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Crohn Disease: HELP
Articles by Peter D. R. Higgins
Based on 55 articles published since 2010
(Why 55 articles?)
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Between 2010 and 2020, P. Higgins wrote the following 55 articles about Crohn Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Characterization of inflammation and fibrosis in Crohn's disease lesions by magnetic resonance imaging. 2015

Higgins, Peter D R / Fletcher, Joel G. ·Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. · Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA. ·Am J Gastroenterol · Pubmed #25743712.

ABSTRACT: -- No abstract --

2 Review Colorectal Cancer in Inflammatory Bowel Disease. 2018

Stidham, Ryan W / Higgins, Peter D R. ·Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. ·Clin Colon Rectal Surg · Pubmed #29720903.

ABSTRACT: Patients with inflammatory bowel disease (IBD) are at significantly increased risk of colorectal cancer (CRC), principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Epidemiologic studies continue to highlight the increased risk of CRC in IBD. However, the incidence has declined over the past 30 years, attributed to both successful CRC-surveillance programs and improved control of mucosal inflammation. Risk factors that further increase the risk of IBD-related CRC include disease duration, extent and severity, the presence of inflammatory pseudopolyps, coexistent primary sclerosing cholangitis, and a family history of CRC. All major professional societies agree that IBD-CRC surveillance should occur more frequently than in the general population. Yet, guidelines and consensus statements differ on the surveillance schedule and preferred method of surveillance. Improved sensitivity to previously "invisible" flat dysplastic lesions using high definition and chromoendoscopy methods has resulted in many guidelines abandoning requirements for random untargeted biopsies of the colon. While colonic dysplasia remains a worrisome finding, and several clinical scenarios remain best addressed by total proctocolectomy due to concerns of synchronous undetected lesions and the unpredictable tempo of progression to malignancy, better detection techniques have also increased opportunities for endoscopic resection of dysplastic lesions that can be clearly delineated. Finally, the expanding armamentarium of medical options in IBD, including anti-tumor necrosis factor and anti-adhesion biologic therapies, have substantially improved our ability to control severe inflammation and likely reduce the risk of CRC over time.

3 Review Measurement of Fibrosis in Crohn's Disease Strictures with Imaging and Blood Biomarkers to Inform Clinical Decisions. 2017

Higgins, Peter D R. ·Division of Gastroenterology, University of Michigan, Ann Arbor, Mich., USA. ·Dig Dis · Pubmed #28147365.

ABSTRACT: BACKGROUND: Distinguishing fibrosis from inflammation in an intestinal stricture in Crohn's disease is quite difficult. The absence of signs of inflammation on CT or MRI does not prove the absence of inflammation, as most strictures have a mix of fibrosis and inflammation. Identifying refractory fibrosis and distinguishing the patients who will respond to anti-inflammatory therapy from those who will require surgery are important clinical requirements, and several new technologies in imaging and serum biomarkers are being applied to this problem. Key Messages: Delayed gadolinium enhancement of a Crohn's disease stricture on MRI can reliably identify severe fibrosis, and may be helpful in deciding which patients will require surgery. However, this approach does not appear to be able to identify patients with mild or moderate fibrosis. New imaging technologies, including T2/magnetization transfer MRI, shear wave velocity ultrasound, and photoacoustic imaging, offer promising animal data that could prove to accurately assist clinical decision making. Glyoproteomics has identified hepatic growth factor alpha and cartilage oligomeric matrix protein as possible serum biomarkers to detect and measure intestinal fibrosis. The presence of upstream small bowel dilation >3.5 cm or a platelet/albumin ratio >150 helps in identifying Crohn's disease patients at high risk of stricture resection in the next 2 years. CONCLUSIONS: Imaging and biomarker technologies to measure intestinal fibrosis are rapidly evolving, and could soon provide valuable information for clinical decision making for patients with intestinal strictures from Crohn's disease.

4 Review Meta-Analytic Bayesian Model For Differentiating Intestinal Tuberculosis from Crohn's Disease. 2017

Limsrivilai, Julajak / Shreiner, Andrew B / Pongpaibul, Ananya / Laohapand, Charlie / Boonanuwat, Rewat / Pausawasdi, Nonthalee / Pongprasobchai, Supot / Manatsathit, Sathaporn / Higgins, Peter D R. ·Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. · Division of Gastroenterology, Siriraj Hospital, Mahidol University, Bangkok, Thailand. · Department of Pathology, Siriraj Hospital, Mahidol University, Bangkok, Thailand. ·Am J Gastroenterol · Pubmed #28045023.

