Can methotrexate (MTX) cause intermittent fevers?

Methotrexate and Intermittent Fevers

Yes, methotrexate can cause intermittent fevers as a side effect, particularly as a manifestation of drug toxicity or as part of methotrexate-induced pneumonitis. 1, 2

Mechanism and Presentation

• Fever is specifically listed as a potential symptom of methotrexate overdose, which may take 6-23 days to manifest alongside other symptoms like mucositis, diarrhea, and erythema 1
• Fever can occur as part of methotrexate-induced pneumonitis, presenting with dry cough, dyspnea, and infiltrates on chest X-ray 3
• Methotrexate-induced pneumonitis can develop even weeks after discontinuation of treatment, presenting with fever as one of the cardinal symptoms 2
• Chills and fever are specifically listed as potential toxicities of methotrexate in dermatology guidelines 1

Risk Factors and Timing

• Fever itself can be both a symptom of methotrexate toxicity and a risk factor for delayed methotrexate elimination, creating a potentially dangerous cycle 4
• Methotrexate-associated fever may occur:
  • During active treatment 1
  • Within the first 12 weeks of treatment (when opportunistic infections are most common) 5
  • Up to 4 weeks after discontinuation of the medication 2

Clinical Significance

• Fever in patients on methotrexate requires careful evaluation as it may indicate:
  • Direct drug toxicity 1, 3
  • Methotrexate-induced pneumonitis 3, 2
  • Opportunistic infection (particularly Pneumocystis pneumonia) 5, 3
  • Decreased resistance to infection (a known side effect) 1
  • Bone marrow suppression (neutropenia with fever) 6

Management Recommendations

• When fever develops in a patient on methotrexate:
  • Consider temporarily withholding methotrexate until the cause is determined 5
  • Evaluate for signs of methotrexate pneumonitis (dry cough, dyspnea, hypoxemia) 3, 2
  • Rule out infection, particularly opportunistic infections like Pneumocystis pneumonia 3
  • Check complete blood count to assess for neutropenia or other cytopenias 1
  • Monitor renal function, as fever can impair methotrexate clearance 4

Prevention and Monitoring

• Regular monitoring of complete blood count is recommended (every 2-4 weeks initially, then every 1-3 months on stable dosing) 1
• Patients should be educated to report symptoms of methotrexate toxicity, including fever 1
• Patients should be advised that intercurrent illness causing dehydration (which may include febrile illnesses) is a reason to omit methotrexate dosing until recovery 1
• Consider prophylactic measures for patients at high risk of opportunistic infections 5

Important Caveats

• Fever with methotrexate use requires prompt evaluation as it may indicate serious complications requiring immediate intervention 3
• The development of fever can worsen methotrexate toxicity by impairing drug elimination 4
• Methotrexate should be used with extreme caution in patients with active infection 3