bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADVERSE CLINICAL OUTCOMES IN PATIENTS WITH ULCERATIVE COLITIS RECEIVING DIFFERENT SEQUENCES OF FIRST- AND SECOND-LINE BIOLOGIC TREATMENTS: FINDINGS FROM ROTARY
Authors: Cleveland Noa , Chastek Benjamin , Ghosh Tito , Candela Ninfa , Bancroft Timothy , Fan Tao , Umashankar Kandavadivu , Rubin David 
Published: January 2022

Abstract

INTRODUCTION
Inadequate response, loss of response, or intolerance to a first-line biologic typically requires patients with ulcerative colitis (UC) to switch treatment to a second-line biologic therapy. However, the clinical outcomes of patients receiving different sequences of biologic treatment are poorly understood. We assessed the adverse clinical outcomes of different treatment sequences.

METHODS
ROTARY (Real wOrld ouTcomes Across tReatment sequences in inflammatorY bowel disease patients) part B used data from the Optum Clinical Database and included adult patients diagnosed with UC who received at least two biologics successively between January 1, 2013 and February 29, 2020. This retrospective cohort study measured adverse clinical outcomes, including the incidences of inflammatory bowel disease (IBD)-related hospitalization, IBD-related surgery, dysplasia, colorectal cancer (CRC), and infection during each line of therapy individually and for both lines of treatment overall. The start of the first line of therapy (LOT1) was defined as the date of first prescription or infusion of a biologic therapy. The start of the second line of therapy (LOT2) was defined as the first date of prescription or infusion of a second-line biologic therapy. LOT1 biologics included in the analysis were adalimumab (ADA), infliximab (IFX), and vedolizumab (VDZ). LOT2 biologics included were IFX and ADA.

RESULTS
Among all treatment sequences the overall incidences of hospitalization, surgery, CRC, dysplasia, and infection were lowest for the VDZ to ADA treatment sequence (Figure 1). Patients who received VDZ to IFX had similar overall incidences of adverse outcomes as patients who received two sequential anti-tumor necrosis factor (TNF) therapies (either ADA to IFX or IFX to ADA) (Figure 1). When comparing adverse outcomes during LOT2 there were lower incidences of hospitalization and surgery for the IFX to ADA sequence compared with the ADA to IFX sequence (19.17% vs 23.64% and 7.14% vs 14.24%, respectively) (Table 1). When comparing adverse outcomes on LOT2 for the VDZ to ADA and VDZ to IFX sequences, there were lower incidences of hospitalization and surgery with VDZ to ADA compared with VDZ to IFX (12.50% vs 26.89% and 3.13% vs 22.69%, respectively) (Table 1).

DISCUSSION
In this real-world assessment of biologic treatment sequences in UC, we identified the VDZ to ADA treatment sequence to be associated with the lowest incidence of adverse clinical outcomes. In patients who were unsuccessfully treated with VDZ, ADA as a second-line biologic therapy was associated with lower incidences of adverse clinical outcomes compared with IFX. Although our results could be influenced by selection bias, these data provide potential guidance to clinicians in sequencing biologic therapies in patients with UC.
DOSE ESCALATION OF BIOLOGIC THERAPIES IN BIOLOGIC TREATMENT-NAÏVE ADULT PATIENTS WITH ULCERATIVE COLITIS: RESULTS FROM THE ODESSA DATABASE STUDY
Authors: Kathe Niranjan , Umashankar Kandavadivu , Mirchandani Kirti , Hait Arunima , Paul Riyanka , Ghosh Tito , Candela Ninfa , Fan Tao 
Published: January 2022

Abstract

BACKGROUND
In the real-world clinical setting, patients with moderate-to-severe ulcerative colitis (UC) may undergo dose escalation when they lose response to their prescribed biologic treatment. Such dose escalation of biologic agents has an impact on healthcare utilization and costs and may have an impact on patient outcomes. Currently, limited real-world data exist that compare rates of dose escalation between anti-tumor necrosis factor (anti-TNF) biologic therapies and vedolizumab, a gut-selective integrin antagonist, in patients with UC who have not previously been treated with biologic therapies (bio-naïve patients).

