Using Computer Vision to Improve Endoscopic Disease Quantification in Therapeutic Clinical Trials of Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic assessment of ulcerative colitis (UC) typically reports only the maximum severity observed. Computer vision methods may better quantify mucosal injury detail, which varies among patients. METHODS: Endoscopic video from the UNIFI clinical trial (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) comparing ustekinumab and placebo for UC were processed in a computer vision analysis that spatially mapped Mayo Endoscopic Score (MES) to generate the Cumulative Disease Score (CDS). CDS was compared with the MES for differentiating ustekinumab vs placebo treatment response and agreement with symptomatic remission at week 44. Statistical power, effect, and estimated sample sizes for detecting endoscopic differences between treatments were calculated using both CDS and MES measures. Endoscopic video from a separate phase 2 clinical trial replication cohort was performed for validation of CDS performance. RESULTS: Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (-85.0 vs -55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges' g = 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI. CONCLUSIONS: As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.

Legalization of Cannabis Does Not Reduce Opioid Prescribing in Patients With Inflammatory Bowel Disease: A Difference-in-Difference Analysis.

INTRODUCTION: Cannabis may provide inflammatory bowel disease (IBD) patients with an alternative to opioids for pain. METHODS: We conducted a difference-in-difference analysis using MarketScan. Changes over time in rates of opioid prescribing were compared in states with legalized cannabis to those without. RESULTS: We identified 6,240 patients with IBD in states with legalized cannabis and 79,272 patients with IBD in states without legalized cannabis. The rate of opioid prescribing decreased over time in both groups and were not significantly different (attributed differential = 0.34, confidence interval -13.02 to 13.70, P = 0.96). DISCUSSION: Opioid prescribing decreased from 2009 to 2016 among patients with IBD in both states with legalized and state without legalized cannabis, similar to what has been observed nationally across a variety of diseases. Cannabis legalization was not associated with a lower rate of opioid prescribing for patients with IBD.

Artificial Intelligence for Quantifying Cumulative Small Bowel Disease Severity on CT-Enterography in Crohn's Disease.

INTRODUCTION: Assessing the cumulative degree of bowel injury in ileal Crohn's disease (CD) is difficult. We aimed to develop machine learning (ML) methodologies for automated estimation of cumulative ileal injury on computed tomography-enterography (CTE) to help predict future bowel surgery. METHODS: Adults with ileal CD using biologic therapy at a tertiary care center underwent ML analysis of CTE scans. Two fellowship-trained radiologists graded bowel injury severity at granular spatial increments along the ileum (1 cm), called mini-segments. ML segmentation methods were trained on radiologist grading with predicted severity and then spatially mapped to the ileum. Cumulative injury was calculated as the sum (S-CIDSS) and mean of severity grades along the ileum. Multivariate models of future small bowel resection were compared with cumulative ileum injury metrics and traditional bowel measures, adjusting for laboratory values, medications, and prior surgery at the time of CTE. RESULTS: In 229 CTE scans, 8,424 mini-segments underwent analysis. Agreement between ML and radiologists injury grading was strong (κ = 0.80, 95% confidence interval 0.79-0.81) and similar to inter-radiologist agreement (κ = 0.87, 95% confidence interval 0.85-0.88). S-CIDSS (46.6 vs 30.4, P = 0.0007) and mean cumulative injury grade scores (1.80 vs 1.42, P < 0.0001) were greater in CD biologic users that went to future surgery. Models using cumulative spatial metrics (area under the curve = 0.76) outperformed models using conventional bowel measures, laboratory values, and medical history (area under the curve = 0.62) for predicting future surgery in biologic users. DISCUSSION: Automated cumulative ileal injury scores show promise for improving prediction of outcomes in small bowel CD. Beyond replicating expert judgment, spatial enterography analysis can augment the personalization of bowel assessment in CD.

Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience.

INTRODUCTION: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy. METHODS: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions. RESULTS: Of the 25 patients with ASUC treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) of the 18 patients with available data and who did not undergo colectomy experienced steroid-free clinical remission (1 patient did not have complete data), 1 (4%) patient experienced a venous thromboembolic event, while 5 (20%) patients were readmitted. DISCUSSION: Upadacitinib along with intravenous corticosteroids may be an effective treatment for ASUC.

Artificial Intelligence and IBD: Where are We Now and Where Will We Be in the Future?