ABSTRACT: OBJECTIVES: Distinguishing intestinal tuberculosis (ITB) from Crohn's disease (CD) is difficult, although studies have reported clinical, endoscopic, imaging, and laboratory findings that help to differentiate these two diseases. We aimed to produce estimates of the predictive power of these findings and construct a comprehensive model to predict the probability of ITB vs. CD. METHODS: A systematic literature search for studies differentiating ITB from CD was conducted in MEDLINE, PUBMED, and EMBASE from inception until September 2015. Fifty-five distinct meta-analyses were performed to estimate the odds ratio of each predictive finding. Estimates with a significant difference between CD and ITB and low to moderate heterogeneity (I RESULTS: Thirty-eight studies comprising 2,117 CD and 1,589 ITB patients were included in the analyses. Findings in the model that significantly favored CD included male gender, hematochezia, perianal disease, intestinal obstruction, and extraintestinal manifestations; endoscopic findings of longitudinal ulcers, cobblestone appearance, luminal stricture, mucosal bridge, and rectal involvement; pathological findings of focally enhanced colitis; and computed tomographic enterography (CTE) findings of asymmetrical wall thickening, intestinal wall stratification, comb sign, and fibrofatty proliferation. Findings that significantly favored ITB included fever, night sweats, lung involvement, and ascites; endoscopic findings of transverse ulcers, patulous ileocecal valve, and cecal involvement; pathological findings of confluent or submucosal granulomas, lymphocyte cuffing, and ulcers lined by histiocytes; a CTE finding of short segmental involvement; and a positive interferon-γ release assay. The model was validated by gender, clinical manifestations, endoscopic, and pathological findings in 49 patients (27 CD, 22 ITB). The sensitivity, specificity, and accuracy for diagnosis of ITB were 90.9%, 92.6%, and 91.8%, respectively. CONCLUSIONS: A Bayesian model based on the meta-analytic results is presented to estimate the probability of ITB and CD calibrated to local prevalence. This model can be applied to patients using a publicly available web application.

5 Review Imaging of intestinal fibrosis: current challenges and future methods. 2016

Stidham, Ryan W / Higgins, Peter Dr. ·Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Health System, Ann Arbor, MI, USA. ·United European Gastroenterol J · Pubmed #27536361.

ABSTRACT: Crohn's disease (CD) activity assessments are dominated by inflammatory changes without discrete measurement of the coexisting fibrotic contribution to total bowel damage. Intestinal fibrosis impacts the development of severe structural complications and the overall natural history of CD. Measuring intestinal fibrosis is challenging and existing methods of disease assessment are unable to reliably distinguish fibrosis from inflammation. Both the immediate clinical need to measure fibrosis for therapeutic decision-making and the near-future need for tools to assess pipeline anti-fibrotic medications highlight the demand for biomarkers of fibrosis in CD. Developing non-invasive technologies exploit changes in intestinal perfusion, mechanical properties, and macromolecular content to provide quantitative markers of fibrosis. In this review of existing and experimental technologies for imaging intestinal fibrosis, we discuss the expanding capabilities of quantitative MR and ultrasound imaging, encouraging developments in non-invasive elastography, and emerging novel methods including photoacoustic imaging.

6 Review Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease. 2014

Stidham, R W / Lee, T C H / Higgins, P D R / Deshpande, A R / Sussman, D A / Singal, A G / Elmunzer, B J / Saini, S D / Vijan, S / Waljee, A K. ·Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA. ·Aliment Pharmacol Ther · Pubmed #24749763.

ABSTRACT: BACKGROUND: Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown. AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD. METHODS: After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17-2.36 and RR: 1.43, 95% CI: 1.17-1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51-2.09 and RR: 1.68, 95% CI: 1.46-1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21-7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients. CONCLUSIONS: All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.

7 Review Results of the 4th scientific workshop of the ECCO (Group II): markers of intestinal fibrosis in inflammatory bowel disease. 2014

Rieder, Florian / de Bruyn, Jessica R / Pham, Bao Tung / Katsanos, Konstantinos / Annese, Vito / Higgins, Peter D R / Magro, Fernando / Dotan, Iris. ·Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Gastroenterology & Hepatology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. Electronic address: riederf@ccf.org. · Academic Medical Center Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands. Electronic address: j.r.debruyn@amc.uva.nl. · Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, The Netherlands. Electronic address: b.t.pham@rug.nl. · Department of Gastroenterology, University Hospital of Ioannina, Medical School of Ioannina, Greece. Electronic address: khkostas@hotmail.com. · Division of Gastroenterology, University Hospital Careggi, Florence, Italy. Electronic address: annesev@aou-careggi.toscana.it. · Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. Electronic address: phiggins@med.umich.edu. · Department of Pharmacology & Therapeutics, Institute for Molecular and Cell Biology, Faculty of Medicine University of Porto, Porto, Portugal; Department of Gastroenterology, Hospital de Sao Joao, Porto, Portugal. Electronic address: fm@med.up.pt. · IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: irisd@tasmc.health.gov.il. ·J Crohns Colitis · Pubmed #24726695.

