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Methotrexate Dose Escalation Not Effective Alternative for Rheumatoid Arthritis Patients Refractory to Conventional Methotrexate

Higher doses of methotrexate do not improve disease activity in patients with rheumatoid arthritis (RA) who did not respond to conventional doses of methotrexate, according to a randomised, double-blind, placebo-controlled study.

Methotrexate has shown favourable efficacy and toxicity both as monotherapy and as combination therapy in patients with RA. However, complete response is achieved in only a small proportion of patients.

There are a number of treatment options for these patients, including increasing the dose of methotrexate or the introducing other agents. Currently, there is limited information available regarding the efficacy of methotrexate above conventional doses.

C. Michael Lambert, MD, FRCP, and colleagues at the University of Edinburgh, United Kingdom, evaluated the effectiveness of higher doses of methotrexate in patients with active RA who were refractory to conventional methotrexate.

The study included 54 adults with active RA who did not respond after oral and intramuscular methotrexate (15-20 mg/week). The mean duration of disease in this cohort was 9 to 10 years, and they had been receiving methotrexate for a median of 2.5 years. Furthermore, 85% were seropositive for rheumatoid factor and 88% had erosive disease.

Patients were randomised to receive either intramuscular methotrexate (15 mg/week) plus monthly placebo escalation or methotrexate escalation (up to 45 mg/week) for 22 weeks. Doses were escalated every 4 weeks if the European League Against Rheumatism (EULAR) Disease Activity Score in 28 joints (DAS28) was greater than 2.5.

Similar and minimal DAS28 and ACR responses were seen in both groups. Specifically, 3.7% in each group achieved a DAS28 score of less than 3.2, and 18.5% in each group showed a greater than1.2-unit DAS28 improvement. Moreover, only 3.7% of patients in each group showed an ACR20 response.

No clinically significant haematologic toxicity was noted in either group. However, hair loss and dizziness occurred more frequently in the methotrexate escalation group.

One serious adverse event was reported in each group. One patient in the methotrexate escalation group had recurrent chest infections and 1 patient in the control arm had a significant rise in liver enzyme levels.

Overall, 78% of patients in the methotrexate escalation arm reached the maximum dose of 45 mg/week.

The authors conclude that "there is no benefit in escalating the dose [of methotrexate] and an alternative strategy should be tried" in the majority of patients. However, they also note that "the response to dose escalation in patients with early disease or who are DMARD naive was not examined and may be different."

Notably, in the initial phase of this study some patients responded when switched from oral to parenteral methotrexate (15 mg/week) during the screening period before randomisation.


Arthritis Rheum 2004 Feb;50:2:364-71. "Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of methotrexate: A randomized, controlled trial"

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