Should leflunomide be given weekly?

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Rheumawire

Mar 2, 2004

Should leflunomide be given weekly?

Mexico City, Mexico - Following debate last year about reducing the

loading dose of leflunomide (Arava®, Aventis) in patients with

rheumatoid arthritis (RA) before continuing with daily dosing, a group

of Mexican doctors has proposed a new approach giving the drug weekly.

Writing in the February 2004 issue of Arthritis & Rheumatism [1], Dr

Jakez-Ocampo and colleagues report that weekly leflunomide dosing

is associated with fewer side effects than the currently recommended

daily dosing regimen as well as conventional weekly methotrexate.

Although it took longer for those taking weekly leflunomide to improve,

by 6 months all the groups had comparable responses, and these lasted to

the end of the year-long study.

However, the researchers caution that concept of weekly leflunomide

dosing has been tested only in a small number of patients, so larger

studies will be required to validate it. But comments from readers in

the email forum of jointandbone.org show that already some

rheumatologists are adopting this approach.

Jakez-Ocampo et al conducted the study in 30 patients with recent onset

RA and compared:

a.. Weekly administration of leflunomide (100 mg/week after a loading

dose of 100 mg/day for 3 days).

b.. Conventional dosing of leflunomide (20 mg/day after loading dose

of 100 mg/day for 3 days).

c.. Conventional dosing of methotrexate (7.5 mg/week adjusted up to 15

mg/week as needed).

Patients were evaluated every other month for 6 months and at months 9

and 12. By month 2, all patients had improved, but the ACR response in

the daily leflunomide group was more evident (p=0.0001) than in the MTX

(p=0.03) or the weekly leflunomide (p=0.001) groups. The clear-cut

improvement seen in the daily leflunomide group also prevailed at month

4 over the other 2 groups. But from 6 months to the end of the study,

there were no significant differences between groups at any given time

in all the evaluations performed.

Jakez-Ocampo et al say the development of side effects " deserves

particular attention. " Of the 10 patients taking daily leflunomide, 8

developed adverse events, including diarrhea, alopecia, and transient

transaminasemia. The 2 patients who dropped out of the study (at months

5 and 10) were both taking daily leflunomide and withdrew because of

untreatable diarrhea. Of the 10 MTX patients, 6 developed side effects,

including nausea, alopecia, and gastritis. But in the weekly leflunomide

group, only 4 of 10 patients presented with adverse effectsthese were

transitory diarrhea, nausea, alopecia, or mild transaminasemia, which

all resolved without treatment, the doctors say.

The Mexican physicians note that they have previously reported on 16

patients with refractory RA, comparing weekly and daily leflunomide [2].

Again, the improvement after 2 months was not as evident in the weekly

dose group as in the daily dose group, but by the fourth to sixth month,

they found that the response was comparable in both groups and prevailed

through to the end of the study (1 year).

In conclusion, however, they advise, " Given the small number of patients

. . we cannot affirm that such a treatment schedule is as effective as

daily leflunomide or weekly MTX. " Nevertheless, " this report proposes a

novel therapeutic modality for disease control for recent-onset RA that

deserves to be explored further. "

The issue of leflunomide dosing has been the subject of much debate in

the email forum of jointandbone.org. Many of the correspondents feel

that the loading dose currently recommended is too high and that it

causes unnecessary adverse events, so they have reduced the loading dose

or eliminated it altogether.

Among the alternative approaches that have been tried are loading

patients with leflunomide over 3 consecutive weeks as opposed to giving

the loading dose of 300 mg daily for 3 days. (So the first loading dose

would be 100 mg, followed by 20 mg a day for a week, then another 100

mg, followed by 20 mg for another week, followed by the final 100 mg on

the third week, to be followed by a maintenance dose of 20 mg a day.)

Meanwhile, some doctors completely omit the loading dose and just start

with the maintenance dose, 20 mg/day, while others begin even more

cautiously, using 10 mg/day and then slowly ascending the dose. And some

rheumatologists have reported that they are using the drug weekly.

Nainggolan

Sources

1. Jakez-Ocampo J, Richaud-Patin Y, Granados J, -Guerrero J,

Llorente L. Weekly leflunomide as monotherapy for recent-onset

rheumatoid arthritis. Arthritis Rheum 2004 Feb 15; 51(1):147-8.

2. Jakez-Ocampo J, Richaud-Patin Y, Simon JA, Llorente L. Weekly dose of

leflunomide for the treatment of refractory rheumatoid arthritis: an

open pilot comparative study. Joint Bone Spine 2002 May; 69(3):307-11.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org