Leflunomide (LF) is a promising drug that belongs to the class of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. It has shown potential in the treatment of autoimmune diseases due to its ability to inhibit the DHODH enzyme, which plays a crucial role in the synthesis of pyrimidine nucleotides. This blog post will explore the mechanism of action and therapeutic applications of leflunomide in autoimmune diseases.

Mechanism of Action:

  1. Inhibition of DHODH: Leflunomide inhibits the DHODH enzyme, which is responsible for converting dihydroorotate into orotate, a key step in pyrimidine nucleotide synthesis. By inhibiting this enzyme, leflunomide leads to cellular depletion of pyrimidine nucleotides, which are essential for cell growth and proliferation.
  2. Immunomodulation: Leflunomide exhibits immunomodulatory effects by inhibiting protein tyrosine kinases and interfering with immunological events. It inhibits the proliferation of mononuclear and T-cells, leading to immunosuppression. Leflunomide also inhibits the production of immunosuppressant cytokines and the release of immunoglobulins.

Therapeutic Applications:

  1. Autoimmune Arthritis: Leflunomide is approved for the treatment of autoimmune arthritis, specifically rheumatoid arthritis and psoriatic arthritis. Its disease-modifying antirheumatic properties help reduce joint damage and improve symptoms in patients with these conditions.
  2. Multiple Sclerosis: Leflunomide has been used off-label for the treatment of relapsing-remitting multiple sclerosis. Its immunomodulatory effects may help reduce the frequency and severity of relapses in patients with this autoimmune disease.

In conclusion, Leflunomide, as a DHODH enzyme inhibitor, offers a novel approach for the treatment of autoimmune diseases. By inhibiting the DHODH enzyme and exerting immunomodulatory effects, leflunomide can suppress immune responses and reduce inflammation in conditions such as rheumatoid arthritis and multiple sclerosis.


[1] Alamri RD, et al. Int Immunopharmacol. 2021 Apr;93:107398.

[2] Xu X, et al. J Biol Chem. 1995 May 26;270(21):12398-403.

[3] Fox RI, et al. Clin Immunol. 1999 Dec;93(3):198-208.