The mechanism of action for the immunosuppression caused by corticosteroids is complex. In the study by Ammersbach et al. (2006), the authors demonstrated decreased neutrophil migration and survival, decreased cytokines, decreased adhesion expression, and a decrease in the cytotoxic lymphocyte function as well as lymphocyte apoptosis. The dose used in this study in dogs was approximately 2 mg/kg per day for 3 days.

Corticosteroids increase the circulating numbers of mature neutrophils. There is a release of cells from the marginal pool of neutrophils and decreased migra-tion and egress into inflammatory sites. This effect is attributed to decreased expression of adhesion molecules, reduced adherence to the vessel endothelium, and reduced diapedesis from the vessels. Subsequently, there is decreased movement of inflammatory cells into tissues in response to chemotactic stimuli.

Glucocorticoids also affect many functions of macro-phages. They suppress the function of macrophages and decrease the inflammatory response, generation of cytokines, and the ability of macrophages to process antigens. They also inhibit phagocytosis by macrophages.

Glucocorticoids affect leukocyte traffic more than cellular function. Corticosteroids decrease the numbers of lymphocytes in the peripheral circulation – caused by a redistribution of circulating lymphocytes – depress lymphocyte activation, and decrease participation of lymphocytes in inflammation. T cells are affected more than B cells. Because B cells are more resistant to the immunosuppressive effects of glucocorticoids, there is minimal effect on immunoglobulin synthesis. However, high corticosteroid doses will decrease immunoglobulin levels, probably because of increased catabolism, as well as through the secondary effects to suppress accessory cells and cytokine synthesis. At antiinflammatory doses, glucocorticoids do not decrease an animal’s ability to mount a normal immune response (e.g., from vaccinations) (Nara et al., 1979). Other effects of glucocorticoids include inhibited release of inflammatory cytokines from leukocytes (e.g., IL-1, TNF-α, prostaglandins) and decreased expression of cytokines from lymphocytes (e.g., IL-2).

It is difficult to separate the antiinflammatory from the immunosuppressive effects of glucocorticoids. For a complete review of these effects the articles by Cohn (1991) and Barnes (2006) should be consulted. For immune-mediated disorders (e.g., autoimmune skin disease, IMHA, and thrombocytopenia, SLE, immune-mediated polyarthritis) glucocorticoids suppress the immune system response to alleviate clinical signs. In a study in which various treatments for IMHA were examined, corticosteroids alone were as effective as combination treatments (for example, with azathioprine, cyclophosphamide, etc.) (Grundy and Barton, 2001).

For long-term therapy, intermediate-acting steroids (prednisone, prednisolone) are used most often because they can be administered on an every-other-day (EOD) basis. However, injections of dexamethasone are often used for acute, short-term treatment. There are no demonstrated differences in response between dexamethasone and prednisone/prednisolone for acute treatment, but long-term adverse effects may be less for the shorter-acting agents such as prednisone/prednisolone.

The immune-suppressing effects require higher dosages of corticosteroids than are necessary for antiinflammatory therapy (often by a factor of at least 2-fold), although dose-response relationships have not been fully studied in veterinary medicine. In one study in which the authors documented response to treatment of IMHA, the starting dose of prednisolone was 2 mg/kg per day, followed by a tapering schedule (Piek et al., 2008). In a systematic review of treatment for IMHA, the authors found that glucocorticoids alone will result in a successful outcome in a high proportion of cases, although there is no consensus on the drug dose or duration of treatment (Swann and Skelly, 2013).

Initial (induction) dosage regimens employ daily doses of 2.2 to 6.6 mg/kg (prednisolone or prednisone). Doses greater than 6 mg/kg are rarely used in dogs. Initial doses generally are in the range of 2–4 mg/kg/day. One study reported that the optimal induction doses for skin diseases were 4.4 mg/kg/day for dogs and 6.6 mg/kg/day for cats. A systematic review of treatment outcomes from IMHA in dogs concluded that prednisolone greater than 2 mg/kg every 12 hours are likely to result in unacceptable adverse effects without apparent improvement in short- or long-term outcomes. After an induction period, if the patient responds favorably, the dose may be decreased by approximately 50%. Eventually, one should attempt to maintain the patient on this low dose on an every-other-day EOD basis. Some diseases are slow to respond and a reduction of doses should be performed on a gradual and prolonged schedule. For example, lowering the dose based on an evaluation every 2–4 weeks may be necessary. Eventually, for immune-mediated disease, maintenance doses of 1 mg/kg, EOD are possible but higher doses or adjunctive therapy may be necessary in individual patients.

