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2013 121: 4046-4055


doi:10.1182/blood-2012-09-457036 originally published
online April 3, 2013

Intensity of factor VIII treatment and inhibitor development in children


with severe hemophilia A: the RODIN study
Samantha C. Gouw, H. Marijke van den Berg, Kathelijn Fischer, Gnter Auerswald, Manuel Carcao,
Elizabeth Chalmers, Herv Chambost, Karin Kurnik, Ri Liesner, Pia Petrini, Helen Platokouki,
Carmen Altisent, Johannes Oldenburg, Beatrice Nolan, Rosario Prez Garrido, M. Elisa Mancuso,
Anne Rafowicz, Mike Williams, Niels Clausen, Rutger A. Middelburg, Rolf Ljung and Johanna G. van
der Bom

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Regular Article

CLINICAL TRIALS AND OBSERVATIONS

Intensity of factor VIII treatment and inhibitor development in children


with severe hemophilia A: the RODIN study
Samantha C. Gouw,1 H. Marijke van den Berg,2 Kathelijn Fischer,2,3 Gunter Auerswald,4 Manuel Carcao,5
Elizabeth Chalmers,6 Herve Chambost,7 Karin Kurnik,8 Ri Liesner,9 Pia Petrini,10 Helen Platokouki,11 Carmen Altisent,12
Johannes Oldenburg,13 Beatrice Nolan,14 Rosario Perez Garrido,15 M. Elisa Mancuso,16 Anne Rafowicz,17 Mike Williams,18
Niels Clausen,19 Rutger A. Middelburg,20 Rolf Ljung,21 and Johanna G. van der Bom20,22 for the PedNet and Research of
Determinants of INhibitor development (RODIN) Study Group
1
Department of Paediatrics, Wilhelmina Childrens Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; 2Julius Center for Health Sciences
and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; 3Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The
Netherlands; 4Gesundheit Nord, Klinikum Bremen Mitte, Prof.-Hess-Kinderklinik, Bremen, Germany; 5Division of Haematology/Oncology, Hospital for Sick
Children, Toronto, Canada; 6Department of Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK; 7Service dhematologie pediatrique, Hopital
La Timone & Aix-Marseille Univ, Marseille, France; 8Dr. v. Haunersches Kinderspital, University of Munich, Munich, Germany; 9Hemophilia Center, Department
of Haematology, Great Ormond Street Hospital for children, London, UK; 10Department of Pediatrics, Clinic of Coagulation Disorders, Karolinska Hospital,
Stockholm, Sweden; 11St. Sophia Childrens Hospital, Haemophilia-Haemostasis Unit, Athens, Greece; 12Unitat Hemofilia, Hospital Traumatologica, Hospital
Vall dHebron, Barcelona, Spain; 13Institut fur Experimentelle Hamatologie und Transfusionsmedizin, Universitatsklinikum Bonn, Bonn, Germany; 14Department
of Paediatric Haematology, St. Jamess Hospital, Dublin, Ireland; 15Hospital General Unidad de Hemofilia, Hospitales Universitarios Virgen del Rocio,
Sevilla, Spain; 16Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca Granda, Ospedale
Maggiore Policlinico, Milan, Italy; 17Centre Regional de Traitement de lHemophilie et Autres Maladies Bicetre, Service Hematologique, Paris, France; 18Department
of Haematology, The Childrens Hospital, Birmingham, UK; 19Department of Pediatrics, University Hospital of Aarhus at Skejby, Aarhus, Denmark; 20Center for
Clinical Transfusion Research, Sanquin Foundation, Leiden, The Netherlands; 21Department of Pediatrics and Malmo Centre for Thrombosis and Haemostasis,
Skanes Universitetssjukhus, Malmo, Sweden; and 22Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

The objective of this study was to examine the association of the intensity of treatment,
Key Points
ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment,
High-dose intensive factor VIII with the inhibitor incidence among previously untreated patients with severe hemophilia
treatment increases the risk A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL,
for inhibitor development in born between 2000 and 2010, and observed during their first 75 FVIII exposure days.
patients with severe Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was
associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95%
hemophilia A.
confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher
In patients with severe
inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was
hemophilia A, factor VIII only associated with a decreased overall inhibitor incidence after 20 exposure days of
prophylaxis decreases inhibitor FVIII. The association with prophylaxis was more pronounced in patients with low-risk
risk, especially in patients with F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0
low-risk F8 mutations. and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in
previously untreated patients with severe hemophilia A, high-dosed intensive FVIII
treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8
mutations. (Blood. 2013;121(20):4046-4055)

Introduction
Patients with severe hemophilia A (factor VIII [FVIII] activity , 0.01 Most patients with hemophilia do not mount a clinically measur-
IU/mL) have a bleeding diathesis characterized by spontaneous able immune response toward FVIII. In ;30% of patients, however,
joint and muscle bleeding. The current standard of care of children such FVIII antibodies develop, rendering FVIII treatment ineffective
with severe hemophilia A is primary prophylaxis: regular FVIII and impairing the functional status of patients.3,4
infusions aimed at prevention of joint damage that are started from The capacity to develop inhibitors varies from one individual to
the rst joint bleeding onward or earlier.1,2 another and depends on the interaction of multiple genetic and

Submitted September 19, 2012; accepted March 12, 2013. Prepublished The online version of this article contains a data supplement.
online as Blood First Edition paper, April 3, 2013; DOI 10.1182/blood-2012-09-
The publication costs of this article were defrayed in part by page charge
457036.
payment. Therefore, and solely to indicate this fact, this article is hereby
Presented in abstract form at the XXIII International Society of Thrombosis marked advertisement in accordance with 18 USC section 1734.
and Haemostasis Congress, Kyoto, Japan, July 23-28, 2011; and the World
Federation of Haemophilia World Congress 2012, Paris, France, July 8-12,
2012. 2013 by The American Society of Hematology

