Introduction

Despite recent advances in IBD therapy, there is a need for novel effective, safe oral drugs. Mufemilast has demonstrated sustained efficacy and safety in plaque psoriasis¹. Here we report the efficacy and safety of Mufemilast at 12 weeks from this phase 2 trial (NCT05486104).

Aims & Methods

Patients with moderate to severe UC were randomized (1:1:1) to placebo (n=31), mufemilast 45mg (n=31) or 60mg (n=30) twice daily (BD) for 12 weeks. Eligibility criteria required participants to have a modified Mayo score (mMS) of 4-9, including an endoscopy score of ≥ 2 , inadequate /loss of response to conventional therapy (5-ASA, Steroids, immunomodulators), or biologics (anti-TNF, anti-integrin, anti-interleukin 12/23). Stable co-treatment with oral 5'ASAs and corticosteroids was permitted if it was stable for at least ≥2 weeks before microscopy within the screening period and needed to remain stable for the duration of the study. Patients with positive Quantiferon tests were also eligible. Efficacy definitions were according to FDA guidance².

Results

Conclusion

Mufemilast efficacy and safety were consistent across subgroups regardless of previous biologic use, suggesting Mufemilast is a viable potential future treatment option in patients with moderate to severe UC that breaks through the current 20% ceiling for clinical remission. A phase 3 study will be conducted to confirm these results.

References

¹Jones, C.; Zhang, J.; Wang, L.; Dai, X.; Wang, H.; Bi, X.; Duan, X.; Meng, Z.; Tian, Z.; Xu, A.; et al. A Double-Blind, Placebo-Parallel Controlled Phase III Clinical Study of the Efficacy and Safety of Hemay005 Tablets in Patients with Moderate to Severe Chronic Plaque Psoriasis in China. Arthritis Rheumatol ACR Converg. 2023, 75.
² Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment. Guidance for Industry - Draft Guidance; 2022. Accessed May 11, 2025. https://www.fda.gov/media/158016/download

Introduction

Barrier healing (BH) has emerged as a novel treatment target in Inflammatory Bowel disease (IBD). Persistence of barrier impairment despite endoscopic and histological remission has been associated with worse long-term outcomes. However, accurate real-time assessment of intestinal barriers remains challenging in clinical practice. This study explores the role of advanced endoscopy (ultra-high magnification endocytoscopy [ECS] and confocal laser endomicroscopy [CLE]) for real-time, in vivo, structural and functional assessment of epithelial and vascular intestinal barrier. Further, we aim to investigate their correlation with automated barrier protein expression and clinical outcomes in IBD.

Aims & Methods

IBD patients undergoing endoscopic evaluation and healthy controls (HC) were recruited from two tertiary university centres.
The intestinal mucosa was assessed with ECS or CLE by novel scoring systems including epithelial and vascular features. BH was defined as ECS score ≤1 or CLE score ≤4, with preserved villi/crypt architecture, normal vessels, and, for CLE, absence of fluorescein leakage.
Biopsies were collected from both inflamed and non-inflamed areas. Epithelial (ZO-1, Claudin-2, E-cadherin) and vascular (PV-1 and CD-31) barrier markers were analysed through confocal microscopy, and their mean expression was automatically quantified using QuPath (v0.5.1). A biopsy-wise analysis assessed the correlation between endoscopic and histopathological evaluation. Moreover, occurrence of clinical outcomes at 6-month follow-up according to imaging-detected barrier impairment was evaluated.

Results

A total of 74 IBD patients (39 Crohn’s disease [CD], 35 Ulcerative colitis [UC]) and 9 HC) were considered. 46% (34/74) and 42% (30/74) IBD patients were in endoscopic and histological remission, respectively, while advanced imaging-defined BH was present in 24.3% (18/74) patients (Table 1). Barrier impairment was significantly associated with clinical outcomes at 6-month follow-up (p<0.01).
Mean expression of Claudin-2 was significantly higher in UC with ECS-based barrier impairment (85.5 vs 175.1, p 0.02), while PV1 expression was elevated in CD with CLE-based barrier dysfunction (362.1 vs 442.2, p 0.1). Significant correlations were found between ECS/CLE scores and epithelial and vascular barrier proteins.
In UC, Claudin-2 showed a moderate correlation with altered crypt architecture, goblet cell depletion and ECS total score (r 0.5), while PV-1 was moderately associated with altered vascular pattern and ECS total score (r -0.4).
In CD, Claudin-2 demonstrated a moderate correlation with crypt distortion, goblet cell depletion and total CLE scores (r 0.5), while PV-1 moderately correlated with fluorescein leakage, altered vessel architecture and total CLE score (r 0.4).

