Introduction

The decompensation occurrence constitutes the main factor affecting survival for compensated advanced chronic liver disease (cACLD) patients. Based on the type of first decompensation event (DE), two distinct modalities of progression, with relatively different prognostic implications, have been described: “Non-Acute” (NAD) [slow ascites onset, mild hepatic encephalopathy (HE), or progressive jaundice] or “Acute” (AD) [grade 2/3 ascites within 2 weeks, severe HE, or acute bleeding]. Clinically significant portal hypertension (CSPH), defined by Hepatic Venous Pressure Gradient (HVPG) values > 10 mmHg, represents the best predictor for decompensation. However, it’s affected by the invasiveness, the general availability, and the relative strict operator dependence. Alternatively, various noninvasive tools (NITs), usually adopted to estimate liver function and hepatic fibrosis, have been proposed to predict decompensation.
Red cell distribution width (RDW)/Platelet ratio (RPR) has recently been suggested as a routinely assessable NIT predicting fibrosis severity in chronic hepatopathies. However, its predictive role in ACLD patients has never been explored.

Aims & Methods

We aimed to evaluate the accuracy of the RPR in predicting the occurrence and modalities (NAD or AD) of the first DE in cACLD patients.
In this observational study, 140 controls and 680 cACLD patients of various etiologies were prospectively enrolled and followed up (FU) semiannually for 7 years. At baseline, biochemical, clinical, and Liver Stiffness Measurement (LSM) data were collected, as well as the Child-Pugh (CP), MELD, AST/Platelet Ratio Index (APRI), Fibrosis-4 score (FIB-4), Albumin-Bilirubin (ALBI), ALBI-FIB-4, and RPR were calculated. CSPH was defined by the presence of endoscopic esophageal varices and/or assumed for LSM values > 25 kPa. During FU the DEs were recorded.

Results

208 (30.5%) cACLD patients progressed to decompensated ACLD (dACLD): 141 (67.8%) presented NAD and 67 AD (32.2%) as first DE. Baseline RPR resulted significantly higher in dACLD patients compared to cACLD and controls, as well as in AD patients compared to NAD (all p<0.0001). RPR positively correlated with APRI, FIB-4, ALBI, ALBI-FIB-4, MELD, CP, and LSM [R:0.88, R:0.81, R:0.61. R:0.74, R:0.68, R:0.75, R:0.74, R:0.94; all p<0.0001]. ROC analysis revealed RPR > 0.472 and > 0.894 as the best cut-offs [AUC: 0.95; AUC: 0.94] in the prediction respectively of 7-year first DE and relative modality (AD), as well as better predictive performance if compared to APRI [AUC:0.87; AUC:0.90], FIB-4 [AUC: 0.71; AUC:0.80], ALBI [AUC:0.90; AUC:0.77], ALBI-FIB-4 [AUC: 0.93; AUC:0.79], MELD [AUC:0.78; AUC:0.89], CP [AUC:0.77; AUC:0.71], and LSM [AUC:0.87; AUC:0.94] for both first DE and AD occurrence (all p<0.0001). Multivariable analysis revealed the RPR [adjusted hazard ratio (aHR): 2.24[MD1] [MR2] ] and the presence of baseline CSPH (aHR:1.84) as the variables independently and significantly influencing both outcomes (all p <0.0001). The Kaplan-Meier Log-Rank Test analysis on DE occurrence showed HR:4.62 [C.I. 95% 3.110-5.810] for baseline RPR > 0.472 and HR: 5.10 [C.I. 95% 3.481-6.125] for patients presenting simultaneously baseline RPR >0.472 and CSPH.

Conclusion

The availability of a non-invasive tool predicting the decompensation is an unmet need. RPR non-invasively predicts the timing and modalities of decompensation in cACLD patients representing a potential clinically useful biomarker in this context.

