bluuebunny/crossref_metadata_2025 huggingface dataset:
728 Second-Line Biologic Therapy After Vedolizumab
Authors: Ritter Timothy E. , Fourment Chris , Kuten Samantha A. , Hardin Thomas C. , Van Anglen Lucinda J.
Published: October 2019

INTRODUCTION:

Vedolizumab (VDZ), an anti-integrin monoclonal antibody approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly being utilized as first-line biologic therapy in bio-naïve inflammatory bowel disease (IBD) patients (pts) with moderate-to-severe disease. While prior studies have described the efficacy of VDZ after anti-TNF failure, there is little guidance on the use of alternative biologics following initial VDZ therapy. This study describes the clinical response of IBD pts treated with a second (2nd) biologic following VDZ discontinuation.

METHODS:

We performed a retrospective review of all bio-naïve IBD pts started on VDZ as first-line therapy at a large multicenter gastroenterology private practice since drug approval in 2014. Pts were identified who failed initial VDZ treatment and were switched to a 2nd biologic agent. Data collection included demographics, diagnosis, therapy, and disease activity scores using the partial Mayo score (pMayo) for UC pts and the Harvey-Bradshaw Index (HBI) for CD pts. Clinical remission was assessed for those pts with ≥6 months of data and defined as pMayo less than 2 or HBI less than 5.

RESULTS:

A total of 135 IBD pts receiving VDZ as first-line biologic therapy were identified, of which VDZ was discontinued in 30 (22%). Our study cohort included 25 pts who received a 2nd line biologic following VDZ failure (11 primary non-response, 14 secondary non-response). Second-line biologic agents included 19 infliximab, 3 adalimumab, 2 ustekinumab, and 1 tofacitinib. Baseline demographics of the 25 pts were as follows: mean age 47 ± 18 years, male gender 13 (52%), UC 19 (76%), CD 6 (24%), time to 2nd biologic 8.2 ± 4.5 weeks. Disease severity scores prior to and following initiation of the 2nd line biologic are depicted in Figure 1. Clinical remission assessment was available for 18 of 25 patients. Remission was achieved in 11 of 18 pts (61%), driven by UC pts treated with infliximab [Figure 2]. Overall, pts treated with anti-TNF agents following VDZ had higher rates of remission compared to those treated with other biologics.

CONCLUSION:

Biologic-naïve IBD pts treated initially with VDZ have high treatment persistence. In addition, rates of remission with 2nd-line biologic therapy are significantly greater than expected when first-line failure is VDZ. Further studies are warranted to determine the optimal order in which advanced therapies should be initiated.
739 Development and Validation of an Administrative Codes Algorithm to Identify Abdominal Surgery and Bowel Obstruction in Patients With Inflammatory Bowel Disease
Authors: Gandle Cassandra , Scott Frank , Waljee Akbar , Hou Jason
Published: October 2019

INTRODUCTION:

International Classification of Diseases (ICD) codes are utilized in reporting patient diagnoses while current procedural terminology (CPT) codes identify medical, surgical, and diagnostic procedures. Use of administrative codes may be used to efficiently identify patients with inflammatory bowel disease and related outcomes, but require validation due to variability of coding patterns. The aim of this study was to determine the accuracy of ICD and CPT codes for surgery and post-operative obstructive complications in a cohort of IBD patients at the VA.

METHODS:

We performed a retrospective study of patients with IBD at the Michael E. DeBakey VA Medical Center in Houston, Texas between February 1, 2000 and August 30, 2015. IBD patients with with administrative codes for abdominal surgery and post-operative complications were reviewed by manual chart review to confirm type and date of surgery and type and date of post-operative complication. A total of 710 abdominal surgery ICD-9 and CPT codes and 3 post-operative obstruction related ICD-codes (560.81, 560.89, and 560.9) were evaluated. Analyses were performed on a per encounter basis. Codes were considered accurate if the procedure or complication occurred within 3 months of the coded date. Sensitivity analyses were performed, broadening the time window to 6 months. Positive predictive values (PPV) and negative predictive value (NPV) were calculated for each code and overall.

RESULTS:

A total of 77 IBD patients had at least one encounter with ICD-9 or CPT codes for abdominal surgery. The PPV for abdominal surgery codes overall was 96.4%, which remained unchanged on sensitivity analyses extending time window to 6 months. Evaluating the accuracy of post-operative obstructive-type complications, 39 patients were identified utilizing 3 ICD-9 codes for obstructive complications in 67 individual encounters. The PPV of any obstruction-type ICD-9 code for confirmed bowel obstruction was 80.5%. The NPV for obstructive complications in patient encounters without a corresponding obstruction-related code was 96%. On sensitivity analyses extending window to 6 months prior to date of code, the PPV for obstructive ICD-9 codes increased to 82.1%.

CONCLUSION:

ICD-9 and CPT codes for abdominal surgery and post-operative obstructive-type complications can be accurately utilized in IBD patients at the VA.
747 Pilot Study of Gut Dysbiosis and Bile Acid Dysmetabolism in Active Ulcerative Colitis
Authors: Gaidos Jill , Kang Jason D. , Kakiyama Genta , Pandak William M. , Hylemon Phillip B.
Published: October 2019

INTRODUCTION:

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colon associated with an increased risk for Clostridioides difficile infection (CDI). C. difficile is a spore-forming organism that colonizes the GI tract and is potentially pathogenic. Under healthy conditions, homeostasis of the gut microbiome plays a role in preventing germination of C. difficile spores while bile acids are vital to the germination process. Primary bile acids can stimulate germination of C. difficile spores while secondary bile acids inhibit growth of the vegetative form. The aim of this study is to assess for changes in the gut microbiome and bile acid profile with active UC as compared to remission that may explain the increased CDI risk.

