Philipp Lutz

Fidanacogene elaparvovec is an adeno-associated virus (AAV)-based gene therapy that enables endogenous factor IX (FIX) expression in hemophilia B, potentially eliminating the need for prophylactic FIX replacement. Post-treatment monitoring focuses on FIX durability, hepatic safety, and immune-mediated loss of expression. A 40-year-old man with severe hemophilia B received a single intravenous dose of fidanacogene elaparvovec in the phase 3 BENEGENE-2 trial (NCT03861273). FIX activity was assessed by one-stage and chromogenic assays. Liver enzymes, clinical parameters, and adverse events were monitored. Prednisolone was initiated for liver enzyme elevation and later switched to budesonide in response to declining FIX levels. Follow-up continued for 4 years. FIX activity peaked at week 6 (~30 IU/dL) and remained stable until week 16. Moderate ALT elevation (peak ~70 U/L) responded to prednisolone. Between weeks 22–28, FIX levels declined without ALT elevation. Budesonide (9 mg/day) was started at week 25 for 3 months and gradually tapered, stabilizing FIX activity at 10-20 IU/dL. This level has been maintained for 4 years without bleeding episodes or FIX replacement. Fidanacogene elaparvovec provided sustained, clinically meaningful FIX expression. Budesonide may offer an effective hepatocyte-targeted alternative to systemic corticosteroids while supporting long-term transgene expression.

Background: Liver cirrhosis leads to an impaired liver function with reduced metabolic capacity, which affects the pharmacokinetics of several drugs, requiring dose adjustments. Although limited literature provides guidance on appropriate administration of drugs in cirrhosis, no guidelines currently exist for dose selection or adjustment. Objective: The objective of this study is to provide guidance on the selection, dosing, and appropriate use of drugs in patients with liver cirrhosis and evaluate the clinical application of these recommendations. Methods: Three steps are planned to establish dose recommendations for patients with liver cirrhosis. First, a systematic literature search will be conducted to identify specific recommendations for drug selection and dosing in cirrhosis, and the literature will be assessed for reporting quality and evidence level. Subsequently, the resulting recommendations will undergo an internal preassessment procedure for relevance of the covered drugs with regard to availability, the clinical impact of adverse drug reactions, the frequency of use, and the expected benefit of dose adjustment. Second, a modified Delphi procedure will be conducted to (1) analyze the clinical handling of the identified drugs by experts in clinical practice in a first round and (2) parse changes resulting from the inclusion of medication-related information and further harmonize differing dose recommendations in a second round. Finally, the adopted dose recommendations will be implemented in a clinical study involving patients with liver cirrhosis to analyze the impact of the recommendations on patient safety. Results: The planned clinical validation phase started in January 2025 and is currently underway. As of May 2026, 121 patients have been enrolled. Statistical analyses will be conducted in accordance with the predefined analysis plan. Findings from the literature review, the Delphi consensus process, and the clinical validation phase will be reported in subsequent publications. Final study results and data analysis are anticipated in August 2026. Conclusions: This protocol outlines a structured approach combining a systematic literature review of specific dose recommendations in patients with cirrhosis that integrates a quality assessment to ensure the inclusion of only high-quality evidence, expert opinions through a Delphi consensus aligning differing recommendations, and a clinical validation to support safer drug therapy in patients with liver cirrhosis.

Interleukin (IL) 17A antagonists are increasingly used for psoriasis and other indications such as ankylosing spondylitis or hidradenitis suppurativa but can paradoxically trigger inflammatory bowel disease (IBD). We present a 51-year-old male patient with psoriatic arthritis who developed ulcerative colitis (UC) 12 months after initiating secukinumab therapy. Colonoscopy revealed continuous colonic inflammation with large ulcers in the rectum (Montreal E3). Faecal calprotectin was 87 µg/g. Secukinumab was discontinued and therapy with mesalazine was initiated. To ensure continued psoriasis control and treatment of UC, risankizumab, a selective IL-23 inhibitor, was administered at the standard psoriasis regimen. Over 12 months, the patient achieved clinical, endoscopic and histological remission. This case illustrates the dual role of IL-17A in mucosal immunity and risk of IBD induction by IL-17A blockade. Selective IL-23 inhibition may represent an effective strategy for managing IL-17A antagonist-induced UC while preserving psoriasis control.

