Advertisement

2022 International Autoimmune Hepatitis Group non-response criteria in autoimmune hepatitis: A too early endpoint?

  • Renato Medas
    Correspondence
    Corresponding author. Address: Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto. Al. Prof. Hernâni Monteiro 4200 - 319 Porto, Portugal; Tel.: +351 91 848 7035, fax: +351 22 551 3601.
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal
    Search for articles by this author
  • Rodrigo Liberal
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal
    Search for articles by this author
  • Hélder Cardoso
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal
    Search for articles by this author
  • Guilherme Macedo
    Affiliations
    Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal

    Faculty of Medicine of the University of Porto, Porto, Portugal
    Search for articles by this author

      Linked Article

      To the Editor:
      We have read with great interest the manuscript by Pape et al.
      • Pape S.
      • Snijders R.J.A.L.M.
      • Gevers T.J.G.
      • Chazouilleres O.
      • Dalekos G.N.
      • Hirschfield G.M.
      • et al.
      Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.
      regarding an international consensus on response criteria and treatment endpoints in autoimmune hepatitis (AIH). The main goal was to standardize the criteria used among studies, enabling comparisons and the generation of more robust evidence. In this paper, the International Autoimmune Hepatitis Group (IAIHG) defined complete biochemical response (CBR) as normalisation of aminotransferases and IgG after no more than 6 months. The inability to achieve this endpoint was defined as insufficient response. Response was defined as ≥50% decrease of serum aminotransferases within 4 weeks after initiation of treatment.
      Another recent paper from Pape et al.
      • Pape S.
      • Gevers T.J.G.
      • Vrolijk J.M.
      • van Hoek B.
      • Bouma G.
      • van Nieuwkerk C.M.J.
      • et al.
      Rapid response to treatment of autoimmune hepatitis associated with remission at 6 and 12 months.
      had previously reported that patients with a significant decrease of aminotransferases after 8 weeks of treatment (rapid responders: defined as a decrease of ≥80% in level of aspartate aminotransferase [AST]) were more likely to achieve normalization of aminotransferases at week 26 and 52 (p <0.001).
      Herein, we aim to validate the new IAIHG criteria and the 8-week response criteria in our cohort. We performed a retrospective analysis of a prospectively collated database including all adult patients with AIH diagnosed between 2004 and 2020. A liver biopsy was performed in all patients at the time of diagnosis; fibrosis was classified according to METAVIR scoring system. Clinical, biochemical and immunological parameters were assessed at baseline, 4, 8, 12, 26 and 52 weeks, and at last follow-up. Patients were included if the following criteria were met: 1. Age >18 years old at the time of diagnosis; 2. Definite diagnosis of AIH according to IAIHG simplified criteria
      • Hennes E.M.
      • Zeniya M.
      • Czaja A.J.
      • Parés A.
      • Dalekos G.N.
      • Krawitt E.L.
      • et al.
      Simplified criteria for the diagnosis of autoimmune hepatitis.
      ; 3. Induction therapy with oral steroids (prednisolone or budesonide) followed by introduction of azathioprine according to a well-established local protocol. Patients with variant syndromes or concurrent liver diseases or presenting with acute severe or fulminant AIH were excluded.
      A total of 60 patients were eligible for the study (80% females). At diagnosis, the median age was 52 years (IQR 29-62). Type 1 AIH was predominant (86.7%). 23 patients had evidence of cirrhosis at diagnosis, 10 had advanced fibrosis (F3), while the remaining 27 patients had mild-to-moderate fibrosis (F1-2). Median follow-up time was 6.5 years (IQR 3.3-9.0).
      Patients were initially treated per local protocol with prednisolone 40 to 60 mg/day (n = 55, 91.7%) or budesonide 9 mg/day (n = 5, 8.3%) for 2 weeks. The dose of prednisolone or budesonide was then tapered according to response; at the same time, therapy with azathioprine was commenced at 1 mg/kg/day, and then increased up to 2 mg/kg/day.
      In accordance with IAIHG validation cohort, most of our patients were classified as responders after 4 weeks of treatment. Response (i.e., decrease of >50% of AST levels after 4 weeks of treatment) was achieved in 50 (83%) patients. However, unlike in the original study, patients fulfilling response criteria had the same probability of cirrhosis at diagnosis (38.0% vs. 40.0%, p = 0.9).
      CBR at month 6 was also achieved for most patients (n = 37, 61.7%). Despite a lower percentage of patients with CBR at month 6 having cirrhosis at diagnosis, this was not statistically significant (29.7% vs. 54.5%, p = 0.1).
      We further evaluate the potential implications of IAIHG response criteria on the disease behaviour over time. In our cohort, IAIHG response criteria were not able to predict CBR at 6 and 12 months (66% vs. 60% p = 0.72; 65% vs. 50% p = 0.36, respectively). However, patients who achieved CBR at month 6 were able to maintain CBR over time (12-month CBR: 81% vs. 18% p <0.05; last follow-up: 73% vs. 28% p <0.05).
      Lastly, we aimed to validate the impact of 8-week response criteria on the outcome of patients with AIH. Eight-week response criteria (i.e., a decrease of more than 80% in the level of AST) was achieved in 50% (n = 30) of patients in our cohort. Rapid responders had a higher probability of CBR at 6 and 12 months compared to non-rapid responders (75% vs. 50%, p = 0.05; 79% vs. 54%, p <0.05).
      In conclusion, in our cohort, the 8-week response predicted a more favourable disease course, with higher probability of achieving and sustaining CBR, while the 4-week response as proposed by the IAIHG was not able to predict it. Assessment of CBR at 6 months performed well as an endpoint, since it was associated with maintenance of response over time. An early identification of non-response may enable the earlier identification of patients who would benefit from second-line therapies, but a 4-week assessment may be too early.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      R.M. collected the patient data, planned the manuscript, performed the statistical analysis, did the literature review, and created the first draft. R.L. collected patient data, validated the statistical analysis and reviewed the manuscript. H.C. and G.M. did a critical expert review and revision of the manuscript.

      Conflict of interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Pape S.
        • Snijders R.J.A.L.M.
        • Gevers T.J.G.
        • Chazouilleres O.
        • Dalekos G.N.
        • Hirschfield G.M.
        • et al.
        Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.
        J Hepatol. 2022; 76: 841-849
        • Pape S.
        • Gevers T.J.G.
        • Vrolijk J.M.
        • van Hoek B.
        • Bouma G.
        • van Nieuwkerk C.M.J.
        • et al.
        Rapid response to treatment of autoimmune hepatitis associated with remission at 6 and 12 months.
        Clin Gastroenterol Hepatol. 2020; 18: 1609-1617.e4
        • Hennes E.M.
        • Zeniya M.
        • Czaja A.J.
        • Parés A.
        • Dalekos G.N.
        • Krawitt E.L.
        • et al.
        Simplified criteria for the diagnosis of autoimmune hepatitis.
        Hepatology. 2008; 48: 169-176