Methotrexate-Induced Neutropenia
The most likely cause is methotrexate-induced neutropenia (Answer A), as the triad of fever, chills, and mouth ulcers (oral mucositis) is the classic presentation of methotrexate-induced bone marrow suppression. 1, 2
Clinical Reasoning
Why Methotrexate-Induced Neutropenia is Most Likely
Oral mucositis with fever is the hallmark presentation of MTX-induced pancytopenia. In a case series of 46 patients with MTX-induced pancytopenia, oral mucositis was present in 80% (37/46) and fever in 52% (24/46) of cases. 2
The American Academy of Dermatology identifies mucocutaneous effects such as stomatitis and mouth ulcers as very common early toxicities of methotrexate. 1
Pancytopenia can occur after even a single dose of methotrexate and can develop at any time during treatment, typically in patients with at least one risk factor. 1
The FDA drug label specifically lists "chills and fever" along with "ulcerative stomatitis" and "leukopenia" as the most frequently reported adverse reactions to methotrexate. 3
Why Other Options Are Less Likely
Felty syndrome (Answer C) presents with the triad of rheumatoid arthritis, splenomegaly, and neutropenia—but typically develops in patients with long-standing, severe RA with high rheumatoid factor titers. The acute presentation with fever and mouth ulcers points more toward drug toxicity. 1, 2
Concomitant SLE (Answer B) would not explain the acute presentation of fever with mouth ulcers in a patient on methotrexate. While oral ulcers occur in SLE, the temporal relationship with MTX therapy and the fever pattern suggest drug toxicity.
Viral infection (Answer D) is possible but less likely given the specific constellation of symptoms. While methotrexate increases infection risk, the combination of oral mucositis with fever is more characteristic of bone marrow suppression than simple viral infection. 1, 4
Immediate Management Required
Obtain urgent complete blood count with differential to confirm neutropenia. This is the critical first step. 1
Discontinue methotrexate immediately if neutropenia is confirmed. 5, 1
Initiate leucovorin (folinic acid) rescue therapy if severe bone marrow suppression is present. Leucovorin should be given intravenously at an initial dose of up to 100 mg/m² every 6 hours until hematological abnormalities normalize and mucosal ulceration heals. 5
Consider filgrastim (G-CSF) at 5 mcg/kg daily subcutaneously for toxic bone marrow suppression to accelerate myeloid recovery. 5
Monitor carefully for signs of sepsis as there is high mortality risk associated with MTX-induced pancytopenia. In the case series, 13 of 46 patients (28%) died, with WBC at admission being the most important prognostic factor. 2
Common Risk Factors to Assess
Renal insufficiency is a major modifiable risk factor for MTX-induced myelosuppression. 1
Drug interactions, particularly NSAIDs (which decrease renal clearance), trimethoprim-sulfamethoxazole (dual folic acid antagonist), and penicillins. 1, 6
Dosing errors, such as daily instead of weekly administration. 1