Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats

Abstract

Objectives: Methotrexate (MTX) is administered once or thrice weekly to patients with rheumatoid arthritis (RA). Even though RA continually progresses, MTX is not administered daily. Therefore, we investigated whether the daily administration of a low dose of MTX inhibits the progression of arthritis in collagen-induced arthritis (CIA) rats.

Methods: Methotrexate was orally administered once weekly, thrice weekly and once daily to CIA rats, and arthritis scores were measured.

Key findings: When the same dose of MTX was administered, the exacerbation of arthritis was inhibited significantly more in the once-daily group than in the other groups. When the dose in the once-daily group was reduced to one-fourth that of the current standard dosing method, arthritis scores were markedly lower in the once-daily group than in the once and thrice-weekly groups.

Conclusions: The daily administration of a low dose of MTX not only maintained normal levels that estimated adverse effects but also suppressed the progression of arthritis significantly more than the current standard dosing method. The results indicate that the reconsideration of dosing schedules based on the characteristics of MTX will lead to more effective RA therapy than that currently used in clinical practice.

Keywords: arthritis; dosing schedule; low dose; methotrexate; myelosuppression.

Figure 1

Influence of the dosing schedule of methotrexate on arthritis scores in collagen‐induced arthritis rats after the second immunization. methotrexate was orally administered at a dose of 7.0 mg/kg once weekly (closed triangles), 2.33 mg/kg thrice weekly (closed diamonds) and 1.0 mg/kg once daily (open circles) for 3 weeks. The total dose per week was equal among all dosing groups. Sodium bicarbonate was administered to the control group (closed square). Each value represents the mean ± SD (n = 12). An arrow showed start date of methotrexate administration. Arthritis scores were significantly lower in the once‐daily group than in the 2.33 mg/kg thrice‐weekly and control groups on day 15 (P < 0.01, respectively).

Figure 2

Influence of the dosing schedule of methotrexate on arthritis scores in collagen‐induced arthritis rats after the first immunization. methotrexate was orally administered at a dose of 7.0 mg/kg once weekly (closed triangle), 2.33 mg/kg thrice weekly (closed diamond) and 1.0 mg/kg once daily (open circle) for 3 weeks. Sodium bicarbonate was administered to the control group (closed square). Each value represents the mean ± SD (n = 6). An arrow showed start date of methotrexate administration. **P < 0.01 vs the control group, ^## P < 0.01 vs the once‐weekly group, ^† P < 0.05 vs the thrice‐weekly group. The inhibition of arthritis was the greatest in the once‐daily group among all the dosing groups tested.

Figure 3

Influence of the dosage of methotrexate on arthritis scores in collagen‐induced arthritis rats when methotrexate was administered once a day. Methotrexate was orally administered at a dose of 0.1 (open diamonds), 0.25 (open squares), 0.5 (open triangles) and 1.0 (open circles) mg/kg once daily. Methotrexate was orally administered at a dose of 7.0 mg/kg once weekly (closed triangles) and 2.33 mg/kg thrice weekly (closed diamonds). Sodium bicarbonate was administered to the control group (closed squares). Each value represents the mean ± SD (n = 6–18). An arrow showed start date of methotrexate administration. **P < 0.01 and ***P < 0.001 vs the control group, ^# P < 0.05 and ^## P < 0.01 vs the once‐weekly group. Although the total dose per week in the 0.25 mg/kg once‐daily group was one‐quarter that in the thrice‐weekly group, arthritis scores in 0.25 mg/kg once‐daily group were markedly lower than in the thrice‐weekly group.

Figure 4

Influence of the dosing schedule of methotrexate on serum type II collagen antibody levels in collagen‐induced arthritis rats. Methotrexate was orally administered thrice weekly (2.33 mg/kg per time) and once daily (0.25 or 1.0 mg/kg) for 3 weeks. Sodium bicarbonate was administered to the normal group and collagen‐induced arthritis groups. Each value represents the mean ± SD (n = 6). ***P < 0.001 vs the collagen‐induced arthritis group, ^### P < 0.001 vs the thrice‐weekly group, ^††† P < 0.001 vs the 0.25 mg/kg once‐daily group. Serum type II collagen antibody levels were similar between the 0.25 mg/kg once‐daily (1.75 mg/kg per week) and 2.33 mg/kg thrice‐weekly (7 mg/kg per week) groups. Type II collagen antibody levels were below the detection limit in the 1.0 mg/kg once‐daily group, in which the inhibition of arthritis was the greatest.

Figure 5

Influence of the dosing schedule of methotrexate on leucocyte counts on days 3, 7, 17 and 21. Methotrexate was orally administered thrice weekly (2.33 mg/kg per time) and once daily (0.25 mg/kg or 1.0 mg/kg) for 3 weeks. Sodium bicarbonate was administered to the normal group and collagen‐induced arthritis groups. Each value represents the mean ± SD (n = 6). On day 3, leucocyte counts in the thrice‐weekly group were significantly lower than those in the other groups (P < 0.05 and <0.01, respectively).