ABSTRACT: The fourth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on intestinal fibrosis in inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms and markers of intestinal fibrosis as well as to suggest new therapeutic targets to prevent or treat fibrosis. The results of this workshop are presented in three separate manuscripts. This section describes markers of fibrosis in IBD, identifies unanswered questions in the field and provides a framework for future studies addressing the unmet needs in the field of intestinal fibrosis.

8 Review Anti-adhesion therapies and the rule of 3 for rare events. 2013

Govani, Shail M / Waljee, Akbar K / Higgins, Peter D R. ·Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. ·Am J Gastroenterol · Pubmed #24300858.

ABSTRACT: During the open-label trial of natalizumab for Crohn's disease, an isolated case of progressive multifocal leukoencephalopathy (PML) was found. This prompted a more careful review by regulators, physicians, and the pharmaceutical industry. A new gut-specific monoclonal antibody, vedolizumab, has been shown to be effective in inflammatory bowel disease, and in continued trials no patients have developed PML. Given the mortality of PML and lack of effective treatments, patients may remain concerned that PML is a possible risk factor. So, going forward, how do we quantify the risk of this serious adverse event? This review details how we define the maximum risk when no (or very few) events have occurred with an easy-to-use equation.

9 Review How early to take arms against a sea of troubles? The case for aggressive early therapy in Crohn's disease to prevent fibrotic intestinal strictures. 2013

Govani, Shail M / Stidham, Ryan W / Higgins, Peter D R. ·Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, United States. ·J Crohns Colitis · Pubmed #23880128.

ABSTRACT: While potent anti-inflammatory medications have reduced the symptoms of Crohn's disease, more than 60% of patients eventually require surgery due to the development of fibrosis. Even after the introduction of biologic drugs, the population-based rate of surgery for Crohn's disease has not decreased. We suspect this is due to late initiation of these therapies, after the fibrosis cascade is unstoppable. We review the evidence that suggests early aggressive therapy is beneficial, especially in patients diagnosed before age 40, and with ileal or perianal disease. Patients with symptomatic strictures may benefit from early surgery (before penetrating complications) followed by initiation of biologics. With increased early use of biologics and better control of inflammation, we hope to see a global reduction in intestinal fibrosis and related complications of Crohn's disease.

10 Review Results of the 2nd scientific workshop of the ECCO (III): basic mechanisms of intestinal healing. 2012

Rieder, Florian / Karrasch, Thomas / Ben-Horin, Shomron / Schirbel, Anja / Ehehalt, Robert / Wehkamp, Jan / de Haar, Colin / Velin, Dominique / Latella, Giovanni / Scaldaferri, Franco / Rogler, Gerhard / Higgins, Peter / Sans, Miquel. ·Department of Gastroenterology & Hepatology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, USA. riederf@ccf.org ·J Crohns Colitis · Pubmed #22405177.

ABSTRACT: The second scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal healing for the disease course of inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms, markers for disease prediction, detection and monitoring of intestinal healing, impact of intestinal healing on the disease course of IBD as well as therapeutic strategies. The results of this workshop are presented in four separate manuscripts. This section describes basic mechanisms of intestinal healing, identifies open questions in the field and provides a framework for future studies.

11 Review The prognostic power of the NOD2 genotype for complicated Crohn's disease: a meta-analysis. 2011

Adler, Jeremy / Rangwalla, Sujal C / Dwamena, Ben A / Higgins, Peter D R. ·Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, MI, USA. jeradler@umich.edu ·Am J Gastroenterol · Pubmed #21343918.

ABSTRACT: OBJECTIVES: Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease. METHODS: An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years). RESULTS: The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95% CI) 1.10-1.24; P<0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95% CI 1.11-1.60; P=0.002). NOD2 did not predict perianal disease (P=0.4). The RR of surgery was 1.58 (95% CI 1.38-1.80; P<0.001). There was substantial heterogeneity across all studies (I(2)=66.7%). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73%, with the area under the receiver operating characteristic curve 0.56. CONCLUSIONS: The presence of a single NOD2 mutation predicted an 8% increase in the risk for complicated disease (B2 or B3), and a 41% increase with 2 mutations. Surgery risk is increased by 58% with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17% across 36 studies. However, the presence of two NOD2 mutations had 98% specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.

12 Review The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? 2011

D'Haens, Geert R / Panaccione, Remo / Higgins, Peter D R / Vermeire, Severine / Gassull, Miquel / Chowers, Yehuda / Hanauer, Stephen B / Herfarth, Hans / Hommes, Daan W / Kamm, Michael / Löfberg, Robert / Quary, A / Sands, Bruce / Sood, A / Watermeyer, G / Lashner, Bret / Lémann, Marc / Plevy, Scott / Reinisch, Walter / Schreiber, Stefan / Siegel, Corey / Targan, Stephen / Watanabe, M / Feagan, Brian / Sandborn, William J / Colombel, Jean Frédéric / Travis, Simon. ·Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands. g.dhaens@amc.uva.nl ·Am J Gastroenterol · Pubmed #21045814.

