Introduction

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Current therapies include monoclonal antibodies, such as adalimumab (ADA) and infliximab (IFX), that target the inflammatory cytokine tumor necrosis factor alpha, collectively known as anti-TNF. While it has been shown that anti-TNF is effective at inducing and maintaining remission in patients with CD, this treatment fails in up to 40% of CD patients^​. Ineffective treatment results in disease progression and complications, emphasizing the need to understand mechanisms behind non-response and to define prognostic biomarkers. We previously identified differences in the peripheral blood DNA methylome associated with response and non-response. However, it is unclear how differential methylation can affect the transcriptome.

Aims & Methods

In this study, we assembled a cohort of 58 adult CD patients that were scheduled to start ADA or IFX treatment. Response to treatment was assessed after 6-9 months based on strict combination of endoscopic (≥50% reduction SES-CD), biochemical (CRP reduction ≥50% or CRP≤5 mg/L and FCP reduction ≥50% or FCP ≤250 µg/g) and clinical criteria (≥3 point drop in HBI or HBI ≤4 without corticosteroids). Whole peripheral blood leukocytes (PBL) were collected from patients before baseline endoscopy or at first infusion/injection, and 6-9 months later. mRNA was extracted using QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq at the Amsterdam UMC Core Facility Genomics. Differential expression (DE) analysis was carried out within the R statistical environment (v 4.3.1) using the Bioconductor package DESeq2 (v 1.40.2).

Results

Prior to the start of treatment, we identified 504 and 750 differentially expressed genes (DEGs) distinguishing responders from non-responders in ADA and IFX cohorts, respectively. While 13 genes presented response-associated differential expression for both ADA and IFX, no overall correlation was observed between response-associated differential expression profiles. However, based on canonical pathway analysis, we found that expression differed in both ADA and IFX responders and non-responders at the level of neutrophil degranulation, B-cell receptor regulation, and cell growth and differentiation.

Conclusion

Our data suggest that response to ADA and IFX can be associated to the PBL transcriptome prior to treatment. Furthermore, while the differences between responders and non-responders to ADA and IFX display limited overlap in DEGs, we observe that response-associated pathways are shared.

Introduction

Previous studies reported a positive correlation between serum and tissue drug levels in IBD receiving intravenous (IV) infliximab (IFX) therapy, except in those with severely inflamed tissue (1). Tissue drug levels in patients with IBD receiving SC IFX have not yet been investigated. We aimed to compare both the serum and tissue drug levels between SC and IV IFX maintenance therapy in IBD patients.

Aims & Methods

Any IBD patients under maintenance therapy with SC or IV stable doses IFX who underwent a colonoscopy for routine follow-up were eligible. Patient and disease characteristics, as well as clinical and endoscopic activity were recorded. Clinical activity was defined by high activity score (CDAI or pMAYO score) with at least one elevated biomarker (fecal calprotectin >250 mg/g, serum CRP >5 mg/L). Endoscopic disease activity was categorized as absent (normal), low (mild inflammation), moderate (friability, aphthoid lesions), or severe (ulcerations), as reported by the endoscopist blinded to the results of serum and tissue drug levels. Two biopsies were taken from the same location (either the most active area or randomly if no endoscopic lesion), and tissue and serum IFX levels were measured simultaneously in a centralized manner blinded to clinical and endoscopic disease activity. Frozen biopsy specimens were treated with the Bio-Plex® Cell Lysis Kit after tissue cutting and homogenates were sonicated at 4°C (Omni Ruptor 205). Tissue extracts were then frozen at -80°C prior drug measurements (iTrack10; Theradiag).

Results

Thirty-five patients were enrolled (CD in 65%, Sex ratio 1.4, 14 % with clinically and 57 % with endoscopically active disease, and 23 under SC IFX therapy). The characteristics of both IV and SC IFX groups were comparable, except for drug dose intensification in 90% of those treated with IV IFX group and 5% in the SC IFX cohort (p < 0.001). In patient in endoscopic remission, tissue levels were undetectable or very low for both IV and SC IFX therapy. Serum and tissue drug levels were significantly higher in the SC IFX cohort compared with the IV IFX group (22 mg/mL vs 9 mg/mL for serum; p < 0.001 and 25 mg/g vs 10 mg/g for tissue; p = 0.002, respectively). A moderate correlation was found between serum and tissue drug levels for both IV and SC IFX therapy (Spearman r = 0.42; p = 0.014 and r = 0.43; p = 0.001, respectively). Tissue drug levels increased gradually in patients with minimal or moderate endoscopic activity and were lower in those with severe endoscopic activity for both IV and SC IFX groups (p < 0.001). Tissue drug levels remained significantly higher in minimal or moderate endoscopically active disease in SC compared with IV route of IFX administration. The two independent factors associated with drug tissue levels > 14 mg/g (median levels) were the SC IFX route (OR: 2.25, 95% CI = [1.19–2.23]; p = 0.001) and the serum IFX levels (OR: 1.63, 95% CI = [1.19–2.23]; p = 0.002). A serum IFX level greater than 16.1 mg/mL was highly predictive of a tissue drug level > 14 mg/g tissue (Se: 0.94, Spe: 0.94, PPV: 0.94, NPV: 0.94, and Accuracy = 94.3%).

