Is Methotrexate Considered an Immunosuppressant?
Yes, methotrexate is definitively classified as an immunosuppressant drug by major dermatology and oncology guidelines, though its therapeutic effects in inflammatory conditions also involve significant anti-inflammatory mechanisms. 1
Official Classification and Mechanism
Methotrexate is explicitly categorized as an immunosuppressant in authoritative guidelines:
The British Association of Dermatologists' 2016 guidelines state unequivocally: "MTX is an immunosuppressant drug that occupies a key place in the management of many autoimmune and inflammatory skin diseases." 1
The NCCN guidelines describe methotrexate as "an antimetabolite that exerts immunosuppressive effects by inhibiting the activity of dihydrofolic acid reductase, resulting in impaired DNA synthesis and lymphocyte proliferation." 1
The Joint AAD-NPF guidelines confirm that "low-dose methotrexate (<25 mg per week) decreases proliferation of lymphoid cells, and this direct immunosuppressive effect is considered to be the mechanism by which methotrexate improves psoriatic disease." 1
Dual Mechanism: Immunosuppression and Anti-Inflammatory Action
Methotrexate functions through both immunosuppressive and anti-inflammatory pathways:
Immunosuppressive effects occur through inhibition of nucleic acid synthesis in activated T cells and keratinocytes, along with effects on Janus kinase/signal transducers and activators of transcription signaling pathways. 1
Anti-inflammatory effects are mediated via adenosine pathways, with postulated mechanisms involving inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, resulting in increased endogenous adenosine. 1
Methotrexate also demonstrates direct antioxidant properties by scavenging superoxide and reducing oxidative stress. 2
Clinical Implications of Immunosuppression
The immunosuppressive properties of methotrexate carry important clinical consequences:
The FDA label explicitly warns: "Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes." 3
Immunization may be ineffective during methotrexate therapy, and live virus vaccines are generally not recommended. 3
Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. 3
Hypogammaglobulinemia has been reported, and disseminated vaccinia infections after smallpox immunization have occurred in patients on methotrexate. 3
Vaccine Response Considerations
Methotrexate's immunosuppressive effects significantly impact vaccine efficacy:
All disease-modifying antirheumatic drugs (DMARDs) can affect antibody responses, but methotrexate specifically suppresses humoral response by interacting with B cell activation factor (BAFF). 1
It is reasonable to withhold methotrexate for at least two weeks before and after vaccination to optimize immune response, though withholding for more than two weeks may risk disease flare. 1
When used concurrently with other immunosuppressants (anti-TNFs, IL-6 inhibitors, JAK inhibitors), methotrexate can further impair vaccine-induced immunity. 1
Important Caveats
The degree of immunosuppression differs from high-dose chemotherapy regimens:
At low doses used for inflammatory conditions (7.5-25 mg weekly), one older study suggested methotrexate may not significantly inhibit DNA synthesis in peripheral blood lymphocytes, questioning whether immunosuppression is the primary mechanism at these doses. 4
However, this finding is contradicted by current guideline consensus and clinical experience showing increased infection risk and impaired vaccine responses even at low doses. 1, 3
The drug is best considered a prodrug that converts to polyglutamyl derivatives with increasing anti-inflammatory and immune-modulating activity. 1
In summary, methotrexate is unequivocally classified as an immunosuppressant by major medical organizations, with this classification carrying significant implications for infection risk, vaccination strategies, and patient counseling. 1, 3