Relevant BNF section: 10.1.3
Disease-modifying antirheumatic drugs (DMARDs) are given to patients with rheumatoid arthritis (RA) to prevent synovitis, slow destruction of articular cartilage and bone, preserve function and control systemic manifestations of the disease. Recognition that irreversible joint damage often occurs early in RA has led to much prompter use of DMARDs, with sulfasalazine or methotrexate commonly considered the treatment of first choice.1 ▼Leflunomide (Arava - Aventis) is a new DMARD, licensed for the treatment of adults with active RA. The manufacturer claims that leflunomide has "comparable efficacy to methotrexate and sulphasalazine", with a "faster onset of action", and an "acceptable tolerability profile". Here, we consider the place of leflunomide in the management of patients with RA.
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Relevant BNF section: 10.1.3
Leflunomide is an isoxazol derivative and is structurally unrelated to other available DMARDs. It is a prodrug of A771726 (a malononitrilamide)2 which, in animal models, prevents or suppresses autoimmune disease and reactions that lead to graft rejection.3 The main mechanism of action of A771726 appears to be inhibition of dihydroorotate dehydrogenase, a mitochondrial enzyme essential for the de-novo synthesis of pyrimidines.2 By this action, A771726 arrests replication and prevents proliferation of activated T-lymphocytes,2 which are thought to play a key role in initiating and maintaining synovial inflammation in RA.4,5
After oral administration, at least 80% of a dose of leflunomide is absorbed and converted in the gut wall and liver to A771726, the plasma concentration of which peaks at around 1-24 hours.6 A771726 has a long plasma half-life (15-18 days) due to extensive plasma protein binding and enterohepatic recirculation.2 About half of the dose of leflunomide is eventually eliminated as A771726 in the faeces, and half as metabolites in the urine.7 Limited data suggest that the pharmacokinetics of leflunomide are unaffected by renal impairment but there are no data on the effects of liver impairment.6
Dose and administration
Leflunomide is taken by mouth. The manufacturer recommends a loading dose of 100mg on three successive days to accelerate steady-state plasma levels of A771726 (which would otherwise take around 2 months), followed by a maintenance dose of 10-20mg once daily.
Four fully published, multicentre, double-blind, randomised controlled trials have compared leflunomide with placebo, sulfasalazine or methotrexate in patients with active RA.8–11 All participants were asked to stop other DMARDs for at least 28 days before entering the trials but could continue oral corticosteroid therapy (up to 10mg prednisolone daily or equivalent) and their usual non-steroidal anti-inflammatory drugs (NSAIDs). All the trials included as the main primary outcome measure the proportion of patients meeting the American College of Rheumatology (ACR) definition for clinical response. This measure (ACR 20%) specifies improvement (compared to baseline) of at least 20% in tender and swollen joint counts, plus at least 20% improvement in three of the following: the patient's overall assessment of disease activity; the physician's overall assessment of disease activity; the patient's assessment of pain intensity; the patient's score on the Stanford Health Assessment Questionnaire (HAQ), which scores functional ability and health-related quality of life; and the ESR and/or C-reactive protein (CRP) concentration in the blood.12
In a double-blind, dose-ranging study, 402 patients with severe active RA (for a mean duration of 8 years) were randomised to 24 weeks' treatment with leflunomide 5mg daily, 10mg daily or 25mg daily (preceded by a single loading dose) or with placebo.8 The response rate (ACR 20%) was 30% in those taking placebo or leflunomide 5mg daily, 52% with leflunomide 10mg daily and 60% with 25mg daily.
In another 24-week study, 358 patients with RA (mean duration 7 years) received leflunomide (20mg daily, after 100mg loading doses on days 1-3), sulfasalazine (2g daily, introduced gradually over 4 weeks), or placebo.9 By 24 weeks, response rates (ACR 20%) were higher in both the leflunomide group (55%) and in the sulfasalazine group (56%) than in the placebo group (29%). Compared with placebo, both leflunomide and sulfasalazine slowed the progression of joint erosions on X-ray (a secondary endpoint). With leflunomide, an improvement in most clinical scores (exceeding that with sulfasalazine) was evident by 4 weeks.
In a third trial, lasting 52 weeks and involving 480 patients with RA (mean duration 7 years), leflunomide (20mg daily, after 100mg loading doses on days 1-3), was compared with methotrexate (7.5mg once weekly, increasable to 15mg once weekly if the disease remained active after 7 weeks), and placebo.10 Patients who failed to respond by 16 weeks, or who developed unacceptable unwanted effects, could switch (without unblinding the trial) to: leflunomide, if they were originally allocated to methotrexate or placebo; or methotrexate, if originally allocated to leflunomide. All participants received folate 1mg once or twice daily throughout the study. The primary endpoint measures (achievement of ACR 20% response criteria with completion of 52 weeks of the initially allocated treatment: together termed the 'ACR success' rate) were similar in the leflunomide (41%) and in the methotrexate (35%) groups and higher than in the placebo group (19%). Compared with placebo, both leflunomide and methotrexate slowed disease progression as measured by X-ray (a secondary endpoint), with leflunomide appearing the more effective. Results (reported in an abstract) in 116 patients who switched from their original allocated treatment suggest that both leflunomide and methotrexate were useful, though less effective, as second-line treatments.13
In a fourth study involving 999 patients with RA (mean duration around 3.5 years), leflunomide (20mg daily after three 100mg loading doses) was compared with methotrexate (7.5mg once weekly, titrated to 10-15mg once weekly in patients not initially responding).11 Each treatment was taken for 12 months, with an option of continuing double-blind therapy for up to 2 years. At 1 year, the response rate (ACR 20%) was higher with methotrexate (65% vs. 51% with leflunomide; p<.0001). However, the mean time to the first response was shorter with leflunomide (74 days vs. 101 days with methotrexate). In the subset of patients who continued treatment, response rates at 2 years were similar with the two drugs (72% with methotrexate vs. 64% with leflunomide). Disease progression measured by X-ray (a secondary endpoint) was similar with both drugs at 1 year, but was less with methotrexate at 2 years.
