Introduction

A deeper understanding of the pathogenesis of UC has led to the emergence of new therapeutic strategies. One of them consists of targeted exposure with biological drugs to certain molecules that regulate the interaction between leukocytes and endothelial cells in the inflammatory zone (mainly leukocyte integrins and endothelial cell adhesion molecules of the immunoglobulin superfamily).

Aims & Methods

Purpose of the study: To study the content of adhesion molecules ICAM-1, ICAM-2 and L-selectin in the peripheral blood of patients with ulcerative colitis (UC) and the effect of vedolizumab (Intivio) on their levels.
Materials and methods: We examined 12 patients with moderate and severe forms of UC and the ineffectiveness of previous standard therapy. The severity of the UC attack was calculated according to the Mayo index. Antivio® 300 mg was administered to patients intravenously according to the attached instructions. The content of adhesion molecules in the peripheral blood was studied before and 6 weeks after the first injection of vedilizumab. The control group consisted of 15 healthy volunteers. The content of ICAM-1, ICAM-2 and L-selectin in blood serum was determined by multilayer ELISA analysis (Bender med.Systems, Austria). Statistical processing of the obtained results was carried out using SPSS 13.0 software.

Results

It was found that the initial levels of ICAM-1 (461.9±28.4 ng/ml), ICAM-2 (323.3±18.4 ng/ml) and sL-selectin (1650±12.25 U/ml) ) in the peripheral blood of patients with UC were increased (P<0.05 with control), the Mayo index was 9 points. After four infusions of Vedolizumab (week 14), the levels of soluble molecules decreased in 4 patients, with a predominant decrease in sL-selectin (201±9.32 ng/ml, 197±8.54 pg/ml and 1008±15.3 U/ml respectively). The Mayo index was 5 points. In 8 patients, by the 6th week of treatment, the levels of the studied adhesive molecules did not change, although the Mayo index decreased by 3 points.

Conclusion

The initial level of ICAM-1, ICAM-2 and sL-selectin in the peripheral blood of patients with severe forms of UC is increased. The dynamics of the synthesis of adhesive molecules by immunocompetent cells under the influence of the fourth administration of Vedolizumab may predict the possibility of continuing the administration of the drug.

Introduction

Fibrostenosis represents one of the major clinical complications of Crohn’s Disease (CD). However, the molecular mechanisms underlying intestinal fibrogenesis remain poorly understood and anti-fibrotic therapy has not yet been developed. Growing evidence supports that oxidative stress and the epithelial-mesenchymal transition (EMT) process contribute to the development and progression of fibrosis.

Aims & Methods

Based on these evidences, we assessed the role of lipids in fibrogenesis and whether mitochondria dysfunction can support fibrosis formation.
Spatial metabolomics analysis and adipophilin (ADFP) staining were performed on surgical specimens from fibrotic ileum and the surrounding region (healthy) derived from CD patients. Fibroblasts isolated from fibrotic and healthy ileum and human induced pluripotent stem cell-derived intestinal organoids (iHOs) were treated for 1-3 weeks with lipid mix (2%) and analyzed by RNA sequencing. Pathways significantly modulated were validated by RT-PCR, WB, FACS analysis, and proliferative, migratory and contraction assays, and mitochondrial functions by Seahorse analyzer.

Results

Spatial metabolomics revealed a significant accumulation of lipids characterized by very long-chain fatty acids in the fibrotic area compared to surrounding healthy regions, which was further confirmed by ADFP staining. RNA-seq analysis showed overlapping dysregulated pathways between healthy fibroblasts stimulated with lipids and fibrotic fibroblasts, in particular genes related to cell cycle, cytoskeletal reorganization, migration, contractility and cell metabolism (oxidative stress) which were further confirmed by functional assays. Among the genes related to oxidative stress, lipid stimulation significantly decreased NFE2L2 and promoted an increase in CPT1A, gene encoding for a fatty oxidation mediator.
Moreover, lipid-stimulated fibroblasts showed a reduction in mitochondrial respiration, particularly basal and maximal respiration, and spare respiratory capacity by Seahorse analysis. On the other hand, long exposure of iHOs to lipids promoted the EMT process through the upregulation of TWIST, ZEB, and VIM.

Conclusion

Lipid stimulation induced myofibroblast activation through oxidative stress and alteration of mitochondrial metabolism, and increased the expression of EMT transcription factors in intestinal epithelial cells (iHOs) that may support fibroblast-mediated pro-fibrotic activity. These data indicate that regulators of fatty acid oxidation involved in the fibrotic process may represent new potential targets for the treatment of fibrostenotic CD patients.

Introduction

The efficacy and safety of risankizumab (RZB), an anti-interleukin 23p19 monoclonal antibody, as induction and maintenance therapy for adults with moderately to severely active ulcerative colitis (UC) was recently reported.^1,2 Influences of baseline disease characteristics on clinical outcomes are important to consider when optimizing UC treatment. Herein we analyze the efficacy of RZB stratified by baseline UC disease characteristics.

