Immunosuppressive drugs: Beyond glucocorticoids (Proceedings)
There is no question that glucocorticoids (GCs) remain the mainstay of immunosuppressive therapy in small animal medicine. However other drugs are available that can be used in conjunction with GCs in order to provide synergistic immunosuppression and thus allow lower GC dosage, more specifically target certain arms of the immune system, and provide proven superior immunosuppression to GCs in a few diseases. Unfortunately only a few controlled studies have been performed to evaluate these alternative drugs despite anecdotal evidence that they may be of benefit.
Azathioprine is a purine analog; its biologic structure is similar to the basic building blocks of DNA, but when incorporated into DNA during cell replication it results in slowed cell growth and death via mutations or apoptosis. Although activated lymphocytes are the primary target of this drug, other rapidly dividing cells, particularly bone marrow stem cells, are affected as well. Azathioprine is metabolized in the liver to the active metabolite 6-mercaptopurine; although 6-MP is available in an oral form it is more toxic than azathioprine in people and possibly dogs as well.Azathioprine is the non-GC immunosuppressant with which we as a profession have the most anecdotal experience, although few controlled studies exist on its use in veterinary patients. For example, use of azathioprine in immune-mediated diseases that require long-term immunosuppressive treatment (such as IMHA, ITP, myasthenia gravis, or SLE) is considered routine. The primary benefit of azathioprine is that because it has a different mechanism of action than GCs, simultaneous use may allow lower doses of GCs or more rapid tapering. However azathioprine requires several weeks to reach therapeutic serum concentrations; therefore many clinicians (including myself) routinely start azathioprine in cases of severe immune-mediated disease at the time of diagnosis. The strongest published evidence for use of azathioprine is a retrospective which examined short and long-term survival of dogs with IMHA. Dogs were treated with prednisone with or without azathioprine (with subgroups receiving other adjunctive therapies). Regardless of the adjunctive therapies, dogs which received azathioprine had better outcomes than those which received prednisone alone in previous reports.
Azathioprine causes hepatic necrosis or bone marrow suppression in some dogs. Frequent monitoring is recommended in people; ideally a full CBC, serum chemistry panel, and urinalysis should be performed every 3 months while receiving azathioprine. Hepatotoxicity in dogs is due to widespread necrosis, with massive increases in ALT activity noted. Withdrawal of the drug and aggressive supportive care is required if this occurs. Bone marrow suppression usually first affects the neutrophil line, although all cell lines may eventually be decreased. Toxicity is partially related to tissue concentrations of thiopurine methyltransferase, an enzyme responsible for degrading 6-MP. 10% of dogs may have decreased concentrations of TPMT, with some breeds (Giant Schnauzers) possibly having lower concentrations.
Cats routinely develop severe bone marrow suppression and/or toxicity with azathioprine, and thus should not routinely receive this drug. I have used this drug at a very low dose as a last-ditch effort in cats with IMHA; if this is being considered I recommend consulting with an internist to discuss appropriate dosing and monitoring.
Cyclophosphamide is an alkylating agent: it cross-links DNA strands, preventing the disassociation that must occur for cell division to progress. Most immunosuppressive drugs preferentially exert their mechanism of action on actively dividing cells; however, because cyclophosphamide-induced DNA cross-linking occurs regardless of whether a cell is actively dividing, it is cell-cycle independent. Unfortunately this means that there is the potential for more severe immunosuppression and toxicity. Side-effects include bone marrow suppression, gastrointestinal tract signs, and severe hemorrhagic cystitis.
Unfortunately, although cyclophosphamide has a clear benefit for the treatment of neoplasia (particularly lymphoproliferative neoplasms), it may worsen prognosis in dogs with IMHA. Because this drug affects all cells, bone marrow stem cells are also suppressed, and thus erythrocyte regeneration was slowed and recovery was delayed in onestudy. Because of these discouraging results, cyclophosphamide has fallen out of favor as a treatment option for IMHA, and its use in other immune-mediated diseases has likewise diminished.