title: 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.
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.
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.|Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.
authors: Takuya
authors: T
authors: Hirai
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan. keigo@juntendo.ac.jp.|Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan. keigo@juntendo.ac.jp.
authors: Keigo
authors: K
authors: Ikeda
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.
authors: Maki
authors: M
authors: Fujishiro
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.
authors: Hiroshi
authors: H
authors: Tsushima
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.
authors: Kunihiro
authors: K
authors: Hayakawa
authors: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Suzuki
authors: The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental health, Kitakyushu, Fukuoka, Japan.
authors: Ayako
authors: A
authors: Yamaguchi
authors: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Kazuhisa
authors: K
authors: Nozawa
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.|Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.
authors: Shinji
authors: S
authors: Morimoto
authors: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Yoshinari
authors: Y
authors: Takasaki
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.
authors: Hideoki
authors: H
authors: Ogawa
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.
authors: Kenji
authors: K
authors: Takamori
authors: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Naoto
authors: N
authors: Tamura
authors: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan.|Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.
authors: Iwao
authors: I
authors: Sekigawa
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001862:Bone Resorption; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D012263:Ribonucleosides / Q000008:administration & dosage*; D012720:Severity of Illness Index; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D018501:Antirheumatic Agents; D012263:Ribonucleosides; C010052:mizoribine; D056657:Cathepsin K; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus; D008727:Methotrexate
keywords: Disease-modifying anti-rheumatic drugs; Methotrexate; Mizoribine; Rheumatoid arthritis; Tacrolimus