Introduction

Adequacy of bowel preparation (ABP) directly affects colonoscopy performance and adenoma detection rate. Studies attributed a role to the dosing regimen of the bowel cleansing agent, social and economic factors and comorbidities. However, data on the impact of kidney failure and renal replacement therapy (RRT) are lacking.

Aims & Methods

This study investigated how ABP compares between patients on RRT and age-matched subjects with normal kidney function.
All patients on RRT undergoing an elective colonoscopy between January 2016 and December 2021 were identified from the medical records of a university hospital, and matched to 2 closest age controls undergoing colonoscopy at the same date ± 7 days. Study subjects and controls were compared for demographics, comorbidities including history of abdominal surgery, use of bowel transit-influencing drugs, residential care stay and colonoscopy-related data (bowel preparation regimen, sedation type, colonoscopy findings, ABP defined as a cumulative Bristol Bowel Preparation Score >= 6 and a score of >= 2 for each colon segment). Statistical significant contributors to ABP were assessed by logistic regression.

Results

Ninety-one patients on RRT (76 on haemodialysis and 15 on peritoneal dialysis) and 182 controls were identified. Patients on RRT were older (69±12 vs. 64±14y, p=.008) and less frequently women (34% vs. 50%, p=.013). They had more diabetes (40% vs. 24%, p=.008), more history of abdominal surgery (32% vs. 21%, p=.047) and took more bowel transit-influencing drugs (50% vs. 28%, p<.0001). Bowel preparation regimens were equally distributed between both groups. There was no difference in the rate of ABP between groups (87% vs. 81%, p=NS). Logistic regression analysis did not reveal an association between RRT and ABP. ABP was negatively influenced by residency in residential care, overnight stay in the hospital before colonoscopy, history of central nervous system disease, and positively by split-dose regimen (Nagelkerke R square 0.329, p=<.001).

Conclusion

Despite less favourable associated conditions, ABP in RRT patients remains comparable to controls. Split-dose regimen, neurological conditions and in-hospital stay are significant predictors of adequate bowel preparation.

References

Clark BT, Rustagi T, Laine L. What level of bowel prep quality requires early repeat colonoscopy: systematic review and meta-analysis of the impact of preparation quality on adenoma detection rate. Am J Gastroenterol. 2014;109(11):1714-23; quiz 24.
Hassan C, East J, Radaelli F, Spada C, Benamouzig R, Bisschops R, et al. Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2019. Endoscopy. 2019;51(8):775-94.
Saumoy M, Jesudian AB, Aden B, Serur D, Sundararajan S, Sivananthan G, et al. High prevalence of colon adenomas in end-stage kidney disease patients on hemodialysis undergoing renal transplant evaluation. Clin Transplant. 2016;30(3):256-62.
24. Calderwood AH, Schroy PC, 3rd, Lieberman DA, Logan JR, Zurfluh M, Jacobson BC. Boston Bowel Preparation Scale scores provide a standardized definition of adequate for describing bowel cleanliness. Gastrointest Endosc. 2014;80(2):269-76.
25. Clark BT, Protiva P, Nagar A, Imaeda A, Ciarleglio MM, Deng Y, et al. Quantification of Adequate Bowel Preparation for Screening or Surveillance Colonoscopy in Men. Gastroenterology. 2016;150(2):396-405; quiz e14-5.
artel M, Barkun AN, Menard C, Restellini S, Kherad O, Vanasse A. Split-Dose Preparations Are Superior to Day-Before Bowel Cleansing Regimens: A Meta-analysis. Gastroenterology. 2015;149(1):79-88

