Dec. 18, 2003 St. Louis, Dec. 12, 2003 -- Researchers at the Veterans Affairs (VA) Medical Center and Washington University School of Medicine in St. Louis have analyzed a national database of VA patients to investigate the effects of the rheumatoid arthritis drug leflunomide in the first years after its approval.
The Food and Drug Administration (FDA) approved the use of leflunomide for rheumatoid arthritis in October 1998 and recommends starting treatment with high doses to rapidly trigger the drug's benefits. But the study, which appears in the Dec. 15 issue of the journal Arthritis Care & Research, shows that such high doses may cause adverse side effects that lead some patients to stop taking the drug.
The findings may prompt physicians to consider slightly modifying the standard leflunomide treatment regimen.
"Our data suggest that by starting on a lower dose initially, patients tolerate the drug better," says Seth Eisen, M.D., a VA staff physician and professor of medicine and psychiatry at the School of Medicine. "The disadvantage is that it may take a little bit longer for patients to improve clinically; the advantage is that patients may be more likely to continue treatment."
Eisen and Chuck Siva, M.D., a rheumatology fellow, were principal investigators of the study, which was conducted in collaboration with several other VA medical centers across the country.
Rheumatoid arthritis, one of the most crippling forms of arthritis, afflicts about 2 million Americans with joint pain and inflammation. It is a chronic condition linked to immune system malfunctions. Leflunomide is one of about a dozen drugs available for treatment.
In addition to suggesting an alternative approach to initial treatment, the new findings also help put to rest lingering concerns about whether leflunomide's toxicity was adequately assessed in phase III FDA clinical trials that ended in 1998.
"As far as we could tell there were no surprises in terms of toxicity," Eisen says. "Sometimes it takes a lot more patients than the 3,300 we studied to pick up rare adverse outcomes, but I think our findings are reassuring to the larger community of patients and clinicians."
Eisen emphasizes that since the study is a review of already existent data, no control and intervention groups could be established and assessment of side effects could not be standardized.
"In a subset of the patients for whom the medication was discontinued, we examined their medical records in an attempt to determine the reason the medication was stopped," Eisen explains. "We were particularly looking for evidence of severe toxicity and did not find any. But still, it's a matter of trying to interpret clinical notes."
Although researchers were aware of the disadvantages of this type of study, there also are a number of potential advantages. Only a relatively small investment of money and time were required, and the patient population at the VA offered a chance to study portions of the general population that typically do not enroll in clinical trials.
Eisen explains that clinical trials often enroll more women and younger patients from higher socio-economic groups. The sex bias is particularly prevalent in clinical trials for treatments for rheumatological diseases, which afflict women more often than men.
"VA medical data complements information obtained from other sources because VA patients are predominantly male and older and include a higher proportion of African-Americans and individuals from lower socio-economic groups than general studies do," Eisen says.
The scientists' work with VA database records was closely monitored by the VA's Human Studies Committee to ensure patient information was appropriately accessed and used.
Eisen suggests that researchers should consider conducting studies like this on other drugs already approved for clinical use.
"Post-approval follow-up is very important because it may demonstrate problems, sometimes decades later, that weren't appreciated," Eisen says, citing the example of premarin, a treatment for post-menopausal symptoms. Risks recently linked to the drug were only identified several decades after it was approved for clinical use.
"Because post-approval studies tend to require large numbers of people in order to evaluate the less-common adverse outcomes, they are typically very, very expensive to do," Eisen says. "Studying large databases like the VA's is relatively inexpensive, and it is very feasible to collect and analyze important information."
C Siva, S Eisen, R Shepherd, F Cunningham, MA Fang, W Finch, D Salisbury, J Singh, R Stern, SA Zarabadi. Leflunomide use during the first 33 months after FDA approval: experience with a national cohort of 3,325 patients. Arthritis Care & Research, Dec. 15, 2003.
Funding from the Arthritis Foundation and Washington University School of Medicine supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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