Immunosuppressive therapy (Proceedings)

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.

Initial Treatment

Since effective treatment can not proceed without a correct diagnosis, a thorough work-up is always recommended during the initial management of IMHA and IMT. A thorough investigation will typically include a comprehensive history and physical examination, a complete blood count, serum biochemistry, careful examination of a stained blood smear, urinalysis and (usually) thoracic and abdominal radiographs and abdominal ultrasound. Anemic patients should typically also have a reticulocyte count, slide agglutination test, Coombs test, and testing for blood-borne parasites (via serology and/or PCR) such as Babesia canis and gibsoni (dogs), Mycoplasma hemofelis (Haemobartonellafelis) (cats) and, arguably, rickettsial diseases, while thrombocytopenic patients should be tested for rickettsial infection. Marrow analysis is indicated if the patient is pancytopenic, or if either anemia or thrombocytopenia appear to be 'non-regenerative'. Cats should be tested for retroviruses. Given a working diagnosis of primary immune-mediated blood disease, standard therapy during an initial crisis will typically include immunosuppressive doses of glucocorticoids with or without other immunosuppressive agents, and transfusion as needed.

Immunosuppressive Therapy

The cornerstone of the management of IMHA and IMT is immunosuppressive therapy, particularly with glucocorticoids. The major mechanisms of immunosuppressive therapy in general are to decrease anti-RBC antibody synthesis, decrease the binding affinity between antibodies and erythrocytes, and decrease destruction of antibody-coated cells by the mononuclear phagocytic system (MPS). However, since even if new anti-RBC antibody synthesis by plasma cells is arrested immediately, pre-existing immunoglobulins may survive in the circulation for a week or more, reduction of antibody synthesis is usually not an important part of the initial treatment of IMHA.

Glucocorticoids

Glucocorticoid therapy for IMHA and IMT has changed little in the past few decades. The most important short-term effect of glucocorticoids is inhibition of the MPS via blockage of the normal macrophage Fc receptor-mediated binding of antibody-coated cells, sometimes termed a 'medical splenectomy'. Oral prednisolone (or prednisone) dosage at the commencement of therapy should be 2 mg/kg once or twice daily. Although some clinicians prefer to start with an initial dose of intravenous dexamethasone (0.1 to 0.2 mg/kg) or high dose methylprednisolone (11 mg/kg daily for up to 3 days), there is minimal hard evidence that starting with intravenous steroid therapy hastens recovery. Typically, regardless of route of administration or starting dose, steroids are not immediately effective: thrombocytopenia and/or anemia often take 3-7 days to begin to improve, and on occasion may take as long as 10-14 days. One relatively recent trend is to commence medications that may, arguably, prevent or minimize steroid-associated gastrointestinal ulceration: sucralfate, misoprostol, omeporazole and histamine (H2) blockers such as cimetidine, famotidine or ranitidine are most commonly recommended. Although there is minimal evidence that this prophylactic antiulcer therapy is necessary, and even if it were necessary there is even less evidence that these kinds of drugs can actually prevent ulcers, other than making treatment regimes more complicated it is unlikely to do any harm.

Glucocorticoid side effects may jeopardize both patient health and owner compliance. One of the most common causes of death in IMHA or IMT patients is euthanasia due to unacceptable drug side-effects and, in my opinion, the drug class that confers the most unacceptable side-effects is the glucocorticoids. Alternate-day or tapered glucocorticoid therapy minimizes both predictable side-effects (polydipsia, polyuria, polyphagia, and hyperventilation) and eventual iatrogenic hyperadrenocorticism (alopecia, weight gain, muscle wasting, weakness and predisposition to infection, hypertension and pancreatitis). Adjunctive therapy (immunosuppressive agents, danazol or splenectomy) may enable further glucocorticoid dose reduction.