ABSTRACT: The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

13 Clinical Trial Development and Validation of Machine Learning Models in Prediction of Remission in Patients With Moderate to Severe Crohn Disease. 2019

Waljee, Akbar K / Wallace, Beth I / Cohen-Mekelburg, Shirley / Liu, Yumu / Liu, Boang / Sauder, Kay / Stidham, Ryan W / Zhu, Ji / Higgins, Peter D R. ·Michigan Integrated Center for Health Analytics and Medical Prediction, Ann Arbor. · VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, Michigan. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor. · Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor. · Department of Statistics, University of Michigan, Ann Arbor. ·JAMA Netw Open · Pubmed #31074823.

ABSTRACT: Importance: Biological therapies have revolutionized inflammatory bowel disease management, but many patients do not respond to biological monotherapy. Identification of likely responders could reduce costs and delays in remission. Objective: To identify patients with Crohn disease likely to be durable responders to ustekinumab before committing to long-term treatment. Design, Setting, and Participants: This cohort study analyzed data from 3 phase 3 randomized clinical trials (UNITI-1, UNITI-2, and IM-UNITI) conducted from 2011 to 2015. Participants (n = 401) were individuals with active (C-reactive protein [CRP] measurement of ≥5 mg/L at enrollment) Crohn disease who received ustekinumab therapy. Data analysis was performed from November 1, 2017, to June 1, 2018. Exposures: All included patients were exposed to 1 or more dose of ustekinumab for 8 weeks or more. Main Outcomes and Measures: Random forest methods were used in building 2 models for predicting Crohn disease remission, with a CRP level lower than 5 mg/dL as a proxy for biological remission, beyond week 42 of ustekinumab treatment. The first model used only baseline data, and the second used data through week 8. Results: In total, 401 participants, with a mean (SD) age of 36.3 (12.6) years and 170 male (42.4%), were included. The week-8 model had a mean area under the receiver operating characteristic curve (AUROC) of 0.78 (95% CI, 0.69-0.87). In the testing data set, 27 of 55 participants (49.1%) classified as likely to have treatment success achieved success with a CRP level lower than 5 mg/L after week 42, and 7 of 65 participants (10.8%) classified as likely to have treatment failure achieved this outcome. In the full cohort, 87 patients (21.7%) attained remission after week 42. A prediction model using the week-6 albumin to CRP ratio had an AUROC of 0.76 (95% CI, 0.71-0.82). Baseline ustekinumab serum levels did not improve the model's prediction performance. Conclusions and Relevance: In patients with active Crohn disease, demographic and laboratory data before week 8 of treatment appeared to allow the prompt identification of likely nonresponders to ustekinumab without the need for costly drug-level monitoring.

14 Clinical Trial Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study. 2019

Panés, Julián / D'Haens, Geert R / Higgins, Peter D R / Mele, Linda / Moscariello, Michele / Chan, Gary / Wang, Wenjin / Niezychowski, Wojciech / Su, Chinyu / Maller, Eric. ·Inflammatory Bowel Diseases Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Inflammation & Immunology, Pfizer Inc, Collegeville, Pennsylvania. ·Aliment Pharmacol Ther · Pubmed #30663107.

ABSTRACT: BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. AIMS: This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease. METHODS: Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks' fixed, open-label treatment. RESULTS: Sixty-two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non-responder imputation). Study design prevented between-dose efficacy comparisons. CONCLUSIONS: No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.

15 Clinical Trial Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study. 2017

Sands, Bruce E / Chen, Jingjing / Feagan, Brian G / Penney, Mark / Rees, William A / Danese, Silvio / Higgins, Peter D R / Newbold, Paul / Faggioni, Raffaella / Patra, Kaushik / Li, Jing / Klekotka, Paul / Morehouse, Chris / Pulkstenis, Erik / Drappa, Jörn / van der Merwe, René / Gasser, Robert A. ·Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: bruce.sands@mssm.edu. · MedImmune, Gaithersburg, Maryland. · Robarts Clinical Trials, University of Western Ontario, London, Ontario. · MedImmune, Cambridge, United Kingdom. · Humanitas Clinical and Research Center, Milan, Italy. · University of Michigan, Ann Arbor, Michigan. · MedImmune, Mountain View, California. · Amgen, Thousand Oaks, California. ·Gastroenterology · Pubmed #28390867.

