Liver leflunomide

Low-dose methotrexate is used for treatment of rheumatoid arthritis despite side effects such as disorders of the gastrointestinal tract and the liver. Leflunomide is also approved for this indication, however, hepatoxicity limits its use as first option. 

The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. The ALT should be monitored monthly initially and periodically thereafter. Leflunomide may cause bone marrow toxicity a complete blood cell count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter. It is teratogenic and should be avoided during pregnancy. 

Toxicities include elevation of liver enzymes with some risk of liver damage, renal impairment, and teratogenic effects. A low frequency of cardiovascular effects (angina, tachycardia) was reported in clinical trials of leflunomide. 

Adverse Side Effects. Leflunomide s primary side effects include gastrointestinal distress, allergic reactions (skin rashes), and hair loss.57 This drug can also affect the liver liver function may need to be monitored periodically.19,70... 

Adverse effects The most common of these are headache, diarrhea, and nausea. Other untoward effects are weight loss, allergic reactions including a flu-like syndrome, skin rash, alopecia, and hypokalemia. Leflunomide is teratogenic in experimental animals, and is therefore contraindicated in pregnancy, and in women of childbearing potential. It should be used with caution in patients with liver disease, because it is cleared by both biliary and renal excretion. Cholestyramine increases the clearance of leflunomide. 

Leflunomide has been used as an immunosuppressive agent in kidney and liver transplant recipients to spare cal-cineurin inhibitors and glucocorticoids and to slow progression of chronic kidney graft dysfunction (28,37) (Table 1). 

In 3325 patients who took leflunomide, the rate of drug withdrawal was 42% within 33 months after approval by the US Food and Drugs Administration, and was more likely in patients who received a loading dose. The most common causes of discontinuation were inefficacy (30%), gastrointestinal symptoms (29%), non-adherence to therapy or loss to follow-up (14%), and raised liver enzymes (5%) (50). 

Leflunomide can cause abnormal liver function tests, but the risk of serious and non-serious hepatic adverse events is not higher than with methotrexate (71). In the MN301, US301, and MN302 trials, there were abnormal liver enzymes in 6-10% (9,10,12). The co-administration of methotrexate is a risk factor (18,72-74). According to the National Cancer Institute Common Toxicity Criteria, 8.9% of patients developed grade 2 or 3 hepato-toxicity within the first year, mainly within 6 months and in combination with methotrexate, after the start of leflunomide therapy based on liver enzyme determinations (72). The use of folate was also associated with less... 

A 67-year-old woman with rheumatoid arthritis developed diarrhea and raised liver enzymes after taking leflunomide for 15 days. Histologically, the liver showed acute hepatitis. She was homozygous for the CYP2C9 3 allele. The liver damage subsided within a few weeks. 

Imose M, Nagaki M, Kimura K, Takai S, Imao M, Naiki T, Osawa Y, Asano T, Hayashi H, Moriwaki H. Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor kappaB. Hepatology 2004 40(5) 1160-9. 

Anonymous. Severe liver damage with leflunomide. Prescrire Int 2001 10(55) 149. 

Sevilla-Mantilla C, Ortega L, Agundez JA, Fernandez-Gutierrez B, Ladero JM, Diaz-Rubio M. Leflunomide-induced acute hepatitis. Dig Liver Dis 2004 36(l) 82-4. 

Thomasset SC, Ong SL, Large SR. Post-coronary artery bypass graft liver failure a possible association with leflunomide. Ann Thorac Surg 2005 79(2) 698-9. 

B-lymphocytes. It is currently approved for use in rheumatoid arthritis. Bioavailability is 80% after oral administration. Leflunomide is metabolized in the liver to the active metabolite A77,1726. Biliary recirculation of A77,1726 contributes to the long half-life of 15 to 18 days. Adverse effects noted with leflunomide in solid-organ transplantation studies include skin rash, anemia, and elevated liver enzymes. 

Studies of leflunomide in kidney and liver transplant recipients utilized a loading dose of 200 mg daily for 7 days, followed by a maintenance dose of 40 to 60 mg daily. The target concentration appears to be 50 to 80 mcg/mL, which also allows for lower doses of steroids and CIs. A small open-label pilot study reported potential benefit with leflunomide in reversing chronic renal allograft dysfunction. ... 

Leflunomide has efficacy similar to that of methotrexate for treating rheumatoid arthritis. The drug may cause liver toxicity and is contraindicated in patients with pre-existing liver disease. Patients taking the drug should have ALT monitored monthly initially, and periodically thereafter as long as they continue treatment. 

