Personal non-commercial use only. The Journal of Rheumatology. Copyright © 2004. All rights reserved The Journal of Rheumatology 2004; 31:10 1906 From the Veterans Affairs Salt Lake City Health Care System and Division of Rheumatology, University of Utah, Salt Lake City, Utah; Aventis Pharmaceuticals, Bridgewater, New Jersey; and Galt Associates, Inc., Sterling, Virginia, USA. G.W. Cannon, MD, Professor of Medicine, Veterans Affairs Salt Lake City Health Care System and University of Utah; W.L. Holden, PhD; J. Juhaeri, PhD; W. Dai, MD, DrPH; L. Scarazzini, MD, Aventis Pharmaceuticals; P. Stang, PhD, Galt Associates, Inc. Address reprint requests to Dr. G.W. Cannon, Division of Rheumatology 4B200, University of Utah Medical Center, 30 North 1900 East, Salt Lake City, UT 84132-2404. E-mail: grant.cannon@med.va.gov Submitted June 16, 2003; revision accepted April 19, 2004. Hepatic and other adverse events (AE) during treatment of patients with rheumatoid arthritis (RA) with leflunomide (LEF) have been reported in clinical trials prior to approval by regulatory authorities. The frequency of these reported events as well as other rare AE may not be well described during clinical trials because of small sample sizes. The use of large databases in postmarketing surveillance allows identification of uncommon AE and a comparison of the incidence rates of AE during different RA treatments. These postmarketing data are also important to evaluate AE during clinical practice other than clinical trials 1-4 . This retrospective cohort study of 40,594 patients with RA compared AE during treatment with disease modifying antirheumatic drugs (DMARD). The investigation encom- passed more than 83,000 person-years (PY) of followup. The principal aim of the study was to determine and compare the incidence rates of serious hepatic (e.g., liver necrosis, hepatitis, acute liver failure), cutaneous (Stevens- Johnson syndrome, toxic epidermal necrolysis), hemato- logic (aplastic anemia, pancytopenia), hypertensive, respiratory (bronchitis, influenza), and pneumonitis AE during treatment with LEF, methotrexate (MTX), and other DMARD as monotherapy and combination therapy. In addi- tion, the rates of AE were also compared to rates in patients with RA not receiving DMARD therapy. MATERIALS AND METHODS This retrospective cohort study utilized data from the Aetna-US Healthcare claims database. This database contains health information on 6,470,000 covered persons, with linkage to medical, pharmacy, and laboratory data. Adverse Events with Disease Modifying Antirheumatic Drugs (DMARD): A Cohort Study of Leflunomide Compared with Other DMARD GRANT W. CANNON, WILLIAM L. HOLDEN, JUHAERI JUHAERI, WANJU DAI, LINDASCARAZZINI, and PAUL STANG ABSTRACT. Objective. To determine and compare the incidence of serious adverse events (AE) during treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARD), focusing on leflunomide (LEF). Methods. A retrospective cohort study of a large US insurance claims database was performed. Study groups were patients with RA classified by DMARD exposure as either no-DMARD therapy, single- agent DMARD (monotherapy), or combination-DMARD therapy. Specific DMARD examined were leflunomide (LEF) and methotrexate (MTX), compared to other DMARD (penicillamine, hydroxy- chloroquine, sulfasalazine, gold, etanercept, infliximab) and no DMARD (nonsteroidal antiinflam- matory drugs, COX-2 inhibitors). All AE reported were considered endpoints; primary endpoints included hepatic, dermatologic, hematologic, infectious, respiratory, hypertension, and pancreatitis AE. Results. The 40,594 RA patients of the study period (September 1998 to December 2000) accumu- lated 83,143 person-years (PY) of followup. Followup for each of the groups was: DMARD- monotherapy, 46,054 PY (55% of total); combination-DMARD, 25,830 PY (14%); and no-DMARD, 11,259 PY (14%). The incidence rate of all AE combined was significantly lower for LEF monotherapy (94 events/1000 PY) than MTX (145 events/1000 PY), other DMARD (143 events/1000 PY), or no DMARD (383 events/1000 PY) (p < 0.001 for all comparisons). The “all- AE” rates during combination therapy with LEF + MTX (43/1000 PY) and LEF + other DMARD (59/1000 PY) were lower than the “all-AE” rate for DMARD + MTX (70/1000 PY; p = 0.002). LEF monotherapy had the lowest rate of hepatic events in the DMARD monotherapy groups. Conclusion. The rates of AE in the LEF group, alone and combined with MTX, were generally lower than or comparable to the AE rates seen with MTX and other agents. (J Rheumatol 2004;31:1906–11) Key Indexing Terms: ADVERSE EFFECTS ANTIRHEUMATIC AGENTS METHOTREXATE COHORT STUDIES Personal, non-commercial use only. The Journal of Rheumatology. Copyright © 2004. All rights reserved. www.jrheum.org Downloaded on September 30, 2021 from