bluuebunny/crossref_metadata_2025_split huggingface dataset:
705 Tofacitinib for the Treatment of Ulcerative Colitis: An Update on the Analysis of Malignancy Rates From the UC Clinical Program
Authors: Lichtenstein Gary R. , Ciorba Matthew A. , Rogler Gerhard , Quirk Daniel , Thorpe Andrew J. , Pedersen Ronald D. , Lawendy Nervin , Chan Gary , Panés Julian 
Published: October 2019

INTRODUCTION:
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the UC clinical development program as of Sep 2018.

METHODS:
Malignancies were evaluated from 4 randomized placebo (PBO)-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], 1 maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612).
1–3
Three cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or OLE studies). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for malignancies (excl. non-melanoma skin cancer [NMSC]) and NMSC. For Overall Cohort analysis, pts were categorized based on the average daily tofacitinib dose: predominant dose (PD) 5 or 10 mg BID. For P3 studies, an independent adjudication committee reviewed all potential malignancies.

RESULTS:
1157 pts were evaluated for malignancies (2404 PY of tofacitinib exposure; up to 6.1 years of treatment). Malignancies (excl. NMSC) occurred in 0 Induction Cohort pts, 1 PBO-treated Maintenance Cohort pt, and 17 Overall Cohort pts (IR 0.69; 3 received a PD of tofacitinib 5 mg BID [IR 0.49] and 14 a PD of 10 mg BID [IR 0.75]; Table 1). NMSC occurred in 2 tofacitinib-treated Induction Cohort pts, 4 Maintenance Cohort pts (3 with 10 mg BID-treated pts, IR 1.91; and 1 PBO-treated pt, IR 0.97), and 19 Overall Cohort pts (IR 0.78; 4 had received a PD of 5 mg BID and 15 a PD of 10 mg BID).

CONCLUSION:
Malignancies (incl. NMSC) were observed with tofacitinib in UC. There was no malignancy type clustering (excl. NMSC). The IR of malignancies (excl. NMSC) reported here is similar to those previously reported for UC [4] – suggesting no treatment duration impact on the IR – and for tofacitinib in pts with rheumatoid arthritis and in pts with UC treated with biologics.
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710 Relationship Between Partial Mayo Score and Patient-Reported Outcomes for Ulcerative Colitis Patients in the United States
Authors: Ding Zhijie , Obando Camilo , Izanec James , Sikirica Mirko , Lucas James , Kemp Jessalyn , Muser Erik 
Published: October 2019

INTRODUCTION:
Measuring Patient-Reported Outcomes (PROs) is important in understanding how ulcerative colitis (UC) patients perceive their own health status and emotional well-being. This study aims to establish the association between PROs and disease severity measured by partial Mayo score (PMS) using real-world data.

METHODS:
Data were drawn from the Adelphi Disease Specific Programme (a real-world survey of gastroenterologist-completed retrospective chart review and patient self-completion questionnaires) conducted in the US in 2015 and 2017. UC patients (pts) with current or history of moderate-to-severe (mod/sev) disease and/or those having ever been treated with steroids, an advanced therapy (immunomodulator or biologic therapy) or ever had a Mayo score >4 were included in the analysis. Pts self-completed a form containing the EQ-5D and the SIBDQ. Comparisons between pts with a PMS of 0-1 (remission), 2-4 (mild) and 5-9 (mod/sev) at the time of the survey were made using Kruskal-Wallis and Chi-squared tests for continuous and categorical variables, respectively.

RESULTS:
Of the 1389 UC pts included, 410 were classified as being in remission, 646 mild and 333 mod/sev based on PMS at the time of completing the survey. Remission patients had a mean age of 44.8 years, mild 42.6 and mod/sev 39.4 (P < 0.001), with 48.8%, 52.2% and 45.9% female (P = 0.166) and 7.0, 4.5 and 3.0 mean years since diagnosis (P < 0.001), respectively. 7.4% of remission pts, 16.8% mild and 66.8% of mod/sev were currently experiencing a flare or flare-like symptom (P < 0.001). Remission pts had a higher mean overall SIBDQ score compared with mild and mod/sev (Table 1), and higher systemic, social, bowel and emotional subdomain scores (Table 1). Remission pts had a higher EQ-5D score and EQ-5D VAS compared with mild and mod/sev pts. Compared with those of remission patients, subdomains of usual activities, pain/discomfort and anxiety/depression for mod/sev patients were significantly impacted, whilst mobility and social care subdomains showed no significant differences across severity groups.