METHODS
ODESSA (real wOrld Dose EScalation and outcomeS with biologics in IBD pAtients) was a retrospective cohort study investigating dose escalation in bio-naïve patients with UC receiving vedolizumab or anti-TNFs (adalimumab, golimumab, and infliximab) using data from the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental Databases. Adult patients with ≥1 claim for a study drug between January 1, 2017 and December 31, 2018 were selected for inclusion, with the first claim date defined as index date 1 (Figure). Patients were eligible if they had a diagnosis of UC, identified based on UC diagnosis codes, had ≥2 claims for the study drug ≥10 days apart with ≥1 claim on or before index date 1, and had received the study drug for ≥60% of days in the first 6 months after index date 1. Patients were excluded if they had received any biologic treatment before index date 1. The maintenance period began on the date of the third (adalimumab or golimumab) or fourth (infliximab or vedolizumab) pharmacy claim. Dose escalation was defined as a ≥20% increase in mean average daily dose relative to expected daily dose based on the approved prescribing information for UC. The primary endpoint was to compare the proportions of patients experiencing dose escalation of each of the study drugs in the first 6 and 12 months after initiation of maintenance dosing and in the entire maintenance period.

RESULTS
The final analysis cohort included 2,628 patients (vedolizumab, n=554; infliximab, n=758; adalimumab, n=1,316). As a consequence of low patient count, patients treated with golimumab were excluded. At 12 months, the proportion of patients experiencing dose escalation was lowest in the vedolizumab group (36%) and highest in the adalimumab group (44%) (Table).

CONCLUSION
In this retrospective, real-world cohort of bio-naïve patients with UC receiving vedolizumab or anti-TNFs, rates of dose escalation were lowest among patients receiving vedolizumab during the maintenance period. These data seem to indicate that vedolizumab maintains efficacy with less need for dose escalation; however, additional studies are required to investigate dose-escalation requirements for all biologic treatments.
IDENTIFYING THE MOST EFFECTIVE TREATMENT ALGORITHM FOR THERAPIES TO TREAT MODERATE TO SEVERE ULCERATIVE COLITIS
Authors: Scott Frank , Afzali Anita , Dulai Parambir , Lu Mei , Candela Ninfa , Fan Tao , Ghosh Tito , Lewis James 
Published: January 2022

Abstract

BACKGROUND
There has been an ongoing expansion in available biologic and small molecule therapies to treat moderate to severe ulcerative colitis (UC). The sequence in which these therapies are used has been a topic of high interest among clinicians. In the absence of precision medicine for UC, it would be useful to define the sequence of therapies that may predict the best outcomes. Limited data exists regarding the most effective treatment algorithms for achieving optimal patient outcomes. As such, this study endeavors to identify treatment algorithms when considering the UC therapies of vedolizumab, infliximab, ustekinumab, and tofacitinib.

METHODS
A Markov model was used to identify the UC treatment algorithm that would potentially yield the greatest quality adjusted life years (QALYs) over 1 year. The base case was a 35-year old male with moderate to severe UC who had not previously received biologic or immunomodulator therapy. Four medical therapies were considered: (1) infliximab + azathioprine, (2) tofacitinib, (3) ustekinumab, and (4) vedolizumab. Colectomy was assumed to be the least desirable treatment option. These four therapies were combined in eight separate potential treatment algorithms (Figure 1). Tofacitinib was only included after anti-TNF therapy per its USA prescribing indication. With each therapy, simulated individuals could enter remission or response, develop a significant adverse event or infection, or lose response to the therapy. Transition probabilities for response, remission, and adverse event rates were derived from relevant clinical trials. Lymphoproliferative risks were derived from age-specific SEER (Surveillance, Epidemiology, and End Results) data and treatment-specific risks from CESAME. Utility estimates were derived from previously published studies. The time horizon was 1 year. Primary analyses consisted of first order Monte Carlo simulation of 100 trials of cohorts consisting of 100,000 individuals.

RESULTS
Algorithms incorporating vedolizumab as first-line therapy resulted in the greatest quality of life and proportion of patients in remission at 1 year in comparison to strategies where combination therapy with infliximab + azathioprine or ustekinumab were included as first line therapy (Table 1). Vedolizumab followed by infliximab + azathioprine and then ustekinumab resulted in the greatest quality of life advantage. The benefit of this treatment sequence over other sequences ranged from 0.008 to 0.011 QALYs at 1 year.

