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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Leflunomide

Last Update: April 15, 2019.

OVERVIEW

Introduction

Leflunomide is an immunomodulatory agent used in the therapy of rheumatoid arthritis and psoriatic arthritis. Leflunomide therapy is associated with frequent elevations in serum aminotransferase levels and with rare instances of clinically apparent acute liver injury which can be severe and even fatal.

Background

Leflunomide (le floo' noe mide) is an isoxazole derivative that is rapidly converted to its active metabolite teriflunomide (ter" i floo' noe mide: A77-1726) in the gut wall and liver. Leflunomide acts by inhibition of dihydroorotate dehydrogenase, which is a rate limiting step in pyrimidine synthesis necessary for DNA replication of rapidly dividing cells. Activated T lymphocytes are particularly sensitive to the inhibition of pyrimidine synthesis caused by leflunomide. Leflunomide is effective in reducing pain, improving functional status and decreasing the rate of injury in rheumatoid and psoriatic arthritis and is considered a “disease modifying antirheumatic agent (DMARD).” Leflunomide was approved for use in the United States in 1998 and is currently in wide use. Leflunomide is available in tablets of 10, 20 and 100 mg generically and under the brand name of Arava. The usual recommended dose is 100 mg daily for three days followed by 20 mg daily, reducing the dose of 10 mg daily if tolerance is poor. Common side effects include fever, rash, alopecia, gastrointestinal upset, nausea and diarrhea. Rare but potentially severe adverse events include hypertension, peripheral neuropathy, interstitial lung disease, severe infections, hepatotoxicity, hypersensitivity reactions, Stevens-Johnson syndrome and embryo-fetal toxicity.

Hepatotoxicity

Up to 15% of subjects treated with leflunomide develop transient serum aminotransferase elevations that are usually asymptomatic and mild, in the range of 1 to 3 times the upper limit of normal (ULN). Elevations above 3 times the ULN occur in 1% to 4% of patients.

In addition, leflunomide is associated with rare instances of clinically apparent liver injury that can be severe. The liver injury usually arises after 1 to 6 months of therapy (often associated with diarrhea) and presents with a range of patterns of enzyme elevations from cholestatic to hepatocellular. Rash and fever can occur, but are usually not prominent. Autoimmune features are often present, but are usually related to the underlying rheumatic condition rather than leflunomide therapy or liver injury. The injury begins to resolve within a week of stopping therapy, although several cases of acute liver failure resulting in death or need for urgent liver transplantation have been described.

Finally, leflunomide has been associated with reactivation of hepatitis B in patients with rheumatoid arthritis who are also HBsAg positive. Without prophylaxis (using an oral antiviral agent with activity against HBV), the frequency of reactivation is at least 50% in HBsAg positive individuals. Severe hepatitis and deaths have been described.

Likelihood score: B (well known cause of idiosyncratic clinically apparent liver injury as well as reactivation of hepatitis B).

Mechanism of Injury

The hepatic injury due to leflunomide is thought to be due to production of a toxic intermediate. Leflunomide is extensively metabolized by the liver and is a potent inhibitor of CYP 2C9. Hepatotoxicity of leflunomide has been linked to the cytochromic alleleic variants CYP 2C9*2 and *3, both of which are associated with impaired metabolism of the substrate. The mechanism of injury from HBV reactivation is believed to be due to immunosuppression which causes increases in HBV replication and subsequent immune reaction to the increase in viral antigens.

Outcome and Management

The mild ALT elevations associated with leflunomide therapy are usually asymptomatic, self limited and rarely require dose modification or discontinuation. Nevertheless, monitoring of serum enzymes is recommended, monthly for the first 6 months and then every other month. In instances in which ALT levels rise above 3 times ULN, repeat testing and dose modification is recommended as well as discontinuation if levels remain above this cut off. The acute liver injury due to leflunomide is usually self limited once therapy is stopped, but severe and fatal cases have been reported. Because of the enterohepatic circulation and long half life of leflunomide, therapy with a bile acid resin such as cholestyramine (4 grams every 6 hours for 2 weeks) is recommended to speed clearance of the drug. Patients with clinically apparent liver disease due to leflunomide should not be reexposed to the drug. There does not appear to be cross reactivity in regard to hepatic injury with other disease modifying rheumatologic agents such as azathioprine, thioguanine, mycophenolate, cyclosporine, or tacrolimus.

Patients who are scheduled to start leflunomide therapy should be screened for hepatitis B status: HBsAg and anti-HBc and possibly anti-HBs. Patients with HBsAg in serum should be provided with antiviral prophylaxis preferably with a potent nucleoside analogue with a high barrier to resistance such as tenofovir or entecavir for the duration of therapy. Patients with anti-HBc without HBsAg in serum may be offered prophylaxis but may also be monitored for HBV replication status (HBV DNA) and perhaps offered HBV immunization to boost titers of anti-HBs. Patients who have rises in HBV DNA levels during leflunomide therapy should be started on antiviral therapy.