Immunosuppressive Agents: Dogs

Many practitioners treat IMHA and IMT with glucocorticoids alone, and reserve immunosuppressive agents for very severe cases and for patients that fail to respond to initial steroid therapy. In my personal opinion (note, this is not an opinion that is shared by all clinicians with an interest in hematology), however, just about every dog with IMHA or IMT should, at the time of diagnosis, be given concurrent immunosuppressive agents in addition to glucocorticoids. Why? Firstly, because immunosuppressive agents can take weeks to be effective, if such agents are only started after glucocorticoids alone have failed, a dangerous delay of up to one month can ensue before combination therapy becomes maximally effective. Secondly, since prolonged therapy now appears to be the best way of minimizing relapses, and since long-term glucocorticoids alone often cause unacceptable side effects, 'steroid-sparing' combination therapy will usually eventually be needed in order to enable reductions in steroid doses. The three drugs that are most commonly used as a first line immunosuppressive agent alongside glucocorticoids are azathioprine, cyclosporine, and cyclophosphamide. Choosing which of these three drugs to commence with is mostly a matter of individual preference, since there is little concrete evidence to suggest that one drug has clear benefits over the other two.

Although I tend to start therapy with both glucocorticoids AND another immunosuppressive agent, it is also reasonable, in patients with milder disease, to just start with steroids and add other agents at a later date only if needed. Even when not given during the initial therapy, other immunosuppressive agents often need to be added within a few weeks of starting treatment with corticosteroids. Indications for adding concurrent immunosuppressive agents include a failure to respond to glucocorticoids alone, or intolerable steroid side-effects such as polydipsia, polyuria, polyphagia and tachypnea. Addition of these extra immunosuppressive agents often enables a more rapid reduction in corticosteroid doses.

Commencing initial treatment with glucocorticoids and concurrent azathioprine, cyclosporine or cyclophosphamide is definitely recommended at the time of diagnosis in those dogs with clinical evidence that IMHA is severe, such as:

1. Marked anemia (PCV of less than 10%).

2. Signs of marked clinical compromise, particularly weakness, stupor and collapse.

3. Strong positive slide agglutination.

4. Marked jaundice or hemoglobinemia/hemoglobinuria.

5. Transfusion dependency.

Commencing initial therapy with glucocorticoids and concurrent azathioprine, cyclosporine or cyclophosphamide (and intravenous vincristine) is also often indicated, in my opinion, at the time of diagnosis in most IMT dogs with severe thrombocytopenia because, until the low platelet count is resolved, such patients are 'ticking time bombs'. While we can always prevent death due to blood loss anemia and hypovolemic shock, simply by giving transfusions as needed, we are therapeutically practically helpless if the patient bleeds into a vulnerable location, such as the brain, spinal cord, eye or pericardium. Anything that we can do that has a chance of hastening recovery to a normal platelet count and carrying a patient out of this initial severely thrombocytopenic danger period as quickly as possible is worth considering.

Azathioprine (starting dose 2 mg/kg/day orally) is relatively inexpensive and, although the purine analogue is often considered not to be as powerful an immunosuppressive agent as cyclophosphamide, it is still often effective in combination with steroids. In my experience, azathioprine is usually effective within a few weeks of commencing therapy, rather than the six weeks or more that has previously been reported. Azathioprine is usually well-tolerated, and the potential side effects of pancreatitis and hepatotoxicity are uncommon to rare. Azathioprine can infrequently cause an idiosyncratic severe myelosuppression (usually within a few weeks of commencing therapy, or after therapy is recommenced following a break), which is usually reversible if white cell counts are closely monitored and leukopenia is promptly detected. Chronic azathioprine therapy almost invariably causes a mild non-regenerative anemia that is subclinical and of no real concern except that this drug-associated anemia may fool the clinician into thinking that an IMHA patient has not completely responded to therapy.

