (%) 19 (70.4) 19 (50.0) 0.10 On immunomodulator, n(%) 6 (22.2) 7 (18.4) 0.71

Diminishing lengths of subsequent bowel resections in the surgical management of ileal Crohn's disease.

Crohn's disease is a chronic inflammatory bowel disease that most commonly affects the ileum. As a result, it is associated with a high lifetime risk of one or more surgical resections. The surgical paradigm is to preserve intestinal length. This study aims to assess the length of ileum resected at the index operation and at subsequent ileocolic resections for Crohn's disease. This is a retrospective study assessing the clinical and pathological data of patients undergoing ileocolic resection for the management of Crohn's disease over the period 01/01/2002 to 31/07/2020 in two metropolitan Australian hospitals. One hundred and seventy-six patients were analysed: 130 underwent a single resection; 31 underwent two resections; and 15 underwent three resections. The median age at the first operation was 37.2 years (range 18-69) with 60% of patients female. The median length resected at the first surgery was 17.8cm (IQR 12.0) for small bowel, and 5.0cm (IQR 1.0) for large bowel. The length of ileum resected at the first surgery was significantly greater than that of the second (P= 0.0001), without significant differences between the second and third resections (P= 0.49). The time interval from diagnosis to the first surgery had no significant impact on the length of intestine resected at the index ileocolic resection. In Crohn's disease, the length of ileum removed at first resection is the greatest, with subsequent resection lengths less than the first.

Fecal Calprotectin, Chitinase 3-Like-1, S100A12 and Osteoprotegerin as Markers of Disease Activity in Children with Crohn’s Disease

Fecal calprotectin (FC), chitinase 3-like-1 protein (CHI3L1), S100A12 and osteoprotegerin (OPG) are biomarkers of intestinal inflammation. This cross-sectional study aimed to evaluate these biomarkers in a cohort of children with Crohn’s disease (CD) and compare them with other measures of disease activity. Stool samples from children with CD were used to measure FC, CHI3L1, S100A12 and OPG by enzyme-linked immunosorbent assay. Serum inflammatory markers were measured and pediatric CD disease activity index (PCDAI) scores calculated. The simple endoscopic score for CD (SES-CD) was reported for a subgroup who underwent ileocolonoscopy corresponding with the stool samples. Sixty-five children were recruited. Children in clinical remission had lower FC and CHI3L1 levels than those with active disease (FC: 277 vs. 1648 µg/g, p = 0.012; CHI3L1: 23 vs. 227 ng/g, p = 0.013). FC levels differed between patients with clinically active or inactive isolated ileal CD. Although FC and CHI3L1 levels correlated strongly (r = 0.83), none of the fecal markers correlated well with serum markers. Only FC and OPG correlated with SES-CD scores (r = 0.57 and r = 0.48, respectively). In conclusion, FC correlated with both endoscopic and clinical disease activity and was the only biomarker that differentiated between active and inactive ileal CD. CHI3L1 also predicted clinical disease activity and correlated highly with FC. Further investigation of the role of CHI3L1 is required.

MRI-Based Characterization of Intestinal Motility in Children and Young Adults With Newly Diagnosed Ileal Crohn Disease Treated by Biologic Therapy: A Controlled Prospective Study.

