Publications by authors named "Stephen B Hanauer"

289 Publications

5-ASAs Combined With a Biologic or Tofacitinib: Predetermined Cost-Effectiveness?

Am J Gastroenterol 2021 09;116(9):1958-1959

Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.14309/ajg.0000000000001296DOI Listing
September 2021

Low-dose Methotrexate Therapy Does Not Affect Semen Parameters and Sperm DNA.

Inflamm Bowel Dis 2021 Aug 31. Epub 2021 Aug 31.

Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Background: Methotrexate is widely used in inflammatory diseases during the patients' reproductive years. The effect on male fertility and sperm DNA integrity is largely unknown. We evaluated sperm DNA integrity and basic semen parameters according to the World Health Organization (WHO) in male patients with inflammatory diseases treated with methotrexate.

Methods: Semen samples from 14 patients on low-dose maintenance methotrexate were compared with samples from 40 healthy volunteers. Further, 5 patients delivered samples on and off methotrexate therapy for paired comparison. Sperm DNA fragmentation index (DFI), concentration, motility, and morphology were evaluated. Blood sex hormones and methotrexate levels were measured in blood and semen.

Results: DNA fragmentation index in methotrexate-treated patients was comparable with that in healthy volunteers (DFI, 11.5 vs 15.0; P = .06), and DFI did not change significantly on and off methotrexate in the paired samples (DFI, 12.0 vs 14.0; P = 0.35). Sperm concentration, motility, and morphology did not differ between men treated with methotrexate and healthy volunteers. Sperm progressive motility increased off therapy compared with on therapy (65.0% vs 45.0%, P = .04), but all fluctuations in progressive motility were within the WHO reference interval. All methotrexate polyglutamates1-5 were detected in blood, but only methotrexate polyglutamate1 in semen. Serum testosterone was unaffected by methotrexate therapy.

Conclusions: Patients treated with low-dose methotrexate have a sperm quality comparable with that of healthy volunteers, and methotrexate treatment does not increase sperm DNA fragmentation. This study does not support cryopreservation of semen before treatment initiation nor a 3-month methotrexate-free interval prior to conception.
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http://dx.doi.org/10.1093/ibd/izab205DOI Listing
August 2021

Epidemiology of Colorectal Cancer in Inflammatory Bowel Disease - the Evolving Landscape.

Curr Gastroenterol Rep 2021 Aug 2;23(9):16. Epub 2021 Aug 2.

Feinberg School of Medicine, Northwestern University, 676 N Saint Clair, Chicago, IL, 60611, USA.

Purpose Of Review: To update changes in the epidemiology of colorectal cancer in patients with ulcerative colitis and Crohn's disease over the past decades.

Recent Findings: Since the mid twentieth century, studies have found that the incidence of colorectal cancer in patients with IBD has been greater than that of the general population, especially for patients with a family history of colorectal cancer, a diagnosis of primary sclerosing cholangitis, and/or pancolitis. While Crohn's disease and ulcerative colitis are still associated with a risk of colorectal cancer, current treatment approaches and surveillance measures have markedly reduced the risk according to population-based cohort studies such that the risk is now more comparable to that of the general population. It is predicted that by 2025, more than two million patients will be living with inflammatory bowel disease in the United States. As advanced treatment options become available to achieve histologic remissions and as surveillance techniques to detect neoplasia improve, guidelines for surveillance will continue to evolve.
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http://dx.doi.org/10.1007/s11894-021-00816-3DOI Listing
August 2021

Patient Perspectives on Medical Trauma Related to Inflammatory Bowel Disease.

J Clin Psychol Med Settings 2021 Jul 22. Epub 2021 Jul 22.

Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 1400, Chicago, IL, 60611, USA.

