Complications of immunosuppressive therapy (Proceedings)

While there is no doubt that administration of immunosuppressive drugs to dogs, and sometimes cats, is critical for control of immune-mediated disease, administration of these drugs can cause adverse effects. In general, the complications tend to result from one of two things: direct adverse effects of the drug, or consequences of immune suppression.  This presentation will review some of the complication of immune suppressive therapy with an emphasis on supporting literature evidence for these complications.

Direct adverse effects

All of the commonly used immunosuppressive drugs (glucocorticoids, azathioprine, cyclosporine) have some potential for direct adverse effects. The direct side effects of glucocorticoids are well-known to small animal clinicians, including polyuria/polydipsia, polyphagia, effects on skin and hair coat, muscle wasting, and steroid hepatopathy. One concern the author commonly hears regarding dogs on glucocorticoids is that increases in liver enzyme activity, especially AP, may lead to clinical hepatic disease. The author is not aware of any evidence that would bear out this concern, and has not yet seen any cases that would support this concern. Recall also that cats do not develop glucocorticoid increases in liver enzymes, so increases in AP, ALT or other liver enzymes in cats treated with glucocorticoids should be viewed as indicative of some other pre-hepatic, hepatic or post-hepatic disease

Glucocorticoids often raise concern for other direct complications such as gastric ulcers, and thromboembolic disease. There is actually scant literature evidence to support a pathogenic role of glucocorticoids in the formation of gastric ulcers in dogs or cats, and surveys of the human literature suggest that glucocorticoid-induced ulcers are uncommon in people. Nonetheless, the author has seen features consistent with gastric ulcers associated with high-dose glucocorticoid therapy in dogs. Likewise, there is no literature evidence that the author is aware of that indicates that administration of glucocorticoids at immunosuppressive doses directly causes thromboembolic disease, and their role in thromboembolic disease in people is also questioned.  There is evidence that glucocorticoids in some species (mostly people) can increase the concentration of some pro-coagulant factors, but similar studies have not been done in dogs; some literature would suggest a risk of thromboembolism in dogs with spontaneous hyperadrenocorticism. It is the author's opinion, based on anecdotal evidence only, that glucocorticoids may contribute to a risk of thromboembolism in patients that already have pre-existing risk factors (e.g. inflammatory disease, protein-losing enteropathy/nephropathy, vascular stasis).  Other consequences to remember when using high doses of glucocorticoids for extended periods are their potential to induce diabetes mellitus in either dogs or cats.

The author commonly starts azathioprine in conjunction with glucocorticoids for most patients with immune-mediated disease, primarily to have a “safety net” in place in case there is a need to withdraw glucocorticoids more quickly than desired; in the author's experience, the usual cause is client intolerance of pu/pd or polyphagia. Still, azathioprine can cause some adverse effects. In the author's experience, neutropenia or thrombocytopenia are the most commonly observed side effects of azathioprine in dogs (the author does not routinely use this drug in cats). Azathioprine can also cause anemia, which poses a problem in the occasional dog being treated with this drug for immune-mediated hemolytic anemia or thrombocytopenia, in which a decision to stop therapy in the face of persistent hematologic abnormalities may be needed. Azathioprine has been linked to acute pancreatitis in dogs, although the published information regarding this association is sparse and the strength of this association is tentative in the author's opinion. The author will still use in azathioprine in dogs with a history of pancreatitis and has not yet become aware of a pancreatitis as a result. Acute hepatopathy has been described in people as a result of treatment with azathioprine, and while the author is aware of dogs that may have had an azathioprine-induced hepatopathy, the literature supporting this complication in dogs is sparse. Azathioprine has been described in one paper as being associated with bone marrow necrosis in four dogs.

Cyclosporine comes with its own set of direct adverse effects. Gastrointestinal upset in the form of inappetance or vomiting can be seen. Gingival hyperplasia is a known adverse effect of cyclosporine in dogs. Compared to glucocorticoids and azathioprine, cyclosporine is less likely to cause hematologic or biochemical profile abnormalities. Cyclosporine is metabolized by the cytochrome P450 system, so the potential for interactions with drugs that also share this metabolic pathway exists, which could add another facet of complication to cyclosporine therapy.

Complications of immunosuppressive drugs secondary to immune suppression

Small animal clinicians are fortunate in that opportunistic infections as a complication of administration of immunosuppressive drugs seems to be a relatively infrequent event given the frequency and duration with which some patients are treated with high-dose glucocorticoids, or other immunosuppressive drugs.  Surveying the literature, and based on cases from the author's hospital, there do tend to be some general patterns of secondary infection when they do occur.

When administered at high doses and/or for prolonged periods of time, glucocorticoids are most commonly associated with bacterial urinary tract infection.  In one study of dogs treated with long-term (greater than 6 months) glucocorticoids for pruritic diseases, urinary tract infections were documented in almost 20% of treated patients. An important clinical point to keep in mind is that dogs with hypercortisolemia, be it of exogenous or endogenous origin, may exhibit no clinical signs of urinary tract infection, and may have little sediment evidence of urinary tract infection, making urine cultures the most definitive diagnostic test to establish the presence of urinary tract infection in such animals. Long-term administration of cyclosporine in dogs tends to be associated with infection from opportunistic organisms, parasitic, or viral infections. In the author's practice, we have seen several dogs on cyclosporine for immune-mediated hematologic disease develop either dermatophytosis, or subcutaneous infections with uncommon opportunistic fungal organisms.  The literature would support this pattern of post-immune suppression complication. Infections with other organisms, such as Toxoplasma gondii, have also been described in dogs and cats treated with immunosuppressive drugs.  Please refer to Table 1 for a survey of some of the infectious complications of immunosuppressive therapy that have been described in the veterinary literature.  The breadth of organisms causing clinical disease in immunosuppressed dogs and cats is likely to be much more extensive than noted in this table.

