Correspondence
Requirements for Registration of
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ICH E10 step 5. Firstly, the placebo-
controlled period was only 6 weeks.
Secondly, we used Bayesian statistics
to allow inclusion of historical placebo
data to minimise the number of
placebo-treated patients (n=6).
We also thank Thrasivoulos Tzellos
and colleagues for requesting additional
information about the observed cases
of neutropenia and leucopenia. All
were asymptomatic laboratory cases,
without fever or infection reported
at any time during the study. Four
patients receiving secukinumab, but
none of those receiving placebo, had
mild neutropenia (grade 1), defined
as absolute neutrophil count (ANC)
between 1·5×103 cells per μL and
2·0×103 cells per μL. Two of these
patients also had concurrent mild
leucopenia. The lowest ANC was
1·7×103 cells per μL. Recent definitions
consider ANC ≥1·5×103 cells per μL
to be normal, with no increased risk
for infections.4 One patient had four
isolated episodes of mild leucopenia on
day 8, week 6, week 10, and week 16
without concurrent neutropenia. In two
patients, the decrease in ANC below the
lower limit of normal occurred within a
few days of an infusion of secukinumab
(day 23 and day 29, respectively).
We agree with Tzellos and colleagues
that decreases in ANC after inhibition
of interleukin-17 or interleukin-17
receptor could be consistent with
effects of interleukin-17 on neutrophil
biology. Importantly, changes in ANC
did not have a clinical consequence in
any of the patients affected. Moreover,
by contrast with the study of
brodalumab in psoriasis,5 mentioned
by Tzellos and colleagues, we did not
see a challenge–rechallenge effect in
patients with ankylosing spondylitis.
Our observations are consistent with
results with secukinumab in psoriasis.6
In our opinion, potential risks related
to neutropenia were adequately
reported for our trial, consistent with
applicable CONSORT guidelines.
Pivotal, ongoing secukinumab
www.thelancet.com Vol 383 March 1, 2014
studies in ankylosing spondylitis will
allow a comprehensive risk–benefit
assessment, including potential effects
on neutrophils.
WH is an employee of, and owns stock options in,
Novartis. DB has participated in advisory boards for
Abbott, BMS, Boehringer Ingelheim, Janssen-Cilag,
MSD, Novartis, Pfizer, Roche, and UCB, and has
received unrestricted study grants from Abbott,
Centocor, Janssen-Cilag, MSD, Novartis, and Pfizer.
Dominique Baeten, *Wolfgang Hueber
wolfgang.hueber@novartis.com
Department of Clinical Immunology and
Rheumatology, Academic Medical Center, University
of Amsterdam, Amsterdam, Netherlands (DB); and
Translational Medicine—Autoimmunity, Novartis
Institutes for BioMedical Research WSJ.386.10.48,
Basel CH-4002, Switzerland (WH)
1 Baeten D, Baraliakos X, Braun J, et al.
Anti-interleukin-17A monoclonal antibody
secukinumab in treatment of ankylosing
spondylitis: a randomised, double-blind,
placebo-controlled trial. Lancet 2013;
382: 1705–13.
2 Sieper J, Porter-Brown B, Thompson L,
Harari O, Dougados M. Assessment of short-
term symptomatic efficacy of tocilizumab in
ankylosing spondylitis: results of randomised,
placebo-controlled trials. Ann Rheum Dis 2014;
73: 95–100.
3 Pathan E, Abraham S, Van Rossen E, et al.
Efficacy and safety of apremilast, an oral
phosphodiesterase 4 inhibitor, in ankylosing
spondylitis. Ann Rheum Dis 2013; 72: 1475–80.
4 Newburger PE, Dale DC. Evaluation and
management of patients with isolated
neutropenia. Semin Hematol 2013; 50: 198–206.
5 Papp KA, Leonardi C, Menter A, et al.
Brodalumab, an anti-interleukin-17-receptor
antibody for psoriasis. N Engl J Med 2012;
366: 1181–89.
