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Leflunomide-Associated Pancytopenia With or Without Methotrexate

Senior Registrar in Clinical Pharmacology; Lecturer, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia

Daniela C Sanders, BPharm

Clinical Pharmacist, Princess Alexandra Hospital

Leanne Du, MB BS BSc

Medical Officer, Princess Alexandra Hospital

Peter I Pillans, MD FRACP

Director, Clinical Pharmacology; Senior Lecturer, Department of Medicine, University of Queensland, Princess Alexandra Hospital

Reprints: Peter I Pillans MD FRACP, Department of Clinical Pharmacology, 5/F Medical Specialties, Ipswich Rd., Princess Alexandra Hospital, Queensland 4102, Australia, fax 61 7 32407131, peter_pillans{at}health.qld.gov.au

OBJECTIVE: To report 18 cases of pancytopenia associated with leflunomide use in Australia, 5 of which were treated at Princess Alexandra Hospital, Brisbane.

CASE SUMMARIES: Leflunomide was used in the treatment of rheumatoid arthritis in 17 of 18 patients; the other patient was diagnosed with systemic lupus erythematosus. Median age was 65.5 years (range 18–79), and 15 of the patients were female. Fourteen patients were on combined treatment with methotrexate. Pancytopenia was typically severe, requiring hospital admission, withdrawal of the immunosuppressant(s), intensive supportive therapy, and treatment of neutropenic sepsis. Five patients died, 4 of whom were receiving concomitant methotrexate. Time to onset of pancytopenia ranged from 11 days to 4 years (median 4 mo). In one case in which the patient had been stable while receiving leflunomide, methotrexate, and hydroxychloroquine for 4 years, fatal pancytopenia was triggered by acute renal failure secondary to dehydration and use of nonsteroidal antiinflammatory drugs. The Naranjo probability scale suggested a probable causal association in 5 cases and possible association in the remainder.

DISCUSSION: Leflunomide, indicated for treatment of active rheumatoid arthritis, inhibits pyrimidine synthesis in lymphocytes and other rapidly dividing cells and may rarely be associated with life-threatening pancytopenia. Combination therapy with methotrexate may increase the risk. Time to onset is variable, and clinicians should remain vigilant, particularly when there is a change in the patient's baseline health status.

CONCLUSIONS: The risk of pancytopenia during leflunomide therapy appears to be increased when the drug is combined with methotrexate and in older patients. Onset may be delayed, and ongoing monitoring of blood counts is essential.

Key Words: leflunomide, methotrexate, pancytopenia

Published Online, June 8, 2004. www.theannals.com, DOI 10.1345/aph.1E012

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