Post-traumatic stress symptoms (PTSS) in response to medical trauma are understudied in inflammatory bowel disease (IBD). Two studies identify surgery, hospitalizations, and disease severity as risk factors. We aimed to document IBD-related patient experiences and how these relate to PTSS via a qualitative study. Adult patients with confirmed IBD recruited from two gastroenterology clinics underwent a semi-structured interview with a psychologist and completed the Post Traumatic Stress Disorder Symptom Scale for DSM5 (PSSI-5). Interviews were analyzed using an interpretive phenomenological approach. Themes and subthemes with representative quotations were documented based on thematic saturation. 16 participants, five met PSSI-5 criteria for PTSD. Five themes emerged: disease uncertainty, information exchange/quality, medical procedures, surgery, and coping. Patients with IBD may experience medical PTSS from several sources. Information, communication, and trust in clinicians is vital but may be sub-optimal. Both adaptive and maladaptive coping strategies are used to mitigate PTSS.
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http://dx.doi.org/10.1007/s10880-021-09805-0DOI Listing
July 2021

Which Diet for Crohn's Disease? Food for Thought on the Specific Carbohydrate Diet, Mediterranean Diet, and Beyond.

Gastroenterology 2021 Sep 30;161(3):798-800. Epub 2021 Jun 30.

Northwestern University Feinberg School of Medicine, Digestive Health Center, Northwestern Medicine, Chicago, Illinois. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.06.058DOI Listing
September 2021

Posttraumatic Stress in Patients With Inflammatory Bowel Disease: Prevalence and Relationships to Patient-Reported Outcomes.

Inflamm Bowel Dis 2021 Jun 17. Epub 2021 Jun 17.

Northwestern University Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA.

Background: Patients with chronic illness are at increased risk for traumatic stress because of medical trauma. Initial studies of posttraumatic stress (PTS) in patients with inflammatory bowel disease (IBD) have found that approximately one-third of patients may experience significant PTS symptoms including flashbacks, nightmares, hypervigilance, disrupted sleep, and low mood. We aim to better characterize PTS in IBD and its relationship with patient outcomes in a large cohort of patients with IBD.

Methods: Adult patients registered with the Crohn's & Colitis Foundation/University of North Carolina IBD Partners database were invited to complete a supplementary survey between February and July 2020. The Post Traumatic Stress Disorder Checklist-5th edition was administered as a supplemental survey. Additional data from IBD Partners included disease severity, surgery and hospital history, demographics, and health care utilization.

Results: A total of 797 patients participated (452 with Crohn disease, 345 with ulcerative colitis). No impacts on response patterns because of the COVID-19 pandemic were found. Although 5.6% of the sample reported an existing PTS diagnosis because of IBD experiences, 9.6% of participants met the full IBD-related PTS diagnostic criteria per the Post Traumatic Stress Disorder Checklist-5th edition. Female patients, younger patients, those with less educational attainment, non-White patients, and Hispanic patients reported higher levels of PTS symptoms. Patients with higher PTS symptoms were more likely to have been hospitalized, have had surgery, have more severe symptoms, and not be in remission. Increased PTS was also associated with increased anxiety, depression, pain interference, fatigue, and health care utilization.

Conclusions: The present findings support prior research that approximately one-quarter to one-third of patients with IBD report significant symptoms of PTS directly from their disease experiences, and certain demographic groups are at higher risk. In addition, PTS is associated with several IBD outcomes. Patients with higher PTS symptoms are less likely to be in remission and may utilize more outpatient gastrointestinal services. Intervention trials to mitigate PTS symptoms in patients with IBD are warranted.
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http://dx.doi.org/10.1093/ibd/izab152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344426PMC
June 2021

Neutrophils Alter DNA Repair Landscape to Impact Survival and Shape Distinct Therapeutic Phenotypes of Colorectal Cancer.

