A busy clinician's review of cyclosporine

Most familiar as a drug used to prevent organ transplant rejection, cyclosporine has gained popularity over the last two decades in treating inflammatory skin diseases in both people and animals. It can be difficult to keep the vast available information straight. With this article, we want to give you the need-to-know information about cyclosporine's mechanism of action, pharmacokinetics, and adverse effects and how cyclosporine can be used in companion animals with atopic dermatitis, sebaceous adenitis, and perianal fistula.

MECHANISM OF ACTION

Cyclosporine is a potent immunosuppressive agent that modulates the adaptive immune system. At doses indicated for dermatologic conditions, cyclosporine has anti-inflammatory effects on various leukocytes.1,2

By binding to cyclophilin (an intracellular receptor), cyclosporine inhibits the activity of calcineurin, a key enzyme in T cell activation. Calcineurin inhibition results in impaired cytokine transcription, namely of interleukin-2, interleukin-4, and alpha-interferon, thereby inhibiting activation of helper and cytotoxic T lymphocytes, macrophages, and monocytes.1-3

Decreased cytokine production subsequently inhibits activation of various inflammatory cells. Cyclosporine impairs mast cell and eosinophil production and survivability, and it impairs mast cell degranulation. Activation and proliferation of most T lymphocytes are decreased, thereby modulating the humoral and cell-mediated immune system. The number of Langerhans cells may be decreased in patients receiving cyclosporine, leading to decreased antigen presentation by these epidermal dendritic cells.1,2 In addition, cyclosporine alters keratinocyte function, leading to diminished cytokine production. A decrease in keratinocyte proliferation has also been noted in vitro; however, the clinical relevance of this finding is unknown.2

PHARMACOKINETICS

The pharmacokinetics of cyclosporine depends on the formulation (modified vs. unmodified) and on the patient's species. Concurrent medications and a patient's weight also influence cyclosporine's effects.

Formulation

For dermatologic conditions, oral formulations are preferred, specifically the microemulsion (modified) forms (Atopica—Novartis Animal Health, Neoral—Novartis Pharmaceuticals) since they have improved absorption in animals. Unmodified formulations (e.g. Sandimmune—Novartis Pharmaceuticals, generic cyclosporine capsules) have poor bioavailability and extreme variability in their treatment efficacy in animals,4 so we do not recommend them.

The pharmacokinetics of modified cyclosporine (5 mg/kg orally daily) was studied in normal fasted beagles. Peak blood concentrations were reached after a mean of 1.4 hours, and the terminal half-life was determined to be roughly 9.4 hours. Based on these findings, once-daily dosing was deemed sufficient.5

Species

Species differences also account for variability in cyclosporine metabolism and distribution. In dogs, hepatic metabolism is rapid, and the drug is primarily concentrated in tissue (skin, liver, kidneys, fat). In rats, however, hepatic metabolism is much slower, and cyclosporine is concentrated in the plasma and tissues, which increases rats' susceptibility to hepatotoxicosis and nephrotoxicosis.4 Less is known about the specific pharmacokinetics of cyclosporine in cats.

Concurrent medications

Marked individual variation in peak and trough cyclosporine concentrations has been noted in both people and dogs.4 Since cyclosporine is primarily metabolized by the cytochrome P-450 enzymes in the liver, hepatic function likely plays an important role in that variation. Concurrently administering other medications that also are metabolized by the hepatic P-450 enzyme system (e.g. ketoconazole) may alter cyclosporine concentrations in the blood. This effect may be clinically useful as concurrent administration of ketoconazole and cyclosporine often allows for a lower dose of cyclosporine to be administered with similar clinical effects.3,4 However, administer cyclosporine with care in dogs receiving medications primarily metabolized by cytochrome P-450 (e.g. ketoconazole, diltiazem, cimetidine, phenobarbital, rifampin) for other conditions. Closely monitor hepatic function in these patients.4

Weight

Obesity may also influence the pharmacokinetics of cyclosporine in various species. The concentration in adipose tissue and the hydrophobic nature of the compound lend support to dosing based on a patient's ideal weight rather than its actual weight.4,6

ADVERSE EFFECTS

Most studies show that adverse effects from cyclosporine are rare in dogs and cats at the dosages used for most dermatologic conditions.

