Cyclosporine. A third drug gaining acceptance in treating IMHA is cyclosporine (2.5 to 5 mg/kg orally twice daily). An intravenous form is available, but no clinical trials with this form have been published in the veterinary literature. The one retrospective study that investigated cyclosporine (which was given at a slightly higher than recommended dosage) showed no benefit compared with other drug protocols.²⁹

Cyclosporine is a potent T-cell suppressor that blocks production of immune activating factors in both T-helper cells and T-cytotoxic cells, as well as blocks the expression of IL-2 and gamma-interferon. The outcome is a reduction of cell-mediated immunity and antibody production. Side effects include gastrointestinal upset, gingival hyperplasia (can regress with dose tapering), increased susceptibility to infection, and lethargy. Although it is recommended that cyclosporine concentrations are measured every two to four weeks (maintaining trough concentrations, depending on the method used, between 100 and 300 ng/ml), it is now questionable whether blood concentrations of this drug need to be measured if clinical disease is well-controlled.¹⁷

Cyclophosphamide. In addition to the above therapeutic options, a handful of other medications have been used with varying degrees of success. Cyclophosphamide, an alkylating agent that suppresses the immune system, can be given as a single intravenous or oral dose initially in the course of treatment (200 mg/m² ) or as a four days on/three days off (50 mg/m² /day) protocol. Cyclophosphamide harms B and T cells by cross-linking DNA, inhibiting humoral and cell-mediated immunity, and suppressing neutrophil and macrophage function. Side effects include gastrointestinal upset, myelosuppression, and hemorrhagic cystitis. Because of the severity of some of these signs, cyclophosphamide is not widely used in the long-term treatment of IMHA. Instead, it is commonly used in early treatment of severe refractory IMHA.

Mycophenolate mofetil. Mycophenolate mofetil (10 to 20 mg/kg orally or intravenously twice daily), similar to azathioprine, targets B and T lymphocytes by inhibiting an enzyme necessary for de novo purine biosynthesis.¹⁵ This drug was developed to help prevent allograft rejection in people and has been used in dogs to treat myasthenia gravis and glomerulonephritis. At therapeutic doses, mycophenolate is minimally myelosuppressive, but gastrointestinal side effects can be substantial in dogs (gastrointestinal hemorrhage, anorexia, and diarrhea). To minimize these side effects, the dose can be lowered to well-tolerated levels when used in conjunction with other myelosuppressive drugs.³¹ Few reports have been published on the use of this drug for IMHA.³²

Danazol. Danazol (5 mg/kg orally two to three times daily), a synthetic androgen, has been used to treat
immune-mediated disease in people and is sometimes recommended in addition to standard therapies to treat IMHA in dogs. Danazol likely exerts its immunomodulatory effects by decreasing the production of IgG and cytokines, inhibiting complement activation, and reducing the binding of antibody and complement to erythrocytes.²⁴ Danazol is not widely used for three main reasons: it is expensive, it can take weeks to observe a clinical response, and it is potentially hepatotoxic.¹ While one study did not show improved outcome with this drug, the small number of reports in the veterinary literature makes the use of this drug difficult to assess.³³

Leflunomide. Leflunomide (4 mg/kg orally once daily), an inhibitor of pyrimidine biosynthesis, has been used to treat rheumatoid arthritis in people and granulomatous meningoencephalomyelitis, neoplasia, and graft rejection in dogs. Limited but favorable reports exist on the use of this drug for treating IMHA. Side effects in dogs appear to be minimal but can include vomiting, lymphopenia, and anemia. The recent introduction of a generic form may make it less costly for routine treatment. The dose should be adjusted to maintain a serum trough concentration of 20 µg/ml.³¹