Publications by authors named "Edward V Loftus"

343 Publications

Efficacy and Safety of Tofacitinib Retreatment for Ulcerative Colitis After Treatment Interruption: Results From the OCTAVE Clinical Trials.

J Crohns Colitis 2021 Apr 22. Epub 2021 Apr 22.

Division of Gastroenterology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.

Background And Aims: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Here, we evaluate the efficacy and safety of tofacitinib retreatment following treatment interruption in patients with ulcerative colitis.

Methods: Here, patients with clinical response to tofacitinib 10mg b.d. induction therapy were randomised to receive placebo in OCTAVE Sustain. Those experiencing treatment failure after Week 8 of OCTAVE Sustain entered OCTAVE Open and reinitiated tofacitinib 10mg b.d. [retreatment subpopulation]; efficacy and safety data are presented up to Month 36 of OCTAVE Open.

Results: Median time to treatment failure following interruption was 169 [95% CI, 94.0-179.0] and 123 [95% CI, 91.0-168.0] days for induction remitters and induction responders but nonremitters, respectively. Following retreatment with tofacitinib, rates (non-responder imputation after a patient discontinued; last observation carried forward imputation after a patient advanced to a subsequent study [NRI-LOCF]) of clinical response, remission, and endoscopic improvement were 74.0%, 39.0%, and 55.0% at Month 2, and 48.5%, 37.4%, and 42.4% at Month 36, respectively. Among induction remitters and induction responders but non-remitters, clinical response rates at Month 36 were 60.6% and 42.4% [NRI-LOCF], respectively. Efficacy was recaptured regardless of prior tumour necrosis factor inhibitor failure status. The safety profile of tofacitinib 10mg b.d. retreatment was consistent with the overall cohort and demonstrated no new safety risks associated with exposure ≤36 months.

Conclusions: Median time to treatment failure was numerically higher in induction remitters versus induction responders but non-remitters. Following treatment interruption, efficacy was safely and successfully recaptured with tofacitinib 10mg b.d. retreatment in a substantial proportion of patients. ClinicalTrials.gov:NCT01458574;NCT01470612.
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http://dx.doi.org/10.1093/ecco-jcc/jjab065DOI Listing
April 2021

Novel risk factors and outcomes in inflammatory bowel disease patients with infection.

Therap Adv Gastroenterol 2021 12;14:1756284821997792. Epub 2021 Mar 12.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.

Background: Patients with inflammatory bowel disease (IBD) are at significantly increased risk for infection (CDI) with an increased risk of adverse outcomes including increased in-hospital mortality, IBD treatment failure, re-hospitalization, and high CDI recurrence rates. The existing literature on predictors of these adverse outcomes is limited. We evaluated four potentially modifiable novel risk factors [body mass index (BMI), statin use, opioid use, and antidepressant use] on CDI risk and adverse outcomes in these patients.

Methods: Using a retrospective design, variables were abstracted from records for patients with IBD and CDI from 2008 to 2013. Statistical analysis comprised descriptive statistics and univariate and multivariate logistic regression analyses.

Results: There were 137 patients with IBD and CDI included in this study. On multivariate analysis controlling for age, 43% of patients in the overweight BMI category had severe or severe, complicated CDI, compared with 22% of patients in the underweight/normal BMI [odds ratio (OR) 2.85,  = 0.02] and 19% in the obese category (OR 3.95,  = 0.04). Statin use was associated with severe or severe, complicated CDI when controlling for age and BMI (OR 5.66,  = 0.01). There was no association between statin use and IBD exacerbations following CDI. Opioid and antidepressant use were not associated with disease severity or frequency of IBD exacerbations following CDI.

Conclusions: An overweight BMI and statin use were associated with severe or severe, complicated CDI in IBD patients. Further studies are needed to better understand how these factors impact management of patients with IBD to improve clinical outcomes and potentially reduce the risk of complications from CDI.
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http://dx.doi.org/10.1177/1756284821997792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958162PMC
March 2021

The increasing burden of inflammatory bowel disease.

Authors:
Edward V Loftus

Med J Aust 2021 05 27;214(8):361-362. Epub 2021 Mar 27.

Mayo Clinic, Rochester, MN, United States of America.

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http://dx.doi.org/10.5694/mja2.51001DOI Listing
May 2021

Quality of Life and Work Productivity Improvements with Upadacitinib: Phase 2b Evidence from Patients with Moderate to Severe Crohn's Disease.

Adv Ther 2021 May 23;38(5):2339-2352. Epub 2021 Mar 23.

University of Birmingham, Birmingham, UK.

Introduction: In the phase 2 CELEST study, positive efficacy results were obtained with the Janus kinase 1 inhibitor upadacitinib for adult patients with moderate to severe Crohn's disease. We present the health-related quality of life and work productivity improvement results with upadacitinib from CELEST.

