- Email: [email protected]
Etanercept and methotrexate in rheumatoid arthritis
CORRESPONDENCE
combined paroxetine safety and efficacy dataset in paediatric and adolescent depression as well as data on obsessive compulsive disorder and social anxiety disorder. We recognise the need to improve management of depression and other psychiatric illnesses in children and adolescents, and will continue our efforts to meet that need.
summarising any adverse event reported during the study. In addition, the investigators do not specify what haematological monitoring has been done during the study, so it is impossible to understand the criteria used to evaluate the safety of the combination with respect to blood dyscrasias.
Alastair Benbow
Renato Bertini Malgarini, *Giuseppe Pimpinella
European Medical Director, GlaxoSmithKline Pharmaceuticals, 980 GSK House, Great West Road, Brentford TW8 9GS, UK (e-mail: [email protected])
Italian Ministry of Health, Directorate General for Drugs and Medical Devices, Viale della Civiltà Romana 7, 00144 Rome, Italy (e-mail: [email protected])
1 2
3
4
The Lancet. Depressing research. Lancet 2004; 363: 1335. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomised, controlled trial. J Am Acad Child Adolesc Psychiat 2001; 40: 762–72. Milin RP, Simeon J, Spenst WP. Doubleblind study of paroxetine in adolescents with unipolar major depression. Annual Academy of Child and Adolescent Psychiatry (AACAP) Annual Meeting; Chicago, IL, USA; Oct 19–21, 1999; NR67: 104–05. Wagner KD, Wetherhold E, Carpenter DJ, et al. Safety and tolerability of paroxetine in children and adolescents: pooled results from five multicenter, placebo-controlled trials. American Academy of Children and Adolescent Psychiatry (AACAP) Annual Meeting; San Francisco, CA, USA; Oct 22-27, 2002.
Etanercept and methotrexate in rheumatoid arthritis Sir—Lars Klareskog and colleagues (Feb 28, pp 675–81)1 conclude that the combination of etanercept and methotrexate in the treatment of rheumatoid arthritis is more effective in achieving clinical remission and repair of structural damage than each treatment alone, and no new safety findings were noted in the study. A Public Statement of the European Agency for Medicines Evaluation in October, 2000, stated that blood dyscrasias have been reported in patients treated with etanercept in combination with other possibly myelotoxic drugs, such as methotrexate.2 We believe that the presentation of safety data in the study does not allow clear analysis of possible risk factors arising from the combination therapy. The authors state that no cases of serious blood dyscrasias were reported, but no definition of serious blood dyscrasia is given and whether cases judged as not serious have been excluded from the analysis is not clear. In fact, no cases of haematological events were listed in the table
1
2
Klareskog L, van der Hiejde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double blind randomised controlled trial. Lancet 2004; 363: 675–81. EMEA. Revised EMEA public statement on etanercept (Enbrel): serious hematological reactions and demyelination disorders. http://www.emea.eu.int/pdfs/human/press/ pus/3087100en.pdf (accessed Mar 12, 2004).
Authors’ reply Sir—The information requested by Renato Bertini Malgarini and Giuseppe Pimpinella on safety data for the haematological system is indeed important. We are glad to provide the details here since this information could not be included in our manuscript owing to length restrictions. As stated in our article, no cases of serious blood dyscrasias—defined as pancytopenia and aplastic anaemia on the basis of the etanercept (Enbrel) summary of product characteristics1— were reported in this study. The safety analysis, however, included all adverse
Adverse event Anaemia Eosinophilia Leucocytosis* Leucopenia Thrombocytopenia
events irrespective of their seriousness or intensity. Adverse events were recorded monthly for the duration of the study, and blood sampling was undertaken monthly for the first 6 months and bimonthly from week 32 until week 56. Table 3 in the article included adverse events that occurred in at least 10% of patients, but did not include haematological events since they were reported in less than 10%. More detailed information on the frequency of adverse events that occurred or worsened during the study—based on the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology, and haematology laboratory test results of potential clinical importance (defined as grade 3 or grade 4)—is summarised in the table here. Adverse events related to the haematological/lymphatic system were reported infrequently in this study and, with the exception of leucocytosis, there were no notable differences between the treatment groups. Thus, data from the TEMPO trial do not raise new concerns related to the haematological events resulting from treatment with etanercept or with a combination of etanercept and methotrexate compared with treatment with methotrexate alone. *Lars Klareskog, Désirée van der Heijde, Saeed Fatenejad *Rheumatology Unit, Department of Medicine, Karolinska Institute/Karolinska Hospital, Stockholm 17176, Sweden (LK); and Rheumatology Department, University Hospital, Maastricht, Netherlands (DvdH); Wyeth Research, Collegeville, PA, USA (SF) (e-mail: [email protected]) 1
Anon. Enbrel: summary of product characteristics. Taplow, UK: Wyeth Europa LTD, 2004.