CONCLUSION
In this model, using vedolizumab prior to infliximab + azathioprine, ustekinumab and tofacitinib is predicted to yield greater quality of life and a greater percentage of patients with clinical remission at the end of 1 year. Further analyses assessing model inputs, probabilistic analyses, and strategy cost-effectiveness are required.
POPULATION PHARMACOKINETICS OF OZANIMOD AND ACTIVE METABOLITE CC112273 IN PATIENTS WITH ULCERATIVE COLITIS
Authors: Shen Jun , Tatosian Daniel , Sid-Otmane Lamia , Teuscher Nathan , Chen Lu , Zhang Peijin , Tirucherai Giridhar , Chitkara Denesh , Marta Cecilia 
Published: January 2022

Abstract

BACKGROUND
Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and moderately to severely active ulcerative colitis (UC) and under development for Crohn’s disease (CD). Following multiple dosing of ozanimod in healthy subjects, ozanimod and two of the active metabolites CC112273 and CC1084037 represent approximately 6%, 73%, and 15% of circulating total active drug exposure, respectively. Two separate pharmacokinetic (PK) models were developed for the most prominent metabolite CC112273 and ozanimod. CC1084037 was not modeled due to the high correlation between CC112273 and CC1084037 plasma concentrations. Therefore, this analysis aims to characterize the PK of ozanimod and the major metabolite CC112273 in UC and RMS population.

METHODS
Subjects from 11 studies (Phase 1 to Phase 3) in healthy volunteers, RMS, and UC patients were included in this population PK analysis. The analyses included a total of 18901 concentrations from 2890 subjects for CC112273 and 18834 PK concentrations from 2977 subjects for ozanimod. A 2-compartment model was used to describe the concentration-time profiles of both ozanimod and CC112273, separately. The influence of weight, age, sex, race, disease, or smoking status and hepatic function on the PK of ozanimod and CC112273 were explored. The impact of concomitant corticosteroids on CC112273 PK were evaluated post hoc.

RESULTS
While the overall apparent clearance of ozanimod was 7% lower in RMS patients compared to UC, similar exposures were observed in both populations. The most influential covariate on ozanimod PK was body weight, with a modest 23% increase in apparent clearance for a 102-kg subject relative to a 70-kg subject (Figure 1). The apparent clearance of CC112273 was 16% greater in RMS patients compared to UC patients, resulting in a slightly higher exposure for UC patients. Increasing body weight had a modest reduction in clearance, while smoking had the largest influence on CC112273 PK of approximately 108% increased clearance (Figure 2). Post-hoc results showed no impact of concomitant prednisone or prednisolone on the PK of CC112273. Other factors, including age, race, sex, or hepatic impairment did not impact the PK of ozanimod or CC112273 PK.

CONCLUSION
The population PK model of CC112273 indicates that covariates with the largest effect on CC112273 PK parameters were body weight and smoking status. However, no covariate impacted clearance by more than 25%. The PK of ozanimod and CC112273 were not meaningfully impacted by age including in the elderly, body weight, race, sex, hepatic function, or concomitant prednisone or prednisolone. Overall, the PK of ozanimod and CC112273 were comparable in UC and RMS patients.
DEVELOPMENT AND VALIDATION OF A MACHINE LEARNING TOOL FOR EARLY DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE IN THE PRIMARY CARE SETTING: A POPULATION BASED STUDY
Authors: Ber Tahel Ilan , Tov Amir Ben , Gazit Sivan , Steinberg-Koch Shlomit , Getz Benny , Jenudi Yonatan , Underberger Dan , Ramni Or , Ben-Horin Shomron 
Published: January 2022

Abstract

BACKGROUND
Although 3,000,000 Americans are afflicted with Inflammatory Bowel Disease (IBD) encompassing Crohn’s Disease (CD) and Ulcerative Colitis (UC)1, timely diagnosis is a challenge due to non-specific and overlapping symptoms.2 More than 20% of patients may be initially misdiagnosed3 causing delayed diagnosis and treatment, potentially leading to increased risk of complications2 and irreversible mucosal damage.4 Artificial intelligence (AI) models can alert physicians to patients who would otherwise be misdiagnosed, potentially improving patient outcomes and reducing costs. We aimed to develop PredictAI, a proprietary AI Gradient Boosted Decision Tree based machine learning algorithm and test its accuracy in identifying undiagnosed CD and UC in the primary care setting.

METHODS
This was a retrospective study of 2,471,267 patients’ electronic medical records (EMR) from Maccabi Healthcare Services in Israel. Sufficient data was available between the years 2010-2020, of which 2 consecutive years (2015-2016) were pre-assigned to the test set. Inclusion criteria were: (i) CD or UC ICD code as defined by Maccabi’s Registry,5 (ii) no other autoimmune disease diagnosis, (iii) at least 4 years of data antedating first suspicion by primary care physician (PCP) of IBD were available. First suspicion was defined as any diagnostic test, procedure, or referral to a specialist, indicating suspicion of IBD. Here we included adult data only.