The most common side effects in dogs receiving cyclosporine at a therapeutic dosage of 5 mg/kg once daily or less are gastrointestinal problems (diarrhea, nausea, vomiting, anorexia).1,3,4,6 These side effects may occur within the first few weeks of administration and are generally transient. By starting at a lower dosage and gradually increasing to a therapeutic dosage or by administering the medication with food, the side effects may be minimized. Metoclopramide may also be administered 30 to 60 minutes before cyclosporine to help reduce gastrointestinal side effects in patients exhibiting nausea or vomiting.7 Diarrhea or soft stool is the most common side effect noted in cats receiving cyclosporine.4

Field study data from the manufacturer and a recent retrospective study on the long-term use (six to 30 months) of cyclosporine in dogs showed that cyclosporine administration may cause abnormalities on routine blood work (e.g. elevated alkaline phosphatase and alanine aminotransferase activities, increased cholesterol concentrations, hypoalbuminemia).8,9 However, these changes were not associated with clinical signs of disease. In addition, urinary tract infections may occur. Whether these infections are related to the medication is unknown. Some evidence suggests that atopic dogs are generally more prone to urinary tract infections.8,10 In people, cyclosporine is considered to be nephrotoxic, hepatotoxic, and associated with hypertension. These effects have not been observed in dogs or cats receiving therapeutic doses for dermatologic conditions.4

Table 1. Less Common and Rare Adverse Effects of Cyclosporine in Dogs and Cats

Other adverse effects and those noted at higher dosages of cyclosporine in dogs and cats are summarized in Table 1.

CAUTIONS

The safety and efficacy of cyclosporine in dogs < 6 months old or < 4 lb are unknown. The drug is contraindicated for use in dogs with a history of malignant neoplasia and should not be given to breeding dogs and pregnant or lactating bitches.9 In addition, because of the drug's mechanism of action, the manufacturer recommends the use of killed vaccines in patients receiving cyclosporine. In a small study, 16 dogs received either 20 mg/kg daily of cyclosporine or placebo for 56 days and were vaccinated on day 27 with a killed rabies vaccine and a multivalent vaccine that included a modified live virus.9 Antibody titers measured on days 0, 27 (before vaccination), 42, and 56 revealed no antibody titer rise in any dog to any of the components of the multivalent vaccine but appropriate antibody titer response in all dogs to the killed rabies vaccine by day 42. Whether this response occurs at therapeutic dosing recommendations (5 mg/kg daily) is unknown. Studies have not been conducted on what length of drug withdrawal is necessary before vaccination.

Studies on the safety of cyclosporine have been limited to 12 months. The long-term effects of this potent immunosuppressive drug are unknown.

DERMATOLOGIC USES

Cyclosporine has been used to treat a wide range of inflammatory and immune-mediated skin diseases including canine and feline atopic dermatitis, feline eosinophilic granuloma complex, cutaneous lupus erythematosus, feline pseudopelade (noninflammatory alopecia in which hair loss is usually permanent), pemphigus foliaceus and erythematosus, sebaceous adenitis, perianal fistula, sterile nodular panniculitis, dirty face syndrome (Persian cats), chronic pedal furunculosis, erythema multiforme, follicular hyperkeratosis, German shepherd deep pyoderma, sterile pyogranulomatous syndrome, alopecia areata, and proliferative otitis externa.6 For some of these diseases, strong evidence exists that the drug is efficacious; however, for most of the other diseases, reports of efficacy are limited to single cases or anecdotal reports. Of these diseases, cyclosporine (Atopica) is FDA-approved only for use in dogs with atopic dermatitis. This drug is also approved in some countries outside the United States.

The primary use of cyclosporine in clinical practice is in treating atopic dermatitis. However, we would also like to briefly describe its use in treating sebaceous adenitis and perianal fistulas.

1. Self-trauma resulting from atopic dermatitis in a 3-year-old cat. Note the preauricular erythema.

Atopic dermatitis

Atopic dermatitis is one of the most common pruritic skin diseases in dogs and cats (Figures 1 & 2). While diagnosing atopic dermatitis is beyond the scope of this article, it is imperative that you definitively diagnose it by ruling out other causes of pruritus (e.g. a parasitic or bacterial infection, a food or flea allergy).before starting treatment. Allergy testing (intradermal or in vitro testing) may not be needed to confirm the diagnosis, but it is necessary to formulate an allergen-specific immunotherapy protocol.

2. The same cat as above. Note the papular eruption and facial inflammation caused by facial rubbing.

When deciding on a treatment plan, considerations include the duration and severity of clinical signs, whether the pet is a working animal (e.g. avoid drugs such as antihistamines that may interfere with a guide dog's ability to stay alert), and concurrent medical conditions (e.g. diabetes mellitus). Other considerations are described in the boxed text "Cyclosporine therapy: Things to consider before prescribing."

