medwireNews: Older adults with chronic kidney disease (CKD) who start low-dose methotrexate have a significantly higher 90-day risk for serious adverse events than those who take hydroxychloroquine, indicate findings from a retrospective study published in JAMA Network Open.
There was a twofold increase in the risk for the primary composite outcome of adverse events (hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects) among 2309 patients taking methotrexate at a weekly dose of 5–35 mg compared with 2309 taking hydroxychloroquine 200–400 mg/day. The 90-day rates were 3.55% versus 1.73%, respectively, giving an absolute risk difference of 1.82 percentage points.
Flory Muanda (Western University, London, Ontario, Canada) and colleagues report that the population-based study “confirms and extends the findings of 50 case reports and 2 retrospective cohort studies that reported an association between methotrexate use and toxic effects in patients with CKD.”
The study, conducted in Ontario using linked administrative healthcare databases, involved 4618 adults with CKD diagnosed between 2008 and 2021, who had an estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2 and were not receiving dialysis. The participants were aged an average of 77 years, and the majority (69%) were women.
The median time from prescription to experiencing an adverse event was 49 days among patients in the methotrexate group and 43 days in the hydroxychloroquine group.
Pneumotoxic effects were the most common adverse events, hospitalization for which was a significant 2.28 times more common among patients in the methotrexate group, occurring in 57 patients versus 25 in the hydroxychloroquine group.
Patients taking methotrexate versus hydroxychloroquine also had a significant 4.4-fold increased risk for hospital visits due to myelosuppression and a significant 1.39-fold increased risk for all-cause hospitalization.
However, there was no significant increase in the risk for hospital visits due to sepsis or for all-cause mortality with methotrexate use compared with hydroxychloroquine, and hepatoxic effects occurred in fewer than six patients overall.
The researchers note that the risk for adverse events was “amplified at lower levels of eGFR.”
In a subgroup analysis, patients with an eGFR below 45 mL/min per 1.73 m2 or of 45–59 mL/min per 1.73 m2 were a significant 2.79 times and 1.25 times more likely to have adverse events if they were taking methotrexate rather than hydroxychloroquine. However, the risk was not increased with methotrexate use in an additional comparison cohort of 20,554 individuals with normal kidney function (eGFR above 60 mL/min per 1.73).
Muanda et al report that “[f]or every 28 patients with moderate-to-severe CKD (ie, an eGFR <45mL/min/1.73 m2) who were prescribed low-dose methotrexate vs hydroxychloroquine, 1 patient was hospitalized with a serious adverse event.”
Furthermore, the researchers found in a secondary comparison that “the risk of toxic effects was greater” among patients who started methotrexate at a dose of 15–35 mg/week than those taking hydroxychloroquine, with respective rates at 90 days of 3.83% versus 1.18%, and a risk ratio (RR) of 3.25.
By contrast, there was no significant difference in the risk for adverse events in patients using a lower 5 to less than 15 mg/week dose of methotrexate compared with hydroxychloroquine (2.81 vs 1.82%; RR=1.55).
The researchers conclude that “patients with CKD starting low-dose methotrexate should have active surveillance, including blood tests and chest radiographs performed regularly to monitor for signs of myelosuppression, infection, hepatotoxic effects, and pneumotoxic effects.”
They recommend that “[t]he US Food and Drug Administration and Health Canada should also consider issuing warning labels to inform prescribers of the study’s findings.”
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