PredIcting sterOid depeNdEnt livEr injuRy With Polyreactive Immunoglobulin G (PIONEER)

Prospective Multicenter Study: PredIcting sterOid depeNdEnt livEr Injury (PIONEER) With Polyreactive Immunoglobulin G

The investigators identified polyreactive immunoglobulin G (pIgG) in adults (published in Hepatology: https://doi.org/10.1002/hep.32134) and children (in preparation). Quantification of these pIgG using a "home-made" ELISA facilitates the diagnosis of autoimmune hepatitis (AIH) as compared to non-AIH liver diseases and healthy controls. Positivity for pIgG was independent from ANA/SMA positivity and equally diagnostic for AIH even when conventional autoantibodies (ANA/SMA/SLA/LKM) were negative.

Additionally, the frequency of pIgG was lower than conventional autoantibodies (ANA, SMA) in vaccinia/drug associated severe liver injury in a retrospective multicenter study after Covid-19 vaccination (https://doi.org/10.1016/j.jhepr.2022.100605).

Aims of the study The study aims to evaluate the diagnostic capacity of pIgG to predict AIH in comparison to other liver diseases prospectively. To avoid diagnostic inaccuracy between AIH with long-term need for an immunosuppression and drug induced liver injury with autoimmune features, which can be indistinguishable from AIH at baseline and which has a very low relapse rate after a short steroid course, a follow-up after six months is obligatory for inclusion.

Therefore, the investigators will collect one serum sample from every patient (without immunosuppressive treatment) that presents to the respective hospital for evaluation of liver disease by liver biopsy within one year after initiation of the study and that provided written informed consent. Follow-up for evaluation of steroid dependency at six months after diagnosis is obligatory.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Liver Disease; Autoimmune Hepatitis
• Intervention / Treatment: Diagnostic test: polyreactive immunoglobulin G

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Bastian Engel, Dr.; Phone Number: +49 511 532 6766; Email: Engel.Bastian@mh-hannover.de
• Study Contact Backup: Name: Richard Taubert, Dr.; Phone Number: +49 511 532 6766; Email: Taubert.Richard@mh-hannover.de

Study Locations

• Germany
  • Aachen, Germany
    • Not yet recruiting
    • RWTH Aachen
    • Contact: Karsten Große, MD; Email: kargrosse@ukaachen.de
    • Contact: Tony Bruns, MD; Email: tbruns@ukaachen.de
  • Hamburg, Germany, 20251
    • Not yet recruiting
    • University Medical Center Hamburg-Eppendorf
    • Contact: Marcial Sebode, MD
  • Hanover, Germany, 30625
    • Recruiting
    • Hannover Medical School
    • Contact: Bastian Engel, MD; Phone Number: +495115326766; Email: Engel.Bastian@mh-hannover.de
    • Contact: Richard Taubert, MD; Phone Number: +495115326766; Email: Taubert.Richard@mh-hannover.de
    • Sub-Investigator: Norman Junge, MD
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • University Medical Center Heidelberg
    • Contact: Uta Merle, MD, Prof.
    • Contact: Jessica Seessle, MD
  • Lübeck, Germany, 23562
    • Not yet recruiting
    • University Hospital Schleswig-Holstein, Location Lübeck
    • Contact: Carolin Zimpel, MD
  • Rostock, Germany, 18057
    • Not yet recruiting
    • Rostock University Medical Centre
    • Contact: Theresia Blattmann, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Any patient that presents to the respective hospital for evaluation of a so far unknown-liver disease and consents is eligible if the treating physician orders a liver biopsy for the diagnostic evaluation of the liver disease. Patients are not eligible if a liver biopsy is performed for staging or grading of an already known liver disease or if the patient is treated with immunosuppressive drugs at the time of the liver biopsy.

Description

Inclusion Criteria:

• Diagnostic liver biopsy for the work-up of any liver disease
• Informed consent
• Definition of any liver disease according to current societal guidelines

Exclusion Criteria:

• Ongoing immunosuppression at the liver biopsy or prior to the liver biopsy

• Liver biopsies for the grading or staging of an already known liver disease (e.g. non-alcoholic fatty liver disease (NAFLD), Hepatitis B/D Virus Infections (HBV/HDV Infection), …)

