Requirement of Methotrexate in Combination with Anti-Tumor Necrosis Factor-a Therapy for Adequate Suppression of Osteoclastogenesis in Rheumatoid Arthritis

HIROAKI MATSUNO, KAORU YOSHIDA, AKIRA OCHIAI, and MASAHIRO OKAMOTO

ABSTRACT.

Objective. To determine that concomitant use of methotrexate (MTX) is required to achieve adequate suppression of bone destruction in treating rheumatoid arthritis (RA) with tumor necrosis factor-a (TNF-a)-inhibiting biologic therapy. We quantitatively compared the suppressive effects of treatment with a combination of infliximab and MTX and treatment with each of these 2 agents alone on bone destruction in SCID-HuRAg-pit mice.

Methods. Tissue derived from human RA pannus was implanted with a slice of dentin subcutaneously in the backs of SCID mice (SCID-HuRAg-pit model). Infliximab was administered daily to SCID-HuRAg-pit mice using an osmotic pump for 2 weeks with or without oral administration of MTX. Histological changes in tissue and the pits formed on the dentin slice were examined 8 weeks after transplant. Serum concentrations of TNF-a and interleukin 6 (IL-6) were also measured.

Results. Treatment with a combination of infliximab and MTX suppressed pit formation significantly, while treatment with neither infliximab alone nor MTX alone had a significant effect on pit formation. Synovial inflammation and serum TNF-a and IL-6 levels were suppressed by infliximab with or without MTX.

Conclusion. This is the first evidence in an animal model of arthritis that concomitant use of MTX is required to achieve adequate suppression of bone destruction when treating RA with a TNF-a-inhibiting biologic. Our findings suggest that infliximab suppresses bone destruction through a mechanism of action different from that mediating its antiinflammatory effects in the treatment of RA. (First Release Nov 15 2007; J Rheumatol 2007;34:2326-33)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
TUMOR NECROSIS FACTOR
OSTEOCLASTOGENESIS
SCID MOUSE

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From the Matsuno Clinic for Rheumatic Diseases, Toyama; the Center for Advanced Research of Biomedical Engineering, Toin University of Yokohama, Yokohama; and Santen Pharmaceutical Co., Ltd., Osaka, Japan.

Supported by the Ministry of Education, Science, Sports, and Culture, Grant-in-Aid for Scientific Research (B) no. 15390454, 2003-2005.

H. Matsuno, MD, PhD, Matsuno Clinic for Rheumatic Diseases; K. Yoshida, MD; A. Ochiai, MD, The Center for Advanced Research of Biomedical Engineering, Toin University of Yokohama; M. Okamoto, PhD, Santen Pharmaceutical Co., Ltd.

Address reprint requests to Dr. M. Okamoto, Santen Pharmaceutical Co., Ltd., 3-9-19, Shimoshinjo, Higashiyodogawa-ku, Osaka 533-8651, Japan. E-mail: masahiro.okamoto@santen.co.jp

Accepted for publication August 4, 2007.

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