ABSTRACT: BACKGROUND & AIMS: MEDI2070 is a human monoclonal antibody that selectively inhibits interleukin 23 (IL23), a cytokine implicated in the pathogenesis of Crohn's disease (CD). We analyzed its safety and efficacy in treatment of CD in a phase 2a study. METHODS: We conducted a double-blind, placebo-controlled study of 119 adults with moderate to severe CD failed by treatment with tumor necrosis factor antagonists. Patients were randomly assigned (1:1) to groups given MEDI2070 (700 mg) or placebo intravenously at weeks 0 and 4. Patients received open-label MEDI2070 (210 mg) subcutaneously every 4 weeks from weeks 12 to 112. The CD Activity Index was used to measure disease activity. RESULTS: The primary outcome, clinical response (either a 100-point decrease in CD Activity Index score from baseline or clinical remission, defined as CD Activity Index score <150) at week 8 occurred in 49.2% of patients receiving MEDI2070 (n = 59) compared with 26.7% receiving placebo (n = 60; absolute difference, 22.5%; 95% confidence interval, 5.6%-39.5%; P = .010). Clinical response at week 24 occurred in 53.8% of patients who continued to receive open-label MEDI2070 and in 57.7% of patients who had received placebo during the double-blind period and open-label MEDI2070 thereafter. The most common adverse events were headache and nasopharyngitis. Higher baseline serum concentrations of IL22, a cytokine whose expression is induced by IL23, were associated with greater likelihood of response to MEDI2070 compared with placebo. CONCLUSIONS: In a phase 2a trial of patients with moderate to severe Crohn's disease who had failed treatment with tumor necrosis factor antagonists, 8 and 24 weeks of treatment with MEDI2070 were associated with clinical improvement. ClinicalTrials.gov ID: NCT01714726.

16 Clinical Trial Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. 2017

Panés, Julian / Sandborn, William J / Schreiber, Stefan / Sands, Bruce E / Vermeire, Séverine / D'Haens, Geert / Panaccione, Remo / Higgins, Peter D R / Colombel, Jean-Frederic / Feagan, Brian G / Chan, Gary / Moscariello, Michele / Wang, Wenjin / Niezychowski, Wojciech / Marren, Amy / Healey, Paul / Maller, Eric. ·Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA. · Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany. · Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium. · Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Department of Medicine, University of Calgary, Calgary, Alberta, Canada. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. · Robarts Research Institute, London, Ontario, Canada. · Pfizer Inc, Collegeville, Pennsylvania, USA. · Pfizer Inc, Groton, Connecticut, USA. ·Gut · Pubmed #28209624.

ABSTRACT: OBJECTIVE: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD). DESIGN: We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. RESULTS: 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. CONCLUSIONS: Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. TRIAL REGISTRATION NUMBERS: NCT01393626 and NCT01393899.

17 Clinical Trial Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. 2012

Hueber, Wolfgang / Sands, Bruce E / Lewitzky, Steve / Vandemeulebroecke, Marc / Reinisch, Walter / Higgins, Peter D R / Wehkamp, Jan / Feagan, Brian G / Yao, Michael D / Karczewski, Marek / Karczewski, Jacek / Pezous, Nicole / Bek, Stephan / Bruin, Gerard / Mellgard, Bjoern / Berger, Claudia / Londei, Marco / Bertolino, Arthur P / Tougas, Gervais / Travis, Simon P L / Anonymous2870726. ·Novartis Institutes for BioMedical Research, Basel, Switzerland. wolfgang.hueber@novartis.com ·Gut · Pubmed #22595313.

ABSTRACT: OBJECTIVE: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. DESIGN: In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. RESULTS: 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). CONCLUSIONS: Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. CLINICAL TRIAL REGISTRATION: This trial was registered at ClinicalTrial.gov with the number NCT01009281.

18 Article Prevalence and Effect of Intestinal Infections Detected by a PCR-Based Stool Test in Patients with Inflammatory Bowel Disease. 2020

Limsrivilai, Julajak / Saleh, Zachary M / Johnson, Laura A / Stidham, Ryan W / Waljee, Akbar K / Govani, Shail M / Gutermuth, Brian / Brown, Alexandra M / Briggs, Emily / Rao, Krishna / Higgins, Peter D R. ·Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. · Division of Gastroenterology, Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. · VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA. · Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA. · Department of Internal Medicine, South Texas VA, San Antonio, TX, USA. · Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. · Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. phiggins@med.umich.edu. ·Dig Dis Sci · Pubmed #31981111.

ABSTRACT: 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.

19 Article Imaging Features Associated With Failure of Nonoperative Management of Intraabdominal Abscesses in Crohn Disease. 2019

Perl, Daniel / Waljee, Akbar K / Bishu, Shrinivas / Higgins, Peter D R / Wasnik, Ashish P / Stidham, Ryan W. ·Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. · VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, Michigan, USA. · Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA. · University of Michigan Medical School, Institute for Healthcare Policy and Innovation, Ann Arbor, Michigan, USA. · Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA. ·Inflamm Bowel Dis · Pubmed #31294779.