Clinical Case Summary

A 39-year-old woman was admitted on June 20, 2024, with a right middle cerebral artery stroke, nine weeks after starting Upadacitinib for ulcerative colitis. She presented with dysarthria, dysphagia, and severe left-sided weakness. CT imaging revealed a wedge-shaped infarction without intracranial hemorrhage (CT head/ Brain MRI).
She was diagnosed with ulcerative colitis in November 2023, she initially responded to Mezavent and steroids but was hospitalized on March 31, 2024 for moderate UC flare, requiring infliximab rescue therapy. The patient presented with four bloody bowel movements and elevated inflammatory markers (CRP>100), confirmed by a Mayo score of 2 on flexible sigmoidoscopy and cytomegalovirus (CMV) infection was excluded. Clostridium difficile tests were negative twice and a CT scan revealed pancolitis. Despite minimal response to rescue therapy, she opted for medical treatment over colectomy.
On April 23, 2024, she began an eight-week induction of Upadacitinib 45 mg, which she tolerated well. However, on June 20, she developed sudden stroke symptoms while eating dinner, including difficulty swallowing, choking, left-sided weakness, and numbness. She had no vascular risk factors or family history of premature cardiovascular conditions. Lupus, and vasculitis work up were unremarkable and extensive thrombophilia screenings were all negative.
Discussion: Thrombosis in IBD patients can result from various potential causes. First of all, Inflammation and hypercoagulability, driven by elevated cytokines like TNF, interleukins, and CRP, activate the coagulation cascade, increasing thrombosis risk.
Conclusion: IBD is a known risk of thromboembolic disease, this risk increased during flare up will raise future research questions regarding extended anticoagulation prophylaxis during flare and uses of Jak stats inhibitor.

References

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7. Lou JS, Effect of expectancy and personality on cortical excitability in Parkinson's disease.Mov Disord. 2013 Aug;28(9):1257-62.DOI: 10.1002/mds.25471PMID: 23630185

8. Parra-Izquierdo I,Janus kinase inhibitors ruxolitinib and baricitinib impair glycoprotein-VI mediated platelet function.Platelets. 2022 Apr 3;33(3):404-415.DOI: 10.1080/09537104.2021.1934665Epub 2021 Jun 7.

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Introduction

Guselkumab (GUS), interleukin-23p19 subunit inhibitor, has been approved for moderately to severely active Crohn’s disease (CD) in Japan. CNTO1959CRD3003 is a Phase 3, open-label, multicenter study designed to evaluate the safety and efficacy of GUS in Japanese patients with moderately to severely active CD. We report the efficacy of GUS on small bowel lesions.

Aims & Methods

The primary objective was to evaluate safety, and the secondary objective was to evaluate the efficacy of GUS at week 48 (W48). An exploratory objective was to assess the efficacy of GUS for small bowel lesions, evaluated using retrograde balloon-assisted enteroscopy (BAE). Eligible patients in this study were patients with active ileocolonic CD or small bowel CD, as clarified by endoscopic evaluation. GUS 200 mg was administered intravenously on Weeks 0, 4, and 8 and subcutaneously every 4 weeks from week12 until W44. As optional, small bowel lesions were assessed using modified simple Endoscopic Score for Crohn’s Disease [mSES-CD], excluding stricture evaluation. The sum of the proximal ileum (10-300 cm from ileocecal valve) and terminal ileum sub-scores was defined as a partial modified SES-CD (pmSES-CD). Within patients with pmSES-CD score of 4 or more at baseline, those with a score reduction of 50% at W48 from the baseline were defined as endoscopic responder; a pmSES-CD score of less than 4 points was defined as ulcer-free, and a pmSES-CD score of 0 was defined as complete mucosal healing.

