Description

Leflunomide is an isoxazole immunomodulatory agent and a disease-modifying anti-rheumatic drug (DMARD). It is an oral medication used for the long-term management of autoimmune diseases. Leflunomide is a prodrug that is rapidly metabolized in the body into its active form, A77 1726 (teriflunomide), which is responsible for its therapeutic effects. Its action is primarily on the immune system, where it helps to reduce inflammation and slow the progression of joint damage.

Indication

Leflunomide is indicated for the treatment of active arthritis in adult patients. Its main indications include:

• Rheumatoid Arthritis (RA): It is used to reduce signs and symptoms, inhibit the progression of structural damage, and improve physical function in patients with active RA.

• Psoriatic Arthritis: It is also indicated for the treatment of active psoriatic arthritis.

As a DMARD, leflunomide is not for immediate pain relief; its full therapeutic effect may take several weeks or even months to become apparent.

Mechanism of Action

Leflunomide’s mechanism of action is based on its ability to inhibit the proliferation of activated lymphocytes, particularly T-lymphocytes, which play a central role in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. The process is as follows:

1. Prodrug Activation: After oral administration, leflunomide is rapidly converted to its active metabolite, A77 1726. This active metabolite has a very long half-life, allowing for once-daily dosing.
2. Inhibition of Dihydroorotate Dehydrogenase (DHODH): The active metabolite, A77 1726, acts as a non-competitive inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). This enzyme is a crucial and rate-limiting step in the de novo pyrimidine synthesis pathway.
3. Disruption of Pyrimidine Synthesis: Pyrimidines (cytosine, uracil, and thymine) are essential building blocks for DNA and RNA. Lymphocytes, especially activated T-lymphocytes, are highly dependent on the de novo pathway for their pyrimidine supply to support rapid proliferation. Other cells in the body can use a “salvage” pathway for pyrimidine synthesis, making them less dependent on the DHODH enzyme.
4. Reduced Lymphocyte Proliferation: By inhibiting DHODH, leflunomide effectively blocks the proliferation of activated T-lymphocytes. This leads to a reduction in the inflammatory cascade and the production of autoantibodies that cause joint damage in autoimmune diseases. This selective action on lymphocytes, while sparing other cell types, is a key feature of its therapeutic effect.