Introduction

Most immune-mediated disorders display a degree of heritability, with specific genetic variants linked to disease susceptibility. Variants in Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) have been associated with numerous inflammatory conditions, including Inflammatory Bowel Disease (IBD). As several species (rodents included) lack the ERAP2 gene, functional studies have been relatively limited. Several immunological functions of ERAP2 beyond peptide trimming have been proposed, yet most of these findings have been reported in immune cell populations. As the epithelial involvement in IBD pathogenesis is getting increasingly recognized, we set out to explore the impact of epithelial ERAP2 presence during inflammatory encounter using human-derived colonoids as a model system. To investigate the effect of genotype on ERAP2 expression in different disease states, patient material from a IBD cohort was used to correlate genotype to ERAP2 expression in inflamed and noninflamed colonic biopsies.

Aims & Methods

Two single nucleotide polymorphisms (SNPs) linked to ERAP2 expression (rs2910686/rs2248374) were analyzed in a cohort of IBD patients. Genotypes for both SNPs were correlated with colonic ERAP2 expression levels in noninflamed and inflamed biopsies. Based on rs2910686 genotype, ERAP2-proficient (n=4) and ERAP2-deficient (n=4) colon organoids were established to study differential expression between proficient and deficient donors after proinflammatory stimulation.

Results

Conditioning on genotype reveals upregulation of ERAP2 in the inflamed colon of IBD patients. ERAP2 expression proficiency correlates with rs2910686 genotype. IFNɣ induces colonic epithelial ERAP2 expression. Western blot confirms that mechanisms independent of the frequently studied SNP rs2248374 can cause ERAP2-deficiency. A total of 586 genes involved in various molecular mechanisms are differentially expressed between ERAP2-proficient and -deficient colonoids upon proinflammatory stimulation, including AOC1, CPE, ANPEP and MEP1A (catalytic activity), TNFSF9, MDK, GDF15, ILR6A, LGALS3 and FLNA (regulator activity), SLC40A1 and SLC5A1 (transmembrane transporter activity), FGL2, HMCN2, and MUC17 (extracellular matrix structural constituents).

Conclusion

Our findings demonstrate that ERAP2 expression is significantly upregulated in the inflamed colon of IBD patients, and expression levels correlates with rs2910686 genotype. Although rs2248374 is commonly used to assess ERAP2 expression proficiency, our findings confirm that mechanisms independent of rs2248374 can lead to ERAP2-deficiency. We further demonstrate that stratifying organoid donors based on genotype is a useful way of exploring the impact of genetic variants. Our data support that ERAP2 play a multifaceted role in modulating the inflammatory response in epithelial cells.

Introduction

In perianal fistulizing Crohn’s disease (PFCD), higher infliximab (IFX) serum trough concentrations are associated with improved outcomes. Most PFCD patients require dose intensification to achieve therapeutic target concentrations. IFX pharmacokinetics (PK) in PFCD have not been previously characterized. We hypothesized that IFX clearance (CL) is increased in PFCD compared to Crohn’s disease with luminal disease only (CD).

Aims & Methods

Patients with CD and PFCD starting standard-dose intravenous IFX (5 mg/kg at week 0, 2, 6, thereafter every 8 weeks) were enrolled. Pre-infusion samples were collected from week 2 to 26 to measure IFX trough levels (TL), and anti-drug antibodies if IFX TL was below 1.0 μg/mL. Target TL were 20 μg/mL (week 2), 15 μg/mL (week 6), and 10 μg/mL (week 14) for PFCD, and 5.0 μg/mL (week 14) for CD. A population PK model was constructed using nonlinear mixed-effects modeling and adjusted for clinically relevant covariates.