PURPOSE OF REVIEW: Artificial intelligence (AI) is quickly demonstrating the ability to address problems and challenges in the care of IBD. This review with commentary will highlight today's advancements in AI applications for IBD in image analysis, understanding text, and replicating clinical knowledge and experience. RECENT FINDINGS: Advancements in machine learning methods, availability of high-performance computing, and increasing digitization of medical data are providing opportunities for AI to assist in IBD care. Multiple groups have demonstrated the ability of AI to replicate expert endoscopic scoring in IBD, with expansion into automated capsule endoscopy, enterography, and histologic interpretations. Further, AI image analysis is being used to develop new endoscopic scoring with more granularity and detail than is possible using conventional methods. Advancements in natural language processing are proving to reduce laborious tasks required in the care of IBD, including documentation, information searches, and chart review. Finally, large language models and chatbots that can understand language and generate human-like replies are beginning to exhibit clinical intelligence that will revolutionize how we deliver IBD care. Today, AI is being deployed to replicate expert judgement in specific tasks where disagreement, subjectivity, and bias are common. However, the near future will herald contributions of AI doing what we cannot, including new detailed measures of IBD, enhanced analysis of images, and perhaps even fully automating care. As we speculate on future technologic capabilities that may improve how we care for IBD, this review will also consider how we will implement and fairly use AI in practice.

Artificial Intelligence for Disease Assessment in Inflammatory Bowel Disease: How Will it Change Our Practice?

Artificial intelligence (AI) has arrived and it will directly impact how we assess, monitor, and manage inflammatory bowel disease (IBD). Advances in the machine learning methodologies that power AI have produced astounding results for replicating expert judgment and predicting clinical outcomes, particularly in the analysis of imaging. This review will cover general concepts for AI in IBD, with descriptions of common machine learning methods, including decision trees and neural networks. Applications of AI in IBD will cover recent achievements in endoscopic image interpretation and scoring, new capabilities for cross-sectional image analysis, natural language processing for automated understanding of clinical text, and progress in AI-powered clinical decision support tools. In addition to detailing current evidence supporting the capabilities of AI for replicating expert clinical judgment, speculative commentary on how AI may advance concepts of disease activity assessment, care pathways, and pathophysiologic mechanisms of IBD will be addressed.

Development of the Endoscopic Pouch Score for Assessment of Inflammatory Conditions of the Pouch.

Pouchoscopy provides a critical objective measure in the evaluation of patients with suspected inflammatory conditions of the pouch; however, there remain significant gaps in the reliability of the endoscopic scales used in the assessment of these conditions.1,2 Reliability and reproducibility in the assessment of patients after ileal pouch-anal anastomosis (IPAA) are critical, as evidenced by recent efforts to improve standardization in the evaluation of patients with pouch-related disorders.3.

Characteristics of Patients with Crohn's Disease With or Without Perianal Fistulae in the CorEvitas Inflammatory Bowel Disease Registry.

BACKGROUND: There are limited real-world data characterizing perianal fistulae in patients with Crohn's disease (CD). AIM: To describe characteristics of patients with CD with and without perianal fistulae. METHODS: In this cross-sectional study, characteristics, treatment history, and health outcomes of patients with CD enrolled in the CorEvitas IBD Registry were described according to perianal fistula status (current/previous or none). RESULTS: Eight hundred and seventy-eight patients were included. Compared with patients with no perianal fistulae (n = 723), patients with current/previous perianal fistulae (n = 155) had longer disease duration since CD diagnosis (mean 16.5 vs 12.3 years; difference 4.3 years; 95% CI, 2.0, 6.6) and fewer had Harvey-Bradshaw Index scores indicative of remission (0-4, 56.8% vs 69.6%; difference - 12.9%; 95% CI, - 21.6, - 4.2). More patients with current/previous fistulae reported a history of IBD-related emergency room visits (67.7% vs 56.1%; difference 11.6%; 95% CI, 3.4, 19.8), hospitalizations (76.1% vs 58.4%; difference 17.7%; 95% CI, 10.1, 25.4), and surgeries (59.4% vs 27.7%; difference 31.7%; 95% CI, 23.3, 40.1), and a history of treatment with tumor necrosis factor inhibitors (81.3% vs 60.7%; difference 20.6%; 95% CI, 13.5, 27.7), immunosuppressants (51.6% vs 31.2%; difference 20.4%; 95% CI, 11.9, 29.0), and antibiotics (50.3% vs 23.7%; difference 26.6%; 95% CI, 18.2, 35.1) than patients without perianal fistulae. CONCLUSIONS: Patients with CD with current/previous perianal fistulae have more symptomatic experiences of disease, higher medication use, hospitalization rates, and emergency room visits than patients without perianal fistulae. Interventions to prevent/reduce risk of developing fistulae may help improve outcomes in CD.

Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature.

BACKGROUND: Dual targeted therapy (DTT) has emerged as an attractive therapeutic option for select patients with active inflammatory bowel disease (IBD) who are unable to achieve remission with biologic or small molecule monotherapy. We conducted a systematic review of specific DTT combinations in patients with IBD. METHODS: We conducted a systematic search of MEDLINE, EMBASE, Scopus, CINAHL Complete, Web of Science Core Collection, and Cochrane Library to identify articles related to the use of DTT for the treatment of Crohn Disease (CD) or ulcerative colitis (UC) published before February 2021. RESULTS: Twenty-nine studies were identified comprising 288 patients started on DTT for partially or non-responsive IBD. We identified 14 studies with 113 patients receiving anti-tumor necrosis factor (TNF) and anti-integrin therapies (i.e., vedolizumab and natalizumab), 12 studies with 55 patients receiving vedolizumab and ustekinumab, nine studies with 68 patients receiving vedolizumab and tofacitinib, five studies with 24 patients receiving anti-TNF therapy and tofacitinib, six studies with 18 patients receiving anti-TNF therapy and ustekinumab, and three studies with 13 patients receiving ustekinumab and tofacitinib. CONCLUSION: DTT is a promising approach to improve IBD treatment for patients with incomplete responses to targeted monotherapy. Larger prospective clinical studies are needed to confirm these findings as is additional predictive modeling to identify the patient subgroups most likely to require and benefit from this approach.

Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review.

BACKGROUND AND AIMS: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. METHODS: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). RESULTS: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. CONCLUSIONS: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.

Outcomes of cold snare piecemeal EMR for nonampullary small-bowel adenomas larger than 1 cm: a retrospective study.

BACKGROUND AND AIMS: Nonampullary small-bowel adenomas ≥10 mm are typically resected using cautery-based polypectomy, which is associated with significant adverse events. Studies have demonstrated the safety and efficacy of piecemeal cold snare EMR for removing large colon polyps. Our aim was to assess the safety and efficacy of cold snare EMR for removal of large adenomas in the small bowel. METHODS: A retrospective study of patients who underwent lift and piecemeal cold snare EMR of small-bowel adenomas ≥1 cm between January 2014 and March 2019 was conducted at a tertiary care medical center. Polyp characteristics at the time of index and surveillance endoscopy were collected. Primary outcomes were residual or recurrent adenoma (RRA) seen on surveillance endoscopy, polyp eradication rate, and number of endoscopic procedures required for eradication. Adverse events including immediate and delayed bleeding, perforation, stricture, pancreatitis, and postpolypectomy syndrome were assessed. RESULTS: Of 43 patients who underwent piecemeal cold snare EMR, 39 had follow-up endoscopy. Polyps ranged in size from 10 to 70 mm (mean, 26.5 mm). RRA was found in 18 patients (46%), with increased polyp size correlating with higher recurrence (P < .001). Polyp eradication was observed in 35 patients (89%), requiring a median of 2 (range, 1-6) endoscopic procedures. Only 1 patient (2.3%) had immediate postprocedural bleeding. No cases of perforation or postpolypectomy syndrome were seen. CONCLUSIONS: Piecemeal cold snare EMR may be a feasible, safe, and efficacious technique for small-bowel polyps >10 mm. Prospective, randomized studies are needed to assess how outcomes compare with traditional cautery-based polypectomy.

Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study.

BACKGROUND & AIMS: Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC. METHODS: A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes. RESULTS: Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10-0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02-0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21-2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls. CONCLUSIONS: Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Fully automated endoscopic disease activity assessment in ulcerative colitis.

