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Leflunomide
Indications
Leflunomide is a disease-modifying antirheumatic drug (DMARDs), which is FDA approved to treat individuals with rheumatoid arthritis.[1][2] It is a non-biological novel isoxazole derivative that has demonstrated anti-inflammatory and immunomodulatory characteristics.[3] Leflunomide maintains function in rheumatoid arthritis by delaying articular cartilage and bone disintegration and limiting irreversible joint damage. The medication is also useful in preventing synovitis and managing systemic symptoms of the disease.[4] Leflunomide is also indicated for the treatment of psoriatic arthritis and would be a reliable and beneficial option for individuals with the disease.[5] Despite the efficacy of improving swollen and tender joints, there is no FDA approval for the treatment of psoriatic arthritis due to minimal impact on the improvement of skin psoriasis.[6] Being a potent dihydro-orotate dehydrogenase inhibitor, leflunomide has been clinically assessed for cancer treatment but failed to secure FDA approval.[7] The indication for its use as a treatment of cancer comes from the inhibition of dihydro-orotate dehydrogenase, which arrests the S-phase in the cell cycle and can slow the rapid proliferation of cancer cells.[7]
Mechanism of Action
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Mechanism of Action
Leflunomide is an immunomodulatory oral medication that becomes metabolized in the body to its active form metabolite A77-1726, also known as teriflunomide. This metabolite acts by inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase.[8][9] This action prevents the synthesis of ribonucleotide uridine monophosphate pyrimidine (rUMP) and decreases rUMP levels, further activating P53. The activation of P53 restricts the progression of the G1 to S-phase in the cell cycle.[8][9] This restriction halts the proliferation of activated and autoimmune lymphocytes promoting anti-inflammatory and immunomodulatory effects.[8][9][3]
Administration
Leflunomide is available in oral tablets and comes in the following dosages:
- 10 mg
- 20 mg
- 100 mg
Patients can be started on an oral loading dose of 100 mg once a day for three days, followed by a maintenance dose of 10 mg or 20 mg per day -depending on the patient's tolerance. These are the recommended dosages for the treatment of Rheumatoid arthritis.[10][11] Patients may start to notice the effectiveness of leflunomide after 4 to 8 weeks of treatment.[10] The 100 mg loading dose is only for administration to select individuals due to an initial increased rate of adverse events.[2][12]
Adverse Effects
Common adverse effects of leflunomide include:
- Diarrhea
- Elevation in liver enzymes
- Hypertension
- Rash
- Nausea
- Abdominal pain
- Back pain
- Alopecia
Less common effects are hematological disorders, such as pancytopenia, and pulmonary disorders such as interstitial lung disease and pneumonitis.[2][10][13] Hepatic injury can begin to resolve within seven days of terminating the medication.[11] If ALT levels soar above three times the normal limits, repeat liver function tests, and modify the medication dosage.[11] If levels remain elevated, the prescriber should discontinue the medication.
Leflunomide can also cause reversible inhibition of MAO-A and MAO-B receptors but is only slightly effective as an MAO inhibitor. Researchers studied it for the treatment of Parkinson disease.[14]
Contraindications
Pregnancy
Teratogenicity with leflunomide contraindicates its use during pregnancy and warrants discretion in females during childbearing years.[15] Discontinuing leflunomide due to concerns for fetal safety during a planned pregnancy is indicated.[16] The recommendation is that the patient stops leflunomide three months prior to pregnancy.[17]
Liver impairment
Leflunomide is contraindicated in severe hepatic impairment due to hepatotoxicity.
Lung Disease
Leflunomide is also contraindicated in patients with underlying Interstitial lung disease and can cause symptoms within three months of starting leflunomide.[18]
Other contraindications include hypersensitivity, previous or current skin reactions, immunosuppression, and impaired bone marrow function.
