Low-dose methotrexate may pose serious adverse event risk for older adults with CKD

For older adults with chronic kidney disease (CKD) who are initiating a disease-modifying antirheumatic drug (DMARD), low-dose methotrexate appears to be associated with a heightened 90-day risk of serious adverse events compared with hydroxychloroquine, as shown in a study.

In a propensity score–based analysis of 4,618 adults with CKD (median age 76 years, 69 percent women), the primary outcome of a composite of serious adverse events within 90 days of starting DMARD occurred with greater frequency among new low-dose methotrexate users than among new hydroxychloroquine users (3.55 percent vs 1.73 percent; risk ratio [RR], 2.05, 95 percent confidence interval [CI], 1.42–2.96). The median time from starting the prescription to the outcome was 49 days in the methotrexate group and 43 days in the hydroxychloroquine group. [JAMA Netw Open  2023;6:e2345132]

“For every 28 patients with moderate-to-severe CKD (ie, an eGFR <45mL/min/1.73 m²) who were prescribed low-dose methotrexate vs hydroxychloroquine, one patient was hospitalized with a serious adverse event,” the investigators said.

When the events were assessed individually, starting low-dose methotrexate vs hydroxychloroquine was associated with an elevated risk of a hospital visit with myelosuppression (RR, 4.40, 95 percent CI, 1.73–11.20), pneumotoxic effects (RR, 2.28, 95 percent CI, 1.43–3.63), and all-cause hospitalization (RR, 1.39, 95 percent CI, 1.13–1.69) but not a hospital visit with sepsis or all-cause mortality.

Subgroup analysis showed that the risk of the primary outcome associated with low-dose methotrexate initiation was greater at lower levels of estimated glomerular filtration rate (eGFR <45 mL/min/1.73 m²: RR, 2.79, 95 percent CI, 1.51–5.13).

Furthermore, in a secondary comparison, methotrexate users at 15 to 35 mg/week had a higher risk of the primary outcome compared with hydroxychloroquine users.

Results were consistent across multiple sensitivity analyses.

Drug elimination by kidneys

In the study cohort, a DMARD was indicated for rheumatoid arthritis in 56 percent of patients, atopic dermatitis or eczema in 28 percent, dermatomyositis in 8 percent, systemic sclerosis in 7 percent, and psoriasis in 5 percent. The median prescribed doses were 15 mg/week for methotrexate and 400 mg/day for hydroxychloroquine. These medications were dispensed for a median of 145 and 124 days, respectively.

Most patients (69 percent) had an eGFR of 45 to 59 mL/min/1.73 m², 26 percent had an eGFR of 30–45 mL/min/1.73 m², and 5 percent had an eGFR <30 mL/min/1.73 m².

“Methotrexate is primarily eliminated by the kidneys, with 80 percent to 90 percent excreted unchanged in the urine. To avoid toxic effects, product monographs and prescribing guidelines recommend that methotrexate be started at a low dose in patients with CKD,” the investigators noted. [https://tinyurl.com/ymtsj2sy; https://pdf.hres.ca/dpd_pm/00064334.PDF]

“This population-based study … confirms and extends the findings of [previous] case reports and retrospective cohort studies that reported an association between methotrexate use and toxic effects in patients with CKD,” they added.

As such, the investigators stressed that patients with CKD starting low-dose methotrexate undergo active surveillance, with blood tests and chest radiographs performed regularly to monitor for signs of myelosuppression, infection, hepatotoxic effects, and pneumotoxic effects.

While acknowledging that the study did not assess whether low-dose methotrexate had more benefits than risks, the investigators highlighted the importance of balancing the benefits of using low-dose methotrexate in patients with CKD against the risks.

“If our findings are replicated in other jurisdictions, we recommend improving and updating product monographs and prescribing guidelines. The US Food and Drug Administration and Health Canada should also consider issuing warning labels to inform prescribers of the study’s findings,” they said.