Introduction

Inflammatory Bowel Diseases (IBD) can lead to various complications, with Acute Severe Colitis (ASC) being among the most critical. ASC is a medical and surgical emergency that poses a significant risk to life, necessitating prompt and effective diagnosis and management. The first-line treatment typically involves intravenous corticosteroids. However, some cases are resistant to corticosteroids and require second-line medical therapy or immediate surgical intervention.

Aims & Methods

The objective was to identify factors associated with the failure of first-line medical treatment in patients with ASC. A retrospective descriptive and analytical study was conducted over ten years (January 2014 to March 2024) in the gastroenterology department of Charles Nicolle Hospital. The study included patients with IBD complicated by ASC, defined by the Truelove and Witts criteria and a Lichtiger score greater than 10.Patients with bacterial superinfection were not included.

Results

Forty-five patients over 18 years old were included, with a mean age of 37.87 years (range: 18–74 years). There was a slight female predominance (53%), with a male-to-female ratio of 0.87. In 31% of cases, ASC was the initial presentation of the disease. Endoscopic signs of severity at admission were observed in 49% of patients. All patients received intravenous corticosteroid therapy with hydrocortisone hemisuccinate as the first-line treatment. The response rate to first-line treatment was 64.5%. Second-line medical therapy was administered to 24.4% of patients, consisting of cyclosporine in 11.1% and infliximab in 13.3%. Five patients (11.1%) underwent subtotal colectomy due to corticosteroid failure.
In univariate analysis, factors associated with corticosteroid failure included male gender (p=0.011), absence of extraintestinal manifestations (p=0.017), higher average number of stools on the first day (p=0.013), Lichtiger score >10 on the third (p=0.011) and fifth day (p<0.001), hemoglobin levels >11 g/dL on the first day (p<0.001), >10 g/dL on the third day (p=0.009), >9 g/dL on the seventh day (p=0.013), white blood cell count >10,000/mm³ on the first day (p=0.008), >12,000/mm³ on the third (p=0.001) and seventh day (p=0.004), C-reactive protein (CRP) level >30 mg/L on the seventh day (p=0.005), and persistent endoscopic signs of severity after three to five days of corticosteroid therapy (p=0.001).
Multivariate Analysis showed that only the presence of severe endoscopic signs on follow-up endoscopy after three to five days of corticosteroid therapy was predictive of corticosteroid failure (Odds Ratio = 42.2; p=0.028).

Conclusion

Acute Severe Colitis is a potentially life-threatening complication. The presence of severe endoscopic signs after five days of corticosteroid therapy should prompt the initiation of second-line therapy. Understanding the predictive factors for corticosteroid failure is essential for individualized management to improve both immediate and long-term outcomes.

Disclosure

The authors declare no conflicts of interest.

Introduction

Tulisokibart is a monoclonal antibody that targets tumor necrosis factor-like cytokine 1A (TL1A), a regulator of inflammation and fibrosis in inflammatory bowel disorders. In the Phase 2 ARTEMIS-UC study, a significantly higher proportion of participants on tulisokibart compared to placebo achieved clinical remission after 12 weeks of induction treatment in patients with moderate to severe active ulcerative colitis (UC) and conventional or advanced treatment failure.¹ In a post hoc analysis from ARTEMIS-UC, re-induction and delayed induction treatment with tulisokibart were effective in participants who did not respond during the initial induction period.² We explored the efficacy and safety of tulisokibart maintenance therapy up to 1 year during the open-label extension of ARTEMIS-UC among patients who responded to induction, re-induction, and delayed induction.

Aims & Methods

Participants (≥18 years) were randomized to intravenous (IV) tulisokibart 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10 or placebo. The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in this analysis. Participants were classified as induction responders (defined as reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤1 at week 12) or induction nonresponders. Induction non-responders in the tulisokibart and placebo groups were assigned to an open label 12-week re-induction with the aforementioned tulikosibart induction dosing regimen. Cohort 1 induction, re-induction, and delayed induction responders were randomized (stratified by Dx status) to open-label IV tulisokibart 100 mg or 250 mg every 4 weeks.

Results

In Cohort 1, 47 tulisokibart induction responders, 13 re-induction responders, and 29 delayed induction responders were randomized to open-label maintenance treatment with tulisokibart 100 mg or 250 mg every 4 weeks. Maintenance of treatment effect was generally similar with a trend for higher efficacy with tulisokibart 250 mg vs 100 mg maintenance treatment observed across the 3 groups. The safety profile of tulisokibart maintenance treatment was similar across the 3 groups, with no new safety signals being observed.