METHODS:

After obtaining IRB approval, we performed a single center, prospective, cohort study of Veteran's with active UC at the McGuire VA Medical Center. After obtaining consent, subjects with active UC, based on markers of inflammation and elevated Simple Clinical Colitis Activity Index score (≥5), provided a stool sample for analysis of the gut microbiome (using fingerprinting of the 16S rRNA), bile acid profile (using high performance liquid chromatography) and for the presence of Clostridioides species (using 7α-dehydroxylating bacteria analysis). Subjects were treated for their active UC and a second stool sample was collected in the setting of clinical remission for repeat analyses.

RESULTS:

Four males with active UC enrolled, median age 61 yrs, however subject 2 was excluded due to suboptimal sample size. The total bile acids were relatively unchanged in both samples however there were less secondary bile acids (deoxycholic acid and lithocholic acid) in the remission samples in 2 of 3 subjects (Table 1). With active UC, study subjects had a higher concentration of C. scindens (Figure 1). Inversely, subjects had higher concentrations of the C. difficile toxin B gene during clinical remission (Figure 2). The results of the microbiome analysis are pending.

CONCLUSION:

In this limited pilot study, we found that patients with UC have a decreased luminal concentration of both total and secondary bile acids compared to healthy controls. Active UC seems to lead to a decrease in secondary bile acids, including C. scindens, with a subsequent increase in the presence of C. difficile toxin. This change in bile acid profile could be contributing to the increased prevalence of CDI in IBD patients.
751 Safety, Tolerability, and Pharmacokinetics of PTG-200, an Oral GI-Restricted Peptide Antagonist of IL-23 Receptor, in Normal Healthy Volunteers
Authors: Cheng Xiaoli , Lee Tien-Yi , Ledet Grace , Zemade Genet , Tovera James , Campbell Robert , Purro Nobert , Annamalai Thamil , Masjedizadeh Mohammad , Liu David , Nawabi Roya , Kanwar Bittoo
Published: October 2019

INTRODUCTION:

PTG-200 (JNJ-67864238) is an oral peptide that acts locally in intestinal tissues to block IL-23 signaling by selectively binding the IL-23 receptor (IL-23R). The gastrointestinal (GI)-restriction of PTG-200 is demonstrated in vivo by marked drug concentrations in GI tissues and feces and limited systemic blood exposure. PTG-200 therapeutic potential was established in a rat model of TNBS-induced colitis, where its threshold concentration in colonic tissue and luminal feces associated with efficacy was determined to inform the human efficacious dose.
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The objectives of this Phase 1 study were to assess safety, tolerability, and pharmacokinetics (PK) of PTG-200.

METHODS:

This first-in-human (FIH) Phase 1 study was a single-center, randomized, double-blind, placebo-controlled trial comprising single and 14-day multiple ascending dose (SAD and MAD) arms in 82 healthy male volunteers. Oral doses ranged from 150 mg to 900 mg once daily (QD, fasted or fed) or twice daily (BID, fed). Subjects were monitored for safety and tolerability. PK in plasma, urine and feces was evaluated.

RESULTS:

Oral administration of PTG-200 was well-tolerated. There were no serious adverse events, dose-limiting toxicities, or clinically significant adverse events. PTG-200 plasma exposure was low (Table 1), below that expected to result in systemic biological activity. Following single-dose oral administration under fasted conditions, plasma PTG-200 concentrations exhibited dose-related increases with a median time to maximal concentration (Tmax) at 2 h. Administration of a high-fat meal prolonged the median Tmax to 4 h and had a modest effect on peak concentration (Cmax) and estimated overall exposure. Repeat dosing led to dose-related increases in plasma exposure. Consistent with a terminal half-life of ∼1.5 h in plasma, PTG-200 showed no evidence of accumulation except for the 900 mg BID group. Fecal concentrations in several cohorts met or exceeded the targeted threshold concentration associated with efficacy as established using the preclinical colitis model.

CONCLUSION:

Orally administered PTG-200 was well-tolerated in this FIH study. Systemic PK was consistent with the GI-restricted design of PTG-200. These safety and PK characteristics, combined with fulfillment of fecal drug threshold concentrations, support further clinical development of PTG-200 for the treatment of IBD. A Phase 2 study in patients with moderate-to-severe Crohn's disease is planned.
753 Public Cervix Announcement: Provider Gender May Influence Cervical Cancer Screening in IBD Women
Authors: Kirelik Danielle , Pascual Lauren , Dawit Lillian , Borum Marie
Published: October 2019

INTRODUCTION:

Females with inflammatory bowel disease (IBD), specifically those on immunosuppressive therapy, may be at increased risk of cervical dysplasia and cervical cancer. Women with IBD have been reported to be screened less frequently than those at average risk. In addition, annual cervical cancer screening is recommended for IBD women who are on immunosuppressive therapy. This study evaluated the influence of provider gender on counseling for cervical cancer screening in IBD women.

METHODS:

A retrospective chart review of all IBD women seen in the gastroenterology clinic at a university medical center during a 5 year period was performed. Patient age, race, IBD diagnosis, medications, primary gastroenterology provider and documentation of cervical cancer screening or counseling within the past three years were recorded. Women who had a hysterectomy or those <21 or >65 years of age were excluded. A database was generated using Microsoft Excel. Statistical analysis was performed using Fisher's Exact Test with significance set at P < 0.05. The study was approved by the institutional IRB.

