Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors

H. Marijke van den Berg, S. Mojtaba Hashemi, Kathelijn Fischer, Pia Petrini, Rolf Ljung, Anne Rafowicz, Manuel Carcao, Günter Auerswald, Karin Kurnik, Gili Kenet, Elena Santagostino

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII<1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per fiveyear birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990–1994 (lowest) to 30.9 % in 2000–2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990–1994 to 10.5 % in 2005–2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06–2.83) in 2000–2004 and 2.34 (1.42–4.92) in 2005–2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

Original languageEnglish
Pages (from-to)729-737
Number of pages9
JournalThrombosis and Haemostasis
Volume115
Issue number4
DOIs
Publication statusPublished - Apr 1 2016

Fingerprint

Hemophilia A
Incidence
Parturition
Therapeutics

Keywords

  • Epidemiological studies
  • Factor VIII inhibitors
  • Haemophilia A / B
  • Risk factors

ASJC Scopus subject areas

  • Hematology

Cite this

Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors. / van den Berg, H. Marijke; Hashemi, S. Mojtaba; Fischer, Kathelijn; Petrini, Pia; Ljung, Rolf; Rafowicz, Anne; Carcao, Manuel; Auerswald, Günter; Kurnik, Karin; Kenet, Gili; Santagostino, Elena.

In: Thrombosis and Haemostasis, Vol. 115, No. 4, 01.04.2016, p. 729-737.

Research output: Contribution to journalArticle

van den Berg, HM, Hashemi, SM, Fischer, K, Petrini, P, Ljung, R, Rafowicz, A, Carcao, M, Auerswald, G, Kurnik, K, Kenet, G & Santagostino, E 2016, 'Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors', Thrombosis and Haemostasis, vol. 115, no. 4, pp. 729-737. https://doi.org/10.1160/TH15-08-0692
van den Berg, H. Marijke ; Hashemi, S. Mojtaba ; Fischer, Kathelijn ; Petrini, Pia ; Ljung, Rolf ; Rafowicz, Anne ; Carcao, Manuel ; Auerswald, Günter ; Kurnik, Karin ; Kenet, Gili ; Santagostino, Elena. / Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors. In: Thrombosis and Haemostasis. 2016 ; Vol. 115, No. 4. pp. 729-737.
@article{963eee6da87c4a5fb6aca990dc245070,
title = "Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors",
abstract = "Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII<1 {\%}). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per fiveyear birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 {\%}. The inhibitor incidence increased from 19.5 {\%} in 1990–1994 (lowest) to 30.9 {\%} in 2000–2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 {\%} in 1990–1994 to 10.5 {\%} in 2005–2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 {\%} CI 1.06–2.83) in 2000–2004 and 2.34 (1.42–4.92) in 2005–2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.",
keywords = "Epidemiological studies, Factor VIII inhibitors, Haemophilia A / B, Risk factors",
author = "{van den Berg}, {H. Marijke} and Hashemi, {S. Mojtaba} and Kathelijn Fischer and Pia Petrini and Rolf Ljung and Anne Rafowicz and Manuel Carcao and G{\"u}nter Auerswald and Karin Kurnik and Gili Kenet and Elena Santagostino",
year = "2016",
month = "4",
day = "1",
doi = "10.1160/TH15-08-0692",
language = "English",
volume = "115",
pages = "729--737",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Schattauer GmbH",
number = "4",

}

TY - JOUR

T1 - Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors

AU - van den Berg, H. Marijke

AU - Hashemi, S. Mojtaba

AU - Fischer, Kathelijn

AU - Petrini, Pia

AU - Ljung, Rolf

AU - Rafowicz, Anne

AU - Carcao, Manuel

AU - Auerswald, Günter

AU - Kurnik, Karin

AU - Kenet, Gili

AU - Santagostino, Elena

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII<1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per fiveyear birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990–1994 (lowest) to 30.9 % in 2000–2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990–1994 to 10.5 % in 2005–2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06–2.83) in 2000–2004 and 2.34 (1.42–4.92) in 2005–2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

AB - Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII<1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per fiveyear birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990–1994 (lowest) to 30.9 % in 2000–2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990–1994 to 10.5 % in 2005–2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06–2.83) in 2000–2004 and 2.34 (1.42–4.92) in 2005–2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

KW - Epidemiological studies

KW - Factor VIII inhibitors

KW - Haemophilia A / B

KW - Risk factors

UR - http://www.scopus.com/inward/record.url?scp=84964720994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964720994&partnerID=8YFLogxK

U2 - 10.1160/TH15-08-0692

DO - 10.1160/TH15-08-0692

M3 - Article

AN - SCOPUS:84964720994

VL - 115

SP - 729

EP - 737

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 4

ER -