Conclusion

Tulisokibart was effective as a maintenance treatment in patients with moderate to severe UC. The effect was generally similar across Cohort 1 tulisokibart induction responders, re-induction responders, and delayed induction responders. Tulisokibart maintenance treatment was well tolerated across the 3 groups, with no identified safety signals. Altogether, this suggests that a second induction regimen in tulisokibart non-responders may result in a long-term efficacy benefit without increased safety risk. Larger trials are needed to confirm these findings.

Table: Efficacy and fecal calprotectin

References

1. Sands et al. N Engl J Med 2024; 26;391:1119-1129
2. Hoque et al. J Crohns Colitis 2025; 19(suppl 1):i1158-i1159

Disclosure

Sami Hoque: ​Received Lecture fees and research grants from Tillotts, Ferring and Eli Lilly.
Bruce E. Sands: Travel fees from Eli Lilly and Company, Janssen Research & Development, LLC, Takeda Development Center Americas, Inc.; Received food & beverage from AnX Robotica Corp.; Grant from Janssen Research & Development, LLC; Owns stock options in Ventyx Biosciences; Consulting fees from AbbVie, Abivax, Aclaris Therapeutics, Adiso Therapeutics, Agomab Therapeutics, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb Company, Celltrion Healthcare, Celltrion Healthcare, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Entera, Enveda Biosciences, Equilium, Evommune, F. Homann-La Roche AG, Ferring, Fresenius Kabi USA, LLC, Galapagos, Genentech USA, Inc., Gilead Sciences , GlaxoSmithKline, GossamerBio, HMP Acquisition, Imhotex, Immunic, Immunyx Pharma Ltd., Index Pharmaceuticals, Innovation Pharmaceuticals, Janssen Biotech, Inc., Janssen Scientific Affairs, LLC, Johnson & Johnson Health Care Systems Inc., Kaleido, Kallyope, Kyowa Kirin Co., Ltd, Merck & Co., Inc., Microba, Microbiotica Limited, MiroBio, Mobius Care, Morphic Therapeutic, MRM Health, Nexus Therapeutics, Nimbus Therapeutics, Odyssey Therapeutics, Pfizer, Progenity Inc., Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Recludix Pharma, SANOFI US SERVICES INC., Spyre Therapeutics, Surrozen, Synlogic Operating Company, Takeda Pharmaceuticals International, Inc., Target RWE, Teva Branded Pharmaceutical Products R&D, Theravance Biopharma Inc., TLL Pharmaceutical, VectivBio AG, Ventyx Biosciences
Brian G. Feagan: Consulting fees from Abbvie, Adiso Therapeutics, Agomab, Alimentiv Inc, Allianthera, Amgen Canada, AnaptysBio, Applied Molecular Transport, Arena Pharma, Biora Therapeutics, Blackbird Laboratories, Boehringer Ingelheim AB, Bristol-Myers Squibb, Celgene, Celsius Therapeutics, Connect BioPharma, Duality, Eli Lilly and Company, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Global Services, LLC, JapanTobacco, Klick Health, Mage Biologics, Mestag Therapeutics, Mobius Therapeutics, LLC, Monte Rosa Therapeutics, Nexys Therapeutics, Nimbus Discovery Inc, Orphagen Inc., PFIZER CANADA INC, Prometheus, SANOFI US SERVICES INC., Seres Therapeutics, Sobi, Inc, Spyre Therapeutics, Surrozen, Synedgen, Takeda Canada, Takeda Development Center Americas, Inc., Televant, Tillotts, Triastek Inc.
Mark Yen: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Bin Dong: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Wen Zhou: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Silvio Danese: Consulting fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Ferring, Gilead Sciences, Hospira, Inc., Janssen Biotech, Johnson & Johnson Health Care Systems Inc., Pfizer, Sandoz, UCB Inc., Vifor (International) Ltd.

Introduction

​​​​​PSC is chronic infammatory disease of bile ducts leading to strictures of bile duct and eventually to liver cirrhosis. Chronic inflammation is associated with markedly increased risk of cholangiocancer (CCA). In addition, gall bladder abnormalities are common in patients with PSC¹ such as cholecystitis, gallstones, polys and gallbladder carcinoma (GBCA). Increased fasting gallbladder volume has been reported with normal gallbladder emptying². Due to the increased risk of GBCA³ cholecystectomy is recommended in PSC with gallbladder polyps ≥8 mm and smaller polyps growing⁴. However, cholecystectomy has been associated with impaired PSC outcome. A study consisting of 11 PSC patients with cholecystectomy suggested protective role of gallbladder based on MRCP changes and elevated AST levels in patients with cholecystectomy. No significant difference in serum bile acids was observed in patients with or w/o cholecystectomy⁵. Another small study including five PSC patients with cholecystectomy showed that cholecystectomy was associated with worse Mayo scores and an elevated FIB4⁶. More than 50% of PSC have enlarged gallbladder which is suspected to be caused by hyperpressure in the biliary tract⁵. Cholecystectomy may thus eliminate this reserve function and lead to progression of bile duct strictures.