RESULTS:

218 IBD women were identified, with 192 women meeting criteria for analysis. 137 (71.35%) had Ulcerative Colitis (UC), 46 (23.96%) Crohn's disease (CD), 5 (2.60%) microscopic colitis, and 4 (2.08%) indeterminate colitis. Mean age was 44.26 (range: 21-65). 98 (51.04%) were White, 53 (27.60%) Black/African American, 7 (3.65%) Asian, 6 (3.13%) Hispanic, 14 (7.29%) identified as other, and 14 (7.29%) declined to disclose. Male providers managed 125 (65.1%) and female providers managed 67 (34.9%) patients. 61 of 192 patients (31.77%) were counselled about cervical cancer screening. Female (50.75%; 34 of 67) versus male (21.6%; 27 of 125) providers counseled significantly more patients (P < 0.0001). There was no significant difference in the rate of counseling based on race (P = 0.8724), age (≤40 versus >40) (P = 0.5319), IBD diagnosis (P = 0.5863), or medication type (P = 0.6235).

CONCLUSION:

This study revealed that women with IBD were inconsistently counseled about cervical cancer screening. While female providers were significantly more likely to provide screening education, there was a clear need to improve counseling by all providers. Although this study was limited by retrospective design and single institution cohort, it highlights the need for patient education on the importance of cervical cancer screening to optimize clinical outcomes.
754 Keep IBD Flu Free: Annual Influenza Vaccination Is Inconsistently Administered to Inflammatory Bowel Disease Patients
Authors: Dawit Lillian , Kirelik Danielle , Pascual Lauren , Borum Marie
Published: October 2019

INTRODUCTION:

It is recommended that all patients with IBD receive annual influenza vaccinations. Compared to age-matched healthy individuals, patients with IBD, particularly those on immunosuppressants, are at an increased risk of acquiring influenza. Furthermore, IBD patients who acquire influenza are more likely to be hospitalized or have a superimposed pneumonia. It is uncertain if IBD patients are consistently counselled about or administered the influenza vaccine. This study investigated rates of annual influenza vaccination in IBD patients at a university medical center.

METHODS:

A retrospective chart review evaluating all IBD patients seen in the gastroenterology clinic during a five year period was performed. Patient gender, age, race, IBD diagnosis, and documentation of flu vaccine within one year of the most recent gastroenterology visit were collected. A database was generated using Microsoft Excel. Statistical analysis using Fisher's Exact Test was performed with significance set at P < 0.05. The study was approved by the institutional IRB.

RESULTS:

392 IBD patients (218 females, 174 males) were analyzed. 206 were self-reported as White (52.55%), 99 African-American (25.25%), 11 Asian (2.81%), 35 other (8.93%), and 41 declined to disclose (10.46%). Mean age was 44.44 (range: 20-82). 279 had Ulcerative Colitis (71.17%), 96 Crohn's (24.49%), 11 Microscopic colitis (11, 2.81%), and 6 Indeterminate colitis (1.53%). 102 of 392 (26.02%) patients had a documented flu vaccine. There was a significant difference in the flu vaccination rate between patients age ≥50 (35.56%) and age < 50 (21.01%) (P = 0.0024). No significant difference was found between gender (P = 0.274), race (White vs. AA) (P = 0.274), IBD diagnosis (UC vs. Crohn's) (P = 0.416), or medications (biologics/immunomodulators vs. other) (P = 0.907).

CONCLUSION:

This study revealed that, despite current guidelines, there may be insufficient rates of influenza vaccinations among IBD patients. Individuals who were ≥50 more often had documented flu vaccination compared to younger patients. While this study it limited based upon size and single institution design, the results emphasize the need to improve administration of flu vaccine in all IBD patients. Recommendation for flu vaccination and/or assessment of the receipt of the vaccine should be performed by gastroenterologists to ensure optimal IBD health care delivery.
762 Comorbidities and Opioid Use Among Patients With Crohn's Disease
Authors: Pilon Dominic , Obando Camilo , Ding Zhijie , Voelker Jennifer , Muser Erik , Manceur Ameur M. , Kinkead Frederic , Lafeuille Marie-Hélène , Lefebvre Patrick
Published: October 2019

INTRODUCTION:

Comorbidities associated with Crohn's disease (CD) add to the symptoms of disease and may contribute to substantial disease burden. There is a lack of information on the development of comorbidities in CD patients in the real world. This study aims to compare comorbidities, including opioid use, in CD patients relative to patients without inflammatory bowel disease (IBD), using a large database and long-term follow-up.

METHODS:

This was a retrospective matched cohort study. Working age adults with CD (≥2 independent claims with a CD diagnosis ≥30 days apart and within 1 year; first CD diagnosis was the index date) and controls without diagnosis for IBD (random index date) were identified in a US healthcare claims database (OptumHealth Care Solutions, Inc.) of privately-insured patients (01/1999-03/2017). CD patients were matched 1:5 with non-IBD controls using baseline characteristics, including the Quan-Charlson comorbidity index and cardiovascular disease. Comorbidities during the 12-month baseline period before the index date were reported. During the follow-up, lasting at least 12 months, the incidence of new comorbidity, including opioid use as a proxy for pain, was compared to the non-IBD controls by Kaplan-Meier (KM) rate with log-rank test.

RESULTS:

The study sample was composed of 6,715 CD patients and 33,575 non-IBD matched patients (average age of 45 years old, and 54% female). Pain, anemia, and fatigue were significantly higher in the CD cohort at baseline (Figure 1). Over the follow-up, new cases of cardiovascular disease were significantly higher in the CD compared to the matched non-IBD cohort with a rate of 11.5 vs 7.8%, respectively, by year 6 (Figure 2). In addition, the rates of new cases of fatigue (5.3 vs 3.2%), anemia (6.0 vs 1.9%), respiratory disease (3.5 vs 1.8%), and anxiety (5.3 vs 2.8%) were also significantly higher in the CD cohort compared to the non-IBD cohort by year 6 (log-rank P-value < 0.001). When new cases of pain diagnosis or opioid use were analyzed, the rate was significantly higher in the CD cohort, reaching 74.0% compared to 59.1% in the non-IBD cohort at year 6 (Figure 3).

