Insights into Methotrexate Toxicity in Elderly Patients with Rheumatic Disease

ACR CONVERGENCE 2022—For patients with moderate to severe rheumatoid arthritis (RA) disease activity, methotrexate monotherapy is recommended when initiating treatment with a disease-modifying anti-rheumatic drug (DMARD). Methotrexate, a dihydrofolate reductase inhibitor immunosuppressant, is preferred over other agents, such as Janus kinase inhibitors, because of its established safety and efficacy as a first-line DMARD and its low cost.¹

Although the use of low-dose methotrexate to treat rheumatic conditions is usually safe, it sometimes causes life-threatening events. A study by Martin Aringer, MD, Division of Rheumatology, Department of Medicine III, University Medical Center and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany, and colleagues examined severe cases of methotrexate toxicity for outcome, presentation and associated risk factors.²

Methods

The investigators identified patients with rheumatic diseases and severe methotrexate toxicity between 2011 and 2020. Using electronic health records, they collected patient data on age, sex, diagnosis, methotrexate dose, methotrexate duration of treatment, concomitant medication(s), toxicity symptoms, infections and patient outcome. The estimated glomerular filtration rate (eGFR), an indication of renal function, was assessed before methotrexate toxicity occurred, at admission to the hospital, during hospitalization and at hospital discharge. Additionally, data from a group of 150 patients with RA who were 70 years of age and older were analyzed for comparison.

Results

In the study, 11 patients—four men and seven women—aged 71–88 years were admitted to the hospital for severe methotrexate toxicity. Of these patients, seven had RA, two had giant cell arteritis, one had psoriasis and one had psoriatic arthritis. When admitted, all 11 patients had severe mucositis, eight patients had pancytopenia, 10 patients had renal impairment and six patients had skin lesions (not defined). Five patients had septicemia, and four patients had pulmonary infiltrates.

One patient died from complications related to septicemia. Nine patients were discharged from the hospital after an average of 26 days. The 11th patient’s outcome was not reported.

Two patients had recently started methotrexate. In the remaining eight patients, methotrexate had been used for a mean of 5.8 years (range: 3 months to 20 years). The last dose of methotrexate prescribed was a weekly dose of 13.3 mg ± 3.5 mg (mean ± SD), ranging from 7.5–20 mg. Plasma methotrexate levels were detectable in four of nine patients (range: 0.02–0.10 µmol/L). An accidental methotrexate overdose was clinically suspected in one patient.

Concomitant medications included non-steroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors (n=4) and angiotensin receptor blockers (ARBs; n=4); angiotensin-converting enzyme inhibitors (ACEi; n=2); and diuretics (n=5). Two patients took a combination of NSAIDs, ARBs or ACEi and diuretics.