Methods: CELEST (NCT02365649) was a double-blind study where patients were randomized 1:1:1:1:1:1 in the 16-week induction period to placebo or upadacitinib 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily (QD). Patients completing the induction period were re-randomized 1:1:1 to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks or 3 mg BID, 6 mg BID, or 12 mg BID (after amendment). Inflammatory Bowel Disease Questionnaire (IBDQ), European Quality of Life-5 Dimensions visual analog scale (EQ-5D VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire outcomes were assessed at baseline and Weeks 8, 16, and 52.

Results: At Week 16, a significant percentage (P ≤ 0.05) of patients receiving upadacitinib 6-mg BID dose or higher achieved IBDQ response (IBDQ score change ≥ 16 points; 49%-57% for upadacitinib vs. 24% for placebo) and IBDQ remission, except 24 mg QD (IBDQ score ≥ 170; 26%-39% for upadacitinib vs. 11% for placebo). Greater improvements in IBDQ total score, EQ-5D VAS, and activity impairment from baseline (P ≤ 0.1) versus placebo were also observed. Larger improvements (P ≤ 0.1) in IBDQ response and total score and EQ-5D VAS were observed at Week 8 with 6 and 24 mg BID versus placebo, with improvements for all dosages maintained or greater at Week 52 for IBDQ, EQ-5D VAS, and WPAI endpoints, in particular for the 12-mg BID group.

Conclusion: Improvements in health-related quality of life and work productivity were achieved and sustained with upadacitinib in patients with moderate to severe Crohn's disease.

Trial Registration: ClinicalTrials.gov identifier, NCT02365649.
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http://dx.doi.org/10.1007/s12325-021-01660-7DOI Listing
May 2021

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program.

Inflamm Bowel Dis 2021 Mar 20. Epub 2021 Mar 20.

aPfizer Inc, Collegeville, Pennsylvania, USA.

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program.

Methods: Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.

Results: Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors.

Conclusions: For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.
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http://dx.doi.org/10.1093/ibd/izab056DOI Listing
March 2021

Isolated Colonic Post-Transplantation Lymphoproliferative Disease.

Clin Gastroenterol Hepatol 2021 Jan 29. Epub 2021 Jan 29.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1016/j.cgh.2021.01.041DOI Listing
January 2021

Inflammatory Bowel Disease Does Not Impact Mortality but Increases Length of Hospitalization in Patients with Acute Myocardial Infarction.

Dig Dis Sci 2021 Jan 25. Epub 2021 Jan 25.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Health, University of California Davis School of Medicine, 4150 V Street, Ste 3500, Sacramento, CA, 95817, USA.

Background And Aim: Inflammatory bowel diseases (IBD) have been associated with increased risk of cardiovascular events. We aimed to investigate the outcomes of myocardial infarction (MI) in patients with IBD.

Methods: We performed a cross-sectional study utilizing data from the Nationwide Inpatient Sample from the years 1998 to 2010. ICD-9-CM codes were used to identify patients with Crohn's disease (CD) (555.X), ulcerative colitis (UC) (556.X), and acute MI (410.X). Outcomes in patients with MI with and without IBD were compared. Univariate analysis was performed. Multivariate logistic regression was used to determine the effect of UC and CD on in-hospital MI mortality after adjusting for confounders.

Results: A total of 2,629,161 MI, 3,607 UC and 3784 CD patients were analyzed. UC (odds ratio [OR], 1.12; 95% CI 0.98-1.29) and CD (OR 0.99; 95% CI 0.86-1.15) did not affect in-hospital mortality in patients with MI. There was no difference between in-hospital mortality in patients with MI with or without UC (7.75% vs. 7.05%; p = 0.25) or in patients with MI with or without CD (6.50% vs. 6.59%; p = 0.87). The length of stay (LOS) was higher in IBD patients and total charges were statistically higher in patients with UC as compared to non-IBD patients ($65,182 vs. $53,542; p < 0.001).

Conclusions: This study shows that IBD does not impact in-hospital mortality from MI. However, patients with MI with IBD have longer LOS. Patients with UC have higher total hospitalization charges than patients with MI without IBD. Further prospective studies are needed to assess the outcomes of MI in IBD patients.
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http://dx.doi.org/10.1007/s10620-020-06818-xDOI Listing
January 2021

Factors associated with major radiological progression of primary sclerosing cholangitis in patients with inflammatory bowel disease.

Hepatol Int 2020 Dec 28;14(6):1114-1124. Epub 2020 Dec 28.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.

Background/purpose Of The Study: Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of inflammatory bowel disease (IBD). Magnetic resonance cholangiography (MRC) has become the primary diagnostic modality for PSC. However, data on radiological progression over time of large-duct PSC-IBD are limited.

Methods: We performed a nested case-control study to estimate the frequency of PSC in adult patients with IBD from a Middle Eastern population to assess the risk factors associated with major disease progression (formation of dominant strictures or cholangiocarcinoma) over time.

