Leflunomide Peripheral Neuropathy

Abstract & Commentary

Synopsis: Leflunomide’s immunomodulatory activity derives from its action as a competitive inhibitor of the rate-limiting enzyme necessary for pyrimidine synthesis.

Source: Bonnel RA, et al. Peripheral Neuropathy in Patients Treated With Leflunomide. Clin Pharmacol Ther. 2004;75:580-585.

Following its FDA approval and marketing release for rheumatoid arthritis (RA) in 1998, leflunomide has been associated with 80 cases of new onset-peripheral neuropathy. Most patients were treated for RA (n = 57) but also included were those with psoriatic arthritis (n = 2), undifferentiated connective tissue disease, dermatomyositis, or polyarthritis (n = 1, each), as well as 18 with unstated disease. Sixteen patients had other risk factors for neuropathy, including diabetes, prior chemotherapy known to be associated with neuropathy (cisplatin, chloroquine, isoniazid), spinal stenosis, or hypothyroidism. Daily dose never exceeded the recommended range of 10-20 mg. Symptoms began 3 to 1126 days following onset of therapy and included distal numbness, tingling, burning, cold, or weakness. Onset did not correlate with age, gender, or dose. Electrodiagnostic studies, reported in 46% (n = 37) indicated axonopathy (n = 12), demyelinating, or mixed neuropathy (n = 2 each). Sensory neuropathy was the predominant feature in 13, with sensorimotor neuropathy documented in 9 and motor neuropathy in 1. Sural nerve biopsy performed in a single patient showed only axonal loss without vasculitis. Improvement or recovery followed medication withdrawal and occurred more rapidly when medication was stopped within, rather than beyond, 30 days of symptom onset (median time, 135 days vs 755 days, respectively), but was not associated with age, sex, daily dose, or duration of treatment. Post-marketing analysis has revealed an adverse event with leflunomide not reported among the 816 patients involved in its pre-marketing clinical trial. In this event, neurologists should be forewarned and should recommend immediate discontinuation of the medication.

Commentary

Leflunomide’s immunomodulatory activity derives from its action as a competitive inhibitor of the rate-limiting enzyme necessary for pyrimidine synthesis. This activity has similar efficacy to, and complements, the anti-purine synthesis effect of methotrexate, resulting in potentially additive anti-proliferative activity and benefit in rheumatoid arthritis. A77 1726, the active metabolite of leflunomide, accounts for 95% of drug levels in the blood, is highly protein bound, and has a half-life of 15 to 18 days, requiring up to 2 months to achieve steady-state levels. Enterohepatic recirculation further enables drug levels to be detected even 2 years after discontinuation of treatment.

Hepatotoxicity is the most serious adverse effect, with 5% demonstrating elevated liver enzymes, usually less than twice the normal. However, 15 deaths have resulted from hepatic failure or associated illness, leflunomide being possibly implicated in 10. Weight loss, diarrhea, hypertension, alopecia, pancytopenia, and interstitial pneumonitis are also reported. Peripheral neuropathy now must also be added to the list. Its etiopathogenesis remains unknown but vigilance is warranted (N Engl J Med 2004;350:2167-2179). — Michael Rubin

Dr.Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.