Key Findings

This study explored the benefits and harms of folic acid and folinic acid in reducing side effects associated with methotrexate (MTX) treatment for rheumatoid arthritis (RA). The study analyzed data from six double-blind randomized placebo-controlled trials ( 1 ), revealing that concurrent use of folic acid or folinic acid significantly reduced the incidence of gastrointestinal side effects (nausea, vomiting, abdominal pain), liver dysfunction (elevated serum transaminase levels), and discontinuation of MTX treatment due to any reason. Notably, these beneficial effects were observed without any impact on the efficacy of MTX.

Reasons for Side Effects

Methotrexate's mechanism of action involves inhibiting dihydrofolate reductase (DHFR), an enzyme crucial for cell proliferation and DNA synthesis. DHFR is required for the conversion of folate to tetrahydrofolate, a vital component for cell growth and repair. Consequently, methotrexate's inhibition of DHFR can hinder cell growth and repair, leading to various side effects. Supplementation with folic acid or folinic acid, which serve as substrates for DHFR, is believed to alleviate the DHFR inhibition caused by methotrexate, thereby mitigating side effects.

Common Side Effects

Gastrointestinal Side Effects

The study observed a significant reduction in the incidence of gastrointestinal side effects, such as nausea, vomiting, or abdominal pain, among patients receiving MTX therapy who were concurrently supplemented with folic acid or folinic acid ( 1 ).

Liver Dysfunction

The study revealed a substantial reduction in the incidence of abnormal serum transaminase elevation, an indicator of liver dysfunction, among patients receiving MTX therapy who were concurrently supplemented with folic acid or folinic acid ( 1 ).

Side Effect Management

Gastrointestinal Side Effects Management

Concurrent use of folic acid or folinic acid has shown effectiveness in reducing gastrointestinal side effects associated with MTX therapy for RA ( 1 ).

Liver Dysfunction Management

Concurrent use of folic acid or folinic acid has proven beneficial in mitigating liver dysfunction, as evidenced by the reduction in abnormal serum transaminase elevation, among patients receiving MTX therapy for RA ( 1 ).

Comparison between Studies

Commonalities between Studies

A consistent finding across these studies is the positive effect of concurrent supplementation with folic acid or folinic acid in reducing side effects associated with MTX treatment for RA.

Differences between Studies

The studies might differ in the extent or specific types of side effects observed or in the specific doses of folic acid or folinic acid used. This study did not directly compare the effects of folic acid and folinic acid, warranting further investigation to determine if there are any differences in their effectiveness.

Implications for Real Life

This study's findings may be particularly relevant for patients with RA undergoing MTX therapy. However, it's crucial to remember that this research focused specifically on RA, and the findings may not directly apply to other conditions. Furthermore, while the study demonstrates a reduction in side effects, it doesn't guarantee their complete absence. It's essential to adhere to your doctor's instructions regarding MTX therapy, including the appropriate dosage and timing of folic acid or folinic acid supplementation, and to undergo regular checkups.

Limitations of Current Research

This study did not directly compare the effects of folic acid and folinic acid, leaving their relative effectiveness unanswered. Moreover, the underlying mechanisms by which these supplements mitigate side effects were not thoroughly explored. Future research is needed to clarify the specific mechanisms involved and to determine any potential differences in the effectiveness of folic acid and folinic acid.

Future Research Directions

Future research should prioritize a direct comparison of the effects of folic acid and folinic acid in reducing MTX-related side effects. Further investigation into the mechanisms by which these supplements mitigate side effects is also essential, potentially leading to more targeted and effective interventions for side effect management.

Conclusion

The results of this systematic review strongly suggest a protective effect of concurrent folic acid or folinic acid supplementation during MTX therapy for RA. Patients receiving MTX treatment for RA may experience a significant reduction in the incidence of gastrointestinal side effects, liver dysfunction, and overall discontinuation of treatment. However, while these findings are encouraging, it's vital to remember that individual responses may vary. Consulting with your doctor for personalized guidance and regular follow-ups is crucial to ensure optimal treatment outcomes and minimize the risk of side effects.