Side effects associated with treatment are discussed in Chapter 29. These effects are not necessarily reasons for discontinuing therapy, and include polyuria/polydipsia, increased appetite (polyphagia), and behavior changes (increased restlessness for example). Adverse effects from immunosuppressive doses of corticosteroids include risk of infectious diseases, adrenal suppression, pancreatitis, delay of healing, catabolic effects on muscle and connective tissues, and hepatopathy.

If a glucocorticoid is used that has a duration of action of 12–36 hours (intermediate-acting), the hypothalamic–pituitary–adrenal (HPA) axis has an opportunity to recover before the next dose. It is important that one chooses a glucocorticoid that does not have a long duration of action for EOD therapy – for example, dexamethasone is unacceptable because its duration is at least 36–48 hours. After 1 mg/kg every 48 hours of prednisolone, adrenocorticotropic hormone (ACTH) was suppressed in dogs for 18 to 24 hours, and returned to normal until the next scheduled dose (Brockus et al., 1999). EOD therapy will minimize, but will not prevent adrenal atrophy, and other adverse effects such as those on the immune system and the effects on metabolism.

Cyclosporine has been used for a number of diseases in veterinary medicine and since the introduction into veterinary medicine over 10 years ago, the number of potential uses, particularly in dogs and cats, has increased substantially. Many of these diseases have been dermatological, as reviewed by Robson and Burton (2003). In dogs, when used in the treatment of perianal fistulas, (Mathews and Sukhiani, 1997; Griffiths et al., 1999) an 85% healing rate was found in one study (Mathews et al., 1997) (2.5–6 mg/kg/day); in sebaceous adenitis, good response was reported in one case (Carothers et al., 1991); and in idiopathic sterile nodular panniculitis, excellent results were seen in two reported cases, which were followed for 6 months following discontinuance of the cyclosporine (Guaguère, 2000).

In August 2011, a cyclosporine oral solution (Atopia) was the first drug approved by the FDA for treating allergic dermatitis in cats. Capsules also can be used and one 25-mg capsule has been used for a dose of 25 mg/cat, once daily. The FDA-approved dose is 7 mg/kg per day, which is higher than the canine dose. Higher doses are needed because of the more variable absorption in cats compared to dogs. Other uses for cats include immunosuppression for kidney transplantation (Mathews and Gregory, 1997) at a dose of 3–4 mg/kg q 12 h. It also has been used to treat inflammatory diseases in cats, including stomatitis and eosinophilia granuloma complex (Guaguère and Prèlaud, 2000; Vercelli et al., 2006). For treatment of pemphigus foliaceous in cats it was more effective than in dogs. At a dose of 5 mg/kg per day, it was effective in some cats and steroid sparing (Irwin et al., 2012).

The pharmacokinetics of cyclosporine are complicated because of the differences between dosage forms, presence of many metabolites, influence of drug interactions, and variability in oral absorption. The formulation called Sandimmune was used for many years but was absorbed inconsistently and is not used today. The common human formulation is a microemulsion called Neoral, which has a much more consistent rate and extent of absorption that is less affected by factors such as feeding than Sandimmune (Lown et al., 1997). There are now over 20 human generic formulations of this formulation. There is no evidence available to show that the human generic formulations are bioequivalent to the brand-name product in dogs and cats. The introduction in late 2003 of Atopica represents the first oral veterinary formulation of cyclosporine. The formulation is exactly the same as Neoral microemulsion (absorption, kinetics, and dissolution), except that there is a greater variety of capsule sizes available (10, 25, 50, and 100 mg) for veterinary use. Compounded formulations can have variable strength and are not recommended for clinical use in dogs and cats.

The pharmacokinetics of cyclosporine in treated animals has been examined (Steffan et al., 2004). Cyclosporine is metabolized in the intestine and liver. Twenty-five to thirty metabolites have been identified. The prehepatic intestinal enzymes account for significant metabolism of cyclosporine (Wu et al., 1995), and systemic absorption in dogs is only 20–30% (Myre et al., 1991). Systemic absorption in cats is similar at 25–29% (Mehl et al., 2003). The intestinal metabolism by cytochrome P450 enzymes (CYP) and the efflux caused by intestinal p-glycoprotein (P-gp) account for most of the loss in systemic availability after oral administration. Drug enzyme inhibitors can inhibit the presystemic metabolism and produce an increase in systemic availability of cyclosporine (see Section Drug Interaction). For example, 5–10 mg/kg of ketoconazole once daily can decrease the dose of cyclosporine because clearance is reduced by 85% (Myre et al., 1991).

