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.
Before methotrexate toxicity occurred, eGFR was available for many of the patients. Five patients (63%) had mild renal insufficiency (60–89 mL/min/1.73 m²) and three patients (38%) had moderate renal insufficiency (30–59 mL/min/1.73m²). At the time of admission, four patients had mild renal insufficiency, five patients had moderate renal insufficiency, and one patient had severe renal insufficiency with an eGFR of 9 mL/min/1.73m².
By comparison, the group of 150 patients with RA received 14.3 mg ± 4.9 mg of methotrexate a week. These patients used ARBs or ACEis and NSAIDs or COX-2 inhibitors at similar rates as the study group but were less likely to use diuretics (n=18) than the study group (n=5; P=0.01 Fisher’s exact test). The comparator group’s eGFR was 70 mL/min/1.73m², which was higher than that of the patients with methotrexate toxicity (median 61 [32–77] mL/min/1.73m²; P=0.0171). Eight (5%) of the patients from the comparator group had normal renal function, 105 (70%) had mild renal insufficiency, 35 (23%) had moderate renal insufficiency and one had an eGFR of 19 mL/min/1.73m².
Conclusion
These data show that life-threatening methotrexate reactions still occur. In the evaluated patients who were older than 70 and had prior mild to moderate renal function impairment, the risk of serious methotrexate toxicity was increased. In many of these patients, acute renal failure that may have improved by the time of hospital admission seemed to be the cause of methotrexate toxicity. While one patient was clinically suspected of accidental methotrexate overdose, researchers also found measurable levels in three other patients that suggest overdose. Compared with an RA population of similar age, the renal function of the study group was slightly worse, and the use of diuretics was more common in those with severe toxicity.
Reminders: When treating patients with low-dose methotrexate, liver and kidney disease should be excluded prior to use, as well as alcohol use.3 Chest radiograph and pregnancy testing should be obtained prior to starting treatment.
Physicians and other members of the healthcare team should obtain a patient’s complete blood count, and liver and kidney function tests prior to prescribing methotrexate. Monitor these levels throughout treatment. A complete blood count, creatinine and liver function tests should be assessed every two to four weeks during the first three months of treatment, every eight to 12 weeks for the following three to six months and every 12 weeks thereafter.
Methotrexate may cause bone marrow suppression, and hepatic and pulmonary disorders. Decreased clearance, drug-to-drug interactions and dosing errors are risk factors for toxicity.
Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.
References
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021 Jul;73(7):1108–1123.
- Kumar C, Herrmann K, Aringer M, et al. Severe low-dose methotrexate toxicity in elderly patients with inflammatory rheumatic diseases [abstract 0929]. Arthritis Rheumatol. 2022;74(suppl 9).
- Pivovarov K, Zipursky JS. Five things to know about low-dose methotrexate toxicity. CMAJ. 2019 April 15;19:E423.
