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High plasma levels of IgG4 anti-FVIII is the hallmark of immune tolerance failure in patients with hereditary hemophilia A: results from the BrazIT Study

1Fundação Hemominas, Belo Horizonte, Brazil, Belo Horizonte, Minas Gerais, Brazil, 2Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands, Belo Horizonte, Minas Gerais, Brazil, 3Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, Belo Horizonte, Minas Gerais, Brazil, 4Centro de Hematologia e Hemoterapia da Paraíba (HEMOÍBA), João Pessoa, Paraiba, Brazil, 5Fundação HEMOMINAS, Belo Horizonte, Minas Gerais, Brazil, 6Centro de Hematologia e Hemoterapia de Santa Catarina (HEMOSC), florianópolis, Santa Catarina, Brazil, 7Centro de Hematologia e Hemoterapia de Goiás (HEMOGO), Goiânia, Goias, Brazil, 8Centro de Hematologia e Hemoterapia do Piauí (HEMOPI), Teresina, Piaui, Brazil, 9Centro de Hematologia e Hemoterapia do Ceará (HEMOCE), Fortaleza, Ceara, Brazil, 10Fundação de Hematologia e Hemoterapia de Pernambuco (HEMOPE), Recife, Pernambuco, Brazil, 11Centro Regional de Hematologia e Hemoterapia de Londrina, Londrina, Parana, Brazil, 12Instituto de Hematologia do Estado do Rio de Janeiro (HEMORIO), Rio de Janeiro, Rio de Janeiro, Brazil

Abstract Number: PB0178

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic

Background: Immune tolerance induction (ITI) eradicates anti-factor VIII (FVIII) inhibitors in about 70% of patients with inherited hemophilia A (PwHA). Of all immunoglobulins (Ig), anti- FVIII IgG4 is known to correlate with inhibitor titre. Therefore, we hypothesized that it could be a biomarker of ITI outcome.

Aims: To evaluate the association of IgG4 anti-FVIII levels with the outcome of ITI in patients with severe hemophilia A (FVIII < 2%) with high response inhibitors.

Methods: We included PwHA who completed ITI from nine hemophilia centers. ELISA was used to detect specific IgG4 anti-FVIII in plasma samples from all patients after ITI conclusion. Most patients (66.7%) were treated with a low-dose regimen (50 international units [IU] of FVIII concentrate per kilogram 3 times weekly). ITI outcome was defined as total/partial success and failure, based on inhibitor levels and FVIII pharmacokinetics. Comparison of IgG4 anti-FVIII levels was performed using Mann Whitney test. ROC curve analysis was performed to calculate sensitivity and specificity of the ELISA. The study was approved by Ethical Committees and all participants/guardians signed a consent form.

Results: A total of 50 PwHA who completed ITI were included. Levels of IgG4 anti-FVIII were significantly higher in patients who failed ITI (median OD, 2.18; IQR 1.69-2.44) compared with those who had partial (median OD, 0.15; IQR 0.05-0.52) and complete success (median OD, 0.05; IQR 0.00-0.14) (p < 0.0001 for both). There was no difference of anti-FVIII IgG4 levels in patients with total and partial success (p = 0.07). Considering the OD cut-off of 0.62, the test had a sensitivity of 93.8% and a specificity of 82.4% for ITI failure.

Conclusion(s): PwHA who had total and partial success on ITI presented similar levels of IgG4 anti-FVIII in plasma. High levels of plasma IgG4 anti-FVIII is a hallmark of ITI failure.

To cite this abstract in AMA style:

Chaves D, Camelo R, Ayala B, Etto L, De Oliveira A, Franco V, Roberti M, De Cerqueira M, Ribeiro R, Callado F, Anegawa T, Cerqueira M, Rezende S. High plasma levels of IgG4 anti-FVIII is the hallmark of immune tolerance failure in patients with hereditary hemophilia A: results from the BrazIT Study [abstract]. https://abstracts.isth.org/abstract/high-plasma-levels-of-igg4-anti-fviii-is-the-hallmark-of-immune-tolerance-failure-in-patients-with-hereditary-hemophilia-a-results-from-the-brazit-study/. Accessed September 29, 2023.

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