Clinical characteristics and treatment of low-dose methotrexate-related adverse reactions in rheumatoid arthritis: a...

Low-dose methotrexate (MTX) (5-25 mg/week) is widely used in the treatment of autoimmune diseases and is considered relatively safe. There have been reports of toxicities caused by MTX, but the characteristics remain unclear. Through a retrospective case series at our hospital, we describe the clinical features, management, and outcomes of adverse reactions caused by MTX. This is a retrospective, single-center case series of patients with rheumatoid arthritis (RA) who developed adverse reactions while receiving low-dose MTX (5-25 mg/week) between March 2022 and August 2025. Exclusion criteria included adverse reactions due to other drugs, viral infections, or vitamin B12/folate deficiency. We present only descriptive statistics (median, range, frequency). The series included 18 patients. Of these, 77.78% were female. Median age was 72 years (51-77 years). Median MTX dosage was 10 mg (7.5-35 mg) weekly. Adverse reactions involved multiple organ systems. Hematological adverse reactions were primarily characterized by cytopenia, anemia, and bleeding. Gastrointestinal adverse reactions were nausea and vomiting. Skin-related adverse reactions included skin ulcers, erythema, swelling, and pain. Leucovorin calcium rescue therapy via intravenous administration was given in 77.78% of patients. Additionally, 9 patients (50.00%) required blood transfusion, 8 patients (44.44%) received recombinant human granulocyte-stimulating factor, and 5 patients (27.78%) were treated with sodium bicarbonate for urine alkalization. During hospitalization, 2 patients (11.11%) died, both due to severe infectious complications. Most adverse reactions caused by low-dose MTX were manageable with supportive care. However, severe toxicity (including fatalities) occurred in elderly or frail patients. Serum MTX concentration showed inconsistent associations with adverse reactions and should not be relied upon to predict low-dose MTX toxicity.