Gastroenterology 2021 Jul 19;161(1):225-238.e15. Epub 2021 Mar 19.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Background & Aims: Tumor-infiltrating neutrophils (polymorphonuclear neutrophils [PMNs]) are a prominent feature of colorectal cancer (CRC), where they can promote cytotoxicity or exacerbate disease outcomes. We recently showed that in acute colon injury, PMNs can increase DNA double-strand break (DSB) burden and promote genomic instability via microRNA-dependent inhibition of homologous recombination (HR) repair. In this study, we aimed to establish whether in inflamed colon, neutrophils shape the DSB-repair responses to impact CRC progression and sensitivity/resistance to DNA-repair targeted therapy.

Methods: Human sporadic CRC biopsies, The Cancer Genome Atlas gene expression analyses, tumor xenografts, and murine CRC models, as well as small-molecule inhibition of key DSB-repair factors were leveraged to investigate changes in the DSB-repair landscape and identify unique CRC responses with/without tumor infiltration by PMNs.

Results: We reveal that neutrophils exert a functional dualism in cancer cells, driving temporal modulation of the DNA damage landscape and resolution of DSBs. PMNs were found to promote HR deficiency in low-grade CRC by miR-155-dependent downregulation of RAD51, thus attenuating tumor growth. However, neutrophil-mediated genotoxicity due to accumulation of DSBs led to the induction of non-homologous end-joining (NHEJ), allowing for survival and growth of advanced CRC. Our findings identified a PMN-induced HR-deficient CRC phenotype, featuring low RAD51 and low Ku70 levels, rendering it susceptible to synthetic lethality induced by clinically approved PARP1 inhibitor Olaparib. We further identified a distinct PMN-induced HR-deficient CRC phenotype, featuring high Ku70 and heightened NHEJ, which can be therapeutically targeted by specific inhibition of NHEJ.

Conclusions: Our work delineates 2 mechanism-based translatable therapeutic interventions in sporadic CRC.
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http://dx.doi.org/10.1053/j.gastro.2021.03.027DOI Listing
July 2021

Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial.

Clin Gastroenterol Hepatol 2021 Feb 19. Epub 2021 Feb 19.

Janssen Research & Development, LLC, Spring House, Pennsylvania.

Background & Aims: The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years.

Methods: Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively.

Results: Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE.

Conclusions: Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.
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http://dx.doi.org/10.1016/j.cgh.2021.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374005PMC
February 2021

Executive Summary of 'Development of Entrustable Professional Activities for Advanced Inflammatory Bowel Disease Fellowship Training in the United States'.

Am J Gastroenterol 2020 09;115(9):1362-1366

Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.14309/ajg.0000000000000809DOI Listing
September 2020

Development of Entrustable Professional Activities for Advanced Inflammatory Bowel Disease Fellowship Training in the United States.

Inflamm Bowel Dis 2020 08;26(9):1291-1305

Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: The level of inflammatory bowel disease (IBD) training in general gastroenterology fellowship is often insufficient to prepare trainees to deliver advanced IBD care in practice. Advanced IBD fellowships have been developed to fill this training gap, but there is no established curriculum, and significant variability exists across programs. Entrustable professional activities (EPAs) are practical and realistic objectives that define essential tasks of a specialty that physicians should master to be competent during independent practice. The American College of Gastroenterology (ACG) and Crohn's & Colitis Foundation (Foundation) established a task force to develop and appraise EPAs for advanced IBD fellowship.

Methods: Entrustable professional activities were developed using a multistep approach in a similar manner to other specialties. Initial EPAs identified via focus groups were evaluated, critiqued, and changed using an iterative model of feedback. The final EPAs were selected after the task force conducted a 3-phase modified Delphi method consisting of 2 sequential rounds of web-based voting and an in-person consensus meeting.

Results: Ten EPAs for advanced IBD fellowship were established including detailed descriptions with the associated knowledge, skills, and attitudes for each that can serve as curricular milestones.

Conclusion: Ten EPAs describing the core work of an advanced IBD fellowship-trained physician have been established by a multisociety task force. Creating EPAs for an advanced curriculum comes with unique challenges, particularly the need to prevent duplication of prior training competencies while demonstrating the potential for unique milestones.
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http://dx.doi.org/10.1093/ibd/izaa177DOI Listing
August 2020

Association between inflammatory bowel disease and prostate cancer: A large-scale, prospective, population-based study.

