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.


VETERINARY MEDICINE


Most support for azathioprine therapy has been gathered from retrospective studies of dogs with IMHA. In the largest retrospective study evaluating treatment of IMHA in dogs with prednisone and azathioprine, most dogs that survived the initial 14-day high-mortality period could be weaned off drugs within three 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.3 Other retrospective studies of dogs with IMHA that did not have uniform treatment protocols also suggest that azathioprine improves outcome.4,5 Determining whether azathioprine truly increases the survival rate in dogs with IMHA 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.




Using azathioprine for adjunctive treatment of other immune-mediated conditions, including ITP, Evans' syndrome (concurrent IMHA and ITP), immune-mediated neutropenia, immune-mediated skin diseases, and systemic lupus erythematosus, has also been suggested.6-10 Azathioprine monotherapy has been used to treat newly diagnosed disease in dogs with myasthenia gravis, atopy, and perianal fistulae.11-13 Although three of four dogs with myasthenia gravis were successfully managed, the time until remission was up to three months, with one dog dying because of myasthenic crisis before therapeutic serum concentrations had been presumptively attained.13 Likewise, clinical signs were completely controlled in only some dogs with atopy or perianal fistulae.11,12

Adverse effects

Azathioprine may result in rare but severe adverse effects in dogs. These effects include fulminant hepatic necrosis with massive (i.e. > 10,000 IU) increases in alanine transaminase (ALT) activity 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.14 The prevalence of bone marrow suppression in dogs with IMHA treated long-term with azathioprine was 12.5% in one study; fortunately, cell numbers rapidly returned to normal after azathioprine was discontinued.3 Frequent monitoring for hepatic and bone marrow adverse effects is recommended in people, with complete blood counts and liver enzyme activity reevaluated about every three months. Toxicosis in people depends in large part on tissue concentrations of thiopurine methyltransferase (TPMT), the enzyme responsible for 6-MP degradation.15 About 10% of dogs may have decreased tissue concentrations of TPMT, with some breeds (e.g. giant schnauzers) possibly being predisposed to toxic effects.16

Healthy cats have significantly lower TPMT concentrations than dogs or people, so severe, fatal bone marrow suppression is induced when azathioprine is mistakenly prescribed at the same dose as that used in dogs.17 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 after failure of other agents, consultation with an internist to discuss appropriate drug dosing and monitoring is highly recommended.


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Source: VETERINARY MEDICINE,
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