CONCLUSION:
UC pts with more severe disease according to the PMS self-reported lower quality of life in terms of overall SIBDQ score and worse individual subdomain scores compared to mild patients and patients in remission. They were also more likely to report lower EQ-5D score, likely driven by a significant impact on usual activities, pain/discomfort, and anxiety/depression subdomains.
712 Predictors of Ectopic Pregnancy Among Women With Inflammatory Bowel Disease: A Population-Based Cohort Analysis
Authors: Berera Shivali , Saxena Akriti P. , Dalal Rahul S. , Lichtenstein Gary R. 
Published: October 2019

INTRODUCTION:
We have previously demonstrated that there is a higher odds of ectopic pregnancy among women with Crohn's disease (CD) but not ulcerative colitis (UC) compared to those without inflammatory bowel disease (IBD) (Gastroenterol 2019 Abstract 1861). We aimed to further characterize underlying predictors and the incidence rates of ectopic pregnancies over time in this cohort.

METHODS:
A population-based retrospective cohort study using the Healthcare Cost and Utilization Project's (HCUP) Nationwide Inpatient Sample (NIS) was performed from 2005 to 2014. The NIS is the largest all-payer inpatient health care database in the United States. Unique pregnancies were identified using ICD-9-CM diagnosis and procedure codes. National estimates of ectopic pregnancy were created using appropriate weights for each NIS admission. Multivariable logistic regression was used to evaluate the association of UC and CD with ectopic pregnancy while adjusting for age, race, income, primary insurance, hospital size, hospital region, Charlson-Deyo comorbidity index, obesity, chronic steroid use, smoking status, and prior cesarean section. The trend in the incidence rate of ectopic pregnancy was plotted and compared in IBD and non-IBD patients within the study period.

RESULTS:
There were significantly higher rates of ectopic pregnancy in patients with CD versus non-IBD patients (1% vs 0.6%, P < 0.001) and patients with UC (0.5%). Observed predictors for ectopic pregnancy included lack of insurance, higher comorbidity index, chronic steroid use, and smoking (Table 1). While the rate of ectopic pregnancy declined in all patients during the time period, the overall incidence rate was highest in patients with IBD (Figure 1). While further exploring this trend, the incidence of ectopic pregnancy in IBD patients was observed to be higher in age groups 31-40 and 41-50 as compared to younger counterparts (Figure 2a) and patients without IBD (Figure 2b).

CONCLUSION:
Compared to women without IBD, the odds of a pregnancy being ectopic is higher among women with CD but not UC, particularly in patients with lack of insurance, higher comorbidity index, chronic steroid use, and smoking. While the incidence rate of ectopic pregnancy is declining in both patients with and without IBD, older individuals with IBD have an increased risk of ectopic pregnancy compared with younger patients and non-IBD patients. Prospective studies are warranted to further examine this trend and identify mechanisms behind these associations.
714 Increased Risk of Colectomy in Hospitalized Patients With Inflammatory Bowel Disease and Cytomegalovirus Infection
Authors: Castaneda Daniel , Melendez-Rosado Jose , Hasan Badar , Charles Roger 
Published: October 2019

INTRODUCTION:
Patients with inflammatory bowel disease (IBD) present flares during the disease course, which could be triggered by aggressive disease, infection, microbiota changes or medication compliance, among other. Cytomegalovirus (CMV) infection has been found to be more prevalent among IBD patients requiring hospitalization. The aim of this study is to compare the inpatient outcomes for patients admitted with an IBD flare with and without concomitant CMV infection.

METHODS:
This was a retrospective cohort study using the 2014 National Inpatient Sample, the largest publicly available inpatient database in the United States. Inclusion criteria were age older than 18 years and a primary ICD-9 CM code for any diagnosis of IBD flare. There were no exclusion criteria. The primary outcome was in-hospital mortality. The secondary outcomes were morbidity measured by intensive care unit (ICU) admission, shock, multi-organ dysfunction syndrome (MODS), malnutrition and need for partial/total colectomy, and resource utilization measured by length of hospital stay (LOS), total hospitalization charges, ultrasound (US), CT abdomen and colonoscopy need. Patients with IBD flare were classified as having or not CMV infection diagnosis using ICD-9 CM codes. Odds ratios and means were adjusted for the following confounders using multivariate regression analysis models: age, sex, race, median income in the patient's zip code, hospital region, rural location, size and hospital teaching status.

