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Weekly pulse therapy of methotrexate improves survival compared with its daily administration in MRL/lpr mice
Yu Asanuma1, Kasumi Nagai, Miyako Kato
1Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kanagawa 216-8512, Kawasaki, Japan.
Abstract:
The purpose of this study was to determine whether weekly pulse therapy was superior to daily administration of methotrexate in MRL/lpr mice. Oral methotrexate was given to 6-week-old MRL/lpr mice at doses of 0.3, 1.0, or 3.0 mg/kg 5 days a week or at a dose of 15.0 mg/kg once a week until 35 weeks of age. The effects of methotrexate on physical, serological, and pathological findings were assessed. The survival rate and articular destruction on X-ray films were also evaluated. Both weekly pulse therapy and daily administration of methotrexate at the same weekly dose improved nephropathy and articular destruction of MRL/lpr mice when compared with control. However, weekly pulse therapy with methotrexate prolonged the survival of MRL/lpr mice when compared with the daily administration of the same weekly dose of methotrexate and control. Methotrexate did not suppress the increase in anti-DNA antibody and rheumatoid factor. Daily administration of methotrexate reduced the red and white blood cell counts, whereas weekly pulse therapy caused little reduction. In conclusion, weekly pulse therapy was superior to daily administration of methotrexate with respect to the survival rate, possibly due to a reduction in toxicity.
Insights
Weekly pulse therapy with methotrexate offers superior survival benefits for MRL/lpr mice compared to daily dosing. This method reduces toxicity while improving physical and pathological outcomes in autoimmune disease models.
Area of Science:
- Immunology
- Pharmacology
- Toxicology
Background:
- Methotrexate (MTX) is a common immunosuppressant.
- Optimal dosing strategies for MTX in autoimmune conditions require further investigation.
- MRL/lpr mice serve as a model for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Purpose of the Study:
- To compare the efficacy and toxicity of weekly pulse therapy versus daily administration of methotrexate in MRL/lpr mice.
- To evaluate the impact of different methotrexate dosing regimens on disease progression and survival.
Main Methods:
- MRL/lpr mice received oral methotrexate at varying doses and schedules (daily vs. weekly pulse).
- Assessment included physical, serological, and pathological evaluations.
- Survival rates and articular destruction via X-ray were quantified.
Main Results:
- Both dosing regimens improved nephropathy and articular destruction compared to controls.
- Weekly pulse therapy significantly prolonged survival compared to daily administration.
- Neither regimen suppressed anti-DNA antibody or rheumatoid factor increases.
- Daily MTX reduced blood cell counts, while weekly pulse showed minimal reduction.
Conclusions:
- Weekly pulse methotrexate therapy is superior to daily administration in MRL/lpr mice, primarily due to enhanced survival.
- Reduced toxicity, indicated by less impact on blood cell counts, may explain the improved survival with weekly pulse therapy.
- Methotrexate efficacy in managing autoimmune markers like anti-DNA antibodies and rheumatoid factor requires further study.