Correspondence
Secukinumab for ankylosing spondylitis
CNRI/Science Photo Library
We read with great interest the Article by Dominique Baeten and colleagues (Nov 23, p 1705) 1 on treatment of active ankylosing spondylitis. Tumour necrosis factor ( TNF)-inhibition therapy is a recommended treatment option in patients with ankylosing spondylitis who do not respond to non-steroidal anti-inflammatory drugs. 2,3 In view of the effectiveness of TNFinhibition therapy for ankylosing spondylitis, we strongly believe that it is not ethical to do a trial of the new anti-interleukin-17A monoclonal antibody secukinumab versus placebo. Secukinumab efficacy should be tested in comparison with the best therapy currently recommended for the disease. Alternatively, investigators should enrol patients who had an inadequate response or who were intolerant to anti-TNF therapies, such as infliximab and etanercept. Unfortunately, in their study, Baeten and colleagues considered only ten of 30 patients who received previous TNF-inhibition therapy. We suggest that secukinumab should be used for treatment of patients who did not respond to anti-TNF therapy. We declare that we have no competing interests.
*Maria Valentina Abate, Chiara Sandrin, Serena Pastore [email protected] University of Trieste, Trieste 34137, Italy 1
2
3
780
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. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1187–93. Braun J, van der Horst-Bruinsma IE, Huang F, et al. Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial. Arthritis Rheum 2011; 63: 1543–51.
In their Article, Dominique Baeten and colleagues1 report several cases of leucopenia and neutropenia, with no apparent relation to infections. However, they do not report the exact number of patients in each group and other important variables such as the timing of these possible adverse events. They report that the incidence of infections was higher for patients given secukinumab than for those given placebo. Cases of neutropenia (grade ≤2) have been reported previously in patients with plaque psoriasis treated with secukinumab.2 Cases of neutropenia were also reported in plaque psoriasis for patients receiving treatment with anti-interleukin-17 monoclonal antibody ixekizumab (grade 2) and anti-interleukin-17 receptor antibody brodalumab (grade 3).3 A dechallenge–rechallenge effect has been documented with brodalumab. 3 Mycophenolic acid suppresses neutrophil production by inhibiting interleukin-17 expression, suggesting that measurement of this interleukin might be useful to estimate the risk of neutropenia in clinical settings.4 Neutropenia can be associated with increased morbidity and mortality, but it is preventable. In view of these data,2–4 the small sample size of the trial, 1 and the extension of the CONSORT statement for better reporting of harms in randomised trials, 5 it is important that the authors report in more detail the development of leucopenia and neutropenia for further analysis and assessment of the benefit to risk ratio. TT has received funding to attend congresses from Janssen-Cilag, MSD, and Novartis. EV and AT have participated in clinical trials for chronic plaque psoriasis sponsored by Abbott, Janssen-Cilag, Pfizer, and MSD. AK declares that he has no competing interests.
*Thrasivoulos Tzellos, Athanassios Kyrgidis, Efstratios Vakirlis, Anastasia Trigoni [email protected] Hospital for Skin and Venereal Diseases, Thessaloniki 54643, Greece
1
2
3
4
5
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. 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. 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. von Vietinghoff S, Ouyang H, Ley K. Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production. Kidney Int 2010; 78: 79–88. Ioannidis JP, Evans SJ, Gøtzsche PC, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004; 141: 781–88.