Int J Cancer 2020 11 29;147(10):2735-2742. Epub 2020 May 29.

Department of Epidemiology and Biostatistics, University of California San Francisco (UCSF), San Francisco, California, USA.

Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218 084 men in the population-based UK Biobank cohort, aged 40 to 69 at study entry between 2006 and 2010, with follow-up through mid-2015. We assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of PC and previous prostate-specific antigen testing. Mean age at study entry was 56 years, 94% of the men were white, and 1.1% (n = 2311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.03-1.67, P = .029). The association with PC was only among men with the ulcerative colitis (UC; aHR = 1.47, 95% CI = 1.11-1.95, P = .0070), and not Crohn's disease (aHR 1.06, 95% CI = 0.63-1.80, P = .82). Results are limited by lack of data on frequency of health care interactions. In a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis.
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http://dx.doi.org/10.1002/ijc.33048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577830PMC
November 2020

Segmental Histological Normalisation Occurs in Ulcerative Colitis but Does Not Improve Clinical Outcomes.

J Crohns Colitis 2020 Oct;14(10):1345-1353

Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA.

Background And Aims: Complete histological normalisation and reduction of inflammation severity in patients with ulcerative colitis are associated with improved clinical outcomes, but the clinical significance of normalisation of only segments of previously affected bowel is not known. We examined the prevalence, pattern, predictors, and clinical outcomes associated with segmental histological normalisation in in patients with ulcerative colitis.

Methods: Medical records of patients with confirmed ulcerative colitis and more than one colonoscopy were sought. Segmental histological normalisation was defined as histological normalisation of a bowel segment [rectum, left-sided or right-sided colon] that had previous evidence of chronic histological injury. We assessed the variables influencing these findings and whether segmental normalisation was associated with improved clinical outcomes.

Results: Of 646 patients, 32% had segmental and 10% complete histological normalisaton when compared with their maximal disease extent. Most [88%] had segmental normalisation in a proximal-to-distal direction. Others had distal-to-proximal or patchy normalisation. On multivariate analysis, only current smoking [p = 0.040] and age of diagnosis ≤16 years [p = 0.028] predicted segmental histological normalisation. Of 310 who were in clinical remission at initial colonoscopy, 77 [25%] experienced clinical relapse after median 1.3 [range 0.06-7.52] years. Only complete histological normalisation of the bowel was associated with improved relapse-free survival (hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.08-0.68; p = 0.008].

Conclusions: Segmental histological normalisation occurs in 32% of patients with ulcerative colitis and is increased in those who smoke or were diagnosed at younger age. Unlike complete histological normalisation, segmental normalisation does not signal improved clinical outcomes.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533894PMC
October 2020

Time to Symptom Resolution in Ulcerative Colitis With Multimatrix Mesalazine Treatment: A Pooled Analysis.

J Crohns Colitis 2020 Sep;14(9):1274-1281

Shire, Basingstoke, UK.

Background And Aims: Patients with ulcerative colitis [UC] require rapid and complete relief of symptoms, particularly stool frequency and rectal bleeding. The aim of this study was to determine time to symptom resolution in patients with UC during induction treatment with multimatrix mesalazine, and the proportion of patients remaining symptom-free and in endoscopic remission after 12 months of maintenance.

Methods: A pooled analysis of 5 pivotal clinical trials, including >1300 patients, evaluating multimatrix mesalazine for treatment of mild-to-moderate active UC was conducted. Time to symptom resolution was defined as the period between first drug dosage date and first 3 consecutive days of induction therapy when the patient achieved a score of 0 [normal] on a modified UC Disease Activity Index for stool frequency and/or rectal bleeding.