Cyclosporine therapy: Things to consider before prescribing

Efficacy in studies. Cyclosporine is the newest option available for treating atopic dermatitis, and numerous reports have evaluated its use.11-13

In a systematic review and meta-analysis, 799 dogs in 10 studies had been treated with cyclosporine (n=672), placebo (n=160), oral glucocorticoids (n=74), or antihistamines (n=23).11 Dogs were treated from two weeks to six months, and doses were 2.5 to 5 mg/kg.

After four to six weeks of cyclosporine (5 mg/kg once daily), a 40% decrease in skin lesions and at least a 30% decrease in pruritus were noted. The percentage of dogs showing at least a 50% improvement in clinical signs increased from 20% to 60% after four weeks of treatment and from 63% to 87% after 12 to 16 weeks of therapy.

At the end of four weeks, in most of the studies, 40% to 50% of dogs had their cyclosporine dosage reduced to every other day, and in 20% to 26% of dogs, dosages could be reduced to twice weekly after 14 to 16 weeks of therapy. When cyclosporine was compared with placebo, a significant difference in efficacy was noted; however, no significant difference was noted when cyclosporine was compared with glucocorticoids.

There are several take-home points from this review.

• Unlike with glucocorticoids, a lag exists between the start of cyclosporine therapy and the appearance of clinical benefits. Clients should expect to see some indication of response between four and six weeks of cyclosporine therapy.

• The best clinical response was seen in patients in which the cyclosporine dosage was not decreased after the initial four weeks (the package insert suggests tapering the dose after four weeks).

• Less improvement was noted in dogs that were considered glucocorticoid failures or those that had unacceptable adverse effects from glucocorticoids.

• Overall, cyclosporine had a good to excellent response in 65% to 76% of patients, with better responses noted in dogs receiving longer treatment regimens.

• The most common adverse effects were vomiting, nausea, soft stools, or diarrhea. These side effects were noted in the first month, and most dogs acclimated to the drug. In our experience, vomiting can often be avoided by starting with a lower dose and administering the drug with food during the induction period.

• Secondary skin infections must be monitored and controlled while the patient is receiving cyclosporine. Even with good control of atopic dermatitis, breakthrough infections may still occur.

Our experience. Our starting dose is 5 mg/kg orally once daily in both dogs and cats. Clients are advised to give the medication with food to decrease adverse gastrointestinal effects, especially during the induction phase, if the dog or cat cannot tolerate the drug on an empty stomach.

In our practice, serum concentrations of cyclosporine are not routinely monitored; improvement in clinical signs (pruritus) is the most important measurement of efficacy (Figure 3). If the pet does not respond to therapy, then serum concentrations of the drug are monitored to ensure that adequate absorption is occurring. When necessary, cyclosporine concentrations should be checked just before administering a dose in order to obtain trough serum concentrations (12 hours if administering twice daily, or 24 hours if administering once daily). The serum cyclosporine concentration should be between 200 to 500 ng/ml; however, we usually recommend concentrations closer to 200 ng/ml.

3. The same cat as in Figures 1 & 2 six weeks after beginning cyclosporine therapy. Note the resolution of the lesions around the mouth. The lesion near the ear had resolved as well. The cat was no longer traumatizing itself.

Sebaceous adenitis

Sebaceous adenitis, a skin disease with an unknown cause that is uncommon in dogs and rare in cats, is characterized by inflammatory destruction of the sebaceous glands. A strong breed predilection for standard poodles exists, but sebaceous adenitis has been diagnosed in many breeds. As the disease progresses, dogs develop scaling, follicular casts, and hair loss characterized by broken, dry, dull hairs in a symmetrical pattern. Dogs are susceptible to secondary bacterial infections or colonization of the skin with bacteria and yeast. Cats show multifocal, annular areas of alopecia with scaling and crusting.

Successful treatment (resolution of clinical signs) of sebaceous adenitis was first reported in 1991 in one dog receiving unmodified cyclosporine.14 In a 2005 study, 12 dogs with sebaceous adenitis were treated with cyclosporine at 5 mg/kg once daily for 12 months and were evaluated at four-month intervals.15 After four months of treatment, the dogs showed marked clinical improvement that continued throughout the study. Histologically, decreased inflammation and an increase in the number of hair follicles with sebaceous glands, suggesting gland regeneration, occurred with continued treatment. Continued treatment was needed as clinical signs recurred if cyclosporine was discontinued. Two cats with sebaceous adenitis have also responded to treatment.16

Inform clients that sebaceous adenitis is not curable. Nonetheless, using cyclosporine as an adjuvant therapy may be markedly beneficial for affected animals and their owners. The following is a treatment protocol for sebaceous adenitis:

• Treat concurrent bacterial and yeast infections with appropriate antibiotics and antifungal medications (preferably based on culture and sensitivity results; empirically, however, we generally recommend 22 to 30 mg/kg cephalexin orally twice daily and 5 to 10 mg/kg ketoconazole orally once daily initially) for at least 30 days.

