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2022 International Autoimmune Hepatitis Group non-response criteria in autoimmune hepatitis: Quick vs. slow responders.

  • Bastian Engel
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

    Member of the European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
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  • Author Footnotes
    # Current address: Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada.
    Elmar Jaeckel
    Footnotes
    # Current address: Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada.
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

    Member of the European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
    Search for articles by this author
  • Richard Taubert
    Correspondence
    Corresponding author: Richard Taubert, MD, Phone +49-511-532 6766;
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

    Member of the European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
    Search for articles by this author
  • Author Footnotes
    # Current address: Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada.
Published:October 12, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.026

      Abbreviations:

      AIH (autoimmune hepatitis), ALT (alanine aminotransferase), AST (aspartate aminotransferase), CBR (complete biochemical remission), [email protected] (complete biochemical remission at 6 months), IgG (immunoglobulin G), SF (serum ferritin), SOC (standard of care), ULN (upper limit of normal)

      Linked Article

      To the Editor,
      We read with interest the article “Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group” by Pape and Snijders et al. and the subsequent Letters to the Editors by Medas et al., Li et al. and Snijders et al. recently published in the Journal of Hepatology
      • 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.
      • Medas R.
      • Liberal R.
      • Cardoso H.
      • Macedo G.
      2022 International Autoimmune Hepatitis Group non-response criteria in autoimmune hepatitis: A too early endpoint?.
      • Li Y.
      • Xiao X.
      • Miao Q.
      • Ma X.
      Rapid response predicts complete biochemical response and histological remission in autoimmune hepatitis.
      • Snijders R.J.A.L.M.
      • Gevers T.J.G.
      • Heneghan M.A.
      • Drenth J.P.H.
      Reply to: “Correspondence on ‘Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.
      .
      We have recently been able to establish and validate an AIH treatment response score involving two baseline routine laboratory parameters, immunoglobulin G (IgG) and serum ferritin (SF)
      • Taubert R.
      • Hardtke-Wolenski M.
      • Noyan F.
      • Lalanne C.
      • Jonigk D.
      • Schlue J.
      • et al.
      Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis.
      . The combination of low SF (< 2.09x upper limit of normal (ULN); 1 score point) and high IgG (> 1.89x ULN; 1 score point) predicted treatment failure to standard of care (SOC) with steroids and/or azathioprine, i.e. no achievement of complete biochemical remission (CBR; normalization of ALT, AST and IgG), at any time point with an AUC of 0.741-0.749. This was higher than the AUC of the later published ≥80% AST decline at eight weeks of therapy (AUC=0.65) for the prediction of CBR at months six to twelve
      • 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.
      .
      We assessed the predictive capacity of our score with regard to the new 2022 definition of CBR at six months ([email protected]) by Pape and Snijders 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.
      in our previously published retrospective single center cohort of 109 patients with biopsy proven AIH
      • Taubert R.
      • Hardtke-Wolenski M.
      • Noyan F.
      • Lalanne C.
      • Jonigk D.
      • Schlue J.
      • et al.
      Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis.
      . While 76% of these patients achieved CBR with SOC at any time point, [email protected] was achieved by 38% of patients. Follow-up data at six months was not available from five patients. The median time to CBR was 6.5 months. When we applied our treatment response score with 0, 1 and 2 score points (Suppl. Figure 1) the rate of CBR at any time point was 98%, 68%, and 40% (p<0.001 in Chi-Square test and Log rank test) and the rate of [email protected] was 50%, 34% and 10% (p=0.048 in Chi-Square test and p=0.059 in Log rank test).
      While only baseline IgG and SF were independently associated with the achievement of CBR at any time point
      • Taubert R.
      • Hardtke-Wolenski M.
      • Noyan F.
      • Lalanne C.
      • Jonigk D.
      • Schlue J.
      • et al.
      Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis.
      , IgG and histological scores for interface hepatitis (mHAI A) and liver fibrosis (Ishak F) were significantly different in the comparison of those AIH patients that achieve [email protected] and those that did not (Table 1). In conclusion, our treatment response score was more useful for the prediction of overall CBR but less predictive for the short-term endpoint [email protected] However, our finding should not question the clinical unmet need of a commonly accepted endpoint, which is absolutely necessary to design studies and compare results which is fundamental for the urgently needed improvement of immunosuppressive therapy in AIH. Nonetheless, this finding raises the question, if the proposed short-term remission endpoint inadequately selects “quick responders” as discussed by Medas et al.
