Evidence-based management of IMHA (Proceedings)

Immune-mediated hemolytic anemia is one of the most common reasons for referral to veterinary internists. The most common presenting complaint is that the patient is inadequately responding to appropriate immunosuppression. In all cases referral is welcome (we appreciate your trust and your business!); however many times this reflects an unfamiliarity with some of the treatment options beyond glucocorticoids, or a difficult-to-diagnose causative underlying disease. This presentation will briefly review the more common causes of secondary immune-mediated hemolytic anemia (IMHA) and the diagnostic tests which I routinely consider prior to instituting immunosuppresive therapy, and then discuss in depth treatment options for dogs with this disease.

IMHA: DIAGNOSTIC WORK-UP

Primary versus Secondary causes of IMHA

Development of anti-erythrocyte antibodies can occur idiopathically (primary IMHA), or secondary to a number of infectious or neoplastic diseases, toxins and envenomations, and commonly used drugs. Other diseases (i.e. neoplasia, zinc, heartworms) can cause hemolytic anemia without the presence of anti-erythrocyte antibodies. Differentiation can be difficult, as dogs with IMHA are not reliably autoagglutinating or Coomb's positive. For this reason intense history-taking and physical examination are required in every case, as well as screening tests to ensure that there are no concurrent diseases. Diseases which are definitely associated with hemolytic anemia and secondary IMHA include:

     • Non-immune mediated hemolytic anemia:

     • Caval syndrome (secondary to heartworm disease)

     • Hemangiosarcoma

     • Zinc toxicity (especially after ingestion of pennies)

     • Hypophosphatemia

     • Any cause of Heinz bodies

Secondary IMHA (more common causes, not a complete list)

     • Drugs: sulfonamides, cephalosporins, anti-thyroidal drugs

     • Recent vaccination?

     • Neoplasia: Lymphoma, malignant histiocytosis; solid tumors (carcinomas, sarcomas), particularly when metastatic

     • Infectious diseases: Babesia sp.; Ehrlichia sp.; Mycoplasma haemominutum (aka Hemobartonella felis); FeLV

     • Immune-mediated diseases: SLE

     • Other: bee stings; rattlesnake envenomations

Diagnostic testing

The majority of patients with IMHA that present to first-line practitioners are relatively stable. Although immunosuppression in most cases is appropriate and will rapidly lead to resolution of clinical signs, internists (including myself) always recommend some diagnostic testing to ensure that there is no secondary cause of disease. If the history or physical examination reveal any clinical signs or findings that do not fit with a 'classic' case of IMHA then these should be pursued. The more difficult cases are those dogs that present slightly depressed and have normal physical examinations, but are obviously anemic and autoagglutinating. In these cases I definitely balance my diagnostic testing with the owner's budget; I always make sure to not result in the euthanasia of my patient just because the owner cannot afford the 'just in case' work-up. At a minimum I always insist on a full minimum database—complete blood count, full serum chemistry panel, and urinalysis. I only recommend a urine culture if the urinalysis suggests an infection may be present; however other internists have reported anecdotal cases of IMHA secondary to UTIs. I always perform some form of imaging studies. Thoracic and abdominal radiographs and abdominal ultrasound are ideal; however the abdominal ultrasound is only really required on my part if I detect an abnormality on physical examination, or if the patient's signalment is not typical for IMHA (fpr example, if the dog is greater than 8 years old or so). High quality radiographs are usually sufficient screening tests for mass lesions and heavy metal densities. I consider a fundic examination to be part of a normal physical examination; vasculitis (suggesting rickettsial disease or hematologic malignancies), granulomas (fungal lesions), or neoplastic cells (particularly lymphoma) may be detected using this test. Careful palpation of lymph nodes is done multiple times, and if there is any hint of lymphadenopathy, I aspirate and at a minimum look at the slide myself. Lymphoma is the most common cause of secondary IMHA!

The final diagnostic test I consider in every case of IMHA is a bone marrow aspirate. If any other cell line is decreased in addition to the erythrocyte lineage, or if there is no evidence of regeneration, I will always collect bone marrow. Period. Either of these CBC findings requires that primary bone marrow disease be ruled out, particularly infiltrative neoplasia. For other cases I still offer it to owners, discussing it as a gold standard diagnostic test. As mentioned above, lymphoma is the most common cause of secondary IMHA, and this disease must be diagnosed prior to instituting immunosuppression. All the drugs used to treat IMHA, particularly glucocorticoids, result in lysis of lymphocytes; therefore treatment may put these dogs into remission. Although this may be an apparent advantage, prednisone alone is not the optimal therapy for lymphoma—dogs with lymphoma treated with prednisone alone have a median survival of only 3 months, as opposed to longer survival rates with combination chemotherapy. Additionally administration of prednisone prior to the diagnosis of lymphoma worsens long-term prognosis, as glucocorticoids induce multi-drug resistance against many other chemotherapeutic agents.