In published and unpublished studies, involving a total of 1339 patients treated with leflunomide, unwanted effects were more frequent in general with the drug than with either sulfasalazine or methotrexate.7 Those most commonly reported were gastrointestinal symptoms such as diarrhoea, dyspepsia and nausea (44% of patients); other common effects (each in up to around 10% of patients) included mild allergic reactions (e.g. rashes and pruritus); dry skin or eczema; alopecia (often resolving during treatment); headache and/or dizziness; mild elevations of blood pressure; leucopenia (total white cell count no lower than 2 x 10/L); and mildly elevated liver enzymes.6,7 Rare effects (occurring in fewer than 0.1% of patients) include: severe disturbance of liver function; severe cutaneous reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis); anaphylaxis; severe leucopenia (total white cell count below 2 x 10/L); agranulocytosis and pancytopenia.6,7 In most reported cases of pancytopenia, leflunomide was administered concomitantly, or soon after treatment, with another DMARD, or had been switched to another DMARD with potential for haematological toxicity.14
Accelerating drug removal
In the event of any suspected serious unwanted effect, leflunomide should be stopped. To accelerate elimination of A771726, the patient should take cholestyramine (8g three times daily) or activated powdered charcoal (50g four times daily), for 11 days; the duration of this 'washout' procedure can be modified depending on clinical judgement.6 Women should be warned that both cholestyramine and activated charcoal may make hormonal contraception unreliable, so alternative contraception is needed during the treatment.
Contraindications and precautions
Leflunomide is contraindicated in patients with: moderate or severe renal impairment; impaired liver function; severe hypoproteinaemia (e.g. in nephrotic syndrome); serious infections; known immunodeficiency; bone marrow dysfunction, anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than RA; or known hypersensitivity to the drug. Patients should be advised not to take leflunomide if they have a serious infection, and to seek medical advice promptly if they notice paleness, tiredness, bruising, sore throat, increased proneness to infections, or lesions on the skin, in the mouth or on other mucous membranes. Leflunomide has not been tested, and so is contraindicated, in people under 18 years old.
A771726 is teratogenic in animals. Leflunomide should not be given to women who are, or may become, pregnant, or who are breast-feeding. The manufacturer advises that before trying to conceive a woman should wait for 2 years after stopping leflunomide (to ensure clearance of A771726 from the body), and have their plasma analysed to check that the A771726 level is below 0.02mg/L, which the manufacturer deems as presenting minimal teratogenic risk.6 The blood test can be arranged through the manufacturer. In women wishing to become pregnant, accelerated removal procedure using cholestyramine or activated charcoal should shorten the clearance time for A771726 to 3 months. Women should be advised to be sure they are not pregnant before starting leflunomide. While taking the drug, they should use reliable contraception. As a precaution, the manufacturer recommends that men wishing to father a child should stop leflunomide and should undergo an accelerated removal procedure as outlined for women.
Because of the increased risk of toxicity, leflunomide should not be taken concomitantly with another DMARD.6,7 Before switching from leflunomide to another DMARD, an accelerated removal should be performed. Because of the potential for additive unwanted effects on the liver, alcohol should be avoided during treatment with leflunomide. In-vitro studies indicate that A771726 inhibits cytochrome P4502C9 activity. The manufacturer therefore advises caution when leflunomide is given concomitantly with drugs metabolised by cytochrome P4502C9 (e.g. phenytoin, warfarin and tolbutamide). Patients on leflunomide, currently or recently, should not be given a live vaccine.
Before beginning treatment with leflunomide, patients should have their blood pressure measured, and a full blood count (including differential white cell count and platelet count) and liver function tests performed. The manufacturer recommends monitoring blood counts fortnightly for the first 6 months, then every 8 weeks. Blood pressure and liver function tests should be checked at intervals (although the manufacturer gives no guidance on frequency); leflunomide should be stopped if transaminase levels persist at above 2-3 times the upper limits of normal.
▼Leflunomide is an effective disease-modifying antirheumatic drug (DMARD) in adults with active rheumatoid arthritis (RA). Benefit, which may be evident by 4 weeks after starting treatment, is manifest as improvement in tender and swollen joints and overall improvement as assessed by patients and physicians.
Compared with sulfasalazine or methotrexate, leflunomide appears similarly effective but more likely to cause unwanted effects. Serious unwanted effects with leflunomide include leucopenia, agranulocytosis, skin toxicity, hepatotoxicity and anaphylaxis. These appear more likely if leflunomide is given concomitantly with, or started just after switching from, another DMARD with similar toxicity, or is switched to another DMARD without elimination of leflunomide's active metabolite. Leflunomide is potentially teratogenic in women who are or may become pregnant. As with other DMARDs, laboratory monitoring is mandatory during treatment.
Leflunomide adds to the range of effective disease-modifying treatments for patients with RA. However, it costs much more than methotrexate or sulfasalazine and experience with these drugs is greater. On available evidence, leflunomide should not displace sulfasalazine and methotrexate as first-line treatments but is a useful second-line alternative where these drugs fail.