Cyclosporine is a powerful selective T-cell immunosuppressive agent that is usually well tolerated, and that is not myelosuppressive. Cyclosporine would probably be the drug of choice for most dogs with IMHA or IMT if it were not for the high cost associated with therapy. The high cost of cyclosporine is compounded by the added expense of regular monitoring of therapeutic blood levels. Cyclosporine has an oral bioavailability that varies widely between formulations, and oral therapy must therefore adjusted to attain an acceptable trough whole blood drug level (500 ng/ml is the standardly recommended trough level, although some clinicians anecdotally report success at lower trough levels). The effective dose of oral cyclosporine in an olive oil base (Sandimmune) is usually 10 to 25 mg/kg daily (split into two doses), while the microemulsified form (Neoral or Atopica, or generic equivalents) is better absorbed, and therefore requires lower starting doses (5 to 10 mg/kg daily, split into two doses). Cyclosporine doses can often be effectively halved (thereby reducing expense) by the concurrent administration of ketoconazole, which impedes hepatic cyclosporine metabolism. Cyclosporine can cause gastrointestinal disturbances, gingival hyperplasia and, less commonly, nephrotoxicity or hepatotoxicity. Administering cyclosporine capsules directly from the freezer seems to reduce vomiting and nausea. Cyclosporine is available in a solution for intravenous use (6 mg/kg, given over 4 hours), although there is minimal strong evidence that intravenous administration hastens recovery during crises.

Cyclophosphamide (standard starting dose 50 mg/m2 every second day orally) is a relatively inexpensive alkylating agent that is also a powerful immunosuppressive drug, and since it is believed to work a little more quickly than agents such as azathioprine (although strong evidence of this purported benefit is largely lacking), the drug is sometimes also given intravenously (200 mg/m2 ) in dogs with acute, severe disease. Maintenance doses of cyclophosphamide can then be used to sustain early remission, although anorexia, gastrointestinal signs and myelosuppression may occasionally be dose-limiting. Such side effects are usually manageable with careful monitoring and dose adjustments. However, because of the association between cyclophosphamide use and hemorrhagic cystitis, cyclophosphamide is not the drug of choice for long-term usage. Unfortunately, cyclophosphamide-induced cystitis can be very distressing to the affected patient, and is not always readily reversible. For this reason, I prefer to use either azathioprine or cyclosporine for long-term immunosuppressive therapy.

Other agents that affect the immune system, such as vincristine, danazol and chlorambucil, may be useful in certain circumstances.

Dogs with IMT may respond to a single intravenous bolus of vincristine (0.02 mg/kg). The vinca alkaloid is inexpensive and usually well tolerated, and in some patients hastens recovery of platelet numbers by several days. The vinca alkaloids have both mild immunosuppressive (impairment of MPS function, and inhibition of humoral and cell-mediated immunity) and thrombocytotic (stimulation of transient megakaryocyte platelet release) properties. Intravenous vinca alkaloids induce transient platelet number increases in many IMT patients: circulating platelet life-span may be prolonged following treatment, suggesting that the increased platelet number is due to decreased destruction as well as enhanced megakaryocyte platelet release. Vinca alkaloids avidly bind to tubulin, a major component of platelet microtubules. The antibody-coated vinca-containing platelets of IMT patients are subsequently phagocytosed by tissue macrophages. Vinca alkaloids are therefore selectively delivered in cytotoxic doses to the macrophages involved in platelet destruction. Vincristine is the vinca alkaloid most commonly used in the dog. Intravenous vincristine markedly increases platelet numbers in some canine IMT patients, often within two to three days. Vincristine (a single intravenous dose) is therefore recommended for the emergency management of canine IMT.

Intravenous vinca alkaloid boluses are cleared from the circulation too rapidly for optimal vinca-platelet binding. Although weekly vinca boluses maintain remission in some human IMT patients, most eventually become refractory. Techniques maximizing vinca-platelet binding have improved remission rates: either constant vinca infusion over four to eight hours, or transfusion with platelets pre-incubated with vinca alkaloid ('vinca-loaded' platelets). Although reported, similar techniques have not been thoroughly clinically evaluated in the dog. Such techniques are labor-intensive, and are not commonly used in veterinary medicine.

Vincristine is extremely corrosive if extravasated. Single vincristine doses are otherwise well tolerated. Chronic vincristine therapy has been associated with reversible peripheral neuropathy in humans, and a comparable vincristine-associated neuropathy has recently been reported in the dog. Vincristine has been shown to, in certain circumstances, inhibit platelet function. However, in at least one prospective study, the benefits associated with a rapid recovery of platelet numbers and shorter hospitalization stays in dogs with IMT receiving vincristine seemed to outweigh any potential risks associated with decreased platelet function.

