Methotrexate is a powerful medication used to treat a wide range of conditions, from autoimmune disorders like rheumatoid arthritis and psoriasis to certain types of cancer. Its effects on the body are highly dependent on the dose, targeting cellular processes in different ways for different purposes.
How Methotrexate Works in the Body
Methotrexate is an antimetabolite, meaning it interferes with the normal metabolic processes of cells. Its primary mechanism of action is as a folate antagonist, but it also has immunomodulatory effects, particularly at lower doses.
The Folate Antagonism Pathway
Methotrexate is structurally similar to folic acid (vitamin B9) and works by blocking the enzyme dihydrofolate reductase (DHFR), which is crucial for converting folate into its active form. This inhibition disrupts the synthesis of DNA and RNA, which are necessary for cell division and replication. Because cancer cells and certain immune cells divide rapidly, they are more susceptible to this effect, leading to slowed growth or cell death. Inside cells, methotrexate is converted into polyglutamated forms, which prolongs its action. In cancer treatment, this cytotoxic effect is the primary goal.
The Adenosine Signaling Pathway
At lower doses, commonly used for autoimmune diseases, the anti-inflammatory effects of methotrexate are not primarily due to cytotoxicity. Instead, they are largely mediated by a different mechanism involving adenosine. Methotrexate inhibits an enzyme called AICAR transformylase (ATIC), causing a buildup of AICAR inside cells. This, in turn, leads to increased extracellular adenosine, a natural anti-inflammatory molecule. Adenosine binds to receptors on the surface of inflammatory cells, suppressing the release of pro-inflammatory cytokines like TNF-α and interleukins, and calming the immune system.
Other Immunomodulatory Effects
Beyond adenosine, methotrexate also has other effects on the immune system, including:
- Suppressing key inflammatory pathways like NF-κB and JAK/STAT.
- Modulating the balance of T-helper cell subsets (e.g., reducing Th1 and Th17 cells while increasing anti-inflammatory Treg cells).
- Inhibiting the function of other inflammatory cells, such as neutrophils and macrophages.
Dosage-Dependent Effects and Therapeutic Uses
The effects of methotrexate differ significantly depending on the dosage and frequency of administration.
Low-Dose (Immunosuppressive) Therapy
For chronic inflammatory and autoimmune conditions, methotrexate is typically taken once per week at a low dose (7.5–25 mg). In this context, it functions as a disease-modifying anti-rheumatic drug (DMARD).
- Rheumatoid Arthritis and Juvenile Idiopathic Arthritis: It reduces inflammation and pain, slowing joint damage and preventing long-term disability.
- Psoriasis and Psoriatic Arthritis: It slows the overproduction of skin cells and reduces inflammation, leading to clearance of skin lesions.
- Crohn's Disease: It helps manage inflammation in the digestive tract.
High-Dose (Chemotherapy) Therapy
In oncology, methotrexate is administered at much higher doses, often intravenously, to kill cancer cells.
- Cancers: It is used to treat various malignancies, including acute lymphoblastic leukemia, osteosarcoma, and certain lymphomas.
- Ectopic Pregnancy: Methotrexate is used to terminate ectopic pregnancies by stopping the growth of the embryo.
Common and Serious Side Effects
Side effects can range from mild to severe, depending on the dosage and individual patient factors. Regular monitoring helps detect and manage adverse effects.
Mild to Moderate Side Effects
- Gastrointestinal Issues: Nausea, vomiting, and diarrhea are common, especially around the time of the weekly dose.
- Fatigue and "Methotrexate Fog": Many patients experience tiredness, drowsiness, or a general feeling of being unwell.
- Mouth Sores (Stomatitis): Sores or ulcers in the mouth are a known side effect.
- Hair Loss: Slow hair loss can occur in some patients, though it is often reversible upon discontinuation.
Serious Side Effects and Long-Term Risks
- Liver Damage: Long-term use can potentially cause liver fibrosis or cirrhosis. Regular blood tests are necessary to monitor liver function. Alcohol use significantly increases this risk.
- Lung Problems: In rare cases, methotrexate can cause pneumonitis, or inflammation of the lungs. Symptoms include persistent cough, fever, and shortness of breath.
- Bone Marrow Suppression: Methotrexate can lower blood cell counts, increasing the risk of infection (due to low white blood cells) or bleeding (due to low platelets).
- Kidney Damage: High doses can cause acute kidney injury. Patients with pre-existing kidney problems may be at higher risk.
- Infections: As an immunosuppressant, methotrexate increases the risk of developing infections.
- Infertility: Methotrexate can impair fertility in both men and women.
Important Considerations for Treatment
The Critical Importance of Weekly Dosing
For non-cancer conditions like rheumatoid arthritis and psoriasis, methotrexate must be taken once a week, not daily. Daily dosing for these conditions can be fatal due to accumulated toxicity. Prescribing and dispensing protocols have been put in place to prevent such dangerous medication errors.
Comparison Table: Low-Dose vs. High-Dose Methotrexate
| Feature | Low-Dose (e.g., Rheumatoid Arthritis) | High-Dose (e.g., Cancer) |
|---|---|---|
| Primary Mechanism | Immunosuppressive, anti-inflammatory via adenosine release | Cytotoxic via folate antagonism, kills rapidly dividing cells |
| Typical Dose | Low, typically 7.5–25 mg weekly | High, often administered intravenously in cycles |
| Primary Use | Autoimmune diseases (RA, psoriasis) | Cancers (leukemia, lymphoma) |
| Onset of Effect | Gradual, weeks to months | Rapid |
| Folic Acid Rescue | Often prescribed to reduce side effects | Leucovorin rescue is required to protect healthy cells |
| Primary Side Effects | Nausea, fatigue, mouth sores | Severe myelosuppression, mucositis, organ damage |
Conclusion
In conclusion, what methotrexate does to your body is complex and depends heavily on the dosage and purpose of treatment. At low, weekly doses, it acts as an immunosuppressant by promoting the release of adenosine, effectively controlling inflammatory conditions. At high, often intravenous, doses, it functions as a potent chemotherapy agent by inhibiting DNA synthesis in rapidly dividing cells. While it is a foundational and highly effective medication, it requires careful management, regular monitoring, and strict adherence to the prescribed dosage to minimize the risk of significant side effects, some of which can be severe. Proper patient education and close collaboration with healthcare providers are essential for a safe and successful treatment course.
