Rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval.[7][10] Arava was developed by Sanofi Aventis and approved by the U.S. Food and Drug Administration in 1998. Clinical studies regarding the following diseases have been conducted:[11] There has been reports on potential re-purposing of leflunomide for treatment of solid tumors with tumor suppressor, PTEN, loss.[12][13] In PTEN negative tumors, leflunomide causes synthetic lethality potentially due to increased demand on pyrimidines in these faster growing cells.[13]
Other immunomodulatory treatments should be avoided due to the potential for additive immunosuppressant effects, or in the case of immunostimulants like echinacea or astragalus, reduced therapeutic effects.[7] Likewise live vaccines (like haemophilus influenzae type b vaccine and yellow fever vaccines) should be avoided due to the potential for severe infection due to the immunosuppressive nature of the treatment.[7]
The concomitant use of methotrexate, in particular, may lead to severe or even fatal liver-damage or hepatotoxicity. Seventy-five percent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy leflunomide plus methotrexate.[30] However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.[30]
Pharmacology
Mechanism of action
Leflunomide is an immunomodulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA. Hence, leflunomide inhibits the reproduction of rapidly dividing cells, especially lymphocytes.[27]
The inhibition of human DHODH by teriflunomide, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA).[31] Teriflunomide also inhibits several tyrosine kinases.[27] Teriflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their ribonucleotides by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.[31] Teriflunomide also has antiviral effects against numerous viruses including CMV, HSV1 and the BK virus, which it achieves by inhibiting viral replication by interfering with nucleocapsid tegumentation and hence virion assembly.[27]
Teriflunomide is the main active in vivo metabolite of leflunomide. Upon administration of leflunomide, 70% of the drug administered converts into teriflunomide. The only difference between the molecules is the opening of the isoxazole ring. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.[32]
Teriflunomide is the active metabolite of leflunomide, responsible for its therapeutic actions. It results from the reaction of isoxazole ring opening, which occurs in vivo. Teriflunomide then can interconvert between the E and Zenolic forms (and the corresponding keto-amide), with the Z-enol being the most stable and therefore most predominant form.[33][34]
"Regardless of the substance administered (leflunomide or teriflunomide), it is the same molecule (teriflunomide)—the one exerting the pharmacological, immunological or metabolic action in view of restoring, correcting or modifying physiological functions, and does not present, in clinical use, a new chemical entity to patients."[32] Because of this, the European Medicines Agency (EMA) initially had not considered teriflunomide to be a new active substance.[35]
^Pirildar T (May 2003). "Treatment of adult-onset Still's disease with leflunomide and chloroquine combination in two patients". Clinical Rheumatology. 22 (2): 157. doi:10.1007/s10067-002-0667-0. PMID12740686. S2CID41656726.
^Clinical trial number NCT00004071 for "Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer" at ClinicalTrials.gov
^Clinical trial number NCT00802243 for "Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)" at ClinicalTrials.gov
^ abcdefTeschner S, Burst V (September 2010). "Leflunomide: a drug with a potential beyond rheumatology". Immunotherapy. 2 (5): 637–50. doi:10.2217/imt.10.52. PMID20874647.
^"Arava : EPAR - Product Information"(PDF). European Medicines Agency. Sanofi-Aventis Deutschland GmbH. 21 November 2013. Archived from the original(PDF) on 11 March 2014. Retrieved 11 March 2014.
^"Data Sheet Arava"(PDF). Medsafe. sanofi-aventis new zealand limited. 29 June 2012. Retrieved 11 March 2014.
^ abLee SS, Park YW, Park JJ, Kang YM, Nam EJ, Kim SI, et al. (2009). "Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis". Scandinavian Journal of Rheumatology. 38 (1): 11–4. doi:10.1080/03009740802360632. PMID19191187. S2CID205543918.
^ abFox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, et al. (December 1999). "Mechanism of action for leflunomide in rheumatoid arthritis". Clinical Immunology. 93 (3): 198–208. doi:10.1006/clim.1999.4777. PMID10600330.