Danazol, an impeded androgen (5 mg/kg 2-3 times daily orally), has been recommended in combination with glucocorticoids in order to reduce the dose of steroid that is needed. Danazol's most important mechanism of action is probably to reduce MPS Fc receptor/antibody binding affinity. Danazol also competes with glucocorticoids for combination with steroid-binding globulin, consequently increasing the availability of active unbound glucocorticoid. Concurrent danazol therefore enables significant glucocorticoid dose reduction. Side effects are uncommon, and include hepatotoxicity and masculinization of female dogs. However, although some dogs with refractory disease may benefit from danazol, the drug has fallen out of favour in the past few years, probably because it is very expensive, and response to therapy is sluggish and highly unpredictable.

Chlorambucil, an alkylating agent that does not cause cystitis, is now being used by some clinicians (at an oral dose of 0.1 to 0.2 mg/kg/day) as an alternative to long-term cyclophosphamide for maintaining immunosuppression, although to date there is little data regarding its efficacy.

One relatively new drug that may hold great promise for the treatment of immune-mediated blood disorders is leflunomide (Arrava), an inhibitor of pyrimidine biosynthesis. Leflunomide, at a starting oral dose of 4mg/kg daily adjusted to attain a serum trough level of 20 µg/ml, has been used in dogs to prevent transplant rejection, and has also been used to treat successfully refractory cases of IMHA and IMT. Leflunomide appears to be very well tolerated.

Mycophenolate mofetil (Cellcept) has also been evaluated in dogs with immune disease, including dogs with myasthenia gravis. Mycophenolate inhibits an enzyme needed for purine synthesis, and has a relatively specific effect on lymphocytes. Mycophenolate can cause significant gastrointestinal side-effects, and concurrent immunosuppressive drugs may need to be given to enable reduction of mycophenolate doses down to well-tolerated levels. Mycophenolate has the advantage of being minimally myelosuppressive. Based on extrapolation from human medicine, a starting dose might be 600 mg /m2 per dose given orally twice a day or 400 mg /m2 per dose given orally three times daily. The exact dose in dogs has yet to be determined, although one published canine case of myasthenia gravis responded to an initial mycophenolate dose of 20 mg/kg twice daily (a dose roughly equivalent to 600 mg/m2 twice daily), and was eventually successfully tapered to 10 mg/kg twice daily.

Immunosuppressive Agents: Cats

Cats do not tolerate immunosuppressive agents as well as dogs, and it is often difficult to formulate standard dosage forms down to a size that is safe for cats. Fortunately, cats are remarkably tolerant of long-term high doses of glucocorticoids, and most cats with IMHA or IMT will respond to steroids alone. For this reason, oral azathioprine (at a markedly reduced dose of 0.3 mg/kg/day) or cyclophosphamide (same dose as dogs), or cyclosporine (4-15 mg/kg/day [Sandimmune] or 1-5 mg/kg/day [Neoral or Atopica], split twice daily, for a whole blood trough level of 250-500 ng/ml) are very rarely needed.

Tablet sizes that are too big to allow appropriate cat dosages can present a real problem with azathioprine and cyclophosphamide. Azathioprine must usually be compounded into a suspension, a process that is best done by an experienced compounding pharmacist since, otherwise, unequal mixing throughout the bottle and settling of the active ingredient can lead to inadvertent underdoses and overdoses. Since azathioprine can be highly toxic to cats (standard dog doses can cause profound myelosuppression) and since oral cyclosporine (and potentially chlorambucil) now offer viable alternatives, I no longer give azathioprine to cats. Cyclophosphamide tablets should not be split because, firstly, this increases owner exposure to this mutagenic and carcinogenic drug and, secondly, the active ingredient is often unequally dispersed throughout the tablet. Attaining a dosing regime of 50 mg/m2 every other day is often not possible. One trick that can be used to ensure that, at least, an appropriate weekly dose of cyclophosphamide is attained is to calculate the total weekly dose required (50 mg/m2 every other day translates into 175 mg/m2 weekly), and then to dose this at an interval that allows entire tablets to be used. For example, a 4 kg cat has a body surface area of 0.25 m2 , and therefore at a dose of 175 mg/m2 weekly requires about 44 mg of cyclophosphamide every week. Since the smallest tablet size is 25 mg, the closest that we can get to this ideal dose of 44 mg/week is 50 mg/week, which can be administered as one 25 mg tablet twice weekly (so the dosing interval has been expanded out to 3-4 days).