Authors’ reply We thank Maria Valentina Abate and colleagues for sharing their ethical concerns about the use of a placebo in our proof-of-concept trial of use of anti-interleukin-17A monoclonal antibody secukinumab in ankylosing spondylitis.1 Their main argument against the use of placebo is the availability of anti-tumour necrosis factor (TNF) therapy to treat patients with ankylosing spondylitis. The ethical concern with placebo, however, should be balanced with the ethical concern of suboptimum trial design, which could lead to unnecessary exposure of patients to ineffective drugs. Therefore, the use of a placebo for 12 weeks (or longer if early escape is included in the trial design) is still deemed necessary and acceptable by the ankylosing spondylitis research community, as evidenced by recently published ankylosing spondylitis trials of other compounds.2,3 By contrast with other rheumatic conditions, a major consideration with ankylosing spondylitis is that 12 weeks of active disease does not lead to irreversible structural damage. Importantly, we considered these ethical concerns when designing our trial, which conforms to the International Conference on Harmonisation of Technical
www.thelancet.com Vol 383 March 1, 2014
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
Secukinumab for ankylosing spondylitis
CNRI/Science Photo Library
We read with great interest the Article by Dominique Baeten and colleagues (Nov 23, p 1705) 1 on treatment of active ankylosing spondylitis. Tumour necrosis factor ( TNF)-inhibition therapy is a recommended treatment option in patients with ankylosing spondylitis who do not respond to non-steroidal anti-inflammatory drugs. 2,3 In view of the effectiveness of TNFinhibition therapy for ankylosing spondylitis, we strongly believe that it is not ethical to do a trial of the new anti-interleukin-17A monoclonal antibody secukinumab versus placebo. Secukinumab efficacy should be tested in comparison with the best therapy currently recommended for the disease. Alternatively, investigators should enrol patients who had an inadequate response or who were intolerant to anti-TNF therapies, such as infliximab and etanercept. Unfortunately, in their study, Baeten and colleagues considered only ten of 30 patients who received previous TNF-inhibition therapy. We suggest that secukinumab should be used for treatment of patients who did not respond to anti-TNF therapy. We declare that we have no competing interests.
*Maria Valentina Abate, Chiara Sandrin, Serena Pastore [email protected] University of Trieste, Trieste 34137, Italy 1
2
3
780
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. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1187–93. Braun J, van der Horst-Bruinsma IE, Huang F, et al. Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial. Arthritis Rheum 2011; 63: 1543–51.
In their Article, Dominique Baeten and colleagues1 report several cases of leucopenia and neutropenia, with no apparent relation to infections. However, they do not report the exact number of patients in each group and other important variables such as the timing of these possible adverse events. They report that the incidence of infections was higher for patients given secukinumab than for those given placebo. Cases of neutropenia (grade ≤2) have been reported previously in patients with plaque psoriasis treated with secukinumab.2 Cases of neutropenia were also reported in plaque psoriasis for patients receiving treatment with anti-interleukin-17 monoclonal antibody ixekizumab (grade 2) and anti-interleukin-17 receptor antibody brodalumab (grade 3).3 A dechallenge–rechallenge effect has been documented with brodalumab. 3 Mycophenolic acid suppresses neutrophil production by inhibiting interleukin-17 expression, suggesting that measurement of this interleukin might be useful to estimate the risk of neutropenia in clinical settings.4 Neutropenia can be associated with increased morbidity and mortality, but it is preventable. In view of these data,2–4 the small sample size of the trial, 1 and the extension of the CONSORT statement for better reporting of harms in randomised trials, 5 it is important that the authors report in more detail the development of leucopenia and neutropenia for further analysis and assessment of the benefit to risk ratio. TT has received funding to attend congresses from Janssen-Cilag, MSD, and Novartis. EV and AT have participated in clinical trials for chronic plaque psoriasis sponsored by Abbott, Janssen-Cilag, Pfizer, and MSD. AK declares that he has no competing interests.
*Thrasivoulos Tzellos, Athanassios Kyrgidis, Efstratios Vakirlis, Anastasia Trigoni [email protected] Hospital for Skin and Venereal Diseases, Thessaloniki 54643, Greece
1
2
3
4
5
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. 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. 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. von Vietinghoff S, Ouyang H, Ley K. Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production. Kidney Int 2010; 78: 79–88. Ioannidis JP, Evans SJ, Gøtzsche PC, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004; 141: 781–88.
Authors’ reply We thank Maria Valentina Abate and colleagues for sharing their ethical concerns about the use of a placebo in our proof-of-concept trial of use of anti-interleukin-17A monoclonal antibody secukinumab in ankylosing spondylitis.1 Their main argument against the use of placebo is the availability of anti-tumour necrosis factor (TNF) therapy to treat patients with ankylosing spondylitis. The ethical concern with placebo, however, should be balanced with the ethical concern of suboptimum trial design, which could lead to unnecessary exposure of patients to ineffective drugs. Therefore, the use of a placebo for 12 weeks (or longer if early escape is included in the trial design) is still deemed necessary and acceptable by the ankylosing spondylitis research community, as evidenced by recently published ankylosing spondylitis trials of other compounds.2,3 By contrast with other rheumatic conditions, a major consideration with ankylosing spondylitis is that 12 weeks of active disease does not lead to irreversible structural damage. Importantly, we considered these ethical concerns when designing our trial, which conforms to the International Conference on Harmonisation of Technical
www.thelancet.com Vol 383 March 1, 2014
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
