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    Oral Communication

    Hemophilia and Rare Bleeding Disorders

    Hemophilia Clinical - Inhibitors

    OC 50.1 - Levels of IgG4 distinguish immune tolerance induction outcome in patients with inherited hemophilia A: results from the BrazIT Study

    Tuesday, June 27, 2023
    10:45 – 11:00 ET
    Room: 516
    Session Available As: Live-Stream and On-Demand

      Presenting Author(s)

    • Daniel G. Chaves, Msc, PhD (he/him/his)

      Researcher
      Fundação Centro de Hematologia e Hemoterapia de Minas Gerais (Hemominas), Minas Gerais, Brazil
      Belo Horizonte, Minas Gerais, Brazil

      • Co-Author(s)

    • BA

      Brendon Ayala

      Researcher
      Faculdade de Medicina, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
      Belo Horizonte, Minas Gerais, Brazil

    • Ricardo M. Camelo, MD, MSc, MBA

      Physician
      Faculty of Pharmacy, Universidade Federal de Minas Gerais
      Belo Horizonte, Minas Gerais, Brazil

    • Maíse M. Dias

      Researcher
      Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
      Ribeirão Preto, Sao Paulo, Brazil

    • TA

      Tânia H. Anegawa

      Researcher
      Centro Regional de Hematologia e Hemoterapia de Londrina, Paraná, Brazil
      Londrina, Parana, Brazil

    • Ad

      Andrea G. de Oliveira

      Researcher
      Fundação Centro de Hematologia e Hemoterapia de Minas Gerais (Hemominas), Minas Gerais, Brazil
      Belo Horizonte, Minas Gerais, Brazil

    • RR

      Rosângela A. Ribeiro

      Researcher
      Centro de Hematologia e Hemoterapia do Ceará (Hemoce), Ceará, Brazil
      Fortaleza, Ceara, Brazil

    • MC

      Mônica H. Cerqueira

      Researcher
      Instituto de Hematologia do Estado do Rio de Janeiro (Hemorio), Rio de Janeiro, Brazil
      Rio de Janeiro, Rio de Janeiro, Brazil

    • LE

      Leina Y. Etto

      Researcher
      Centro de Hematologia e Hemoterapia da Paraíba (Hemoíba), Paraíba, Brazil
      João Pessoa, Paraiba, Brazil

    • FC

      Fábia M R A Callado

      Researcher
      Fundação de Hematologia e Hemoterapia de Pernambuco (Hemope), Pernambuco, Brazil
      Recife, Pernambuco, Brazil

    • VF

      Vivian K B Franco

      Researcher
      Centro de Hematologia e Hemoterapia de Santa Catarina (Hemosc), Santa Catarina, Brazil
      Florianópolis, Santa Catarina, Brazil

    • MR

      Maria do Rosário F. Roberti

      Researcher
      Centro de Hematologia e Hemoterapia de Goiás (Hemogo), Goiás, Brazil
      Goiânia, Goias, Brazil

    • MC

      Maria Aline F. Cerqueira

      Researcher
      Centro de Hematologia e Hemoterapia do Piauí (Hemopi), Piauí, Brazil
      Teresina, Piaui, Brazil

    • IP

      Ieda S. Pinto

      Researcher
      Fundação Centro de Hematologia e Hemoterapia do Pará (Hemopa), Pará, Brazil
      Belém, Para, Brazil

    • Suely Rezende, MD, PhD (she/her/hers)

      Professor of Internal Medicine
      Universidade Federal de Minas Gerais, Brazil

    Background: The development of inhibitors in patients with inherited hemophilia A (PwHA) lead to inefficient FVIII replacement therapy. Immune tolerance induction (ITI) is recommended to eradicate inhibitors, but the biology and biomarkers related with ITI outcome are still missing.

    Aims: This study aimed to investigate cytokines, chemokines and anti-FVIII immunoglobulin (Ig)G4 as biomarkers of ITI outcome.

    Methods: We assessed plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, TNF, IFN-, IL-17A, CXCL8, CCL5, CXCL9, CCL2, CXCL10 by flow cytometry and anti-FVIII IgG4 in ELISA using immobilized plasma-derived (pd) and recombinant (r) FVIII. We included 98 moderately-severe and severe ( < 2% FVIII), high-responders (>5.0BU/mL) PwHA after completion of ITI. Patients were divided into three groups accordingly ITI outcome: failure (n=40), partial (n=37) and complete success (n=21). Local ethics committees approved this study and patients signed informed consent.

    Results: No difference concerning the plasma levels of cytokines and chemokines was detected between the groups. Levels of anti-FVIII IgG4 were considerably higher in PwHA who failed ITI (median optical density [OD], 2.19; IQR 0.74-2.52 using rFVIII; median OD, 1.33; IQR 0.50-2.33 using pdFVIII) compared with those who had partial (median OD, 0.39; IQR 0.09-1.11 using rFVIII; p< 0.0001; median OD, 0.15; IQR 0.04-0.67 using pdFVIII; p< 0.0001) and complete success (median OD, 0.07; IQR 0.06-0.40 using rFVIII; p< 0.0001; median OD, 0.08; IQR 0.02-0.16 using pdFVIII; p< 0.0001). Anti-FVIII IgG4 levels were higher in PwHA presenting partial success compared with those with complete success when rFVIII was immobilized in the microplate (p=0.02) (Figure 1).

    Conclusion(s): Levels of anti-FVIII IgG4 associated with ITI outcome in a dose-dependent effect, with failure>partial>complete success. Anti-FVIII IgG4 using immobilized rFVIII could further distinguish between partial and complete success. Levels of cytokines and chemokines had no role as biomarkers of ITI outcome. This study was supported by Fapemig, CNPq and Ministry of Health of Brazil.

    Learning Objectives:

    • Verify that levels of IgG4 distinguish immune tolerance induction outcome in patients with inherited hemophilia A.
    • Verify that no difference concerning the plasma levels of cytokines and chemokines could be detected between groups of haemophilia A that had total success, partial success or failed the immune tolerance induction.
    • Verify that the detection of anti-FVIII IgG4 in ELISA can distinguish between partial and complete success after immune tolerance induction in patients with inherited haemophilia A.