CONCLUSION:

In this study, comorbidities, in particular new cases of pain diagnosis or opioid use, were significantly higher in CD patients relative to non-IBD patients, suggesting that the development of comorbidities may contribute to the long-term disease burden of CD.
767 Inflammatory Bowel Disease Patients Prior to Starting on Anti-TNF Are Over 5 Times More Likely to Be Screened for Hepatitis B Infection Compared to Those Starting High Dose Corticosteroids
Authors: Ho Edith Y. , Marshall Vanessa , Alsamman Yasser , Chung Grace , Burant Christopher , Dave Maneesh , Falck-Ytter Yngve
Published: October 2019

INTRODUCTION:

Screening for hepatitis B virus (HBV) infection in inflammatory bowel disease (IBD) patients prior to initiating anti-tumor necrosis factor alpha (anti-TNF) therapy has significantly improved over the past decade. HBV screening prior to initiating high dose corticosteroids (HDC) is largely unknown despite potentially greater risks of HBV reactivation compared to anti-TNF. This study aims to determine the factors associated with HBV screening and whether the type of immunosuppression affects screening practices.

METHODS:

This retrospective chart review included Veterans with diagnostic codes for Crohn's Disease (CD: ICD-9-CM 555.x and ICD-10-CM K50.x) and ulcerative colitis (UC: ICD-9-CM 556.x and ICD-10-CM K51.x) first recorded between 01/2013 to 08/2016 at the Cleveland Veterans Affairs Medical Center. IBD patients who were started on anti-TNF or HDC were assessed whether HBV screening was conducted within 12 months of initiating therapy. HDC was defined as ≥10 mg for ≥4 consecutive weeks. Patient factors including gender, age, race, service connectivity (SC), and type of immunosuppression were assessed as independent predictors for screening.

RESULTS:

Among 571 Veterans, 56 started immunosuppression with 17 on anti-TNF and 39 on HDC. A total of 31/56 (56%) were screened: 90% male, mean age 49, 32% mean SC, 45% on anti-TNF and 55% on HDC. A total of 25/56 (44%) were not screened: 96% male, mean age 58,17% mean SC, 12% on anti-TNF and 88% on HDC. In those on anti-TNF, 88% were screened compared to 44% on HDC (P = 0.007). In multivariate analysis, immunosuppression type was significantly associated with screening where patients initiated on anti-TNF were 5.5 times more likely to be screened compared to those on HDC (OR 0.18, P = 0.025). Age, gender, race, and service connectivity did not have any impact on screening.

CONCLUSION:

Overall, 56% of IBD patients receiving immunosuppression were screened for HBV. 88% were screened prior to anti-TNF compared to 44% prior to HDC. Patients initiated on anti-TNF were over 5 times more likely to be screened compared to those on HDC. Importance of HBV screening prior to high dose corticosteroids in IBD patients should be emphasized in societal guidelines and clinical practice, given that HDC poses a potentially greater risk of HBV reactivation compared to a biologic.
770 Relationship Between Protocol Specified Corticosteroid Tapering Regimens and Achieving Outcome Measures in Patients With Moderate-Severe Ulcerative Colitis and Crohn's Disease
Authors: George John , Singh Siddharth , Dulai Parambir , Ma Christopher , Nguyen Tran , Feagan Brian G. , Sandborn William J. , Jairath Vipul
Published: October 2019

INTRODUCTION:

Corticosteroid-free clinical remission is an important clinical outcome, yet is inconsistently defined and reported in clinical trials. We summarized the protocol specified corticosteroid tapering regimens in clinical trials of moderate-severe ulcerative colitis (UC) and Crohn's disease (CD), and calculated differences in rates of clinical remission versus corticosteroid-free clinical remission (CSF-CR).

METHODS:

Through a systematic literature review through February 28, 2019, we identified 16 randomized controlled trials (RCTs) of biologics or small molecules in patients with moderate-severe UC or CD that reported CSF-CR as an outcome. We estimated relative risk (RR) [and 95% confidence interval (CI)] of achieving CSF-CR vs. overall clinical remission in patients treated with active intervention or placebo, through random effects meta-analysis.

RESULTS:

Across trials of UC (11 trials) and CD (5 trials), median 53% (range, 28-81%) and 49% (range, 42-56%) participants were on corticosteroids at time of trial entry, respectively. Participants were allowed to enter trials at median corticosteroid dose 35 mg/d (range, 20-40 mg/d). Doses were kept stable for median 8 weeks (range, 5-10 weeks) during induction therapy, after which a mandatory and structured tapered was implemented, albeit with investigators discretion depending on clinical status. For maintenance trials, pooled rates of CSF-CR in patients with UC (n = 11) treated with placebo was 9.7% (95% CI, 6.8-13.6% vs. overall clinical remission: 14.2%; 95% CI, 10.6-18.7) and with CD (n = 5), 19.1% (95% CI, 11.3-30.2 vs. overall clinical remission: 25.7%; 95% CI, 16.4-37.7). In UC trials, the rate of CSF-CR was 24% lower than the rate of overall clinical remission (RR, 0.76; 95% CI, 0.67-0.86; placebo: RR, 0.74; 95% CI, 0.56-0.97). In patients with CD, rate of CSF-CR was 18% lower than rate of overall clinical remission (RR, 0.82; 95% CI, 0.72-0.94; placebo: RR, 0.75; 95% CI, 0.57-0.98).

