bluuebunny/crossref_metadata_2025_split huggingface dataset:
832 Pharmacokinetics and Exposure-Response Relationships of Ustekinumab in Patients With Ulcerative Colitis: Results From the UNIFI Induction and Maintenance Studies
Authors: Adedokun Omoniyi J. , Xu Zhenhua , Marano Colleen , O’Brien Christopher , Szapary Philippe , Zhang Hongyan , Johanns Jewel , Leong Rupert W L , Hisamatsu Tadakazu , Van Assche Gert , Danese Silvio , Abreu Maria T. , Sands Bruce E. , Sandborn William J. 
Published: October 2019

INTRODUCTION:
Serum concentrations of monoclonal antibody-based biologics have been shown to correlate with their efficacy. PK, exposure-response (ER), and immunogenicity of ustekinumab (UST) were evaluated in UNIFI induction and maintenance studies in UC. Induction results were presented previously.

METHODS:
PK, immunogenicity, efficacy & safety data were obtained from induction and maintenance Phase 3, double-blind, PBO-controlled trials in adults with moderate-severe UC. Pts (n = 961) in the induction study received a single IV infusion at Wk0 of PBO, UST 130 mg, or UST ∼6 mg/kg UST. Responders to a single IV infusion of UST (n = 523) were randomly assigned to receive SC PBO, UST 90 mg q12w, or UST 90 mg q8w. Blood samples were collected to measure serum UST concentration and antibodies to ustekinumab. Relationships between serum UST concentrations & efficacy measures, and safety outcomes were evaluated.

RESULTS:
Serum UST concentrations over time were dose proportional, unaffected by concomitant immunosuppressants, & similar between pts who were biologic failures & non-failures. Median peak serum UST concentrations in the induction study were 43.2 μg/mL & 127.0 μg/mL for the 130 mg & ∼6 mg/kg dose groups, respectively. At induction Wk8, median UST concentrations were 2.51 μg/mL & 8.59 μg/mL, respectively. Steady-state was reached by the start of the second SC maintenance dose. Median steady-state trough serum UST concentrations over time in the UST q8w group (2.69 to 3.09 μg/mL) were 3-fold higher than in the q12w group (0.92 to 1.19 μg/mL). Serum UST concentrations were positively associated with response & remission rates (Table 1), and there was an inverse association between serum UST concentrations and CRP and fecal calprotectin levels. No relationship was observed between serum UST concentrations & the incidence of infections, serious infections or SAEs during induction or maintenance. 3.4% of pts receiving UST maintenance had antibodies to UST through 1 year using a drug-tolerant assay vs. 9.1% with PBO; no impact of antibodies on efficacy was observed.

CONCLUSION:
Serum UST concentrations were approx. dose-proportional. A positive ER of serum UST with clinical efficacy measures and an inverse relationship with inflammatory markers was observed during UST IV induction & SC maintenance. Adverse events including infections did not increase with increased serum UST concentrations. These findings are consistent with those in UST for Crohn’s disease.
837 Short Chain Fatty Acid Profiles Are Altered by Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease and Recurrent Clostridioides difficile Infection
Authors: Allegretti Jessica R. , Mullish Benjamin , Hurtado Jonathan , Carrellas Madeline , Marcus Jenna , Phelps Emmalee , Pettee William , Marchesi Julian , McDonald Julie A.K. , Barker Grace , Blanco Jesus Miguens , Garcia Perez Isabel , Kelly Colleen R. , Grinspan Ari , Fischer Monika 
Published: October 2019

INTRODUCTION:
Recurrent C. difficile infection (rCDI) is a major challenge among patients with inflammatory bowel disease (IBD). Perturbation of microbiota-mediated metabolism of short chain fatty acids (SCFA) has been reported in IBD patients. Fecal microbiota transplantation (FMT), an established therapy for rCDI, alters gut microbiota composition, but effects on SCFA are unclear. Accordingly, this study assessed SCFA profiles in IBD patients with rCDI pre- and post-FMT.

METHODS:
This open-label, prospective, single-arm multi-center cohort study enrolled patients from 4 tertiary care centers. Patients with IBD and ≥2 episodes of CDI received a single colonoscopic FMT from a universal stool bank. The primary outcome was CDI recurrence up to week 8 defined as diarrhea and EIA-positive toxin testing for C. difficile. Stool for metabolomic profiling was collected pre-FMT and week 1, 8 and 12 weeks post-FMT. A targeted gas chromatography-mass spectrometry protocol was used for the identification and quantification of SCFA. SCFA concentrations were analyzed via univariate analysis, comparing groups (e.g. pre- vs post-FMT).