RESULTS:
90,920 patients with IBD flare were included in the study, from which 195 (0.21%) had a diagnosis of CMV infection. Mean age was 42.4 years and 53.5% of patients were female. The population was predominantly Caucasian (73%). The in-hospital mortality was higher among patients without CMV infection (0.28% vs 0%). On multivariate analysis, patients with CMV infection had higher risk of undergoing total/partial colectomy (OR 6.72, P < 0.01) and need for colonoscopy (OR 6.72, P = 0.01), with longer LOS and higher hospital charges (P < 0.01). There were no differences for other markers of morbidity or resource utilization. All adjusted odds ratios, adjusted means and P values are shown in Table 1.

CONCLUSION:
CMV coinfection in patients admitted to the hospital with IBD flare had higher odds of undergoing colectomy, while presenting higher hospitalization costs and length of stay. However, no impact in mortality was found in this specific group.
719 Utilization Analysis of a Treat to Target Approach for Inflammatory Bowel Disease: A Multi-Center Health Care System Review
Authors: Berkowitz Joshua , Becher Noah , Shah Samip , Swaminath Arun , Sultan Keith 
Published: October 2019

INTRODUCTION:
A treat-to-target (TT) strategy, setting mucosal healing (MH) in inflammatory bowel diseases (IBD) as the desired treatment endpoint, is currently favored by experts. Advocates of this approach recommend the intensification of medical therapy to reach the goal of MH, even in patients who are in steroid free clinical remission. The utilization and practice of the TT strategy is unknown.

METHODS:
A retrospective chart review was performed for all IBD patients in the Northwell Health system to identify those in clinical remission who underwent colonoscopy between 01/01/2016 and 12/31/2018. Clinical remission at the time of colonoscopy was defined by a stable, steroid free IBD drug regimen and no IBD related surgery or hospitalization for 6 months prior. Patients in clinical remission but without MH reported on colonoscopy were defined as TT candidates. Demographic and treatment data were extracted from the medical record. We examined the frequency and type of TT utilization, defined as escalation of medical therapy within 1 month of the index colonoscopy. Analysis of variables associated with TT utilization was performed using the chi-square test.

RESULTS:
960 patients had a colonoscopy by 34 different gastroenterologists during the study period. 382 patients met criteria for clinical remission, 248 of whom had gross disease activity classifying them as TT candidates, Table 1. None of the 134 patients with MH had a change in their medication regimen within 1 month of colonoscopy. Among TT candidates 42 (16.93%) had utilization of TT during the 1 month follow-up. Patients utilizing TT were more likely to have no baseline medication use, 39.5% vs. 20.87 (P = 0.0102). There was decreased utilization of TT among those patients already using immunologic and/or biologic therapies, 21.42% vs. 38.88% (P = 0.03), Table 2. Patients utilizing vs. not utilizing TT where similar by age, gender, IBD type, and CD surgical history. For patients utilizing TT, strategies included initiation or modification of biologic therapy more commonly among CD vs. UC/indeterminate colitis patients, 64.29% vs. 10.71% (P = 0.0005). TT utilizing 5-ASA was more common for UC/indeterminate colitis vs. CD, 82.14% vs. 35.71% (P = 0.003), Table 3.

CONCLUSION:
We have demonstrated a low rate of TT utilization in our study population. When used, a TT strategy favoring biologic therapy was more common in CD. Further validation of TT, along with physician and patient education, will likely be needed if TT is to become widely adopted.
723 Evolution in Hospitalization and Outcomes of Patients With Inflammatory Bowel Disease: Nationwide Study From 1998-2014
Authors: Radadiya Dhruvil K. , Devani Kalpit H. , Charilaou Paris , Young Mark , Reddy Chakradhar 
Published: October 2019

INTRODUCTION:
Approval of the first biologic agent by the FDA in 1998, revolutionized the management of inflammatory bowel disease (IBD). We hypothesized that this paradigm shift would improve outcomes amongst the hospitalized IBD patients. Hence we investigated the trends in the hospitalization of IBD patients and related outcomes using National database.

METHODS:
We queried the Nationwide inpatient sample (NIS) database from the year 1998 to 2014. Hospitalized adult patient with IBD, i.e., Crohn's disease (CD) or ulcerative colitis (UC), their outcomes and procedures (including surgeries), were identified using ICD-9-CM diagnosis and procedure codes. Trends were analyzed using Cochrane Armitage test for categorical variables and the nonparametric test for continuous variables. We calculated the national estimates using the discharge weights.

