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; for the PedNet Study group

doi:10.1160/TH15-08-0692

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 115(04): 729-737
DOI: 10.1160/TH15-08-0692

Coagulation and Fibrinolysis

Schattauer GmbH

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

H. Marijke van den Berg^*

¹Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

,

S. Mojtaba Hashemi^*

¹Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

,

Kathelijn Fischer

¹Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

²Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands

,

Pia Petrini

³Department of Pediatrics, Clinic of Coagulation Disorders, Karolinska Hospital, Stockholm, Sweden

,

Rolf Ljung

⁴Department of Clinical Sciences, Lund University, Lund; Department of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skånes University Hospital, Malmö, Sweden

,

Anne Rafowicz

⁵Centre de Référence pour le Traitement des Maladies Hémorragiques (CRTH), Hôpital Bicêtre, Paris, France

,

Manuel Carcao

⁶Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada

,

Günter Auerswald

⁷Gesundheit Nord, Klinikum Bremen Mitte, Prof.-Hess-Kinderklinik, Bremen, Germany

,

Karin Kurnik

⁸Dr. v. Haunersches Kinderspital, University of Munich, Munich, Germany

,

Gili Kenet

⁹National Haemophilia Center, Ministry of Health, Sheba Medical Center, Tel Hashomer, Israel

,

Elena Santagostino

¹⁰Haemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

,

for the PedNet Study group

› Institutsangaben

Abstract

Summary

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.

Keywords

Risk factors - haemophilia A / B - factor VIII inhibitors - epidemiological studies

Volltext

Referenzen

References
1 Mannucci PM, Tuddenham EG. The haemophilias; From royal genes to gene therapy. N Eng J Med 2001; 344: 1773-1779.
2 Fischer K, Steen Carlsson K, Petrini P. et al. Intermediate-dose versus high-dose prophylaxis for severe haemophilia: comparing outcome and costs since the 1970s. Blood 2013; 15: 1129-1136.
3 Gouw SC, van den Berg HM, Fischer K. et al.; PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. . Intensity of factor VIII treatment and inhibitor development in children with severe haemophilia A: the RODIN study. Blood 2013; 121: 4046-4055.
4 Gouw SC, van der Bom JG, Ljung R. et al.; PedNet and RODIN Study Group. Factor FVIII products and inhibitor development in severe haemophilia A. N Eng J Med 2013; 368: 231-239.
5 Gouw SC, van der Bom JG, van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with haemophilia A: the CANAL cohort study. Blood 2007; 109: 4648-4654.
6 Kruse-Jarres R. Inhibitors: our greatest challenge. Can we minimize the incidence? Haemophilia 2013; 1: 2-7.
7 Di Minno MN, Di Minno G, Di Capua M. et al. Cost of care of haemophilia with inhibitors. Haemophilia 2010; 16: 190-201.
8 Teitel JM, Sholzberg M. Current status and future prospects for the prophylactic management of haemophilia patients with inhibitor antibodies. Blood Rev 2013; 27: 103-109.
9 Goudemand J, Rothschild C, Demiguel V. et al.; FVIII-LFB and Recombinant FVIII study groups. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A. Blood 2006; 107: 46-51.
10 Franchini M, Coppola A, Rocino A. et al.; Italian Association of Haemophilia Centres (AICE) Working Group. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe haemophilia a: a 2013 update. Semin Thromb Hemost 2013; 39: 752-766.
11 Ehrenforth S, Kreuz W, Scharrer I. et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
12 Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A pa-tients—a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999; 05: 145-154.
13 Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Hemost 2002; 28: 273-476.
14 Franchini M, Lippi G. Recombinant factor VIII concentrates. Semin Thromb Hemost 2010; 36: 493-497.
15 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 09: 418-435.
16 Iorio A, Halimeh S, Holzhauer S. et al. Rate of inhibitor development in previously untreated haemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 08: 1256-1265.
17 Favaloro EJ, Meijer P, Jennings I. et al. Problems and solutions in laboratory testing for haemophilia. Semin Thromb Hemost 2014; 40: 135.
18 Mannucci PM. Effects of factor VIII concentrates on the immune system of patients with haemophilia. Thromb. Haemost 1995; 74: 437-439.
19 Fischer K, Ljung R, Platokouki H. et al. Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry. Haemophilia 2014; 20: e280-286.
20 Gouw SC, van den Berg HM, Oldenburg J. et al. F8 gene mutation type and inhibitor development in patients with severe haemophilia A: systematic review and meta-analysis. Blood 2012; 119: 2922-2934.
21 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006; 12: 15-22.
22 Peto J. Asysmptotically efficient rank invariant test procedures. J Royal Stat Soc A 1972; 135: 185-207.
23 Van der Heijden GJ, Donders AR, Stijnen T. et al. Imputation of missing values is superior to complete case analysis and the missing indicator method in multivariable diagnostic research: a clinical example. J Clin Epidemiol 2006; 59: 1102-1109.
24 Nijdam A, Altisent C, Carcao MD. et al. Bleeding before prophylaxis in severe haemophilia: paradigm shift over two decades. Haematologica 2015; 100: e84-86.
25 Iorio A, Halimeh S, Holzhauer S. et al. Rate of inhibitor development in previously untreated haemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 08: 1256-1265.
26 Franchini M, Coppola A, Rocino A. et al.; Italian Association of Haemophilia Centres (AICE) Working Group. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe haemophilia a: a 2013 update. Semin Thromb Hemost 2013; 39: 752-766.
27 Verbruggen B, van Heerde WL, Larosvan Gorkom BA. Improvements in factor VIII inhibitor detection: From Bethesda to Nijmegen. Semin Thromb Hemost 2009; 35: 752-759.
28 Key NS, Negrier C. Coagulation factor concentrates: past, present and future. Lancet 2007; 370: 439-448.
29 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
30 Giles AR, Verbruggen B, Rivard GE. et al. A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor VIII:C inhibitors in the haemophilia A population of Canada. Association of Haemophilia Centre Directors of Canada. Factor VIII/IX Subcommittee of Scientific and Standardisation Committee of International Society on Thrombosis and Haemostasis. Thromb Haemost 1998; 79: 872-887.