RESEARCH - Arava/MTX response maintained to 48 weeks in RA

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Leflunomide/MTX response maintained to 48 weeks in RA

Rheumawire

Sep 1, 2004

Janis

Albany, New York - An open-label extension of the randomized,

double-blind, placebo-controlled trial that established the efficacy of

combination leflunomide (LEF)/methotrexate (MTX) in treating

MTX-resistant rheumatoid arthritis (RA) showed that response is

maintained to 48 weeks. Patients treated without the loading dose of

leflunomide used in the original protocol had similar response rates and

considerably less liver toxicity, Dr Kremer (Center for

Rheumatology, Albany, NY) reports in the August 2004 issue of the

Journal of Rheumatology [1].

" A loading dose was used in the original study, as that was what was

recommended at the time. We live and learn, " Kremer tells rheumawire.

The 24-week extension study enrolled 168 of the 200 patients who had

completed the 24-week double-bind study of adding placebo or leflunomide

to stable MTX therapy. Patients (n=86) who had originally been

randomized to added leflunomide continued that regimen (LEF 10 mg/day

with MTX). This group had initially received a higher loading dose of

LEF of 100 mg/day for 2 days. Patients (n=82) who had been randomized to

placebo plus MTX switched after week 24 to LEF (10 mg/day) with MTX, but

without the loading dose.

The study patients all had been diagnosed with RA at least 6 months

before enrollment in the initial double-blind study, and all continued

to have active RA (defined by 3 of 4 criteria: 6 or more swollen joints,

9 or more tender joints, 45 minutes or longer of morning stiffness,

erythrocyte sedimentation rate [ESR] of 28 mm/hour or more). Both

studies were supported by Aventis Pharmaceuticals.

The primary efficacy end point was ACR20 response at week 48. Secondary

end points included ACR50 and ACR70 responses, mean changes from

baseline for individual ACR components and rheumatoid factor (RF), and

physical function as assessed by changes in the Health Assessment

Questionnaire Disability Index (HAQ DI) and health-related quality of

life assessed by changes in the Outcome Study Short Form Health Survey

(SF-36). Safety assessment included standard adverse-event reporting,

hematology, and blood-chemistry tests, including liver-function tests.

Kremer says that the most important findings in the extension study were

that the benefit observed with combined LEF/MTX at 24 weeks were durable

and maintained to 48 weeks and that patients who had LEF added at 24

weeks reached ACR20-response levels similar to those who had been taking

LEF/MTX throughout, although they had somewhat smaller HAQ improvements.

The patients who added LEF in the extension study without taking the

loading dose had strikingly less liver toxicity than those who took LEF

with the loading dose in the double-blind study. " Patients who switched

from placebo to LEF for the second 24 weeks of treatment without a

loading dose exhibited an incidence of elevated transaminase enzymes

(ALT 14.6%; AST 13.7%) that was lower than in those initially randomized

to LEF with a loading dose (ALT 31.5%; AST 16.9%) but higher than in

patients initially randomized to placebo (ALT 6.8%; AST 4.6%) [in the

original trial]. All elevations of transaminase enzymes in this group

reversed with no intervention, or a dose reduction, or discontinuation

of study medication at or before the end of the study. No patient

initiating LEF at week 24 discontinued due to elevated liver-function

tests during the open-label phase, " Kremer reports.

Kremer has some advice for clinicians starting a patient on LEF in

addition to background MTX. " I would monitor AST, ALT, and serum albumin

every 2 weeks for the first 4 weeks and then monthly for the first 6

months. If there are increases into the abnormal range in AST or ALT,

than I would adjust the dose of either MTX or LEF downward until they

disappeared. I would do the same for a significant decrease in serum

albumin (for example, to <3.5 from baseline normal), " he says.

Source

Kremer J, Genovese M, Cannon GW, et al. Combination

leflunomide and methotrexate (MTX) therapy for patients with active

rheumatoid arthritis failing MTX monotherapy: open-label extension of a

randomized, double-blind, placebo controlled trial. J Rheumatol 2004;

31:1521-1531.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org