THU0170 Outcomes of the rapid dose escalation of methotrexate in japanese patients with early rheumatoid arthritis; results from a randomized controlled trial
Authors: M Tsutsumino, R Sakai, M Kihara, K Amano, R Yoshimi, M Inoo, H Dobashi, T Sugihara, T Hidaka, H Kohsaka, N Miyasaka, M Harigai
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Methotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis (RA), but tolerance to MTX is substantially different across ethnics and few studies have assessed efficacy and safety of rapid dose escalation regimen of MTX in Japanese patients with early RA. <h3>Objectives</h3> To evaluate outcomes of rapid dose escalation regimen of MTX compared with conventional treatment. <h3>Methods</h3> We implemented a randomized, controlled trial that enrolled patients with RA who fulfilled all of the following criteria: 20 to 70 years-old, disease duration ≤2 years, SDAI ≥11, and without prior use of MTX, tacrolimus (TAC) or biologics. Patients were randomized into rapid escalation (RE) group or conventional treatment (CT) group at 1:1 ratio. In RE group, doses of MTX were escalated up to 0.25 mg/kg/wk within 8 wks after start of MTX and increased maximum tolerable dose or 16 mg/wk until wk 12. If a patient achieved SDAI remission at wk 12, MTX was continued at the same dose. If a patient did not achieve SDAI remission at wk 12 or showed intolerance to MTX, use of TAC or TNF inhibitor (TNFi) were allowed. In CT group, patients were treated with either MTX, TAC, salazosulfapyridine, or bucillamine by the discretion of physicians until wk 12. If a patient achieved SDAI remission at wk 12, same treatment was continued. If a patient did not achieve remission at wk 12, use of TNFi was allowed. Patients were treated by the discretion of physicians at wk 24 and onward. We set two primary endpoints; the percentage of patients achieving SDAI remission and Boolean remission at wk 24. We planned to enroll 120 patients per arm based on expected SDAI remission rates at wk 24, alpha and beta errors and dropout rates. <h3>Results</h3> Enrollment was terminated prematurely and all patients were followed for 48 wks. Of 115 enrolled patients, 57 were randomly assigned to RE group and 58 to CT group. Baseline demographics were similar between the two groups. The median baseline values (RE vs. CT) were 24.9 and 25.9 for SDAI, 0.88 and 0.69 for HAQ, and 0.64 and 0.61 for EQ-5D, respectively. At wk 24, the percentages of patients achieving remission in RE and CT groups were 42% and 28% by SDAI criteria (p=0.1, χ<sup>2</sup> test), and 35% and 17% (p=0.03, χ<sup>2</sup> test) by Boolean criteria, respectively. Median values of HAQ at wk 24 in RE and CT groups were 0 and 0.13 (p=0.096, M-W U test), and those of EQ-5D were 0.78 and 0.77 (p=0.12, M-W U test), respectively. At wk 48, these values were not statistically different between the two groups. There were no significant differences between the two groups with incidence of severe adverse events. <h3>Conclusions</h3> The rapid dose escalation regimen of MTX provided significantly superior Boolean remission rate and tended to provide superior SDAI remission than conventional treatment in patients with early RA in the short term. <h3>Disclosure of Interest</h3> M. Tsutsumino Grant/research support from: Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., and Teijin Pharma Ltd., R. Sakai Grant/research support from: Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd., and Bristol-Meyers Squibb., M. Kihara: None declared, K. Amano Grant/research support from: Pfizer Japan Inc., R. Yoshimi Grant/research support from: Bristol-Myers K.K., M. Inoo: None declared, H. Dobashi: None declared, T. Sugihara Grant/research support from: Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K, Santen Pharmaceutical Co., Ltd., Astellas Pharma Inc., Bristol Myers Squibb K.K., Abbvie Japan Co., Ltd., Takeda Pharmaceutical Co., Ltd, and Astellas Pharma Inc., T. Hidaka: None declared, H. Kohsaka Grant/research support from: Ayumi Pharmaceutical Co., Pfizer Japan Inc., Mitsubishi-Tanabe Pharma Corp., Takeda Pharmaceutical Co. Ltd., AbbVie Japan Co. Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co. Ltd., Bristol-Meyers Squibb, Astellas Pharma Inc., UCB Japan, N. Miyasaka: None declared, M. Harigai Grant/research support from: Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd., Eisai, Pfizer Japan Inc., Sanofi-Aventis KK., Santen Pharmaceutical Co., Ltd and Sekisui Medical Co., Ltd.