What is the most likely cause of chills, mouth ulcers, and fever in a patient with rheumatoid arthritis (RA) on methotrexate (MTX) with normal vital signs?

Methotrexate-Induced Neutropenia

The most likely cause is methotrexate-induced neutropenia (Option A), and you must obtain an urgent complete blood count with differential immediately to confirm this diagnosis. 1, 2

Clinical Reasoning

The constellation of chills, mouth ulcers (stomatitis), and fever in a patient on methotrexate is the classic presentation of methotrexate-induced bone marrow suppression with neutropenia:

• Mouth ulcers (ulcerative stomatitis) are identified as very common early toxicities of methotrexate and are among the most frequently reported adverse reactions alongside leukopenia, chills, and fever 1, 3

• The combination of oral mucositis with fever is more characteristic of bone marrow suppression than simple viral infection, and the temporal relationship with MTX therapy strongly suggests drug toxicity rather than other etiologies 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, 2

Why Other Options Are Less Likely

Felty syndrome (Option C) would present with chronic splenomegaly and is accompanied by large granular lymphocytic leukemia in 40% of cases—this is not an acute presentation 4

Concomitant SLE (Option B) would not explain the acute presentation of fever with mouth ulcers in a patient on methotrexate, whereas the temporal relationship with MTX therapy and fever pattern suggest drug toxicity 2

Viral infection (Option D) is possible but less likely given the specific constellation of symptoms that are pathognomonic for methotrexate toxicity 2

Immediate Management Steps

1. Obtain urgent complete blood count with differential to confirm neutropenia—this is the critical first diagnostic step 1, 2

2. Discontinue methotrexate immediately if neutropenia is confirmed 1, 2

3. 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 2

4. Consider filgrastim (G-CSF) at 5 mcg/kg daily subcutaneously for toxic bone marrow suppression to accelerate myeloid recovery 2, 5

Critical Risk Factors to Assess

Evaluate for the following modifiable risk factors that increase methotrexate-induced myelosuppression risk:

• Renal insufficiency is a major modifiable risk factor 1, 2
• Drug interactions, particularly NSAIDs, trimethoprim-sulfamethoxazole, and penicillins 1, 2, 6
• Dosing errors such as daily instead of weekly administration 1, 2
• Hypoalbuminemia increases free drug levels 1, 2
• Folic acid deficiency or non-supplementation 1, 2, 6
• Vitamin B12 deficiency may also contribute to toxicity 6

Common Pitfall

The "normal vital signs" mentioned in the question should not provide false reassurance—methotrexate-induced neutropenia with fever represents a potentially life-threatening condition even with relatively stable vital signs initially, as infection risk increases dramatically with neutropenia 3, 4