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Open Access 03-05-2013 | Original Article

Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study

Authors: Norihiro Nishimoto, Koichi Amano, Yasuhiko Hirabayashi, Takahiko Horiuchi, Tomonori Ishii, Mitsuhiro Iwahashi, Masahiro Iwamoto, Hitoshi Kohsaka, Masakazu Kondo, Tsukasa Matsubara, Toshihide Mimura, Hisaaki Miyahara, Shuji Ohta, Yukihiko Saeki, Kazuyoshi Saito, Hajime Sano, Kiyoshi Takasugi, Tsutomu Takeuchi, Shigeto Tohma, Tomomi Tsuru, Yukitaka Ueki, Jiro Yamana, Jun Hashimoto, Takaji Matsutani, Miho Murakami, Nobuhiro Takagi

Published in: Modern Rheumatology

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Abstract

Objectives

To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration.

Methods

Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan–Meier curves.

Results

A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan–Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks.

Conclusions

TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare.
Literature
1.
go back to reference Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370:1861–74.PubMedCrossRef Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370:1861–74.PubMedCrossRef
2.
go back to reference Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer assisted management in early rheumatoid arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66:1443–9.PubMedCrossRef Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer assisted management in early rheumatoid arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66:1443–9.PubMedCrossRef
3.
go back to reference Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263–9.PubMedCrossRef Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263–9.PubMedCrossRef
4.
go back to reference Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146:406–15.PubMedCrossRef Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146:406–15.PubMedCrossRef
5.
go back to reference Mierau M, Schoels M, Gonda G, et al. Assessing remission in clinical practice. Rheumatology (Oxford). 2007;46:975–9.CrossRef Mierau M, Schoels M, Gonda G, et al. Assessing remission in clinical practice. Rheumatology (Oxford). 2007;46:975–9.CrossRef
6.
go back to reference Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375–82.PubMedCrossRef Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375–82.PubMedCrossRef
7.
go back to reference Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis. 1995;54:944–7.PubMedCrossRef Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis. 1995;54:944–7.PubMedCrossRef
8.
go back to reference Sokka T, Hetland ML, Mäkinen H, et al. Remission and rheumatoid arthritis: data on patients receiving usual care in twenty four countries. Arthritis Rheum. 2008;58:2642–51.PubMedCrossRef Sokka T, Hetland ML, Mäkinen H, et al. Remission and rheumatoid arthritis: data on patients receiving usual care in twenty four countries. Arthritis Rheum. 2008;58:2642–51.PubMedCrossRef
9.
go back to reference Sato K, Tsuchiya M, Saldanha J, et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993;53:851–6.PubMed Sato K, Tsuchiya M, Saldanha J, et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993;53:851–6.PubMed
10.
go back to reference Choy EH, Isenberg DA, Garrood T, et al. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin 6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum. 2002;46:3143–50.PubMedCrossRef Choy EH, Isenberg DA, Garrood T, et al. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin 6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum. 2002;46:3143–50.PubMedCrossRef
11.
go back to reference Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol. 2003;30:1426–35.PubMed Nishimoto N, Yoshizaki K, Maeda K, et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol. 2003;30:1426–35.PubMed
12.
go back to reference Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761–9.PubMedCrossRef Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761–9.PubMedCrossRef
13.
go back to reference Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006;54:2817–29.PubMedCrossRef Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006;54:2817–29.PubMedCrossRef
14.
go back to reference Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162–7.PubMedCrossRef Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162–7.PubMedCrossRef
15.
go back to reference Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97.PubMedCrossRef Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97.PubMedCrossRef
16.
go back to reference Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968–80.PubMedCrossRef Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968–80.PubMedCrossRef
17.
go back to reference Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516–23.PubMedCrossRef Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516–23.PubMedCrossRef
18.
go back to reference Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19:12–9.PubMedCrossRef Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19:12–9.PubMedCrossRef
19.
go back to reference Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69:88–96.PubMedCrossRef Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69:88–96.PubMedCrossRef
20.
go back to reference Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63:609–21.PubMedCrossRef Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63:609–21.PubMedCrossRef
21.
go back to reference Nishimoto N, Miyasaka N, Yamamoto K, et al. Relationship between serum IL-6 levels after tocilizumab treatment and clinical remission in active rheumatoid arthritis (RA) patients (abstract). Ann Rheum Dis. 2008;67(Suppl 2):90. Nishimoto N, Miyasaka N, Yamamoto K, et al. Relationship between serum IL-6 levels after tocilizumab treatment and clinical remission in active rheumatoid arthritis (RA) patients (abstract). Ann Rheum Dis. 2008;67(Suppl 2):90.
22.
go back to reference Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112:3959–64.PubMedCrossRef Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112:3959–64.PubMedCrossRef
23.
go back to reference Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol. 2010;20:222–32.PubMedCrossRef Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol. 2010;20:222–32.PubMedCrossRef
24.
go back to reference Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.PubMedCrossRef Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.PubMedCrossRef
25.
go back to reference Felson DT, Smolen JS, Wells G, et al. America college of rheumatology/European league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70:404–13.PubMedCrossRef Felson DT, Smolen JS, Wells G, et al. America college of rheumatology/European league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70:404–13.PubMedCrossRef
26.
go back to reference Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69:964–75.PubMedCrossRef Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69:964–75.PubMedCrossRef
27.
go back to reference van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2009;68:914–21.PubMedCrossRef van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2009;68:914–21.PubMedCrossRef
28.
go back to reference Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis. 2010;69:1286–91.PubMedCrossRef Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis. 2010;69:1286–91.PubMedCrossRef
29.
go back to reference Ribbens C, Andre B, Jaspar JM, et al. Matrix metalloproteinase-3 serum levels are correlated with disease activity and predict clinical response in rheumatoid arthritis. J Rheumatol. 2000;27:888–93.PubMed Ribbens C, Andre B, Jaspar JM, et al. Matrix metalloproteinase-3 serum levels are correlated with disease activity and predict clinical response in rheumatoid arthritis. J Rheumatol. 2000;27:888–93.PubMed
Metadata
Title
Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study
Authors
Norihiro Nishimoto
Koichi Amano
Yasuhiko Hirabayashi
Takahiko Horiuchi
Tomonori Ishii
Mitsuhiro Iwahashi
Masahiro Iwamoto
Hitoshi Kohsaka
Masakazu Kondo
Tsukasa Matsubara
Toshihide Mimura
Hisaaki Miyahara
Shuji Ohta
Yukihiko Saeki
Kazuyoshi Saito
Hajime Sano
Kiyoshi Takasugi
Tsutomu Takeuchi
Shigeto Tohma
Tomomi Tsuru
Yukitaka Ueki
Jiro Yamana
Jun Hashimoto
Takaji Matsutani
Miho Murakami
Nobuhiro Takagi
Publication date
03-05-2013
Publisher
Springer Japan
Published in
Modern Rheumatology
Print ISSN: 1439-7595
Electronic ISSN: 1439-7609
DOI
https://doi.org/10.1007/s10165-013-0894-z
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