Results

A total of 38 patients were enrolled and received GUS treatment. Most participants were male (24/38; 63.2%), and the median age was 40.5 (range: 20-69) years. This group included 8 with ileal type, 9 with colonic type, and 21 with ileocolonic type. The median duration of CD was 7.97 (0.4–33.0) years. Overall, 33/38 patients (86.8%) experienced an adverse event (AE) and 3/38 (7.9%) experienced a serious AE. There were no CD-related hospitalizations or surgeries, and no new safety concerns were identified regarding GUS treatment through W48.
Among the 38 patients, 15 patients were evaluated for small bowel lesion using retrograde BAE, defined as the small bowel (SB) group. Among these, the median age was 41.0 (24-69) years, and the median duration of CD was 2.92 (0.4-16.9) years. The median pmSES-CD was 8.0 (0-14) at baseline and 5.0 (0-13) at W48. 7/15 patients (46.7%) were endoscopic responders, 4/15 patients achieved ulcer-free (26.7%), and 2/15 patients (13.3%) achieved complete mucosal healing at W48 (Table.1). Three participants (20.0%) showed improvement of 5 points or more in the lesions of the proximal ileum as measured by pmSES-CD. Two of three ileal type patients achieved ulcer-free at W48. No AE of strictures were reported through W48.

Table 1. Result of efficacy of guselkumab treatment on small bowel lesions.

Conclusion

Overall, this study showed that GUS is well-tolerated and effective for treating patients with moderately to severely active CD, and the results also suggested the effectiveness of GUS in small bowel lesions.

Disclosure

TH: Grant: EA pharma Co. Ltd., AbbVie GK, Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co.Ltd, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Zeria Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Kissei Pharmaceutical, Boston Scientific
Consulting fees: EA pharma Co. Ltd.,AbbVie GK,Pfizer Inc.,Mitsubishi Tanabe Pharma Corporation,Takeda Pharmaceutical Co. Ltd.,Gilead Sciences, Inc.,Eli Lilly and Co.,Janssen Pharmaceutical K.K.,Bristol Myers Squibb,Abivax
Payment or honoraria for lectures, presentations, speakers;
EA pharma Co. Ltd.,AbbVie GK,Pfizer Inc.,Mitsubishi Tanabe Pharma Corporation,Kyorin Pharmaceutical Co. Ltd.,JIMRO Co.Ltd,Mochida Pharmaceutical Co., Ltd.,Takeda Pharmaceutical Co. Ltd.,Zeria Pharmaceutical Co. Ltd.,Nippon Kayaku Co. Ltd.,Janssen Pharmaceutical K.K.
TK: Grant: Abbie GK, Alfresa Pharma Corporation, EA Pharma, Gilead Sciences, Inc. Nippon Kayaku Co., Ltd., Eli Lilly Japan K.K., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Sekisui Medical, Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, Zeria Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Consulting fees :Takeda Pharmaceutical Co., Ltd., Alfresa Pharma Corporation, Zeria Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Abbie GK, Pfizer Japan Inc., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Galapagos, Takeda Pharmaceutical Co., Ltd., Expert testimony : EA Pharma Co., Ltd., KISSEI Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd., Pfizer Japan Inc., Nippon Kayaku Co., Ltd., Alfresa Pharma Corporation, Abbie GK, Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K.
KW: Consulting fees: EA Pharma Co., Ltd., Payment or honoraria for lectures, presentations, speakers: Takeda Pharmaceutical Co., Ltd., AbbVie Japan Co., Ltd., EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., JIMRO Co., Ltd.
Participation on a Data Safety Monitoring Board or Advisory Board: Takeda Pharmaceutical Co., Ltd., Leadership or fiduciary role in other board, society, committee : Japanese Society of Gastroenterology, Japanese Society of Gastrointestinal Endoscopy, Japanese Gastroenterological Association, Japan Society of Coloproctology, Japanese Society of Mucosal Immunology, Japan Society for Inflammatory Bowel Disease, Japanese Society of Small Intestinal Disease, Japanese Association for Capsule Endoscopy, Research group of intractable IBD, the Ministry of Health, Labor and Welfare in Japan
KO All support for the present manuscript : J&J Innovative Medicine, Payment or honoraria for lectures, presentations, speakers: AbbVie Inc, EA Pharma Co.,Ltd, Janssen Pharmaceutical, KYORIN Pharmaceutical, Mitsubishi Tanabe Pharma, MOCHIDA PHARMACEUTICAL, Nippon Kayaku Co.,Ltd, OLYMPUS CORPORATION, Takeda Pharmaceuticals, Zeria Pharmaceutical Co., Ltd.
ME: Grant: Kyorin Pharmaceutical Co. Ltd, Payment or honoraria for lectures, presentations, speakers: AbbVie GK, Mitsubishi Tanabe Pharma, EA Pharma Co., Ltd, Janssen Pharmaceutical, Takeda Pharmaceuticals, Pfizer Japan Inc., Gilead Sciences Inc., Mochida Pharmaceutical Co. Ltd
TO: Payment or honoraria for lectures, presentations, speakers: AbbVie GK., Takeda Pharmaceutical Co. Ltd., and KISSEI Co. Ltd
NH: Expert testimony : J&J Innovative Medicine
TM: None
TS, KM, MC, HH and SY are employees of Johnson & Johnson.

