Ciclosporin is a lipophilic cyclic polypeptide with powerful immunosuppressive and immunomodulatory properties that has been used in veterinary medicine for two decades. It is a calcineurin inhibitor whose principal mode of action is to inhibit T cell activation. The drug is principally absorbed from the small intestine and is metabolised in the intestine and liver by the cytochrome P450 enzyme system. Ciclosporin is known to interact with a wide range of pharmacological agents. Numerous studies have demonstrated good efficacy for the management of canine atopic dermatitis and this has been a licensed indication since 2003. In addition to the treatment of atopic dermatitis, it has been used as an aid in the management of numerous other dermatological conditions in animals including perianal fistulation, sebaceous adenitis, pododermatitis, chronic otitis externa and pemphigus foliaceus. This article reviews the mode of action, pharmacokinetics, indications for use and efficacy of ciclosporin in veterinary dermatology.
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CICLOSPORIN is a lipophilic cyclic polypeptide with powerful immunosuppressive and immunomodulatory properties that is isolated from the fungus Beauveria nivea (formerly Tolypocladium inflatum Gams). It was first used in human medicine to prevent rejection of transplanted organs and later for the treatment of atopic dermatitis (AD) and psoriasis. It has now been used in veterinary medicine for over two decades and this article marks the fact that ciclosporin has now been licensed for the treatment of canine AD for 10 years. Ciclosporin has also been shown to be effective in, and is licensed for, the treatment of feline allergic skin disease (Wisselink and Willemse 2009). In addition to the treatment of allergic disease in cats and dogs, it has proved to be useful for the treatment of many other dermatological conditions in animals and there are many reports in the literature to this effect.
Mechanisms of action
Ciclosporin is a calcineurin inhibitor whose principal mode of action is to inhibit T cell activation. Ciclosporin achieves its immunosuppressive activity by binding to the intracellular receptor protein cyclophilin-1. The resulting ciclosporin-cyclophilin complex inhibits calcineurin, which prevents the dephosphorylation and activation of the transcription factor, nuclear factor of activated T cells (NF-AT) (Guaguère and others 2004). NF-AT helps regulate the production of several important pro-inflammatory cytokines including interleukin (IL)-2, IL-4, interferon-γ and tumour necrosis factor-α (Taylor and others 2005). It is the specific inhibition of IL-2, which plays a critical role in the activation and proliferation of T cells, that is thought to account for ciclosporin's main mechanism of immunosuppression, although there is recent evidence that NF-AT also interacts with other transcriptional factors that regulate T helper cell differentiation, T cell tolerance and thymocyte development (Macian 2005). In addition to the effect on T cells, there is increasing evidence that the NF-AT signalling pathway is also involved in innate immunity and regulates the homeostasis of cells involved in innate immune mechanisms. Therefore, ciclosporin influences both innate and adaptive immune responses (Fric and others 2012) and there is an increasing list of other cells involved in inflammatory and immune responses that may be affected by ciclosporin including B cells, antigen presenting cells, keratinocytes, endothelial cells, mast cells, basophils and eosinophils. The principal effects are listed in Table 1. The overall effect of ciclosporin is a reduction in the number and activity of proinflammatory cells at sites of inflammation.
Ciclosporin was first produced as a vegetable oil formulation (Sandimmune; Novartis). The drug is principally absorbed from the small intestine and the absorption of this early formulation was dependent on bile flow and other factors resulting in variable and poor bioavailability (Guaguère and others 2004). A microemulsified (ME) product was subsequently developed that improved oral bioavailability, that was not dependent on bile flow for absorption and had less variable absorption. This formulation is licensed for treatment of canine AD (Atopica; Novartis Animal Health) and is available in 10, 25, 50 and 100 mg soft gelatin capsules; the active product being identical to the human formulation (Neoral; Novartis Pharmaceuticals). Administration of the microemulsion formulation to healthy beagles with food decreased the bioavailability by 22 per cent and increased the individual variability of drug absorption(Steffan and others 2004b) and the datasheet recommendation is that ciclosporin should be administered at least two hours before or after feeding. However, another study found that administration of ciclosporin with food to dogs treated for AD did not influence the clinical response (Thelen and others 2006) and clinical experience has shown that efficacy seems unaffected by administration with food. As will be discussed in more detail, absorption is also limited by the effects of p-glycoprotein efflux pumps present in the small intestine enterocytes (Wu and others 1995) and by metabolism of the drug by cytochrome P450 3A (CYP3A) enzymes also within the intestines (Whalen and others 1999). The bioavailability after oral administration of the ME formulation is 35 per cent in the dog (Guaguère and others 2004). The drug is metabolised mainly in the liver and intestine by CYP3A enzymes (Whalen and others 1999). There are numerous pharmacologically inactive metabolites (Fahr and others 1990) that are eliminated via the biliary system. The high margin of safety and the relatively long half-life of the drug (nine hours) mean once daily dosing is sufficient in the dog (Guaguère and others 2004). In addition, ciclosporin has been shown to concentrate in the skin after oral administration (Steffan and others 2003), further supporting once daily dosing.
Clinical aspects of drug interactions
Ciclosporin is known to interact with a wide range of pharmacological agents. These interactions have been well researched in people but only limited information is available in dogs. The two main mechanisms of drug interaction involve the CYP3A enzyme system and/or competition with the ATP binding transport protein P-glycoprotein (P-gp) (Steffan 2004). Commonly used veterinary medicines and other pharmacologically active compounds that may interact with ciclosporin include azole antifungals, metoclopramide, cimetidine, erythromycin, clindamycin, phenobarbital, vitamin E, grapefruit juice and St John's wort.