Methotrexate Etanercept (n=228) (n=223)
Methotrexate plus etanercept (n=231)
3 (1·3%) 0 3 (1·3%) 5 (2·2%) 0
6 (2·6%) 0 0 11 (4·8%) 1 (0·4%)
Laboratory grade 3 or 4 abnormalities Haemoglobin* Grade 3 (65–80 g/L) 1 (<1%) Lymphocytes* 9 3 (1%) Grade 3 (<0·5⫻10 /L) Neutrophils* 9 Grade 3 (0·5–1⫻10 /L) 2 (<1%) Grade 4 (<0·5⫻109/L) 0 Platelet count* Grade 3 (25–50⫻109/L) 0 White blood cells* Grade 3 (1–2⫻109/L) 1 (<1%)
8 (3·6%) 1 (0·4%) 5 (2·2%) 8 (3·6%) 2 (0·9%)
2 (<1%)
0
2 (<1%)
4 (2%)
0 2 (<1%)†
1 (<1%) 0
2 (<1%)
0
0
0
*p=0·0475 Fisher’s exact p value. †In one patient, neutrophil concentrations were diminished (0·17⫻109/L) at one isolated visit; patient continued in study with partial recovery. In another patient, neutrophil concentrations were reduced to 0·41⫻109/L after conclusion of year 1 portion of study; patient continued in study, and follow-up neutrophil counts were reported to be normal.
Treatment-emergent adverse events and grade 3 or 4 laboratory abnormalities of haematological or lymphatic system
THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com
1733
For personal use. Only reproduce with permission from The Lancet publishing Group.
combined paroxetine safety and efficacy dataset in paediatric and adolescent depression as well as data on obsessive compulsive disorder and social anxiety disorder. We recognise the need to improve management of depression and other psychiatric illnesses in children and adolescents, and will continue our efforts to meet that need.
summarising any adverse event reported during the study. In addition, the investigators do not specify what haematological monitoring has been done during the study, so it is impossible to understand the criteria used to evaluate the safety of the combination with respect to blood dyscrasias.
Alastair Benbow
Renato Bertini Malgarini, *Giuseppe Pimpinella
European Medical Director, GlaxoSmithKline Pharmaceuticals, 980 GSK House, Great West Road, Brentford TW8 9GS, UK (e-mail: [email protected])
Italian Ministry of Health, Directorate General for Drugs and Medical Devices, Viale della Civiltà Romana 7, 00144 Rome, Italy (e-mail: [email protected])
1 2
3
4
The Lancet. Depressing research. Lancet 2004; 363: 1335. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomised, controlled trial. J Am Acad Child Adolesc Psychiat 2001; 40: 762–72. Milin RP, Simeon J, Spenst WP. Doubleblind study of paroxetine in adolescents with unipolar major depression. Annual Academy of Child and Adolescent Psychiatry (AACAP) Annual Meeting; Chicago, IL, USA; Oct 19–21, 1999; NR67: 104–05. Wagner KD, Wetherhold E, Carpenter DJ, et al. Safety and tolerability of paroxetine in children and adolescents: pooled results from five multicenter, placebo-controlled trials. American Academy of Children and Adolescent Psychiatry (AACAP) Annual Meeting; San Francisco, CA, USA; Oct 22-27, 2002.
