Leflunomide

Leflunomide is a disease-modifying anti-rheumatic drug (DMARDs), approved by Food and Drug Administration (FDA) to treat rheumatoid arthritis (RA). [1] It exhibits a substantial immunomodulatory and anti-inflammatory effect. It has shown significant efficacy in reducing the signs and symptoms and delaying disease progression in RA patients. It also helps to maintain function, limits irreversible joint damage and prevents synovitis in patients with RA. [2]

Pharmacological class: Pyrimidine synthesis inhibitor 

• Rheumatoid arthritis

Leflunomide acts by suppressing dihydro-orotate dehydrogenase enzyme, which may further prevent synthesis of ribonucleotide uridine mono-phosphate pyrimidine (rUMP) and reduced rUMP levels. This series of steps leads to activation of p53, which restricts the proliferation of autoimmune T cells and the production of auto-antibodies by B cells. [2]

• The recommended dose of leflunomide is 20 mg once daily
• The loading dose of leflunomide for people at low risk of liver toxicity and myelosuppression is 100 mg daily for three days
• The maintenance dose and maximum recommended daily dose of leflunomide is 20 mg daily
• The dose should be reduced to 10 mg once daily, if the maximum recommended daily dose is not tolerated [3]

• Absorption: Well absorbed and achieve peak plasma concentrations 6-12 hours after dosing
• Volume of Distribution (Vd): 0.13 L/kg
• Protein Binding: >99.3%
• Metabolism: It is metabolized hepatically to its active form teriflunomide
• Route of elimination: Primarily renal or biliary
• Half-life: 2 weeks [1]

Leflunomide is contraindicated in:

• People having a severe hepatic impairment
• People having known hypersensitivity to leflunomide or any of the other components of leflunomide
• Patients being treated with teriflunomide
• Pregnant women [3]

Leflunomide is metabolized to teriflunomide after oral administration. All the drug interactions studies of leflunomide have been carried out with its active metabolite teriflunomide.

These studies have reported that:

• Teriflunomide can increase the exposure of drugs metabolized by CYP2C8, BCRP, OAT3 transporters, OATP1B1/B3 transporters, ethinylestradiol and levonorgestrel
• Teriflunomide can decrease the exposure of agents metabolized by CYP1A2
• The dose of rosuvastatin should not exceed 10 mg once daily in patients administered with teriflunomide
• Teriflunomide may decrease the international normalized ratio (INR) in patients administered with warfarin

Therefore, close monitoring of people should be done, and the dose of teriflunomide should be modified if co-administered with above-mentioned drugs. [3] 

Common adverse events associated with the leflunomide were:

Nausea, diarrhea, dyspepsia, respiratory infection, headache, rash, and abnormal liver enzymes

Serious adverse events associated with leflunomide were:

Hepatoxicity, immunosuppression, bone marrow suppression, peripheral neuropathy, interstitial lung disease and Stevens-Johnson syndrome

Less common adverse events associated with leflunomide were:

• Gastrointestinal: Vomiting, anorexia, flatulence, bilirubinemia, gamma-GT increased, enlarged salivary glands, sore throat and dry mouth
• Cardiovascular: Palpitation, chest pain, thrombophlebitis of the leg, and varicose veins
• Nervous System: Dizziness, headache, somnolence
• Infection: Vaginal moniliasis, Abscess, flu syndrome
• Eye: Retinal hemorrhage, blurred vision, papilledema, eye disorder, retinal disorder
• Blood and Lymphatic System: Leukocytosis, thrombocytopenia
• Other disorders: Dyspnea, malaise and anaphylactic reaction [3]