4046 BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20


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BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20 FVIII TREATMENT AND INHIBITORS IN HEMOPHILIA A 4047

nongenetic risk factors. The causative F8 genotype is an important point, which was either the development of a clinically relevant
genetic risk factor.5,6 Other reported genetic risk factors are a family inhibitor or a cumulative number of 75 exposure days.
history of inhibitor development,7 ethnicity,7 HLA genotype8,9 and The determination of clinically relevant inhibitor development
polymorphisms in immune regulatory genes.10-14 was based on all performed inhibitor tests and recovery measure-
Nongenetic risk factors for the occurrence of inhibitory anti- ments (in case of borderline positive inhibitor test results) in patients
bodies are largely related to FVIII treatment. It has been suggested that who ever had a positive inhibitor measurement.
this may be partly explained by the immunologic danger theory.15 In the majority of centers (92%), patients were routinely screened
According to the immunologic danger theory, inhibitor develop- for inhibitor development after every 1 to 5 exposure days during the
ment may be inuenced by the extent of tissue damage at the time of rst 20 exposure days and at least every 3 months thereafter. All
FVIII infusions. This model proposes that antigen-presenting cells centers closely monitored patients for clinical signs of inhibitor de-
need to be activated by alarm signals to elicit an effective antibody velopment and performed inhibitor and recovery testing at any
response.15 Because the FVIII protein itself does not contain alarm clinical suspicion of inhibitor development.
signals,16 immune tolerance should occur on exposure to infused All data collected were repeatedly checked for completeness and
FVIII, unless FVIII is accompanied by alarm signals that trigger the inconsistencies using prespecied protocols. Data-monitor visits were
maturation of dendritic cells.17 During FVIII treatment of major performed at least annually at each center, including ascertainment of
bleeding or surgery, a patient is exposed to high doses of FVIII in 100% of included and excluded patients, hemophilia diagnosis, and
combination with tissue damage and inammation. According to F8 genotype, as well as ascertainment of a minimal 10% of source
the danger theory, substances released from damaged tissue could data on FVIII treatments.
activate antigen-presenting cells, which might subsequently present Relatively few data were missing (supplemental Methods). For
FVIII antigen with up-regulated costimulatory signals to T lympho- the current analyses, data collected until May 1, 2011, were used.
cytes. These cells then enhance antibody formation.15 Indeed, repeated
high-dose FVIII treatment given for major bleeding and surgery has Outcomes
been associated with an increased risk for inhibitor development.18-21
The primary outcome of the study was clinically relevant inhibitor
Low-dose prophylactic FVIII infusions, however, are given in the
development, dened as at least 2 positive inhibitor titers combined
absence of tissue damage. Antigen-presenting cells present the FVIII
with a decreased in vivo FVIII recovery up to the 75th exposure
antigen to T lymphocytes in the absence of costimulatory signals. This
day.18 A positive inhibitor titer was dened according to the cutoff
may cause the induction of immune tolerance by the generation of
level of the inhibitor assay used in each centers laboratory. The FVIII
regulatory T cells from nave T cells or cause anergy of previously
recovery was considered to be decreased when it was less than 66%
primed T cells.17 Observations that prophylaxis is associated with
of the expected FVIII activity level 15 minutes after infusion of
a reduced risk for inhibitor development support this hypothesis.18,22,23
FVIII. The expected level of FVIII activity was calculated according
However, it is currently unclear whether the timing of the introduction
to Lee et al.24
of prophylaxis and the dose and the frequency of prophylactic FVIII
The secondary outcome was high titer inhibitor development,
infusions affect the risk for inhibitor development.
dened as the occurrence of a clinically relevant inhibitor with a
We set up a large, international cohort study to examine the
peak titer of at least 5 Bethesda Units per mL (BU/mL).25
association of the intensity of treatment with inhibitor incidence
among previously untreated patients with severe hemophilia A. We Determinants
studied high-dose intensive FVIII treatment of bleeds or surgery
and prophylactic FVIII treatment, including the dose, frequency, Intensive FVIII treatment. Intensive FVIII treatment was evalu-
and time of onset of prophylaxis. ated by peak treatment moments, surgical procedures, duration
between exposure days, and dose of FVIII product.
Peak treatment moments and surgical procedures. Peak
treatment moments were dened as episodes of treatment with
Patients and methods FVIII for bleeding or surgery on at least 3, 5, or 10 consecutive
days. We studied surgical procedures for which replacement therapy
Patients lasting at least 3 consecutive days was given.18 The corresponding
time-dependent variables were dened as the after peak treatment
We aimed to include consecutive previously untreated patients
moment or after surgical procedure.
with severe hemophilia A (FVIII activity ,0.01 IU/mL) born
Duration between exposure days. Duration between exposure
between January 1, 2000, and January 1, 2010, diagnosed in one
days was the measure for frequency of exposures; it was dened as
of the 29 participating hemophilia treatment centers. Patients
the period between each exposure day and 5 exposure days before
who were referred because of the presence of an inhibitor were
this exposure day.
excluded. Approval was obtained from every centers institutional
Dose of FVIII product. To study the association between
review board. Written informed consent was obtained from the
inhibitor occurrence and the dose of FVIII product, we calculated
parents or guardians of all participants in accordance with the
at each time point the mean FVIII dose per kilogram bodyweight of
Declaration of Helsinki.
the previous 5 exposure days.
Data collection Because prophylaxis inuences these factors to a large extent, the
analyses of duration between exposure days and the dose of FVIII
Detailed data on potential treatment-related determinants were uni- product were performed in patients who were treated on demand only.
formly collected in all centers: all administrations of FVIII up to 75 Prophylaxis. Ascertaining the moment when prophylaxis was
exposure days or inhibitor development, including dates of infusion, truly started is not always clear-cut, because of venous access
doses and brands of FVIII products, reasons for treatment, types of problems or lack of cooperation of the child. Therefore, we dened
bleeding, and surgery. Patients were monitored until the study end prophylaxis in 2 ways, analogous with the analysis of randomized
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4048 GOUW et al BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20