Conclusion

Serum and tissue drug levels are positively correlated in IBD patients under IV and SC maintenance IFX therapy. Interestingly, drug levels were higher both in serum and tissue in patients under SC IFX compared with IV IFX and tissue drug levels gradually increased in minimally to moderately inflamed intestine but were lower or undetectable in more severe inflamed areas.

References

1. Yarur AJ, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut 2016; 65: 249-255.

Introduction

An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios for both (normal to obese) adults and children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy.

Aims & Methods

By combining two previous published infliximab models (1,2) we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration time curve (AUC) was calculated.

Results

Peak levels were higher after IV dosing compared to SC dosing, while trough levels were higher after SC dosing leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady state plasma levels.

Conclusion

Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for morbidly obese patients, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.

References

1) Hanzel J, Bukkems LH, Gecse KB, D’Haens GR, Mathôt RAA. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2021;54:1309–19.
2) Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn’s Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials. Clin Ther. 2011;33:946–64.

Disclosure

RW has no conflicts of interest. RK is an employee and stockholder of Insight RX, a company developing clinical decision software. LD has served as a speaker for AbbVie, Celltrion, Janssen-Cilag and Takeda and has developed continuing education materials for Ferring, all outside the submitted work.

Introduction

Early detection of gastric neoplasms in esophagogastroduodenoscopy (EGD) remains challenging due to the subtle and indistinct appearance of the lesions. In addition to white light imaging (WLI), image-enhanced endoscopy techniques, such as linked color imaging (LCI), are commonly used to detect such lesions. Recently, a computer-aided detection (CADe) system compatible with WLI and LCI (CAD EYE; Fujifilm Co., Tokyo, Japan) has been developed. However, evidence of its effectiveness in real-world clinical settings remains limited.

Aims & Methods

We conducted a multicenter, non-randomized confirmatory trial to evaluate the performance of CAD EYE in detecting gastric neoplasms. Between July 2023 and January 2024, patients undergoing EGD for known early gastric neoplasms were recruited at four institutions in Japan. While systematically observing the entire stomach with WLI and LCI, we investigated whether these lesions were detected by CAD EYE. The primary outcome was the sensitivity of CAD EYE (WLI-CADe and LCI-CADe) in detecting tumors. Secondary outcomes included identifying tumor characteristics and factors associated with missed detections by CAD EYE. To determine the sample size, we presumed the sensitivity of CAD EYE to be 95% based on pre-approval data, with a threshold set at 90%. The number of lesions required was calculated to be 150, ensuring that the lower limit of the 95% confidence interval (CI) exceeded the threshold of 90%. Assuming one lesion per patient and accounting for a 5% dropout rate, we recruited a total of 160 patients.

Results

A total of 174 lesions from 162 patients (mean age: 73.7±9.5 years, male: 69.7%) were analyzed. Current or past history of Helicobacter pylori (H. pylori) infection was observed in 158 patients (97.5%). The mean tumor diameter was 15.1 ± 11.3 mm, and the morphology consisted of 6 protruded, 51 flat elevated, and 117 flat types. Histology included 151 differentiated adenocarcinoma, 20 undifferentiated adenocarcinoma, 2 adenocarcinoma of fundic-gland type, and 1 tubular adenoma. The sensitivities of WLI-CADe and LCI-CADe in detecting tumors were 92.0% (95% CI: 86.9%–95.5%) and 96.5% (95% CI: 92.6%–98.7%), respectively. The sensitivity of LCI-CADe met expectations, as the lower limit of the 95% CI exceeded the threshold of 90%; however, WLI-CADe failed to meet the same standard. In WLI-CADe, lesions located on the anterior/posterior wall were missed significantly more often than those on the greater/lesser curvature (13.9% [11 of 79] vs. 3.2% [3 of 95]; P = 0.020); whereas no difference was observed in LCI-CADe. Other factors, such as H. pylori infection status, tumor morphology, location, and histology, showed no differences between lesions detected and missed by WLI-CADe and LCI-CADe.

Conclusion

The use of CADe with LCI demonstrated satisfactory sensitivity in detecting gastric neoplasms in real-world clinical settings, suggesting its potential to assist endoscopists in tumor detection. However, CADe with WLI did not meet the expected standards, possibly due to limitations, such as detecting lesions located on the anterior/posterior wall.

Disclosure

CAD EYE was temporarily provided by Fujifilm Co. Osamu Dohi has received a research grant, not related to this study, from Fujifilm Co. The remaining authors declare no conflicts of interest.