Methotrexate Mouth Sores: Causes, Treatment, and Prevention

Methotrexate is widely used to treat rheumatoid arthritis, psoriasis, and certain cancers. Despite its effectiveness, it can cause side effects, including painful mouth sores that interfere with eating and speaking. These sores, known as oral mucositis or stomatitis, result from methotrexate’s effects on rapidly dividing cells in the mouth.

Understanding their causes and management is essential for those undergoing treatment.

Mechanisms Leading To Mouth Sore Formation

Methotrexate-induced mouth sores arise from its interference with cellular processes that maintain oral mucosa integrity. As an antifolate drug, it inhibits dihydrofolate reductase, an enzyme necessary for DNA synthesis and repair. This disruption disproportionately affects tissues with high cellular turnover, such as the epithelial lining of the mouth. The basal layer, responsible for generating new cells, experiences impaired proliferation, leading to thinning and increased fragility. Minor mechanical stress from chewing or speaking can then cause microtrauma, progressing into painful ulcers.

Beyond inhibiting DNA synthesis, methotrexate induces oxidative stress in oral tissues. Studies have shown that treatment elevates reactive oxygen species (ROS) levels, leading to lipid peroxidation and mitochondrial dysfunction in epithelial cells. This oxidative damage weakens cellular membranes and disrupts healing, prolonging mucosal injury. A 2021 study in Frontiers in Pharmacology found that methotrexate patients exhibited significantly higher markers of oxidative stress in oral tissues, correlating with increased mucositis severity.

Methotrexate also impairs angiogenesis by reducing endothelial cell proliferation, limiting the mucosa’s ability to repair itself. A reduction in capillary density restricts oxygen and nutrient delivery, exacerbating tissue breakdown. This vascular insufficiency delays healing and allows minor lesions to develop into larger, more painful ulcers.

Oral Tissue Changes During Therapy

As methotrexate therapy continues, the oral mucosa undergoes structural and functional changes that increase ulceration risk. Early signs include erythema—redness due to increased vascular permeability and mild inflammation. While often painless initially, histological analyses show that even in the absence of visible lesions, subclinical epithelial damage accumulates, disrupting normal mucosal turnover.

Epithelial atrophy becomes more pronounced over time. The protective stratified squamous epithelium thins due to impaired cell proliferation. A 2022 study in Oral Diseases found that rheumatoid arthritis patients on low-dose methotrexate exhibited a 30% reduction in basal cell mitotic activity compared to healthy controls. This decline weakens tissue integrity, making it more susceptible to irritation from routine activities like chewing or brushing teeth.

As epithelial thinning progresses, desquamation—shedding of superficial mucosal layers—further compromises the oral barrier. This exposes underlying connective tissue, increasing sensitivity to acidic or spicy foods and worsening discomfort. Many patients also report dryness or roughness in the mouth, exacerbated by reduced salivary flow. Saliva buffers pH levels and provides antimicrobial peptides that help maintain mucosal health. Reduced salivary production accelerates tissue breakdown, facilitating painful erosions.

Methotrexate also disrupts connective tissue by impairing fibroblast function, reducing collagen synthesis, and weakening the extracellular matrix. A 2023 review in The Journal of Oral Pathology & Medicine noted that methotrexate-treated individuals exhibited delayed fibroblast migration and reduced collagen deposition at oral injury sites, prolonging healing.

Interactions With Folic Acid Metabolism

Methotrexate’s effect on folic acid metabolism plays a central role in mouth sore development. Folate is essential for maintaining rapidly dividing cells, including those in the oral mucosa. By inhibiting dihydrofolate reductase, methotrexate disrupts the conversion of dietary folate into its active form, tetrahydrofolate (THF), impairing DNA replication and repair. Without sufficient THF, epithelial cells struggle to regenerate, increasing susceptibility to ulcer formation.

Folate depletion also affects methylation pathways crucial for cellular function. Methotrexate-induced deficiency reduces S-adenosylmethionine (SAM) synthesis, a key methyl donor involved in DNA methylation and gene regulation. This disruption alters gene expression related to cellular proliferation and inflammation, further contributing to mucosal fragility. A 2020 study in The Journal of Clinical Pharmacology found that patients with lower serum folate levels during methotrexate therapy had a higher incidence of severe oral mucositis.

Folic acid supplementation is widely recommended to mitigate methotrexate-related side effects, including mouth sores. The American College of Rheumatology advises folic acid supplementation (1-5 mg daily) for patients on methotrexate to reduce toxicity while preserving therapeutic efficacy. Research shows supplementation significantly lowers mucositis incidence without compromising methotrexate’s effectiveness. A meta-analysis in Annals of the Rheumatic Diseases reported a 79% reduction in gastrointestinal and mucosal side effects among patients taking folic acid.

Types Of Lesions

Methotrexate-induced mouth sores vary in severity and presentation. The most common type is aphthous-like ulcers, resembling canker sores with a yellowish or white fibrinous center surrounded by an erythematous halo. These ulcers typically develop on non-keratinized mucosal surfaces, such as the inner cheeks, lips, and mouth floor, where the epithelium is thinner and more vulnerable to methotrexate’s effects. Unlike traditional aphthous ulcers linked to immune dysregulation or nutritional deficiencies, methotrexate-induced ulcers stem from impaired cellular regeneration and direct cytotoxicity.

Some patients experience diffuse mucositis, where large sections of the oral mucosa become inflamed and ulcerated rather than presenting as isolated sores. This widespread damage can make speaking and swallowing painful. In severe cases, lesions coalesce, forming extensive areas of epithelial breakdown that increase the risk of secondary infections. Fungal overgrowth, particularly Candida species, can further complicate healing, as the compromised mucosal barrier allows opportunistic pathogens to thrive.

Nutritional Factors Affecting Oral Health

Dietary habits and nutrient intake influence the severity of methotrexate-induced mouth sores. Oral tissues require a steady supply of vitamins and minerals for cellular integrity and repair. Patients on methotrexate often experience reduced appetite or altered taste perception, leading to nutrient deficiencies that can worsen mucosal fragility and delay healing.

Vitamin B12 and iron are essential for epithelial turnover and wound healing. Both support DNA synthesis and red blood cell production, which facilitates oxygen delivery to regenerating tissues. A 2021 study in Clinical Oral Investigations found that individuals with recurrent oral ulcers, including those caused by methotrexate, frequently had lower serum B12 and iron levels. Zinc also plays a role in epithelial regeneration by supporting metalloproteinases involved in tissue remodeling. Patients with low zinc levels experience delayed wound healing and increased susceptibility to mucosal lesions. Ensuring adequate intake of these nutrients or supplementing deficiencies may help reduce methotrexate-related mouth sores.

Immunological Considerations

Methotrexate alters immune function, which can influence oral lesion frequency and severity. As an immunomodulatory drug, it suppresses T-cell activity and cytokines involved in inflammation. While this helps treat autoimmune diseases, it also weakens the mucosal immune barrier, making the oral cavity more vulnerable to irritation and secondary infections. Patients with weakened mucosal immunity may experience prolonged ulcer duration or increased susceptibility to bacterial overgrowth, further delaying healing.

The balance of pro-inflammatory and anti-inflammatory cytokines plays a role in oral lesion formation. Methotrexate reduces tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), both involved in acute inflammatory responses. While lowering these cytokines helps control autoimmune diseases, it can also impair wound healing. A 2022 study in Immunopharmacology and Immunotoxicology found that methotrexate-treated patients had lower levels of epithelial growth factors in oral tissues, correlating with slower ulcer resolution. This suggests that while methotrexate reduces systemic inflammation, it may simultaneously hinder mucosal repair.