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Factor IX antibodies and tolerance in hemophilia B in the Nordic countries - The impact of F9 variants and complications

Kihlberg, Kristina LU ; Baghaei, Fariba ; Bruzelius, Maria ; Funding, Eva LU ; Holme, Pål Andre ; Lassila, Riitta ; Martin, Myriam LU ; Nummi, Vuokko LU ; Ranta, Susanna and Strandberg, Karin LU , et al. (2022) In Thrombosis Research 217. p.22-32
Abstract

INTRODUCTION: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited. The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant.

MATERIALS AND METHODS: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence-immunoassay (xFLI) and an ELISA method were conducted.

RESULTS:... (More)

INTRODUCTION: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited. The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant.

MATERIALS AND METHODS: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence-immunoassay (xFLI) and an ELISA method were conducted.

RESULTS: Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful attempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified.

CONCLUSION: A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tentatively enhances the chances of ITI success. No NNA were observed.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antibodies, Neutralizing, Factor IX/genetics, Factor VIII, Hemophilia A, Hemophilia B/genetics, Humans, Immune Tolerance/genetics, Immunosuppression Therapy
in
Thrombosis Research
volume
217
pages
22 - 32
publisher
Elsevier
external identifiers
  • scopus:85134297881
  • pmid:35842956
ISSN
1879-2472
DOI
10.1016/j.thromres.2022.06.015
language
English
LU publication?
yes
additional info
Copyright © 2022. Published by Elsevier Ltd.
id
578bdee6-5ad9-4923-9405-a8af5a28628a
date added to LUP
2022-09-23 09:31:46
date last changed
2024-10-02 21:33:31
@article{578bdee6-5ad9-4923-9405-a8af5a28628a,
  abstract     = {{<p>INTRODUCTION: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited. The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant.</p><p>MATERIALS AND METHODS: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence-immunoassay (xFLI) and an ELISA method were conducted.</p><p>RESULTS: Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful attempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified.</p><p>CONCLUSION: A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tentatively enhances the chances of ITI success. No NNA were observed.</p>}},
  author       = {{Kihlberg, Kristina and Baghaei, Fariba and Bruzelius, Maria and Funding, Eva and Holme, Pål Andre and Lassila, Riitta and Martin, Myriam and Nummi, Vuokko and Ranta, Susanna and Strandberg, Karin and Andersson, Nadine Gretenkort and Berntorp, Erik and Astermark, Jan}},
  issn         = {{1879-2472}},
  keywords     = {{Antibodies, Neutralizing; Factor IX/genetics; Factor VIII; Hemophilia A; Hemophilia B/genetics; Humans; Immune Tolerance/genetics; Immunosuppression Therapy}},
  language     = {{eng}},
  pages        = {{22--32}},
  publisher    = {{Elsevier}},
  series       = {{Thrombosis Research}},
  title        = {{Factor IX antibodies and tolerance in hemophilia B in the Nordic countries - The impact of F9 variants and complications}},
  url          = {{http://dx.doi.org/10.1016/j.thromres.2022.06.015}},
  doi          = {{10.1016/j.thromres.2022.06.015}},
  volume       = {{217}},
  year         = {{2022}},
}