RESULTS
Of 2,471,267 patients, 1,214 had a first-time diagnosis of IBD and available antedating data in the years 2015-2016. Of these, PredictAI identified 126, 120, 104, 93 patients 1, 2, 3 and 4 years prior to initial PCP suspicion, respectively. For CD, it predicted 83/229 (36%) of patients 1 year prior to PCP initial suspicion of disease, 70/211 (33%) patients 2 years prior, 60/179 (33%) patients 3 years prior and 56/148 (38%) patients 4 years prior. Discriminatory accuracy area under the curve (AUC) was 76%, 75%, 75% and 78%, 1, 2, 3 and 4 years before initial PCP suspicion, respectively (Figure 1). Corresponding early-identification ratio and discriminatory accuracy for UC was 42/238 (17%, AUC=71%), 50/225 (22%, AUC=70%), 44/187 (23%, AUC=72%) 37/161 (23%, AUC=74%), for 1,2,3 and 4 years before initial PCP suspicion of UC, respectively (Figure 2). Specificity for CD and UC each was above 90%.

CONCLUSIONS
PredictAI accurately identified CD and UC diagnosis in 17-38% of patients presenting to primary care up to 4 years prior to PCP’s initial suspicion, potentially reducing time to diagnosis.
REAL-TIME CONTINUOUS REPORTING OF IBD BIOMARKERS IN SWEAT
Authors: Jagannath Badrinath , Pali Madhavi , Lin Kai-chun , Sankhala Devangsingh , Sardesai Abha , Muthukumar Sriram , Prasad Shalini 
Published: January 2022

Abstract

INTRODUCTION
Calprotectin and C-reactive protein (CRP) are key biomarkers to assess a flare-up and inflammation in IBD patients. Flare-ups in IBD patients can create excruciating pain, discomfort, and occur in a random way. Therefore, continuous monitoring of these biomarkers in real-time can aid in providing active feedback and decision support on the health state for better IBD patient management. This work demonstrates a novel way of empowering IBD patients with actionable data through capturing temporal profiles of IBD markers (Calprotectin and CRP) from sweat for patient-driven outcomes.

MATERIALS AND METHODS
10 healthy and one IBD subject were recruited in compliance with an approved IRB at UT Dallas. The levels of Calprotectin were quantified using the SWEATSENSER and ELISA. The basal levels of Calprotectin were compared between healthy and IBD cohort. Further, the wearable SWEATSENSER was used to measure CRP and Calprotectin continuously for a minimum of 6 hours. The levels of the study biomarkers were compared between healthy and IBD subjects to determine the statistical significance in differentiating between both the cohorts.

RESULTS
CRP levels between healthy and IBD subjects were measured through continuous monitoring using the SWEATSENSER for up to 24 hours over multiple days. Figure 1A shows a comparison between healthy (n=108 data points) and IBD (n=43 data points) CRP levels in sweat and a statistically significant difference between(p&lt;0.05) was achieved. The levels were computed as a time-average of every 2 hours. Further, healthy calprotectin levels ranged 379 ng/mL while, the basal levels in IBD subject were reported to be 620 ng/mL as demonstrated in Figure 1B. The basal levels of calprotectin were significantly different between healthy and IBD subjects confirming the first proof-of-feasibility of real-time monitoring of IBD markers from sweat in detecting elevated IBD levels and an impending flare-up.

CONCLUSION
The SWEATSENSER device can differentiate the marker levels between healthy and IBD subjects. The developed device can be useful in better management of IBD patients by monitoring biomarker levels in real-time to report an impending flare-up. Further, the feasibility of real-time monitoring of CRP and Calprotectin using SWEATSENSER enables actionable data to patients during transition from remission to relapse of the disease. This is the first in-human demonstration of a wearable technology for tracking and stratification between healthy and IBD subjects.
AMINO ACID SENSING PATHWAYS IN INFLAMMATORY BOWEL DISEASE
Authors: Solanki Sumeet , Lee Jun-Hee , Shah Yatrik 
Published: January 2022