Results: Median [95% confidence interval] time to resolution of stool frequency was 52 (45-not estimable [NE]) days for placebo versus 38 [34-41] days for multimatrix mesalazine [combined dose groups, 2.4 or 4.8 g/day]; time to resolution of rectal bleeding was 35 [20-NE] days for placebo versus 15 [14-17] days for multimatrix mesalazine [combined dose groups]. Among those who achieved resolution of both stool frequency and rectal bleeding during induction, 67.4% maintained symptom scores of 0 at Month 12. No relationship was observed between rapidity of symptom resolution during induction treatment and achievement of endoscopic remission at Month 12.

Conclusions: Induction with multimatrix mesalazine provided rapid and prolonged symptom resolution in addition to endoscopic remission at Month 12.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa041DOI Listing
September 2020

Early vs Late Use of Anti-TNFa Therapy in Adult Patients With Crohn Disease: A Systematic Review and Meta-Analysis.

Inflamm Bowel Dis 2020 11;26(12):1808-1818

Northwestern University Feinberg School of Medicine, Internal Medicine Department, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA.

Objectives: While anti-tumor necrosis factor alpha (anti-TNFa) therapies for Crohn disease (CD) were initially introduced in 1998 for biologic therapies are often introduced after a minimum of 6 years after diagnosis. The benefit of anti-TNFa early in the course of CD is still controversial, with some studies showing better outcomes but others not. To determine whether earlier introduction of anti-TNFa therapy improves efficacy in clinical trials or clinical series, we aimed to perform a meta-analysis comparing early vs late anti-TNFa use in the management of CD.

Methods: A comprehensive search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus was conducted from each database's inception to November 3, 2019. We included comparative studies of early vs late use of anti-TNFa therapy in adult patients with CD.

Results: Eleven studies were included in the analysis, with a total of 2501 patients. Meta-analysis demonstrated that the early use of anti-TNFa was associated with a statistically significant decrease in the need for surgery (relative risk [RR] = 0.43; 95% confidence interval [CI], 0.26-0.69; I2 = 68%) and disease progression (RR = 0.51; 95% CI, 0.35-0.75; I2 = 61%). Early use also showed an increase in early remission (RR = 1.94; 95% CI, 1.54-2.46; I2 = 0%) and clinical response. There was no statistically significant difference in achieving late remission (RR = 1.39; 95% CI, 0.94-2.05; I2 = 65%) or mucosal healing (RR = 1.10; 95% CI, 0.63-1.91; I2 = 0%).

Conclusion: This systematic review suggests that using anti-TNFa earlier in the treatment of CD (within 3 years) may improve clinical outcomes compared to late administration in terms of achieving early clinical remission, clinical response, disease progression, and the need for surgery.
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http://dx.doi.org/10.1093/ibd/izaa031DOI Listing
November 2020

One man's trash-another man's treasure: fecal transplantation.

Hepatobiliary Surg Nutr 2019 Dec;8(6):623-625

Digestive Health Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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http://dx.doi.org/10.21037/hbsn.2019.06.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943020PMC
December 2019

Reply to critique of "A randomized trial of the effects of the no-carrageenan diet on ulcerative colitis disease activity".

Nutr Healthy Aging 2019 23;5(2):159-163. Epub 2019 Sep 23.

Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

This article is an invited response to a critique by industry of our published study about the impact of carrageenan supplement on the interval to relapse in ulcerative colitis patients on a no-carrageenan diet.
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http://dx.doi.org/10.3233/NHA-190068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951440PMC
September 2019

The Evolving Role of Thiopurines in Inflammatory Bowel Disease.

Curr Treat Options Gastroenterol 2019 Dec;17(4):435-448

Northwestern University, Chicago, IL, USA.

Purpose Of Review: With the advent of biologic therapies for the treatment of IBD, the roles of thiopurines have continued to evolve. This review will focus on recent advances in pharmacology and the safety and efficacy of thiopurines as maintenance therapies for steroid-induced remissions, post-surgical maintenance of remission, and as combination therapies to reduce immunogenicities of biologic agents.