CONCLUSION:

This is the first systematic review and meta-analysis to study corticosteroids handling across clinical trials. Protocol specified corticosteroid tapering regimens varies across trials with considerable investigator discretion. Rates of CSF-CR is 20-25% lower than overall clinical remission. These findings will help to inform design and interpretation of future clinical trials and highlight the need for standardization.
772 Long-Term Mucosal Healing, Clinical Response and Clinical Remission in Patients With Ulcerative Colitis Treated With the Anti-MAdCAM-1 Antibody Ontamalimab: Results From the Open-Label Extension Study TURANDOT II
Authors: Danese Silvio , Sandborn William J. , Reinisch Walter , Hébuterne Xavier , Kłopocka Maria , Tarabar Dino , Vaňásek Tomáš , Greguš Miloš , Hellstern Paul A. , Kim Joo Sung , Sparrow Miles , Gorelick Kenneth J. , Goetsch Martina , Bliss Caleb , Gupta Charu , Cataldi Fabio , Vermeire Séverine
Published: October 2019

INTRODUCTION:

Ontamalimab (SHP647), a human monoclonal IgG2 antibody, targets mucosal addressin cell adhesion molecule-1 (MAdCAM-1), to reduce lymphocyte homing to the gastrointestinal (GI) tract. In the TURANDOT II trial, ontamalimab was well-tolerated and clinical benefit was seen up to 144 wks in patients with ulcerative colitis (UC). Here we report long-term mucosal healing, response and remission in a subset of patients in TURANDOT II.

METHODS:

TURANDOT II (NCT01771809) is a phase 2, 2-part open-label (OL) extension study of ontamalimab in patients with UC who received placebo or ontamalimab 7.5, 22.5, 75 or 225 mg in the feeder study (TURANDOT). At TURANDOT II baseline (TURANDOT wk 12), patients were randomized to ontamalimab 75 or 225 mg every 4 wks for 72 wks (OL1). In cases of clinical exacerbation or no response, escalation from 75 to 225 mg was permitted from wk 8. In OL2, patients received 75 mg every 4 wks for 72 wks. Endoscopies were carried out at wk 16, and a subset of patients undergoing routine cancer surveillance had at least one follow-up endoscopy between wks 40 and 72 of OL1: all endoscopies were centrally-read. Mucosal healing (Mayo endoscopy subscore ≤1), clinical remission (total Mayo score ≤2, no subscore >1) and clinical response (≥3-point decrease in total Mayo score from TURANDOT baseline, ≥30% change; ≥1-point decrease in or ≤1 rectal bleed absolute score) were measured.

RESULTS:

Of 330 patients in TURANDOT II, 101 had follow-up endoscopies (Table 1), 25.7% (n = 26) of whom had mucosal healing at TURANDOT II baseline. At wk 16, 43.6% (n = 44) had mucosal healing, and 33 of these patients (75%) maintained mucosal healing up to wk 40–72. Of 65 responders in TURANDOT, 37 (56.9%) had mucosal healing at both wk 16 and wk 40–72. Of 36 non-responders, 7 (19.4%) and 9 (25%) achieved mucosal healing at wk 16 and wk 40–72, respectively (Figure 1). Of the responders, 58 (89.2%) maintained response and 27 (41.5%) were in remission at wk 16; at wk 40–72, 53 (81.5%) maintained response and 33 (50.8%) were in remission. Of non-responders, 22 (61.1%) achieved response and 5 (13.9%) achieved remission by wk 16; by wk 40–72, 17 (47.2%) had responded and 8 (22.2%) were in remission. Overall, the mean Mayo endoscopic subscore of 2 (SD, 0.1) was maintained to wk 40–72.

CONCLUSION:

Mucosal healing, response and remission persisted in a subset of patients who continued ontamalimab treatment up to 72 wks and underwent surveillance endoscopies between wks 40 and 72.
774 Use of Formal Pharmacokinetic Analysis to Optimize Therapy in Patients With Secondary Loss of Response to Infliximab
Authors: Khattab Ahmed , Ehrenpreis Eli
Published: October 2019

INTRODUCTION:

Infliximab (IFX) exhibits a wide range of inter-individual pharmacokinetic (PK) variability. During maintenance therapy, more than 50% of patients with inflammatory bowel disease have sub-optimal trough concentrations. In the 1st year of IFX therapy, 40% experience a loss of response (LOR) due to non-immune mediated PK failure from suboptimal drug exposure. Currently, dose optimization relies on dose escalation or reduction by trial and error. Our aim was to formulate a model that maximizes the efficiency of IFX dose optimization using formal PK analysis.

METHODS:

We analyzed serum IFX levels obtained during the slow-decay portion of the drug concentration-versus-time curves of 30 normal volunteers that received a single standard dose (5 mg/kg) of IFX.
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Using Prism (GraphPad Software, Seattle, WA), we determined the minimal number of serum IFX levels required to calculate the elimination rate constant (Kel). Volume of distribution (Vd) was determined by estimating blood volume. Peak drug concentration (Peak) was calculated by dividing IFX dose by Vd. Optimal dosing interval (T) was determined by the equation: T = ln (peak/trough) ÷ Kel. The equation was used to calculate T to achieve a specific trough concentration. IFX doses required to achieve a specific trough at a predetermined time interval was also calculated.

RESULTS:

Data for all patients is shown in Table 1. Five serum levels of IFX were required to accurately determine Kel. To maintain a trough >5 µg/mL, calculated T ranged from 5.6 to 23.2 weeks. Calculated T was 7-9 weeks in 9 subjects, <7 weeks in 11 subjects and >9 weeks in 10 subjects. Conversely, optimum doses required to achieve a trough of ≥5 µg/mL with 8 week infusions ranged from 1.0 to 16.8 mg/kg (Table 2). Our model shows a direct relationship between administered doses and predicted troughs. There is a complex relationship between T and trough such that halving T usually showed a higher trough than a doubled dose (P < 0.0001, Wilcoxon matched-pairs signed-ranks test) (Figure 1).

