A retrospective cohort study of more than 40,000 rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs) has found that leflunomide produced fewer serious adverse events (AEs), either alone or in combination, compared with methotrexate (MTX), other DMARD agents, or no DMARD therapy.

In an analysis of 40,594 RA patients, researchers at the University of Utah reported that leflunomide had the lowest incidence rate of all AEs (94.1 events/1000 person years[PY]; adjusted for age, sex, comorbidities), compared with 143.7 events/1000 PY in DMARD users (P <.0001) and 145.0/1000 PY among patients taking MTX (P <.0001).

Of the 651 hepatic events reported in this trial, the event rate among leflunomide patients (4.1/1000 PY) was significantly lower than that of non-DMARD users (13.02/1000 PY; P <.001), but not significantly lower than AEs observed among those taking other DMARD monotherapy (4.2/1000 PY) or MTX (6.2/1000 PY), according to the research team, led by Grant W. Cannon, MD, professor of medicine at the University of Utah and the Veterans Affairs Salt Lake City Health Care System, in Salt Lake City, Utah.

Other DMARDs included D-penicillamine, hydroxychloroquine, sulfasalazine, gold, etanercept, and infliximab. Patients treated with no DMARD received either non-steroidal anti-inflammatory agents or COX-2 inhibitors.

"Overall, only a small number of hepatic events were identified in this analysis," Dr. Cannon and colleagues reported in The Journal of Rheumatology. "No cases of biliary cirrhosis, hepatic coma, cirrhosis, unspecified chronic liver disease, or jaundice were observed in the leflunomide monotherapy cohort."

The Utah researchers also showed that the leflunomide plus MTX combination had an overall AE rate of 42.8/1000 PY, significantly lower than the nonleflunomide DMARD + MTX combinations (69.5/1000 PY; P = .0005). The leflunomide plus MTX rate was also lower than that of the leflunomide plus DMARD group (58.7/1000 PY; P = .03). However, among 2-drug therapy groups hepatic event rates were not statistically different. Two-drug combinations under evaluation included leflunomide plus MTX, leflunomide plus other DMARD, and other DMARD plus methotrexate.

"Dr. Cannon's publication is the result of years of effort and analysis to ascertain if there is a substantial risk of hepatic damage or dysfunction when using leflunomide alone or in combination with other drugs," said John J. Cush, MD, clinical professor of medicine at The University of Texas Southwestern Medical School, and chief of rheumatology and clinical immunology, Presbyterian Hospital, in Dallas, Texas.

Dr. Cush, a member of the Arthritis Drugs Advisory Committee of the FDA that met in March 2003 to investigate reports of adverse events associated with leflunomide, added that although 2% - 4% of RA patients taking leflunomide appear to have a 3-fold elevation of liver enzymes compared with 1% - 2% of placebo-treated patients, "no increased risk of serious hepatotoxicity could be ascribed to the use of leflunomide."

"One interesting finding was that the AE rates associated with monotherapy use were generally higher than the AE rates with two-drug combination therapy," the authors observed. This may be attributable to "depletion of susceptibles" effect, whereby the patients who continue taking the drugs are the ones who can tolerate them, while those "susceptible" to an AE "select themselves (or are selected) out of the population at risk."

The current investigation included an analysis of more than 83,000 PY of data, drawn from a major US insurance claims database (Aetna-US Healthcare), which contains information on more than 6,000,000 people, with links to medical, pharmacy, and laboratory records. All reported AEs were considered endpoints.

Primary endpoints included ICD-9 codes for hepatic events (acute and subacute necrosis, biliary cirrhosis, hepatic coma, noninfectious hepatitis, cirrhosis, other specified and unspecified chronic liver disease, jaundice, elevated enzymes), hematologic events (acquired pancytopenia, aplastic anemia), cutaneous events (Stevens-Johnson syndrome, toxic epidermal necrolysis), hypertension, pneumonitis, acute pancreatitis, and respiratory tract infections (influenza and bronchitis). A representative sample of serious hepatic events was validated by chart review.

The authors also noted that although MTX is well known for its association with hepatic toxicity, in this study it was the "other DMARD" cohort that had the highest rates of individual hepatic disease.

Although the rate of acute and subacute necrosis was higher in the leflunomide monotherapy group (2.4 cases/10,000 PY, based on one case) than that of MTX (0.6 cases/10,000 PY, 2 cases) and lower than the rate for other DMARDs (6.6 cases/10,000 PY, 7 cases), these rates were not statistically different.

Overall, the researchers concluded, AE rates in the leflunomide group, alone or in combination with MTX, "were generally lower than or comparable to the AE rates seen with MTX and other agents."

The study was sponsored in part by Aventis Inc, of Bridgewater, New Jersey.

Reference

Cannon GW, Holden WL, Juhaeri J, et al. Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. J Rheumatol 2004;31:1906-1911.