Results

A total of 148 patients were included (63 PFCD, 85 CD), contributing 761 serum samples. Baseline demographics were comparable, except for higher luminal disease activity and concomitant immunomodulator use in CD. During induction, target IFX TL were achieved in significantly fewer PFCD patients (43% vs. 57%, P = .038). At week 14, median IFX TLs were lower in PFCD (2.8 μg/mL [IQR 1.0-5.4] than in CD (4.8 μg/mL [IQR 2.0–6.6], P = .014), with target TL attainment in only 9% of PFCD versus 46% of CD patients (P < .001). In multivariate regression analysis, PFCD was independently associated with a sevenfold increased risk of underdosing at week 14 (adjusted risk ratio [aRR] = 7.14, P < .001). Anti-drug antibodies (ADA) against infliximab were detected in 10/19 (53%) of PFCD patients and 9/25 (36%) CD patients with IFX TL below 1 μg/mL (P = .36) after a median of 20 weeks, with 35% of cases being transient during follow-up. While more PFCD patients had very low infliximab levels at week 14 (<1 μg/mL; 22% vs. 10%, P = .07), ADA presence and median ADA levels at that time did not differ significantly between these groups (P = .99 and P = .25, respectively).
IFX PK was described by a two-compartment model with linear elimination. Population PK modeling of the first 14 weeks revealed an 18% increase in IFX CL among patients with active perianal fistulas adjusted for dose, weight, serum albumin and presence of anti-drug antibodies (P < 0.01).

Conclusion

Active perianal fistulas are independently associated with increased infliximab clearance in patients with Crohn’s disease, resulting in significantly lower and frequently subtherapeutic serum trough levels despite standard induction dosing. At week 14, patients with PFCD had a sevenfold higher risk of underexposure compared to those with luminal CD only. These findings highlight a critical need for intensified or personalized infliximab dosing strategies during induction in PFCD to optimize therapeutic exposure and improve clinical outcomes.

Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that was efficacious in double-blind, placebo-controlled, treat-through trials in participants (pts) with moderately to severely active Crohn’s disease (CD) using IV induction and SC maintenance (GALAXI 2 & 3) or SC induction and maintenance (GRAVITI). Assessment of histologic disease activity is becoming increasingly important as a measure of treatment efficacy. Here we report histologic outcomes at Weeks (W) 12 & 48 from GRAVITI.

Aims & Methods

Pts were randomized 1:1:1 to GUS 400 mg SC every 4 weeks (q4w)→200 mg SC q4w, GUS 400 mg SC q4w→100 mg SC every 8 weeks (q8w), or placebo (PBO). Biopsies were obtained from the most affected area (or if no disease activity present, from normal-appearing mucosa) in 5 segments: terminal ileum, ascending colon, transverse colon, descending colon, and rectum. Histologic response, histologic remission, and the composite endpoints of histo-endoscopic response and histo-endoscopic remission were evaluated using Robarts Histopathology Index (RHI), Global Histologic Activity Score (GHAS), and Geboes scoring. Histologic response was assessed in pts with baseline histologic disease; histologic remission, histo-endoscopic response, and histo-endoscopic remission were assessed in the full analysis set (see definitions in table legend). Pts who met rescue criteria at W16 were considered non-responders at W48. Histologic endpoints in GRAVITI were exploratory and not controlled for multiple comparisons; p-values are nominal.

Results

Of the 347 pts in the full analysis set, 273 (78.7%) had baseline histologic disease per RHI score. SC induction with GUS (400 mg SC at W0, W4, & W8) resulted in greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to placebo at W12 (Table). At W48, greater proportions of pts receiving GUS 100 mg SC q8w or GUS 200 mg SC q4w maintenance also achieved histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to PBO. Comparable outcomes were observed using GHAS or Geboes scoring criteria.

Conclusion

Compared to PBO, pts with moderately to severely active CD receiving SC induction and maintenance treatment with GUS achieved greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission through W48. These results support the use of histologic and composite histologic and endoscopic endpoints as a measure of CD activity, and the efficacy of SC guselkumab in CD.

