WASHINGTON – "Blanket" monitoring guidelines for liver toxicity in patients taking methotrexate may do more harm than good.
That’s according to Dr. Gabriela Schmajuk, who found that up to a third of patients taking the drug for rheumatoid arthritis may have the drug discontinued unnecessarily in the presence of mildly elevated liver function tests (LFTs).
"We need more research to say what the best strategies are [when it comes to] LFT monitoring, and what our response to abnormal LFTs should be," she said at the annual meeting of the American College of Rheumatology.
In a poster presented at the meeting, Dr. Schmajuk of the University of California, San Francisco, and her colleagues looked at 899 new methotrexate users (97% male, mean age 71 years) aged 65 years and older treated at the Veterans Health Administration (VHA) during 2007-2008.
The study was conducted in response to the recent measure issued by the National Quality Forum, which assesses whether rheumatoid arthritis patients prescribed methotrexate received an LFT within 120 days of their prescription claim. The measure is for public quality reporting purposes.
First, Dr. Schmajuk looked at how many patients met the National Quality Forum’s measure.
Patients all had at least a 28-day supply of methotrexate with follow-up at the VHA for 3 months after the drug was dispensed.
Patients were excluded from the study if they had any diagnosis of inflammatory bowel disease or if they sought medical care outside the VHA, and the researchers correlated the first abnormal LFT with the rate of methotrexate discontinuation.
Overall, they found that 148 patients (16.5%) did not have any LFT testing after methotrexate was initiated.
Among the patients who did have their LFTs monitored, 136 (15.1%) had any abnormality of AST or ALT, and only 49 patients (5%) had an elevation of at least 1.5 times the upper limit of normal; among these, methotrexate was discontinued in 27 patients.
However, the researchers also found that methotrexate was discontinued in 28 (32%) of 87 patients with LFT elevations less than 1.5 times the upper limit of normal.
In an e-mail interview, Dr. Schmajuk conceded that a full chart review on these patients has not yet been completed, and that "it is entirely possible that patients were discontinuing [methotrexate] for reasons not related to the LFTs."
However, "We need more research to help decide what a safe cutoff of discontinuation should be – it is possible that it is higher than previously thought."
She added: "In the future, we should be able to tailor monitoring frequency to individual patients."
A second poster, also presented at the meeting, offered a step forward toward just that.
In that study, Dr. Monica Ramirez of Brigham and Women’s Hospital, Boston, attempted to identify clinical predictors of liver enzyme elevation in methotrexate-treated rheumatoid arthritis patients.
Dr. Ramirez and her colleagues conducted detailed chart evaluations of 500 rheumatoid arthritis patients treated at a single center since 1992 who were identified as ever having received treatment with methotrexate and who had LFTs greater than two times the upper limit of normal.
Patients were excluded if they had ever been diagnosed with hepatitis or any other liver disease, or if they had any concurrent hospital or clinic visits for cardiac disease, sepsis, acute kidney disease, metastatic cancer, trauma, or surgery.
A total of 90 (18%) cases were confirmed as having LFT elevations attributed to methotrexate usage.
The authors then assessed the relationship between several known risk factors for liver toxicity to see whether any of them predicted methotrexate dose reduction or discontinuation: age, sex, obesity, hyperlipidemia, methotrexate dose (2.5-7.5 mg, 10-17.5 mg, or 20-25 mg), alcohol use, statin use, and NSAID use.
In univariate analysis, only obesity was significantly associated with a likelihood of methotrexate discontinuation or dose reduction (odds ratio, 2.89; 95% confidence interval, 1.20-7.00; P = .02). Similarly, in multivariate analysis, obesity was the lone predictor (OR, 2.60; 95% CI, 1.01-6.66; P = .05).
"This suggests a potentially heightened risk of hepatotoxicity among obese patients," the authors concluded.
Dr. Schmajuk and her fellow researchers reported no disclosures and no outside funding for their study. The authors of the second study, led by Dr. Ramirez, reported funding from the National Institutes of Health, and one of the investigators reported financial support from Amgen, Abbott, and other companies.