Methotrexate: Finding the Right Starting Dose



Decades of experience have narrowed the most effective dose of methotrexate (MTX) for rheumatoid arthritis to somewhere between 15 mg and 25 mg per week. However, experience has also suggested that early and rapid control of the disease activity minimizes damage. The result has been a quicker escalation of MTX dosing, with a starting dose of 10 mg to 15 mg per week and escalating by 5 mg every month, rather than the more traditional 5 mg every 3 months.

But researchers from Post Graduate Institute of Medical Education and Research in Chandigarh, India, point out that the recommendation to start with the higher dose of 15 mg is based on “weak evidence.” What’s more, they say, only a limited number of studies had compared fixed MTX doses head-to-head, and of those studies, many are 20 to 30 years old. No study had compared starting doses of 7.5 mg and 15 mg MTX, the researchers say.

Starting higher may have some benefits of efficacy, but that higher dose can also lead to adverse effects (AEs), intolerance, and withdrawal from therapy, say the researchers. They decided to find a balance between efficacy, speed, and tolerability by comparing 2 dosage regimens of oral MTX, starting at either 7.5 mgor 15 mg per week and escalating 2.5 mg every 2 weeks over 12 weeks, to a possible maximum of 25 mg per week. In group one, 47 patients were started on the lower dose, reaching a mean dose at 12 weeks of 17.3 mg per week. In group two, 53 patients were started on the higher dose and reached a mean dose of 23.6 mg per week. In patients who completed the study, the mean doses were 19.2 mg per week and 24.5 mg per week, respectively (P < .001).

Nine patients withdrew from group 1, and 7 patients withdrew from group 2. The numbers withdrawing from each group due to AEs were not statistically significant (P = .9). However, group 2 had a higher incidence of nausea and vomiting (42%, vs 19% in group 1), although the severity and duration of nausea were similar in both groups. There were no significant differences in frequency of cytopenia (P = .09) or transaminitis (P = .08). There was no difference in disease activity at weeks 4, 8, or 12.

The researchers say one limitation of their study is the short duration. They chose 12 weeks, because guidelines had suggested 3 months as a decision point, when other drugs could be added if the patient did not respond to MTX. However, they note that the European League Against Rheumatism 2013 update now specifies that the 3-month period relates “solely to assessing improvements” and says it takes 6 months to see maximal efficacy. The researchers, agreeing with this, say they found “a relatively poor response” by week 12. Indeed, they say, in view of the relatively slow decline in disease activity, future studies might benefit from extending the follow-up period to 24 weeks.

Dhir V, Singla M, Gupta N, et al. Clin Ther. 2014;36(7):1005-1015.
doi: 10.1016/j.clinthera.2014.05.063.

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