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 five-year 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.
authors.affiliation: H. Marijke van den Berg, MD, PhD, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA Utrecht, The Netherlands, Tel.: +31 88 7568189, Fax: +31 88 7568099, E-mail: H.M.vandeBerg@umcutrecht.nl.
authors.forename: H Marijke
authors.initials: HM
authors.lastname: van den Berg
authors.forename: S Mojtaba
authors.initials: SM
authors.lastname: Hashemi
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Fischer
authors.forename: Pia
authors.initials: P
authors.lastname: Petrini
authors.forename: Rolf
authors.initials: R
authors.lastname: Ljung
authors.forename: Anne
authors.initials: A
authors.lastname: Rafowicz
authors.forename: Manuel
authors.initials: M
authors.lastname: Carcao
authors.forename: Günter
authors.initials: G
authors.lastname: Auerswald
authors.forename: Karin
authors.initials: K
authors.lastname: Kurnik
authors.forename: Gili
authors.initials: G
authors.lastname: Kenet
authors.forename: Elena
authors.initials: E
authors.lastname: Santagostino
mesh_terms: D019774:Blood Coagulation Factor Inhibitors / Q000627:therapeutic use*; D015331:Cohort Studies; D005169:Factor VIII / Q000037:antagonists & inhibitors*; D006467:Hemophilia A / Q000188:drug therapy / Q000453:epidemiology*; D006801:Humans; D015994:Incidence; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII
keywords: Risk factors; epidemiological studies; factor VIII inhibitors; haemophilia A / B