ABSTRACT: BACKGROUND: Intraabdominal abscess management decisions in the treatment of Crohn disease (CD) can be challenging. Our aim was to determine the effect of clinical, medication use, and imaging disease characteristics on the need for future surgical management. METHODS: A retrospective chart review was performed in patients with CD hospitalized for abscess confirmed by imaging between 2008 and 2016. Selection criteria included nonoperative management with intravenous antibiotics at the index hospitalization and a minimum of 2 years of follow up. Demographic, disease, and medication history were extracted from electronic medical records. Radiographic disease features were assessed by an expert abdominal radiologist, blinded to clinical data. The primary outcome was resection of the bowel segment involving the abscess within 2 years of index hospitalization. Cox proportional hazards regression and statistical methods were performed using SAS 9.4. RESULTS: Of the 121 patients meeting the selection criteria, 36.4% avoided surgery after 2 years of follow up. On adjusted multivariable analysis, disease-activity factors including bowel wall thickness (HR 3.08, 95% CL 1.20-6.21), disease length (HR 2.67, 95% CL 1.40-6.20), bowel dilation (HR 2.19, 95% CL 1.02-4.68), and abscess size of greater than 6 cm (HR 2.47, 95%CL 1.17-5.21) were independent risk factors for future surgery in patients not undergoing immediate bowel resection for abscess management. Biologic use and percutaneous drainage were not risk factors for ultimate surgical management. CONCLUSIONS: Radiographic CD features and abscess size over 6 cm are predictors of ultimately requiring bowel resection. Radiographic measures may help stratify patients to immediate surgery or conservative management for intraabdominal CD-related abscesses.

20 Article Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease. 2019

Wu, Jing / Lubman, David M / Kugathasan, Subra / Denson, Lee A / Hyams, Jeffrey S / Dubinsky, Marla C / Griffiths, Anne M / Baldassano, Robert N / Noe, Joshua D / Rabizadeh, Shervin / Gulati, Ajay S / Rosh, Joel R / Crandall, Wallace V / Higgins, Peter D R / Stidham, Ryan W. ·Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. · Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. · Division of Digestive Diseases, Hepatology, and Nutrition, Department of Pediatrics, Connecticut Children's Medical Center, Hartford, Connecticut, USA. · Department of Pediatrics, Division of Gastroenterology and Nutrition, Icahn School of Medicine, Mount Sinai New York, New York, USA. · Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, the Hospital for Sick Children, University of Toronto, Toronto, Canada. · Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Pennsylvania, Philadelphia, Pennsylvania, USA. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. · Division of Pediatric Gastroenterology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Division of Pediatric Gastroenterology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey, USA. · Division of Pediatric Gastroenterology, Department of Pediatrics, Nationwide Children's Hospital, the Ohio State University College of Medicine, Columbus, Ohio, USA. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. ·Am J Gastroenterol · Pubmed #31058681.

ABSTRACT: 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.

21 Article Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis. 2019

Imai, Jin / Kitamoto, Sho / Sugihara, Kohei / Nagao-Kitamoto, Hiroko / Hayashi, Atsushi / Morhardt, Tina L / Kuffa, Peter / Higgins, Peter D R / Barnich, Nicolas / Kamada, Nobuhiko. ·Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. · Department of Gastroenterology, Tokai University School of Medicine, Isehara, Kanagawa, Japan. · Research Laboratory, Miyarisan Pharmaceutical Co., Ltd., Tokyo, 114-0016, Japan. · Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA. · UMR1071 Inserm/University Clermont Auvergne, INRA USC2018, M2iSH, CRNH Auvergne, Clermont-Ferrand, France. · Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. nkamada@umich.edu. ·Mucosal Immunol · Pubmed #30742042.

ABSTRACT: Intestinal fibrosis is a severe complication in patients with Crohn's disease (CD). Unfortunately, the trigger leading to the development of intestinal fibrosis in the context of CD remains elusive. Here, we show that colonization by a CD-associated pathobiont adherent-invasive Escherichia coli (AIEC) promotes the development of intestinal fibrosis. Exogenously inoculated AIEC strain LF82 and commensal E. coli HS were gradually eradicated from the intestine in healthy mice. In Salmonella- or dextran sodium sulfate-induced colitis models, AIEC exploited inflammation and stably colonize the gut. Consequently, persistent colonization by AIEC LF82 led to substantial fibrosis. In contrast, commensal E. coli HS was unable to derive a growth advantage from inflammation, thereby failing to colonize the inflamed intestine or promote intestinal fibrosis. AIEC colonization potentiated the expression of the IL-33 receptor ST2 in the intestinal epithelium, which is crucial for the development of intestinal fibrosis. The induction of ST2 by AIEC LF82 was mediated by flagellin, as the ΔfliC mutant failed to induce ST2. These observations provide novel insights into pathobiont-driven intestinal fibrosis and can lead to the development of novel therapeutic approaches for the treatment of intestinal fibrosis in the context of CD that target AIEC and/or its downstream IL-33-ST2 signaling.

