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When the immune system goes awry: immune-mediated diseases (Proceedings)
Prednisone is almost always included in immunosuppressive protocols. The dose is approximately 2.2 mg/kg once daily for most cases; 1 mg/kg in less severe diseases.
Since many immune-mediated diseases are treated similarly, this talk will start with a general immunosuppressive treatment plan and discussion of commonly used drugs. At the end is a description of commonly diagnosed immune-mediated diseases.
Treatment of immune-mediated disease
Prednisone is almost always included in immunosuppressive protocols. The dose is approximately 2.2 mg/kg once daily for most cases; 1 mg/kg in less severe diseases. The dose may be divided into twice daily administration but there is no obvious benefit. Some dogs are intolerant to prednisone and will develop side effects (polyuria, polydipsia, polyphagia, panting, and/or lethargy) that are unacceptable to the owner. Attempting therapy with an equipotent dose of another steroid (prednisolone, methylprednisolone, or dexamethasone) may resolve the unacceptable signs. Some cats do not effectively respond to prednisone and should be tried on an alternate steroid.
Corticosteroids are administered at full dose until the disease is in complete remission. Complete remission may be defined as resolution of signs of disease as well as radiographic or laboratory changes that were initially present. Once remission is attained the dose is tapered, generally in half, for 4 weeks. Reevaluation is performed and if signs of disease are absent (on physical or laboratory data), the dose is again halved. This protocol is followed monthly until the animal either relapses or medication is stopped. The minimum duration of therapy for any immune-mediated disease is 6 months.
Many patients will experience a relapse as the dose is tapered. Relapse is treated with return to full dose administration, with again monthly tapering, but as the dose is approached that previously allowed relapse the dosage may then either be held constant or tapered more slowly.
Corticosteroids are effective immunosuppressive agents. Many animals tolerate their administration with only mild side effects, or their disease goes into remission and the corticosteroid may be stopped. For many animals, single agent therapy with corticosteroids is adequate.
Combination immunosuppresion therapy is very useful, however, because the addition of another agent may allow a lower dose of corticosteroid to be used (prednisone-sparing effect). Additional medications may also increase the strength of immunosuppression because they work by different mechanisms. The drug most frequently used in dogs is azathioprine.
Azathioprine (Imuran®) is orally administered and generally free of adverse side effects. The dose is approximately 2.2 mg/kg once daily until remission occurs, then the same dose is administered every other day. A potential side effect is bone marrow suppression and a CBC should be evaluated after 7 days and then every 2 weeks while the patient is receiving daily treatment. Once receiving every other day therapy, a CBC should be evaluated every 3 months, but bone marrow suppression is unusual at this dose. Rarely hepatotoxicity may occur and liver profile monitoring may be appropriate.
Prednisone and azathioprine are frequently used in combination. The drugs are administered together once daily and then tapered after remission is attained. The method of tapering is somewhat arbitrary; if signs of prednisone intolerance are experienced then the prednisone is tapered first; if bone marrow disease is encountered the azathioprine should be tapered or discontinued first. If the disease was difficult to get into remission then only one drug should be tapered at a time; if the disease easily went into remission, then both drugs may be tapered concurrently. Tapering should be performed every 4 weeks, with the minimum duration of therapy being 6 months. Relapse is treated with the administration of full dosage of both medications and gradual taper to the previously lowest effective dose. The dosage may then either be held constant or tapered more slowly.
I do not use azathioprine in cats. Instead, I recommend chlorambucil or cyclosporine for cats that require immunosuppression in addition to prednisolone.
Chlorambucil (Leukeran®) is dosed in cats at 2 mg/cat q 48 h. Potential side effects include anorexia and bone marrow suppression. A complete blood count should be evaluated every two weeks initially. If after two or more evaluations the CBC remains normal (no leukopenia) further monitoring may be performed less frequently. If leukopenia is detected (absolute neutrophil count <3,000/µl), the medication should be stopped. Signs of infection (loss of appetite along with fever) should be aggressively treated with fluids, amoxicillin and enrofloxacin. The administration of chlorambucil may be tapered to every 3 days once remission is attained.
Cyclosporine (use only the microencapsulated formulation) is dosed in cats at 5-10 mg/kg/d (commonly 25 mg/cat/d). Cyclosporine is especially useful when avoidance of cytopenias is important. Side effects are usually gastrointestinal. Monitoring of serum blood levels should be performed if side effects or lack of clinical response occurs.