controlled trials: the per-protocol analysis and intention-to-treat 1 and 22 inversions; low-risk F8 gene mutations were small deletions
analysis. and insertions, missense mutations, and splice site mutations.
Regular prophylaxis. First, the per-protocol analysis was
used to study the effect of regular prophylaxis on inhibitor devel- Sensitivity analyses of prophylaxis
opment. Prophylactic FVIII infusions were all infusions of FVIII
given to prevent bleeding. The start of regular prophylaxis was Several sensitivity analyses on the effect of prophylaxis were
dened as the moment on which at least 3 consecutive prophylactic performed. The methods and results are described in supplemental
FVIII infusions had been given within a period of at least 15 days. Its material.
effect was compared with on-demand treatment, which was dened
Data analyses
as FVIII treatment without any prophylactic FVIII exposures. From
the moment that at least 1 prophylactic infusion was given, until the We used survival analysis methods with the cumulative number
criteria of regular prophylaxis were met, patients were categorized of exposure days as the time variable instead of calendar time
into a residual group, which was not included in the comparison. (pooled logistic regression). This method accounts for varying risks
This analysis was designed to assess the maximal effect of according to the cumulative number of exposure days, and its
prophylactic FVIII infusions. interpretation is similar to that of a Cox regression, with exposure
Intention to start prophylaxis. Second, in the intention-to-treat days as time-variable and time-dependent covariates.26 Patients who
analysis, we assessed the effect of the intention to start prophylaxis on had not yet reached the study end point were included in the
inhibitor development, regardless of any delays or failures to start analyses and were censored at the last exposure day. In the analyses
regular prophylaxis. This analysis was designed to estimate the effect with high titer inhibitor development as the outcome, censoring
of a prophylactic treatment regimen in clinical practice, including any occurred at the last exposure day in noninhibitor patients and at the
surgery for venous access needed to accomplish prophylaxis. With this last exposure day at inhibitor development in patients with low titer
analysis, we aimed to avoid potential overestimation of the effect inhibitors. HRs are interpreted as relative risks throughout the study.
of prophylaxis. Because the intention to start prophylaxis was not Crude as well as adjusted hazard ratios (aHRs) are presented. The
registered as such, we dened it as the moment when either at least aHRs for time-xed determinants (treatment-related factors at the rst
1 prophylactic infusion was given or at the time of any surgical exposure) and associations assessed in patients treated on demand
procedures to facilitate venous access (implantation of a central only (FVIII dose and duration between exposure days) were calculated
venous access device or creation of an arteriovenous stula). using multivariable pooled logistic regression models. We used
We assumed that after prophylaxis was started, its effect marginal structural models with an inverse probability of treatment
continued during the period up to the 75th exposure. weighting to adjust the associations between time-varying determi-
Dose and frequency of prophylaxis. To investigate the effect of nants and inhibitor development for confounders.27 We adjusted for
the dose and frequency of FVIII infusions in prophylaxis, regular possible determinants that could have confounded the specic
prophylaxis was categorized into 4 arbitrarily dened categories of associations studied, independent of their statistical signicance in
prophylaxis: (1) once a week, less than 30 IU/kg/infusion; (2) once a univariate analyses.
week, more than 30 IU/kg/infusion; (3) more than once a week, less S.G. and J.G.v.d.B. analyzed the data. All authors have access
than 30 IU/kg/infusion; and (4) more than once a week, more than to the primary data.
30 IU/kg/infusion. On-demand treatment was the reference.
Start of prophylaxis. To assess the effect of starting prophylaxis Role of the funding source
early, we dened start of prophylaxis <15ED as the start of regular
prophylaxis before a cumulative number of 15 or fewer exposure The RODIN Study was supported by unrestricted research grants from
days of on-demand treatment. Fifteen exposure days was chosen Bayer Healthcare and Baxter Bioscience. The companies did not have
because this was the median number of exposure days at which a role in the study design, data collection, data analysis, or the writing
patients started prophylaxis. Prophylaxis exposure days before a of this manuscript. As agreed in the contracts, the companies received
cumulative number of 15 or fewer exposure days were compared a copy of this manuscript 2 weeks before submission.
with on-demand treatment days. In these analyses, all prophylaxis
exposure days of patients who started prophylaxis after their rst 15
exposure days were censored.
Varying prophylaxis effect. The cumulative inhibitor incidence Results
curves for patients receiving prophylaxis and patients treated on
demand showed that the difference between these patients only Patient characteristics
occurred later during treatment. For this reason, we also estimated Figure 1 presents an overview of the study population. In this
the values of the HR allowing it to vary during 75 exposure days. study, 576 patients were included on whom detailed exposure data
The period of 1 to 75 exposure days was categorized into arbitrarily were available. The baseline and treatment characteristics are
dened periods (1-10, 11-20, 21-30, 31-40, and 40-75 days). presented in supplemental Table 1 and Table 1.

Effect of prophylaxis in patients with high-risk and Inhibitor development


low-risk genotypes
The overall cumulative incidence of inhibitors was 32.0% (95% CI,
Prophylaxis may have a different effect in patients, dependent on 28.1-35.9). The cumulative incidence of high titer inhibitor devel-
their F8 genotype. To investigate this, we assessed the relationship opment was 22.2% (95% CI, 18.7-25.8) (Figure 2).
between prophylaxis and inhibitor development according to the Of the 179 patients with inhibitors, 118 (65.9%) had high titer
presence of a high-risk or low-risk F8 genotype. High-risk F8 gene inhibitors and 61 (34.1%) had low titer inhibitors. Table 2 summarizes
mutations were large gene deletions, nonsense mutations, and intron the characteristics of the patients with inhibitors. Inhibitor development
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BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20 FVIII TREATMENT AND INHIBITORS IN HEMOPHILIA A 4049

Figure 1. Overview of included patients. A total of


648 patients were eligible for this study. Of these, 17
patients were eligible but were not yet included in the
study, and 25 patients were excluded by the centers
investigators for various reasons. Baseline data were
available in 606 patients (93.5%). Of these 606 patients,
6 were not treated with FVIII products during the study
period, 15 had an unknown inhibitor status because of
unavailable data, 59 were treated on less than 75 expo-
sure days (median, 18 days; IQR, 7-36 days; range,
1-69 days), 179 had development of clinically relevant
inhibitors, and 347 patients were treated with FVIII on 75
exposure days without the development of inhibitors.

