Methotrexate (MTX) was first developed as a chemotherapy agent but is now widely used at much lower doses for chronic inflammatory conditions. Classified as an antimetabolite and a disease-modifying anti-rheumatic drug (DMARD), MTX definitively causes immunosuppression. Its therapeutic effect relies on systematically suppressing the immune system.
Therapeutic Applications of Methotrexate
Methotrexate is most frequently prescribed for autoimmune diseases, where the immune system mistakenly attacks its own tissues. These conditions are characterized by chronic inflammation and an overactive immune response causing pain and tissue damage. Low-dose weekly MTX is a standard treatment for conditions like Rheumatoid Arthritis, Psoriasis, and Psoriatic Arthritis.
The goal of treatment is to suppress the excessive activity of immune cells driving the inflammatory process. Reducing this immune response helps MTX control symptoms, decrease inflammation, and prevent long-term damage to joints or skin. In Psoriasis, for example, it slows the rapid proliferation of skin cells that cause scaly patches.
While high-dose, daily methotrexate is used in oncology to treat cancers like leukemia and lymphoma, its weekly low-dose application functions primarily as an immunosuppressant and anti-inflammatory agent for autoimmune disorders. The drug is also used to treat other inflammatory conditions, including some forms of vasculitis and Inflammatory Bowel Disease, such as Crohn’s disease.
The Underlying Mechanism of Action
Methotrexate’s immunosuppressive power stems from its structural similarity to folic acid, a B vitamin essential for cell growth and division. MTX acts as a folic acid antagonist by competitively inhibiting the enzyme dihydrofolate reductase (DHFR).
The DHFR enzyme is responsible for converting dietary folate into its active form, which is necessary for the synthesis of purine and pyrimidine nucleotides. These nucleotides are the building blocks of DNA and RNA. By blocking their production, MTX impairs the replication and proliferation of rapidly dividing cells.
This effect is pronounced in immune cells, such as T and B lymphocytes, which must divide rapidly to mount an immune response. Suppressing the proliferation of these cells reduces the overall immune activity and inflammation in autoimmune diseases. MTX also contributes to an anti-inflammatory effect by increasing the extracellular release of adenosine.
Adenosine acts on specific receptors on immune cells to suppress inflammation. By interfering with adenosine metabolism, MTX causes it to accumulate outside of cells, providing an anti-inflammatory benefit. This dual mechanism—inhibiting immune cell division and promoting anti-inflammatory signaling—underpins its effectiveness in chronic inflammatory diseases.
Clinical Consequences of Immunosuppression
Infection Risk
The intentional suppression of the immune system carries the consequence of increased susceptibility to infections. Patients taking methotrexate are more vulnerable to bacterial, viral, and fungal infections, particularly those affecting the respiratory tract. Since the body’s ability to fight off pathogens is reduced, common infections can become more severe or prolonged.
Patients should be vigilant for signs of infection requiring immediate medical attention, such as a persistent fever, chills, or a severe sore throat. Because the drug can suppress the bone marrow, regular monitoring of blood counts is performed to ensure white blood cell levels remain within a safe range. Delaying treatment for an infection while on MTX can lead to serious complications.
Vaccination Guidelines
Individuals on immunosuppressive therapy must follow specific vaccination guidelines for safety and effectiveness. Non-live vaccines, such as the seasonal flu shot, Tdap, and the standard pneumococcal vaccine, are generally recommended for protection. However, the immune response may be lower or shorter-lived than in healthy individuals, sometimes requiring temporary adjustments to the MTX schedule to boost the vaccine’s effect.
Conversely, live-attenuated vaccines, which contain a weakened form of a living virus or bacteria, are avoided while on methotrexate. Live vaccines, such as the Measles-Mumps-Rubella (MMR) or the nasal spray flu vaccine, carry a risk of causing a disseminated infection in a person with a suppressed immune system. Patients must discuss upcoming vaccinations with a healthcare provider to determine the appropriate timing and type of vaccine.
Management and Monitoring
Due to the drug’s mechanisms, patients on methotrexate require consistent medical monitoring to ensure safety. This monitoring includes routine blood tests, often performed every 1 to 3 months, to check for potential toxicity. These tests assess liver function, kidney function, and a complete blood count (CBC) to watch for bone marrow suppression.
Folic acid supplementation is routinely prescribed alongside methotrexate to help mitigate many non-immune related side effects. These side effects, which include nausea, mouth sores (stomatitis), and gastrointestinal issues, are linked to the drug’s folate-antagonist properties on healthy, rapidly dividing cells. A weekly dose of folic acid, taken on a different day than the MTX dose, reduces these uncomfortable symptoms without compromising the drug’s anti-inflammatory and immunosuppressive effects.