6 Papp KA, Langley RG, Sigurgeirsson B, et al.
Efficacy and safety of secukinumab in the
treatment of moderate-to-severe plaque
psoriasis: a randomized, double-blind,
placebo-controlled phase II dose-ranging
study. Br J Dermatol 2013; 168: 412–21.
Cardiomyopathy in
children: importance of
aetiology in prognosis
We read with great interest
Steven Lipshultz and colleagues’ Article
(Dec 7, p 1889),1 which retrospectively
analysed prognostic determinants
in children with hypertrophic
cardiomyopathy. The Pediatric
Cardiomyopathy Registry, funded by
the National Heart, Lung, and Blood
Institute of the US National Institutes
of Health from 1994, along with the
Australian Pediatric Cardiomyopathy
Registry, represents the largest
source of epidemiological and
clinical information for children with
cardiomyopathies so far.2,3 Over the past
decade, the North American Pediatric
Cardiomyopathy Registry Study Group
have produced valuable data for
the epidemiology, aetiology, clinical
presentation, natural history, and
outcome of the principal phenotypic
subtypes of cardiomyopathies.1,2,4 A
subanalysis by aetiology and age at
presentation revealed that infants with
inherited errors of metabolism and
malformation syndromes have a poorer
survival compared with the other
groups (idiopathic and neuromuscular
disorders).4
Lipshultz and colleagues1 reanalysed
the same cohort of patients seeking
further correlations between clinical
presentation and adverse outcome.
They compared clinical characteristics
and prognosis in patients with so-called
pure hypertrophic cardiomyopathy
with those in patients with mixed
hypertrophic cardiomyopathy
(with left ventricular dilatation
and systolic impairment or with
restrictive physiology), and concluded
that presentation in infancy, an
association with inherited errors of
metabolism, and a mixed phenotype
led to an increased risk of death or
transplantation.1
Although we understand the
rationale for using this descriptive
approach, we have some concerns
about their conclusions. It is certainly
true that the clinical presentation of
patients with all cardiomyopathies
is very heterogeneous and includes
various phenotypes that can be difficult
to classify, particularly during infancy
when left ventricular hypertrophy
often coexists with left ventricular
dilatation, severe diastolic dysfunction,
and structural abnormalities, such as
hypertrabeculation of the apex and the
inferolateral walls. Our major issue is
that the outcome of patients is largely
determined by the underlying aetiology
781
 Correspondence
rather than a specific phenotype. This
discrepancy is highlighted by the fact
that patients with mixed phenotypes
seem to have a worse prognosis than
do those with idiopathic hypertrophic
cardiomyopathy or malformation
Ria Novosti/Science Photo Library
syndromes, yet these phenotypes
can occur in patients with various
underlying disorders, including
inherited errors of metabolism
and neuromuscular disease, but
also malformation syndromes and
idiopathic disease.
Furthermore, the new category
in this study, mixed hypertrophic
cardiomyopathy, includes some
patients identified as having idiopathic
hypertrophic cardiomyopathy
or hypertrophic cardiomyopathy
associated with inherited errors of
metabolism, malformation syndromes,
or neuromuscular disorders in the
authors’ previous reports,4 in which
attempts at risk stratification on the
basis of phenotype were also made.
Finally, to develop a specific risk-
stratification algorithm applicable
to each phenotypic category is
problematic, because of the small
numbers in each group and, in
particular, the heterogeneous and non-
uniform nature of the hypertrophic
cardiomyopathy groups compared.5
Ultimately, heart failure at presentation
seems to be the main determinant of
the outcome, particularly in infancy,
irrespective of the phenotype.
Paediatric cardiomyopathies are
a very heterogeneous group of
disorders, and early diagnosis and
aggressive clinical management
are needed in children with specific
aetiologies and heart failure at
presentation. Although this study
is an important attempt to describe
real clinical scenarios, we believe that
the emphasis on the phenotype alone
could be misleading and future studies
should concentrate on determining
the specific aetiology, which is likely
to be a stronger determinant of
the natural history and outcome of
hypertrophic cardiomyopathy in the
paediatric population.
782
We declare that we have no competing interests.