THERAPY

Immunosuppression

Glucocorticoids

Regardless of whether I feel my case of IMHA is primary or secondary, and regardless of the severity of clinical signs or severity of decrease in the hematocrit, I begin prednisone at 1 mg/kg PO q12h (in other words, an immunosuppressive dose—2 mg/kg/day). Although other clinicians have advocated higher doses of prednisone during the 'induction' period, or feel that higher doses offer greater immunosuppression, I have not appreciated this; in my experience increases above this dose only worsen signs of hyperadrenocorticism and lead to more adverse side-effects. There are only rare instances where I choose to use alternative glucocorticoids. In animals that are vomiting or have evidence of gastrointestinal bleeding (for reasons other than drugs) I opt for hospitalization and intravenous dexamethasone. If this is necessary, recall that dose adjustments are needed to account for the difference in potency: dexamethasone has a potency of approximately 5 to 7 times that of prednisone, so instead of 1.0 mg/kg in one dose, I give 1.0 mg/kg÷= 0.2 mg/kg IV q12h. Some clinicians do feel that those dogs that do not respond to one glucocorticoid may respond to an alternate one; these clinicians will start oral dexamethasone or methylprednisolone after 3-4 weeks of unsuccessful immunosuppressive prednisone. Again, I am not an advocate of this, although I agree in principal that this may be true. Instead I prefer to repeat basic screening tests to look for secondary diseases that may have been missed, and then add a non-glucocorticoid immunosuppressive (cyclosporine) or less commonly, IVIG (see below).

Azathioprine

Azathioprine is a purine analog; its biologic structure is similar to the basic building blocks of DNA, but when incorporated into new DNA during cell replication it results in slowed cell growth and death through mutations or apoptosis. Activated lymphocytes are the primary target of this drug. Although few controlled studies exist on the use of azathioprine in veterinary patients, it is the non-GC immunosuppressant with which we as a profession have the most anecdotal experience. 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.

Use of azathioprine in IMHA is well accepted. However azathioprine requires several weeks to reach therapeutic concentrations; therefore many clinicians (including myself) start azathioprine in every case of IMHA at the time of diagnosis. The most commonly used dose is 2 mg/kg PO q24h for 7-10 days, and then q48h thereafter. The strongest 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 cases which received prednisone alone in previous reports. Potential side effects of azathioprine include hepatic necrosis or bone marrow suppression; the severity of the bone marrow suppression precludes the use of this drug in cats. Mycophenolate mofetil is a newer immunosuppressive drug that may eventually serve as an alternative to azathioprine. A single abstract has reported that this drug may be of use for management of IMHA.

Cyclosporine

Prednisone alone with or without azathioprine is still considered first-line therapy for IMHA; however non-responding patients (immunosuppressive doses of glucocorticoids for 3-4 weeks) may benefit from cyclosporine. Published reports have shown that prognosis is not worsened, and many internists anecdotally feel there is a benefit when used. The pharmacokinetics of cyclosporine are highly variable in dogs; because of this variability serum cyclosporine concentrations are required to ensure adequate dosing. Trough cyclosporine concentration should be approximately 400-600 ng/ml, and can be measured immediately prior to the next pill as soon as 48 hours after a change in drug dose. Gastrointestinal tract signs are most common and often correlate with drug dose. Some internists believe that azathioprine and cyclosporine should not be used simultaneously, as the risk of secondary infections due to profound immunosuppression are too high.

Cyclophosphamide

Although cyclophosphamide has a clear benefit for the treatment of neoplasia (particularly lymphoproliferative neoplasias), it appears to worsen prognosis for IMHA. Because this drug affects all dividing cells, bone marrow stem cells are also suppressed, and erythrocyte regeneration was slowed and recovery was delayed in a prospective study. Because of these discouraging results, cyclophosphamide has fallen out of favor as a treatment option for IMHA.

Adjunctive therapies

Red blood cell transfusion

Patients with IMHA typically present with clinical signs secondary to their anemia. Regardless of which immunosuppressive regimen is chosen it is rare for these clinical signs to resolve immediately, as a lag time of several days exists before red blood cell destruction slows. The decision to transfuse or not should be made on the basis of clinical signs rather than hematocrit. Transfusion of red blood cells or synthetic oxygen carrying molecules is definitely called for when there is any evidence of tissue hypoxemia; tachycardia, tachypnea, and weakness should be triggers for hospitalization and transfusion. Historic concerns that transfused red blood cells decrease endogenous erythropoietin production and thus regeneration, that the foreign red blood cells would 'feed' the disease prior to establishment of immunosuppression, or that increased red blood cell lysis will lead to hemoglobin nephropathy have not been proven.

