Requirement of methotrexate in combination with anti-tumor necrosis factor-alpha therapy for adequate suppression of osteoclastogenesis in rheumatoid arthritis.

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-alpha (TNF-alpha)-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-alpha 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-alpha 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-alpha-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.

• Authors: Hiroaki Matsuno, Kaoru Yoshida, Akira Ochiai, Masahiro Okamoto
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 34 Issue 12 Pg. 2326-33 (Dec 2007) ISSN: 0315-162X [Print] Canada
• PMID: 18050387 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antirheumatic Agents
• Interleukin-6
• Tumor Necrosis Factor-alpha
• Infliximab
• Methotrexate

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antirheumatic Agents (pharmacology, therapeutic use)
• Arthritis, Rheumatoid (drug therapy)
• Drug Therapy, Combination
• Humans
• Infliximab
• Interleukin-6 (blood)
• Methotrexate (pharmacology, therapeutic use)
• Mice
• Mice, SCID
• Osteoclasts (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, blood)