RESULTS:
37 participants were enrolled, with mean age of 37.6 years (range 20-76) and primarily female (n = 21, 57%). 14 had Crohn’s disease (CD) (mean HBI = 6.4) and 23 had ulcerative colitis (UC) (mean Partial Mayo Score = 4.5). Mean baseline fecal calprotectin was 1804.8 +/- 2307.7 Overall, 3 participants (8%) experienced FMT failure with confirmed EIA-positive stool, and the there were no related serious adverse events. Among the nine SCFAs assessed, including two branched chain fatty acids (isovalerate and isobutyrate) most were significant altered by FMT, with rapid and sustained changes (with the exception of acetate, in which no change was appreciated) (Figure 1). Additionally, 2-hydroxybutyrate and lactate, two markers of metabolic stress, were significantly reduced after FMT. Furthermore, the baseline stool samples of those who went on to recur were compared to those who did not (Figure 2); though not significant, there was a trend towards reduced baseline levels for butyrate, propionate and caproate among those who recurred.

CONCLUSION:
To our knowledge, this is the largest prospective trial to assess the effect of FMT in patients with IBD-CDI. The data suggests the efficacy and safety profile is better than previous reports. SCFAs were increased significantly post-FMT, and may offer insight into mechanism of clinically efficacy seen in this study.
840 Patient Characteristics and Outcomes Associated With Cannabis Abuse or Dependence Among Hospitalized Patients With IBD: A U.S. Time-Trend Analysis and Population-Based Cohort Study
Authors: Dalal Rahul S. , Lichtenstein Gary R. 
Published: October 2019

INTRODUCTION:
Cannabis is a commonly used yet restricted substance with potential anti-inflammatory and analgesic properties. Patients with inflammatory bowel disease (IBD) use cannabis specifically for symptom relief, however its safety and efficacy in ulcerative colitis (UC) and Crohn’s disease (CD) are poorly characterized. Among hospitalized patients with IBD, temporal trends of heavy cannabis use and its effects on hospitalization outcomes are unclear. We therefore attempted to assess yearly trends in cannabis abuse or dependence (CAoD) and associated hospitalization outcomes among hospitalized patients with IBD.

METHODS:
This was a retrospective population-based cohort study utilizing the Healthcare Utilization Project (HCUP) National Inpatient Sample (NIS) database from 2005 to 2014. We performed a time-trend analysis of CAoD among IBD patients using International Classification of Disease, ninth revision clinical modification (ICD-9-CM) diagnosis codes for cannabis dependence, non-dependent cannabis abuse, CD, and UC, in any diagnosis position. For a multivariable analysis of the effect of CAoD on hospitalization outcomes, IBD-specific hospitalizations were identified by a primary diagnosis of IBD or a secondary diagnosis of IBD with a primary diagnosis of an IBD-related complication. Multivariable linear or logistic regression was used to assess the association of CAoD on hospital length of stay (LOS), total charges, in-hospital mortality, and IBD surgery. The weighted NIS sample was used for all analyses.

RESULTS:
Between 2005 and 2014, we identified 2,788,246 discharges with a diagnosis of IBD and 1,049,837 discharges for IBD-specific hospitalizations, among which 10,293 (1.0%) were associated with CAoD. Among those with CAoD, 74.9% had CD (vs. 25.1% UC, P < 0.01), 64.9% were male, 56.9% were cigarette smokers, and 38.6% were in the 21-30 y age group (Table 1). There was an average annual increase of 9.1% (P < 0.01) for CAoD among hospitalized IBD patients from 2005 to 2014 (Figure 1). After multivariable regression, CAoD was independently associated with decreased LOS (-0.4 d; 95% CI -0.6–-0.2 d) and odds of IBD surgery (OR 0.8, 95% CI 0.7–0.9) (Table 2). There was no association with total charges and no IBD patients with CAoD died during their hospitalization.