In the cat, IMHA is often secondary to either FeLV or Mycoplasma hemofelis. Cats with IMHA should therefore always be tested for FeLV. FeLV-positive cats with IMHA often initially respond well to standard immunosuppressive therapy, although long-term prognosis is poor. Cats with M.hemofelis typically present with recurring episodes of hemolytic anemia. During anemic crises, organisms may not be apparent, since affected cells are either destroyed or sequestered in the spleen. Organisms reappear on red cells during remission of anemia, and will be discovered by serial blood smears. Cats with IMHA should probably therefore receive oral tetracycline or oxytetracycline at a dose rate of 20 mg/kg three times daily, or doxycycline, even if organisms are not seen on initial smears. Concurrent immunosuppressive therapy in cats with M.hemofelis is not contraindicated. In fact, since anemia due to M.hemofelis has an immune-mediated component, glucocorticoids are indicated during acute crises.

Additional Therapy

Unfortunately, some animals with IMHA and IMT, despite appropriate standard therapy and multiple transfusions, succumb to severe anemia or blood loss during the first weeks of treatment. Additional treatment options which may be used in a crisis include gammaglobulin, plasmapheresis and splenectomy.

High intravenous doses of human gammaglobulin (HIVIG), as a 12 hour infusion at doses ranging from 0.5 to 1.5 g/kg, occasionally cause rapid and sometimes sustained remission of various immune-mediated disorders, including IMHA, PRCA and IMT. The main proposed mechanism of action of HIVIG is that the 'antibody soup' bathing the MPS binds to and overwhelms available macrophage Fc receptor sites, leaving no receptors left to bind antibody-coated cells. Alternatively, there may be some antibodies in the HIVIG soup that actually bind to and inactivate circulating anti-platelet or anti-RBC antibodies. The use of this product in dogs is associated with few side effects, although there is some concern that treated dogs with IMHA have a higher incidence of pulmonary thromboembolism. A recent study in IMT dogs demonstrated that a single dose of HIVIG at 0.5 g/kg shorted the duration of initial severe thrombocytopenia by several days, a response that was comparable (albeit more expensive) to that seen with vincristine. Human gammaglobulin has not attained common usage in veterinary medicine, probably because of high cost and very limited availability.

Plasmapheresis and splenectomy, although reported to be useful in isolated cases, have also not entered into common use, and are usually considered treatments of last resort. Plasmapheresis, when available, is a very effective method of rapidly removing unbound anti-RBC or anti-platelet antibodies from the circulation, although antibodies that are already bound to cell membranes will persist and may cause ongoing disease.

Splenectomy is potentially a particularly effective treatment for IMT and IMHA because many splenic elements contribute to the mechanisms reducing circulating blood cell numbers: anti-RBC or anti-platelet antibody production (splenic lymphocytes), antibody-coated platelet or RBC destruction (splenic MPS), and platelet or RBC sequestration (splenic vasculature). Splenectomy is the treatment of choice for many humans with chronic IMT or IMHA, with higher remission rates than medical therapy. In IMT patients, platelet numbers often rise within several hours of splenectomy, with maximal increases within one to two weeks. Most human IMT and IMHA patients (60% to 80%) subsequently maintain adequate platelet or RBC counts without further medical therapy. Splenectomized patients that do require further treatment frequently demonstrate an improved response to medical therapy. Splenectomy is therefore often recommended early in the course of chronic human IMT or IMHA.

Splenectomy has not been thoroughly clinically evaluated in a large group of canine IMT or IMHA patients. Published post-splenectomy remission rates for canine IMT and IMHA (each study limited to small patient groups) vary from poor to excellent. Since response rates appear to be unpredictable, early splenectomy currently cannot be recommended for canine IMT or IMHA, particularly as medical therapy is often far better tolerated than it is in people. Splenectomy may be indicated in canine patients refractory to glucocorticoids and immunosuppressive agents, particularly if associated drug side effects are unacceptable.