Results: Data of IBD patients who were registered in the Saudi IBD Information System at tertiary care center were analyzed. Among 960 patients [477 ulcerative colitis (UC); 483 Crohn's disease (CD)], 40 PSC-IBD patients with at least two MRC performed in a one-year interval were matched with 141 IBD patients without PSC. The frequency of PSC was 4.1%. UC patients (6.2%) compared to CD (2%), 65% had extensive colitis. The incidence rate of PSC among our cohort was increased from 2.62 to 10 per 1000 patient-years between 2005 and 2019. MRC features stabilized in (46.7%); worsened in (36.9%) and 15.4% of patients developed CCA. Alkaline phosphatase (ALP) levels of PSC patients who had major changes or CCA increased significantly after 44 months of follow-up (p = 0.01). The propensity score adjusted showed that hospitalization rate among PSC patients was higher than their non-PSC counterparts (OR 8.24; 95% CI 3.16-21.47; p < 0.01).

Conclusion: ALP rise and hospitalization history as clinical outcome were the only factors associated with PSC-IBD major progression on MRCP.
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http://dx.doi.org/10.1007/s12072-020-10110-5DOI Listing
December 2020

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.

J Crohns Colitis 2020 Nov 27. Epub 2020 Nov 27.

Pfizer Inc, Collegeville , PA,  USA.

Background And Aims: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes.

Methods: Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious] and opportunistic infections [OIs] are reported [censored at time of event].

Results: In the Induction Cohort [N=1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10mg twice daily [BID] developed SIs. Maintenance Cohort [N=592] SI IRs [95% CI] were 1.94 [0.23-7.00] for placebo, and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00] and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N=1157; 82.9% predominantly received tofacitinib 10mg BID], SI, HZ and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30] and 0.15 [0.04-0.38], respectively. No SIs resulted in death.

Conclusions: During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 versus 5mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa233DOI Listing
November 2020

The Impact of Vedolizumab on Pre-Existing Extraintestinal Manifestations of Inflammatory Bowel Disease: A Multicenter Study.

Inflamm Bowel Dis 2020 Nov 9. Epub 2020 Nov 9.

Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA.

Background: There are limited data on how vedolizumab (VDZ) impacts extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD). The aim of this study was to determine the clinical outcomes of EIMs after initiation of VDZ for patients with IBD.

Methods: A multicenter retrospective study of patients with IBD who received at least 1 dose of VDZ between January 1, 2014 and August 1, 2019 was conducted. The primary outcome was the rate of worsening EIMs after VDZ. Secondary outcomes were factors associated with worsening EIMs and peripheral arthritis (PA) specifically after VDZ.

Results: A total of 201 patients with IBD (72.6% with Crohn disease; median age 38.4 years (interquartile range, 29-52.4 years); 62.2% female) with EIMs before VDZ treatment were included. The most common type of EIM before VDZ was peripheral arthritis (PA) (68.2%). Worsening of EIMs after VDZ occurred in 34.8% of patients. There were no statistically significant differences between the worsened EIM (n = 70) and the stable EIM (n = 131) groups in term of age, IBD subtype, or previous and current medical therapy. We found that PA was significantly more common in the worsening EIM group (84.3% vs 59.6%; P < 0.01). Worsening of EIMs was associated with a higher rate of discontinuation of VDZ during study follow-up when compared with the stable EIM group (61.4% vs 44%; P = 0.02). Treatment using VDZ was discontinued specifically because of EIMs in 9.5% of patients.

Conclusions: Almost one-third of patients had worsening EIMs after VDZ, which resulted in VDZ discontinuation in approximately 10% of patients. Previous biologic use or concurrent immunosuppressant or corticosteroid therapy did not predict EIM course after VDZ.
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http://dx.doi.org/10.1093/ibd/izaa293DOI Listing
November 2020

Nonbiologic Immune Suppression in Ulcerative Colitis.

Gastroenterol Clin North Am 2020 12 19;49(4):731-738. Epub 2020 Sep 19.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA. Electronic address:

This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American guidelines, azathioprine, mercaptopurine, and methotrexate monotherapy are not recommended for induction therapy. Thiopurines are recommended in combination with infliximab. Tofacitinib has been shown to be an effective induction agent. Cyclosporine or tacrolimus are calcineurin inhibitors that can be used as induction therapy. Thiopurine monotherapy is suggested or recommended as maintenance therapy for patients who have achieved steroid-induced remission. Methotrexate monotherapy is not recommended. Tofacitinib has been shown to be an effective maintenance agent in moderate to severe disease.
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http://dx.doi.org/10.1016/j.gtc.2020.07.003DOI Listing
December 2020

Effects of Race and Ethnicity on Diagnosis and Management of Inflammatory Bowel Diseases.

Gastroenterology 2021 Feb 21;160(3):677-689. Epub 2020 Oct 21.

Multidisciplinary Center for Inflammatory Bowel Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Division of Pediatric Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Although Crohn's disease (CD) and ulcerative colitis (UC) have been considered as disorders that affect individuals of European ancestry, the epidemiology of the inflammatory bowel diseases (IBDs) is changing. Coupled with the increasing incidence of IBD in previously low-incidence areas, the population demographics of IBD in the United States are also changing, with increases among non-White races and ethnicities. It is therefore important to fully understand the epidemiology and progression of IBD in different racial and ethnic groups, and the effects of race and ethnicity on access to care, use of resources, and disease-related outcomes. We review differences in IBD development and progression among patients of different races and ethnicities, discussing the effects of factors such as access to care, delays in diagnosis, and health and disease perception on disparities in IBD care and outcomes. We identify research priorities for improving health equity among minority patients with IBD.
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http://dx.doi.org/10.1053/j.gastro.2020.08.064DOI Listing
February 2021

Comparative Safety and Effectiveness of Vedolizumab to Tumor Necrosis Factor Antagonist Therapy for Ulcerative Colitis.