BACKGROUND AND AIMS: Endoscopy is essential for disease assessment in ulcerative colitis (UC), but subjectivity threatens accuracy and precision. We aimed to pilot a fully automated video analysis system for grading endoscopic disease in UC. METHODS: A developmental set of high-resolution UC endoscopic videos were assigned Mayo endoscopic scores (MESs) provided by 2 experienced reviewers. Video still-image stacks were annotated for image quality (informativeness) and MES. Models to predict still-image informativeness and disease severity were trained using convolutional neural networks. A template-matching grid search was used to estimate whole-video MESs provided by human reviewers using predicted still-image MES proportions. The automated whole-video MES workflow was tested using unaltered endoscopic videos from a multicenter UC clinical trial. RESULTS: The developmental high-resolution and testing multicenter clinical trial sets contained 51 and 264 videos, respectively. The still-image informative classifier had excellent performance with a sensitivity of 0.902 and specificity of 0.870. In high-resolution videos, fully automated methods correctly predicted MESs in 78% (41 of 50, κ = 0.84) of videos. In external clinical trial videos, reviewers agreed on MESs in 82.8% (140 of 169) of videos (κ = 0.78). Automated and central reviewer scoring agreement occurred in 57.1% of videos (κ = 0.59), but improved to 69.5% (107 of 169) when accounting for reviewer disagreement. Automated MES grading of clinical trial videos (often low resolution) correctly distinguished remission (MES 0,1) versus active disease (MES 2,3) in 83.7% (221 of 264) of videos. CONCLUSIONS: These early results support the potential for artificial intelligence to provide endoscopic disease grading in UC that approximates the scoring of experienced reviewers.

Clinical applications of artificial intelligence and machine learning-based methods in inflammatory bowel disease.

Our objective was to review and exemplify how selected applications of artificial intelligence (AI) might facilitate and improve inflammatory bowel disease (IBD) care and to identify gaps for future work in this field. IBD is highly complex and associated with significant variation in care and outcomes. The application of AI to IBD has the potential to reduce variation in healthcare delivery and improve quality of care. AI refers to the ability of machines to mimic human intelligence. The range of AI's ability to perform tasks that would normally require human intelligence varies from prediction to complex decision-making that more closely resembles human thought. Clinical applications of AI have been applied to study pathogenesis, diagnosis, and patient prognosis in IBD. Despite these advancements, AI in IBD is in its early development and has tremendous potential to transform future care.

Evaluating When and Why Patients Discontinue Chronic Therapy for Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation.

INTRODUCTION: To inform the patient-centered discussion regarding comparative outcomes with irritable bowel syndrome/chronic idiopathic constipation pharmacotherapy, we evaluated reasons and timing of discontinuation of FDA-approved pharmacotherapy for irritable bowel syndrome and chronic idiopathic constipation in a large observational real-world cohort. METHODS: We identified patients initiating lubiprostone or linaclotide within the University of Michigan Electronic Medical Record (2012-2016). Medication start and stop dates were determined in manual chart review including detailed review of all documentation including office notes and telephone encounters. A Cox model was constructed to predict the hazard of discontinuation. RESULTS: On multivariate analysis of 1,612 patients, linaclotide users had a lower risk of discontinuing therapy than lubiprostone users for any reason (hazard ratio [HR] = 0.6, 95% confidence interval [CI] 0.5-0.8). At 3 and 12 months, the overall discontinuation rates were 23% and 43% for lubiprostone compared with 14% and 24% for linaclotide. Over the first year of therapy, more than half of discontinuations due to intolerance occurred in the first 3 months for both drugs. Linaclotide users were more likely to discontinue due to intolerance (HR = 1.6 [95% CI, 1.2-2.3]) but less likely to discontinue due to insufficient efficacy of therapy (HR = 0.5 [95% CI, 0.4-0.8]). IBS diagnosis increased the hazard of discontinuation of lubiprostone relative to linactolide (HR = 1.4, 95% CI, 1.1-1.6). Loss of prescription drug coverage remained a common reason for discontinuation over the first year of therapy. DISCUSSION: Individuals appear more likely to discontinue lubiprostone than linaclotide overall, but more likely to discontinue linaclotide compared with lubiprostone due to intolerance (mostly diarrhea). Most discontinuations due to intolerance occur in the first 3 months. These results may be useful in individualized treatment selection and enhancing patient knowledge regarding long-term outcomes.

Use of Accelerated Induction Strategy of Infliximab for Ulcerative Colitis in Hospitalized Patients at a Tertiary Care Center.

