Over the years it seems that more and more veterinary patients are presenting with immune mediated disease, the causes of which often remain unknown. When I started my internship at Angell in 1996 it seemed we had 3 immunosuppressant medications to choose from: prednisone, Catalan and Azathioprine. Today, we have a multitude of medications to choose from that have shown benefit in treating immune mediated disease, including cyclosporine, methotrexate, Leflunamide, IVIG, and of course Mycophenolate Mofetil (Cellcept/ Roche Laboratories).
The major mechanisms of immunosuppressive therapy are to: decrease antibody synthesis, and to decrease the destruction of antibody – coated cells by the mononuclear phagocytic system. Mycophenolate Mofetil (MMF), is an inhibitor of an enzyme required for purine biosynthesis by lymphocytes (inosine monophosphate dehydrogenase). Because T and B cells are dependent upon de novo synthesis of purines, proliferation of these cells is inhibited by suppressing antibody formation by B cells, and cell-mediated responses by T cells. MMF has 5 times the affinity for the enzyme isoform in T and B cells, as compared with the isoform in most cell types. As a result, this drug has a relatively specific effect on cytostatic effect on T and B lymphocyte proliferation during the S phase of the cell cycle. In humans, MMF was originally used for and is presently only labeled for use in transplant patients in preventing host-vs – graft reactions. It has also been shown to have ‘off label’ effectiveness for myasthenia gravis, SLE (lupus nephritis), Crohn’s disease, and IMHA. Studies are ongoing to investigate its effect on ischemia –reperfusion injury as well as renal fibrosis.
Diseases where Mycophenolate has shown promise in dogs include IMHA, aplastic anemia and myasthenia gravis. We are also considering its use in IBD, ITP, autoimmune skin diseases, polyarthropathies and glomerulonephropathies, especially in cases where renal fibrosis is present. At Angell, we are using MMF and prednisone as first lines of defense in severe IMHA cases. Cyclosporine is also an excellent choice as a first line therapy, however its cost is multitudes higher than mycophenolate.
In cats, 2 case reports were described in the Journal of Veterinary Emergency and Critical Care (J Vet Emerg Crit Care. February 2011;21(1):45-9) where myocophenolate was prescribed, with success, to treat primary IMHA. Side effects were negligible. This was the first reported use of oral MMF to treat IMHA in the cat.
After oral administration as the prodrug, MMF is rapidly hydrolyzed to the active form mycophenloic acid. The drug is absorbed better on an empty stomach. The elimination half- life is approximately 8 hours in the dog, so TID dosing might maintain steady state drug concentrations more appropriately. MMF is excreted almost exclusively in the urine in both unchanged and in glucuronidated forms. It has been proposed that MMF achieves immunosuppression well before Azathioprine; some publications report rapid immune suppression to occur within hours after dosing. In our experience we expect immunosuppression to occur within 48 hours of initiation of therapy.
Side effects are mostly confined to the gastrointestinal system and can be significant in the form of anorexia and diarrhea. Gastrointestinal hemorrhage is also a reported side effect in dogs, but we infrequently encounter this. As a result, dose reductions may be warranted, as well as combination therapy with other immunosuppressant medications to allow lower doses to be used. MMF is not myelosuppressive, and was actually developed as an alternative to azathioprine in human transplant patients.
The recommended dose range in the dog is 7- 20 mg/kg PO or IV BID for 3-4 weeks, then 10 mg/kg SID. At our hospital, we usually start at 10-15 mg /kg BID. Mycophenolate comes in 250 mg capsules and 500 mg tablets. The IV formulation is a 200 mg/ml suspension. Mild allergic reactions may be observed with the parenteral preparation.
Although the use of MMF has not been extensively studied in veterinary medicine, we do believe this drug is a promising new addition to our armory of immunosuppressant medications.