Background: We analyzed the performance of a multiplex PCR application (Unyvero IAI) in comparison to culture in a cohort of peritonitis patients undergoing peritoneal dialysis or with liver cirrhosis. Methods: We performed a single-center study of 47 patients with clinically suspected peritonitis and compared pathogen detection rates of culture and PCR. The main outcome of interest was a comparison of accuracy and time to final positive result. Results: In the total cohort, the pathogen detection rate in culture was 58.14% versus 34.88% in PCR (p = 0.03). Detection rates of bacteria in peritoneal dialysis patients were even higher by culture (70.83%) but comparably low by PCR (37.50%; p = 0.04). The majority of discordant results were in the Gram-positive spectrum (81.82%). Differential time to final positive result was 37.39 ± 16.75 h. Conclusion: Time gains by using PCR diagnostic have to be weighed against lower detection rates, mainly in Gram-positive infections.

Background: Development of cirrhosis and hepatocellular carcinoma (HCC) in patients with high alcohol intake is modulated by genetic predispositions. Genetic variation in angiotensin II type 1 receptor (AGTR1) has been described as a risk factor for non-alcoholic fatty liver disease in Asian patients. Methods: We analysed Caucasian patients with alcohol–associated cirrhosis without (n = 238) and with (n = 339) HCC, healthy controls (n = 200), and HCV–infected cirrhotic patients with and without HCC (n = 263) for association with the polymorphisms rs3772622 and rs2276736 in AGTR1. Results: Rs2276736 in AGTR1 was associated with both low–density lipoprotein (LDL) cholesterol levels and hepatic steatosis in patients with alcohol–associated liver disease. The distribution of genotypes for both rs3772622 and rs2276736 in AGTR1 were comparable between controls, cirrhosis patients, and those with HCC. Minor allele frequencies were 32% (44%) in healthy controls, 35%/34% (46%/45%) in alcohol–associated liver disease without/with HCC and 31%/38% (43%/39%) in HCV cirrhosis and HCV HCC, respectively. The genotype of the most important genetic risk factor for fatty liver disease, PNPLA3 I148M, did not interact with the AGTR1 polymorphisms. Conclusion: Genetic variation in AGTR1, although associated with blood lipid levels and hepatic steatosis, is not a risk factor for alcohol–associated cirrhosis or HCC in Caucasians.

The aim of this study was to retrospectively evaluate the long-term results of lymphatic interventions in adults with abdomino-thoracic lymphatic pathologies. Management of abdomino-thoracic chylous effusions in adults undergoing X-ray-lymphangiography with or without lymph-vessel embolization (LVE) from 2010–2018 was reviewed. Patients underwent lymphangiography alone when imaging showed normal findings or lymphatic obstruction without leakage or reflux; otherwise, LVE was performed (leakage, reflux, obstruction with leakage or reflux, lymphatic masses). Technical and clinical success, complications, and long-term outcomes were assessed. 78 patients (47 male, median age 56.3 years) were treated for chylous effusions (60.3% traumatic, 39.7% non-traumatic). Lymphangiography showed leakage (48.7%), reflux (14.1%), obstruction (28.2%), lymphatic masses (5.1%), and normal findings (3.8%). Embolization was performed in 49/78 (62.8%) cases. Overall, treatment was clinically successful in 74.4% (mean follow-up of 28 months), with significant differences between LVE and lymphangiography (91.8% vs. 44.8%; p < 0.001), traumatic and non-traumatic etiologies (89.4% vs. 51.6%; p < 0.001), and leakage locations (p = 0.003). The clinical success of LVE did not differ between leakage etiologies or locations. Complications occurred in 5 patients (2/5 needed treatment). Patients survived significantly longer after successful treatment (2679 vs. 927 days; p = 0.044) and without malignancy (3214 vs. 1550 days; p = 0.043). Lymphatic interventions are safe and effective. LVE should be attempted whenever feasible, as success is high (>90%). Successful intervention has a positive effect on patient survival.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6–dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS: We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS: In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4⁺ T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3–positive CD4⁺ T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3–positive cells were enriched in the peribiliary liver stroma and represented CD4⁺ T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION: Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.