Ansgar Wilhelm Lohse

Bepirovirsen achieved a functional cure in 19–20% of nucleos(t)ide analogue (NUC)-treated participants in the phase 3 B-Well trials. These trials enrolled patients with baseline quantitative hepatitis B surface antigen (qHBsAg) levels >100–≤ 3000 IU/mL, but the potential reach of this treatment in routine care remains uncertain. We evaluated 706 patients with chronic hepatitis B monoinfection at a German tertiary-care center. qHBsAg levels were ≤100, >100–≤1000, >1000–≤3000, and >3000 IU/mL in 145/706 (20.5%), 175/706 (24.8%), 142/706 (20.1%), and 244/706 (34.6%) patients, respectively. Overall, 317/706 (44.9%) patients fell within the B-Well qHBsAg window. Of these, 109/317 (34.4%) were receiving NUC therapy; among the remaining 208 untreated patients, 23/208 (11.1%) met an operationalized EASL 2025 indication for NUC initiation. The primary implementation scenario therefore comprised 132/706 (18.7%) patients. Excluding patients with identifiable B-Well trial exclusion proxies in a sensitivity analysis reduced this number to 102/706 (14.4%). Applying stratum-specific B-Well response rates of 26.0% and 7.3% yielded hypothetical functional cure rates of 17.2% (approximately 23 modeled functional cures) in the primary scenario and 16.1% (approximately 16 modeled functional cures) in the restricted scenario. These findings estimate the potential clinical reach of bepirovirsen and associated hypothetical functional cure outcomes at our center, highlighting the absence of current NUC therapy as a key factor limiting its implementation.

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Background: Autoimmune hepatitis (AIH) is an important indication for liver transplantation (LT), but recurrence affects over 30% of recipients, threatening long-term survival. Current strategies to prevent recurrence and progressive graft fibrosis remain suboptimal, with limited evidence to guide selection of immunosuppressive regimens. We aimed to develop a dynamic, individualized, artificial intelligence–powered model for post-transplant recurrent AIH. Methods: We conducted a multicenter, retrospective cohort study of 706 patients who underwent LT for AIH between January 1987 and June 2020 at 33 centers in North America, South America, Europe, and Asia. We trained 4 predictive machine learning models—Logistic Regression, Random Forest, XGBoost, and Gradient Boost—to predict recurrent AIH (rAIH) using 62 clinical and laboratory variables, including demographic, biochemical features, and immunosuppressive drugs up to 1-year post-transplant. Feature importance was assessed using SHapley Additive exPlanations (SHAP) to enable interpretability at both individual and population levels. Results: AIH recurred in 16.5% of patients after LT. SHAP analysis identified younger age at LT, higher necroinflammatory activity in the explanted liver, and elevated MELD score at LT as key predictors of rAIH in the overall population. Tacrolimus-based therapy was associated with a lower risk of recurrence, while cyclosporine use conferred a higher risk. The addition of long-term prednisone to a regimen of tacrolimus and mycophenolate mofetil did not provide additional protective effect against rAIH. Conclusions: Our AI-powered clinical decision model provides personalized prediction of post-transplant rAIH. While it offers insight into modifiable and non-modifiable predictors, prospective validation is required before informing immunosuppressive decisions.

The clearance of apoptotic cells by phagocytes is crucial for restoring tissue balance after injury. In autoimmune liver diseases like primary sclerosing cholangitis, cell death is thought to result from accumulation of toxic bile acids within parenchymal cells. Whether, in this context, bile acid–loaded dying cells impact the efficiency of phagocytic macrophages in restoring tissue balance remains unknown. Here, we demonstrate that in a murine model of cholangitis, bile acids accumulate in a subpopulation of efferocytic macrophages with pro-inflammatory features. Our in vitro results indicate that, upon their engulfment, apoptotic hepatocytes laden with bile acids can serve as Trojan horses, delivering bile acids into efferocytic macrophages and thereby shaping macrophage function. This contrasts with the characteristics of macrophages that engulf apoptotic parenchymal cells lacking bile acids. Together, our findings delineate a system in which the content of the phagocytosed dying cells, specifically bile acid–laden hepatocytes, drives a pro-inflammatory program in the corresponding efferocytic macrophages, potentially contributing to chronic hepatic inflammation.

Background & Aims: The distinction of drug‐induced liver injury (DILI), drug‐induced autoimmune‐like hepatitis (DI‐ALH), and autoimmune hepatitis (AIH) can be challenging due to overlapping clinical characteristics. Recently, polyreactive immunoglobulin G (pIgG) was identified as a novel biomarker in AIH. This retrospective study aimed to evaluate the diagnostic accuracy of pIgG to distinguish between AIH, DI‐ALH, and DILI and thus identify patients in need of immunosuppression. Methods: Samples from 120 patients (AIH = 81, DI‐ALH = 16, DILI = 23) were compared to a control group (non‐AIH‐non‐DILI‐liver disease = 596 and healthy controls = 190). Results: No patient in the DILI‐group but 98% in the AIH‐ and 94% in the DI‐ALH‐group received immunosuppressive treatment. PIgG levels were significantly higher in the AIH‐group 1.9 normalised arbitrary units (nAU) compared to DILI (1.1 nAU, p < 0.001), non‐AIH‐non‐DILI‐LD (1.0 nAU, p < 0.001) and healthy controls (0.27 nAU, p < 0.001). PIgG levels for DI‐ALH (1.7nAU) were significantly higher compared to DILI ( p = 0.044) and non‐AIH‐non‐DILI‐LD and healthy controls (both p < 0.001). Highest AUC was seen for pIgG (0.818) compared to conventional autoantibodies. The overall accuracy of pIgG to distinguish AIH from DILI (74%) and liver injuries with and without the need for immunosuppression (73%) was like that of ANA (71%/73%) and SMA (74%/69%) at cut‐offs of ≥ 1/40. PIgG was positive in up to 79% of patients with AIH that were negative for a conventional autoantibody and was positive in 90% of DI‐ALH cases compared to 25% in DILI that were caused by the same drugs. Conclusions: PIgG may complement current serologic tests to identify patients with liver injury in need of immunosuppressive treatment.

Autoimmune hepatitis (AIH) is a severe, chronic disease where IgG elevation and autoantibody profile are defining features. However, linking autoantibodies to AIH pathogenesis remains elusive. We employed phage-display immunoprecipitation sequencing and uncovered a novel humoral signature specific to AIH. Embedded within this signature were antibodies against the known AIH autoantigen SLA/LP and novel reactivities to disco-interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). Fine mapping of the DIP2A epitope revealed preferential enrichment for a nearly identical 9–amino acid sequence derived from the U27 protein of human herpesvirus 6 (HHV6). Preincubation with the HHV6 epitope blocked DIP2A binding, consistent with cross-reactivity. AIH patients positive for anti-DIP2A had higher titers of HHV6 IgG, suggestive of reactivation. AIH patients had antibodies against the antifibrotic receptor, RXFP1, which inhibited relaxin-2 signaling in an IgG-dependent manner. These data provide evidence for a novel serological profile in AIH, linking HHV6 reactivation anti-RXFP1 antibodies to disease pathogenesis.