occurred in patients after a median of 14.5 exposure days (interquartile reasons other than implantation of venous access devices compared
range [IQR], 9.75-20.0 days) at a median age of 15.5 months (age with treatment of other reasons than surgery was 2.1, but this result
range, 8 days-6.8 years). was not statistically signicant (95% CI, 0.77-5.8).
Peak treatment moments. At the rst treatment, 25.9% of
Intensive FVIII treatment
patients were treated with FVIII for a bleed or surgery on at least 3
consecutive days. Peak treatment moments of 3 to 5 days at the rst
The crude and adjusted relative risks for inhibitor development FVIII treatment were associated with a 40% higher risk for inhibitor
according to intensive FVIII treatment are presented in Table 3. development (aHR, 1.4; 95% CI, 0.87-2.3). Peak treatment mo-
Features of the rst FVIII exposure. Reason for rst FVIII ments of 5 to 10 days and peak treatment moments of more than 10
treatment. Most patients rst FVIII treatments were for hemor- days were associated with an almost twice higher risk for inhibitor
rhages (85%). At the rst FVIII treatment, the estimated aHR for development (aHR, 2.0; 95% CI, 1.3-3.0 and aHR, 1.7; 95% CI,
the development of inhibitors after major surgical procedures for 1.0-2.9, respectively).
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4050 GOUW et al BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20

Table 1. Treatment characteristics of included patients with detailed or before inhibitor development. In 194 patients, the indication was
data (N 5 576) a hemorrhage; in 83 patients, it was a surgical procedure. After the
No. (%) or occurrence of a peak treatment moment of at least 5 days, patients had
Characteristics median (IQR) Range
a 41% higher risk for inhibitor development (aHR, 1.4; 95% CI, 0.97-
Age at first exposure (mo.) 9.8 (5.3-13.4) 0-55.8 2.0). After peak treatment moments of at least 10 days, the risk was
Age at 75th exposure day (mo.)* 26.0 (19.5-34.5) 2.9-115.0
increased by 30% (aHR, 1.3; 95% CI, 0.77-2.2). These ndings did
Duration between 1st and 75th exposure 15.6 (10.2-23.8) 2.6-84.8
not reach statistical signicance.
day (mo.)*
Intensity of treatment
Surgery. After a major surgical procedure, the risk for inhibitor
Treatment characteristics at first treatment
development was equal to that before surgery (aHR, 1.0; 95% CI, 0.60-
Reason of first exposure to FVIII 1.8). The aHR for inhibitor development after surgical procedures for
Hemorrhage, including head trauma 488 (84.7) NA reasons other than for central venous access was 1.4 (95% CI, 0.74-2.6),
Prophylaxis 68 (11.8) NA whereas the aHR after surgery for central venous access was 0.84 (95%
Surgery 20 (3.5) NA CI, 0.51-1.4). However, this nding was not statistically signicant.
Peak treatment moment at first exposure Duration between exposure days. The duration as a measure
to FVIII for frequency of FVIII exposures was not independently associated
Peak treatment moment at least 3 days 149 (25.9) NA
with the risk for inhibitor development.
Peak treatment moment at least 5 days 98 (17) NA
Mean FVIII dose. Compared with a mean dose of FVIII of
Peak treatment moment at least 10 days 40 (6.9) NA
5 consecutive exposure days of ,35 IU/kg, the risk for inhibitor
Major surgery at first exposure to FVIII 13 (2.3) NA
Treatment characteristics at subsequent
development was 2.4 (95% CI, 1.2-5.2) times higher when the mean
exposure days dose was between 35 and 50 IU/kg, and it was 2.3 (95% CI, 1.0-4.8)
Peak treatment moment during first 75 times higher when the mean dose was more than 50 IU/kg.
exposure days Prophylaxis. Characteristics of patients who started regular
Peak treatment moment at least 3 days 386 (67.0) NA prophylaxis. A total of 412 patients (71.5%) started regular
Peak treatment moment at least 5 days 277 (48.1) NA prophylaxis within the rst 75 exposure days. Patients started
Peak treatment moment at least 10 days 93 (16.1) NA prophylaxis at a median age of 16.7 months (IQR, 12.4-24.4
Ever had a major surgery during first 75 144 (25) NA
months) and after a median number of 15 exposure days (IQR, 7-25
exposure days
days). Twenty-ve patients started prophylactic treatment from the
Prophylaxis
rst exposure onward. The crude and adjusted relative risks for
Regular prophylaxis
No. patients who started regular prophylaxis 412 (71.5) NA
inhibitor development according to the treatment regimen (on
Age start regular prophylaxis (mo.) 16.7 (12.4-24.4) 0.95-96.9 demand or prophylaxis) are presented in Table 4.
No. exposure days at start prophylaxis 15 (7-25) 2-74 Regular prophylaxis. Patients who started prophylaxis within
Dose of FVIII at start of prophylaxis (IU/kg) 44.6 (32.3-50.0) 18.9-235.3 the rst 75 exposure days had a 32% lower risk for inhibitor
Frequency of FVIII at start of prophylaxis, 1 (1-2) 1-7 development compared with patients treated on demand (crude HR,
no. infusions per week 0.68; 95% CI, 0.47-0.99). After adjustment for confounding factors,
Start of regular prophylaxis the HR was similar. Prophylaxis was associated with a 42% lower
No. patients who started prophylaxis 208 (50.5) NA
risk for the development of high-titer inhibitors (crude HR, 0.58;
,15 exposure days
95% CI, 0.36-0.92). The time-dependent Kaplan-Meier graph
No. patients who started prophylaxis 79 (19.2) NA
(Figure 3) demonstrates that the inhibitor incidences of patients
,5 exposure days
Regular prophylaxis at least twice a week
receiving prophylaxis and patients receiving on-demand treatment
No. patients who started regular prophylaxis 316 (54.9) NA did not differ during the rst 20 exposure days. After 20 exposure
at least twice a week days, however, there was a markedly lower inhibitor incidence among
Age start regular prophylaxis at least twice 18.7 (12.9-27.2) 1.0-96.9 those receiving prophylaxis.
a week (mo.) Intention to start prophylaxis. In total, in 470 patients (81.6%)
No. exposure days at start prophylaxis at 22 (14-40) 2-74 there was an intention to start prophylaxis. The median number of
least twice a week exposure days at the intention to start prophylaxis was 5 days
Intention to start prophylaxis
(IQR, 2-12 days). The crude relative risk for the intention to start
No. patients who had an intention to start 470 (81.6) NA
prophylaxis was 0.63 (95% CI, 0.46-0.88; supplemental Figure 1).
prophylaxis
For high-titer inhibitor development, the crude relative risk was 0.56
Age at intention to start prophylaxis (mo.) 14.6 (10.2-21.4) 0-96.5
No. exposure days at intention to start 5 (2-12) 0-74
(95% CI, 0.38-0.83). After adjustment for confounding factors, the
prophylaxis relative risks were similar.
Timing of start of prophylaxis. Of the 412 patients who started
NA, not applicable.
regular prophylaxis, 208 (50%) started prophylaxis before a maxi-
*In noninhibitor patients who reached the study end point and had available data
on exposure days (n 5 340). mum of 15 exposure days of on-demand treatment. These patients
The start of regular prophylaxis was defined as the moment on which at least 3 had a 31% lower risk for inhibitor development than the other
consecutive prophylactic FVIII exposure days are given for a period of at least 2 weeks. patients (crude HR, 0.69; 95% CI, 0.47-1.0).
The intention to start prophylaxis was defined as the moment on which at least 1
prophylactic infusion was given or at the time of any surgical procedures to facilitate
Dose and frequency of prophylaxis. No clear trend was observed
venous access (implantation of a central venous access device or creation of an in the effect of prophylaxis according to increasing dose or frequency
arteriovenous fistula). of prophylaxis (Table 4).
Prophylaxis in patients with high-risk and low-risk F8 genotypes.
Features of subsequent exposure days to FVIII. Peak treatment In patients with low-risk F8 gene mutation types, the aHR for
moment. A total of 277 (48.1%) patients had at least 1 major peak inhibitor development was 0.61 (95% CI, 0.19-2.0); in patients with
treatment moment of at least 5 days during the rst 75 exposure days high-risk F8 gene mutations, it was 0.85 (95% CI, 0.51-1.4)
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BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20 FVIII TREATMENT AND INHIBITORS IN HEMOPHILIA A 4051