CONCLUSION:
CAoD may be associated with decreased LOS and odds of IBD-related surgery among hospitalized IBD patients. Further research is needed to assess the impact of heavy cannabis use on long-term outcomes in patients with IBD.
842 Impact of Response and Inflammatory Burden at Start of Maintenance Therapy on Clinical Efficacy of Ustekinumab Dosing Regimen in UC: Week 44 Results From UNIFI
Authors: Panaccione Remo , Peyrin-Biroulet Laurent , Danese Silvio , Marano Colleen , O’Brien Christopher D. , Szapary Philippe , Zhang Hongyan , Johanns Jewel , Leong Rupert W L , Arasaradnam Ramesh P. , Rowbotham David , Abreu Maria T. , Sands Bruce E. 
Published: October 2019

INTRODUCTION:
The UNIFI maintenance study was a Phase 3, double-blind, placebo-controlled, randomized-withdrawal study in pts with moderate to severely active ulcerative colitis (UC) who failed conventional or biologic therapy and were in clinical response 8 wks after receiving a single ustekinumab (UST) IV induction dose. In this study, pts were randomized to placebo, UST 90 mg SC q8w or q12w.

METHODS:
To examine the relative efficacy of the UST 90 mg SC q8w or q12w maintenance regimens, subgroup analyses were performed for outcomes of clinical remission, symptomatic remission, and endoscopic improvement at Wk44 for pts who did and did not achieve these endpoints at the start of maintenance. Analyses of clinical remission and endoscopic improvement at Wk44 based on pre-specified cut-points of the concentrations of inflammatory biomarkers (CRP [≤3 mg/L, >3 mg/L] and fecal calprotectin [≤250 mg/kg, >250 mg/kg]) at maintenance baseline were also conducted.

RESULTS:
For pts who had achieved clinical remission, symptomatic remission, or endoscopic improvement at maintenance baseline, efficacy of UST q8w and q12w regimens for the respective endpoint at Wk44 was similar (Table 1). By contrast, for pts who did not achieve clinical or symptomatic remission or endoscopic improvement at maintenance baseline, UST q8w demonstrated greater efficacy than UST q12w for that endpoint at Wk44. Pts with low inflammatory burden marked by CRP ≤3 mg/L at maintenance baseline achieved similar efficacy at Week 44 with UST q8w and q12w dosing regimens as measured by clinical remission and endoscopic improvement (Table 1). By contrast, pts with high inflammatory burden, marked by CRP >3 mg/L at maintenance baseline, achieved greater efficacy at Wk44 with UST q8w versus q12w dosing over the endpoints. Generally similar trends were seen in pts with fecal calprotectin measurements for low (≤ 250 mg/kg) and high (>250 mg/kg) inflammatory burden at maintenance baseline.

CONCLUSION:
Among pts with a clinically meaningful response to a single IV induction dose of UST, maintenance treatment with UST q8w or q12w demonstrated similar efficacy at Wk44. By contrast, the efficacy of UST q8w at Week 44 was greater than the q12w regimen for pts with higher inflammatory burden or who did not achieve clinical or symptomatic remission or endoscopic improvement at Wk8. These data suggest that multiple clinical measures can help inform the decision on the most appropriate maintenance dosing regimen for UST in the treatment of pts with UC.
845 Patient and Physician Assessment of Disease Burden in Patients With Early UC: 2-Year Data From ICONIC
Authors: Ghosh Subrata , Sensky Tom , Casellas Francesc , Kligys Kristina , Petersson Joel , Peyrin-Biroulet Laurent 
Published: October 2019

INTRODUCTION:
ICONIC is an observational study assessing disease burden in adults with ulcerative colitis (UC) under routine care over 2 years. The final analysis of the study is presented.

METHODS:
Adults with early UC (diagnosed ≤36 months) were enrolled irrespective of disease severity or treatment. The primary objective was to evaluate Pictorial Representation of Illness & Self-Measure (PRISM) as a tool to assess disease associated suffering. Lower PRISM scores represent greater suffering associated with illness. Correlation between pt and physician perception of disease was also assessed. Patient self-assessments included PRISM, Patient Health Questionnaire-9 (PHQ-9), Short IBD Questionnaire (SIBDQ), and patient-modified Simple Clinical Colitis Activity Index (P-SCCAI). Physician assessments included clinical parameters, PRISM, and SCCAI. Data are presented as-observed. Mean differences between pt and physician measures, and differences between the 2-year and first visits were calculated using Wilcoxon signed-rank test. Correlation between PRISM and SIBDQ, PHQ-9, and SCCAI were performed using Spearman correlation.

