Citations

Background/Objectives: Inflammatory bowel disease (IBD) is a chronic inflammatory condition encompassing ulcerative colitis (UC) and Crohn’s disease (CD). The role of environmental factors in the pathogenesis of IBD remains elusive. Nevertheless, evidence suggests a pivotal role of viruses, specifically Epstein–Barr virus (EBV), in the progression of IBD through mechanisms such as molecular mimicry and bystander activation. Our previous findings demonstrate EBV DNA’s significant role in exacerbating colitis symptoms and elevating the levels of the pro-autoimmune cytokine interleukin-17A (IL-17A) in an IBD mouse model via toll-like receptor 9 (TLR9). Therefore, we aimed to examine the role of EBV particles in the pathogenesis of IBD, and the potential role of TLR9 inhibition in ameliorating disease outcomes. Methods: Three days post colitis induction, EBV particles were intra-rectally injected into female C57BL/6J mice, followed by the intra-peritoneal administration of TLR9 inhibitor. Thereupon, mice were monitored daily and the disease activity index (DAI), colon lengths, and damage scores, as well as the number of cells, double-positive for IL-17A+ and IFN-γ+, and triple-positive for IL-17A+, IFN-γ+, and FOXP3+, were evaluated. Results: Our findings revealed a significant role of TLR9 inhibition in mitigating colitis features in an EBV-injected IBD mouse model compared to the control group. Conclusions: These results indicate an essential role of TLR9 in initiating immune responses against recurrent EBV reactivation events, which ultimately contributes to inflammation aggravation in IBD patients. Consequently, TLR9 could serve as a potential therapeutic target to alleviate the severe symptoms of IBD in EBV-infected individuals.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, are disorders caused by inflammation in the gastrointestinal tract leading to a wide variety of symptoms. The presence of symptoms may not always correlate with active intestinal inflammation, and the lack of symptoms does not always indicate control of inflammation. Owing to the variable correlation between clinical symptoms and active intestinal inflammation, the targets for IBD management have been updated to include objective measures of inflammation to complement clinical end points. In addition to clinical remission, these targets include improvements in biochemical markers and endoscopic measures to objectively measure and monitor disease remission. In this review, we will discuss the different strategies for assessing disease activity and the timing of evaluation for each treatment target for outpatient IBD care. We will also highlight the role of radiographic assessment with a focus on intestinal ultrasound for monitoring these treatment end points.

Abstract Introduction Limited data exist on the natural history and treatment persistence in ulcerative colitis (UC) patients on 5-aminosalicylic acid (5-ASA) in the era of biologic agents and small molecules. Methods This was a retrospective cohort study utilizing the US Collaborative Network in patients with UC who were initiated on 5-ASA between 2015 and 2019. The 1-, 3-, and 5-year incidence rates of advanced therapy use and colectomy were calculated. Predictors of advanced therapy use and colectomy within 5 years were analyzed and expressed as adjusted odds ratios (aORs) with 95% confidence intervals (CIs) after 1:1 propensity score matching (PSM). Results Among 15 177 patients in the UC 5-ASA cohort (mean age 47.2 ± 19.1 years old, 49.2% female and 70.3% White), the 1-, 3- and 5-year incidence of advanced therapy use was 5.37%, 11.56% and 15.8%, respectively. After PSM, age < 40 years old (aOR 1.93, 95% CI, 1.73-2.15), male sex (aOR 1.13, 1.02-1.25), obesity (aOR 1.18, 95% CI, 1.05-1.31), pancolitis (aOR 1.18, 95% CI, 1.03-1.36), steroid use (aOR 1.79, 95% CI, 1.53-2.09), and CRP ≥ 12 mg/L (aOR 1.39, 95% CI, 1.05-1.83) prior to 5-ASA initiation were associated with advanced therapy use within 5 years. The 1-, 3- and 5-year incidence of colectomy was 0.74%, 1.28%, and 1.64% respectively. After PSM, male sex (aOR 1.36, 95% 1.06-1.74), obesity (aOR 1.32, 95% CI, 1.02-1.69), primary sclerosing cholangitis (aOR 2.37, 95% CI, 1.11-5.06), pancolitis (aOR 1.90, 95% CI, 1.29-2.78), and steroid use (aOR 1.96, 95% CI, 1.35-2.84) were associated with colectomy within 5 years. Conclusion Our study provides updated estimates of advanced therapy utilization and colectomy as well as predictors of disease progression in patients with UC on 5-ASA in the biologic era.