Figure 2. Cumulative incidence of inhibitor de-


velopment according to cumulative number of
factor VIII exposure days for all inhibitors, high-
titer, and low-titer inhibitors.

(Table 4). For high titer inhibitor development, this difference was At the moment of data analysis, some patients were still at risk for
more evident (aHR, 0.17; 95% CI, 0.028-0.98 and aHR, 0.83; 95% inhibitor development. Survival analyses enabled us to calculate
CI, 0.45-1.6, respectively). unbiased cumulative incidences for the entire cohort. A major asset of
Sensitivity analyses. The results of the sensitivity analyses our study is that we thoroughly checked whether the ndings were
showed similar results, indicating that the results on prophylaxis robust in several sensitivity analyses. In this observational study,
are robust (supplemental Results). potentially high-risk patients may have been given prophylaxis to
benet from an assumed protective effect on inhibitor development.
Collection of detailed information on all 75 exposure days allowed us
to adjust the associations for potential confounding factors. Because
Discussion the Cox proportional hazard model with time-dependent variables can
give biased results, we used marginal structural models with an
In this multicenter cohort study among 606 consecutive previously inverse probability of treatment weighting to avoid this bias.27
untreated patients with severe hemophilia A born between 2000 After adjustment for all measured potential confounding
and 2010, the incidence of inhibitor development was 32%, and factors, the relative risks did not change substantially. Thus,
the incidence of high titer inhibitor development was 22%. either confounding factors may not be important, or the adjusted
High-dose intensive FVIII treatment of bleeding or surgery was relative risks may still be biased, because of residual confound-
associated with an increased risk for the development of inhibitors. ing by unmeasured confounding factors or by model misspeci-
Correspondingly, prophylactic FVIII treatment was associated with a cation of the inverse probability of treatment weights.28,29
decreased risk for inhibitor development. A new and rather surprising Although we made careful efforts to specify the correct model,
nding was that during the rst 20 exposure days, patients receiving we cannot exclude that, in the future, a better model might prove
prophylaxis had exactly the same inhibitor risks as the patients treated to perform better on these data.
on demand. In this study, the frequency and dose of prophylaxis were A low inhibitor incidence during prophylaxis is expected, as the
not associated with the risk for inhibitor development. immunologic danger theory proposes that immune tolerance should
A strength of our study was that we avoided selection bias by occur on exposure to infused FVIII, unless FVIII is accompanied
making every effort to include consecutive patients from a 10-year by alarm signals that trigger the maturation of dendritic cells.17
birth cohort and by carefully excluding patients who were referred These alarm signals may be endogenous substances released by
from other nonparticipating hemophilia centers because of inhibitor tissues, injured by hemorrhages and surgery, thereby explaining the
development. observed increased inhibitor risk during intensive treatment periods.

Table 2. Inhibitor characteristics


All High-titer* Low-titer*
Characteristics inhibitors Range inhibitors Range inhibitors Range
No. patients (%) 179 (100) NA 118 (66) NA 61 (34) NA
No. exposure days at inhibitor development 14.5 (9.75-20) 3-.75 15 (9.5-19) 3-.75 14 (9.5-24.0) 3-66
(IQR)
Peak inhibitor titer (BU/mL) (IQR) 18.0 (3.0-103.0) 0.5-6351.0 50.5 (18.4-308.5) 5.4-6351.0 2 (1.1-3.0) 0.5-4.4
Age at inhibitor development, mo. (IQR) 15.5 (10.8-19.6) 8d-6.8y 14.0 (9.4-18.0) 8d-6.8y 17.1 (13.5-23.9) 20d-3.2y
Duration between first exposure day and 4.3 (1.6-8.2) 7d-5.9y 3.5 (1.4-7.4) 7d-5.9y 5.7 (3.1-10.3) 8d-2.4y
inhibitor development, mo. (IQR)

Values are medians (IQR) or numbers (%). NA, not applicable.


