Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol

Abstract

The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.

High levels of anti–factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors

“…This cross-sectional analysis is a subset of the BrazIT Study, which is a cohort of people with hemophilia A with high-responding inhibitors who completed a first course of ITI [ 14 ]. For this analysis, we included people with hemophilia A who were enrolled in 10 Brazilian hemophilia treatment centers.…”

“…Therefore, we hypothesized that biomarkers (mainly anti-FVIII IgG) could be associated with ITI response. To test this, we assessed plasma levels of cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII IgG total, IgG1, and IgG4 in a cohort of 98 people with hemophilia A and high-responding inhibitors after completion of ITI, participants of the Brazilian Immune Tolerance (BrazIT) Study [ 14 ].…”

Prevalence of sporadic haemophilia A

“…The difference encountered in the year ranges between the two studies were related to the specific aim of each study and, therefore, their inclusion criteria. In the BrazIT study, all patients (100%) had persistent inhibitors and were included in ITI 7 while in the HEMFIL study, PUPs with haemophilia A were followed until inhibitor development. 6 Overall, the prevalence of sporadic haemophilia A was 41.9% (95% CI, 35.9%-48.2%).…”

“…Its aim is to identify predictors of ITI outcome. 7 We then assessed the familial status of haemophilia A by evaluating family history through medical interview, medical records and validated questionnaires of patients included in both studies. To avoid double counting in families with more than one case of haemophilia A, we evaluated only the index case (older sibling) included in the F I G U R E 1 Family history of haemophilia A according to patients' year of birth.…”

Germline variants of the immune checkpoint proteins PD‐1, PD‐l1 and CTLA‐4 and immune tolerance induction outcome in patients with inherited haemophilia A

“…(PD-L1), and CTLA4 (CTLA-4) in a Brazilian cohort of unrelated PwHA with inhibitors who underwent ITI (the BrazIT Study). 7 We searched the three genes for coding (exonic) genetic variants by using whole exome sequencing data of 150 individuals with FVIII activity < 1%…”