• The active metabolite of leflunomide can elevate blood pressure. Therefore, blood pressure should be monitored carefully before and after treatment with leflunomide
• Leflunomide can cause hepatotoxicity, so the usage of leflunomide should be avoided in people having a pre-existing hepatic disease or those with serum alanine aminotransferase (ALT) >2xULN (upper limit of normal). Also, caution should be used while administering leflunomide with other potentially hepatotoxic agents
• Evaluate patients administered with leflunomide for peripheral neuropathy symptoms and if symptoms occur, discontinue use of leflunomide
• Discontinue use of leflunomide if severe adverse events such as interstitial lung disease, toxic epidermal necrolysis, thrombocytopenia, sepsis, pancytopenia, agranulocytosis, and Stevens-Johnson syndrome occurs.
• Leflunomide and its active metabolite, teriflunomide, are slowly eliminated from plasma. Thus, an accelerated drug elimination procedure must be used following leflunomide discontinuation and in patients who had witnessed serious adverse reactions. ^[3]

Various clinical trials have demonstrated the efficacy and safety of leflunomide compared to placebo and other anti-rheumatic drugs in managing patients with RA. A brief summary of these trials is explained as below:

Efficacy and safety of leflunomide to treat rheumatoid arthritis:

In early rheumatoid arthritis people having moderate or mild disease activity, a 50 mg/week leflunomide exhibited comparable benefits to a daily dose of 10 mg leflunomide. This randomized, multi-center study aimed to assess the safety and efficacy of weekly administration of leflunomide for rheumatoid arthritis.

Participants were segregated to either the treatment group (50 mg/week leflunomide, LEF50) or the control group (10 mg/day leflunomide, LEF10). All the recruited subjects were treated for twenty-four weeks. Using European League Against Rheumatism (EULAR) response and disease activity score in 28 joints (DAS28) - erythrocyte sedimentation rate (ESR) response, evaluation of clinical efficacy was done.

Overall, 244 people fulfilling the inclusion criteria and receiving at least 1 medicine dose were evaluated. The DAS28 (ESR) in the study groups declined at week 24 than the baseline. At week 24, no profound differences were noted in DAS28 (ESR) between the study groups. Similarly, no profound differences in EULAR response (good responses + moderate responses) rates were noted in the study groups at weeks eight, twelve, and 24, as shown in the table below:

No severe side effects were witnessed. Thus, management of rheumatoid arthritis with a weekly dose of leflunomide is easy and has an excellent safety profile. [4]

In another retrospective assessment of data from the PLUS study, it was reported that treatment with standard doses of leflunomide is safe and permits a remarkable clinical improvement in people suffering from RA. [5]

Leflunomide vs. methotrexate for rheumatoid arthritis:

In a systematic review and meta-analysis of clinical studies carried out by Roberto Alfaro-Lara et al.,  leflunomide used as the first DMARD in rheumatoid arthritis appeared to be as efficacious as methotrexate.

This study aimed to explore the efficacy and adverse effects of methotrexate and leflunomide in rheumatoid arthritis people as the first disease-modifying anti-rheumatic agent. Overall, 1984 participants were incorporated: 998 were given methotrexate and 986 were given leflunomide.

Leflunomide showed similar efficacy as methotrexate. Fewer gastrointestinal complaints were reported with leflunomide therapy. ^[6]  

1. Leflunomide. Drug bank. Accession no: DB01097. Available online from: https://go.drugbank.com/drugs/DB01097 [Last accessed on: 1 October 2021]
2. Padda IS, Goyal A. Leflunomide. Available online from: https://www.ncbi.nlm.nih.gov/books/NBK557799/ [Last accessed on: 1 October 2021]
3. ARAVA (Leflunomide). FDA LABEL. Available online from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020905s027lbl.pdf [Last accessed on: 1 October 2021]
4. Ren LM, Li R, Chen LN, Zhu P, Gu F, Sun LY et al. Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi‐center study. International journal of rheumatic diseases. 2016 Jul;19(7):651-7.
5. Tłustochowicz ME, Kisiel B, Tłustochowicz W. Quality of life and clinical outcomes in Polish patients with high activity rheumatoid arthritis treated with leflunomide (Arava®) in Therapeutic Program: A retrospective analysis of data from the PLUS study. Advances in Clinical and Experimental Medicine. 2019;28(11):1545-53.
6. Alfaro-Lara R, Espinosa-Ortega HF, Arce-Salinas CA, Precis Study Group. Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis. Reumatologia clinica. 2019 May 1;15(3):133-9.