RESULTS:
A total of 1806 patients were enrolled; 336 (18.6%) discontinued the study. 2-year data were available for 1265 pts. Mean ± SD patient-reported PRISM score and P-SCCAI were significantly different than the physician measures, with pts reporting higher disease burden than that perceived by the physician (pt PRISM: 5.1 ± 2.5 and physician PRISM: 5.6 ± 2.4; P < 0.0001; P-SCCAI: 2.5 ± 2.8 and SCCAI: 1.3 ± 2.1; P < 0.0001; Table 1). A high correlation was observed between pt and physician PRISM scores and between P-SCCAI and SCCAI. Mean ± SD scores for PHQ-9 and SIBDQ were 4.2 ± 4.6 and 55.7 ± 11.6, respectively. Significant differences in mean ± SD scores between the 2-year visit and the first visit were observed for all measures (PHQ-9: -1.8 ± 5.5; P-SCCAI: -1.6 ± 4.0; SCCAI: -1.5 ± 3.2, SIBDQ: 6.8 ± 13.9; patient pt PRISM: 1.2 ± 3.0; physician PRISM: 1.3 ± 2.9; P < 0.0001 for all measures).

CONCLUSION:
PRISM may be a valuable tool to assess disease burden in pts recently diagnosed with UC. Although pt and physician measures of disease related suffering and disease severity were strongly correlated, the perception of UC-related burden significantly differed between physician- and pt- assessments. These discrepancies between pt and physician ratings warrant further investigation.
847 Real World Experience of Ustekinumab for Induction and Maintenance of Remission in Crohn’s Disease: A U.K. Single Center Experience
Authors: Bhandare Anirudh P. , Crooks Benjamin J. , Taylor J , Limdi Jimmy K. 
Published: October 2019

INTRODUCTION:
Ustekinumab(UST),an IgG1 monoclonal antibody targeting IL12/IL23(p40 sub-unit)has been licensed in UK for use in moderate to severe Crohn’s disease(CD) since 2017.We present a real -world experience from our center.

METHODS:
A retrospective analysis of patients commenced on UST was conducted using electronic medical records to evaluate efficacy. Patients were assessed at baseline, induction (week 8) and at 1 year. Our primary end point was reduction in Physicians global assessment (PGA). Secondary endpoints were improvement in CRP (>10 at baseline), Fecal Calprotectin (>250 at baseline) and albumin (<35 at baseline). Concomitant medication and surgical history were also recorded.

RESULTS:
62 patients received UST (42 female; mean age 44.74). Mean age at diagnosis was 33.61 years and average duration of disease was 135 months (median 180, IQR 135.25). Sixteen patients had previous surgery for CD. At baseline 95% patients had PGA of moderate to severe disease with 54 (87%) achieving primary endpoint at induction. 16 patients had annual follow up and 81.25% achieved the primary endpoint. The Harvey Bradshaw index at follow up appointments correlated with the PGA values to account for clinical remission. From baseline to induction, 24 had CRP >10. Of these, 20 (83.3%) patients achieved the secondary endpoint for CRP at induction. At annual follow up 15 patients had CRP recorded, 7 out of them had CRP >10 at baseline and all achieved the secondary endpoint. Albumin was < 35 in 21 patients at baseline and 71.5% showed improvement at induction. At 12 months eight of the above 21 had albumin recorded and 5 achieved the secondary endpoint of improvement in albumin. Fecal calprotectin was elevated in 19 out 47 patients recorded at baseline. Of whom 58% achieved the secondary endpoint. 53 patients (85.5%) had received a previous biologic with 20 receiving Infliximab (IFX), adalimumab (ADA) and vedolizumab (VDZ) prior to UST.15 received only IFX, 11 only ADA and 20 both anti-TNF’s. One patient received IFX and VDZ. Four adverse reactions were noted, 2 had rash after infusion and 1 headache. One patient reported epidydimo-orchitis 7 days post infusion and required hospitalisation. Twelve patients discontinued UST with 6 having surgery and 6 from loss of response (5 secondary and 1 primary loss of response).

CONCLUSION:
UST is effective in induction well as maintenance of remission in CD for biologic experienced and naive patients as also in those with previous surgical resection.There were no significant safety concerns.
848 Comparison of Patient Preferences Between Stool Tests and Colonoscopy for Assessment of Disease Activity in Inflammatory Bowel Diseases
Authors: Barsky Maria , Meserve Joseph , Collins Angelina , Singh Siddharth , Boland Brigid , Sandborn William J. , Dulai Parambir 
Published: October 2019

INTRODUCTION:
Fecal biomarkers are being increasingly suggested as alternatives to colonoscopy for disease activity assessments. We aimed to assess patient preferences between fecal testing and colonoscopy for disease activity assessments.