Clin Gastroenterol Hepatol 2020 Oct 8. Epub 2020 Oct 8.

Mayo Clinic, Rochester, Minnesota.

Background & Aims: We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice.

Methods: A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist-naïve and -exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately.

Results: A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist-naïve and -exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist-treated patients. However, in TNF-antagonist-naïve patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754).

Conclusions: Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist-naïve patients.
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http://dx.doi.org/10.1016/j.cgh.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026779PMC
October 2020

Long-term safety of vedolizumab for inflammatory bowel disease.

Aliment Pharmacol Ther 2020 10 2;52(8):1353-1365. Epub 2020 Sep 2.

Leuven, Belgium.

Background: Vedolizumab, a gut-selective α β integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).

Aim: To report the final results from the vedolizumab GEMINI long-term safety (LTS) study.

Methods: The phase 3, open-label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab-naïve patients. Vedolizumab LTS was evaluated; efficacy and patient-reported outcomes were exploratory endpoints.

Results: Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03-112.2) for UC and 31.5 months (range: 0.03-100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion-related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug-related by local investigators (West Nile virus infection-related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long-term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks.

Conclusions: The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long-term use (NCT00790933/EudraCT 2008-002784-14).
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http://dx.doi.org/10.1111/apt.16060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540482PMC
October 2020

Clinical Trials for Inflammatory Bowel Disease: Global Guidance During the COVID-19 Pandemic.

J Crohns Colitis 2020 Oct;14(Supplement_3):S820

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1093/ecco-jcc/jjaa138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454431PMC
October 2020

Therapeutic Drug Monitoring for Current and Investigational Inflammatory Bowel Disease Treatments.

J Clin Gastroenterol 2021 Mar;55(3):195-206

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn's disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α4β7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this.
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http://dx.doi.org/10.1097/MCG.0000000000001396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960149PMC
March 2021

Comparative safety and effectiveness of vedolizumab to tumour necrosis factor antagonist therapy for Crohn's disease.

Aliment Pharmacol Ther 2020 08 13;52(4):669-681. Epub 2020 Jul 13.

La Jolla, CA, USA.

Background: Direct comparisons are lacking between vedolizumab and tumour necrosis factor (TNF)-antagonist therapy in Crohn's disease (CD).

Aim: To compare safety and effectiveness of vedolizumab and TNF-antagonist therapy in adult CD patients.

Methods: Retrospective observational cohort (May 2014-December 2017) propensity score-weighted comparison of vedolizumab vs TNF-antagonist therapy (infliximab, adalimumab, certolizumab) in CD. Propensity scores were weighted for age, prior treatments, disease complications, extent and severity, steroid dependence, and concomitant immunosuppressive drug use. The primary outcome was comparative risk for infections or non-infectious serious adverse events (requiring antibiotics, antivirals, antifungals, hospitalisation, or treatment discontinuation, or resulting in death). Secondary comparative effectiveness outcomes were clinical remission (resolution of CD-related symptoms), steroid-free clinical remission and endoscopic remission (absence of ulcers/erosions).

Results: We included 1266 patients (n = 659 vedolizumab). Rates of non-infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012-0.242), but not serious infections (OR 1.183, 95% CI 0.786-1.795), were significantly lower with vedolizumab vs TNF-antagonist therapy. Safety comparisons for non-infectious serious adverse events remained significant after adjusting for differences in duration of exposure. No significant difference was observed between vedolizumab and TNF-antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707-1.228), steroid-free clinical remission (HR 1.250, 95% CI 0.677-2.310) or endoscopic remission (HR 0.827, 95% CI 0.595-1.151). TNF-antagonist therapy was associated with higher treatment persistence compared with vedolizumab.

Conclusions: There was a lower risk of non-infectious serious adverse events, but not serious infections, with vedolizumab vs TNF-antagonist therapy, with no significant difference for achieving disease remission.
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http://dx.doi.org/10.1111/apt.15921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496810PMC
August 2020

Combined Fasting Serum C4 and Primary Bile Acids From a Single Stool Sample to Diagnose Bile Acid Diarrhea.

Gastroenterology 2020 11 6;159(5):1952-1954.e2. Epub 2020 Jul 6.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1053/j.gastro.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680346PMC
November 2020

Sustained Corticosteroid-Free Clinical Remission During Vedolizumab Maintenance Therapy in Patients with Ulcerative Colitis on Stable Concomitant Corticosteroids During Induction Therapy: A Post Hoc Analysis of GEMINI 1.

Clin Exp Gastroenterol 2020 11;13:211-220. Epub 2020 Jun 11.

