Immunosuppressive therapy (Proceedings)

Aug 01, 2010

Immunosuppressive therapy in dogs and cats is used to treat a wide range of immune-mediated and inflammatory diseases. Immunosuppressive therapy is best understood, and explained, in the context of the specific disease that is being treated. In order to put the principles of treatment into a clinical context, I will therefore concentrate on treatment of immune-mediated blood disorders. Many of the general principles of immunosuppressive therapy discussed, however, can be applied to many other inflammatory and immune-mediated diseases.

The most common immune-mediated blood disorders in dogs and cats are immune-mediated hemolytic anemia (IMHA) and immune-mediated thrombocytopenia (IMT). Less common blood disorders that may have an immune-mediated component include pure red cell aplasia (PRCA), aplastic anemia, and steroid-responsive neutropenia. Immune-mediated blood disorders can be either primary (idiopathic) or secondary. As a general rule, these disorders in dogs are most commonly primary, whereas in cats they are more likely to be secondary. Since treatment of IMHA and IMT has more similarities than differences, most therapeutic approaches apply equally well to both disorders.

Veterinarians have been effectively treating individual patients with IMHA and IMT for many years. Standard therapy is based around transfusion as needed, coupled with immunosuppressive therapy (prednisolone or dexamethasone, with or without concurrent azathioprine, cyclophosphamide or cyclosporine) that is tapered and then discontinued. Many practitioners have successfully treated individual IMHA and IMT patients with this standard approach, and some clinicians still see little need to change established protocols. Unfortunately, however, there is a mounting body of evidence documenting that, with standard therapy, survival rates for IMT and (particularly) IMHA patients are surprisingly discouraging. For example, one recently reported study from Virginia-Maryland reported that, despite their best therapeutic efforts, one-year survival rate for dogs with IMHA was still only 30%, and many other retrospective studies report mortality rates of around 50%. Deaths (naturally-occurring or euthanasia) occurred either during initial hospitalization, or at a later date due to disease recurrence or owner intolerance of long-term medication. Survival rates reported in the past ten years or so are very similar to rates published for IMHA and IMT in the preceding two decades. Undoubtedly, there is a 'referral bias' that will exaggerate the severity of disease in some studies since, with recent advances in in-house diagnostics, better availability of transfusion products, and a greater understanding of immunosuppressive therapy, many general practitioners can now effectively treat the less severe blood disorders without referral. Critical patients with severe or complicated IMHA and IMT are more likely to be referred to specialist centers, and are also more likely to die despite treatment, contributing to the high mortality rates in studies that originate from referral centers. Nevertheless, despite the potential effects of this referral bias, it is still undeniable that mortality rates for the immune-mediated blood disorders are unacceptably high, and that we are not performing much better than we were doing twenty to thirty years ago. We clearly need to do better.

How can survival rates for patients with IMHA and IMT be improved? Two main priorities can be readily identified: firstly, the rate of in-hospital deaths during the initial immune-mediated crisis must be reduced and, secondly, long-term therapy must be tailored in order to avoid relapses while minimizing expense and drug-induced side effects. Unfortunately, although management decisions that address these two priorities should ideally be 'evidence-based', in reality there is a relative paucity of useable information in the veterinary literature that can be derived solely from the interpretation of hard data derived from well-designed randomized blinded prospective clinical trials. Until much more data is published, management decisions regarding the treatment of IMHA or IMT must also be based on such imperfect sources of information as individual case reports and small case series, extrapolation from human publications, and the personal experiences and recommendations of experienced clinicians. Interpretation of data from such sources will invariably be affected by personal biases. However, since our current therapy for IMHA and IMT is clearly not doing the job, until new data appears we will continue to be forced into making educated guesses rather than suffer from therapeutic inertia. The remainder of these notes represent my best immunotherapeutic educated guesses, with an emphasis on what has changed or been refined in the past few years.