BACKGROUND. Changes in intestinal motility in patients with newly diagnosed Crohn disease have historically been evaluated primarily in a subjective manner. OBJECTIVE. The purpose of this study was to assess longitudinal changes in objective intestinal motility scores in children and young adults with newly diagnosed ileal Crohn disease treated with biologic (anti-tumor necrosis factor-α) medical therapy compared with those in control participants. METHODS. This prospective study included 20 children and young adults (eight female and 12 male patients; mean age, 14.6 ± 2.1 [SD] years) with newly diagnosed ileal Crohn disease who were recruited between December 2018 and October 2021 as well as 15 control participants without any known gastrointestinal conditions (eight female and seven male patients; mean age, 18.1 ± 4.4 years). All participants underwent research MRI examinations of the small bowel, including dynamic cine 2D SSFP sequences. Patients with Crohn disease underwent additional research MRI examinations performed at both 6 weeks and 6 months after initiation of biologic therapy. Two operators independently derived terminal ileal intestinal motility scores from the dynamic cine sequences by use of FDA-approved software (with higher scores indicating greater intestinal motility). Intestinal motility scores were compared between patient and control groups by use of t tests, whereas changes in intestinal motility scores after treatment were assessed using linear mixed models. Interoperator absolute agreement was assessed using the intra-class correlation coefficient (ICC). RESULTS. Mean terminal ileal intestinal motility scores were not significantly different between patients with newly diagnosed ileal Crohn disease and control participants (for operator 1, 180.9 ± 63.3 vs 229.7 ± 115.2, respectively [p = .12]; for operator 2, 175.0 ± 62.2 vs 236.4 ± 117.4, respectively [p = .05]). Mean intestinal motility scores changed over time compared with baseline in response to biologic therapy, for operator 1 (180.9 ± 63.3 at baseline, 248.1 ± 104.9 at 6 weeks after treatment initiation, and 249.1 ± 73.2 at 6 months after treatment initiation [p = .04]) and operator 2 (175.0 ± 62.2 at baseline, 247.8 ± 112.7 at 6 weeks after treatment initiation, and 239.6 ± 72.7 at 6 months after treatment initiation [p = .03]). Absolute agreement in intestinal motility scores was excellent between operators (ICC = 0.89). CONCLUSION. MRI measurements of intestinal motility are dynamic in children and adults with newly diagnosed small-bowel Crohn disease, showing early increases in response to biologic therapy. CLINICAL IMPACT. MRI-based intestinal motility scores may aid individualized assessment of disease activity and treatment response in patients with small-bowel Crohn disease.

Ultrasound shear wave elastography in pediatric stricturing small bowel Crohn disease: correlation with histology and second harmonic imaging microscopy.

Preclinical animal as well as small exploratory ex vivo and in vivo human studies have suggested that bowel wall shear wave speed (SWS) measurements may be a noninvasive biomarker of intestinal damage. To evaluate the relationships between bowel wall stiffness, measured using ultrasound shear wave elastography (SWE), and intestinal fibrosis and smooth muscle hypertrophy as determined by (1) histology and (2) second harmonic imaging microscopy (SHIM) in surgically resected ileal strictures from pediatric Crohn disease patients. Nineteen pediatric Crohn disease patients with symptomatic ileal strictures underwent research ultrasound examinations before surgical resection between December 2017 and September 2020. Two-dimensional SWE was performed through the area of the most severe stenosis, with measurements obtained from the bowel wall at the 9:00, 12:00 and 3:00 o'clock locations with 0%, 10% and 20% abdominal strain. Overall right lower quadrant stiffness also was documented. Median bowel wall and overall right lower quadrant SWS measurements were correlated with bowel wall histological scores of inflammation, fibrosis and smooth muscle proliferation as well as SHIM collagen signal. Diagnostic ultrasound SWE imaging was obtained from 18 participants. The median age was 16.8 years. There were negative correlations between histological mucosal active inflammation and both bowel wall SWS with 10% abdominal strain (r=-0.50, P = 0.04) and overall right lower quadrant SWS with 20% abdominal strain (r=-0.69, P = 0.002). There were positive correlations between histological muscularis propria inner layer smooth muscle hypertrophy and both median bowel wall SWS with 10% abdominal strain (r = 0.72, P = 0.002) and overall right lower quadrant SWS with 20% abdominal strain (r = 0.71, P = 0.002). There were no associations between ultrasound stiffness metrics and bowel wall SHIM collagen measurements. Bowel wall and overall right lower quadrant ultrasound stiffness measurements correlate with mucosal active inflammation and muscularis propria smooth muscle hypertrophy in pediatric stricturing ileal Crohn disease, but not with intestinal fibrosis.

Inflammation and tissue remodeling contribute to fibrogenesis in stricturing Crohn's disease: image processing and analysis study.

BackgroundInflammation and structural remodeling may contribute to fibrogenesis in Crohn’s disease (CD). We quantified the immunoexpression of calretinin, CD34, and calprotectin as a surrogate for mucosal innervation, telocytes (interstitial cells playing a role in networking), and inflammation, respectively, and correlated them with bowel alterations in stricturing CD.MethodsPrimary resection specimens for ileal CD (n = 44, 31 stricturing CD, 13 inflammatory CD) were identified. Left-sided ulcerative colitis and trauma cases were used as controls. Proximal and distal margin and middle (diseased) sections were stained for calretinin, CD34, and calprotectin. Microscopic images were captured from the mucosa (calretinin), submucosa (calprotectin), and myenteric plexus (CD34), and the immunostaining was quantified using image processing and analysis. Bowel thickness at the corresponding sections were measured and correlated with the amount of immunoexpression.ResultsA total of 2,037 images were analyzed. In stricturing CD, submucosal alteration/thickening at the stricture site correlated with calprotectin staining and inversely correlated with calretinin staining at the proximal margin. Muscularis propria alteration/thickening at the stricture site correlated with mucosal calretinin staining at the proximal margin. Submucosal alteration/thickening at the proximal margin correlated with calretinin and CD34 staining at the proximal margin and inversely correlated with CD34 staining at the stricture site. Calretinin immunostaining at the distal margin was significantly higher in stricturing CD than the controls.ConclusionsInflammation and tissue remodeling appear to contribute to fibrogenesis in stricturing CD. Increased mucosal calretinin immunostaining distal to the diseased segment could be helpful in diagnosing CD in the right clinical context.