Takeda Pharmaceuticals International AG, Zurich, Switzerland.

Background: Corticosteroid-free clinical remission is important in ulcerative colitis.

Objective: This GEMINI 1 post hoc analysis evaluated vedolizumab efficacy in achieving sustained corticosteroid-free clinical remission in moderately to severely active ulcerative colitis.

Materials And Methods: GEMINI 1 included a 6-week induction period followed by a 46-week maintenance period. Patients received stable corticosteroid dosing at baseline/during induction and tapered dosing during maintenance. Analysis groups included vedolizumab (induction and maintenance); vedolizumab/placebo (vedolizumab induction, placebo maintenance); and placebo (induction and maintenance). The primary endpoint was sustained corticosteroid-free clinical remission (partial Mayo score ≤2, no individual subscore >1, for ≥32 weeks). Multivariate analyses identified covariates associated with the primary endpoint. Safety endpoints included adverse events.

Results: Baseline demographics and concomitant corticosteroid use were similar across groups (n=454). A greater proportion (95% confidence interval) of the vedolizumab group achieved sustained corticosteroid-free clinical remission (10.2% [6.9 to 13.6]) vs the placebo group (1.4% [0.0 to 7.3]; difference 8.9% [-3.8 to 21.4]). Proportions were similar between the vedolizumab/placebo and placebo groups. Covariates associated with sustained corticosteroid-free clinical remission (odds ratio [95% confidence interval]) were treatment (vedolizumab vs placebo: 9.35 [1.25 to 71.43]; =0.0605), anti-tumor necrosis factor alpha exposure (yes vs no: 0.26 [0.12 to 0.57]; =0.0008), and disease duration (≤2 vs >2 years: 2.66 [0.99-7.19]; =0.0531). Adverse events were similar across groups.

Conclusion: A numerically greater proportion of vedolizumab-treated patients with ulcerative colitis achieved sustained corticosteroid-free clinical remission. Vedolizumab treatment, no previous anti-tumor necrosis factor alpha exposure, and shorter disease duration were associated with sustained corticosteroid-free clinical remission.

Clinicaltrialsgov: NCT00783718.
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http://dx.doi.org/10.2147/CEG.S248597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295209PMC
June 2020

Use of Immune Checkpoint Inhibitors in Patients With Pre-established Inflammatory Bowel Diseases: Retrospective Case Series.

Clin Gastroenterol Hepatol 2021 Jun 19;19(6):1285-1287.e1. Epub 2020 Jun 19.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

The etiology of inflammatory bowel disease (IBD) has yet to be fully understood; however, it is thought to be a result of genetic, immunologic, and environmental factors, including changes in the gut microbiome. Immune checkpoint inhibitors (ICI) have revolutionized treatment of advanced cancer. They activate the immune system by promoting cytotoxic T-cell survival and antitumor effects. A total of 7 ICIs currently are approved by the United States Food and Drug Administration, and target cytotoxic T lymphocyte-associated protein 4 (ipilimumab); anti-programmed cell death 1 (PD-1) (nivolumab, pembrolizumab, and cemiplimab), or anti-PD-ligand 1 (atezolizumab, durvalumab, and avelumab). However, by activating the immune system, these medications also can lead to off-target inflammation and autoimmunity, including ICI-induced colitis, which has been reported in up to 13.6% of patients..
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http://dx.doi.org/10.1016/j.cgh.2020.06.031DOI Listing
June 2021

A 1-Year Cross-sectional Inflammatory Bowel Disease Surveillance Colonoscopy Cohort Comparing High-definition White Light Endoscopy and Chromoendoscopy.

Inflamm Bowel Dis 2021 Apr;27(5):594-602

Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Minnesota, USA.

Background: We sought to compare the dysplasia detection rate of high-definition white light endoscopy (HDWLE) with that of chromoendoscopy in patients with long-standing inflammatory bowel disease (IBD).

Methods: This is a retrospective observational cohort of patients with IBD who underwent surveillance colonoscopy between October 1, 2016 and September 30, 2017. We assessed the association between dysplasia detection and multiple variables.

Results: A total of 808 unique colonoscopies were performed, of which 150 (18.6%) included chromoendoscopy. Primary sclerosing cholangitis was a comorbid diagnosis in 24.5% of patients. The performing endoscopist was an IBD specialist with 37.1% of patients and had >10 years' experience with 64.9% of patients. Prior dysplasia had been seen in 245 (30.3%) patients: 102 (68.0%) and 143 (22.0%) among patients who had chromoendoscopy and HDWLE, respectively. Dysplasia in polyps was found in 129 procedures (15.1%). Among patients who had chromoendoscopy and HDWLE, polypoid dysplasia was identified in 50 (33.0%) and 79 (12.0%) patients, respectively, P < 0.01. Dysplasia in random biopsies was found in 39 patients (4.8%): 15 (10%) who had chromoendoscopy and 24 (3.6%) who had HDWLE (P < 0.001). On multivariate analysis, patient and disease characteristics significantly associated with an increased odds for polypoid dysplasia included older age at diagnosis (odds ratio [OR] = 1.3 per 10 years; 95% confidence interval [CI], 1.07-1.60), having an IBD physician endoscopist (OR = 1.6; 95% CI, 1.01-2.67), having an endoscopist with less than 10 years' experience (OR = 1.8; 95% CI (1.16-2.89), and prior random dysplasia (OR = 4.2; 95% CI (1.93-9.17). Concomitant primary sclerosing cholangitis was significantly associated with random dysplasia (OR = 2.3; 95% CI, 1.02-5.07). After multivariate analysis adjusting for these variables, chromoendoscopy was no more likely to identify dysplasia than was HDWLE.