*Juan Pablo Kaski, Giuseppe Limongelli
j.kaski@ucl.ac.uk
Inherited Cardiovascular Diseases Unit, Department
of Cardiology, Great Ormond Street Hospital,
London WC1N 3JH, UK (JPK); Institute of
Cardiovascular Science, University College London,
London, UK (JPK); and Monaldi Hospital, Second
University of Naples, Naples, Italy (GL)
1 Lipshultz SE, Orav EJ, Wilkinson JD, et al. Risk
stratification at diagnosis for children with
hypertrophic cardiomyopathy: an analysis of
data from the Pediatric Cardiomyopathy
Registry. Lancet 2013; 382: 1889–97.
2 Lipshultz SE, Sleeper LA, Towbin JA, et al. The
incidence of pediatric cardiomyopathy in two
regions of the United States. N Engl J Med
2003; 348: 1647–55.
3 Nugent AW, Daubeney PE, Chondros P, et al.
The epidemiology of childhood
cardiomyopathy in Australia. N Engl J Med
2003; 348: 1639–46.
4 Colan SD, Lipshultz SE, Lowe AM, et al.
Epidemiology and cause-specific outcome of
hypertrophic cardiomyopathy in children:
findings from the Pediatric Cardiomyopathy
Registry. Circulation 2007; 115: 773–81.
5 Weintraub RG, Semsarian C. Paediatric
cardiomyopathy: getting to the heart of the
matter. Lancet 2013; 382: 1866–67.
Authors’ reply
We thank Juan Pablo Kaski and
Giuseppe Limongelli for their
thoughtful comments about
our Article. 1 We appreciate their
recognition of the important findings
from the Pediatric Cardiomyopathy
Registry. Kaski and Limongelli agree
that cardiomyopathy in childhood is
phenotypically heterogeneous, but
they state that their major issue is
that the outcome of patients is mainly
determined by the underlying aetiology
rather than a specific phenotype. We
agree that the cause of cardiomyopathy
might be an important prognostic
factor, but the cause must be identified
quickly and accurately for it to affect
management and subsequent
prognosis. Unfortunately, this is not
always possible. Despite the availability
of a detailed comprehensive algorithm
to determine the cause of pediatric
cardiomyopathies,2 a 2006 Pediatric
Cardiomyopathy Registry study
showed that children with hypertrophic
cardiomyopathy underwent causal
testing only about half as often as
children with other cardiomyopathies.3
Also, genetic testing for paediatric
hypertrophic cardiomyopathy,
which might greatly reduce the
prevalence of idiopathic hypertrophic
cardiomyopathy as a diagnosis, is
still limited. In a rigorous analysis, we
noted that causation was established in
some of these children only years after
presentation, and even then, nearly
75% of cases remained classified as
idiopathic.4
In another disparity between
physician beliefs about the importance
of causal testing, we showed no
differences in outcomes between
children with myocarditis diagnosed
by cardiac biopsy (using the Dallas
criteria as the reference standard) and
those who were diagnosed clinically by
an experienced paediatric cardiologist.5
In another Pediatric Cardiomyopathy
Registry report,6 we reference nine
gene mutations in children with both
Noonan syndrome and hypertrophic
cardiomyopathy. These advances in
identification of specific genetic causes
are tempered by the fact that their
associations with clinical outcomes
have yet to be determined.
Our data from the Pediatric
Cardiomyopathy Registry show
the importance of non-causal
characteristics, such as presentation
in infancy, heart failure at diagnosis,
and specific echocardiographic
abnormalities. 1 Indeed, in our
Article, 1 patients were stratified
both by functional phenotype (pure
hypertrophic cardiomyopathy vs mixed
hypertrophic cardiomyopathy with
either dilated or restrictive features)
and known aetiology, whereas
additional risk stratification was on
the basis of family history and clinical
and echocardiographic characteristics.
While we await results from new causal
studies, including ongoing Pediatric
Cardiomyopathy Registry studies
of hypertrophic cardiomyopathy,
particularly the discovery of genetic
causes and their associations with
outcomes, we believe that our report1
provides the best information available
to help paediatric cardiologists to
www.thelancet.com Vol 383 March 1, 2014