Immunosuppressive drugs: beyond glucocorticoids (Proceedings)
Glucocorticoids are the most commonly used drugs for immunosuppression of dogs and cats with immune-mediated diseases because they induce rapid, non-specific inhibition of the immune system by reducing inflammation-associated gene transcription, inhibiting intracellular signaling pathways, down-regulating cell membrane expression of adhesion proteins, and slowing cell proliferation. Glucocorticoids unfortunately also modulate metabolic pathways in many non-immune system cell populations, which may result in life-threatening side-effects such as hypercoagulability, hypertension, increased susceptibility to opportunistic infections, congestive heart failure, pancreatitis, and insulin resistance and secondary diabetes mellitus. In addition, although weight gain, alopecia, polyuria, polydipsia, and polyphagia are usually only temporary annoyances, some owners may find these signs to be intolerable, leading to frustration or even euthanasia. Newer or alternative immunosuppressive agents may have synergistic immunosuppressive effects and therefore allow clinicians to maintain disease remission with a lower dose of glucocorticoids than would be possible otherwise. Because use of these alternative immunosuppressive drugs is increasing, veterinarians must be aware of those few studies that have evaluated effectiveness, recommended doses, or prognosis when these drugs are administered in conjunction with or in place of prednisone.
Azathioprine is a pro-drug that lacks immunosuppressive effects until it is converted by the liver into 6-mercaptopurine (6-MP). This active metabolite highly resembles adenine and guanine, which are the purine bases that make up much of RNA and DNA. The structural similarity between these molecules results in insertion of 6-MP into DNA which is being synthesized (i.e. replication) immediately preceding cell division. Random insertion of 6-MP into DNA results in nonsense mutations and eventual cell death due to disruption of a critical gene, or due to apoptosis triggered by a high mutation load. Incorporation of 6-MP into DNA is also promoted by azathioprine-induced interference with purine biosynthesis, thus increasing the relative concentration of 6-MP as compared to adenine and guanine. Although 6-MP is commercially available, administration of the activated drug to people increases the prevalence of adverse affects, and therefore is not recommended in dogs or cats.Abundant anecdotal experience exists on the benefits of azathioprine for treatment of immune-mediated diseases in dogs, but few controlled studies have been published. Use of azathioprine in dogs with immune-mediated diseases that typically require prolonged treatment with glucocorticoids (including immune-mediated hemolytic anemia [IMHA], immune-mediated thrombocytopenia [ITP], systemic lupus erythematosus, immune-mediated polyarthritis, and pemphigus foliaceus) is common. The primary benefit of azathioprine in these diseases is due to its steroid-sparing affects; simultaneous use of this drug may allow lower 'maintenance' doses of glucocorticoids or more rapid tapering with reduced risk of disease recurrence. Azathioprine is frequently first prescribed to dogs who fail to achieve remission with glucocorticoids alone, or who following an appropriate tapering protocol still require maintenance doses associated with severe side-effects. Alternatively, because azathioprine requires at least one to two weeks to reach therapeutic serum concentrations, some veterinary internists (including myself) choose to begin azathioprine administration in cases of severe immune-mediated disease at the time of diagnosis (i.e. at the same time that glucocorticoid therapy is initiated).
Most support for use of azathioprine is as part of retrospective studies of dogs with IMHA. In the largest retrospective study evaluating treatment of dogs with prednisone and azathioprine, most dogs which survived the initial 14-day high-mortality period could be weaned off drugs within 3 months, with a 72.6% six-month survival rate for all patients, and a 92.5% six-month survival rate for dogs surviving beyond 14 days. Other retrospective studies of dogs with IMHA that did not have uniform treatment protocols also support the belief that outcome is improved with azathioprine. Whether the presumptive beneficial effects of this drug on survival are true will require additional studies; for example, azathioprine may be preferentially administered to dogs expected to survive long enough for therapeutic serum concentrations to be reached.
Use of azathioprine for adjunctive treatment of other immune-mediated conditions, including ITP, Evan's syndrome, immune-mediated neutropenia, immune-mediated skin diseases, and systemic lupus erythematosus has also been suggested. Azathioprine monotherapy for treatment of newly-diagnosed disease has been reported in dogs with myasthenia gravis, atopy, and perianal fistulae. Although 3 of 4 dogs with myasthenia gravis were successfully managed, time until remission was up to three months, with one dog dying due to myasthenic crisis before therapeutic serum concentrations had been presumptively attained. Likewise, clinical signs were completely controlled in only some dogs with atopy or perianal fistulae.
Azathioprine may result in rare but severe adverse effects in dogs. These include fulminant hepatic necrosis with massive (i.e. >10,000 IU) increases in ALT that should be treated with immediate cessation of azathioprine and aggressive supportive care. Bone marrow suppression may also occur, presumptively because dividing bone marrow stem cells will also incorrectly incorporate 6-MP into newly synthesized DNA. The prevalence of bone marrow suppression in dogs with IMHA treated with long-term azathioprine was 12.5% in one study; fortunately, suppressed cell lines rapidly resolved to discontinuation of azathioprine. Frequent monitoring for hepatic and bone marrow adverse effects is recommended in people, with complete blood counts and liver enzyme activity re-evaluated on an approximately 3-month basis. Toxicity in people is dependent in large part on tissue concentrations of thiopurine methyltransferase (TPMT), the enzyme responsible for 6-MP degradation. Approximately 10% of dogs may have decreased tissue concentrations of TPMT, with some breeds (i.e. giant schnauzers) possibly being predisposed to toxic effects.
Healthy cats have significantly lower TPMT concentrations than dogs or people, and therefore severe, fatal bone marrow suppression is induced when azathioprine is mistakenly prescribed at the same dose as used in dogs. Because of the severe risk involved, azathioprine should not be routinely used as an immunosuppressant in cats. If therapy with this drug must be considered following failure of other agents, consultation with an internist to discuss appropriate drug dosing and monitoring is highly recommended.