Less common than opportunistic infections as a complication of immunosuppressive therapy is the potential for the emergence of neoplasia.  Studies in dogs have not assessed this risk, although there are occasional reports in the literature to suggest an association in veterinary species between immunosuppression and tumors. The phenomenon is well-established as a complication of immunosuppressive therapy in people.

Clinical approach to patients with complications from immunosuppressive therapy

When seeing a patient that has been treated with immunosuppressive drugs that has become ill, it is important to consider three possibilities for the patient's illness. One, the patient could be ill from its immune-mediated disease. Second, the patient could be ill as a consequence of its immunosuppressive drugs, and lastly, the patient could be ill for reasons unrelated to either the immune-mediated disease or the immunosuppressive therapy. Thus, these patients bear careful consideration and evaluation, and the clinician needs to avoid the temptation to leap to unfounded conclusions.

The physical examination is important in patients that become ill while on immunosuppressive therapy to look for clues to known complications of immunosuppressive therapy, and to evaluate the patient for the possibility of other diseases. Fevers, new heart murmurs and cutaneous lesions would be important things to pay attention to. Hematologic and biochemical assessment can provide important information, and the presence of new cytopenias, particularly in patients treated with azathioprine, add to the suspicion of a complication of immunosuppressive treatment.  Other diagnostics, dictated by the patient's physical examination and initial laboratory data base, may be needed to clarify the origins of the patients illness. Measurement of pancreatic lipase activity, abdominal ultrasound or echocardiograms, needle cytology or biopsy and culture of tissues (e.g. skin lesions) or fluids (urine, blood), or other assays for infectious disease may be warranted.

If the patient's problem has been identified as a likely complication of immunosuppressive therapy, then the clinician is often faced with the decision of continuing treatment, or stopping the suspect drug.  Stopping the immunosuppressive drug will be needed if the complication is a direct effect of the drug, such as neutropenia.  In other cases, one may be able to continue the medications if aggressive therapy, like antimicrobial drugs, could be expected to address the complication. In the face of secondary infection, it may be necessary to temporarily stop (cyclosporine with fungal infection) or lower dosages (prednisone with infection) until the complication is controlled or resolved.  While there is little in the way of science to guide practitioners through such dilemmas, at some point, the guiding force for the action taken will be the problem that poses the greatest immediate threat to the health of the animal: the immunosuppressive drug and its complication, or the immune-mediated disease being treated. The author's approach to rapidly stopping glucocorticoids has been to drop the dose to something approaching a physiologic replacement dose (e.g. 0.2-0.4 mg/kg/day of prednisone, or other equivalent based on the glucocorticoid administered and its potency relative to prednisone) for daily administration for 7-10 days, then every other day for 7-10 days. The author has yet to see hypoadrenocorticoid-like clinical signs with this approach, but still warns the owner to be attentive to such. The author does not taper azathioprine or cyclosporine, but will abruptly stop either medication if identified as the probable culprit.

If there is a need to continue immunosuppressive therapy to provide continued control of the primary immune-mediated disease in a patient that needs an immunosuppressive drug discontinued, then the author will typically consider addition or substitution of another immunosuppressive medication.  When adding azathioprine to the treatment regimen, consider the possibility that there may be a lag period before clinical benefits are appreciated, although there are no veterinary studies that show a lag period exists. Nonetheless, this potential lag period may need to be covered by cyclosporine or another drug considered to have a more rapid onset of clinical immunosuppressive activity.

Summary

Clinicians supervising patients receiving immunosuppressive therapy are fortunate that treatment-altering complications occur no more frequently than they do. Nevertheless, a degree of vigilance for complications, particularly secondary/opportunistic infection, should be maintained for these patients.  Changes in the dose, dosing interval, type of drug, or addition of other medications may be necessary to effectively manage side effects of immunosuppressive therapy.

References and suggested reading (additional references available on request)

Moriello KA, et al. Acute pancreatitis in two dogs given azathioprine and prednisone. J Am Vet Med Assoc 1987;191:695-696.

Malik R, et al. Nocardia infections in cats: a retrospective multi-institutional study of 17 cases. Aust Vet J 2006;84:235-245.

Bernsteen L, et al. Acute toxoplasmosis following renal transplantation in three cats and a dog. J Am Vet Med Assoc 1999;215:1123-1126.

Rinkardt NE, Kruth SA. Azathioprine-induced bone marrow toxicity in four dogs. Can Vet J 1996;37:612-613.

Robson D. Review of the pharmacokinetics, interactions and adverse reactions of cyclosporine in people, dogs and cats. Vet Rec 2003;152:739-748.

Levine JM. Adverse effects and outcome associated with dexamethasone administration in dogs with acute thoracolumbar intervertebral disk herniation: 161 cases (2000-2006). J Am Vet Med Assoc 2008;232:411-417.

Torres SM, et al. Frequency of urinary tract infection among dogs with pruritic disorders receiving

long-term glucocorticoid treatment. J Am Vet Med Assoc 2005;227:239-243. 

Table 1. Infectious diseases associated with immunosuppressive therapy reported in dogs and cats

Toxoplasmosis

Cutaneous sporotrichosis

Cutaneous phaeohyphomycosis

Protothecosis

Cutaneous and CNS neosporosis

Cutaneous Alternaria infection

Disseminated nocardiosis

Cysticercosis

Fungal (Conidiobolus) pneumonia

Herpes virus infection (reactivation)

Pericarditis (fungal, bacterial)

Bartonella vinsonii-induced bacillary angiomatosis

Systemic acanthomoebiasis