Introduction

Patients with ulcerative colitis (UC) are at an increased risk of cytomegalovirus (CMV) infection. CMV infection in acute severe ulcerative colitis (ASUC) may worsen disease severity and clinical outcomes. Current guidelines recommend colonic biopsies for the exclusion of CMV in all patients with ASUC. One study found that CMV positivity in ASUC was associated with greater need for rescue therapy, longer hospital length of stay (LOS) and higher readmission rates but found no difference in rate of colectomy.¹ We aimed to investigate the impact of positive CMV result on clinical outcomes in patients presenting with ASUC.

Aims & Methods

A retrospective review included all ASUC presentations to a quaternary hospital over a 10-year period based on modified Truelove and Witts’ criteria. ASUC presentations were grouped based on CMV positivity as determined by colonic biopsy. Data on pre-admission medications was collected. Data was collected on rates of rescue therapy, referral to colorectal surgery, colectomy, total parenteral nutrition (TPN). Outcomes assessed included intensive care unit (ICU) admission, 30- and 90-day readmission rates, 30- and 90-day mortality rates and mean LOS.

Results

A total of 172 ASUC presentations were identified. Of these, 133 had available colonic biopsy CMV results. 11 patients (8%) had positive CMV. Positive CMV result was significantly associated with increased need for TPN (36% vs 11%, p=0.02), ICU admission (27% vs 5%, p=0.004) and referral to colorectal surgery (82% vs 43%, p=0.01). Patients with CMV had longer LOS (27.1±14.0 vs 11.0±7.4, p=0.003). There were no significant differences in rates of rescue therapy, inpatient colectomy, readmission or mortality rates. 9 of the patients (82%) were treated with ganciclovir or valganciclovir. Patients on maintenance advanced UC therapies, including biologics and small molecule inhibitors, had significantly higher rate of CMV (22% vs 5%, p=0.01). Biologic therapy alone was associated with higher rate of CMV (24% vs 7%, p=0.02), whereas small molecule inhibitor alone was not (p=0.6). Pre-admission use of 5-aminosalicylates, high dose steroids, thiopurines or combination therapies were not associated with CMV positivity.

Table 1: Comparison data of clinical outcomes in ASUC between patients with and without CMV positivity on colonic biopsy

Conclusion

Patients with CMV positive colonic biopsies tend to require more inpatient interventions, including increased need for TPN, ICU admission, referral to colorectal surgery and longer hospital length of stay. Despite more complex admission course of ASUC patients with concurrent CMV infection, these patients were not observed to have worse outcomes than those without CMV diagnosis. Maintenance biologic and small molecule inhibitor use was associated with higher rates of CMV, reflecting the immunosuppressant effects of advanced UC therapies. CMV detection needs to be considered as a potential exacerbating factor in disease severity.

References

1. Huang D, Rennie M, Krasovec A, Nagubandi S, Liu S, Ge E, Khehra B, Au M, Sivagnanam S, Kwan V, Rogge C, Mitrev N, Kariyawasam V. Impact of cytomegalovirus on outcomes in acute severe ulcerative colitis: a retrospective observational study. Ther Adv Chronic Dis. 2024 Mar 28;15:20406223241233203. doi: 10.1177/20406223241233203. PMID: 38560721; PMCID: PMC10981253.

