- Email: [email protected]
Cardiomyopathy in children: importance of aetiology in prognosis
Correspondence
Requirements for Registration of Pharmaceuticals for Human Use ICH E10 step 5. Firstly, the placebocontrolled 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 [email protected] 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
2
3
4
5
6
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. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of shortterm symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 2014; 73: 95–100. 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. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol 2013; 50: 198–206. 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. 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
Ria Novosti/Science Photo Library
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 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 riskstratification algorithm applicable to each phenotypic category is problematic, because of the small numbers in each group and, in particular, the heterogeneous and nonuniform 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 [email protected] 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
2
3
4
5
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. 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. Nugent AW, Daubeney PE, Chondros P, et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003; 348: 1639–46. 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. 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
Requirements for Registration of Pharmaceuticals for Human Use ICH E10 step 5. Firstly, the placebocontrolled 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 [email protected] 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
2
3
4
5
6
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. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of shortterm symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 2014; 73: 95–100. 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. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol 2013; 50: 198–206. 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. 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
Ria Novosti/Science Photo Library
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 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 riskstratification algorithm applicable to each phenotypic category is problematic, because of the small numbers in each group and, in particular, the heterogeneous and nonuniform 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 [email protected] 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
2
3
4
5
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. 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. Nugent AW, Daubeney PE, Chondros P, et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003; 348: 1639–46. 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. 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