22 Article CD4+ Tissue-resident Memory T Cells Expand and Are a Major Source of Mucosal Tumour Necrosis Factor α in Active Crohn's Disease. 2019

Bishu, Shrinivas / El Zaatari, Mohammed / Hayashi, Atsushi / Hou, Guoqing / Bowers, Nicole / Kinnucan, Jami / Manoogian, Beth / Muza-Moons, Michelle / Zhang, Min / Grasberger, Helmut / Bourque, Charlie / Zou, Weiping / Higgins, Peter D R / Spence, Jason R / Stidham, Ryan W / Kamada, Nobuhiko / Kao, John Y. ·Division of Gastroenterology, Department of Medicine, University of Michigan, AnnArbor, MI, USA. · University of Michigan Crohn's and Colitis Program, University of Michigan, AnnArbor, MI, USA. · Tokyo R&D Center, Miyarisan Pharmaceutical, Tokyo, Japan. · Department of Surgery, University of Michigan, AnnArbor, MI, USA. · Department of Cell and Developmental Biology, University of Michigan, AnnArbor, MI, US. ·J Crohns Colitis · Pubmed #30715262.

ABSTRACT: BACKGROUND AND AIMS: Tumour necrosis factor [TNF]α- and IL-17A-producing T cells are implicated in Crohn's disease [CD]. Tissue-resident memory T [TRM] cells are tissue-restricted T cells that are regulated by PR zinc finger domain 1 [PRDM1], which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defence but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. METHODS: Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects. Flow cytometry and ex vivo assays were performed to characterise CD4+ TRM cells. RESULTS: CD4+ TRM cells are the most abundant memory T cell population and are the major T cell source of mucosal TNFα in CD. CD4+ TRM cells are expanded in CD and more avidly produce IL-17A and TNFα relative to control cells. There was a unique population of TNFα+IL-17A+ CD4+ TRM cells in CD which are largely absent in controls. PRDM1 was highly expressed by CD4+ TRM cells but not by other effector T cells. Suppression of PRDM1 was associated with impaired induction of IL17A and TNFA by CD4+ TRM cells. CONCLUSIONS: CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting that they are important in CD. PRDM1 is expressed by TRM cells and may regulate their function. Collectively, this argues for prospective studies tracking CD4+ TRM cells over the disease course.

23 Article Incidence and predictors of new persistent opioid use following inflammatory bowel disease flares treated with oral corticosteroids. 2019

Noureldin, Mohamed / Higgins, Peter D R / Govani, Shail M / Cohen-Mekelburg, Shirley / Kenney, Brooke C / Stidham, Ryan W / Waljee, Jennifer F / Waljee, Akbar K. ·Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan. · Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan. · Department of Internal Medicine, Division of Gastroenterology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. · Department of Surgery, University of Michigan, Ann Arbor, Michigan. · Michigan Opioid Prescribing Engagement Network, University of Michigan, Ann Arbor, Michigan. ·Aliment Pharmacol Ther · Pubmed #30430615.

ABSTRACT: BACKGROUND: Opioids are commonly prescribed to manage pain associated with inflammatory bowel disease (IBD). It is unknown what percentage of patients develop new persistent opioid use following a steroid-treated IBD flare. AIM: To identify the incidence and the predictors of new persistent opioid use following an IBD flare. METHODS: We used a national insurance claim dataset to identify patients with IBD who received an opioid medication around the time of a corticosteroid-treated IBD flare. Patients were stratified as previously opioid naïve, intermittent users, or chronic users. The incidence of persistent opioid use among the opioid-naïve cohort was evaluated along with associated predictors. RESULTS: We identified 15 119 IBD patients who received opioids around the time of a flare. 5411 (35.8%) were opioid-naïve patients of which 35.0% developed persistent opioid use after the flare. Factors associated with new persistent opioid use include a history of depression (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13-1.47), substance abuse (HR 1.36, 95% CI 1.2-1.54), chronic obstructive pulmonary disease (COPD) (HR 1.17, 95% CI 1.04-1.3), as well as, Crohn's disease (HR 1.26, 95% CI 1.14-1.4) or indeterminate colitis (HR 1.6, 95% CI 1.36-1.88). CONCLUSIONS: New persistent opioid use is common in IBD patients who experience a flare, especially among those with mental health disorders, COPD, and Crohn's disease or indeterminate colitis. These findings can be helpful in risk-stratifying patients when choosing an acute pain therapy and providing counselling before choosing to prescribe opioids to opioid-naïve patients experiencing an IBD flare.