RESULTS:
Total of 3,876,583 patient with IBD were included in the study. The mean age of the study population was 57.8 years; females were 57.6% and 67.2% White. Baseline characteristics of the patients, hospital characteristics and insurance types are shown in Table 1. Hospitalization of the patient with IBD nearly doubled from 70/100,000 US adult population to 125/100,000 (Figure 1). Since 1998, inpatient mortality remained stable, with an overall mortality rate of 1.5%. Length of stay (LOS) decreased, a numerically small decrease from 6.2 to 5.5 days, while hospital charges increased from $14,771 to $47,548 (Figures 3 and 4). Prevalence of anemia and transfusion utilization increased to 28.6% and 9.2% respectively in 2014. Co-morbidities such as acute kidney injury (1.4% to 13.2%), venous thromboembolism (1.9% to 3.5%) and Clostridium difficile infection (1.4% to 5.2%) also increased along with hospitalization requiring ICU (1.6% to 3%). However, CD and UC related surgery decreased from 15.9% to 10.7% and 5.7% to 3.5% respectively. Utilization of inpatient lower endoscopy also declined from 23% to 13.1%. Table 2 shows trends in complication, outcomes, and resource utilization over the study period.

CONCLUSION:
Over 17 years, hospitalization of patients with IBD has increased. Mortality, perforation rate, colon cancer prevalence, and LOS remained steady with marginal changes numerically. However, hospitalization charges, along with other co-morbidities/complications related to IBD increased significantly even though utilization of endoscopy and surgery has declined.
725 Acute Vascular Insufficiency of the Intestines in Crohn's Disease: Insights From the Healthcare Utilization Project
Authors: Haq Khwaja F. , Kaur Randeep , Solanki Shantanu , Chandra Chakinala Raja , Iqbal Umair , Bhurwal Abhishek , Khan Zubair , Shah Harshil , Haq Khwaja S. , Burney Azam , Khan Muhammad Ali , Mishra Kajali , Patel Neil , Bhatti Faiza 
Published: October 2019

INTRODUCTION:
Inflammatory bowel disease is associated with increased risk of mesenteric ischemia, likely due to factors such as vascular atherosclerosis caused by long-term inflammation, vasculitis, coagulation abnormalities, and abnormal lipid metabolism. Limited data exists for hospitalizations associated with acute vascular insufficiency of the intestines (AVII) in patients with Crohn's disease.

METHODS:
We analyzed the National Inpatient Sample (NIS) database for the years 2005-2011 to identify hospitalizations with Crohn's disease (ICD-9 CM code 555.0, 555.1, 555.2, and 555.9). Hospitalizations complicated by AVII (ICD-9 CM code 557.0) in this cohort were then identified. NIS is the largest all-payer inpatient care database in the United States, containing data on more than seven million hospital stays each year. Its large sample size is ideal for developing national and regional estimates and enables analyses of rare conditions, uncommon treatments, and special populations. Temporal trends of AVII in this cohort, patient demographics, comorbidity measures, and outcomes during the study period were determined using Cochran-Armitage trend test.

RESULTS:
Between 2005 and 2011, hospitalization with CD increased from 56,739 to 65,281 (P-trend < 0.0001, Figure 1a). The proportion of hospitalizations complicated by AVII increased from 0.14% in 2005 to 0.28% in 2011 (P-trend < 0.0001, Figure 1b). AVII was more common in women (57.9%) (P-trend = 0.0007, Figure 1c) and in Caucasians (64.7%). All-cause inpatient mortality increased from 6.3% to 7.6% (P = 0.001, Figure 1d). Analysis of the Agency for Healthcare Research and Quality (AHRQ) comorbidity measures revealed that hypertension, renal failure and psychiatric disorders were some of the most commonly associated comorbidities (Figure 2).

CONCLUSION:
A significant increase in the number of hospitalizations for CD complicated by AVII was seen during the study period. Caucasians and women were more commonly affected than other groups. There was also an increase in the in-hospital mortality associated with these hospitalizations. Although hypertension, renal failure and psychiatric disorders were more commonly associated with AVII in Crohn's disease hospitalizations, there were several other comorbidities including diabetes mellitus, obesity and chronic pulmonary disease that showed increasing trends. Further studies are needed to identify predictors of these trends and factors responsible for such outcomes to better elucidate and perhaps support our findings.
726 Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates in the Tofacitinib Ulcerative Colitis Clinical Program
Authors: Winthrop Kevin L. , Loftus Edward V. , Baumgart Daniel C. , Salese Leonardo , Thorpe Andrew J. , Lawendy Nervin , Chan Gary , Pedersen Ronald D. , Reinisch Walter 
Published: October 2019

INTRODUCTION:
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety in patients (pts) with UC was evaluated in an 8-week induction Phase (P) 2 study (NCT00787202),
1
2 8-week induction P3 studies (OCTAVE Induction 1 & 2; NCT01465763 & NCT01458951),
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a 52-week maintenance P3 study (NCT01458574), and an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612).
3
We present updated infections data (Sep 2018) from the tofacitinib UC clinical program.
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METHODS:
Pts receiving placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as Induction (P2 & P3, n = 1220), Maintenance (P3, N = 592), and Overall (pts in P2, P3 & OLE receiving tofacitinib 5 or 10 mg BID, N = 1157 [Sep 2018]) Cohorts. Proportions and incidence rates (IRs; pts with events per 100 pt-years [PY] of exposure) were evaluated for infections of special interest (incl. serious infections [SIs], opportunistic infections [OIs; independently adjudicated], and herpes zoster [HZ]).

