Methotrexate-Induced Neutropenia (Answer: A)
The most likely cause is methotrexate-induced neutropenia (myelosuppression), which classically presents with fever, chills, and mouth ulcers (mucositis/stomatitis) as early signs of bone marrow toxicity. 1, 2
Clinical Reasoning
Why Methotrexate-Induced Neutropenia is Most Likely
The triad of fever, chills, and mouth ulcers in a patient on methotrexate is pathognomonic for methotrexate-induced myelosuppression. 1, 2
Mouth ulcers (ulcerative stomatitis) are among the most frequently reported adverse reactions to methotrexate and represent a very common early toxicity that signals bone marrow suppression 1, 2
Fever and chills are classic manifestations of neutropenia-related infection or the myelosuppressive process itself 2, 3
Bone marrow suppression generally occurs early in treatment (first 4-6 weeks) and is reversible with cessation 1
Pancytopenia can result after even a single dose of methotrexate and can occur at any time during treatment, typically in patients with at least one risk factor 4
Why Other Options Are Less Likely
Felty syndrome (Option C) would require the presence of splenomegaly and typically presents with chronic neutropenia rather than acute onset with fever and mouth ulcers 5. This is a chronic autoimmune complication of longstanding RA, not an acute presentation.
Concomitant SLE (Option B) would require additional systemic features beyond this acute presentation and would not specifically explain the mouth ulcers in the context of methotrexate therapy 5.
Viral infection (Option D) is possible but less likely as the primary diagnosis because the combination of mouth ulcers with fever specifically points to methotrexate toxicity, which is a known and common adverse effect 1, 2. However, viral infection could be a secondary complication of the neutropenia.
Critical Management Steps
Immediate discontinuation of methotrexate is mandatory when myelosuppression is suspected. 5, 6
Obtain urgent complete blood count with differential to confirm neutropenia 4
A neutrophil count below 0.5 g/L with fever indicates a life-threatening condition requiring emergent treatment 5
Leucovorin (folinic acid) rescue should be initiated for severe toxicity or overdose 1, 6
Consider filgrastim (G-CSF) for toxic bone marrow suppression 1, 3
Maintain hydration and consider urine alkalinization 1
Risk Factors to Assess
Multiple factors increase the risk of methotrexate-induced myelosuppression: 4, 6
- Renal insufficiency (most important modifiable factor)
- Advanced age
- Methotrexate dosing errors (daily instead of weekly dosing)
- Drug interactions (NSAIDs, trimethoprim-sulfamethoxazole, penicillins)
- Hypoalbuminemia
- Folic acid deficiency
- Vitamin B12 deficiency (pernicious anemia)
The concurrent use of trimethoprim-sulfamethoxazole with methotrexate can be associated with severe toxicity due to both drugs being folic acid antagonists 4, 7.
Common Pitfall
The most critical pitfall is failing to recognize that mouth ulcers in a patient on methotrexate represent a warning sign of bone marrow toxicity, not just a minor mucosal side effect. 1, 2 This symptom should trigger immediate laboratory evaluation and consideration of drug discontinuation, as it may herald life-threatening pancytopenia.