*High-titer inhibitor was defined as a clinically relevant inhibitor with a peak titer of at least 5 BU/mL, and alow-titer inhibitor was defined as a clinically relevant inhibitor with
a peak titer of less than 5 BU/mL.
Unknown in 1 high-titer inhibitor patient.
The patient with inhibitor development after 75 exposure days was a newborn who underwent a surgical procedure after birth with subsequent daily prophylaxis 500 IU
until inhibitor detection at age 3 months.
Table 3. Intensive treatment and inhibitor development
4052

All inhibitors High-titer inhibitors


No. exposure Crude HR aHR Crude HR aHR
Characteristics days N inh/N % (95% CI) P value (95% CI) P value N inh/N % (95% CI) P value (95% CI) P value

Treatment characteristics of first


exposure
GOUW et al

Reason of first exposure to FVIII*


Hemorrhage 151/488 32.6 1 1 98/488 21.1 1 1
Prophylaxis 19/68 28.8 0.86 (0.53-1.4) .55 0.91 (0.53-1.6) .73 13/68 22.4 0.91 (0.51-1.6) .75 0.98 (0.51-1.9) .95
Minor and major surgery 7/20 37.1 1.1 (0.52-2.4) .76 1.2 (0.54-2.6) .69 5/20 27.1 1.2 (0.50-3.1) .65 1.2 (0.48-3.1) .68
Major surgery at first exposure*
No major surgery 169/561 31.7 1 1 111/561 22.0 1 1
Venous access surgery 2/4 50.0 1.7 (0.41-7.0) .46 1.8 (0.43-7.7) .42 1/4 33.3 1.3 (0.18-9.3) .81 1.1 (0.14-8.2) .94
Surgery for other indications 6/10 60.0 2.2 (0.95-5.0) .066 2.1 (0.77-5.8) .14 4/10 41.7 2.2 (0.79-6.0) .13 1.9 (0.55-6.6) .31
Peak treatment moment at first
exposure*
None 107/423 26.9 1 1 63/423 16.6 1 1
3-5 days 20/55 37.0 1.5 (0.93-2.4) .099 1.4 (0.87-2.3) .15 14/55 26.8 1.8 (1.0-3.2) .052 1.7 (0.95-3.1) .074
5-10 days 29/58 50.7 2.1 (1.4-3.2) .00037 2.0 (1.3-3.0) .0026 20/58 38.2 2.5 (1.5-4.1) .00047 2.4 (1.4-4.1) .0015
$10 days 21/40 52.5 2.1 (1.3-3.3) .0029 1.7 (1.0-2.9) .047 19/40 49.5 3.1 (1.9-5.3) .000015 2.7 (1.5-4.9) .0014
Treatment characteristics of
subsequent exposure days
Peak treatment moment $3 days* 18 242 1.5 (1.1-2.0) .015 1.5 (1.0-2.2) .039 1.7 (1.2-2.6) .0066 1.6 (1.0-2.6) .046
Peak treatment moment $5 days* 12 975 1.5 (1.1-2.0) .0078 1.4 (0.97-2.0) .071 1.6 (1.1-2.3) .012 1.3 (0.83-2.1) .25
Peak treatment moment $ 10 days* 4282 1.7 (1.2-2.5) .0051 1.3 (0.77-2.2) .32 2.1 (1.4-3.3) .00057 1.7 (0.96-3.1) .068
Surgery* 7361 0.93 (0.64-1.4) .73 1.0 (0.60-1.8) .87 0.76 (0.46-1.3) .29 0.84 (0.38-1.9) .68
Type of surgery*
No or before surgery 22 396 1 1 1 1
After surgery for venous access 5266 0.78 (0.48-1.3) .31 0.84 (0.51-1.4) .50 0.61 (0.32-1.2) .14 0.66 (0.34-1.3) .23
After surgery for other indications 1660 1.5 (0.83-2.6) .19 1.4 (0.74-2.6) .30 1.2 (0.54-2.5) .69 0.95 (0.41-2.2) .91
Unknown indication 435 0.47 (0.066-3.4) .46 0.40 (0.056-2.9) .37 0.72 (0.099-5.2) .74 0.63 (0.085-4.6) .65
Duration between exposure days, .18|| .93|| .030|| .42||
.50 1119 1 1 1 1
10-50 799 1.2 (0.68-2.0) 1.0 (0.64-1.6) 0.99 (0.50-2.0) 0.99 (0.49-2.0)
,10 1238 1.3 (0.87-2.1) 1.2 (0.68-2.0) 1.7 (1.0-2.9) 1.3 (0.71-2.2)
Dose of FVIII product (IU/kg) ,{ .0019|| .11|| .0087|| .49||
,35 640 1 1 1 1
35-50 1093 2.4 (1.2-4.9) 2.4 (1.2-5.2) 2.4 (1.0-5.7) 2.4 (0.95-5.8)
.50 1423 3.0 (1.5-6.0) 2.3 (1.0-4.8) 3.0 (1.3-6.9) 1.8 (0.72-4.7)
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Associations between inhibitor development and duration, dose, and type of surgery were adjusted with multivariable Cox proportional hazards regression. Associations between inhibitor development and surgery were adjusted with
marginal structural models with inverse probability weighting.
Inh/N, number of inhibitor patients per total number of patients.
*Adjusted for ethnicity, F8 genotype, family history, product type, and prophylaxis.
In 1 patient, the indication for surgery at first treatment was unknown.
Adjusted for ethnicity, F8 genotype, family history, dose, and product type.
In patients who were never treated with regular prophylaxis.
||P for trend.
{Adjusted for ethnicity, F8 genotype, family history, duration between ED, product type, and body weight.
BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20
Table 4. Prophylaxis and inhibitor development
Regular prophylaxis Intention to start prophylaxis
All inhibitors High-titer inhibitors All inhibitors High-titer inhibitors
Crude HR aHR Crude HR aHR Crude HR aHR Crude HR aHR
Determinant No. ED (95% CI) P value (95% CI) P value (95% CI) P value (95% CI) P value N ED (95% CI) P value (95% CI) P value (95% CI) P value (95% CI) P value
Regular prophylactic 18 846 0.68 (0.47-0.99) .043 0.70 (0.44-1.1)* .14 0.58 (0.36-0.92) .021 0.61 (0.35-1.1)* .093 23 426 0.63 (0.46-0.88) .0060 0.66 (0.46-0.94) .020 0.56 (0.38-0.83) .0039 0.57 (0.36-0.88) .012
infusions
Dose, frequency of prophylaxis
1/wk, <30 IU/kg 2422 0.84 (0.46-1.5) .58 0.76 (0.37-1.6)* .46 0.92 (0.46-1.8) .82 0.99 (0.44-2.2)* .98 NA NA NA NA NA NA NA NA NA
1/wk, >30 IU/kg 7704 0.58 (0.35-0.94) .027 0.54 (0.29-1.0)* .050 0.48 (0.26-0.89) .020 0.55 (0.26-1.2)* .12 NA NA NA NA NA NA NA NA NA
>1/wk, <30 IU/kg 2243 0.39 (0.14-1.1) .075 0.36 (0.11-1.2)* .086 0.42 (0.13-1.4) .16 0.47 (0.13-1.7)* .25 NA NA NA NA NA NA NA NA NA
BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20