Human CD4+CD8α+ Tregs induced by Faecalibacterium prausnitzii protect against intestinal inflammation.

Abundance of Faecalibacterium prausnitzii, a dominant bacterium of the human microbiota that exhibits antiinflammatory effects, is decreased in patients with inflammatory bowel diseases (IBD). In humans, colonic lamina propria contains IL-10-secreting, Foxp3- Tregs characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet to our knowledge. Here, using a humanized model of a NSG immunodeficient mouse strain that expresses the HLA D-related allele HLA-DR*0401 but not murine class II (NSG-Ab° DR4) molecules, we demonstrated a protective effect of a HLA-DR*0401-restricted DP8α Treg clone combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn's disease.

Isolated Crohn's Colitis: Is Localization Crucial? Characteristics of Pediatric Patients From the CEDATA-GPGE Registry.

IntroductionPediatric patients with inflammatory bowel disease (IBD) are classified into Crohn's disease (CD), ulcerative colitis (UC), and unclassifiable (IBD-U). However, data provide evidence that ileal CD (L1) is distinct from colonic CD (L2). The aim of this study was to investigate the clinical features of isolated Crohn's colitis in a pediatric population.Material and MethodsChildren who were prospectively included in the CEDATA–GPGE registry on diagnosis were compared according to the diagnosis of CD with L2 vs. L1 and ileocolonic (L3) involvement pattern as well as IBD-U and UC. The clinical significance of L2 was investigated with regard to extraintestinal manifestations, treatment, surgery, and disease activity.ResultsFifty-two patients with L2 CD at a median age of 13.4 years (±3.8 SD) were compared with 182 L1 (13.8 ± 2.9 SD), 782 with L3 (12.8 ± 3.3 SD), 653 with UC (12.7 ± 3.8 SD), and 111 patients with IBD-U (11.9 ± 4.7 SD). Bloody stools at diagnosis were more common in L2 (44%) than in L1 (19.7%) and L3 (28.8%), but not as common as in UC (66.5%) and IBD-U (61.3%). Fewer CD patients with L2 (10.2%) received exclusive enteral nutrition therapy (EEN) as induction than patients with L1 (34.3%) and L3 (33.3%). After induction therapy, 42.3% of patients with L2 received immunosuppressants and 21% biologicals during follow-up (L1 56.5/10.5%; L3 59/21%; CU 43.5/11.9%; IBD-U 26.1/12.6%). Extraintestinal manifestations were more frequent in L2 (23.1%) vs. L1 (18.7%), L3 (20.2%), CU (15.8%), and IBD-U (11.7%). The number of patients requiring surgery did not differ within the CD subgroups and was significantly lower in UC and IBD-U. Perianal fistula surgery was significantly more common in L2 (44%) than in L1 (4.8%) or L3 (21.7%). In addition, the frequency of surgery for perianal abscesses was also more frequent in L2 (55.6%) than in L1 (12.7%) or L3 (38.4%).ConclusionsThe consideration of pediatric Crohn's colitis as a distinct disease seems necessary as it is characterized by extraintestinal manifestations (EIMs) with mainly joint involvement and perianal fistulas or abscesses requiring surgery and biologic therapy. Thus, colonic Crohn's disease may have an influence on the therapeutic stratification and should be addressed in further studies.

Neutralizing Anti-Granulocyte Macrophage-Colony Stimulating Factor Autoantibodies Recognize Post-Translational Glycosylations on Granulocyte Macrophage-Colony Stimulating Factor Years Before Diagnosis and Predict Complicated Crohn’s Disease

Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD. We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n= 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis. Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa. Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis.

Diagnostic Accuracy of Magnetic Resonance Enterography for the Evaluation of Active and Fibrotic Inflammation in Crohn's Disease.