Disclosure

GRD’H: consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Galapagos, GlaxoSmithKline, Gossamerbio, Immunic, Index, Johnson & Johnson, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist Therapeutics Inc.; speaker’s bureau for AbbVie, Bristol Myers Squibb, Galapagos, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, and Seres Health.
ALH: lecturer and/or advisory board member for Bristol Myers Squibb, Celltrion, Falk, AbbVie, Johnson & Johnson, Takeda, Pfizer, Galapagos, MSD, and GSK.
RP: consulting fees from Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, AnaptsyBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Spyre Therapeutics, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, and UCB; speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Johnson & Johnson, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and participation in Advisory Boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
FS: consultant, speaker, or researcher for AbbVie, Amgen, Celltrion, Ferring, Johnson & Johnson, Pfizer, Sandoz, and Takeda.
QC: steering committee adviser for Bristol Myers Squibb and Johnson & Johnson; research grants from Takeda and Johnson & Johnson.
SD: consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB and Vifor; and lecture fees from AbbVie, Amgen, Ferring, Gilead, Johnson & Johnson, Mylan, Pfizer and Takeda
TH: grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, and Kissei Pharmaceutical Co. Ltd.; consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Johnson & Johnson, Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Abivax; lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Johnson & Johnson, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., and Kissei Pharmaceutical Co. Ltd.
BES: consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Johnson & Johnson, Pfizer, and Takeda; and stock/stock options from Ventyx Biopharma.
MO, LS, PB, WvD, NT: employees and shareholders of Johnson & Johnson

Introduction

Difficult-to-treat Crohn’s disease (CD), as defined by the International Organization for the Study of IBD (IOIBD), encompasses patients with persistent disease activity despite advanced therapies, complex phenotypes (e.g., penetrating complications), or post-surgical recurrence. Upadacitinib, a selective JAK1 inhibitor, has demonstrated efficacy in Western populations, yet data in Asian cohorts remain sparse. This study evaluates the effectiveness and safety of standardized induction regimen of upadacitinib (45mg qd) in Asian patients meeting IOIBD criteria for difficult-to-treat CD.

Aims & Methods

To assess the efficacy and safety of upadacitinib in Asian patients with difficult-to-treat CD, providing evidence for clinical decision-making, a retrospective, multicenter study was conducted from 8 Chinese tertiary centers (January 2023–January 2025) on difficult-to-treat Crohn’s disease patients who met IOIBD criteria. All patients received upadacitinib 45mg qd for 12 weeks. Clinical outcomes were assessed using the Crohn's Disease Activity Index (CDAI), with the primary outcome being clinical remission (CDAI <150) and the secondary outcome being clinical response (CDAI reduction ≥70) at week 12. Adverse events (AEs) were systematically recorded.

Results

We finally collected 151 patients who met IOIBD criteria(Table1). Among them, 147 patients presented failure of ≥2 biologics with distinct mechanisms, 3 patients had complex perianal disease and 1 patient had postoperative recurrence. The mean disease duration of these patients was 7.6 years (SD 4.5 years). At week 12, 71 patients (47.0%) achieved clinical remission, 66 patients (43.7%) showed clinical response, and 14 patients (9.3%) were non-responders. Adverse events occurred in 40 patients (26.5%): acne (n=13), anemia (n=13), leukopenia (n=3), fever (n=4), urinary tract infection (n=2), herpes zoster (n=2), folliculitis (n=1), amenorrhea (n=1), elevated creatine phosphokinase (n=1), and mediastinal tuberculosis (n=1). Most AEs were mild and resolved with oral medications.

Table1. Baseline Characteristics of Patients with Difficult-to-Treat CD Treated with UPA

Conclusion

This is the largest Asian cohort study of upadacitinib for difficult-to-treat CD. The drug demonstrated robust efficacy and a favorable safety profile. Notably, tuberculosis reactivation was rare. Standard dosing showed comparable effectiveness and tolerability to European data, underscoring upadacitinib as a strong therapeutic option in Asian populations.