  • known liver disease
  • missing informed consent
  • patients or caregivers who can not provide informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Autoimmune Hepatitis; This group includes patients with a diagnosis of Autoimmune Hepatitis according to the simplified diagnostic criteria by Hennes et al. made by the local treating physician. The diagnosis of autoimmune hepatitis additionally requires steroid dependency > six months for this study to discriminate Autoimmune Hepatitis from autoimmune like drug-induced liver injury (DILI) which are hard to discriminate at diagnosis and with the latter often being treating with a short course of corticosteroids less than six months. One serum sample will be stored for anonymized evaluation of serum autoantibodies	Diagnostic test: polyreactive immunoglobulin G; Polyreactive immunoglobulin G will be tested centralized in Hannover as published (Taubert, Engel et al., Hepatology, 2022). The current standard diagnostic autoantibodies (e.g. ANA, anti-SMA, anti-LKM, anti-LC1, anti-SLA/L) will be tested centrally in Hannover according to current guidelines.; Other Names: Conventional diagnostic autoantibodies
non-autoimmune hepatitis liver disease; This group includes patients with a diagnosis of any non-viral liver disease that is not autoimmune hepatitis and whose diagnosis necessitated a diagnostic liver biopsy in the work-up of the liver disease for local care. One serum sample will be stored for anonymized evaluation of serum autoantibodies	Diagnostic test: polyreactive immunoglobulin G; Polyreactive immunoglobulin G will be tested centralized in Hannover as published (Taubert, Engel et al., Hepatology, 2022). The current standard diagnostic autoantibodies (e.g. ANA, anti-SMA, anti-LKM, anti-LC1, anti-SLA/L) will be tested centrally in Hannover according to current guidelines.; Other Names: Conventional diagnostic autoantibodies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity of new simplified pIgG AIH Score	Autoimmune serology will be substituted by pIgG in the 2021 simplified AIH Score. Sensitivity of the new score will be compared to the old score, primarily for non-inferiority and second for superiority if non-inferiority was met.	Assessment of steroid dependency at six months after enrollment
Specificty of pIgG simplified AIH Score	Autoimmune serology will be substituted by pIgG in the 2021 simplified AIH Score. Sensitivity of the new score will be compared to the old score, primarily for non-inferiority and second for superiority if non-inferiority was met.	Assessment at baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic discrimination between AIH and DILI by polyreactive IgG		At enrollment
Prediction of steroid dependent hepatitis by any other autoantibody	Prediction of steroid dependent hepatitis by any other elevated conventional autoantibody according to current guidelines (European Association for the study of the liver: EASL, American Association for the Study of Liver Diseases: AASLD)	Assessment of steroid dependency at six months after enrollment
Age-dependency of autoantibodies	Presence of autoantibodies will be descriptively evaluated with regard to age of the patients as currently it is proposed that lower antibody titers/levels are diagnostic in children (dependent on age) than in adults	Assessment of autoantibodies at baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concordance of different testing methods for autoantibodies	Different methodology to assess presence of autoantibodies (e.g. ELISA, Immunofluorescence on tissue sections) will be tested head-to-head for their diagnostic capacity	At enrollment

Collaborators and Investigators

• Sponsor: Hannover Medical School
• Investigators: Principal Investigator: Bastian Engel, Dr., Hannover Medical School; Principal Investigator: Richard Taubert, Dr., Hannover Medical School

Publications and helpful links

General Publications

• Taubert R, Engel B, Diestelhorst J, Hupa-Breier KL, Behrendt P, Baerlecken NT, Suhs KW, Janik MK, Zachou K, Sebode M, Schramm C, Londono MC, Habes S; UK-AIH Consortium; Oo YH, Lalanne C, Pape S, Schubert M, Hust M, Dubel S, Thevis M, Jonigk D, Beimdiek J, Buettner FFR, Drenth JPH, Muratori L, Adams DH, Dyson JK, Renand A, Graupera I, Lohse AW, Dalekos GN, Milkiewicz P, Stangel M, Maasoumy B, Witte T, Wedemeyer H, Manns MP, Jaeckel E. Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis. Hepatology. 2022 Jan;75(1):13-27. doi: 10.1002/hep.32134. Epub 2021 Dec 5.

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2023
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: March 28, 2023
• First Submitted That Met QC Criteria: April 11, 2023
• First Posted (Actual): April 12, 2023

Study Record Updates

• Last Update Posted (Actual): July 15, 2026
• Last Update Submitted That Met QC Criteria: July 13, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Autoimmune Diseases; Immune System Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Chronic; Hepatitis; Hepatitis, Autoimmune; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; Immunoglobulin G; Autoantibodies
• Other Study ID Numbers: PIONEER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD are not shared with collaborators. Data, in general, is only provided anonymized by contributing centers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No