Safety and effectiveness of high-dose methotrexate (over 8 mg/week) in 2838 Japanese patients with rheumatoid arthritis: a postmarketing surveillance report

Abstract

Objectives: To confirm the safety and effectiveness of high-dose (>8 mg/week) methotrexate (MTX) for the treatment of rheumatoid arthritis in Japan.

Methods: A postmarketing surveillance program enrolled Japanese patients with rheumatoid arthritis starting on high-dose MTX followed up for 24 or 52 weeks. Analyses for safety, risk factors affecting safety, and effectiveness were conducted.

Results: The safety/effectiveness analysis sets included 2838/2779 and 335/326 patients in the 24 and 52-week follow-up groups, respectively. Incidence of adverse drug reactions (ADRs) and serious ADRs was 21.42 and 1.66% in the 24-week and 35.52 and 2.69% in the 52-week groups, respectively. The Disease Activity Score in 28 Joints (DAS28) was significantly decreased as early as four weeks from the start of high-dose MTX; after 24-week (4.09–3.21) and 52-week treatment (3.91–2.80; both p < .001). In a majority of patients at baseline who had high-to-moderate disease activity, the remission rate (defined as DAS28-4ESR <2.6) increased three-fold from 10.6% (baseline) to 33.0% (24-week) compared to patients with low disease activity whose remission rate increased two-fold from 24.0% (baseline) to 53.6% (24 weeks).

Conclusion: High-dose MTX was well tolerated in Japanese patients, resulted in improved disease control, and can be considered a step forward in achieving treat-to-target goals.

Keywords:

• Effectiveness
• high-dose methotrexate
• postmarketing surveillance
• rheumatoid arthritis
• safety

Acknowledgments

The authors would like to thank all of the physicians and patients who participated in this PMS program. This PMS program was sponsored and implemented by Pfizer Japan Inc., on behalf of manufacturers of MTX, which included Sawai Pharmaceutical Co., Ltd., Shiono Chemical Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Towa Pharmaceutical Co., Ltd., and Sandoz Co. Ltd. Pursuant to the Pharmaceutical Affairs Law of Japan and the regulations promulgated thereunder, the Sponsor (Pfizer) was required to conduct a PMS program as a condition for the marketing approval of MTX 8–16 mg/week for RA. Pfizer was responsible for the development of the study protocol (with instructions from the Pharmaceuticals and Medical Devices Agency) and for the analysis of the study data. Editorial support, in the form of medical writing, assembling tables and creating high-resolution images based on authors’ detailed directions, collating author comments, copyediting, fact checking, and referencing, was provided by Shruti Baijal and Shama Buch of Cactus Communications, and funded by Pfizer Japan Inc.

Conflict of interest

Yasuo Suzuki has received research funding from Mitsubishi Tanabe Pharma Co. Ltd., Eisai Co. Ltd., Ono Pharmaceutical Co. Ltd., Astellas Pharma Inc., Taisho-Toyama Pharmaceutical Co. Ltd., Japan Blood Products Organization, and Chugai Pharmaceutical Co. Ltd., and has received speaking fees and/or honoraria from Pfizer Japan Inc., Chugai Pharmaceutical Co. Ltd., Ayumi Industry Co. Ltd., and Eisai Co. Ltd. Naonobu Sugiyama, Yuri Fukuma, Noriko Sugiyama, and Takeshi Kokubo are employees of Pfizer Japan Inc. Naonobu Sugiyama and Noriko Sugiyama are stockowners in Pfizer Japan Inc.

Additional information

Funding

This PMS program was sponsored and implemented by Pfizer Japan Inc., on behalf of manufacturers of MTX, which included Sawai Pharmaceutical Co., Ltd., Shiono Chemical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Towa Pharmaceutical Co., Ltd., and Sandoz Co. Ltd.