Introduction

Ozanimod (OZA), a selective sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator, is approved in multiple countries for the treatment of adults with moderately to severely active ulcerative colitis and relapsing multiple sclerosis. Treatment with OZA and other S1P receptor modulators has been associated with bradycardia likely due to the pharmacologic effect of S1P₁ receptors on heart rate (HR). Thus, dose titration with OZA is implemented to mitigate this risk.

Aims & Methods

This randomized, double-blind, placebo (PBO)–controlled, adaptive phase 1 study evaluated the effects of OZA reinitiation on HR. OZA was reinitiated at a maintenance dose of 0.92 mg (equivalent to OZA HCl 1 mg) after different washout intervals relative to dose escalation in healthy adults. Participants were randomized to receive once-daily OZA (dose titration: 0.23 mg for Days 1–4, 0.46 mg for Days 5–7, and 0.92 mg thereafter) or PBO for 28 days in Period 1, followed by a washout of 3, 7, or 14 days, and then treatment reinitiation with a single dose of either OZA 0.92 mg or PBO in Period 2. The changes at Period 2 Day 1 from Period 1 Day 1 (CFP1) in the HR_Nadir from 0–12 hours postdose were compared between OZA/OZA and PBO/PBO groups after each washout interval and were analyzed using an ANCOVA model with fixed effects for treatment, Period 1 Day 1 HR_Nadir (0–12 hours), sex, and treatment × Period 1 Day 1 HR_Nadir (0–12 hours); least squares (LS) mean differences between OZA/OZA and PBO/PBO with 90% CI were calculated. The maximum reductions in hourly HR using the change from predose HR minimum value from 0–12 hours relative to dosing on the corresponding day of interest (CFP_min HR) and time to HR_Nadir were compared between combined OZA (OZA/OZA and OZA/PBO; n=51) and PBO/PBO participants. Safetywas also assessed.

Results

Of 64 healthy adults who completed the study, 15, 16, and 15 received OZA/OZA and completed the 3-, 7-, and 14-day washout intervals, respectively; 18 individuals received PBO/PBO (6 in each washout period; they were combined for all washout interval comparisons). LS mean CFP1 Day 1 HR_Nadir changes were generally similar between OZA/OZA and PBO/PBO groups at each washout interval: 3 days = 3.51 vs 1.73 beats per minute (bpm), 7 days = 0.85 vs 1.87 bpm, and 14 days = 0.27 vs 1.81 bpm, respectively. The CFP1 Day 1 HR_Nadir LS mean differences between OZA/OZA and PBO/PBO (90% CI) at each washout interval were 3 days = 1.78 bpm (–1.76 to 5.32), 7 days = –1.02 bpm (–3.88 to 1.85), and 14 days = –1.54 bpm (–4.20 to 1.11). During the OZA dose escalation, CFP_min HR changes ranged from –11.90 to –8.70 bpm for OZA (combined) and from –9.45 to –7.79 bpm for PBO/PBO. Predose HR values for OZA (combined) on Days 5 and 8 were ~5 bpm lower than on Day 1. Postdose CFP_min HR changes were similar between Days 5 and 8 for OZA (combined), which were ~3 bpm lower than on Day 1. Median time to HR_Nadir was similar between OZA (combined; 4 hours) and PBO/PBO (3–4 hours). Repeated dosing of OZA for 28 days (including the 7-day dose escalation) and reinitiation of OZA 0.92 mg after all washout intervals was generally safe and well tolerated in healthy participants.

Conclusion

Overall, reinitiation of OZA at the maintenance dose of 0.92 mg once daily after dose interruption of 3, 7, or 14 consecutive days was not associated with meaningful changes in HR. OZA can be safely reinitiated at the maintenance dose without repeating dose titration within 14 days of drug discontinuation.

Disclosure

The study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
PZ, MS, SW, GT, BM, and DT: employees and/or shareholders of Bristol Myers Squibb.