References

1. Parigi TL, D'Amico F, Abreu MT, et al. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023;8(9):853-859. doi:10.1016/S2468-1253(23)00154-1
2. Parigi TL, Massimino L, Carini A, et al. Prevalence, Characteristics, Management, and Outcomes of Difficult-to-Treat Inflammatory Bowel Disease. J Crohns Colitis. 2025;19(3):jjae145. doi:10.1093/ecco-jcc/jjae145
3. Bezzio C, Franchellucci G, Savarino EV, et al. Upadacitinib in Patients With Difficult-to-Treat Crohn's Disease [published correction appears in Crohns Colitis 360. 2025 Mar 25;7(1):otaf022. doi: 10.1093/crocol/otaf022.]. Crohns Colitis 360. 2024;6(4):otae060. Published 2024 Oct 24. doi:10.1093/crocol/otae060
4. Devi J, Xu A, Stone M, et al. Real-World Effectiveness and Safety of Upadacitinib in Crohn's Disease: A Multicenter Study. Clin Gastroenterol Hepatol. Published online March 8, 2025. doi:10.1016/j.cgh.2025.01.012

Introduction

Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease of the bowel of unknown etiology. This disease is characterised by high difficulty in cure, high recurrence and cancer rates, which seriously endangers the lives and health of our population. Taraxasterol (TA), a major constituent of the traditional Chinese medicine dandelion, has been reported in several studies to have good anti-inflammatory and antioxidant activities as well as anti-tumour effects.

Aims & Methods

However, the molecular targets and mechanisms of action of TA against UC have not been fully elucidated.The Swiss Target Prediction, PharmMapper databases were used to obtain relevant targets for the drug TA. Targets for UC were obtained from GeneCards, OMIM, PharmGkb, DrugBank databases. Targets of TA anti-UC identified by intersection of drug target and disease target. The relevant targets of TA anti-UC were uploaded to the String database and the resulting data were imported into Cytoscape 3.9.1 software to construct a protein-protein interaction (PPI) network of drug-disease targets. At the same time, the top 10 hub targets were screened using CytoHubba software. Gene ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) pathway enrichment analyses were performed on TA anti-UC targets using R software, and molecular docking was performed by Autodock Vina 1.1.2. The GEO dataset was used to analyze the differential mRNA expression of the TA anti-UC top 10 hub gene in UC patients and the normal population. Lipopolysaccharide (LPS)-induced intestinal epithelial cells (NCM460) were used to construct an in vitro cellular inflammation model and a Dextran Sulfate Sodium Salt (DSS) induced acute mouse colitis model. The pivotal targets and key signaling pathways were also validated by RT-qPCR and Western blotting.

Results

A total of 129 relevant targets of TA against UC were obtained, of which the top 10 hub targets were GRB2, PTPN11, SRC, PIK3R1, LCK, EGFR, MAPK1, IGF1, ESR1 and JAK2. The PI3K-Akt pathway was significantly associated with TA treatment of UC as identified by KEGG enrichment analysis. GEO dataset analysis demonstrated that EGFR and GRB2 were upregulated in UC patients, while SRC, PIK3R1 and JAK2 were down-regulated. In vitro experiments revealed that TA treatment reversed the expression of EGFR, GRB2, PIK3R1 and JAK2 differential genes. Furthermore, TA was able to up-regulate the mRNA expression of pro-inflammatory factor IL-10 and decrease the mRNA levels of anti-inflammatory factors IL-6, IL-1β and TNF-α in LPS-induced NCM460 cells. In vivo assay confirmed that TA significantly alleviated DSS-induced colonic inflammation in mice, including reversal of weight loss and shortening of colon length, reduction of DAI score in mice, and improvement of intestinal barrier disruption. In vivo and in vitro experiments have confirmed that TA also inhibits the activation of the PI3K/Akt pathway, thus exerting an anti-inflammatory effect.

Conclusion

TA may play a therapeutic role in UC by inhibiting the PI3K-Akt pathway. EGFR, GRB2, PIK3R1 and JAK2 may be the most relevant potential therapeutic targets for TA in the treatment of UC.