Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA). The active metabolite MPA was first isolated from Penicillium brevicompactum in 1896 by Italian microbiologist Gosio, and later developed as an immunomodulator for organ transplantation by Allison and Eugui, receiving FDA approval in 1995.
Currently, it is used not only for preventing organ transplant rejection but also for many autoimmune diseases such as lupus nephritis, SLE, Behçet’s disease, and inflammatory eye diseases. Although it is not covered by insurance for uveitis and is used off-label, it is widely used as a steroid-sparing agent in combination with steroids.
In ocular inflammatory diseases, it is considered an important steroid-sparing agent with a favorable side effect profile, alongside methotrexate 2).
CellCept is the brand name of mycophenolate mofetil, a prodrug of MPA. After oral administration, it is hydrolyzed to MPA. Mycophenolate sodium (Myfortic) is an enteric-coated formulation that produces the same active metabolite MPA but differs in formulation. Mycophenolate mofetil has higher oral bioavailability (approximately 94%) compared to parenteral administration.
Symptoms presented by patients with non-infectious uveitis for whom mycophenolate mofetil is used.
Diseases and situations where mycophenolate mofetil is particularly effective.
The main reasons to consider initiating immunomodulatory therapy with mycophenolate mofetil for uveitis are as follows.
The following screening is recommended before mycophenolate mofetil.
Regular monitoring during mycophenolate mofetil treatment is important.
Although fewer than 20% of patients report side effects, dose-dependent gastrointestinal disorders and bone marrow suppression are the most commonly reported adverse effects.
Efficacy in Vogt-Koyanagi-Harada Disease Patients
Acute Vogt-Koyanagi-Harada disease (mycophenolate mofetil + steroids): 93% of eyes maintained 20/20 vision. Recurrent anterior uveitis and the appearance of “sunset glow fundus” were prevented in all patients (mean follow-up 37 months)1).
Chronic Ocular Inflammation in General
Effective in 85% of adults and 88% of children (patients treated for chronic uveitis).
It has a favorable side effect profile and is valuable as an alternative to other immunosuppressive therapies2).
The most important points are as follows.
| Side effect category | Specific details |
|---|---|
| Gastrointestinal disorders | Nausea, vomiting, diarrhea (dose-dependent) |
| Bone marrow suppression | Neutropenia, thrombocytopenia, anemia |
| Infections | Cytomegalovirus, varicella-zoster virus, opportunistic infections |
| Malignancies | Lymphoma, skin cancer |
Immunomodulators including mycophenolate mofetil require several weeks to months to take effect. Clinical response is usually observed from 2 months after starting treatment. It is common to use oral steroids simultaneously while waiting for the effect of mycophenolate mofetil to appear 2).
Mycophenolate mofetil is rapidly hydrolyzed to mycophenolic acid (MPA) after oral administration.
The main mechanism of action of MPA is as follows.
Reversible inhibition of inosine monophosphate dehydrogenase (IMPDH): It selectively inhibits the rate-limiting enzyme required for the conversion of inosine monophosphate to guanosine monophosphate in DNA replication.
This conversion step is the rate-limiting step in the de novo synthesis of purine nucleotides. Inhibition of this step leads to the following results.
Selective mechanism: Many cells in the body can obtain necessary purine bases via the salvage pathway (a pathway that reuses existing nucleobases). In contrast, immune-competent lymphocytes are highly dependent on de novo synthesis, so mycophenolate mofetil selectively suppresses lymphocyte proliferation. This results in high selectivity with fewer side effects compared to other immunosuppressants.
Induction of apoptosis in activated T lymphocytes: Mycophenolic acid binds to inosine monophosphate expressed on activated T lymphocytes and induces their apoptosis.
In Vogt-Koyanagi-Harada disease, where the pathology involves autoimmune attack on uveal melanocytes, selective suppression of lymphocyte proliferation can control inflammation 1).
In the randomized comparative effectiveness trial (FAST trial) for patients with non-infectious uveitis, methotrexate showed significantly better treatment success than mycophenolate mofetil in posterior and panuveitis, while no significant difference was observed across all uveitis forms 2). This subgroup analysis contributes to refining the indications for mycophenolate mofetil.
Of the 216 cases in the FAST trial, 93 were patients with Vogt-Koyanagi-Harada disease, and a randomized comparison was conducted between methotrexate (25 mg/week) and mycophenolate mofetil (1.5 g twice daily) 1). Analysis of outcomes in the Vogt-Koyanagi-Harada disease subgroup is accumulating evidence toward establishing optimal treatment for acute and chronic phases.
The European Thyroid Association and EUGOGO guidelines recommend a combination of moderate-dose intravenous methylprednisolone and daily oral enteric-coated mycophenolate sodium as first-line treatment for patients with moderate-to-severe and active Graves’ orbitopathy. This indicates the potential applicability of mycophenolate mofetil to ocular inflammatory diseases in general.