Monitoring
- Liver function tests
- CBC
- Blood pressure
- Pregnancy
Leflunomide black box label warning warrants periodic monitoring of hepatic enzymes every four weeks for the initial six months and every other month after that.[11][19][20] In pregnancy, the labeled warnings indicate an enhanced risk of fetal mortality or teratogenic impacts in pregnant women.[20] The active metabolite of leflunomide, A77 1726, has a two-week half-life, a significant limitation to the medication when adverse events occur.[10] This factor can cause the effects to start or continue even after stopping leflunomide therapy. Routine monitoring is advisable when used with other hepatotoxic and hemotoxic agents.[21] Immunosuppression is also a black box warning of leflunomide; a CBC is necessary for all patients before and after beginning leflunomide treatment.[2] Hypertension is an adverse effect of leflunomide, for which blood pressure requires routine monitoring.[2]
Toxicity
Cholestyramine
- Four grams of cholestyramine every 6 hours for 14 days is the recommended intervention for wash-out therapy due to the long half-life of leflunomide.[11]
Leflunomide toxicity can affect the liver by causing acute drug-induced hepatic injury and affect the pulmonary system through pneumonitis and interstitial lung disease. During these complications, discontinuation of leflunomide and empirical cholestyramine wash-out therapy is recommended for toxicity.[22][23] Leflunomide causes aryl hydrocarbon receptor signaling, which acts on pulmonary and hepatic CYP1A enzymes.[24] Excess aryl hydrocarbon receptor signaling leads to several pathologic states in the lung and liver.[24] Pancytopenia can also result due to leflunomide toxicity. The treatment goal is the same as drug-induced hepatic injury and drug-induced pneumonitis, which is leflunomide-eliminating cholestyramine treatment.[13]
Enhancing Healthcare Team Outcomes
Leflunomide is an FDA-approved medication indicated for the treatment of rheumatoid arthritis. Managing the treatment of patients prescribed leflunomide requires excellent communication between the patient and professional healthcare providers. These providers need to function as an interprofessional team to include a primary care physician, a rheumatologist, a nurse, and a pharmacist. The primary care physicians and rheumatologists necessitate excellent patient rapport, so the patient fully understands the importance of medication compliance and education on the treatment and illness. It is vital to be engaged in the patient's care, so relapses, remissions, and disability do not occur long term.
The primary care and specialist should be familiar with leflunomide, its implications, and adverse effects. The patients prescribed leflunomide need routine checkups to observe if the medication is in an optimal range and the patient is not experiencing elevation in liver enzymes. Collective decision-making and interprofessional communication are necessary elements to enhance patient-centered care and achieve the desired outcome. Without the proper care and communication of an interprofessional team of healthcare professionals, the risk of adverse events and leflunomide toxicity, including drug-induced hepatitis, drug-induced pneumonitis, pancytopenia, and harm to the fetus during pregnancy, is highly likely. An interprofessional healthcare team working across disciplinary lines providing an integrated, evidence-based strategy to patients receiving treatment with leflunomide will help deliver the best possible outcomes.[25]
References
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Level 3 (low-level) evidenceGoldenberg MM. Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clinical therapeutics. 1999 Nov:21(11):1837-52; discussion 1821 [PubMed PMID: 10890256]
Alldred A, Emery P. Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. Expert opinion on pharmacotherapy. 2001 Jan:2(1):125-37 [PubMed PMID: 11336574]
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Madak JT, Bankhead A 3rd, Cuthbertson CR, Showalter HD, Neamati N. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacology & therapeutics. 2019 Mar:195():111-131. doi: 10.1016/j.pharmthera.2018.10.012. Epub 2018 Oct 19 [PubMed PMID: 30347213]
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Level 3 (low-level) evidenceFox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ. Mechanism of action for leflunomide in rheumatoid arthritis. Clinical immunology (Orlando, Fla.). 1999 Dec:93(3):198-208 [PubMed PMID: 10600330]
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. Leflunomide. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:(): [PubMed PMID: 31644034]
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Level 2 (mid-level) evidenceFox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Kirschbaum BJ. How does leflunomide modulate the immune response in rheumatoid arthritis? BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 1999 Oct:12(4):301-15 [PubMed PMID: 18031184]
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Level 3 (low-level) evidenceWong SP, Chu CM, Kan CH, Tsui HS, Ng WL. Successful treatment of leflunomide-induced acute pneumonitis with cholestyramine wash-out therapy. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2009 Dec:15(8):389-92. doi: 10.1097/RHU.0b013e3181c3f87e. Epub [PubMed PMID: 19955995]
Level 3 (low-level) evidencePatel A, Zhang S, Paramahamsa M, Jiang W, Wang L, Moorthy B, Shivanna B. Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor. Drug metabolism and disposition: the biological fate of chemicals. 2015 Dec:43(12):1966-70. doi: 10.1124/dmd.115.066084. Epub 2015 Sep 28 [PubMed PMID: 26417045]
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Level 1 (high-level) evidence