Methotrexate-Induced Neutropenia
The most likely cause is methotrexate-induced neutropenia (Option A). The combination of fever, chills, and mouth ulcers in a patient on methotrexate represents a classic presentation of drug-induced bone marrow suppression with associated mucositis, which requires immediate evaluation and management 1, 2.
Clinical Reasoning
The constellation of symptoms strongly indicates MTX toxicity rather than other diagnoses:
Mouth ulcers (stomatitis) are a hallmark early sign of methotrexate toxicity, occurring as one of the most frequently reported adverse reactions alongside leukopenia 2. The American Academy of Dermatology specifically identifies mucocutaneous effects such as stomatitis and mouth ulcers as very common early toxicities of methotrexate 1.
Fever with chills in the context of oral mucositis suggests neutropenic infection, a life-threatening complication of bone marrow suppression 1. The FDA label explicitly lists ulcerative stomatitis, leukopenia, chills and fever, and decreased resistance to infection among the most frequently reported adverse reactions 2.
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. Myelosuppression accounts for the majority (67 out of 164) of methotrexate-associated fatalities 3.
Why Other Options Are Less Likely
Felty syndrome (Option C) is unlikely because it typically presents with chronic neutropenia, splenomegaly, and is accompanied by large granular lymphocytic leukemia in 40% of cases 4. The acute presentation with fever and mucositis is not characteristic of Felty syndrome.
Concomitant SLE (Option B) would not explain the acute presentation of fever with mouth ulcers in a patient on methotrexate, while the temporal relationship with MTX therapy and the fever pattern suggest drug toxicity 1.
Viral infection (Option D) is possible but less likely given the specific constellation of symptoms. The combination of oral mucositis with fever is more characteristic of bone marrow suppression than simple viral infection 1.
Immediate Management Protocol
Critical first steps must be taken urgently:
Obtain urgent complete blood count with differential to confirm neutropenia, which is the critical first step 1, 3.
Discontinue methotrexate immediately if neutropenia is confirmed, as recommended by the British Journal of Dermatology 1.
Initiate leucovorin (folinic acid) rescue therapy if severe bone marrow suppression is present, with an initial dose of up to 100 mg/m² every 6 hours until hematological abnormalities normalize and mucosal ulceration heals 1, 3.
Consider filgrastim (G-CSF) at 5 mcg/kg daily subcutaneously for toxic bone marrow suppression to accelerate myeloid recovery 1, 3.
If neutrophils <1×10^9/L with fever, this represents a medical emergency requiring immediate antibiotics ± G-CSF 3.
Key Risk Factors to Assess
Multiple factors can contribute to MTX-induced neutropenia:
Renal insufficiency is a major modifiable risk factor for MTX-induced myelosuppression, as methotrexate is excreted predominantly by the kidneys 1, 5.
Drug interactions, particularly NSAIDs, trimethoprim-sulfamethoxazole, and penicillins, increase the risk of MTX-induced myelosuppression 1, 6.
Dosing errors, such as daily instead of weekly administration, can lead to severe toxicity 1.
Hypoalbuminemia increases free drug levels, contributing to toxicity 1.
Folic acid deficiency or non-supplementation significantly increases risk 1, 4.
Common Pitfall
The most critical error is delaying CBC evaluation while pursuing other diagnoses. The normal vital signs (except fever) may provide false reassurance, but neutropenic fever can rapidly progress to sepsis even with initially stable hemodynamics. The presence of mucositis with fever in a patient on methotrexate should trigger immediate hematologic evaluation 1, 2.