Case Presentation: A 76-year-old man presented with 4 days of fever, abdominal pain, nausea, vomiting, and confusion. His history included overlap granulomatosis with polyangiitis and giant cell arteritis, treated with rituximab until it was discontinued 6 months earlier for hypogammaglobulinemia. Low-dose methotrexate (MTX) was started 2 months before admission and increased to 20 mg weekly with folic acid. He denied intentional overuse but reported occasional medication errors.On exam, he was febrile (Tmax 39.4°C) with left lower quadrant tenderness. Labs showed profound leukopenia (WBC 1.09 k/µL; ANC 0.03 k/µL), platelets 104 k/µL, and CT abdomen/pelvis demonstrated mild uncomplicated diverticulitis. MTX level was undetectable. Blood and urine cultures were negative.He was treated for neutropenic fever with cefepime and metronidazole. Intravenous leucovorin was started for suspected MTX toxicity, and MTX was held. His symptoms resolved, and by hospital day 5 his WBC normalized to 5.66 k/uL and ANC improved to 1.54 k/uL. MTX was discontinued with plans to transition to azathioprine.
Discussion: We present a case of severe neutropenia and fever attributed to low-dose MTX toxicity, which can occur early in therapy despite standard dosing. Prompt recognition of neutropenic fever is critical, requiring immediate antibiotics, supportive care, and investigation of infection sources. Prior to attributing the presentation to MTX toxicity, other potential causes of neutropenia were excluded including infection (CMV, EBV, Parvovirus), malignancy (peripheral flow cytometry), and micronutrient deficiency (zinc, copper).Despite an undetectable serum MTX level, toxicity remained likely. Notably, serum MTX levels may not reliably identify toxicity in rheumatologic dosing, which is substantially lower than oncologic dosing, due to cellular accumulation. Leucovorin rescue is therefore indicated based on clinical suspicion rather than drug levels alone. Mortality from severe low-dose MTX toxicity may exceed 40%, underscoring the importance of rapid intervention.Low-dose MTX toxicity typically arises from unintentional overdosing or renal impairment; genetic variants in MTHFR may contribute modestly. This patient was a compound heterozygote for 665C>T and 1286A>C, though this likely played a minimal role.
Conclusions: Overall, this case demonstrates that severe MTX toxicity can develop even with correct dosing and undetectable serum levels. Clinical suspicion should guide diagnosis and treatment, with leucovorin administration based on clinical presentation rather than reliance on drug levels alone and emergent treatment if any suspicion for infection. Vigilant monitoring during initiation and in patients with risk factors is essential to prevent potentially fatal complications.