>1/wk, >30 IU/kg 6477 0.86 (0.51-1.5) .58 1.11 (0.48-2.5)* .81 0.57 (0.28-1.2) .13 0.53 (0.23-1.3)* .15 NA NA NA NA NA NA NA NA NA
Start of prophylaxis 10 527 0.69 (0.47-1.0) .057 NA NA 0.64 (0.40-1.0) .059 NA NA 19 509 0.64 (0.46-0.88) .0068 NA NA 0.57 (0.39-0.85) .0056 NA NA
before 15 ED
Start of prophylaxis 3919 0.81 (0.50-1.3) .37 NA NA 0.69 (0.38-1.2) .20 NA NA 10 981 0.67 (0.47-0.96) .031 NA NA 0.60 (0.39-0.94) .024 NA NA
before 5 ED
Start of prophylaxis 3618 0.68 (0.38-1.2) .19 NA NA 0.65 (0.33-1.3) .23 NA NA 6929 0.71 (0.47-1.1) .11 NA NA 0.69 (0.42-1.1) .14 NA NA
before age
11 mo.
Effect of prophylaxis according to no. ED||
1-10 NA 1.0 (0.48-2.2) NA 0.80 (0.37-1.7) NA 1.2 (0.46-2.9) NA 0.97 (0.39-2.5) NA NA 0.65 (0.36-1.2) NA NA NA 0.75 (0.36-1.56) NA 0.79 (0.37-1.7) NA
11-20 NA 0.95 NA 0.93 NA 0.86 NA 0.86 NA NA 0.82 NA NA NA 0.74 NA 0.69 NA
21-30 NA 0.22 NA 0.17 NA 0.13 NA 0.15 NA NA 0.34 NA 0.34 NA 0.21 NA 0.20 NA
31-40 NA 0.27 NA 0.43 NA 0.084 NA 0.26 NA NA 0.21 NA 0.47 NA 0.066 NA 0.12 NA
41-75 NA 0.32 NA 1.3 NA 0.080 NA 0.15 NA NA 0.38 NA 0.97 NA 0.11 NA 0.40 NA
Effect of N ED N ED
prophylaxis
in different
F8 genotypes
Low-risk genotype 10 153 0.30 (0.11-0.83) .020 0.61 (0.19-2.0) .41 0.14 (0.028-0.72) .018 0.17 (0.028-0.98) .047 10 153 0.47 (0.21-1.1) .069 0.42 (0.16-1.1) .079 0.39 (0.13-1.2) .088 0.32 (0.062-1.6) .17
High-risk genotype 16 263 0.94 (0.61-1.4) .77 0.85 (0.51-1.4) .52 0.83 (0.49-1.4) .49 0.83 (0.45-1.6) .57 16 263 0.70 (0.48-1.0) .069 0.78 (0.51-1.2) .25 0.64 (0.40-1.0) .055 0.73 (0.44-1.2) .21

In total, 576 patients were treated on 29 757 EDs to FVIII.


ED, exposure day; N, number; NA, not applicable.
*Adjusted for ethnicity, F8 gene mutation type, family history of hemophilia and inhibitors, duration between first and current exposure day, duration between exposure days, dose, FVIII product type, peak treatment moments, and
surgery. The inverse probability of treatment weights for regular prophylaxis had a mean of 1.0230, median of 0.8503, IQR of 0.5935-1.1043, and a range of 0.11-100.91. The inverse probability of treatment weights for intention to start
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prophylaxis had a mean of 1.0087, median of 0.9798, IQR of 0.7364-1.1184, and a range of 0.08-11.66.
Patients who started prophylaxis later than 15 or 5 EDs were censored at start of prophylaxis.
Patients who started prophylaxis later than age 11 months were censored at start of prophylaxis.
The aHRs for early and late start of prophylaxis were not available as the currently available statistical methods do not allow correct adjustment for confounding and censoring in this specific situation.
||HRs of prophylaxis compared with on-demand treatment during the number of exposure days, categorized in 10-day periods.
Adjusted for ethnicity, family history of hemophilia and inhibitors, duration between first and current ED, duration between exposure days, dose, FVIII product type, and surgery.
FVIII TREATMENT AND INHIBITORS IN HEMOPHILIA A
4053
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4054 GOUW et al BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20

Figure 3. Regular prophylaxis and the cumulative


incidence of inhibitor development. The relative risk
for regular prophylaxis was 1.0 in the period from 1 to
10 exposure days, 0.95 from 11 to 20 exposure days,
0.22 from 21 to 30 exposure days, 0.27 from 31 to 40
exposure days, and 0.32 from 41 to 75 exposure days.

