Leflunomide (Arava) is an oral disease-modifying antirheumatic drug (DMARD) used to manage autoimmune conditions. Its primary indications are active, moderate-to-severe Rheumatoid Arthritis (RA) and Psoriatic Arthritis. As an immunosuppressant, leflunomide dampens the overactive immune response, reducing inflammation, swelling, and joint pain. This article reviews leflunomide’s effectiveness in clinical practice and details its safety profile.
Measuring Therapeutic Effectiveness
Leflunomide’s effectiveness is measured by its ability to reduce disease activity and prevent long-term joint damage. Clinical trials quantify improvement using the Disease Activity Score in 28 joints (DAS28), which assesses tender and swollen joint counts and inflammatory markers. Patients often notice initial effects within four to eight weeks, but the full therapeutic benefit may take four to six months to become apparent.
Leflunomide also slows the physical progression of the disease, a benefit assessed through radiographic evidence. Randomized controlled trials show that treatment results in significantly less radiographic progression, meaning a reduced rate of bone erosion and joint space narrowing, compared to a placebo. This structural protection is a defining characteristic of a successful DMARD. Leflunomide’s overall efficacy is comparable to other established DMARDs, such as methotrexate and sulfasalazine, in both clinical outcomes and delaying joint damage.
Understanding Potential Side Effects
Like all medications, leflunomide is associated with a range of side effects varying in severity and frequency. The most common adverse event is gastrointestinal discomfort, particularly diarrhea, affecting about 20% of users. Other common issues include nausea, abdominal pain, rash, headache, and hair thinning (alopecia).
More serious, though less frequent, adverse reactions involve systemic toxicities. Leflunomide can cause elevations in liver enzymes (ALT and AST), and rarely, severe liver injury, including fatal liver failure. Most severe liver injury occurs within the first six months, often in patients with other risk factors for hepatotoxicity.
The medication also carries a risk of hematologic issues, leading to a reduction in blood cell counts, such as leukopenia (low white blood cell count) or thrombocytopenia (low platelet count). Rarely, severe bone marrow suppression can cause pancytopenia. Interstitial lung disease, a serious respiratory condition, is a rare but possible complication presenting as a persistent cough or shortness of breath.
Administration Protocols and Required Monitoring
Leflunomide is typically administered as an oral tablet once daily, with a standard maintenance dose of 20 mg. If patients experience dose-limiting side effects, the dosage may be decreased to 10 mg daily to improve tolerance. Some protocols use a loading dose of 100 mg once daily for three days to rapidly achieve therapeutic levels, but this is often avoided in high-risk patients, such as those taking other immunosuppressants like methotrexate.
The active metabolite, teriflunomide, has a very long half-life of about two weeks. This prolonged presence requires careful management when adjusting the dose or stopping the medication.
Mandatory and frequent laboratory monitoring is essential due to the risk of liver and blood cell toxicities. Patients must undergo routine testing of liver function tests (LFTs), including ALT levels, and a complete blood count (CBC). Monitoring is intensive at the start of treatment, with checks at least monthly for the first six months, and then every six to eight weeks thereafter, to identify early signs of systemic adverse effects.
Absolute Safety Warnings and Exclusions
The most stringent safety warning concerns leflunomide’s potential to harm an unborn fetus, often highlighted as a boxed warning. Leflunomide is contraindicated in women who are pregnant or planning to become pregnant because its active metabolite is teratogenic (causes birth defects). Females of reproductive potential must use effective contraception during treatment and for an extended period afterward.
Since the active metabolite can remain in the body for up to two years, a specific “washout” procedure is recommended if a patient plans to conceive. This involves administering medication, such as cholestyramine, to accelerate the drug’s elimination.
Leflunomide is also contraindicated in patients with pre-existing acute or chronic liver disease, especially if liver enzyme levels are elevated. It is not recommended for those with severe immunodeficiency or active, uncontrolled infections. Caution is advised regarding drug interactions, as co-administration with other liver-toxic medications, such as methotrexate, significantly increases the risk of hepatotoxicity.