Conclusions: Chromoendoscopy and HDWLE had a similar diagnostic yield for dysplasia detection in patients with chronic IBD-colitis after adjusting for multiple known risk factors.
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http://dx.doi.org/10.1093/ibd/izaa146DOI Listing
April 2021

Clinical Trials for Inflammatory Bowel Disease: Global Guidance During the COVID-19 Pandemic.

J Crohns Colitis 2020 Oct;14(Supplement_3):S815-S819

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

The severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]-causing coronavirus disease [COVID]-19 pandemic poses major challenges for patients with inflammatory bowel disease [IBD] to be recruited and maintained in clinical trials. However, clinical trials offer patients who have failed multiple drugs access to study medications with alternative modes of action and the potential for relief from inflammation-mediated symptoms. Therefore, the continuation of clinical trials in IBD during the COVID-19 pandemic is important both for participants and for the community of IBD patients, due to the dire need for an expanded therapeutic armamentarium. As the safety of patients in clinical trials is the leading principle, we are providing ten specific rules to guide patients and principal investigators safely through the challenging time.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314066PMC
October 2020

Risk of de-novo inflammatory bowel disease among obese patients treated with bariatric surgery or weight loss medications.

Aliment Pharmacol Ther 2020 06 21;51(11):1067-1075. Epub 2020 Apr 21.

Division Gastroenterology & Hepatology, University of California, San Diego, CA, USA.

Background: An association between bariatric surgery and development of de-novo inflammatory bowel disease (IBD) has been observed.

Aim: To evaluate further the association among bariatric surgery, weight loss medications, obesity and new-onset IBD.

Methods: Using Explorys, a population-based Health Insurance Portability and Accountability Act compliant database, we estimated the prevalence of de-novo IBD among patients treated with bariatric surgery (Roux-en-Y gastrojejunostomy, laparoscopic sleeve gastrectomy or gastric banding) (n = 60 870) or weight loss medications (orlistat, phentermine/topiramate, lorcaserin, bupropion/naltrexone and liraglutide) (n = 193 790) compared with obese controls (n = 5 021 210), between 1999 and 2018.

Results: The prevalence of de-novo IBD was lower among obese patients exposed to bariatric surgery (7.72 per 1000 patients) or weight loss medications (7.22 per 1000 patients) compared with patients with persistent obesity not exposed to these interventions (11.66 per 1000 patients, P < 0.0001). The risk reduction for de-novo IBD was consistent across bariatric surgeries and weight loss medications with the exception of orlistat which was not associated with a reduction in risk for de-novo IBD compared with the persistent obese control cohort.

Conclusion: Obese patients undergoing treatment with bariatric surgery or weight loss medications are at a lower risk for developing de-novo IBD compared with persistently obese controls not exposed to these interventions. These data suggest that obesity and ineffective management of obesity are risk factors for de-novo IBD. Further research is needed to confirm these observations and understand potential mechanisms.
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http://dx.doi.org/10.1111/apt.15721DOI Listing
June 2020

Are Biologics Safe in the Immediate Postoperative Period? A Single-Center Evaluation of Consecutive Crohn's Surgical Patients.

Dis Colon Rectum 2020 07;63(7):934-943

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background: There is no study to date examining the safety of initiating or restarting biologic therapy after major abdominal surgery for Crohn's disease.

Objective: The purpose of this study was to determine differences in the rates of 90-day superficial surgical site infections, intra-abdominal sepsis, and overall postoperative infectious complications among patients who were initiated on or restarted a biologic within 90 days postoperatively compared with those who were not.

Design: This was a retrospective cohort study.

Settings: The study was conducted at an IBD referral center.

Patients: Adult patients with Crohn's disease who received a biologic therapy within 90 days of a major abdominal operation between May 20, 2014, and December 31, 2018, were included.

Main Outcomes Measures: Ninety-day superficial surgical site infection, intra-abdominal sepsis, and overall postoperative infectious complications were measured.

Results: A total of 680 patients with Crohn's disease were included: 351 were initiated on biologic therapy within 90 days after surgery and 329 were not. Patients exposed to biologic therapy postoperatively were younger (p < 0.001), had a lower BMI (p = 0.0014), were less often diabetic (p = 0.0011), and were more often exposed preoperatively to biologics (p < 0.0001) and immunomodulators (p < 0.0001) but not corticosteroids (p = 0.8399). Of those exposed postoperatively, nearly all (93.7%) had been on a biologics preoperatively, and most resumed the same biologic (68.0%). The median time to starting biologic therapy postoperatively was 31 days (range, 7-89 d). Postoperative biologic exposure was not associated with an increased risk of superficial surgical site infection (HR = 1.02 (95% CI, 0.95-1.09) per week; p = 0.59), intra-abdominal sepsis (HR = 1.07 (95% CI, 0.99-1.16); p = 0.73), or overall postoperative infectious complications (HR = 1.02 (95% CI, 0.98-1.07); p = 0.338); the overall rates of each at 90 days was 13%, 8%, and 28%.