METHODS:
Prospective interview of UC and CD patients from a single tertiary referral center. A hierarchy matrix survey was built to understand patient preferences around decision making when choosing between approaches (fecal testing or colonoscopy) for achieving a specific goal (monitoring disease activity) based on pre-set criteria (accuracy, preparation, pain, complications). Presumed accuracy of fecal biomarkers was set to 80-90%, and rates of colonoscopy related complication were set to 1 in 100 or 1 in 1,000. Pair wise analyses were used to identify determinants of patient preference and thresholds of acceptability to change preferences.

RESULTS:
N = 100, median age of 44 years (IQR 27-63) with median disease duration of 9 years (IQR 5-21). Disease activity at the time of survey was well distributed with 47% in clinical remission, 24% with mild and 29% with moderate-severe activity. Colonoscopy was the initial preference for 40% of patients and more often being preferred by CD patients (49% vs. 31%, P = 0.069). When choosing between fecal testing or colonoscopy for disease activity assessment, accuracy was significantly more important than preparation, pain, or complications (P < 0.05), but preparation and pain were comparable to complications (P > 0.20). After understanding the limitations in accuracy with fecal testing, 25 patients who initially chose fecal testing changed their preference to colonoscopy (P < 0.001) and at the completion of the survey a total of 65% chose colonoscopy over fecal testing. If the fecal test was wrong at most 1 in 20 times (5%), 40% of patients who ultimately chose colonoscopy were willing to undergo fecal testing. If the fecal test was wrong at most 1 in 50 times (2%), 66% of patients who ultimately chose colonoscopy were willing to undergo fecal testing.

CONCLUSION:
Accuracy appears to be the most important criteria for IBD patients when choosing monitoring strategies, followed by pain/preparation and risk of complications. A significant number of patients changed their preferences to colonoscopy after learning more about the diagnostic accuracy of current fecal testing for disease monitoring. A high degree of confidence is required of fecal test results for patients to choose this strategy.
851 Targeted Intracecal anti-α4β7 Integrin Antibody Results in Reduce Accumulation of α4β7 Memory T-cells in Gut Tissue in DSS-induced Colitis Mice
Authors: Jones Mitchell L. , Lee Shaoying N. , Singh Sharat , Luo Allison , Sandborn William J. , Chuang Emil , Wahl Chris 
Published: October 2019

INTRODUCTION:
Systemically administered anti-α4β7 integrin antibodies such as Vedolizumab have been approved for the treatment of Crohn's disease and ulcerative colitis. The objective of this study was to assess whether intracecally (IC) delivered anti-mouse α4β7 integrin antibody (DATK32) might penetrate the mucosa and confer efficacy compared with systemic intraperitoneal (IP) injection in DSS-induced colitis mice.

METHODS:
Animals underwent implantation of a cecal cannula for topical bolus delivery in the IC groups. Acute colitis was induced by exposure to 3% DSS drinking water from Day 0-5. DATK32 was administrated via IP (25 mg/kg) every 3 days (Q3D), IC (25 mg/kg) Q3D, or IC (25 or 5 mg/kg) every day (QD) from Day 0 to 14. At Day 14, plasma, colon content and tissue were collected for DATK32 measurement; and Peyer’s patches (PP), mesenteric lymph nodes (mLN), and whole blood were collected for α4β7 memory T-cell counts.

RESULTS:
Significantly higher colon content and tissue exposure but limited blood exposure of DATK32 were found in IC QD groups compared to IP Q3D group. Immunohistochemistry staining of DATK32 was found in all layers of colon tissue, and as deep as tunica muscularis when delivered IC. The α4β7 memory T-cell count was significantly reduced in mLN in all IC groups compared to vehicle control and IP groups. Similar findings were observed in PP with IC QD treatment. Finally, the α4β7 memory T-cell count in blood was significantly increased in IC QD but not IC Q3D groups compared to vehicle control and IP group.

CONCLUSION:
In this study, we demonstrated that targeted IC anti-α4β7 integrin antibody lead to significantly higher drug exposure in colon contents and tissues with limited blood exposure compared to IP. Targeted IC QD treatment showed a significantly reduced α4β7 memory T-cell counts in PP and mLN representing populations within inflamed jejunal and colon tissues. Additionaly, an increased number of α4β7 memory T-cells was found in blood with targeted IC DATK32 compared to IP, suggesting T cells that have trafficked from blood to tissue can undergo reverse trafficking. Recent publications have reported a dose dependent increase in efficacy with systemically delivered anti-α4β7 despite full T-cell receptor occupancy in blood. Results of this study point to the potential for increased efficacy with high concentrations in local inflamed tissues. Although the mechanism of action is unclear, results suggest topically delivered anti-α4β7 may be an efficacious treatment in IBD.