Recent Findings: Due to pharmacogenetics of TPMT, thiopurine dosing is more effectively based on monitoring of thiopurine metabolites rather than weight-based dosing. Thiopurines continue to have a role as maintenance therapy after steroid-induced remissions and in combination with biologics to induce and maintain remission. Safety monitoring includes measurements of blood counts, liver chemistries, as well as dermatologic evaluations and protection from sun exposure. Thiopurines appear to be safe during pregnancies and while very uncommon, lymphomas (including hepatosplenic T cell lymphomas) remain a recognized risk, particularly in younger and older males.
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http://dx.doi.org/10.1007/s11938-019-00249-yDOI Listing
December 2019

The Evolving Role of Thiopurines in Inflammatory Bowel Disease.

Curr Treat Options Gastroenterol 2019 Sep;17(3):420-433

Northwestern University, Chicago, IL, USA.

Purpose Of Review: With the advent of biologic therapies for the treatment of inflammatory bowel disease, the roles of thiopurines have continued to evolve. This review will focus on recent advances in pharmacology and the safety and efficacy of thiopurines as maintenance therapies for steroid-induced remissions and post-surgical maintenance of remission and as combination therapies to reduce immunogenicities of biologic agents.

Recent Findings: Due to pharmacogenetics of thiopurine S-methyltransferase, thiopurine dosing is more effectively based on monitoring of thiopurine metabolites rather than weight-based dosing. Thiopurines continue to have a role as maintenance therapy after steroid-induced remissions and in combination with biologics to induce and maintain remission. Safety monitoring includes measurements of blood counts, liver chemistries, and dermatologic evaluations and protection from sun exposure. Thiopurines appear to be safe during pregnancies and while very uncommon, lymphomas (including hepatosplenic T cell lymphomas) remain a recognized risk, particularly in younger and older males.
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http://dx.doi.org/10.1007/s11938-019-00244-3DOI Listing
September 2019

IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn's Disease.

J Crohns Colitis 2020 Jan;14(1):23-32

NIHR Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK.

Background And Aims: Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported.

Methods: At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits.

Results: Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%].

Conclusions: Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355.
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http://dx.doi.org/10.1093/ecco-jcc/jjz110DOI Listing
January 2020

Initial Assessment of Post-traumatic Stress in a US Cohort of Inflammatory Bowel Disease Patients.

Inflamm Bowel Dis 2019 08;25(9):1577-1585

Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Post-traumatic stress (PTS), or the psycho-physiological response to a traumatic or life-threatening event, is implicated in medical patient outcomes. Emerging evidence suggests a complex relationship between PTS, the brain-gut axis, the gut microbiome, and immune function. Inflammatory bowel disease (IBD) may be susceptible to PTS and its subsequent impacts. To date, no study has evaluated PTS in IBD in the United States.

Methods: Adult patients with IBD were recruited from an outpatient gastroenterology practice, via social media, and via a research recruitment website. Patients with irritable bowel syndrome (IBS) were recruited as a comparison group. Participants completed demographic and disease information, surgical and hospitalization history, and the PTSD Checklist-Civilian Version (PCL-C). Statistical analyses evaluated rates of PTS in IBD and IBS, including differences between groups for PTS severity. Regression analyses determined potential predictors of PTS.

Results: One hundred eighty-eight participants (131 IBD, 57 IBS) completed the study. Thirty-two percent of IBD and 26% of IBS patients met the criteria for significant PTS symptoms based on PCL-C cutoffs. Inflammatory bowel disease patients are more likely to attribute PTS to their disease than IBS patients. Crohn's disease (CD) patients appear to be the most likely to experience PTS, including those being hospitalized or undergoing ileostomy surgery. Symptom severity is the greatest predictor of PTS for ulcerative colitis and IBS.

