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The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study

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Abstract

The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.

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Acknowledgments

This study was supported in part by a Grant-in-Aide (S1311011) from MEXT (Ministry of Education, Culture, Sports, Science and Technology) Supported Program for the Strategic Research Foundation at Private University and by a JSPS (Japan Society for the Promotion of Science) KAKENHI Grant Number JP15K08107 (to KI).

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Authors and Affiliations

  1. Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan

    Takuya Hirai, Keigo Ikeda, Maki Fujishiro, Hiroshi Tsushima, Kunihiro Hayakawa, Shinji Morimoto, Hideoki Ogawa, Kenji Takamori & Iwao Sekigawa

  2. Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan

    Takuya Hirai, Keigo Ikeda, Shinji Morimoto & Iwao Sekigawa

  3. Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan

    Satoshi Suzuki, Kazuhisa Nozawa, Yoshinari Takasaki & Naoto Tamura

  4. The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental health, Kitakyushu, Fukuoka, Japan

    Ayako Yamaguchi

Authors
  1. Takuya Hirai
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  2. Keigo Ikeda
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  3. Maki Fujishiro
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  4. Hiroshi Tsushima
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  5. Kunihiro Hayakawa
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  6. Satoshi Suzuki
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  7. Ayako Yamaguchi
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  8. Kazuhisa Nozawa
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  9. Shinji Morimoto
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  10. Yoshinari Takasaki
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  11. Hideoki Ogawa
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  12. Kenji Takamori
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  13. Naoto Tamura
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  14. Iwao Sekigawa
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Corresponding author

Correspondence to Keigo Ikeda.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Additional information

Takuya Hirai and Keigo Ikeda equally contributed to this study.

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Hirai, T., Ikeda, K., Fujishiro, M. et al. The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study. Clin Rheumatol 36, 51–58 (2017). https://doi.org/10.1007/s10067-016-3458-8

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  • DOI: https://doi.org/10.1007/s10067-016-3458-8

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