Conclusion

pCLE and ECS enable real-time intestinal barrier assessment in IBD, showing good correlation with epithelial and vascular barrier proteins and predicting clinical outcomes. This approach shows promise for targeting BH, guiding early and long-term disease management, and enabling flare-up prediction.

Introduction

Chronic low-grade inflammation, known as inflammageing, has been implicated in the pathogenesis of various digestive diseases. However, large-scale systematic evaluations of the association between inflammageing biomarker profiles and digestive system disorders remain scarce. Understanding these associations may have important implications for early detection and intervention strategies.

Aims & Methods

Leveraging the multidimensional data from the UK Biobank, this study aimed to investigate the longitudinal relationships between circulating inflammatory markers and major digestive diseases. A total of 45,475 participants were included, with inflammageing levels calculated as the average of standardized values of four circulating inflammatory markers: TNF, IL1RN, IL18, and IL6.
Digestive disease outcomes were identified from hospital records (HES) and death registries, covering 25 major diagnoses, including gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), and non-alcoholic fatty liver disease (NAFLD). Cox proportional hazards models were used to estimate hazard ratios (HRs), adjusting for age, sex, BMI, smoking, and other potential confounders.
In addition, Mendelian randomization (MR) analysis was conducted using GWAS data derived from inflammageing scores to evaluate potential causal effects on digestive outcomes. Mediation and subgroup analyses were performed to explore possible mediating factors.

Results

In the Cox regression analysis, 22 out of 25 digestive outcomes showed significant associations with baseline inflammageing levels (Bonferroni-corrected P < 0.05), with HRs ranging from 1.2 to 2.4.
Mediation analysis identified neutrophil counts and LDL-C as important mediators in these associations, suggesting potential biological pathways linking inflammageing to digestive disease development.

Conclusion

Elevated baseline inflammageing levels were significantly associated with a wide spectrum of digestive system diseases. The findings highlight a potential mechanistic role of systemic inflammation in digestive disease pathogenesis. The use of inflammageing-related biomarkers may aid in early identification of high-risk individuals, offering opportunities for early prevention and targeted interventions.

Introduction

Immune checkpoint inhibitor (ICI) mediated enterocolitis (IMC) may lead to treatment discontinuation. Corticosteroids for IMC is associated with serious side effects and might affect cancer progression in addition to preclude continued ICI treatment. We hypothesized that vedolizumab, a gut selective α4β7 integrin inhibitor, is effective as a first-line treatment and investigated whether vedolizumab reduces corticosteroid exposure and facilitate ICI resumption.

Aims & Methods

We conducted a single center, open-label, explorative phase 2 trial including patients treated with ICI who developed IMC. Patients were randomized 1:1 ratio to receive vedolizumab (300 mg) or standard treatment with corticosteroids, with infliximab used as recue therapy for corticosteroid failure. The primary outcome was cumulative corticosteroid dose at week 30. Key secondary outcomes included cumulative corticosteroid dose at week 10, corticosteroid free remission at week 10 and ICI resumption rates.

Results

Twenty-two patients received vedolizumab, and 19 patients received standard treatment. At week 10, the mean cumulative corticosteroid use was significantly lower in the vedolizumab arm (1157 mg vs. 2207 mg). By week 30, the mean corticosteroid use remained lower but not statistically significant (1378 mg vs. 2390 mg, estimated difference 1012 mg, 95% CI -229 to 2253, p=0.107), Among patients with less severe IMC, who did not need corticosteroids during screening, vedolizumab-treated patients used in average 1729 mg less corticosteroid (95% CI 631 to 2827). Corticosteroid-free remission at weeks 2 and 10 was more common with vedolizumab. Seven patients (33.3%) in the vedolizumab group resumed with ICI compared to three (16.7%) in the standard arm. In patients with severe colitis, who required upfront corticosteroid treatment, a trend towards longer hospitalization in the vedolizumab arm was observed.

Conclusion

For patients with less severe colitis, not needing corticosteroids during screening, vedolizumab may be a viable corticosteroid-sparing option, enabling faster remission and ICI resumption.

Disclosure

The study was funded by Aage og Johanne Louis-Hansens Fond, National Research grants. Takeda Pharma provided the study drug vedolizumab.