Drug Class: Antirheumatic Agents

CASE REPORTS

Case 1. Acute hepatitis due to leflunomide.

[Modified from: Sevilla-Mantilla C, Ortega L, Agúndez JA, Fernández-Gutiérrez B, Ladero JM, Díaz-Rubio M. Leflunomide-induced acute hepatitis. Dig Liver Dis 2004; 36: 82-4. PubMed Citation]

A 67 year old woman with rheumatoid arthritis with an inadequate response to methotrexate (12.5 mg weekly for 2 years) was switched to leflunomide 20 mg daily and aurothiomalate weekly. Fifteen days later she developed diarrhea and leflunomide was stopped. Two weeks later she still had diarrhea and noted the onset of jaundice. On examination, she was icteric but had no fever, rash or other signs of acute or chronic liver disease. Laboratory results showed a total serum bilirubin level of 2.8 mg/dL and elevations in both serum aminotransferase and alkaline phosphatase levels (Table). She was known to have had normal liver tests in the past during regular monitoring of methotrexate therapy. ANA levels were weakly positive (1:80), but tests for hepatitis A, B and C were negative. A liver biopsy showed mild inflammation and acute liver injury without fibrosis or steatosis. Genetic testing showed that she was homologous for CYP 2C9*3. She was treated with cholestyramine and improved. Three months later serum enzyme levels were normal.

Key Points

Medication:Leflunomide (20 mg daily) for 15 days
Pattern:Hepatocellular (R=5.1)
Severity:3+ (jaundice, hospitalization)
Latency:2 weeks to diarrhea, 4 weeks to jaundice
Recovery:1-2 months
Other medications:Aurothiomalate; ongoing long term therapy with enalapril, prednisone, omeprazole, alendrolate, calcium and vitamin D; previous therapy with methotrexate

Laboratory Values

Time After StartingWeeks After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
4 weeks2 weeks4626022.8ESR 19 mm/hr
2.5 weeks5507773.5Liver biopsy
5 weeks3 weeks5177652.7
6 weeks4 weeks2706731.4
8 weeks6 weeks26390
141750.6
Normal Values<40<265<1.2

Comment

A mild acute hepatitis occurred within a month of starting leflunomide in a patient with a genetic predisposition to toxicity (CYP 2C9*3 homozygosity). The injury may have been more severe had leflunomide not been stopped two weeks before onset of jaundice because of diarrhea. The injury was weakly hepatocellular in pattern and more similar to a mixed hepatocellular-cholestatic pattern. The liver biopsy showed a pattern of acute liver injury without evidence of methotrexate hepatotoxicity or underlying liver disease. The concurrent use of aurothiomate, a gold salt which is also associated with cholestatic liver injury, makes it difficult to definitely attribute the hepatic injury to leflunomide. However, the timing and pattern of onset was not typical for gold induced hepatotoxicity (which typically is associated with fever, rash and eosinophilia). A large proportion of cases of suspected leflunomide induced liver injury in the literature occurred in the context of exposure to other potentially hepatotoxic medications (itraconazole, methotrexate, nonsteroidal antiinflammatory agents). Nevertheless, routine monthly monitoring of serum aminotransferase levels is recommended during the initial six months of leflunomide therapy.

Case 2. Cholestatic hepatitis due to leflunomide.

[Modified from a case in the database of the Drug-Induced Liver Injury Network]

An 84 year old man with polymyalgia rheumatic and incomplete responses to courses of prednisone and methotrexate was placed on leflunomide 20 mg daily. Ten weeks later, his arthritis had improved and leflunomide was stopped and replaced by hydroxychloroquine 200 mg twice daily. Four weeks later he noted darkening of the urine and jaundice and was hospitalized. He denied nausea, vomiting, poor appetite, abdominal pain or itching. He had no history of liver disease and serum enzymes had been normal on many occasions (Table). He did not drink alcohol and had no risk factors for viral hepatitis. On examination, he was jaundiced but without rash, fever or signs of chronic liver disease. Laboratory tests showed a total serum bilirubin of 9.8 mg/dL, with marked elevations in alkaline phosphatase (632 U/L) and modest elevations in ALT (121 U/L) and AST (122 U/L). Serum albumin was borderline low (3.6 g/dL), but the INR was normal (1.2). Tests for hepatitis A, B and C, antinuclear antibody and smooth muscle antibody were negative. CT scan of the abdomen showed no evidence of bile or pancreatic duct dilation and no gallstones. The liver was echogenic, suggestive of fatty infiltration. Hydroxychloroquine was stopped upon admission, but he remained jaundiced. An MRI of the abdomen and subsequent ERCP showed normal pancreatic and extrahepatic bile ducts without evidence of stones or obstruction. He was discharged and followed regularly. Two months later he was no longer jaundiced, but serum ALT and alkaline phosphatase levels remained mildly elevated for more than six months. Because of persistent arthralgias, he was restarted on hydroxychloroquine and had no recurrence of jaundice or serum enzyme elevations.

