Study reveals nasty side-effects which could unnecessarily turn RA patients away from the drug
A large study on low-dose methotrexate has revealed the true toxicity of the medication, but the research cohort is not representative of patients with rheumatic disease, experts say.
In the US study, around 4,800 patients with coronary artery disease and type 2 diabetes were randomised to receive low-dose methotrexate or placebo for around two years.
Those taking methotrexate were more likely to experience gastrointestinal, infectious, pulmonary, and hematologic adverse events than the placebo group, but were slightly less likely to experience renal adverse events, the study found.
And the rate of skin cancer increased from around 1% in the placebo group to around 2% in the group taking methotrexate.
This study provided one of the first objective measurements of true toxicity associated with use of low-dose methotrexate, the researchers said. Previous studies have generally been small or observational.
However, the paper probably had little relevance for patients had rheumatic disease and needed to be carefully interpreted, rheumatologist Professor Michelle Leech said.
None of the patients in the trial had rheumatic disease, she said. Instead, the study cohort were receiving methotrexate as an experimental treatment for the vascular inflammation associated with atherosclerosis.
While patients with rheumatoid arthritis were generally younger women, the study cohort was comprised mostly of older men, she said.
It was possible that the adverse events observed in the study cohort could be different to those seen in patients with rheumatic disease due to the different interactions between the drug and the disease processes, Professor Leech said.
“By way of example, it’s been shown that dermatologists who use methotrexate to treat a psoriasis find a lot more trouble with abnormal liver function than, say, rheumatologists do when they use methotrexate to treat rheumatoid arthritis,” she said.
A similar argument was made by US rheumatologist Dr Vivian Bykerk in an accompanying editorial.
“The question arises whether these data are generalisable to patients with rheumatoid arthritis,” she said.
“Patients with RA differ from the [trial] participants in that they are younger, are predominantly women, and have lower rates of diabetes and obesity,” Dr Bykerk said.
“Although such differences could skew estimates of toxicity and adverse events, the risk estimates from [the trial] are largely congruent with those expected in methotrexate-treated patients with rheumatic diseases.”
The researchers acknowledged their study participants might metabolise methotrexate differently from patients with rheumatic disease.
“However, the relative risks probably do not differ, although this is not testable in our study cohort,” the researchers said.
Potential adverse events always needed to be weighed against the potential benefits in the context of a particular disease, which the paper did not do, Professor Leech said.
There was a lot of evidence that methotrexate prolongs life and reduced the risk of heart attack, she said.
“Methotrexate has had a profound effect on diminishing disability, stopping people going to surgery, stopping people going into wheelchairs.”
Misinterpreting studies such as this one could spread fear about the risks of methotrexate and cause patients with rheumatic disease to stop taking the drug, Professor Leech said.
Annals of Internal Medicine, 18 February
doi: 10.7326/M19-3369
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