Etanercept and methotrexate in rheumatoid arthritis Sir—Lars Klareskog and colleagues (Feb 28, pp 675–81)1 conclude that the combination of etanercept and methotrexate in the treatment of rheumatoid arthritis is more effective in achieving clinical remission and repair of structural damage than each treatment alone, and no new safety findings were noted in the study. A Public Statement of the European Agency for Medicines Evaluation in October, 2000, stated that blood dyscrasias have been reported in patients treated with etanercept in combination with other possibly myelotoxic drugs, such as methotrexate.2 We believe that the presentation of safety data in the study does not allow clear analysis of possible risk factors arising from the combination therapy. The authors state that no cases of serious blood dyscrasias were reported, but no definition of serious blood dyscrasia is given and whether cases judged as not serious have been excluded from the analysis is not clear. In fact, no cases of haematological events were listed in the table
1
2
Klareskog L, van der Hiejde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double blind randomised controlled trial. Lancet 2004; 363: 675–81. EMEA. Revised EMEA public statement on etanercept (Enbrel): serious hematological reactions and demyelination disorders. http://www.emea.eu.int/pdfs/human/press/ pus/3087100en.pdf (accessed Mar 12, 2004).
Authors’ reply Sir—The information requested by Renato Bertini Malgarini and Giuseppe Pimpinella on safety data for the haematological system is indeed important. We are glad to provide the details here since this information could not be included in our manuscript owing to length restrictions. As stated in our article, no cases of serious blood dyscrasias—defined as pancytopenia and aplastic anaemia on the basis of the etanercept (Enbrel) summary of product characteristics1— were reported in this study. The safety analysis, however, included all adverse
Adverse event Anaemia Eosinophilia Leucocytosis* Leucopenia Thrombocytopenia
events irrespective of their seriousness or intensity. Adverse events were recorded monthly for the duration of the study, and blood sampling was undertaken monthly for the first 6 months and bimonthly from week 32 until week 56. Table 3 in the article included adverse events that occurred in at least 10% of patients, but did not include haematological events since they were reported in less than 10%. More detailed information on the frequency of adverse events that occurred or worsened during the study—based on the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology, and haematology laboratory test results of potential clinical importance (defined as grade 3 or grade 4)—is summarised in the table here. Adverse events related to the haematological/lymphatic system were reported infrequently in this study and, with the exception of leucocytosis, there were no notable differences between the treatment groups. Thus, data from the TEMPO trial do not raise new concerns related to the haematological events resulting from treatment with etanercept or with a combination of etanercept and methotrexate compared with treatment with methotrexate alone. *Lars Klareskog, Désirée van der Heijde, Saeed Fatenejad *Rheumatology Unit, Department of Medicine, Karolinska Institute/Karolinska Hospital, Stockholm 17176, Sweden (LK); and Rheumatology Department, University Hospital, Maastricht, Netherlands (DvdH); Wyeth Research, Collegeville, PA, USA (SF) (e-mail: [email protected]) 1
Anon. Enbrel: summary of product characteristics. Taplow, UK: Wyeth Europa LTD, 2004.
Methotrexate Etanercept (n=228) (n=223)
Methotrexate plus etanercept (n=231)
3 (1·3%) 0 3 (1·3%) 5 (2·2%) 0
6 (2·6%) 0 0 11 (4·8%) 1 (0·4%)
Laboratory grade 3 or 4 abnormalities Haemoglobin* Grade 3 (65–80 g/L) 1 (<1%) Lymphocytes* 9 3 (1%) Grade 3 (<0·5⫻10 /L) Neutrophils* 9 Grade 3 (0·5–1⫻10 /L) 2 (<1%) Grade 4 (<0·5⫻109/L) 0 Platelet count* Grade 3 (25–50⫻109/L) 0 White blood cells* Grade 3 (1–2⫻109/L) 1 (<1%)
8 (3·6%) 1 (0·4%) 5 (2·2%) 8 (3·6%) 2 (0·9%)
2 (<1%)
0
2 (<1%)
4 (2%)
0 2 (<1%)†
1 (<1%) 0
2 (<1%)
0
0
0
*p=0·0475 Fisher’s exact p value. †In one patient, neutrophil concentrations were diminished (0·17⫻109/L) at one isolated visit; patient continued in study with partial recovery. In another patient, neutrophil concentrations were reduced to 0·41⫻109/L after conclusion of year 1 portion of study; patient continued in study, and follow-up neutrophil counts were reported to be normal.
Treatment-emergent adverse events and grade 3 or 4 laboratory abnormalities of haematological or lymphatic system
THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com
1733
For personal use. Only reproduce with permission from The Lancet publishing Group.