Aims & Methods

To evaluate the impact of cholecystectomy on liver enzyme levels, biliary bile acid composition, bile duct disease progression, and overall outcomes in a large PSC patient cohort, we analyzed data from 1,009 individuals enrolled in the prospective Helsinki PSC registry. Of these, 114 patients (11.3%) had undergone cholecystectomy—34 prior to and 80 following the PSC diagnosis. Patients with gallbladder cancer were excluded. Clinical and laboratory parameters were collected, along with data on disease progression based on sequential ERC examinations scored by the Helsinki ERC score⁷. Additionally, bile composition was analyzed in a subgroup of 157 patients receiving UDCA therapy, 32 of whom had undergone cholecystectomy.

Results

Demographics, liver function tests, and outcomes stratified by cholecystectomy, are presented in the table. We found no differences between the three groups (no cholecystectomy, cholecystectomy done prior or after PSC dg) regarding the progression of bile duct disease or its severity, liver function tests, development of biliary dysplasia or need for dilatation, Mayo- and MELD-scores. The cumulative incidence of the composite end point (= transplantation, liver related death, HCC or CCA) did not differ between groups. The molar-% of phospholipids were lower and cholic acid and deoxycholic acid (mg) elevated in bile in patients with cholecystectomy, whereas no differences were found in UDCA content.

Conclusion

In this large study investigating the impact of cholecystectomy on PSC outcomes, we found no effect on liver enzyme levels, prognostic indices, bile duct disease progression, or overall prognosis, regardless of whether the procedure was performed before or after the PSC diagnosis.

References

1. Said K, eta al. Journal of Hepatology 2008; 48:598–605
2. Said K, et al. World J Gastroenterol 2009; 15: 3498-3503
3. van Erp LW, et al. Liver Int 2020; 40:382–92.
4. Chazouilleres O et al. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761–806
5. Cazzagon N, et al. JHEP Reports 2023. https://doi.org/10.1016/j.jhepr.2022.100649
6. Miyake N, et al. Cureus 17(3): e80184. DOI 10.7759/cureus.80184
7. Boyd S, et al. Endoscopy. 2016;48:432-9.

Introduction

MicroRNAs (miRNAs) are small, non‑coding RNAs that regulate gene expression and play pivotal roles in carcinogenesis. Distinct miRNA expression signatures can discriminate among tumours and normal tissue, and have emerged as promising, minimally invasive diagnostic biomarkers.

Aims & Methods

To characterise the miRNome of advanced gastric adenocarcinoma (AGC), early gastric cancer (EGC) and its precancerous lesions (GPL) in comparison to normal gastric mucosa, and to identify candidate miRNA biomarkers for early diagnosis.
Gastric mucosa samples were prospectively collected from 60 participants in the EpiGASTRIC/EDGAR consortium: 20 with AGC, 20 with EGC/GPL and 20 tumour‑free controls. During the discovery phase, small‑RNA libraries were prepared from tissue samples and sequenced by next‑generation sequencing (NGS). Reads were processed with miRDeep2 against miRBase, and differential expression was analysed with DESeq2, applying a false discovery rate (FDR) < 0.05. Selected miRNAs were then validated in gastric tissue by reverse‑transcription quantitative PCR (RT‑qPCR) and subsequently in matched serum samples by RT‑qPCR.

Results

A total of 823 miRNAs were detected. Compared with controls, 292 miRNAs were significantly deregulated in AGC and 233 in EGC/GPL, with 170 miRNAs commonly deregulated in both tumour groups. For biomarker prioritisation we applied ≥ 4-fold change and mean read count > 400 and we found 20 miRNAs that were consistently differentially expressed and discriminated AGC, EGC and GPL from normal mucosa. 17 of these 20 miRNAs were successfully validated by RT‑qPCR in gastric tissue. In a subsequent serum analysis, two miRNAs – 148a-3p and 223-3p – showed statistically significant differential expression in serum, distinguishing patients with AGC or EGC/GPL from individuals with histologically normal gastric mucosa.

Conclusion

Deep sequencing followed by RT‑qPCR validation identified a 17‑miRNA signature capable of differentiating normal gastric tissue from AGC and EGC/GPL. Within this set, 148a-3p and 223-3p discriminated serum of patients with AGC or EGC/GPL from those with normal mucosa. External validation and further assessment of their diagnostic performance are required, but these miRNAs are promising non‑invasive biomarkers of prevention and diagnosis of gastric cancer.