Methotrexate (MTX) is a folate analog classified as an immunosuppressive drug with antifolate mechanisms. It is used as an antineoplastic agent, antirheumatic drug, and abortifacient, and its use for ocular inflammatory diseases has been reported since the 1960s.
Methotrexate inhibits dihydrofolate reductase (DHFR), interfering with DNA synthesis, repair, and cell replication. Generally, high doses are used as an anticancer drug, while low doses are used as an anti-inflammatory drug.
According to international clinical practice surveys, methotrexate is one of the most commonly selected conventional immunomodulatory drugs for non-infectious uveitis, with selection frequency varying by disease type1).
In Japan, methotrexate is not covered by insurance for uveitis, but it is often prescribed for pediatric uveitis associated with rheumatism and sclerouveitis.
Methotrexate inhibits dihydrofolate reductase (DHFR) to block DNA synthesis, increases the apoptosis rate of T cells, raises endogenous adenosine levels, and alters cytokine production and humoral immune responses. These combined actions suppress the immune response and control intraocular inflammation.
Symptoms presented by patients with non-infectious uveitis for which methotrexate is used.
The main uveitis diseases treated with methotrexate and the situations in which it is used are shown.
| Disease | Situation for methotrexate use |
|---|---|
| Juvenile idiopathic arthritis-associated uveitis | First-line (93.2% of physicians choose) 1) |
| HLA-B27-positive uveitis | First-line (80.1%) 1) |
| Sarcoidosis-associated uveitis | First-line (62.4%) 1) |
| Pars planitis | First-line (55.2%) 1) |
| Sympathetic ophthalmia | First-line (32.1%) 1) |
The main reasons for considering systemic immunomodulatory therapy with methotrexate for uveitis are as follows:
Methotrexate treatment has been reported to significantly reduce the risk of juvenile idiopathic arthritis-associated uveitis (HR 0.14–0.63) 2), and the risk is further reduced when combined with adalimumab (HR 0.09) 2).
In the management of methotrexate treatment, the following regular monitoring is important:
For patients with non-infectious uveitis in remission, evaluation every 6 to 12 weeks, including drug toxicity screening, is recommended 1). Routine tests (blood biochemistry and complete blood count) are often repeated approximately every 12 weeks.
The standard dosing regimen in Japan is as follows.
In chronic uveitis, it is often combined with prednisolone at less than 10 mg/day.
The efficacy of methotrexate treatment is shown below.
Steroid-sparing effect
6 months after starting treatment: Successful steroid tapering in 46.1% of anterior uveitis, 41.3% of intermediate uveitis, and 20.7% of posterior or panuveitis.
12 months after starting treatment: Rates increased to 62.6%, 68.8%, and 39.1%, respectively.
Anti-inflammatory effect
160-case retrospective study: Inflammation control achieved in over 70% of uveitis patients, and visual improvement or stabilization in 90%3).
Posterior and panuveitis: Methotrexate showed significantly higher treatment success compared to mycophenolate mofetil1).
The most common drug combination is methotrexate and adalimumab, used in 158 out of 188 facilities (84%)1). A randomized controlled trial (ADJUVITE trial) reported that adalimumab plus methotrexate combination therapy for juvenile idiopathic arthritis-associated uveitis showed significant superiority over methotrexate alone.
Taking folic acid the day after or two days after methotrexate administration is known to reduce side effects such as liver dysfunction and nausea. Concurrent folic acid supplementation is recommended as standard practice.
Many immunosuppressive drugs take several weeks to show effects. Methotrexate is similar, and its efficacy is often evaluated 3–6 months after starting treatment. The treatment period usually lasts more than 2 years and is continued as long as inflammation remains in remission1).
Methotrexate inhibits dihydrofolate reductase (DHFR), preventing the production of tetrahydrofolate. Since tetrahydrofolate is essential for DNA synthesis, repair, and cell replication, it selectively acts on proliferating cells.
The specific immunosuppressive mechanisms are diverse4).
By inhibiting the inosine monophosphate dehydrogenase pathway, similar to the inhibition of inosine monophosphate dehydrogenase required for the conversion of inosine monophosphate to guanosine monophosphate, de novo synthesis of purine nucleotides is inhibited.
In the randomized controlled effectiveness trial (FAST trial) for non-infectious posterior and panuveitis, methotrexate showed a higher treatment success rate than mycophenolate mofetil in posterior and panuveitis. Although there was no significant difference across all forms of uveitis, methotrexate was superior when limited to posterior and panuveitis5).
In the Nordic screening guidelines for juvenile idiopathic arthritis-associated uveitis, methotrexate treatment is recognized to significantly reduce the risk of disease onset (HR 0.14–0.63), and rationalization of screening frequency for children on methotrexate or monoclonal tumor necrosis factor inhibitors is being considered2).
