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

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Methotrexate Dose Escalation Not Effective Alternative for Rheumatoid

Arthritis Patients Refractory to Conventional Methotrexate

A DGReview of : " Dose escalation of parenteral methotrexate in active

rheumatoid arthritis that has been unresponsive to conventional doses of

methotrexate: A randomized, controlled trial "

Arthritis & Rheumatism

02/27/2004

By Deanna M Green, PhD

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 randomized, double-blind, placebo-controlled

study.

Methotrexate has shown favorable 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. 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