CONCLUSION:

Using a PK approach to adjust IFX therapy eliminates the requirement for multiple optimizations, and may reduce the need to switch to different drugs after failed optimizations. Our approach has the potential to reduce costs by decreasing IFX doses in some patients, prevention of premature discontinuation of IFX, and reducing the probability of LOR from low troughs in individual patients.
775 Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease
Authors: Abu-Sbeih Hamzah , Faleck David , Ricciuti Biagio , Mendelsohn Robin , Naqash Abdul Rafeh , Cohen Justine , Sellers Maclean , Balaji Aanika , Ben-Betzalel Guy , Hajir Ibraheim , Zhang Jiajia , Awad Mark , Leonardi Giulia , Johnson Douglas , Pinato David , Owen Dwight , Weiss Sarah , Lamberti Giuseppe , Lythgoe Mark , Manuzzi Lisa , Arnold Christina , Naidoo Jarushka , Merkel Gal , Powell Nick , Yeung Sai-Ching , Sharon Elad , Dougan Michael , Wang Yinghong
Published: October 2019

INTRODUCTION:

We characterized gastrointestinal adverse events in patients with underlying inflammatory bowel disease (IBD) who received immune checkpoint inhibitors.

METHODS:

We performed a fourteen-center, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of gastrointestinal adverse events.

RESULTS:

Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4 and 85 received monotherapy targeting programmed death-1 or its ligand. Half the patients had Crohn's disease and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12). Forty-three patients were not receiving treatment for IBD (Table 1). Gastrointestinal adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < 0.001). Gastrointestinal events among patients with IBD included grade 3 or 4 diarrhea in 21 patients. Four patients experienced colonic perforation, 2 of whom required surgery. No gastrointestinal adverse event-related deaths were recorded (Table 2). Anti-cytotoxic T-lymphocyte antign-4 therapy was associated with increased risk of gastrointestinal adverse events on univariate but not multivariate analysis (respectively, odds ratio, 3.19; 95%confidence interval, 1.8-9.48; P = 0.037 and odds ratio, 4.72; 95% confidence interval, 0.95-23.53; P = 0.058).

CONCLUSION:

Preexisting IBD increases the risk of severe gastrointestinal adverse events in patients treated with immune checkpoint inhibitors.
777 Effect of Ustekinumab Dose Escalation on Recapturing Clinical Response in Patients With Crohn's Disease
Authors: Bundschuh Mark , McDonough Gregory , Kumar Priyanka , Kozuch Patricia , Shivashankar Raina
Published: October 2019

INTRODUCTION:

Previous studies have shown that ustekinumab (UST) is an effective induction and maintenance therapy for patients with moderate to severe Crohn's Disease (CD). We sought to examine the real-world efficacy and safety of UST and whether UST dose escalation helps to recapture clinical response.

METHODS:

All patients who received the initial weight-based UST infusion between 4/2017 and 4/2018 were identified through a query of the EMR. Patients were followed from the time they initiated UST through 5/2019 or their date of UST discontinuation, whichever came first. Specifically, patients who lost response to UST 90 mg injection every 8 wk dosing and were then dose escalated to either every 4 or 6 wk dosing were identified. Recaptured clinical response to dose escalation was determined by reviewing clinical documentation and assessing for a reduction of ≥3 in the modified Harvey Bradshaw index (mHBI) after ≥8 wks following dose escalation.

RESULTS:

We included 27 patients with CD [median age 40 (range 24-61); 56% male; 96% tumor necrosis factor (TNF)-antagonist exposed]. Table 1 compares characteristics and outcomes of patients who underwent dose escalation vs. those who remained on regular dosing. Of the 11 dose escalated patients, 9 were switched to an every 4 wk regimen while the other 2 were switched to an every 6 wk regimen. Patients who underwent dose escalation were more likely to be a smoker (18% vs. 13%), have a history of perianal disease (73% vs. 38%), have previously tried a greater number of biologics (2.7 vs. 1.9), and be exposed to concomitant steroid (55% vs. 25%). Moreover, patients who underwent dose escalation were less likely to achieve steroid discontinuation within the first 8 wks compared to those who remained on regular dosing (9% vs. 50%). The only adverse event in the dose escalation group was one case of pneumonia. Table 2 further examines those patients that underwent dose escalation. The median mHBI improved from 9 to 7 following dose escalation. Recaptured clinical response occurred at a rate of 6/11 (55%) based on clinical documentation and 3/11 (27%) based on mHBI.

CONCLUSION:

UST dose escalation from 90 mg every 8 wks to either every 4 or 6 wk dosing allowed for recaptured clinical response in ∼25-50% of CD patients. There were minimal adverse events in patients who were dose escalated. Given its safety profile, dose escalation should be considered in patients with moderate to severe CD who have incomplete response to UST.
784 A Population-Based Analysis of Obesity, Metabolic Syndrome, and Cardiovascular Outcomes Among Patients With Inflammatory Bowel Disease in the National Health and Nutrition Examination Survey 2009-2010
Authors: Tirath Ankita , McHenry Scott , Rhea Lee , Salter Amber , Deepak Parakkal
Published: October 2019

INTRODUCTION:

Prior studies have reported high prevalence of obesity and metabolic syndrome in inflammatory bowel disease (IBD) pts, increasing the risk for stroke and coronary artery disease (CAD). Here, we compare the prevalence of obesity, metabolic syndrome and cardiovascular outcomes in IBD compared to non-IBD controls in a large, nationally representative United States (US) population, controlling for traditional risk factors and dietary habits.