Limitations: The study was limited by its retrospective design and single-center data.

Conclusions: Postoperative initiation or resumption of biologic therapy did not increase 90-day rates of superficial surgical site infection, intra-abdominal sepsis, or total infectious complications after major abdominal surgery for Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B207. ¿SON SEGUROS LOS FÁRMACOS BIOLÓGICOS EN EL POSTOPERATORIO INMEDIATO? UNA EVALUACIÓN DE UN SOLO CENTRO DE PACIENTES QUIRÚRGICOS CONSECUTIVOS CON ENFERMEDAD DE CROHN: No hay ningún estudio hasta la fecha que examine la seguridad de iniciar o reiniciar la terapia biológica después de una cirugía abdominal mayor en enfermedad de Crohn.Determinar las diferencias en las tasas a 90 días de infecciones del sitio quirúrgico superficial, sepsis intraabdominal y complicaciones infecciosas postoperatorias generales entre los pacientes en que se inició o reinició un biológico dentro de los 90 días después de la operación en comparación con aquellos que no lo recibieron.Estudio de cohorte retrospectivo.Centro de referencia de enfermedad inflamatoria intestinal.Pacientes adultos con enfermedad de Crohn que recibieron una terapia biológica dentro de los 90 días de una operación abdominal mayor entre el 20 de mayo de 2014 y el 31 de diciembre de 2018.Infección superficial del sitio quirúrgico, sepsis intraabdominal y complicaciones infecciosas postoperatorias generales a 90 días.Se incluyeron un total de 680 pacientes con enfermedad de Crohn: 351 se iniciaron en terapia biológica dentro de los 90 días posteriores a la cirugía y 329 no. Los pacientes expuestos a terapia biológica después de la operación eran más jóvenes (p <0.001), tenían un índice de masa corporal más bajo (p = 0.0014), eran con menos frecuencia diabéticos (p = 0.0011) y estaban expuestos con mayor frecuencia preoperatoriamente a fármacos biológicos (p <0.0001) e inmunomoduladores (p <0.0001) pero no a corticosteroides (p = 0.8399). De los expuestos postoperatoriamente, casi todos (93.7%) habían estado en terapia biológica en el preoperatorio, y la mayoría reanudó la misma terapia biológica (68%). La mediana de tiempo para comenzar la terapia biológica después de la operación fue de 31 días (rango, 7-89 días). La exposición biológica postoperatoria no se asoció con un mayor riesgo de infección superficial del sitio quirúrgico (HR 1.02 (0.95-1.09) por semana, p = 0.59), sepsis intraabdominal. (HR: 1.07 (0.99-1.16), p = 0.73), o complicaciones infecciosas postoperatorias generales (HR: 1.02, intervalo de confianza del 95% 0.98-1.07, p = 0.338); las tasas generales de cada uno a los 90 días fue del 13%, 8% y 28%.Diseño retrospectivo, y datos de un centro único.El inicio o la reanudación en el postoperatorio de la terapia biológica no aumentaron las tasas a 90 días de infección superficial de sitio quirúrgico, sepsis intraabdominal o complicaciones infecciosas totales después de una cirugía abdominal mayor por enfermedad de Crohn. Consulte el Video Resumen en http://links.lww.com/DCR/B207. (Traducción-Dr Jorge Silva Velazco).
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http://dx.doi.org/10.1097/DCR.0000000000001649DOI Listing
July 2020

Histoplasmosis in Inflammatory Bowel Disease with Tumor Necrosis Factor-Alpha Inhibitors: Safe to Continue Biologics?

Dig Dis Sci 2021 01 7;66(1):190-198. Epub 2020 Mar 7.

Division of Infectious Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.

Background: The advent of tumor necrosis factor-α (TNF-α) inhibitor therapy has transformed inflammatory bowel disease management; however, these medications carry a boxed warning for risk of serious infections, including invasive fungal infections.

Aims: We aimed to study the clinical features, severity, and outcomes of histoplasmosis in patients on TNF-α inhibitors for IBD.

Methods: We performed a retrospective review of IBD patients receiving TNF-α inhibitors who developed histoplasmosis from January 1, 2001, to May 31, 2018. Patients with drug indications other than ulcerative colitis or Crohn's disease were excluded. IBD was diagnosed histologically, radiographically, or endoscopically.

