Leflunomide vs Sulphasalazine

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Leflunomide for RA: Efficacy Study

Paper: Efficacy and safety of leflunomide compared

with placebo and

sulphasalazine in active rheumatoid arthritis: a

double-blind, randomized,

multicenter trial.

Authors: Smolen JS, et al.

Ref: Lancet 1999;353:259-66.

Type: Clinical Study

Summary: Rheumatoid arthritis is a progressive

disease with

severe morbidity and possibly, increased

mortality. There has

been growing interest in early, aggressive

treatment with

disease-modifying antirheumatic drugs

(DMARDs). Few

DMARDs have been shown to definitively slow

disease

progression, have sustained efficacy, and many

patients

cannot tolerate their long-term toxicities.

Leflunomide is a new immunomodulatory agent

that inhibits

de-novo pyrimidine synthesis by selective

inhibition of

dihydro-orotate dehydrogenase. The drug is

approved by the

US FDA for the treatment of adult active

rheumatoid

arthritis, including the retardation of

structural damage as

evidenced by x-ray erosions and joint space

narrowing.

In this phase III trial, the investigators

compared leflunomide

with sulfasalazine and placebo. The primary

endpoints were

swollen joint counts and patient's and

physician's overall

assessments. Other outcome measures included

an

assessment of the proportion of patients with

a clinical

response of at least 20% as defined by the

American College

of Rheumatology criteria. 358 patients were

entered into the

study and randomized to receive one of the

three treatments.

This study was not adequately powered to show

statistical

equivalence between leflunomide and

sulfasalazine.

All variables studied were significantly

improved in the

leflunomide group in comparison to placebo (p

< 0.0001) at

week 24. The proportion of patients responding

as defined by

American College of Rheumatology 20% criteria

was

significantly higher in the leflunomide (55%)

and sulfasalazine

(56%) groups when compared to placebo (29%)(p

< 0.0001).

Significantly less radiological disease

progression was

observed in the two active groups when

compared to

placebo. The most common side effects of

leflunomide

therapy included diarrhea, nausea, alopecia

and rash. Three

cases of abnormal liver function tests were

reported in the

leflunomide group and 5 in the sulfasalazine

group but none

of the events in the leflunomide-group were

considered to be

serious. The overall frequency of serious

adverse events was

low in all three groups (leflunomide 5%,

sulfasalazine 7%,

placebo 5%).

These data confirm the excellent efficacy and

safety profile

of leflunomide. The authors note that

leflunomide is a useful

addition to the management of rheumatoid

arthritis.