24 Article Predicting Corticosteroid-Free Biologic Remission with Vedolizumab in Crohn's Disease. 2018

Waljee, Akbar K / Liu, Boang / Sauder, Kay / Zhu, Ji / Govani, Shail M / Stidham, Ryan W / Higgins, Peter D R. ·VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, MI, USA. · Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA. · Department of Statistics, University of Michigan, Ann Arbor, MI, USA. ·Inflamm Bowel Dis · Pubmed #29668915.

ABSTRACT: Background and Aims: Vedolizumab (VDZ) is effective for Crohn's disease (CD) but costly and is slow to produce remission. Early knowledge of whether vedolizumab is likely to succeed is valuable for physicians, patients, and insurers. Methods: Phase 3 clinical trial data on VZD for CD were used to predict outcomes. Random forest modeling on the training cohort was used to predict the outcome of corticosteroid-free biologic remission at week 52 on the testing cohort. Models were constructed using baseline data, or data through week 6 of VDZ therapy. Results: The clinical trial included 594 subjects who received VDZ with baseline active inflammation [elevated C-reactive protein (>5 mg/L)]. Subjects with missing predictor variables (N = 120) or missing outcome data (N = 2) were excluded to produce a modeling dataset of 472 subjects. The Area Under the Receiver Operating Characteristic curve (AuROC) for corticosteroid-free biologic remission at week 52 using baseline data was only 0.65 (95% CI: 0.53 - 0.77), but was 0.75 (95% CI: 0.64 - 0.86) with data through week 6 of VDZ . Patients predicted to be in corticosteroid-free biologic remission at week 52 by the model achieved this endpoint 35.8% of the time, whereas patients predicted to fail only succeeded 6.7% of the time. Conclusions: An algorithm using laboratory data through week 6 of VDZ therapy was able to identify which CD patients with baseline inflammation would achieve corticosteroid-free biologic remission on VDZ at week 52. A majority of patients can be identified by week 6 as very unlikely to achieve remission.

25 Article Development and validation of the Crohn's disease patient-reported outcomes signs and symptoms (CD-PRO/SS) diary. 2017

Higgins, Peter D R / Harding, Gale / Leidy, Nancy K / DeBusk, Kendra / Patrick, Donald L / Viswanathan, Hema N / Fitzgerald, Kristina / Donelson, Sarah M / Cyrille, Marcoli / Ortmeier, Brian G / Wilson, Hilary / Revicki, Dennis A / Globe, Gary. ·1University of Michigan, Ann Arbor, MI USA. · 0000000086837370 · grid.214458.e · 6IBD Program University of Michigan, SPC 5682, 1650 West Medical Center Drive, Ann Arbor, MI 48109 USA. · 2Evidera, Bethesda, MD USA. · 0000 0004 0510 2209 · grid.423257.5 · 3Genentech Inc., South San Francisco, CA USA. · 0000 0004 0534 4718 · grid.418158.1 · 4University of Washington, Seattle, WA USA. · 0000000122986657 · grid.34477.33 · 5Amgen Inc., Thousand Oaks, CA USA. · 0000 0001 0657 5612 · grid.417886.4 · 7Present address: Allergan Inc., Irvine, CA USA. · 0000 0004 0413 7987 · grid.417882.0 ·J Patient Rep Outcomes · Pubmed #29770803.

ABSTRACT: Background: The clinical course of Crohn's disease (CD) and the effect of its treatment are monitored through patient-reported signs and symptoms (S&S), and endoscopic evidence of inflammation. The Crohn's Disease Patient-reported Outcomes Signs and Symptoms (CD-PRO/SS) measure was developed to standardize the quantification of gastrointestinal S&S of CD through direct report from patient ratings. Methods: The CD-PRO/SS was developed based on data from concept elicitation (focus groups, interviews; Results: Findings from qualitative interviews identified nine S&S items covering bowel and abdominal symptoms. The final CD-PRO/SS daily diary includes two scales: Bowel S&S (three items) and Abdominal Symptoms (three items), each scored separately. Each scale showed evidence of adequate reliability (α = 0.74 and 0.67, respectively); reproducibility (intraclass correlation coefficient > 0.80), and validity, with the last including moderate correlations with the Inflammatory Bowel Disease Questionnaire bowel symptom score and select items (ranging from Conclusions: Results suggest the CD-PRO/SS is a reliable and valid measure of gastrointestinal symptom severity in CD patients. Additional longitudinal data are needed to evaluate the ability of the CD-PRO/SS scores to detect responsiveness and inform the selection of responder definitions.

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