Does Methotrexate Cause Oral Lesions?
Yes, methotrexate definitively causes oral lesions, with rates of alimentary tract mucositis ranging from 20-60% depending on the dose per cycle, and oral ulcers representing one of the most common early toxicities of this medication. 1, 2
Incidence and Risk Profile
The development of oral lesions with methotrexate is dose-dependent and well-established across multiple clinical contexts:
Standard chemotherapy doses: Methotrexate and other antimetabolites cause alimentary tract mucositis in 20-60% of patients according to the drug's given dose per cycle 1
HSCT prophylaxis: When methotrexate is used prophylactically to prevent graft-versus-host disease in hematopoietic stem cell transplantation, WHO grade 3 or 4 oral mucositis can occur in up to 75% of patients 1
Low-dose therapy: Even at low doses (5-20 mg weekly) used for rheumatoid arthritis, oral lesions occur in 78.6% of patients compared to 23.8% of controls, with a relative risk of 11.73 for developing oral lesions 3
Clinical Presentation
The oral manifestations of methotrexate toxicity include:
Ulcerative/erosive lesions are the most common presentation, occurring in 60.7% of patients on low-dose therapy 3
Stomatitis and mouth ulcers are identified as very common early toxicities by the American Academy of Dermatology 2
Mucositis can present as inflammatory and/or ulcerative lesions of the oral mucosa, ranging from mild symptoms to severe pain interfering with oral intake 1
Candidiasis occurs in 10.7% of patients receiving methotrexate 3
Non-healing ulcers and even lymphoma-like lesions have been reported 4
Mechanism and Risk Factors
Methotrexate causes oral lesions through its mechanism as a folic acid antagonist that inhibits rapid cell turnover throughout the body, particularly affecting the rapidly dividing cells of the oral mucosa 5, 6:
Folic acid deficiency or non-supplementation significantly increases risk 2, 7
Renal insufficiency is a major modifiable risk factor, as methotrexate is primarily excreted by the kidneys 2, 7
Drug interactions with NSAIDs, trimethoprim-sulfamethoxazole, and penicillins increase risk 2, 7
Dosing errors such as daily instead of weekly administration can lead to severe toxicity 2
Hypoalbuminemia increases free drug levels 2
Management Algorithm
When oral lesions develop in a patient on methotrexate, follow this structured approach:
Immediate Assessment
- Obtain urgent complete blood count with differential to assess for neutropenia and bone marrow suppression 2
- Check renal function (serum creatinine, eGFR) as impaired renal function increases toxicity risk 2, 7
- Review medication list for interacting drugs (NSAIDs, antibiotics, proton pump inhibitors) 2, 7
Discontinuation Decision
- Discontinue methotrexate immediately if neutropenia is confirmed or severe mucositis is present 2
- Stop methotrexate during active infection or when infection is not responding to standard treatment 8
- Temporarily discontinue if transaminases exceed twice the upper limit of normal 9
Rescue Therapy
- Initiate leucovorin (folinic acid) rescue with initial dose of up to 100 mg/m² every 6 hours if severe bone marrow suppression is present, continuing until hematological abnormalities normalize and mucosal ulceration heals 2
- Consider filgrastim (G-CSF) at 5 mcg/kg daily subcutaneously for toxic bone marrow suppression 2
- Ensure folic acid supplementation in all cases, as deficiency states increase toxicity 7, 6
Pain Management
- Basic oral care: Implement frequent non-medicated oral rinses (saline mouth rinses 4-6 times/day) 1
- Topical anesthetics can provide short-term pain relief on an empirical basis 1
- Morphine mouthwash solution should be considered when traditional therapies (magic mouthwash) do not provide adequate control, as it is a safer alternative to systemic opioids and may positively impact healing 5
- Patient-controlled analgesia with morphine is recommended for severe oral mucositis pain in HSCT patients 1
Common Pitfalls and Caveats
Critical warning: Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur 7
Temporal relationship: Oral lesions can develop at any time during methotrexate therapy, even after a single dose, and may occur in patients with at least one risk factor 2
Misdiagnosis risk: Dental practitioners are often the first doctors involved in assessing oral mucosal diseases, and meticulous questioning of the patient's medication history is essential, as these lesions are frequently not identified as medication side effects 10, 6
Folic acid interaction: Vitamin preparations containing folic acid may decrease responses to systemically administered methotrexate, but folic acid supplementation is still recommended to prevent toxicity 7
Recovery: Methotrexate discontinuation in both cases of toxicity typically results in healing without relapse when combined with appropriate supportive care 6