RESULTS:
A total of 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID (83% predominantly 10 mg BID [avg. daily dose ≥15 mg]), with 2403.6 PY of exposure (median 623 days, up to 6.1 years of treatment). The Table 1 shows infection IRs by Cohort. In the Overall Cohort, nasopharyngitis was the most frequent infection. For SIs, the Overall Cohort “Tofacitinib All” IR (1.75 [95% CI 1.27, 2.36]) was similar to the Maintenance Cohort IRs for tofacitinib 5 and 10 mg BID. No SIs resulted in death. OIs were infrequent (28 pts) and most were HZ (24 pts; IR 0.99 [95% CI 0.63, 1.47]), mostly cutaneous. Not all HZ events were OIs; 83 pts overall had HZ events (IR 3.57 [95% CI 2.84, 4.43]; 6 serious).

CONCLUSION:
In induction, SIs and OIs occurred with tofacitinib but not with placebo. Overall, SIs were generally infrequent and Overall Cohort IRs did not suggest increased risk with longer tofacitinib treatment vs the Maintenance Cohort. Non-HZ OIs were rare. SI incidence was similar in the UC and rheumatoid arthritis programs (incl. increased HZ risk)
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and to other UC therapies incl. biologics.
7
730 Safety, Pharmacokinetics, and Pharmacodynamics of the Novel Oral Peptide Therapeutic PN-10943 (alpha4beta7 Integrin Antagonist) in Normal Healthy Volunteers
Authors: Gupta Suneel K. , Cheng Xiaoli , Kanwar Bittoo , Matheakis Larry , Bhandari Ashok , Liu David , Shames Rich 
Published: October 2019

INTRODUCTION:
Oral gut-restricted α4β7 integrin peptide antagonists represent a new therapeutic strategy for IBD. An example is PTG-100, which in a recent Phase 2 study was associated with higher rates of clinical and histologic remission relative to placebo in ulcerative colitis patients (Sandborn et al, UEGW 2018). PN-10943 is an oral, gut-restricted, potent, and highly selective α4β7 integrin antagonist peptide that has demonstrated preclinical superiority to PTG-100 (Mattheakis et al, DDW 2019). The purpose of this first-in-human Phase 1 study with PN-10943 was to assess safety, tolerability, PK, and PD activity in NHV and confirm previous preclinical observations.

METHODS:
A randomized, placebo-controlled Phase 1 trial of single (SAD) and multiple (MAD) ascending doses of PN-10943 was conducted in 70 male NHV. MAD regimen consisted of 14 daily doses. Subjects are monitored for safety and tolerability while undergoing serial plasma PK and blood PD evaluations as measured by integrin receptor occupancy (RO) and expression (RE) on circulating α4β7+ lymphocyte subsets.

RESULTS:
In the SAD portion of the study, 100, 300, 1000, and 1400 mg cohorts were dosed with no serious adverse events or dose-limiting toxicities. All adverse events were of mild to moderate severity and resolved without complication. In the MAD portion of the study doses studied were 100, 300, & 1000 mg for 14 days. Peak plasma concentration (Cmax) and area under the curve increased in a dose proportional manner and plasma pharmacokinetics were also time invariant between day 1 and day 14 in the MAD cohort. There was a significant dose dependent increase in RO of blood memory T cells (reaching >90% in the 1000 mg cohort). RE of α4β7 on blood memory T cells decreased in a dose dependent manner consistent with α4β7 internalization. The PD responses strongly correlated with plasma Cmax, and the binding activity from subject/time-matched RO on α4β7 memory T cells was comparable to that demonstrated in preclinical studies.

CONCLUSION:
Following oral administration in NHV, PN-10943 was well tolerated. As expected, plasma exposure was very low, and there was significant dose-related PD. The Phase 1 PK/PD relationship confirms previous preclinical observations in which PN-10943 demonstrated superiority to PTG-100. These Phase 1 PD data for PN-10943 together with the previous clinical activity of PTG-100 suggest that PN-10943 may potentially be an effective oral therapy for the treatment of UC.