JNK activation may be a mechanism that is associated with the initiation of mitochondrial permeability transition (MPT) (Hanawa et al. 2008 Latchoumycan-dane et al. 2006, 2007). As discussed above, both JNK activation (Matsumaru et al. 2003) and MPT (Lemasters 1998) are known to occur as a result of increased oxidative stress. MPT leads to additional oxidative stress with loss of mitochondrial membrane potential and loss of the ability of the hepatocyte to synthesize ATP. Latchoumycandane et al. (2006, 2007) found that leflunomide protected mice from mitochondrial permeabilization. Direct evidence for a role of JNK activation in acetaminophen-induced MPT was recently reported by Hanawa et al. (2008). A time course of events indicated GSH depletion by 1-2 h, JNK activation in liver homogenate by 2-4- h, JNK translocation to mitochondria by 4 h, and increased toxicity (serum ALT by 6 h). The JNK inhibitor did not alter GSH depletion but blocked JNK activation in homogenate, JNK translocation to mitochondria, and toxicity. Mitochondria from liver of acetaminophen-treated mice showed decreased State III respiration and decreased respiratory control ratios, whereas mice treated with acetaminophen plus JNK inhibitor were partially protected from these losses. Addition of activated JNKl or JNK2 to mitochondria from acetaminophen-treated mice plus JNK inhibitor showed a decrease in State 111 respiration and decreased respiratory control ratio. Addition of the MPT inhibitor cyclosporine A prevented these decreases. It was hypothesized that activated JNK is an important mediator of acetaminophen-induced MPT (Hanawa et al. 2008). 

Latchoumycandane C, Goh CW, Ong MM, Boelsterli UA (2007) Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. Hepatology 45 412-421... 

A 68-year-old woman who had been taking leflunomide 10 mg daily for about 4 months was started on itraconazole 300 mg daily for a fungal infection. About one month later her leflunomide dose was increased to 20 mg daily, and liver function tests were normal. The following month, she developed abdominal pain, vomiting, and weakness. Despite symptomatic treatment and washout with colestyramine, fatal fulminant hepatic failure occurred. The authors of the report attribute the reaction to additive hepatotoxicity between the leflunomide and itraconazole. This interaction serves to highlight the cautions about the use of other hepatotoxic drugs, see (a) and (h). 

In a retrospective analysis of 10 patients with rheumatoid arthritis treated with a combination of rituximab and leflunomide 20 mg/ day orally, leflunomide had to be reduced to 10 mg/day in two patients because of newly diagnosed arterial hypertension and a rise in liver enzymes and had to be stopped in two others after 3 and 6 months because of rises in liver enzymes with gastrointestinal intolerance and aphthous ulcers [62 ]. 

Liver The incidence of raised aminotransferases associated with methotrexate, leflu-nomide, and methotrexate together with leflunomide has been examined in 10863 patients with rheumatoid or psoriatic arthritis [66% There were abnormal aminotransferase activities in 14—35%. The risks were incrementally greater in those with psoriatic arthritis and in those receiving methotrexate (>10mg/day) together with leflunomide. There were rises to more than twice the upper limit of the reference range in 1-2% of patients on methotrexate or leflunomide monotherapy, compared with 5% of patients taking the combination. 

Cassell S, Greenberg JD, Kavanaugh A, Reed G, Strand V, Kremer JM. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010 69(1) 43-7. 

Weinblatt ME, Dixon JA, Falchuk KR. Serious liver disease in a patient receiving methotrexate and leflunomide. Arthritis Rheum 2000 43 2609 2611. 

Liver Elevated liver enzymes occurs rather frequent (in aroxmd 20%) in patients receiving leflunomide treatment. That this is tiius also often reported in clinical trials is not surprisingly. However, the long-term consequence of this silent elevation of liver enzymes was seen in a prospective study showing that leflunomide may induce liver stiffness and liver fibrosis. 

Elevated liver enzymes were also most frequently reported adverse events in a multicenter, double-blind randomised clinical trial which included adults with rheumatoid arthritis diagnosed within 6 months. Patients were randomised to receive either a 100 mg loading dose or a 20 mg fixed dose of leflunomide for 3 days followed by a 3-month open-label maintenance period of 20 mg leflxmomide daily. Hepatic enzyme elevation occurred in 9.3% of patients randomised to the lOOmg leflunomide loading dose group, whereas only in 1.5% in the 20 mg fixed dose group [73 ]. 

In a prospective open-label study on 15 Takayasu arteritis patients with active disease, patients received leflunomide (20mg/day) for at least 6 months. During follow-up (mean of 9.1 months) three patients (20%) experienced mild adverse events, while 33% of patients showed elevation of liver enzymes two times above the upper limit [74 ]. 

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