As in the clinical trials cited in this chapter, the effective dose for treating dermatitis in dogs has been 5 mg/kg/day. There may be a delay in response when cyclosporine is initiated for as long as 4–6 weeks and some dermatologists administer corticosteroids for the first 2 weeks when initiating treatment. Some clinicians have been able to lower the dose, or administer the dose every other day, and still maintain clinical remission. Approximately half of treated dogs can be maintained by increasing the dose interval.

Although clinical studies evaluating efficacy for treating immune-mediated diseases in dogs or cats are very limited, cyclosporine has been used for diseases listed in Sections Clinical Use in Dogs and Clinical Use in Cats. For these conditions it is generally assumed that higher doses are needed – generally in the range of 10 mg/kg every 12 hours oral. At these doses, cyclosporine consistently suppressed cytokine expression from activated T cells in dogs for a duration of 12 hours (Fellman et al., 2015). The same authors found that at a lower dose of 5 mg/kg once daily in dogs produced a more variable response and inconsistent suppression of activated T cells (Archer et al., 2011).

For organ transplantation in people, doses of 5–10 mg/kg/day are used to achieve targeted whole blood concentrations of 150–400 ng/ml. In people, dosages are adjusted to meet the needs of the individual patient on the basis of clinical response and monitoring trough plasma concentrations. For organ transplantation in cats (Mathews and Gregory, 1997) a dose of 3 mg/kg q 12 h was used to achieve trough blood concentrations of 300–500 ng/ml. For organ transplant in dogs, 10 mg/kg q 12 h to achieve concentrations of 500–600 ng/ml has been used (Mathews et al., 2000).

A report on treating perianal fistulas in dogs (Mathews and Sukhiani, 1997) found that an average dose of 6 mg/kg q 12 h was needed to achieve a targeted blood concentration of 400–600 ng/ml. However, this recommendation was later modified to 2.5–6 mg/kg/day. The most common dose for treating perianal fistulas is 3 mg/kg q 12 h.

Steffan and colleagues (2004) found that when administering approved doses to dogs with atopic dermatitis, routine monitoring of blood cyclosporine concentrations was not necessary. When animals were administered a dose of 5 mg/kg/day, there did not appear to be a strong correlation between blood concentration achieved and clinical response. It is also difficult to interpret blood concentration monitoring results because no therapeutic range has been established for dogs and cats. Nevertheless, because of wide individual variation in cyclosporine pharmacokinetics, monitoring blood concentrations is sometimes used to determine if the lack of therapeutic response is caused by inadequate oral absorption, rapid metabolism, or poor compliance by the pet owner. Monitoring can sometimes be helpful to identify why patients may be nonresponders. Effective treatment has been reported, even when trough blood concentrations are low. However, according to one paper, clinical benefits have not been observed when trough concentrations have fallen below 50 ng/ml; therefore, blood testing of patients failing therapy was suggested to reveal inadequate dosing (Robson and Burton, 2003).

One must be cognizant of the assay used when monitoring cyclosporine. Plasma values will be lower than whole-blood assays because as much as 50–60% and 10–20% of the dose is concentrated in erythrocytes and leukocytes, respectively. Nonspecific immunoassays will report higher values than a more specific (monoclonal or HPLC) assay. Despite the hypothesized higher specificity when using the monoclonal assay, important discrepancies between these assays and the more specific HPLC assay have been reported (Steimer, 1999).

Several drugs may interact with cyclosporine. These drugs include ketoconazole, itraconazole, fluconazole, erythromycin, and diltiazem. All these drugs can potentially increase concentrations of cyclosporine in animals. For example, coadministration of ketoconazole to treat secondary fungal infections will substantially decrease metabolism of cyclosporine (Myre et al., 1991). Ketoconazole has been used deliberately to reduce the need for cyclosporine in some investigations (Patricelli et al., 2002) and doses have been reduced to one-third of the original dose when administered with ketoconazole. In one study with cyclosporine in the treatment of perianal fistulae, the dose of 1 mg/kg cyclosporine combined with 10 mg/kg ketoconazole was used. The author felt that a dose of 0.5 mg/kg combined with 10 mg/kg ketoconazole also could be used (Mouatt, 2002). In people, grapefruit juice will increase concentrations of cyclosporine because of inhibition of metabolizing enzymes. However, the dose of grapefruit required to produce a similar effect in dogs is very high (41 capsules) and not clinically practical (Hanley et al., 2010). Cyclosporine also is an inhibitor of one of the membrane transport proteins P-glycoprotein. It can inhibit transport of ivermectin and increase risk of ivermectin toxicity in dogs.