• Conduct a cyclosporine trial (5 mg/kg orally once daily) for four months.

• The owner should bathe the dog with antiseborrheic (e.g. containing sulfur and salicylic acid) and emollient (e.g. containing lanolin or essential fatty acids) shampoos as needed to control odor, crusting, and scaling (one to three times a week).

• If the dog shows improvement at the end of the trial, continue oral cyclosporine therapy. In addition, administering ketoconazole to decrease the total dose of cyclosporine and to control Malassezia species overgrowth can be considered. It is unknown whether alternate-day cyclosporine therapy is equally effective as daily therapy. The owner should also continue bathing the dog as needed.

Canine perianal fistula

Canine perianal fistula is a chronic, painful skin disease involving the anal and perianal tissues (Figure 4). The skin is ulcerative, and retrocutaneous fistulas (fistulas extending behind the cutaneous zone of the anus) are typical. Dogs present with tenesmus, dyschezia, constipation, and mucopurulent discharge from the perineum. Increasing evidence exists that an immune-mediated cause may be involved in the disease's pathogenesis.

4. Perianal fistula in a dog. Note the swelling and the multiple draining fistulous tracts.

For many years, surgery was the treatment of choice for affected dogs, even though relapse was common. Patients treated medically with traditional anti-inflammatory and immunosuppressive drugs (e.g. prednisolone, azathioprine) responded inconsistently. Cyclosporine was first explored as an alternative treatment in a small number of dogs and then in a larger case series.17-19 Cyclosporine is effective as a sole therapy or in combination with surgery in which it is used to decrease lesion size before surgical correction.

The ideal dosage of cyclosporine to treat perianal fistula is unknown; the dosing regimens in studies vary from 1 to 10 mg/kg once or twice a day. It is difficult to make direct comparisons between the studies because the cyclosporine formulation varied between unmodified and modified, the treatment period varied from four to > 20 weeks, and some studies used ketoconazole concurrently to increase serum cyclosporine concentrations while other studies did not.

The following medical treatment protocol for perianal fistulas is used by the soft tissue surgeons at the University of Wisconsin's School of Veterinary Medicine20 :

• Induce remission of clinical signs by using cyclosporine alone (5 mg/kg orally twice daily) or combined with ketoconazole (cyclosporine: 5 mg/kg orally once daily; ketoconazole: 8 mg/kg orally once daily).

• Monitor the dog for signs of clinical improvement. Most dogs show some benefit within two to four weeks, but complete remission of clinical signs can take 16 to 20 weeks.

• Once clinical remission has been established, treat for an additional four weeks and then discontinue therapy.

• If a relapse occurs, repeat the above treatment protocol and then establish a maintenance dose that keeps the lesions in clinical remission. Some dogs have needed a dose as low as 25 mg daily or every other day.

One study of dogs with perianal fistulas found that serum cyclosporine concentrations did not correlate with clinical response; dogs responded to therapy even though they had serum concentrations below the therapeutic target range.19 Often the first clinical sign of treatment success owners note is a decrease in licking. If a patient is not responding as expected, serum trough cyclosporine concentrations are measured to ensure adequate absorption.

CONCLUSION

Although cyclosporine was once thought of as only a transplant drug, we now know it can be used to treat dermatologic diseases such as atopic dermatitis, sebaceous adenitis, and canine perianal fistula. With few side effects at therapeutic doses, cyclosporine should be added to your list of possible therapies for these diseases.

Alison Diesel, DVM

Karen A. Moriello, DVM, DACVD

Department of Medical Sciences

School of Veterinary Medicine

University of Wisconsin

Madison, WI 53706

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21. Last RD, Suzuki Y, Manning T, et al. A case of fatal systemic toxoplasmosis in a cat being treated with cyclosporin A for feline atopy. Vet Dermatol 2004;15(3):194-198.

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23. Werner AH Psoriasiform-lichenoid-like dermatosis in three dogs treated with microemulsified cyclosporine A. J Am Vet Med Assoc 2003;223(7):1013-1016.