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
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