      • Medas R.
      • Liberal R.
      • Cardoso H.
      • Macedo G.
      2022 International Autoimmune Hepatitis Group non-response criteria in autoimmune hepatitis: A too early endpoint?.
      .
      Table 1
      [email protected][email protected]p-value
      n3965
      female sex27 (69.2)40 (61.5)0.527
      age [months]47 (17 - 83)56 (17 - 73)0.34
      ferritin [xULN]2.6 (0.1 - 41.9)2.0 (0.1 - 16.1)0.195
      iron [xULN]1.1 (0.2 - 3.7) (n=33)1.1 (0.1 - 2.3) (n=49)0.411
      transferrinsaturation [%]47 (16 - 100) (n=30)40 (9 - 98) (n=43)0.346
      CRP [mg/l]8.5 (1 - 38) (n=38)7.5 (1 - 245) (n=60)0.677
      Hb [g/dl]14 (11.4 - 16.5)13.4 (9.8 - 16.3)0.181
      IgG [xULN]1.2 (0.5 - 3.6)1.5 (0.6 - 4.6)0.016
      ANA33 (84.6)55 (84.6)1
      anti-SMA33 (84.6)42 (67.7) (n=62)0.066
      anti-LKM0 (0)0 (0)n/a
      anti-SLA3 (7.7)3 (5.0) (n=60)0.678
      mHAI9 (5 - 14) (n=33)9 (3 - 16)0.154
      mHAI - A3 (0 - 4) (n=33)4 (1 - 4) (n=37)0.022
      mHAI - B0 (0 - 4) (n=33)0 (0 - 5) n=37)0.451
      mHAI - C2 (1 - 4) (n=33)2 (0 - 4) (n=37)0.985
      mHAI - D3 (2 - 4) (n=33)3 (1 - 4) (n=36)0.057
      Ishak F2 (0 - 6) (n=33)3 (0 - 6) (n=45)0.01
      AST [xULN]20.6 (1.2 - 113.2)19.0 (1.4 - 103.6) (n=64)0.754
      ALT [xULN]21.3 (0.6 - 124.9)20.3 (1.5 - 90.6)0.724
      gGT [xULN]3.4 (1.0 - 34.1)5.2 (0.5 - 27.4) (n=63)0.461
      ALP [xULN]1.4 (0.5 - 5.1)1.4 (0.3 - 5.7) (n=64)0.943
      bilirubin [xULN]3.6 (0.3 - 45.2) (n=37)3.8 (0.3 - 33.7) (n=64)0.639
      PT ratio [%]78 (38 - 104)70 (27 - 126) (n=60)0.858
      Values are given as median and range or number and percentage as appropriate. Mann-Whitney-U test or Fisher’s Exact test were used for group comparisons as appropriate. [email protected]: complete biochemical remission at month six; [email protected]: incomplete response at month six; mHAI: modified hepatitis activity index; PT ratio: prothrombin time ratio; xULN: times upper limit of normal.
      To test this hypothesis in our cohort we compared those patients that achieved CBR with SOC before month six (n=39) against patients that achieved CBR later than six months (n=39). Patients with CBR beyond six months had more inferface hepatitis (Ishak A (median (range)): 4 (2-4) vs 3 (0-4); p=0.04), more liver fibrosis (Ishak F (median (range)): 4 (0-6) vs. 2 (0-6); p=0.006) and less frequent anti-smooth-muscle antibodies (63% vs 85%; p=0.040). All other baseline parameters including IgG and SF were not significantly different between patients with early and late achievement of CBR (Suppl. Table 1). The finding of a trend towards less cirrhosis in patients that achieved [email protected] reported by Medas et al. suggests a similar preference of AIH patients with a milder histological disease stage by the early endpoint at six months.
      The other Letters to the Editor of Medas et al.
      • Medas R.
      • Liberal R.
      • Cardoso H.
      • Macedo G.
      2022 International Autoimmune Hepatitis Group non-response criteria in autoimmune hepatitis: A too early endpoint?.
      and Li et al.
      • Li Y.
      • Xiao X.
      • Miao Q.
      • Ma X.
      Rapid response predicts complete biochemical response and histological remission in autoimmune hepatitis.
      tested the prediction of ≥80% AST decline after eight weeks of therapy for the achievement of [email protected] in their Portuguese and Chinese cohorts. Our center was part of the multicenter study of 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.
      that identified this predictor. Therefore, it is not reasonable to validate this predictor in our cohort separately.
      In conclusion, the [email protected] is much needed consensus to design and compare studies using a short-term endpoint and allow comparison of studies by standardization that will hopefully move the field forward in terms of optimization and individualization of therapy. However, this new definition should be applied reasonably to avoid a too early “overtherapy” of patients with more advanced liver disease stage and grade as our data highlight that there might be considerable numbers of patients, especially those with more fibrosis, that still achieve CBR beyond six months with SOC. The recently established AIH registries of the international AIH group and the European reference network for rare liver diseases will help to assess the implication of the [email protected] for SOC, 2nd and 3rd line therapies in the near future on a prospective and multicenter level.

      Conflict of interest

      The authors report no conflicts of interest with regard to this work.

      Financial support

      The work was supported by grants from the German Research Foundation (KFO250 project 7). RT was supported by the Core 100 advanced clinician scientist program and BE by the young clinician scientist program (PRACTIS) both from Hannover Medical School.

      Author contribution

      Study concept and design: BE, RT. Acquisition of data: BE, RT. Analysis and interpretation of data: BE, RT. Drafting of the manuscript: BE, RT. Critical revision of the manuscript for important intellectual content: EJ. Statistical analysis: BE, RT. Obtained funding: BE, EJ, RT. Administrative, technical, or material support: BE, EJ, RT. Study supervision: EJ, RT.

      Acknowledgement

      We thank Konstantinos Iordanidis for his constant assistance in this project.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

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