Chapter 49 Immunosuppressive Drugs
When aberrant or uncontrolled immune responses either target directly, or indirectly affect, the gastrointestinal (GI) tract, immunosuppressive drugs may be prescribed. When used for the treatment of GI disease, immunosuppressive therapy is typically administered with the goal of suppressing antibody and/or cell-mediated immune responses. A number of GI diseases of dogs and cats have either demonstrated, or suspected, pathophysiologic attributes of immune-mediated disease or dysregulated immune responses. Among the most common of GI diseases treated with immunosuppressive therapy are idiopathic stomatitis, megaesophagus secondary to myasthenia gravis, chronic enteropathies, anal furunculosis, and chronic hepatitis.
When treating dogs and cats affected by such disorders with immunosuppressive drugs, commonly accepted goals of therapy should be kept in mind. First and foremost, immunosuppressive therapy is given to control clinical signs. In some cases, control of clinical signs will be accompanied by improvements in other hallmarks of the disease being treated, for example, hypoalbuminemia in patients with protein-losing enteropathy. However, improvements in laboratory or other diagnostic features will not be appreciated in all patients despite improvements in clinical signs.1 Thus, for patients with resolution of clinical signs of GI disease, increasing or altering immunosuppressive therapy with the specific goal of improving a laboratory or other parameter may be met with unwanted side effects or increased cost of therapy or monitoring, and should be carefully considered. The clinician should also keep as a goal of immunosuppressive therapy control of clinical signs with the lowest possible dose of drugs and longest dosing interval. Such goals also help the clinician attain a last objective of immunosuppressive therapy, which is minimization of side effects. For some clients, keeping cost to a minimum will also be a goal of therapy, and such client-driven restrictions will often dictate the immunosuppressive options possible.
For dogs and cats, there are a limited number of drugs used for immunosuppressive treatment of GI disease. The most commonly used classes of drugs are glucocorticoids, calcineurin inhibitors, antimetabolites, and alkylating agents. Because of different mechanisms of action, different classes of immunosuppressive drugs are often given in combination. For most of the diseases treated, there is little high-quality (blinded, placebo-controlled) clinical evidence that supports the use of any given immunosuppressive protocol.
Glucocorticoids are the mainstay of immunosuppressive therapy for most GI diseases needing such treatment. There are many formulations of glucocorticoids, but some of the most commonly used in the treatment of gastrointestinal disease, and their dosage suggestions, are presented in Table 49-1. It is expected that most clinicians will have an appreciation for the common side effects of glucocorticoids in dogs and cats.
|Prednisone/prednisolone||1 to 2 mg/kg PO q12h (D, C)||Prednisolone is preferred by some clinicians for cats.|
|Dexamethasone||0.2 to 0.5 mg/kg PO, IV, SC q24h||Dosage suggested on the premise that dexamethasone is 4 to 5 times as potent as prednisone; may have less sodium and water retentive properties than prednisone.|
|Methylprednisolone acetate||20 mg SC q2wk (C)||Depo forms not recommended. If there is a need for empirical glucocorticoid therapy, use shorter-acting forms.|
|Methylprednisolone sodium succinate||30 mg/kg IV initially, then 15 mg/kg IV every 2 to 6 h||Immediate-acting formulation|
|Budesonide||Considered to have approximately 15 times the potency of prednisone; pharmacokinetic studies that establish optimal dosage guidelines have not been done in dogs or cats.|
C, cat; D, dog; IV, intravenous; PO, per os; SC, subcutaneous.
* Readers are referred to chapters on the specific diseases for more details regarding therapy. Clinicians should familiarize themselves with any drug (dosing, routes of administration, adverse effects) before administration to a patient.
Glucocorticoids have wide-ranging effects on the immune system and are beneficial for suppression of both antibody and cell-mediated immune responses. The mechanisms underlying the immunosuppressive effects of glucocorticoids are complex, and the level of understanding of these mechanisms is still evolving.2,3 Some of the immunosuppressive effects are mediated through the interaction of glucocorticoids with cytoplasmic glucocorticoid receptors (GRs). The steroid–GR complex interacts with specific DNA sites termed glucocorticoid-response elements. Glucocorticoid-response elements are able to suppress, either directly or indirectly, the transcription of genes that encode proteins with proinflammatory and immune-stimulating activity. There is evidence that the antiinflammatory/immunomodulatory effects of glucocorticoids are also mediated by interaction of the glucocorticoid-GR complex with the regulatory factor nuclear factor-kappa B (NF-κB). With appropriate stimuli, NF-κB migrates from the cytoplasm to the nucleus and binds to key sites on DNA to initiate transcription of a variety of inflammatory and immune mediators. In the presence of the glucocorticoid–GR complex, NF-κB is not able to translocate to the nucleus.
Most glucocorticoids used in the treatment of canine and feline GI disease exert their effects systemically. A potential exception is the glucocorticoid budesonide. In people, budesonide has extensive first-pass hepatic metabolism and therefore is associated with fewer systemic effects than other orally administered glucocorticoids. Budesonide is used in the management of human inflammatory bowel disease (IBD).4 A reduction of systemic effects would hold obvious appeal in the treatment of dogs or cats with IBD; however, the pharmacokinetics of budesonide have not been extensively investigated in these species. Available studies of budesonide administration to normal dogs and dogs with IBD have shown suppression of the hypothalamic–pituitary–adrenal axis, suggesting some systemic absorption of biologically active drug. However, these studies did note fewer of the other common side effects of systemically active glucocorticoids, such as polyuria, polydipsia, and increased liver enzymes.5,6
Calcineurin inhibitors are a potent class of immunosuppressive drugs that includes cyclosporine and tacrolimus (FK506). Although these two drugs are structurally different, their mechanism of action depends on inhibition of the protein calcineurin. Calcineurin has serine-threonine phosphatase activity, and substrates of this enzyme include transcription factors that lead to cytokine gene activation. Inhibition of calcineurin activity causes decreased production of key cytokines, such as interleukin-2 and others that support the development of T-cell–dependent immune responses. The immunosuppressive effects of the calcineurin inhibitors encompass both B- (humoral) and effector T-cell (cell-mediated) responses.7
Cyclosporine is available in several proprietary and generic oral formulations. The practitioner must be aware of the different properties of the formulations as there is substantial variability in GI absorption and hepatic metabolism between formulations. Some of the available proprietary formulations include Sandimmune, Neoral, and Atopica; the latter is the only formulation specifically licensed for use in dogs and cats. Sandimmune requires more bile salt-mediated emulsification for GI absorption, and oral bioavailability is unpredictable, making Neoral, Atopica, or another microemulsified preparation preferable. Parenteral (for intravenous administration) formulations are also available, but have seen limited use in dogs and cats. Cyclosporine also comes in topical formulations, but use of these preparations has not been reported, to the author’s knowledge, in dogs or cats with GI disease. Plasma trough levels of cyclosporine can be measured to determine if they are within a therapeutic window, but a common clinical practice is to evaluate drug levels if a desired clinical response is not achieved and adjust dosages if below a therapeutic level.
Evidence in the veterinary literature supports the use of calcineurin inhibitors, especially cyclosporine, in patients with stomatitis, myasthenia-induced megaesophagus, IBD, and anal furunculosis. Tacrolimus comes in formulations for both oral and topical (Protopic) administration; topical tacrolimus (0.1%) has been used successfully in the treatment of dogs with anal furunculosis.8,9