Major Research Findings

Methotrexate (MTX) is an antimetabolite widely prescribed for treating various pediatric cancers, but managing high-dose MTX-related toxicities remains challenging. 11 found that children with acute lymphoblastic leukemia (ALL) who received high-dose MTX infusion had higher serum MTX levels after 48 hours, and showed a significant increase in toxicities such as oral mucositis, neutropenia, elevated liver enzymes, and dermatological toxicities. Patients with severe toxicities experienced dose reduction, extended hospital stays, and treatment delays. 2 comprehensively reviewed the potential side effects of MTX in rheumatoid arthritis (RA) patients. While beneficial for many RA patients, MTX can cause side effects ranging from mild to severe, sometimes leading to treatment discontinuation. 3 investigated the impact of single nucleotide polymorphisms (SNPs) in MTHFR and MTRR genes on disease activity and MTX-related side effects in Polish children with juvenile idiopathic arthritis (JIA). Children with the MTHFR rs1801133 CT/TT variant exhibited higher inflammatory markers, more active joints, and higher JADAS-71 values at baseline MTX treatment.

Reasons for Side Effects

MTX's side effects arise from its ability to inhibit cell DNA synthesis. Since MTX can also affect normal cells, it can cause a variety of side effects. Side effect severity depends on factors such as MTX dose, duration of treatment, patient age, and overall health.

Common Side Effects

Gastrointestinal

MTX can cause gastrointestinal side effects, including nausea, vomiting, abdominal pain, and diarrhea. 2 identified gastrointestinal toxicity as a common side effect. In 11 , children with ALL who received high-dose MTX infusion and had serum MTX levels above 1.0 μmol/L showed higher rates of oral mucositis. This is likely due to MTX affecting mucosal cells in the gastrointestinal tract, causing inflammation and ulcers.

Hematologic

MTX can suppress bone marrow, resulting in bone marrow suppression. This condition reduces the production of blood cells, including red blood cells, white blood cells, and platelets, potentially causing anemia, infections, and bleeding. 2 mentioned hematological side effects as possible consequences of MTX treatment. 11 found that children with ALL who received high-dose MTX infusion and had serum MTX levels above 1.0 μmol/L had higher rates of neutropenia. This is likely due to MTX affecting hematopoietic stem cells in the bone marrow, suppressing white blood cell production.

Liver

MTX can affect the liver, leading to elevated liver enzymes. Increased liver enzyme levels may indicate liver inflammation or damage. 2 mentioned liver toxicity as a potential side effect of MTX. 11 showed that children with ALL who received high-dose MTX infusion and had serum MTX levels above 1.0 μmol/L had higher rates of elevated liver enzymes. This is likely due to MTX affecting liver cells, causing inflammation and damage.

Skin

MTX can cause skin side effects such as rash, itching, and hair loss. 2 mentioned skin side effects. 11 reported that children with ALL who received high-dose MTX infusion and had serum MTX levels above 1.0 μmol/L had higher rates of dermatological toxicities. This is likely due to MTX affecting skin cells, causing inflammation and damage.

Others

MTX can cause side effects beyond the gastrointestinal, hematologic, liver, and skin systems. 2 highlighted potential side effects in the lungs, kidneys, nervous system, and endocrine system. 3 suggested that SNPs in the MTHFR and MTRR genes in JIA patients may influence the occurrence of MTX-related side effects.

Side Effects Management

Folic Acid and Folate Analogs Administration

Folic acid or folate analogs may be administered to mitigate MTX side effects. 1 demonstrated that folic acid or folate analogs can reduce the risk of gastrointestinal side effects and abnormal liver function in RA patients undergoing MTX treatment. 15 showed that both folic acid and folate analogs can reduce gastrointestinal side effects, abnormal liver function, and the risk of stopping MTX treatment in RA patients. found that in arthritis patients experiencing MTX side effects despite folic acid supplementation, additional folinic acid reduced side effects.

Prednisone Concomitant Therapy

5 showed that adding low-moderate dose prednisone to MTX treatment in RA patients can alleviate MTX side effects, particularly nausea and elevated ALT/AST. However, this study compared the MTX + prednisone group to the MTX-only group, not evaluating the effects of prednisone alone.

Other Measures

Other measures to mitigate MTX side effects include:

• Reducing MTX dosage
• Increasing MTX dosing intervals
• Changing MTX administration route
• Consulting a doctor if side effects occur

Comparison Across Studies

Commonalities

Several studies consistently showed that MTX can cause side effects affecting the gastrointestinal, hematologic, liver, and skin systems. Furthermore, using folic acid or folate analogs can potentially reduce MTX-related side effects.

Differences

The frequency and severity of MTX side effects vary across studies due to differences in factors such as study participants' age, conditions, MTX dosage, treatment duration, and other therapies. 11 investigated the relationship between serum MTX levels after high-dose infusion and side effects, while other studies did not. 3 suggested that SNPs in the MTHFR and MTRR genes might influence MTX-related side effects in JIA patients, whereas other studies did not examine this.

Practical Implications and Considerations

While an effective treatment, MTX carries the risk of side effects. Follow your doctor's instructions when taking MTX, and consult them immediately if side effects occur. Folic acid or folate analogs can help mitigate side effects, but always consult a doctor before taking them. MTX is contraindicated for some individuals, such as pregnant or breastfeeding women, and those with liver or kidney problems. Consult your doctor before taking MTX.

Limitations of Current Research

Research on MTX side effects is still incomplete. Long-term side effects of MTX remain unclear. Individual variability in MTX side effects makes it challenging to identify universal side effects. The impact of other therapies on MTX-related side effects needs further investigation, as side effects may differ in patients receiving multiple treatments.

Future Research Directions

Further research is required to better understand MTX side effects, especially long-term effects, individual variability, and interactions with other therapies. Developing novel treatment and preventative strategies to mitigate MTX side effects is essential.

Conclusion

MTX is an effective treatment option, but it comes with the potential for side effects. Follow your doctor's instructions for taking MTX, and seek medical advice immediately if side effects occur. Further research on MTX side effects is necessary.