BACKGROUND: Infliximab can prevent colectomy in patients hospitalized with acute severe ulcerative colitis (ASUC). In cases of ASUC, fecal losses of infliximab may lead to low drug levels and reduced efficacy. AIM: To determine 90-day colectomy risk and postoperative complications in patients receiving single-dose and accelerated induction of infliximab for ASUC. METHODS: We conducted a retrospective review of patients hospitalized with ASUC requiring infliximab therapy between 2013 and 2017 at the University of Michigan. Patients were excluded if they had an enteric infection, received an anti-TNF previously, or received cyclosporine during the same admission. The primary outcome was colectomy within 90 days of admission. Patients receiving single-dose induction infliximab were compared to those receiving accelerated rescue induction with two doses of infliximab prior to day 14. Administration of accelerated induction was guided by a protocol, suggesting administering a second dose of infliximab to those with only a partial response in CRP 3 days after the initial dose. Postoperative outcomes including 30-day readmission rates and complications were compared using descriptive statistics. RESULTS: From 2013 to 2017, 66 patients with ASUC met our criteria. Thirty-three received accelerated induction (50.0%). The colectomy rate in the accelerated induction group was 30.3% versus 24.2% in the single-dose induction group (p = 0.58). There was no detected difference in postoperative outcomes between the accelerated and single-dose rescue induction. CONCLUSIONS: In this retrospective review, 69.7% of those failing to respond to single-dose infliximab were able to avoid colectomy with an accelerated rescue induction strategy without worsening postoperative outcomes. Larger studies of accelerated dosing infliximab are needed.

Prevalence and Effect of Intestinal Infections Detected by a PCR-Based Stool Test in Patients with Inflammatory Bowel Disease.

BACKGROUND: The advent of PCR-based stool testing has identified a greatly increased number of infectious agents in IBD, but their clinical significance is unknown. AIMS: To determine the infectious agent prevalence and the clinical significance of these infectious agents in IBD patients. METHODS: This cross-sectional study compared the prevalence of GI infections among IBD patients with active and quiescent disease versus healthy controls. Among actively inflamed patients, we compared clinical characteristics, medication use, and disease course between those with positive and negative tests. RESULTS: Three hundred and thirty-three IBD patients and 52 healthy volunteers were included. The IBD group was divided into active Crohn's disease (CD, n = 113), inactive CD (n = 53), active ulcerative colitis (UC, n = 128), and inactive UC (n = 39). A significantly higher percentage of actively inflamed patients had positive stool tests (31.1%) compared to those with quiescent disease (7.6%, P = < 0.001) and healthy controls (13.5%, P = 0.01). In actively inflamed patients, shorter symptom duration and the use of multiple immunosuppressive agents were significantly associated with positive stool tests. Escalation of immunosuppressive therapy was less frequent in those with positive (61.3%) than with negative tests (77.7%, P = < 0.01). However, the need for surgery (13.3% vs. 18.7%, respectively, P = 0.31) and hospitalization (14.7% vs. 17.5%, respectively, P = 0.57) in 90 days was not significantly different. CONCLUSION: GI infections are common in IBD patients with active disease. Evaluating patients for infection may help avoid unnecessary escalation of immunosuppressants, especially during an acute flare or combination immunosuppression.

Association Between Plasma Level of Collagen Type III Alpha 1 Chain and Development of Strictures in Pediatric Patients With Crohn's Disease.

BACKGROUND & AIMS: There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2). METHODS: We selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal-Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups. RESULTS: The median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71-0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55-0.83) and a specificity value of 0.83 (95% CI, 0.67-0.93). CONCLUSIONS: We found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00790543.

Efficacy of Induction Therapy With High-Intensity Tofacitinib in 4 Patients With Acute Severe Ulcerative Colitis.

As many as 25% of patients diagnosed with ulcerative colitis are hospitalized with an episode of acute severe ulcerative colitis (ASUC).1 The standard of care for patients hospitalized with ASUC relies on rapid induction with intravenous (IV) corticosteroids. Up to 30% of patients do not respond to corticosteroids alone.2 Rescue therapy with infliximab or cyclosporine has been shown to reduce rates of colectomy to 20% by 90 days.3,4 This still represents a significant rate of treatment failure, which leads to an unplanned and irreversible surgery. In recent years, increasing numbers of patients admitted with ASUC have already failed infliximab therapy, highlighting the need for additional treatment options for these patients. Tofacitinib is a rapidly acting, oral, small-molecule Janus kinase inhibitor that was recently approved by the Food and Drug Administration for treatment of ulcerative colitis.5 We present the first reported use of off-label, high-intensity tofacitinib in 4 patients admitted to our institution with ASUC predicted to fail medical management.

Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease.

OBJECTIVES: Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at diagnosis with the future development of fibrostenotic CD. METHODS: Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring-targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes. RESULTS: In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio [HR] 3.43, 95% confidence limit [CL] 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13). CONCLUSIONS: ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.