METHODS:

IBD pts were identified in the National Health and Nutrition Examination Survey (NHANES) 2009-2010. This population-based survey combines data from pt interviews, physical exam, and lab tests. For analysis, obesity was defined as BMI ≥ 30 and metabolic syndrome by waist circumference, presence of diabetes, hypertension, and hyperlipidemia. IBD pts were propensity matched in a 1:5 ratio to non-IBD controls on age, gender, race, 26-item dietary screener questionnaire (DSQ), smoking, and alcohol usage. Cardiovascular outcomes analyzed included CAD, congestive heart failure (CHF), angina/angina pectoris, myocardial infarction (MI), and stroke with 1:5 propensity matching done on age, gender, race, BMI, body composition, presence of metabolic syndrome, DSQ items, smoking, and alcohol use. Raw data was extrapolated to the US population using provided sample weights and analyses performed using SAS 9.4.

RESULTS:

A total of 62 IBD pts were identified; 3 were excluded due to missing data. Baseline characteristics of the IBD (median age 54, 63% female, 46% white) and the propensity matched non-IBD group can be seen in Table 1. The prevalence of obesity in the IBD cohort was 34% compared to 41% in the non-IBD cohort, and when extrapolated to the U.S. population was not significant (P = 0.13). Similarly, the prevalence of metabolic syndrome in IBD compared to non-IBD, 43% to 45%, was not significant when extrapolated to the US population (P = 0.52). Comparing IBD to non-IBD controls (Table 2), there was no significant difference in prevalence of CAD (7.1% VS 4.4%, P = 0.45) or angina (3.6% vs 2.95, P = 0.97) while there was trend towards significance for stroke (8.9% vs 3.6%, P = 0.0599).

CONCLUSION:

Our findings suggest that when controlled for traditional risk factors and dietary habits, the prevalence of obesity, metabolic syndrome and cardiovascular disease in a nationally representative survey of self-reported IBD population in the US is similar to the non-IBD population.
788 The Natural History and Treatment Outcomes of Concomitant Eosinophilic Esophagitis (EoE) and Inflammatory Bowel Disease (IBD)
Authors: Urquhart Siri A. , Quinn Kevin P. , Ravi Karthik , Loftus Edward V.
Published: October 2019

INTRODUCTION:

Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are distinct chronic inflammatory conditions involving the gastrointestinal tract. The presence of eosinophilic infiltration in gastrointestinal mucosa has been observed as a histopathological feature of IBD, being described in both Crohn's disease (CD) and ulcerative colitis (UC). The natural history of patients with coexisting EoE and IBD has not been extensively studied. Our aim was to determine clinical characteristics and treatment outcomes in patients with concomitant IBD and EoE.

METHODS:

A retrospective cohort study was performed of all EoE patients who also had a diagnosis of IBD from January 2000 to December 2018. Patients were identified using ICD-9 and ICD-10 diagnostic codes. Confirmation of EoE and IBD diagnoses were required for inclusion in the study. Pertinent demographic and clinical data were extracted from the electronic medical record. Treatment outcomes and frequencies of disease-related complications were determined.

RESULTS:

Sixty-nine patients met inclusion criteria (68.1% male) with a median follow-up of 6 years. Forty-one patients had a diagnosis of CD (59.4%), 26 UC (37.7%), and 2 indeterminate colitis (IC) (2.9%). Forty-eight patients were diagnosed with IBD prior to EoE (69.6%). The most common treatments for EoE were proton pump inhibitors (78.3%) and topical steroids (59.4%) with 51.9% and 63.4% demonstrating clinical improvement, respectively (Table 1). The most common treatments for IBD were oral 5-aminosalicyclic acid (5-ASA) (69.6%), oral corticosteroids (66.7%), azathioprine (44.9%), and adalimumab (43.5%), with 37.5%, 43.5%, 35.5%, and 50% demonstrating clinical improvement, respectively (Table 2). Fifteen patients with CD (36.5%), 7 with UC (26.9%) and 1 with IC (50%) required surgical intervention for IBD. Eighteen patients with CD (43.9%), 8 with UC (30.8%), and 1 with IC (50%) required hospitalization for IBD (Table 3).

CONCLUSION:

Recent literature has shown an association between IBD and EoE. In our cohort, IBD is the more frequent initial diagnosis. As such, it is important to be vigilant for signs suggestive of EoE in patients with IBD and evaluate accordingly. It seems most patients with IBD and EoE respond to conventional treatment modalities used for each diagnosis. However, about 40% of patients with CD and EoE required hospitalization and/or surgical intervention, possibly suggesting a more severe phenotype in this specific subset of patients.
789 The Association Between Inflammatory Bowel Disease and Lactose Intolerance
Authors: Asfari Mohammad Maysara , Sarmini Muhammad Talal , Kendrick Katherine , Sridhar Subbaramiah , Sifuentes Humberto
Published: October 2019

INTRODUCTION:

Inflammatory bowel disease (IBD) is a complex condition precipitated by genetic susceptibility and disturbed microbiome. The role of dairy foods in IBD has been controversial. Therefore, we aimed to investigate the association between lactose intolerance (LI) and IBD.

METHODS:

Data on hospital admissions of all IBD adult patients were extracted from the National Inpatient Sample (NIS) database between 2004 and 2014. Comorbidities and outcomes of interest were defined by querying all diagnostic and procedural fields for the corresponding ICD-9 codes. Patients who were diagnosed with IBD were defined (study group). The control group were the patients who did not have a diagnosis of IBD. LI diagnosis was identified in both study and control groups using the ICD-9 codes. Univariable and multivariate logistic regression was performed to study the association between IBD and LI.

