Leflunomide is a pro-drug and its actions occur through its active metabolite, teriflunomide (previously referred to as A77 1726). Teriflunomide has anti-proliferative and anti-inflammatory actions and the onset of effect can occur within 4 weeks, but may take up to three or even six months in some cases.[18,19] Leflunomide's primary immunomodulatory action at therapeutic doses is thought to occur through teriflunomide's inhibition of the mitochondrial enzyme dihydro-oroate dehydrogenase (DHODH), which is essential for de novo pyrimidine synthesis in activated T-lymphocytes (Figure 1).[12,20–23]
Leflunomide actions occur through the active metabolite teriflunomide, which primarily inhibits DHODH, an essential enzyme for the proliferation of activated T-lymphocytes through the de novo pyrimidine pathway.
DHODH: Dihydro-oroate dehydrogenase.
At higher plasma concentrations, which can be achieved clinically, teriflunomide inhibits the activity of various tyrosine kinase enzymes.[12,24–25] It has also been shown to suppress activation of nuclear factor–κB (NF-κB), a transcription factor critical to immune cells and inflammation.[12,26] Reports of teriflunomide's antiviral and immunosuppressive properties have led to leflunomide being investigated in kidney transplant recipients with BK-virus nephropathy.[9–11,27]
Tolerability & Toxicity
The incidence of adverse effects with leflunomide appears comparable to other DMARDs, with the exception of methotrexate which may be better tolerated, as up to 56% of patients discontinued leflunomide within 30 months compared with 40% with methotrexate.[14,28] The most common side effects of leflunomide are gastrointestinal (e.g., diarrhoea, nausea and vomiting), which are experienced by 20–30% of patients. These are most likely to occur early in treatment and may settle if patients persist with therapy.[6,29]
Leflunomide is also associated with hepatic toxicity, which usually occurs within the first six months of treatment, and the incidence may increase when leflunomide is used in combination with other hepatotoxins such as methotrexate.[6,30–32] However, this was not observed by Bird et al. who found that the combination of methotrexate and leflunomide had an adverse event profile comparable to monotherapy with either agent. Age above 75 years and concomitant hydroxychloroquine have also been associated with increased leflunomide discontinuation. Other side effects of leflunomide include hypertension, alopecia, weight loss, skin rashes and allergies, and there have been rare reports of bone marrow suppression, peripheral neuropathy, infections and interstitial lung disease.
Personalized Medicine. 2014;11(4):449-461. © 2014 Future Medicine Ltd.