Key Points

Medication:Leflunomide (20 mg daily) for 12 weeks
Pattern:Cholestatic (R=0.6)
Severity:3+ (jaundice, hospitalization)
Latency:16 weeks (4 weeks after stopping)
Recovery:3-6 months
Other medications:Hydroxychloroquine, multivitamins

Laboratory Values

Weeks After StartingWeeks After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
0Leflunomide (20 mg daily) started
8030950.6
120Leflunomide stopped, hydroxychloroquine started
1641216329.8CT Scan
175985009.3
1861065756.5ERCP
219867043.3
2614675451.4
3018655201.0
3220524140.8
4028451850.6
4836662910.5
5240412630.3
5848351700.4
58Hydroxychloroquine restarted
62241100.4
86291030.5
Normal Values<40<115<1.2

Comment

The initial consideration was malignant obstruction of the biliary tract, but repeated imaging and ERCP failed to show evidence of extrahepatic obstruction. Drug induced liver injury appeared to be the most likely diagnosis, but it was unclear whether the injury was caused by leflunomide or hydroxychloroquine. The delay in onset after stopping leflunomide was unusual, but the agent has a very prolonged half life and undergoes entero-hepatic recirculation. Clinical recovery was complete within a few months of onset, but the patient had persistent abnormalities of serum ALT and alkaline phosphatase that did not fall into the normal range until 9 months after initial presentation. Slow recovery is not unusual in cholestatic forms of drug induced liver disease. Hydroxychloroquine, which has rarely been implicated in drug induced liver injury, was restarted and serum enzyme and bilirubin levels remained normal.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Leflunomide – Generic, Arava®

DRUG CLASS

Antirheumatic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Leflunomide75706-12-6C12-H9-F3-N2-O2
Leflunomide Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2019

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  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to leflunomide)
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 [0.6%] were attributed to leflunomide all of which were jaundiced and one fatal).
  • Mo YQ, Liang AQ, Ma JD, Chen LF, Zheng DH, Schumacher HR, Dai L. Discontinuation of antiviral prophylaxis correlates with high prevalence of hepatitis B virus (HBV) reactivation in rheumatoid arthritis patients with HBV carrier state: a real-world clinical practice. BMC Musculoskelet Disord 2014; 15: 449. [PMC free article: PMC4320507] [PubMed: 25532827]
    (Among 36 patients with rheumatoid arthritis and HBsAg in serum treated with disease modifying antirheumatoid drugs, 13 had reactivation of hepatitis B [2 on lamivudine prophylaxis, 5 after discontinuation and 6 on no antivirals] of whom 6 had hepatitis, [3 on lefeunomide], 3 were icteric and one developed cirrhosis)
  • Sultan SJ, Sameem F, Ashraf M. Drug reaction with eosinophilia and systemic symptoms: manifestations, treatment, and outcome in 17 patients. Int J Dermatol 2015; 54: 537-42. [PubMed: 24738653]
    (Over a 4 year period, 17 patients were seen with DRESS syndrome at a single referral hospital in India, of which 6 wre due to phenytoin 2 phenobarbital, 2 allopurinol and various others including leflunomide in 1; all had ALT elevations and 11 had hyperbilirubinemia and 1 died of liver failure)
  • Ming-Xu H, Chen M, Cai Y, Yan-Jia H. Clinical outcomes of low-dose leflunomide for rheumatoid arthritis complicated with Hepatitis B virus carriage and safety observation. Pak J Med Sci 2015; 31: 320-4. [PMC free article: PMC4476334] [PubMed: 26101483]
    (Among 115 patients with rheumatoid arthritis treated with leflunomide, 8 of 17 with HBsAg, but none of 36 with or 62 without antibody to HBV, developed rises in HBV DNA of whom 5 developed hepatitis [ALT 104 to 826 U/L] which was icteric in two, one of whom died of liver failure).
  • Stine JG, Lewis JH. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert Rev Gastroenterol Hepatol 2016; 10: 517-36. [PMC free article: PMC5074808] [PubMed: 26633044]
    (Comprehensive review of current means of treatment and prevention of drug-induced liver injury mentions that activated charcoal or
    cholestyramine may be beneficial in patients who develop liver injury while on leflunomide as these agents enhance clearance of the leflunomide which has a long half-life and enterohepatic circulation)

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