Although there is a plausible pathogenetic mechanism, the relation- development, the dose and frequency of prophylaxis may be adjusted to
ship between intensive treatment and inhibitor development may be avoid intensive FVIII treatment of bleeding and surgery for venous
partially attributable to reverse causation; intensive treatment may not access.
be the cause but actually may be the effect of as-yet undetected inhi- Our data suggest that starting prophylaxis in patients in whom
bitors. We cannot exclude that this (partially) explained the reported inhibitors are predestined to develop may not have any effect on
association. However, the clear relationship between peak treatment the occurrence of inhibitors. Identifying those patients who might
moments at the start of treatment and a higher inhibitor incidence in- benet from prophylaxis is a challenge that remains to be tackled
dicates that intensive treatment preceded development of the inhibitors. in additional studies.
Our ndings of an increased inhibitor risk after intensive FVIII In conclusion, our ndings suggest that in previously untreated
treatment and a decreased risk with prophylaxis corroborate the patients with severe hemophilia A, high-dose intensive factor VIII
results of earlier studies.18-23 However, our study is the rst to show treatment increases the risk for inhibitor development on the one
that during the rst 20 exposure days, prophylaxis and on-demand hand, and on the other hand, prophylactic factor VIII treatment
treatment confer the same inhibitor risk. Furthermore, the initial decreases the risk for inhibitor development, especially in patients
frequency and dose of prophylaxis were not associated with the risk with low-inhibitor-risk F8 mutations.
for inhibitor development. This nding may seem to contrast with the
conclusions of a previous study that reported a very low inhibitor risk in
patients treated with an early-onset, low-dose prophylaxis regimen.22,23
In the latter study, however, very low doses of FVIII product were used,
and further study is needed to conrm these ndings. Acknowledgments
It is currently not clear which patients may prot from the
potentially protective effect of prophylaxis on inhibitor development. The authors would like to acknowledge study coordinator Ella Smink.
Apparently, there are 3 types of patients with severe hemophilia A: The authors also thank Emma Smid and Mojtaba Hashemi for their
(1) patients in whom inhibitors will never develop; (2) patients in support in data cleaning. The authors are grateful to Yves Guillaume,
whom inhibitor development depends on the treatment regimen; and Kate Khair, Karin Lindvall, Monique Spoor, and Bep Verkerk for their
(3) patients in whom inhibitors will develop in all situations. The results assistance in this study. The authors thank Roswita Neumann and
of this study suggest that the potentially protective effect of prophylaxis Gertrud Schroeder from Bayer Healthcare and Bruce Ewenstein and
may be more pronounced in patients with low-risk F8 genotypes than Hartmut Ehrlich from Baxter Healthcare for supporting this study with
in patients with high-risk F8 genotypes, suggesting that the patients unrestricted research grants.
with high-risk F8 genotypes are more likely to be type 3 patients and,
thus, are not susceptible to the protective effect of prophylaxis.
The current data provide no base for advice regarding how early
prophylaxis should be started to minimize the risk for inhibitors. Authorship
We propose to primarily adjust the onset, frequency, and dose of
prophylaxis to achieve its main aim, which is the prevention of Contributions: S.C.G., J.G.v.d.B., and H.M.v.d.B. designed the re-
hemorrhages and joint damage. According to current guidelines, search, analyzed and interpreted the data, and wrote the manuscript;
prophylaxis should be started at least as early as the occurrence of S.C.G., J.G.v.d.B., and R.A.M. designed the sensitivity analyses; and
the rst joint hemorrhage.30-32 To minimize the risk for inhibitor K.F., G.A., M.C., E.C., H.C., K.K., R. Liesner, P.P., H.P., C.A., J.O.,
From www.bloodjournal.org by guest on November 3, 2014. For personal use only.

BLOOD, 16 MAY 2013 x VOLUME 121, NUMBER 20 FVIII TREATMENT AND INHIBITORS IN HEMOPHILIA A 4055

B.N., R.P.G., M.E.M., A.R., M.W., N.C., and R. Ljung collected by Bayer, Baxter, Pzer, CSL Behring, Novo Nordisk, Kedrion, and
data and critically reviewed the manuscript. Grifols, and acted as a consultant for Bayer, Baxter, Pzer, CSL Behring,
Conict-of-interest disclosures: The RODIN Study was supported Novo Nordisk, Kedrion, and Grifols. M.W. has received honoraria from
by unrestricted research grants from Baxter Bioscience (Deereld, IL) Bayer, Baxter, and Novo Nordisk, and acted as a consultant on an
and Bayer Healthcare. S.C.G. and H.M.v.d.B. have reported receiving advisory board for Novo Nordisk. R. Ljung has received research grant,
unrestricted research support from CSL Behring, Novo Nordisk, speaker fees, and consultation fees from Bayer, Baxter, Novo Nordisk,
Wyeth, Baxter, and Bayer. K.F. has received speaker fees from Baxter, and Octapharma during the last 5 years. J.G.v.d.B. has received
Pzer, Novo Nordisk, and Biotest; performed consultancy for Bayer, unrestricted research/educational funding for various projects from
Baxter, Biogen, and Novo Nordisk; and has received research support the following companies: Bayer Schering Pharma, Baxter, CSL
from Bayer, Wyeth/Pzer, Baxter, and Novo Nordisk. M.D.C. has Behring, Novo Nordisk, and Wyeth. In addition, she has been
received research support and honoraria (speaker fees/participation in a consultant to Baxter and Wyeth, and she has been a teacher on
advisory boards) from Baxter, Bayer, Biogen, CSL Behring, Novo educational activities of Bayer Schering Pharma. The remaining
Nordisk, Octapharma, and Pzer (none of these relate to the present authors declare no competing nancial interests.
study). K.K. has received research support, speaker fees, and A complete list of the members of the PedNet and RODIN
consultation fees from Baxter, Bayer, Biotest, CSL Behring, Pzer, Study Group appears in supplemental Material.
and Novo Nordisk. R. Liesner has received support for meetings Correspondence: Johanna G. van der Bom, Department of
from Baxter, Bayer, Novo Nordisk, and Octapharma and has Clinical Epidemiology, Leiden University Medical Center, Albi-
received consultancy fees from Pzer, Bayer, Baxter, and Novo nusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands;
Nordisk. M.E.M. has received fees as a speaker at meetings organized e-mail: j.g.vanderbom@lumc.nl.

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