ABSTRACTIL‐17 inhibitors effectively treat psoriasis and psoriatic arthritis but may increase the risk of inflammatory bowel disease (IBD). We assessed their association with IBD compared to apremilast. Utilising the TriNetX database, we analysed patients with psoriasis or ankylosing spondylitis initiating IL‐17 inhibitors or apremilast. We used propensity score matching and Cox models to estimate IBD risk. Among 13,216 matched patients per group, 142 developed IBD with IL‐17 inhibitors versus 60 with apremilast (aHR = 2.50, 95% CI: 1.85–3.39). IL‐17 inhibitors increase IBD risk, necessitating careful patient selection and monitoring.

Introduction Targeted immunomodulators (eg, advanced therapies) effectively achieve symptomatic remission in patients with inflammatory bowel disease (IBD). However, ~25%–50% of patients with IBD achieving symptomatic remission with an advanced therapy may have continued endoscopically/radiologically active bowel inflammation, and it is uncertain whether changing alternative advanced therapies in asymptomatic patients with IBD will reduce bowel inflammation and achieve durable deep remission. Methods and analysis The QUality Outcomes Treating IBD to Target (QUOTIENT) study is an open-label, multicentre, pragmatic, randomised, controlled trial that aims to compare the efficacy and safety of switching to an alternative advanced therapy targeting endoscopic/radiological remission (treat-to-target) versus continuing the initial, or index, advanced therapy, in asymptomatic patients with IBD with moderate-to-severe endoscopic/radiological bowel inflammation. Enrolment is planned for ~250 participants in Canada/USA, randomised 1:1 to switching to alternative advanced therapy or continuing index advanced therapy, and then followed 104 weeks within routine clinical practice. Patient-reported outcomes measure efficacy and quality of life/treatment burden/safety. Primary endpoint is the time from randomisation to treatment failure. Ethics and dissemination The study is conducted in compliance with the protocol, ICH Good Clinical Practice, applicable regulatory requirements and appropriate review boards/independent ethics committees (approval numbers: Pro00077486; Pro00061437; STUDY00002062; 22-004171; i22-01269; IRB22-0890; IRB_00154397; 2000032384; SHIRB#2022.095-2; STUDY00007146; MMC#2024-18; REB#125290; 17784; Pro00142214; 20240660-01H), with documented written informed consent. Findings will be disseminated through peer-reviewed journals, scientific presentations, and publicly available Patient-Centered Outcomes Research Institute (PCORI) websites, including lay summaries. The Crohn’s & Colitis Foundation Education, Support, and Advocacy Department, and our patient advocacy stakeholder, will develop educational and marketing resources to communicate findings to a broad audience (>250 000 patients/caregivers/healthcare professionals). Trial registration number NCT05230173 .

Abstract Objectives Oral extraintestinal manifestations (OEIMs) of inflammatory bowel disease (IBD) may impact IBD treatment. The aims of this study were to: (1) determine which OEIMs are most prevalent among patients with IBD, (2) investigate the presence of a temporal association between GI luminal disease activity and OEIMs, and (3) determine how often changes in therapeutic management of IBD are needed in the presence of OEIMs. Study Design A retrospective cohort study was performed for adult patients with IBD evaluated between January 2017 and November 2021 with at least 1 oral complaint. Demographic data were collected from the charts of these patients. Kruskal-Wallis test for continuous measures and Fisher’s Exact test for categorical measures were used. Results A total of 116 patients with IBD who had presented with at least 1 oral finding during the study time period were identified. Aphthous ulcers were the most common oral presentation in both Crohn’s disease (CD) (85.1%) and ulcerative colitis (UC) (75.0%). OEIMs were associated with CD activity in the small intestine (P = .004) and colon (P < .001). UC pancolitis was associated with OEIMs (P = .002). In 32.7% of patients, OEIMs led to either an increase in dose or frequency of IBD therapy. In an additional 16.4% of patients, new systemic agents were started because of the OEIMs. Conclusions This study provides evidence that patients with IBD may develop OEIMs synchronous with IBD flares and may require escalation of IBD therapy when OEIMs occur.

Background/Objectives: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). Methods: In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs’ treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. Results: A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. Conclusions: PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.