Conclusions: Although PTS is relevant in both IBS and IBD, IBD patients are seemingly more susceptible to PTS due their disease experiences, especially CD patients. The nature of PTS symptoms may contribute to IBD disease processes, most notably through sleep disturbance and ANS arousal. Clinicians should assess for PTS in IBD patients as standard of care, especially after a hospitalization or surgery.
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http://dx.doi.org/10.1093/ibd/izz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534390PMC
August 2019

Too Soon to Discard 5-ASAs?

Am J Gastroenterol 2019 03;114(3):534-535

Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.14309/ajg.0000000000000122DOI Listing
March 2019

Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing.

J Clin Invest 2019 02 14;129(2):712-726. Epub 2019 Jan 14.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBDs). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified what we believe is a new, ROS-independent mechanism whereby activated tissue-infiltrating PMNs release microparticles armed with proinflammatory microRNAs (miR-23a and miR-155). Using IBD clinical samples, and in vitro and in vivo injury models, we show that PMN-derived miR-23a and miR-155 promote accumulation of double-strand breaks (DSBs) by inducing lamin B1-dependent replication fork collapse and inhibition of homologous recombination (HR) by targeting HR-regulator RAD51. DSB accumulation in injured epithelium led to impaired colonic healing and genomic instability. Targeted inhibition of miR-23a and miR-155 in cultured intestinal epithelial cells and in acutely injured mucosa decreased the detrimental effects of PMNs and enhanced tissue healing responses, suggesting that this approach can be used in therapies aimed at resolution of inflammation, in wound healing, and potentially to prevent neoplasia.
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http://dx.doi.org/10.1172/JCI122085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355304PMC
February 2019

More Than a Tumor Marker…A Potential Role for Alpha-Feto Protein in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2019 06;25(7):1271-1276

Northwestern University, Feinberg School of Medicine, Chicago Illinois.

Background: Human alpha-fetoprotein (hAFP) is a glycoprotein derived from the gut entoderm and expressed sequentially by cells of the yolk sac, fetal liver, and gastrointestinal tract. By adulthood, serum levels of alpha-fetoprotein (AFP) are undetectable in healthy, nonpregnant adults. Despite the clinical utilities of AFP monitoring in pregnancy and malignancy, much remains to be determined regarding its potential physiological functions.

Methods: We focused on literature related to AFP's immunoregulatory role and its ability to modulate disease activity both in animal models of autoimmune disorders and in human clinical studies.

Results: Evidence suggests that AFP plays an important role in immunoregulation by inducing T-cell suppressor activity, downregulating dendritic-like cell antigen expression, and impairing the function of macrophages. Studies evaluating AFP and its effects in rodent models of autoimmune diseases have shown that AFP is associated with downregulation of inflammation. Observations in studies of pregnant patients with immune-mediated inflammatory diseases have also described potential correlations between AFP expression and disease activity during different stages of pregnancy and postpartum.

Conclusions: We propose further prospective evaluations of AFP expression during pregnancy in inflammatory bowel disease patients to further correlate with disease activity and consider the potential of AFP as a novel therapeutic agent.
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http://dx.doi.org/10.1093/ibd/izy394DOI Listing
June 2019

Inflammatory Bowel Disease and the Risk of Prostate Cancer.

Eur Urol 2019 05 4;75(5):846-852. Epub 2018 Dec 4.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Background: There are limited data examining the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD).

Objective: To compare the incidence of PCa between men with and those without IBD.

Design, Setting, And Participants: This was a retrospective, matched-cohort study involving a single academic medical center and conducted from 1996 to 2017. Male patients with IBD (cases=1033) were randomly matched 1:9 by age and race to men without IBD (controls=9306). All patients had undergone at least one prostate-specific antigen (PSA) screening test.

Outcome Measurements And Statistical Analysis: Kaplan-Meier and multivariable Cox proportional hazard models, stratified by age and race, evaluated the relationship between IBD and the incidence of any PCa and clinically significant PCa (Gleason grade group ≥2). A mixed-effect regression model assessed the association of IBD with PSA level.