BackgroundDespite the success of standard magnetic resonance enterography (MRE) in detecting Crohn’s disease (CD), characterization of strictures and, thus, therapy guidance is still limited. The aim of the study was to determine diagnostic accuracy of MRE in detecting or ruling out active inflammation and identifying fibrotic lesions in patients with terminal ileal CD with histopathology as reference.MethodsSixty-seven consecutive patients (median age 32 years, range 19–79 years) with terminal ileal CD were retrospectively enrolled between January 2015 and October 2020. The median interval between MRE and surgery was 9 days (range 0–86 days). Sensitivity, specificity, positive and negative predictive value (PPV and NPV, respectively), and area under the curve (AUC) with 95% confidence intervals (CIs) were calculated for the MRE-based AIS (acute inflammation score) using the histopathology of surgical specimens as the reference standard.ResultsSensitivity, specificity, PPV, and NPV for detecting or ruling out active inflammation were 100% (CI, 0.94–1.00; 0.44–1.00; 0.93–1.00; 0.31–1.00) using an AIS cut-off of >4.1. AUC was 1.00 (CI, 1.00–1.00; p < 0.01). In all patients with fibrotic changes only and no active inflammation, AIS was <4.1. Interobserver agreement was substantial (κ = 0.65, p < 0.01).ConclusionOur study has shown an excellent diagnostic performance of the MRE-based AIS for determining whether active inflammation is present or lesions are due to chronic changes in ileal CD using the histopathology of surgical specimens as reference. These findings indicate that the MRE-based AIS allows a better determination of the inflammatory stage of terminal ileal CD, which facilitates the decision to perform surgery.

Velocity-Encoded Phase-Contrast MRI for Measuring Mesenteric Blood Flow in Patients With Newly Diagnosed Small-Bowel Crohn Disease.

BACKGROUND. Intestinal inflammation is associated with radiologic and histologic hyperemia. A paucity of studies have used MRI to measure mesenteric blood flow in patients with Crohn disease. OBJECTIVE. The purpose of this study was to evaluate the application of velocity-encoded phase-contrast MRI for measuring mesenteric blood flow in patients with newly diagnosed small-bowel Crohn disease. METHODS. This prospective study included 20 patients with ileal Crohn disease newly diagnosed between December 2018 and October 2021 (eight female participants, 12 male participants; median age, 14.0 years), and 15 healthy control participants (eight female participants, seven male participants; median age, 17.0 years). Patients with Crohn disease underwent investigational MRI and laboratory assessments at diagnosis and at 6 weeks and 6 months after initiating anti-tumor necrosis factor-α medical therapy; control participants underwent a single investigational MRI examination. All MRI examinations included a velocity-encoded phase-contrast acquisition, which was used to measure blood flow in the abdominal aorta, superior mesenteric artery (SMA), and superior mesenteric vein (SMV). Mann-Whitney U test was used to compare blood flow measurements (ratios of SMA and SMV blood flow to aorta blood flow [hereafter, SMA-to-aorta and SMV-to-aorta blood flow, respectively]) between groups; Friedman test was used to evaluate temporal changes in blood flow. Spearman correlation was used to assess relationships between blood flow measurements and laboratory markers of intestinal inflammation. Diagnostic performance was assessed by ROC analysis. RESULTS. At baseline, SMA-to-aorta blood flow in patients versus control participants was 0.44 versus 0.30 (p = .003), and SMV-to-aorta blood flow was 0.36 versus 0.21 (p = .002). At 6 weeks and 6 months, SMA-to-aorta blood flow in patients decreased to 0.30 and 0.27 (p < .001), and SMV-to-aorta blood flow decreased to 0.27 and 0.21 (p = .02), respectively. SMA-to-aorta and SMV-to-aorta blood flow were positively correlated with C-reactive protein (rho, 0.34 [p = .01] and 0.35 [p = .008], respectively) and fecal calprotectin (rho, 0.34 [p = .01] vs 0.47 [p < .001]). AUCs for differentiating patients from controls were 0.79 for SMA-to-aorta (sensitivity, 60%; specificity, 100%) and 0.82 for SMV-to-aorta (sensitivity, 75%; specificity, 87%) blood flow. CONCLUSION. Mesenteric blood flow is quantifiable using velocity-encoded phase-contrast MRI. The measurements differ between patients with ileal Crohn disease and healthy control participants and change in response to medical therapy. CLINICAL IMPACT. MRI-based mesenteric blood flow measurements provide a potential novel marker of intestinal inflammation.