Intravenous immunoglobulin

Human-derived concentrated immunoglobulin (IVIG) is an expensive, sporadically available treatment option for dogs with IMHA. The mechanism of action of IVIG is unclear, but may be by blockade of macrophage receptors which would normally bind to erythrocyte-bound antibody. Theoretical risks of IVIG include anaphylaxis (particularly if given more than once), fluid overload, and possibly increased risk of thromboembolism. Most internists reserve this drug for more severe cases of IMHA that are not responding to conventional immunosuppressive therapy. Prospective controlled studies have not been performed as of yet, but retrospective studies have shown no clear positive influence. Regardless, if one considers that the most severely affected dogs usually receive IVIG, seeing no difference between treated and untreated dogs may argue for a beneficial effect. I tend to reach for IVIG much sooner than many other internists. I am a strong believer of the beneficial effects of this treatment, and usually offer it to owners of dogs with severe IMHA early in the disease treatment course. Typical dose used is 1.0 g/kg IV over 6-12 hours.

Anticoagulants

IMHA is an intensely inflammatory disease, and is commonly associated with thromboembolic events. Pulmonary thromboembolisms (PTE) are frequently noted on necropsy examination of lungs of dogs that have died secondary to IMHA, and DIC, a common cause of death, is itself a consumptive/hypercoagulable state. Many internists avoid jugular catheterization because of the fear that the catheter may serve as a focus for thrombus formation, which if dislodged will lead to PTE. Retrospective studies have suggested that hospitalized dogs with IMHA have better outcomes with heparin therapy. I always measure coagulation status in dogs with IMHA. If aPTT is not significantly prolonged, I start heparin therapy prophylactically. The recommended starting dose is 100 IU/kg SQ q8h; ideally aPTT should be monitored to ensure that coagulation is being effectively prolonged to approximately 1.5 to 2.0 times the upper end of the reference range. However, if aPTT is significantly prolonged at initial measurement prior to heparin therapy, I instead worry of a consumptive state and consider plasma transfusion to replace coagulation factors.

Splenectomy

The spleen is the primary site of erythrocyte removal and destruction by macrophages in dogs with extravascular hemolysis. Therefore splenectomy has been suggested as a possible treatment modality which would slow the rate of hemolysis and provide immediate therapy until immunosuppressive drugs take effect. Splenectomy (in conjunction with standard immunosuppressive therapy) within 2 days of diagnosis of IMHA appeared to be of benefit in dogs with IMHA both short-term (reduced hospitalization) and long-term (increased survival). Until more prospective studies are published and peer-reviewed I do not advocate splenectomy except in the most severe non-responsive cases; I actually haven't been pushed this far yet. As mentioned previously, IMHA dogs are usually hypercoagulable and in an overall inflammatory state; theoretically surgery would be expected to exacerbate this and likely be associated with further risk of embolic disease and DIC. Finally, dogs with intravascular hemolysis primarily have red blood cell destruction secondary to complement-mediated lysis, so splenectomy would not be indicated.

Long term monitoring and therapy

Those animals with IMHA that successfully enter remission should be tapered slowly—rapid taper is more likely to result in disease recurrence that is then less likely to remit again. In general, primary autoimmune diseases should be in remission for a minimum of 1 month, and preferably longer, prior to the first decrease in dose. The first taper may be less risky after shorter periods of remission in those cases where autoimmune disease has developed secondary to a clearly identified concurrent disease that has been adequately resolved. An example is IMHA secondary to lymphoma; in these cases I will attempt to decrease the dose after only two weeks of remission while receiving immunosuppressive doses of prednisone, provided the lymphoma is in remission.

Dose decreases are usually done by either decreasing the mg/kg dose in half or by extending the interval between doses without changing the amount given. The most common tapering technique is to decrease the dose in half from immunosuppressive to anti-inflammatory doses in one or two steps, and then switch to alternate day dosing of the anti-inflammatory dose. Each step should be at least 2, and preferably 4 weeks apart. IMHA dogs should have normal hematocrits prior to every dose reduction—a mild anemia should be considered lack of remission, unless there is a high suspicion of an alternate source of blood loss, such as gastrointestinal tract ulceration. Dogs usually show minimal side-effects of chronic glucocorticoid administration once they are receiving alternate day dosing, so I tend to keep my patients on this dose for several months before withdrawing glucocorticoids completely.