Results: We identified 49 patients (median age 44 years; range 19-76) with histoplasmosis on TNF-α inhibitors. Patients with disseminated disease had a median urine antigen of 10.76 ng/mL compared with pulmonary disease alone 0.375 ng/mL (p < 0.001). Charlson Comorbidity Index and urine antigen levels showed a trend toward predicting disease severity (p > 0.05). Median length of stay was 9.5 days. Itraconazole was used for maintenance in all patients. Median follow-up was 4.7 years. Total treatment duration ranged from 3 to 15 months. TNF-α inhibitor therapy was continued in nine and resumed in ten patients after completing antifungals. Three deaths occurred (6%).

Conclusions: Histoplasmosis outcomes were mostly favorable. Many patients were young with few comorbidities; however, those with more comorbidities experienced more severe histoplasmosis. Compared to prior studies, many of these patients resumed or continued biologic therapy. There were no histoplasmosis recurrences after resuming TNF-α inhibitor therapy. Vigilance for disseminated fungal infections in this patient population is essential.
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http://dx.doi.org/10.1007/s10620-020-06181-xDOI Listing
January 2021

Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center.

Clin Gastroenterol Hepatol 2021 Mar 14;19(3):616-617. Epub 2020 Feb 14.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades. IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal.
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http://dx.doi.org/10.1016/j.cgh.2020.02.017DOI Listing
March 2021

Development and Validation of Clinical Scoring Tool to Predict Outcomes of Treatment With Vedolizumab in Patients With Ulcerative Colitis.

Clin Gastroenterol Hepatol 2020 12 13;18(13):2952-2961.e8. Epub 2020 Feb 13.

Robarts Clinical Trials, London, Ontario, Canada.

Background & Aims: We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).

Methods: We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017.

Results: Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.

Conclusions: We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.
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http://dx.doi.org/10.1016/j.cgh.2020.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899124PMC
December 2020

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

Gastroenterology 2020 06 8;158(8):2123-2138.e8. Epub 2020 Feb 8.

Inflammatory Bowel Diseases Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address:

Background & Aims: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD).

Methods: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%.

Results: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group.

Conclusions: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).
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http://dx.doi.org/10.1053/j.gastro.2020.01.047DOI Listing
June 2020

Biosimilars: concept, current status, and future perspectives in inflammatory bowel diseases.

Intest Res 2020 Jan 30;18(1):34-44. Epub 2020 Jan 30.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

The inflammatory bowel diseases (IBD), which consist of Crohn's disease and ulcerative colitis, are chronic, incurable immunemediated inflammatory disorders of the intestine. As IBD incidence continues to increase globally and its mortality is low, prevalent cases of IBD are rapidly increasing, thereby leading to a substantial increase in health care costs. Although the introduction of biologic agents for IBD management has revolutionized the armamentarium of IBD therapy, the high cost of this therapy is concerning. With the expirations of patents for existing biologic agents (originals), biosimilars with cheaper costs have been highlighted in the field of IBD. Despite concerns regarding their short- and long-term efficacy, safety, immunogenicity, and interchangeability, increasing evidence via prospective observations and phase III or IV clinical trials, which aim to prove the "biosimilarity" of biosimilars to originals, has partly confirmed their efficacy, safety, and interchangeability. Additionally, although patients and physicians are reluctant to use biosimilars, a positive budget impact has been reported owing to their use in different countries. In the near future, multiple biosimilars with lower costs, and efficacy and safety profile similar to originals, could be used to treat IBD; thus, further consideration and knowledge dissemination are warranted in this new era of biosimilars.
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http://dx.doi.org/10.5217/ir.2019.09147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000642PMC
January 2020

A clinical decision support tool may help to optimise vedolizumab therapy in Crohn's disease.

Aliment Pharmacol Ther 2020 03 22;51(5):553-564. Epub 2019 Dec 22.

Paris, France.

Background: A clinical decision support tool (CDST) has been validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn's disease.

Aim: To assess the utility of this CDST for predicting exposure-efficacy and disease outcomes.

Methods: Using data from three independent datasets (GEMINI, GETAID and VICTORY), we assessed clinical remission rates and measured VDZ exposure, rapidity of onset of action, response to dose optimisation and progression to surgery by CDST-defined response groups (low, intermediate and high).

Results: A linear relationship existed between CDST-defined groups, measured VDZ exposure, rapidity of onset of action and efficacy in GEMINI through week 52 (P < 0.001 at all time points across three CDST-defined groups). In GETAID, CDST predicted differences in clinical remission at week 14 (AUC = 0.68) and rapidity of onset of action (P = 0.04) between probability groups. The high-probability patients did not benefit from shortening of infusion intervals, and differences in onset of action between the high-intermediate and low-probability groups within GETAID were no longer significant when including low-probability patients who received a week 10 infusion. CDST predicted a twofold increase in surgery risk over 12 months of VDZ therapy among low- to intermediate-probability vs high-probability patients (adjusted HR 2.06, 95% CI 1.33-3.21).

Conclusions: We further extended the clinical utility of a previously validated VDZ CDST, which accurately predicts at baseline exposure-efficacy relationships and rapidity of onset of action and could be used to help identify patients who would most benefit from interval shortening and those most likely to require surgery while on active therapy.
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http://dx.doi.org/10.1111/apt.15609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028036PMC
March 2020