Efficacy of Intramuscular (IM) Methotrexate in the Treatment of RA
Methotrexate, either as monotherapy or in combination, remains the gold standard therapy for RA. In most patients treated with methotrexate, bioavailability of drug via oral or parenteral routes can roughly be considered equivalent. However, there are documented exceptions (e.g. GI malabsorption) that render equivalent doses of intramuscular (IM) methotrexate more effective than oral. For this reason, experience in clinical practice suggests that changing to IM from oral methotrexate, even at similar doses, can boost the efficacy of this drug in certain patients sparing the need to shift to alternate DMARDS or to introduce the cost and potential toxicities of combination regimens. Here, Lambert et al (Arthritis Rheum 50(2):364, 2004) examine the efficacy and toxicity of dose escalation of IM methotrexate over oral dosing.
Methods: Patients attending rheumatology clinics at the University of Edinburghs Western General Hospital (UK) with RA and active disease (defined as a DAS28 score >3.2), despite stable doses of 15-20mg of methotrexate per week who had previously failed an alternate DMARD, were changed to IM methotrexate at a dose of 15mg per week. Patients failing to achieve a DAS28 score <3.2 after 4 and 6 weeks of treatment with IM methotrexate at this dose were randomized into one of two groups:
Group 1: IM methotrexate was continued at 15mg/week. An equivalent volume of placebo methotrexate was added every 4 weeks to approximate the volumes administered in Group 2.
Group 2: IM methotrexate dose was escalated by an additional 5mg/week every 4-weeks if the DAS28 score was greater than 2.5. The maximum dose of IM methotrexate administered was 45mg/week.
Results: 64 patients were enrolled and switched from oral to IM methotrexate 15 mg/wk. 54 of the 64 failed to achieve a DAS28 score < 3.2 after 6 weeks of IM methotrexate and were randomized to dose escalation vs. placebo escalation. Of the 10 patients who were not randomized, 4 achieved a DAS28 score < 3.2 after 6 weeks of IM methotrexate therapy and were not eligible for randomization, and 6 patients declined further participation. 23 patients in Group 1 and 22 patients in Group 2 continued in the protocol. Baseline characteristics were similar between the two groups. 85% were positive for rheumatoid factor, 88% had erosive disease, mean disease duration was approximately 10 years, and mean baseline DAS28 score was 5.4 (indicating a high level of disease activity).
Only 2 patients (1 from each group) achieved a DAS28 score < 3.2 at any time during the dose escalation phase despite 78% of patients in the dose escalation arm reaching the maximum dose of IM methotrexate of 45 mg/week. 5 patients in each group demonstrated improvement in their DAS28 score of more than 1.2 units. Moreover, no patients in either group improved sufficiently to qualify as a EULAR good responder. Only 1 patient in each group discontinued due to a serious adverse event thought directly related to methotrexate (liver enzyme elevation > 3 times upper limit of normal). Less serious effects of methotrexate (minor elevations in liver function tests, hair loss, and dizziness) were also rare.
Conclusions: Despite the lack of toxicity demonstrated with rapid escalation of IM methotrexate, neither changing oral to IM methotrexate and/or escalating IM methotrexate dosing to 45mg/week were associated with significant clinical improvements.
Editorial Comments: These results are somewhat surprising at two levels. First, that little added efficacy was demonstrated by escalating methotrexate as high as 45 mg/week. And, second, that so little toxicity was observed at these relatively high doses of methotrexate. This study design tended to select for methotrexate non-responders, therefore one should not extrapolate the results to RA patients who are methotrexate or DMARD nave, or to those whose initial response to methotrexate may have been more robust. However, these data do suggest that RA patients with very active disease with little response to 15 mg/ week of oral methotrexate should not be delayed in switching to alternate DMARDS or combination therapies.