Is Folic Acid Truly Needed Beyond Methotrexate? A Critical Review of Csdmards and Conventional Immunosuppressants

Background: Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) remain the cornerstone in the management of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Methotrexate is the most widely prescribed csDMARD and its antifolate activity necessitates folic acid supplementation to reduce gastrointestinal, hepatic, and hematological toxicities. Over time, supplementation practices have been extended to other csDMARDs and immunosuppressants despite limited evidence. This review addresses the gap between guideline-based recommendations and real-world prescribing practices. Objective: The objective of this review was to critically evaluate whether folic acid supplementation is truly necessary beyond methotrexate therapy in patients receiving csDMARDs or conventional immunosuppressants. Methods: A thematic critical review was conducted using PubMed, the Cochrane Library, and Google Scholar. Literature published in English between 1995 and 2024 was included, encompassing randomized controlled trials, observational studies, systematic and narrative reviews, and recommendations from recognized rheumatology guidelines. Inclusion criteria focused on csDMARDs (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine) and immunosuppressants (mycophenolate mofetil, azathioprine, cyclosporine). Exclusion criteria eliminated pediatric oncology, folinic acid rescue in chemotherapy, and non-rheumatology indications. Articles were screened and synthesized thematically. Results: Among the seven drugs evaluated, methotrexate was the only agent where folic acid supplementation was consistently supported by mechanistic and clinical evidence. It accounted for 14.3% of the agents reviewed and demonstrated clear benefit in reducing treatment-related toxicities. Sulfasalazine, representing another 14.3% of the agents, showed only rare relevance in deficiency states. In contrast, the remaining five drugs—leflunomide, hydroxychloroquine, mycophenolate mofetil, azathioprine, and cyclosporine—collectively constituting 71.4% of the agents reviewed, demonstrated no mechanistic link to folate metabolism and no clinical indication for supplementation. Clinical guidelines from EULAR, ACR, and BSR consistently recommended folic acid only for methotrexate. Conclusion: Folic acid supplementation is mandatory with methotrexate therapy but is not supported by evidence in other csDMARDs or immunosuppressants. The persistence of routine supplementation beyond methotrexate appears habitual rather than evidence-based. Rational prescribing should be encouraged to reduce unnecessary pill burden, healthcare costs, and patient confusion.