Life-threatening post-splenectomy complications in humans (overwhelming infection, disseminated intravascular coagulation) are rare in the dog. The most common small animal post-splenectomy complication, erythrocyte parasitemia (Mycoplasma hemofelis, Babesia), usually responds well to medical therapy.

Persistent IMT or IMHA post-splenectomy indicates ongoing platelet or RBC destruction by the non-splenic MPS (usually hepatic macrophages). Uncommonly, post-splenectomy platelet or RBC destruction occurs within an "accessory spleen" (a detached splenic remnant with residual MPS function). Some authors recommend exploratory laparotomy in humans with persistent IMT or IMHA: removal of an accessory spleen may induce complete remission.

Sometimes, one of the emergency treatments for IMHA or IMT, such as splenectomy or intravenous gammaglobulins, may 'kick start' refractory chronic cases and render standard therapy more effective. Splenectomy, in particular, may on occasion permit subsequent significant reductions in immunosuppressive drug dosage. Unfortunately, however, this beneficial effect is inconsistent and unpredictable.

Immune-Mediated Disorders Affecting Marrow Stem Cells

We now recognize that marrow disorders such as PRCA, aplastic anemia, and megakaryocyte hypoplasia may sometimes be due to immune-mediated processes at the level of the stem cell, and such previously 'idiopathic' disorders are therefore now frequently being treated with immunosuppressive agents. Although immunosuppressive therapy in patients with these disorders is speculative, and not all patients will respond, trial immunosuppression makes sense, especially since only a few years ago such conditions were often considered to be incurable. Immunosuppressive therapy for these disorders is very similar to therapy for IMHA and IMT, except that myelosuppressive drugs (cyclophosphamide, for example) should be avoided, particularly in neutropenic patients. Marrow immune-mediated disorders often take many months to measurably respond to immunosuppressive agents.

Chronic Management

      Secondary Immune-Blood Disorders

Whenever an underlying cause of IMHA or IMT can be identified and eliminated, ongoing immunosuppressive therapy is often not needed. In contrast, such therapy is unlikely to be able to be discontinued while the underlying cause persists. Since rickettsial infections can be difficult to diagnose, and often have a strong immunologic component, cats with suspected IMHA should also be treated for M. hemofelis, and dogs with suspected IMT (and, arguably, IMHA) should probably be treated for ehrlichiosis. Medications or vaccines that were given over the few months prior to onset of disease should be avoided in the future when possible. When the original crisis was not associated with recent vaccination, however, there is arguably no need to modify routine vaccinations in the future, since there is little evidence that animals with primary immune-mediated disease have an increased risk of developing secondary IMHA or IMT as well. However, since the cautious reduction of vaccination loads in adult animals is unlikely to do harm, stripping vaccine protocols down to 'the bare essentials' is certainly also a reasonable approach.

Monitoring Response to Therapy

A hematocrit (IMHA) or platelet count (IMT) should be monitored daily until an appreciable response to immunosuppressive therapy is observed and the PCV rises above approximately 15% in cats and 20% in dogs, or the platelet count rises above 50,000 to 100,000/µl, after which the PCV or platelet count should be monitored at least weekly until anemia or thrombocytopenia resolve completely. Given an adequate treatment response, drug therapy should be gradually tapered to an acceptable maintenance dose that can be given safely long-term without significant side effects. In dogs, prednisolone and azathioprine can often both be tapered to 0.5 to 1 mg/kg every second day, a maintenance dose that is usually well tolerated. Similar maintenance doses of prednisolone may be achievable in cats although, since steroid side effects are typically minimal, higher doses are also usually acceptable. Appropriate tapered doses of cyclosporine in dogs and cats have not been established. Since cyclosporine is well-tolerated (apart from expense), one viable alternative is simply not to taper cyclosporine. Alternatively, cyclosporine doses can be tapered to attain a target trough blood drug level of between 100 ng/ml and 250 ng/ml although, in all honesty, the minimum blood cyclosporine dose that still provides some degree of immunosuppression has not been established. Since cyclophosphamide therapy can eventually cause sterile cystitis (which can be irreversible) or even bladder neoplasia, there is no safe maintenance dose of this particular drug. Since both cyclophosphamide and azathioprine can be unpredictably myelosuppressive, white cell counts should be regularly monitored throughout therapy. Furthermore, since azathioprine can (rarely) cause an idiosyncratic hepatotoxicity, liver enzymes should also be monitored regularly for elevations far beyond those expected with glucocorticoid therapy alone.