Commonly encountered immune-mediated disorders
Immune-mediated diseases may affect multiple body systems; for example, polyarthritis may be associated with thrombocytopenia or proteinuria. A CBC, platelet count, chemical profile and urinalysis are considered the minimum database for immune-mediated diseases.
Immune-mediated hemolytic anemia
The diagnosis of hemolytic anemia is suspected upon discovering anemia with normal serum protein levels. Anemia may be regenerative or non-regenerative (red cell destruction may occur in the bone marrow prior to release of reticulocytes). Standard testing includes complete blood count with manual differential count, platelet count, reticulocyte count, chemistry profile, urinalysis, thoracic and abdominal radiographs, coagulation profile, Coomb's test and abdominal ultrasonography. Bone marrow cytology is indicated if the anemia is non-regenerative or infiltration with hemolytic histiocytes is suspected (hemophagocytic syndrome).
Hemolytic anemia may be mild/low grade or rapidly progressive. Mild cases seem to respond well whereas rapidly progressive cases are associated with higher mortality. Red cell or synthetic hemoglobin transfusion is indicated if the PCV drops to less than 15% or the animal becomes dyspneic or tachycardic. Due to a high incidence of pulmonary thromboembolism, prophylactic therapy with dalteparin (150 units/kg sq q 12 hr), aspirin (0.5 mg/kg q 24 h), and/or clopidogrel (1 mg/kg q 24 h) is recommended for cases with rapid rates of hemolysis. Intravenous fluids are recommended for most cases and oxygen therapy for some.
Mild cases with PCV >22% and bilirubin <3: treatment with prednisone alone or prednisone with azathioprine may be effective. The prognosis is guarded to fair.
Aggressive hemolytic cases (PCV rapidly dropping/ bilirubin >3): treatment with intravenous fluids, antithrombotics, and dexamethasone (0.3 mg/kg q 24 h) is indicated. Additional immunosuppressant therapy has yet to be proven more effective than corticosteroid therapy alone. The prognosis is guarded.
The diagnosis of ITP is suspected with the clinical finding of cutaneous petechiae or bleeding from mucosal surfaces. Laboratory testing confirms a platelet count of less than 25,000/µl. Standard testing includes complete blood count with manual differential, platelet count, coagulation profile, chemistry profile, urinalysis (voided), thoracic radiographs and abdominal ultrasound. Bone marrow cytology is usually not helpful unless bicytopenia or pancytopenia is present. Tick titers (Ehrlichia canis, Anaplasma phagocytophilum, Rocky Mountain spotted fever) and/or treatment with doxycycline are indicated in endemic areas.
Most cases respond to immunosuppressive therapy. Vincristine (0.5 mg/m2 IV) may be synergistic with prednisone. Specifically avoid cyclophosphamide because an episode of hemorrhagic cystitis, which may occur after only a single dose, may be fatal. Platelet transfusions are often impractical and instead either whole fresh blood (supplying at least some platelets) or packed red cells are administered as needed. Maintaining the hematocrit above 20% may lessen spontaneous bleeding.
Bleeding into the eyes, brain and/or spinal cord may occur with severe consequences. A guarded prognosis should be given until the platelet count begins to rise.
The diagnosis of immune-mediated polyarthropathy is suspected upon the finding of lameness with swelling of multiple joints. Infectious polyarthropathy (Lyme disease, Anaplasma phagocytophilum, others) is common and at least 3 days of doxycycline (5 mg/kg IV or PO once daily) should be administered before the diagnosis of immune-mediated disease is confirmed. Standard testing includes complete blood count with manual differential, platelet count, chemistry profile, urinalysis, radiographs of affected joints, joint taps of affected joints (tap at least 3 joints, even if palpably normal) and tick titers (or exclusion by a doxycycline trial).
Most cases respond to immunosuppression with good results. Rheumatoid arthritis (evidence of joint destruction on radiographs) carries a worse prognosis and irreversible joint destruction usually develops.
The diagnosis is suspected based upon non-healing skin lesions, especially of the face, ears and/or feet. Biopsy should be performed via scalpel elliptical excision with the intent of obtaining intact pustules. The characteristic pathologic lesions are easy to miss and repeated biopsies are not unusual. At least 3 areas should be biopsied. Standard workup includes complete blood count with manual differential, platelet count, chemical profile, urinalysis and urine culture and thoracic radiographs (paraneoplastic pemphigus has been reported).
Most cases respond well to immunosuppression.