Results And Limitations: PCa incidence at 10yr was 4.4% among men with IBD and 0.65% among controls (hazard ratio [HR] 4.84 [3.34-7.02] [3.19-6.69], p<0.001). Clinically significant PCa incidence at 10yr was 2.4% for men with IBD and 0.42% for controls (HR 4.04 [2.52-6.48], p<0.001). After approximately age 60, PSA values were higher among patients with IBD (fixed-effect interaction of age and patient group: p=0.004). Results are limited by the retrospective nature of the analysis and lack of external validity.

Conclusions: Men with IBD had higher rates of clinically significant PCa when compared with age- and race-matched controls.

Patient Summary: This study of over 10000 men treated at a large medical center suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population.
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http://dx.doi.org/10.1016/j.eururo.2018.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542355PMC
May 2019

Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis.

Clin Gastroenterol Hepatol 2019 07 26;17(8):1525-1532.e1. Epub 2018 Sep 26.

Department of Medicine, Digestive Health Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.

Background & Aims: Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics.

Methods: We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared.

Results: Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy.

Conclusion: Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.
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http://dx.doi.org/10.1016/j.cgh.2018.09.033DOI Listing
July 2019

Evolving Considerations for Thiopurine Therapy for Inflammatory Bowel Diseases-A Clinical Practice Update: Commentary.

Gastroenterology 2019 01 7;156(1):36-42. Epub 2018 Sep 7.

Division of Gastroenterology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Thiopurines (azathioprine, mercaptopurine, thioguanine) and methotrexate are widely used in a variety of clinical management scenarios for ulcerative colitis and Crohn's disease. With the introduction of biologic therapies over the last 2 decades, controversies have emerged as to how these immunomodulators should be used in clinical practice, either alone as monotherapies or in combination with biologic therapies. Here, we provide a summary of evidence and our interpretations regarding how physicians can or should incorporate these agents into clinical practice. We have organized the review into sections regarding their utility as monotherapy or as combination therapy with biologics and safety considerations. Clinical pharmacologic considerations are important regarding both efficacy and safety.
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http://dx.doi.org/10.1053/j.gastro.2018.08.043DOI Listing
January 2019

Improving IBD Care: A Personalized Approach to Management.

Gastroenterol Hepatol (N Y) 2018 Mar;14(3):1-20

Clifford Joseph Barborka Professor of Medicine Medical Director, Digestive Health Center Northwestern University Feinberg School of Medicine Chicago, Illinois.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018320PMC
March 2018

Efficacy and Follow-up of Segmental or Subtotal Colectomy in Patients With Colitis-Associated Neoplasia.

Clin Gastroenterol Hepatol 2019 01 8;17(1):205-206. Epub 2018 May 8.

Inflammatory Bowel Disease Center, Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, Illinois. Electronic address:

The historical approach to neoplasia in the setting of chronic colitis was to perform a total proctocolectomy. Recent consensus and society guidelines suggest that when dysplastic lesions can be removed endoscopically, continued surveillance is appropriate. This is based on improvements in optical technologies and the low risk of metachronous colorectal carcinoma in these patients. We hypothesized that if a lesion was completely removed surgically and followed up endoscopically, metachronous colorectal carcinoma would be a rare occurrence. Thus, segmental resection may be offered as a definitive surgery in patients with chronic colitis and localized colorectal neoplasia in whom endoscopic resection is not feasible. Retention of the distal colon/rectum is expected to result in an overall improved quality of life compared with permanent ileostomy or an ileoanal J-pouch. Here, we report our experience and follow-up evaluation of segmental resections for preoperative neoplasia in patients with Crohn's disease (CD) or ulcerative colitis (UC).
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http://dx.doi.org/10.1016/j.cgh.2018.04.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034413PMC
January 2019
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