Aims & Methods

In the 12-week phase 3 INSPIRE induction study (NCT03398148) patients with moderately to severely active UC were randomized 2:1 to receive intravenous (IV) RZB 1200 mg or placebo (PBO) at weeks 0, 4, and 8. Patients with clinical response to RZB IV induction at week 12 or 24 in the phase 2b/3 induction studies were randomized 1:1:1 to receive subcutaneous (SC) RZB 180 mg, RZB 360 mg, or PBO (RZB withdrawal) every 8 weeks in the 52-week phase 3 COMMAND maintenance study (NCT03398135). This post hoc analysis evaluates clinical response, clinical remission, endoscopic remission, endoscopic improvement, and histological-endoscopic mucosal improvement (HEMI) at week 12 and 52 in subgroups stratified by baseline disease characteristics (Adapted Mayo score, pancolitis, high‑sensitivity C‑reactive protein [hs‑CRP], Mayo endoscopic subscore [ES], and disease duration).

Results

The induction analysis included 650 and 325 patients who received RZB 1200 mg IV and PBO IV, respectively. The maintenance analysis included 179, 186, and 183 patients who received RZB 180 mg SC, RZB 360 mg SC, and PBO (RZB withdrawal) SC, respectively. At induction week 12, the proportions of patients receiving RZB 1200 mg IV who achieved clinical response were numerically higher for the following baseline characteristic subgroups: pancolitis absence (70.5%) vs pancolitis presence (58.4%), Mayo ES of 2 (75.5%) vs Mayo ES of 3 (59.0%), and hs-CRP ≤ 5 mg/mL (68.9%) vs hs-CRP > 5 mg/mL (57.3%); the proportions of patients receiving RZB 1200 mg IV who achieved clinical remission at induction week 12 were also numerically higher for subgroups with pancolitis absence (25.3%) vs pancolitis presence (15.6%), Mayo ES of 2 (31.7%) vs Mayo ES of 3 (14.9%), and hs-CRP ≤ 5 mg/mL (23.7%) vs hs-CRP > 5 mg/mL (14.5%; Table). Differences in outcomes were not observed between subgroups stratified by Adapted Mayo score or disease duration. At week 52 of the maintenance study, there was no impact of baseline disease characteristics on achievement of clinical response and clinical remission with RZB (Table).

Conclusion

RZB induction and maintenance therapy improved clinical outcomes, regardless of baseline disease characteristics. Numerically higher RZB induction efficacy was observed for patients with no baseline pancolitis, Mayo ES of 2, and hs‑CRP ≤ 5 mg/L. These trends are consistent with prior observations that patients with milder UC disease phenotypes tend to be more responsive to therapy.

References

1. Louis E, et al. United Eur Gastroenterol J . 2023;11(S8):26–28. Abstract OP021.
2. Louis E, et al. J Crohns Colitis. 2024;18(S1):i10–12. Abstract OP06.

Disclosure

CH has served as a consultant, advisor, and/or has received education funds from AbbVie, Bausch Health, BMS, the Helmsley Charitable Trust, Janssen, Pfizer, Roivant, and Takeda.
MDL has received consulting fees and/or research grants from AbbVie, BMS, Intercept, Janssen, Lilly, Pfizer, Prometheus, Takeda, and Target RWE.
SRF has served as a consultant or advisor for AbbVie, Janssen, MSD, Takeda, Tillots, and Vitoria.
TF has received research grants and/or speaking honoraria from AbbVie, Ajinomoto, Alfresa, BI, BMS, Celgene, Celltrion, Daiichi Sankyo, EA Pharma, Eisai, Gilead, Janssen, Kissei, Kyorin, Kyowa Hakko Kirin, Lilly, Mebix, Mitsubishi Tanabe, Mochida, Nichiiko, Nippon Kayaku, Pfizer, Sanofi, Taiho, Takeda, and Zeria.
ZR has no disclosures to report.
JK, PL, SC, LC, RV, and PMH are employees of AbbVie and may hold AbbVie stock and/or stock options.
FA-A has served as a consultant and/or has received grants and speaker fees from AbbVie, Celltrion, Kern, MSD, and Takeda.
RA has served as a consultant or advisor for AbbVie, AstraZeneca, BI, Biogen, BMS, CED-Service GmbH, Celltrion, Falk Foundation, Galapagos, Gilead, InDex, Janssen-Cilag, Lilly, MSD, Roche, and Takeda.
Funding
AbbVie funded this study and participated in the study design, research, data collection, analysis, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and the authors thank all trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Morgan A Gingerich, PhD, of JB Ashtin, and funded by AbbVie, and Karen Chien, PhD, of AbbVie.