Delayed Onset of Hepatitis and/or Neutropenia in Patients with Rheumatoid Arthritis Treated with Combination Therapy of Methotrexate and Leflunomide

Seung Won Choi¹, Ji Seon Oh¹, You Jae Kim², Bon San Koo², Min Wook So², Yong-Gil Kim², Chang-Keun Lee² and Bin Yoo², ¹Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea, ²Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: combination therapies, Hepatitis, methotrexate (MTX), neutropenia and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Clinical Aspects I: Drug Studies/Drug Safety/Drug Utilization/Disease Activity & Remission

Session Type: Abstract Submissions (ACR)

Background/Purpose: The adverse effects of combination therapy of methotrexate (MTX) and leflunomide (LEF) have been reported in many studies. Because combination of various doses of each drug is used in clinical practice, the reported incidence of hepatitis and neutropenia is variable. Currently, the incidence of such adverse events according to the duration of combination therapy has not been established. The purpose of this study is to evaluate the incidence of delayed onset of hepatitis or neutropenia in patients with rheumatoid arthritis (RA) treated with combination therapy of MTX and LEF.

Methods: We retrospectively reviewed medical records of 144 RA patients who had been treated with combination of fixed dose of MTX and 20mg of LEF, and who had been followed up with regular laboratory evaluation for longer than 6 months. We evaluated the incidence of hepatitis (serum aminotransferases greater than two times the upper limit of normal) and/or neutropenia (absolute neutrophil count < 1500/uL) according to the treatment duration.

Results: Mean age of patients was 55.3 ± 9.6 (range, 34-77; male:female, 27:117). Mean duration of combination therapy of MTX and LEF was 17.8 ± 13 months (range, 1.6-59.5 months; median 14 months). Mean doses of MTX was 9.8 ± 1.5 mg per week (range, 7.5-15 mg/week). The overall incidence of hepatitis was 19% (20/144). Of 144 patients, 14 (10%), 8 (6%), and 2 (1%) had delayed onset of hepatitis after 6, 12, and 24 months, respectively. Among patients with delayed onset of hepatitis after 6 months, mean duration of combination treatment was 14.5 ± 6.3 months (range, 8.3-26.0 months), and calculated cumulative doses of MTX and LEF, 628.7 ± 307.1 mg and 8.7 ± 6.0 g, respectively. The overall incidence of neutropenia was 6% (8/144). Of 144 patients, 7 (5%), 4 (3%), and 1 (1%) had delayed onset of neutropenia after 6, 12, and 24 months, respectively. Among patients with delayed onset of neutropenia after 6 months, mean duration of combination treatment was 18.0 ± 16.0 months (range, 6-52 months), and calculated cumulative doses of MTX and LEF, 774.0 ± 691.3 mg and 14.0 ± 10.9 g, respectively.

Conclusion: This study suggested that delayed onset of hepatitis and/or neutropenia in patients with combination treatment of MTX and LEF was relatively common during 6-12 months of treatment. In addition, regular monitoring for such adverse events should be required for cumulative toxicity of long-term combination therapy.

Disclosure:

S. W. Choi,
None;

J. S. Oh,
None;

Y. J. Kim,
None;

B. S. Koo,
None;

M. W. So,
None;

Y. G. Kim,
None;

C. K. Lee,
None;

B. Yoo,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/delayed-onset-of-hepatitis-andor-neutropenia-in-patients-with-rheumatoid-arthritis-treated-with-combination-therapy-of-methotrexate-and-leflunomide/