Two Consecutive Days of Low-Dose Methotrexate Toxicity: A Diagnostic Challenge

Methotrexate is an immunosuppressive medication commonly used to treat rheumatological disorders, primarily by inhibiting the folic acid cycle, with dose-dependent toxicity affecting multiple organ systems. A 54-year-old woman with a history of rheumatoid arthritis (RA), previously treated with methotrexate but later switched to leflunomide, etanercept, and prednisone, presented to the emergency department due to abnormal lab results. After running out of leflunomide and experiencing increased joint pain, she resumed methotrexate for two consecutive days without folic acid supplementation. Three days later, she developed oral ulcers, blisters, decreased oral intake, and fatigue. Lab results revealed pancytopenia, with markedly low white blood cells, hemoglobin, platelets, and absolute neutrophil count. Initially, Stevens-Johnson Syndrome (SJS) was considered due to mucosal symptoms, but lack of rash made methotrexate toxicity more likely. Rheumatology and hematology consultations led to the discontinuation of methotrexate, administration of filgrastim and leucovorin, and subsequent clinical improvement. This case highlights the diagnostic challenge in differentiating methotrexate toxicity from SJS, as both can present with mucosal lesions, though pancytopenia pointed toward toxicity. Despite methotrexate's known dose-dependent toxicity, this patient's reaction at a low dose suggests a rare idiosyncratic response, underscoring the importance of vigilance even with standard dosing and the necessity of folic acid supplementation to reduce adverse effects.