References

1. Taefi, Amir, et al. “Red cell distribution width to platelet ratio, a useful indicator of liver fibrosis in chronic hepatitis patients.” Hepatology international vol. 9,3 (2015): 454-60. doi:10.1007/s12072-015-9638-9
2. Abraldes, Juan G, and Guadalupe Garcia-Tsao. “Simple Clinical Tools to Predict Decompensation in Patients With Compensated Cirrhosis: An Unmet Need.” Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association vol. 17,11 (2019): 2179-2181. doi:10.1016/j.cgh.2019.04.026
3. D'Amico, Gennaro et al. “Towards a new definition of decompensated cirrhosis.” Journal of hepatology vol. 76,1 (2022): 202-207. doi:10.1016/j.jhep.2021.06.018

Introduction

The PROFILE trial in patients with newly-diagnosed Crohn’s disease demonstrated that “top-down” therapy, with combination infliximab and immunomodulator from diagnosis, provided superior efficacy and a better safety profile over a one-year follow-up period compared to a conventional “accelerated step-up” management approach.

Aims & Methods

The current study aimed to evaluate cost-effectiveness by assessing the healthcare cost and health outcomes associated with starting anti-TNF medication (intravenous infliximab, subcutaneous infliximab, subcutaneous adalimumab) as soon as possible after diagnosis. A de novo Markov model was developed to model the cost-effectiveness of using a “top-down” compared to “accelerated step-up” strategy in adults newly-diagnosed with active Crohn’s disease (HBI score >7, elevated CRP and/or faecal calprotectin >200ug/g and endoscopic evidence of disease activity with simple endoscopic score of Crohn’s disease activity of >6 [>4 if ileal-only disease]). Parameters were informed by individual patient data from PROFILE and data from the published literature. Use of intravenous infliximab, or subcutaneous infliximab, or subcutaneous adalimumab from diagnosis were modelled with biosimilar costs based on average real-world UK contract drug costs ascertained from 18 PROFILE trial sites in 2024. Key model outcomes included healthcare costs (drug acquisition, drug administration, disease management, hospitalisation, surgery) and health outcomes (quality-adjusted life years gained [QALYs]) measured over a 5-year time horizon.

Results

The base case cost-effectiveness analysis indicated that a “top-down” strategy dominated over an “accelerated step-up” approach. Initiating intravenous infliximab from diagnosis yielded greater clinical benefits, with an incremental gain of 0.17 QALYs per patient over a 5-year period, and was less costly, saving £1,681 per patient over the same time frame. Similar clinical benefits were obtained when modelling use of SC infliximab and adalimumab. The greatest cost savings were with adalimumab, totalling £10,059 per patient over 5 years. Sensitivity analyses further supported the robustness of the results for “top-down” therapy, showing it to be the most cost-effective option in 98.7% of model simulations.

Conclusion

This health economic analysis demonstrates that early effective “top-down” treatment with anti-TNF therapy from diagnosis results in lower healthcare resource use compared to an “accelerated step-up” strategy. The economic benefits align with improved clinical outcomes, as early, effective treatment better controls inflammation. Patients experience longer periods in remission, fewer disease-related flares, and enhanced quality of life. These findings were demonstrated for intravenous infliximab, subcutaneous infliximab and subcutaneous adalimumab. In newly-diagnosed patients with active Crohn’s disease, “top-down” treatment with anti-TNF therapy is more efficacious, safer and cost-effective than “accelerated step-up” based treatment strategies.

References

Noor NM, Lee JC, Bond S et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol. 2024 May;9(5):415-427.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG.

Introduction

Metaplasia refers to the emergence of cells not normally present in a given organ, typically as a result of chronic inflammation. While often linked to cancer development, its role in inflamed epithelium remains unclear. Paneth cell metaplasia (PCM) is a phenomenon in which Paneth cells, normally restricted to the small intestine, appear ectopically in the inflamed colonic epithelium of patients with ulcerative colitis (UC). However, the roles and characteristics of PCM in the inflamed colonic mucosa remain poorly understood. This study aimed to characterize the clinical and molecular features of colonic PCM and investigate its functional role in the inflamed epithelium.