RESULTS:

The total population was comprised of 71,342,237 patients, of which 598,129 (0.83%) were diagnosed with IBD. IBD patients were younger (52 vs 57) with fewer female (57.5% vs 60.1%) and African American patients (10% vs 14.3%) (P < 0.0001 for all). In addition, the IBD patients had more tobacco use (14% vs 12%). After adjusting for the potential cofounding factors including age, race, gender, obesity and tobacco use, the IBD group had a statistically significant higher rate of LI (Odds Ratio [OR], 2.71, 95% confidence interval [CI], 2,55-2.88, P < 0.0001) compared to non-IBD group. The findings were similar on further stratification of IBD into Crohn's disease compared to the control group (OR: 2.7, 95% CI: 2.50–2.92, P < 0.0001) and ulcerative colitis compared to the control group (OR: 2.71, 95% CI: 2.46–2.98, P < 0.0001).

CONCLUSION:

IBD patients have a 2.7 times higher risk of suffering from lactose intolerance. Screening for lactose intolerance in this population warranted to avoid confusing symptomatology with inflammatory bowel disease activity.
794 Admission Risk Factors as Predictors of In-Hospital Colectomy in Acute Severe Ulcerative Colitis
Authors: Dwadasi Sujaata , Goens Donald , Paknikar Raghavendra , Zafer Maryam , Rubin David T. , Micic Dejan
Published: October 2019

INTRODUCTION:

Ulcerative colitis is an immune-mediated disorder characterized by chronic inflammation of the gastrointestinal tract. In the setting of hospitalization and presentation with acute severe ulcerative colitis (ASUC), the risk of colectomy approaches 30-40%. In an effort to improve medical therapies, identifying early predictors for colectomy has the potential to reduce the risk of surgery in ASUC.

METHODS:

We designed a retrospective study including all patients >18 years of age with an admission for ASUC at the University of Chicago Medical Center between the 1/1/2013 and 4/1/2018. Cases of were identified using the ICD-9 code 556.X and ICD-10 code K51.X and separately reviewed based on clinical, radiographic, histologic and endoscopic information. Additional electronic variables of interest were extracted from the electronic data warehouse. Data were analyzed using Wilcoxon rank-sum test for continuous variables and Fischer's exact test for categorical variables. Multivariate logistic regression was performed to identify independent factors predictive of inpatient colectomy.

RESULTS:

We identified 260 unique patient encounters admitted for ASUC, of which 59 (22.7%) underwent inpatient colectomy. Risk factors for inpatient colectomy are demonstrated in Table 1. Among individuals requiring colectomy in univariate analysis, a prior history of DVT/PE, prior admission for intravenous steroids or recent hospitalization were predictive of colectomy. Presenting endoscopic Mayo score, number of prior biologic therapy exposures, and laboratory values suggestive of active inflammation were predictive of colectomy. In a final multivariate model, risk factors of inpatient colectomy included: number of prior biologic exposure (OR: 2.27, 95% CI 1.5-3.4), transfer from an outside hospital (OR: 5.03, 95% CI 1.97-12.86) and platelet count on admission (OR: 1.01, 95% CI 1-1.01).

CONCLUSION:

Early identification of potentially medically refractory disease has the potential to reduce need for colectomy in ASUC. Number of prior exposures to biologic therapies, transfer from an outside institution and platelet count are independently associated with risk of colectomy. Additional studies are required to improve the medical therapies offered to high-risk patients in order to reduce colectomy risk.
797 High Thiopurine Methyltransferase Activity Does Not Affect Concentration of Azathioprine Metabolite 6-Thioguanine Nucleotide in Inflammatory Bowel Disease
Authors: Jonason David , Sievers Tyson , Abraham James M. , Vaughn Byron
Published: October 2019

INTRODUCTION:

Azathioprine (AZA) is commonly used to treat inflammatory bowel disease (IBD). Thiopurine methyltransferase (TPMT) converts AZA to key active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity is associated with high 6-TGN and side effects. Conversely, low 6-TGN is associated with lack of clinical response and has been associated with high TPMT activity but has not been examined in an IBD population. The aim of this study was to identify the independent effect of normal to high TPMT activity on 6-TGN concentrations in an IBD population.

METHODS:

We performed a retrospective chart review of patients aged >18 with IBD treated with AZA and with documented TPMT activity and 6-TGN levels from 2010 to 2017. To account for different assays, TPMT activity was normalized against the established low-normal TPMT activity, with low activity defined as less than 1 and high activity defined as above the 75th quantile of TPMT activity in the cohort. Those with low TPMT were excluded. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for potential confounders. Further assessment of the interaction between dose and TPMT activity on 6-TGN was measured through the Average Causal Mediation Effects (ACME). Statistics performed in R v3.6.0 using mediation package. This study was IRB approved.

RESULTS:

Dosing of AZA in mg/kg, TPMT activity, and 6-TGN concentration were documented in 63 patients, of which 10 had low TPMT activity and were subsequently excluded, leaving 53 patients for analysis. Overall 37% of the cohort had a therapeutic 6-TGN level of >240 pmol/8 × 108 RBC. No patient under 1mg/kg achieved a therapeutic 6-TGN level, whereas 50% of patients taking 2.5 mg/kg did. The median 6-TGN in the normal TPMT range was 191.5 (IQR: 78.8, 296.3) versus 201 (IQR: 45, 312) in the high group (P = 0.57). There was a weak positive correlation between dosing (mg/kg) and 6-TGN (R2 = 0.08), while no correlation was seen between TPMT and 6-TGN (R2 = 0.0). Linear regression to assess the effect of TPMT activity and dose on 6-TGN concentrations including potential confounders of sex, age, smoking status only identified dose (mg/kg) to have a significant effect on 6-TGN concentration (Table 1).

CONCLUSION:

There was no effect on 6-TGN as TPMT activity increased, although 6-TGN was positively affected by dose. Despite normal TPMT activity, therapeutic 6-TGN concentrations were only found in 50% of those dosed at 2.5 mg/kg.