Combination of Arava and MTX is safe & efficacious

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The Combination of Leflunomide (Arava) and Methotrexate is Safe &

Efficacious for the treatment of Rheumatoid Arthritis

Methotrexate (MTX), an anti-metabolite that inhibits purine pathways,

has been the hallmark of standard of care for many years in the

treatment of rheumatoid arthritis (RA). However, many RA patients

continue to have active disease despite maximal doses of methotrexate.

Recent studies indicate that combinations of disease-modifying

anti-rheumatic drug (DMARD) therapy can provide improved clinical

benefit for those patients who continue to have active disease despite

methotrexate.

In contrast to methotrexate, leflunomide is a DMARD that inhibits

pyrimidine pathways. Kremel et al. (Ann Intern Med 2002;137:726-733)

investigated the potential efficacy of this combination of DMARDs in RA.

Methods: 263 patients 18 to 75 years of age with active RA taking stable

doses of methotrexate were randomized into a 24 week double-blind

placebo-controlled trial to determine the safety and efficacy of

leflunomide and MTX and versus placebo and MTX. Patients were required

to take 1 mg of folate daily and also permitted to continue stable doses

of corticosteroids at 10 mg or less daily. Subjects were randomized to

receive either placebo or 10mg of leflunomide daily following a two day

loading dose of 100mg. Persistent adverse events at 10mg daily would

allow for a dose adjustment from daily to every other day. Following at

least eight weeks of study treatment and if tolerated, daily dosing was

increased to 20 mg with persistent active disease. However, if the

increase in dose resulted in significant adverse effects the dose was

decreased to 10 mg daily. Furthermore, a dosage adjustment or

discontinuation of treatment therapy was permitted if liver enzymes (ALT

and AST) were elevated at twice the upper limit of normal.

The primary outcome was the American College of Rheumatology criteria

(ACR20) for 20 % clinical improvement at week 24. Secondary outcomes

were the ACR50 and ACR70. Safety measures included adverse event

reports, laboratory assessments for blood chemistry, liver function,

urinalysis, and physical examination.

Results: 130 patients received treatment with leflunomide and

methotrexate and 133 subjects were randomized to placebo and

methotrexate. The response rate of ACR20 criteria (P<0.001) at week 24

was 46.2% and 19.5% for the leflunomide and placebo groups respectively.

Additionally, the ACR50 (P<0.001) response rates were 26.2% and 6.0% for

the leflunomide and placebo groups respectively at week 24. Furthermore,

the ACR70 (P<0.0155) response rates were 10% and 2.3 % for the

leflunomide and placebo groups respectively. Statistical significance

was reached.

The most common adverse events, mild to moderate in intensity, were

diarrhea, upper respiratory infection, nausea, headache, rash dizziness,

and alopecia. The frequency of infections was less in the leflunomide

(40.8%) group than in the placebo (51.9%) group. Discontinuations of

treatment in the leflunomide group were more commonly due to of adverse

events whereas discontinuations in the placebo group were more often

from lack of efficacy. Liver enzyme elevations were more frequent in the

first three months of treatment. 31.5% of leflunomide treated patients,

compared to 6.8% of placebo treated patients experienced abnormal ALT

levels, whereas 16.9% vs. 4.5% (placebo vs. leflunomide) displayed

abnormal AST levels. Mild LFT elevations association with leflunomide

frequently returned to normal range without any dose adjustment.

However, three leflunomide-treated patients and two placebo-treated

patients were discontinued from the study due to persistent elevations

in liver function values. There were no observed cases of leukopenia or

neutropenia.

Conclusion: Combination treatment with leflunomide and methotrexate was

generally well tolerated and resulted in statistically significant

improvement in RA, in comparison to placebo and methotrexate. Therefore,

combination therapy of leflunomide with methotrexate suggests a possible

alternative for those patients with persistent active RA who fail

methotrexate monotherapy. Vigilant monitoring of liver function should

continue during combination therapy with appropriate dosage adjustments

as needed. Further long-term observations are necessary to establish

long-term clinical efficacy and safety of this DMARD combination.

Editorial Comments: The original open-label study of MTX and leflunomide

suggested more liver toxicity than was actually seen in this

double-blind, placebo-controlled study. The dosing regimen in this study

was conservative in that the loading dose was 200 rather than 300 mg,

and chronic dosing began at 10 mg qd. This may be the reason for less

liver toxicity, or simply because larger numbers of patients were

studied in this protocol. The present results are encouraging but they

are short-term. Also, there are no x-ray data to confirm that the

combination of MTX and leflunomide is superior to MTX alone, in terms of

suppressing radiographic progression.

http://www.hopkins-arthritis.som.jhmi.edu/news-archive/2002/mtx_leflunomide.html

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Mayo Clinic in Rochester

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s Hopkins Medicine

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