Aims & Methods

We first analyzed the clinical characteristics of PCM using biopsy samples and clinical data from UC patients who underwent endoscopic evaluation at our institution. To elucidate the molecular features of colonic PCM, we employed spatial transcriptomics to compare PCM in the colon with Paneth cells in the small intestine from the same individuals. These findings were validated in a knockout mouse model, murine colonic organoids, and patient-derived human colonic organoids. This multi-model approach allowed us to investigate the mechanisms underlying PCM formation and assess its functional relevance in intestinal epithelial biology.

Results

PCM was predominantly observed in the left-sided colon and was associated with longer disease duration and the presence of pathological inflammation. Spatial transcriptomic HD analysis suggested that colonic PCM emerges within an inflammatory microenvironment distinct from that of the small intestine. Notably, the expression of the Wnt target genes HD5 and HD6, which are typically required for Paneth cell differentiation in the mouse small intestine, was reduced in colonic PCM. In contrast, expression of REG3A, a gene known to be induced by the inflammation-associated cytokine IL-22, was maintained. Consistent with previous reports highlighting the role of IL-22 in the differentiation and maturation of human Paneth cells, these findings suggest that IL-22 may contribute to the induction of PCM under inflammatory conditions. Mechanistically, IL-22 was shown to suppress Notch signaling in human colonic organoids, thereby promoting PCM formation and inducing REG3A expression in metaplastic cells. In vitro experiments using mouse colonic organoids demonstrated that Reg3a enhances epithelial cell proliferation and promotes wound healing. In vivo, Reg3a^ΔIEC mice exhibited impaired wound healing in both acute and chronic DSS-induced colitis models. Furthermore, REG3A treatment of human colonic organoids derived from UC patients stimulated epithelial proliferation and accelerated wound closure.

Conclusion

PCM contributes to epithelial protection in UC by promoting REG3A-mediated regeneration. These findings suggest that PCM may play a compensatory role in mucosal healing during colonic inflammation.

Introduction

Intraductal radiofrequency ablation (RFA) has been proposed as an adjunctive therapeutic method for patients with inoperable perihilar
cholangiocarcinoma(pCCA). Because there is limited data regarding the benefits of RFA, we aimed to evaluate the feasibility, efficacy and safety of a RFA based endoscopic palliation protocol.

Aims & Methods

Consecutive inoperable patients presenting biliary obstruction secondary to pCCA were evaluated according to the ongoing, single center, randomized clinical trial(NCT05563870). Native-papilla patients were randomized 1:1 to biliary drainage of the viable liver territories with plastic stents (control) or drainage plus RFA of the entire length of the tumor (active arm). Following index procedure, patients were scheduled for stent exchange and additional RFA treatment (active arm only) at 8-10 weeks intervals. Primary outcome was clinical efficacy defined as bilirubin levels < 3mg/dL at 4 weeks after index ERCP; secondary outcomes included overall survival and safety outcomes.

Results

Heretofore we included 25 patients (13 active arm) undergoing 72 procedures (37 with RFA) for a median follow-up of 3 months (range 2-15). Most patients received either 2 (10/25) or 3 (3/25) plastic stents at index ERCP and 23/25 of the patients reached effective drainage at 4 weeks, only 7 patients receiving undelayed oncologic treatment. There were 11 deaths during follow-up - 6 unrelated to the cholangiocarcinoma, 3 from therapy-related complications and 2 from cancer progression. 20/25 patients experienced at least 1 adverse event - including 15 severe biliary events with no significant differences between the study groups.

Conclusion

Extensive liver drainage followed by iterative stent exchange with intraductal RFA applications seems feasible and effective in the
palliation of biliary obstruction in pCCA patients, with no additional risk related to RFA applications. However, adverse events related to biliary infection remain a frequent and life-threatening occurrence during follow-up in this patient population. Further data on the optimal timing and RFA application protocol is required.

Disclosure

No conflict of interest