Abstract
IBD is a chronic inflammatory disease of the gastrointestinal tract affecting millions of people worldwide. The last few decades have seen rapid increase of IBD cases in the US contributing to exorbitant health-care costs and morbidity rates. IBD comprises of two major subtypes: ulcerative colitis and Crohn’s disease. Although the etiology of IBD is not completely understood, a complex interaction of environmental, genetic, immune, and gut microbial factors contributes to its pathogenesis. These factors ultimately converge to disrupt intestinal epithelial cell homeostasis, compromising mucosal barrier function, leading to unresolved relapsing inflammatory injury. Poor dietary habits such as Western diet are thought to play a pivotal role in the development of colitis. A healthy and balanced diet is important in management of the disease. Epidemiological and experimental studies demonstrate that high-protein diet triggers inflammatory flares and colitis patients are often advised to reduce animal dietary protein. However, colitis patients are also at high risk of a protein malnutrition. Thus, the precise mechanisms by which low dietary protein increases incidence of colitis and/or aggravate already established disease remains unknown.
Our preliminary findings suggest that low dietary protein intake aggravated dextran sulfate sodium (DSS)-induced colitis with reduced body weight, colon length and increased histological injury. Dietary habits impact intestinal epithelial cell homeostasis and regeneration process in the event of an injury. The mechanistic target of rapamycin complex 1 (mTORC1), a ‘master’ regulator of cell growth participates in intestinal tissue regeneration. Remarkably, studies inhibiting mTORC1 activity have shown to disrupt the regenerative capacity of intestinal epithelium and increased susceptibility to colitis while activating mTORC1 had a positive effect. As amino acids potently activate mTORC1, we assessed and found that low dietary protein significantly reduce colonic mTORC1 activation. The newly discovered GAP activity towards Rags (GATOR1 & GATOR2) complexes act as amino acid sensing pathways by which mTORC1 activity is modulated. GATOR1 is a negative regulator, whereas GATOR2 is a positive regulator of mTORC1. CRISPR/CAS9 knockout of Wdr24 (GATOR2) led to inactivation of mTORC1 under amino acid culture conditions. Next, we investigated the role of amino acid sensing pathway in colitis models and found that disruption of intestinal epithelial specific GATOR2 complex (Wdr24ΔIE) attenuated mTORC1 activity and increased susceptibility to colitis. These findings suggest that low protein diet impacts colitis by modulating the intestinal epithelial amino acid sensing pathway.
CORRELATION OF PUCAI BETWEEN MAYO ENDOSCOPIC AND GEBOES PATHOLOGY SCORES IN ASSESSING DISEASE ACTIVITY OF PEDIATRIC PATIENTS WITH UC AMONG HISPANICS AND NON-HISPANICS
Authors: Durazo Francisco , Michail Sonia 
Published: January 2022

Abstract

BACKGROUND
Disease activity in ulcerative colitis (UC) has traditionally been assessed by clinical scoring systems, including the pediatric ulcerative colitis activity index (PUCAI), a non-invasive, reliable way to monitor disease severity and the therapeutic efficacy of interventions in pediatric UC. Practice guidelines have recommended the use of PUCAI in routine clinical pediatric care. Therefore, we aim to investigate the correlation of PUCAI with the endoscopic assessment of disease activity (Mayo endoscopic score) and histologic features of mucosal inflammation (Geboes pathology grading score) in a Hispanic pediatric UC population compared to a non-Hispanic pediatric population.

METHODS
We conducted a retrospective study in pediatric patients aged 7 - 21 with UC enrolled at Children’s Hospital of Los Angeles. We first assess the distribution of the PUCAI, the Mayo, and the Geboes grading scales of disease activity (0=remission, 1=mild, 2=moderate, 3=severe) of the Physician Global Assessment (PGA). Reviewed data was collected directly from the physician report or calculated retrospectively using clinic notes. Although different pathologists graded the samples, the Geboes score is used as a department-wide standard for grading UC. Spearman correlation coefficient was assessed to measure the degree of linear association between two order-valued variables. Bootstrap simulations were used to calculate 95% confidence intervals, and approximate permutation tests were applied to compare these correlations between Hispanics and Non-Hispanics.

RESULTS
In total, 172 patients fit our inclusion criteria. Overall, a modest correlation between PUCAI with the Mayo endoscopic and Geboes pathology grading scores was observed (0.72 and 0.68). The PUCAI-Endoscopic correlations were 0.65 and 0.79 for Hispanics and non-Hispanics, respectively (p-value of difference = 0.084). The correlations between Geboes pathology and PUCAI grading scores were weaker but still larger for non-Hispanics (0.73) than Hispanics (0.64). A linear relationship between PUCAI scores and the two gradings scores, Mayo endoscopy and Geboes pathology, is shown in Figure 1 (p for trend &lt; 0.001).

CONCLUSION
Endoscopic/pathology disease severity generally correlates with clinical disease activity measured by PUCAI score. The PUCAI correlated well with the endoscopy/pathology scores in severe clinical disease, and an agreement was less robust in assessing UC patients’ mild to moderate disease activity. However, the strength of the association varies by ethnic background. Hence, caution should be exercised when using the PUCAI score to assess UC disease activity in Hispanic pediatric patients.