One simple approach to tapering therapy in stable patients with IMHA or IMT is to recheck PCV or platelet counts approximately every 2 weeks and then, if anemia is still in remission, to reduce the dose of one drug by 50% after each visit. In animals receiving several immunosuppressive agents, the drug which is causing the most side effects is tapered first. In most instances, this means that prednisolone is tapered first and, once steroid doses are low enough to cause no side-effects, then the other drug is similarly tapered. Once a well tolerated maintenance dose of all drugs is attained, therapy should ideally be continued for at least a further three months, with monthly monitoring of PCV or platelet count. Presuming that an underlying cause of IMHA has not been identified and eliminated, tapering therapy too rapidly increases the risk of a life-threatening relapse. Clinicians should remember that chronic azathioprine therapy itself can, in dogs, cause a mild non-regenerative anemia (PCV greater than 30%) that causes no patient compromise, and persistent of a very mild anemia in patients on this particular drug should therefore not be misinterpreted as evidence that treatment is inadequate.

Once anemia has been in remission for 3 to 6 months, therapy can be cautiously withdrawn. Hematocrit or platelet count should be monitored regularly over the months following cessation of therapy. Patients with a poor regenerative response, particularly those with severe immune-mediated marrow disease such as PRCA, can take many months to respond to therapy. Such animals should be supported with an initial blood transfusion, followed by standard immunosuppressive therapy. Fortunately, since destruction of peripheral erythrocytes is often minimal in animals with immunological marrow disease, donated red cells may survive in the circulation for up to several months. Although immunosuppression may not cause a rise in PCV for up to 3 months, response to therapy can detected earlier by careful monitoring of serial reticulocyte counts or bone marrow samples.

Discontinuing Therapy

Unfortunately, animals with immune-mediated blood disorders that survive the initial crisis are not out of danger. Ceasing therapy too soon is risky, especially since relapses are notoriously difficult to treat. Drug therapy should probably not be stopped before 3 months or, in my opinion, before 6-12 months and, in a handful of cases with severe initial crises or risk-averse owners, therapy may be continued indefinitely. Glucocorticoid doses should be reduced to well-tolerated levels by using drug combinations. Low-dose prednisolone combined with azathioprine and/or cyclosporine currently seems to be the most effective and best tolerated regime for long term immunosuppression.

Prognosis

Published mortality rates for IMHA are often surprisingly high, ranging from approximately one-third to one-half of all presented cases, with death/euthanasia usually attributable to either severe anemia or pulmonary thromboembolism during the initial acute crisis, or persistent/recurrent disease or unacceptable drug side effects during chronic therapy. Negative prognostic indicators with IMHA include the presence of marked jaundice or hemoglobinemia/hemoglobinuria, a poor regenerative response, and a positive slide agglutination.

Canine IMT patients do a little better than IMHA patients. In one retrospective study of canine IMT, mortality rates during the initial episode of thrombocytopenia exceeded 25%, although more recent studies report a mortality rate of closer to 10%. Principal causes of death are either severe acute gastrointestinal hemorrhage or euthanasia. Recurrence of thrombocytopenia following a variable period of apparent complete clinical remission is common. Chronic thrombocytopenia requiring long-term medical therapy develops in approximately 25% of canine IMT patients. Eventual mortality rates can be high in such patients (over 50%). Unacceptable drug side effects encountered during long-term management of refractory chronic canine IMT are frequently a major reason for eventual euthanasia.

Hopefully, as our understanding of these particular diseases increases, and our treatment options expand, deaths due to IMHA and IMT will become much less frequent.