What Kind of Drug is Leflunomide? A Pharmacological Profile

October 5, 2025 •

3 min read

Leflunomide belongs to a class of medications called disease-modifying antirheumatic drugs (DMARDs) and is used to treat autoimmune conditions like rheumatoid and psoriatic arthritis. As a potent immunosuppressant, its primary function is to suppress the overactive immune system responsible for inflammation and joint damage. What kind of drug is leflunomide and how does it work to treat these inflammatory conditions?

Quick Summary

Leflunomide is a non-biologic disease-modifying antirheumatic drug (DMARD) and immunosuppressant. It treats active rheumatoid and psoriatic arthritis by inhibiting pyrimidine synthesis, which reduces immune cell proliferation and inflammation.

Key Points

DMARD Class: Leflunomide is a disease-modifying antirheumatic drug (DMARD) and immunosuppressant used to treat inflammatory arthritis.
Mechanism: It works by inhibiting pyrimidine synthesis, which prevents the proliferation of activated immune cells (T-lymphocytes) responsible for inflammation.
Indications: Primarily used for moderate to severe active rheumatoid arthritis and psoriatic arthritis.
Significant Risks: The drug carries a boxed warning for severe liver damage and potential fetal harm, and increases the risk of serious infections.
Prolonged Half-Life: Due to its very long half-life, a drug washout procedure is required before stopping the medication, especially if pregnancy is a concern.
Monitoring Required: Regular blood tests are necessary to monitor liver function and blood cell counts for potential side effects.

What is Leflunomide?

Leflunomide is a non-biologic, disease-modifying antirheumatic drug (DMARD) used to treat moderate to severe active rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in adults. It targets the underlying cause of autoimmune inflammation to slow disease progression and prevent joint damage. Available under the brand name Arava and in generic forms, it is taken orally as a tablet.

The active metabolite: Teriflunomide

Leflunomide is converted into its active metabolite, teriflunomide, within the body. This metabolite is responsible for the drug's immunosuppressive effects and has a long half-life, which impacts treatment and pregnancy planning.

Mechanism of Action: Inhibiting the Immune System

Leflunomide works by inhibiting the enzyme dihydroorotate dehydrogenase (DHODH), which is essential for pyrimidine synthesis. Fast-dividing immune cells, like activated T-lymphocytes involved in RA, rely heavily on this process.

Here is how the mechanism works step-by-step:

Enzyme Inhibition: Teriflunomide inhibits the DHODH enzyme.
Pyrimidine Reduction: This reduces pyrimidine production.
Cell Cycle Arrest: Lower pyrimidines stop activated lymphocytes from progressing through the cell cycle.
Immune Suppression: By limiting the growth of these immune cells, leflunomide reduces inflammation and protects joints.

This action primarily affects the immune cells causing the autoimmune disease, minimizing impact on other body cells.

Clinical Applications and Indications

Leflunomide is used for chronic autoimmune inflammatory diseases:

Rheumatoid Arthritis (RA): Treats active RA to reduce symptoms, improve function, and slow joint damage. It can be used alone or with other DMARDs.
Psoriatic Arthritis (PsA): Manages inflammatory arthritis linked to psoriasis.

Administration

Leflunomide is typically taken once daily by mouth. The specific amount prescribed depends on individual medical needs and is determined by a healthcare professional. Regular monitoring of liver function and blood counts is necessary during treatment.

Key Side Effects and Safety Profile

Leflunomide can cause common side effects like diarrhea, nausea, headache, rash, hair thinning, and increased blood pressure. More serious risks include severe liver damage (highlighted by an FDA boxed warning), bone marrow suppression, serious infections, peripheral neuropathy, and interstitial lung disease.

Leflunomide vs. Methotrexate: A Comparison

Leflunomide and methotrexate (MTX) are both DMARDs for RA, but they have key differences. The choice between them depends on the individual patient.


Feature	Leflunomide (Arava)	Methotrexate (Trexall)
Drug Class	DMARD, Immunosuppressant	DMARD, Antimetabolite
Mechanism	Inhibits pyrimidine synthesis.	Blocks folic acid metabolism.
Administration Frequency	Once daily oral.	Typically once weekly oral or injection.
Active Metabolite	Teriflunomide.	Polyglutamated forms.
Half-Life	Very long (up to 2 years).	Shorter.
Washout Procedure	Required to remove drug quickly, especially before pregnancy.	Not required.
Key Side Effects	Diarrhea, rash, liver issues.	Nausea, mouth sores, liver issues.
Folic Acid Supplementation	Not required.	Commonly used to reduce side effects.
Pregnancy	Contraindicated (Cat X). Requires contraception and monitoring after stopping.	Avoided. Shorter washout needed.

Drug Interactions

Leflunomide can interact with other drugs. Interactions include those with warfarin, methotrexate (increased liver toxicity risk), CYP2C8 substrates, and alcohol (increased liver damage risk). Live virus vaccines should be avoided.

Conclusion

Leflunomide is a non-biologic DMARD and immunosuppressant for treating rheumatoid and psoriatic arthritis. It works by inhibiting pyrimidine synthesis, reducing immune cell growth and inflammation. While effective, it requires close medical supervision due to serious side effects like liver damage. Monitoring is crucial, and a washout procedure is necessary if pregnancy is a concern. Leflunomide serves as an important option for managing inflammatory arthritis, alongside or instead of methotrexate.

For more detailed information on DMARDs and autoimmune disease treatments, consult authoritative medical resources such as the American College of Rheumatology.

Frequently Asked Questions

Leflunomide is primarily used to treat active rheumatoid arthritis and psoriatic arthritis in adults to reduce inflammation and slow the progression of joint damage.

No, leflunomide and methotrexate are different DMARDs with distinct mechanisms of action. While both suppress the immune system, leflunomide inhibits pyrimidine synthesis, whereas methotrexate interferes with folic acid metabolism.

The most common side effects include diarrhea, nausea, headache, rash, and hair thinning. These may improve over time.

Leflunomide is contraindicated in pregnancy and can cause serious birth defects. A washout procedure is required, and women of childbearing age must use effective birth control during and for an extended period after treatment.

The full benefits of leflunomide may not be noticeable for 6 to 12 weeks after starting the medication. It is a long-term treatment.

No, it is highly recommended to avoid alcohol while taking leflunomide, as this can increase the risk of serious liver damage.

A washout procedure involves taking medications like cholestyramine or activated charcoal for about 11 days to help rapidly remove leflunomide from the body. It is often done before a planned pregnancy or if serious side effects occur.