Immunosuppressive drugs: Beyond glucocorticoids - Veterinary Medicine
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Immunosuppressive drugs: Beyond glucocorticoids
Prednisone is likely your go-to immunosuppressant. But because of associated adverse effects, having more options would help. Azathioprine, cyclosporine, mycophenolate mofetil, and leflunomide are commonly used for treating immune-mediated human diseases and may soon be incorporated into immunosuppressive protocols in veterinary medicine as well.


Adverse effects

The most common cyclosporine-associated adverse effects in dogs and cats are gastrointestinal tract disturbances, including vomiting and diarrhea. These effects are dose-related in most patients and often do not recur after temporary dose decreases. Other less commonly to rarely reported adverse effects include alopecia, gingival hyperplasia, hypertrichosis, and increased prevalence of secondary infections.18 Lymphoproliferative neoplasms occur more commonly after long-term administration of cyclosporine to cats after renal transplantation.28 Renal toxicosis, a common adverse effect in people, has not been reliably reported in small animals.18


Mycophenolate mofetil, frequently referred to as mycophenolate or MMF, interferes with DNA replication, thus inhibiting lymphocyte proliferation.29,30 Mycophenolate is absorbed from the gastrointestinal tract and converted during absorption or in circulation to mycophenolic acid (MPA), the active drug metabolite. MPA is a noncompetitive inhibitor of inosine monophosphate dehydrogenase, the rate-limiting enzyme in de novo synthesis of guanine and other purines. For most cells, this inhibition does not interfere with DNA synthesis because purines can be salvaged from other sources. Lymphocytes, however, not only lack most purine salvage capability, but at times of cell division upregulate an isoform of inosine monophosphate dehydrogenase that is more sensitive to the inhibitory effects of MPA, thus magnifying their susceptibility to this drug.29,31


Mycophenolate is used primarily as a maintenance immunosuppressive agent in people. Although it may be prescribed at the time of diagnosis, it provides insufficient systemic immunosuppression to induce disease remission when administered alone. Once remission is achieved in combination with other drugs, then MMF administration can be continued for long-term maintenance. Effective immunosuppressive protocols that include MMF have been established for a number of human diseases including rheumatoid arthritis, systemic lupus erythematosus, and some immune-mediated glomerulonephritides as well as for use after organ transplantation.30

Use of prednisolone and MMF has been reported in dogs with IMHA (Table 1), with seven of eight dogs having complete resolution of anemia within one month, only one dog of which had transient, mild enteritis.32 Single case reports include successful treatment of dogs with myasthenia gravis or aplastic anemia that had failed to respond to standard therapy and resolution of suspected glomerulonephritis.33-35 Dogs with pemphigus complex may also be treated with MMF on occasion.10

Prospective studies are required to establish the effectiveness of MMF in treating these various diseases and, in particular, whether its use improves outcome beyond standard therapy. For example, despite the single case of MMF-responsive myasthenia gravis in a dog mentioned above, retrospective analysis of 12 dogs treated with pyridostigmine vs. 15 dogs treated with pyridostigmine and MMF failed to demonstrate improved case outcome with MMF.36 Therefore, MMF should likely be reserved for those dogs in which established immunosuppressive therapies have failed for treatment of a given disease or in which side effects from other drugs are intolerable.


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