The technical aspects of these drug interactions are discussed in the article on pp 3-11 of this supplement (Nuttall and others 2014), so this section will be limited to discussion of the effect on clinical applications.
The azole antifungals inhibit CYP3A and therefore have the potential to reduce the dosage of ciclosporin required to achieve therapeutic concentrations. Ketoconazole, itraconazole and fluconazole have been shown to produce these dose sparing effects in both people and dogs. One study in healthy beagles showed that ketoconazole at dosages of 13.6 mg/kg once a day (sid) and 4.7 mg/kg sid allowed dosage reductions of ciclosporin of 75 per cent and 38 per cent respectively to still achieve similar blood concentrations (Dahlinger and others 1998). Fluconazole has a similar effect (Katayama and others 2008). These drug interactions have been used to decrease the cost of ciclosporin therapy, and a recent study concluded that administration of ciclosporin and ketoconazole concurrently at 2.5 mg/kg each may be as effective as ciclosporin alone at 5.0 mg/kg for treatment of canine AD (Gray and others 2013).
Clinicians should be aware that macrolide antibiotics such as erythromycin are highly metabolised by the hepatic CYP system and therefore have the potential to increase ciclosporin bioavailability. In people, erythromycin has been shown to increase bioavailability of ciclosporin from 75 per cent to 215 per cent (Campana and others 1996). A similar effect has been demonstrated in the dog with clarithromycin and erythromycin, whereas clindamycin and lincomycin did not increase ciclosporin availability (Steffan 2004, Katayama and others 2013). The interaction between ciclosporin and cimetidine, an H2 receptor antagonist and a potent inhibitor of the CYP 3A system, has been studied in dogs (Daigle and others 2001). This work demonstrated that cimetidine delayed but did not decrease the rate of absorption of ciclosporin. Metaclopramide has been shown to have no effect on the pharmacokinetic parameters of ciclosporin in healthy dogs (Radwanski and others 2011).
Two other chemicals that have been shown to affect ciclosporin blood levels are St John's wort and grapefruit juice. St John's wort is a herb that can affect the pharmacokinetics of many different drugs through induction of cytochrome P450 (CYP 2C and CYP 3A). It is this mechanism which is thought to decrease ciclosporin levels in people (Bauer and others 2003). A similar effect was demonstrated when St John's wort was given orally at a dose of 300 mg with ciclosporin at a dose of 5 mg/kg daily to dogs (Fukunaga and Orito 2012). Grapefruit juice contains furanocoumarins, which inhibit intestinal CYP 3A enzymes. This mechanism is thought to be responsible for the increase in bioavailability of ciclosporin in both people (Ku and others 1998) and dogs (Radwanski and others 2011) when grapefruit juice and ciclosporin are administered together.
A single dose of freeze-dried or liquid grapefruit juice significantly increased the bioavailability of orally administered ciclosporin in dogs (Amatori and others 2004). Radwanski (2011) used powdered whole grapefruit juice, which is expensive but has the potential to reduce the required orally administered dose of ciclosporin, although the amount required (at least 10 g) means this is currently not cost-effective (Radwanski and others 2011).
Phenobarbital is known to induce CYP enzymes leading to an increased elimination of ciclosporin. As a result of this phenobarbital has been shown to produce a significant reduction of up to 40 per cent in ciclosporin blood levels (Steffan 2004).
Indications for ciclosporin
Canine atopic dermatitis
Numerous studies have been published over the past 13 years that have demonstrated the safety and efficacy of ciclosporin in the management of canine AD (Table 2). Clinical experience has further supported the value of this drug. Published studies vary from case series to open, unblinded and uncontrolled studies, to high-quality, double-blinded randomised controlled trials (RCTs). The studies listed in Table 2 comprise some 727 dogs treated with ciclosporin. Overall results from the trials show that around one- to two-thirds of dogs will show a 50 per cent or more reduction in pruritus and lesion scores within four to eight weeks. A recent systematic review of RCTs for treatments of canine AD concluded that there were now multiple, high-quality RCTs that show the efficacy of oral ME ciclosporin given at a starting dose of 5 mg/kg for the management of canine AD (Olivry and Bizikova 2013). There was no difference demonstrated in efficacy between oral ciclosporin and prednisolone and oral ciclosporin and methylprednisolone for the management of canine AD with both lesional scores and pruritus responding to treatment (Olivry and others 2002a, Steffan and others 2004a, Kovalik and others 2011).
Ciclosporin is a relatively large molecule with poor dermal penetration but very recently, a nanocapsule ciclosporin spray-on formulation has been developed to enhance penetration with the view to topical therapy. The use of this product in a six-week RCT of 32 dogs showed an 87.5 per cent reduction in pruritus in the treatment group compared to 28.6 per cent in the placebo group. The authors concluded that this was a safe and effective therapy for the control of pruritus in canine AD (Puigdemont and others 2013), but this is a relatively small number of cases and larger scale trials are required.
Dosage and dosage reduction in canine atopic dermatitis
The recommended induction dosage rate of ciclosporin for the treatment of canine AD is 5 mg/kg every 24 hours. In many cases, once maximal response has been achieved generally after four weeks of treatment, it is possible to reduce the amount of drug administered without reducing efficacy. This may be by either reducing the daily dosage or increasing the interval between doses and there seems to be no difference between these two methods (Olivry and others 2003b). In one retrospective study of 51 dogs with AD treated long term with ciclosporin (Radowicz and Power 2005), 36 per cent required daily treatment, 36 per cent required treatment for four or five days per week and 28 per cent required treatment for two or three days per week. In this study, dosage reductions were decreased by drug withdrawal on one day per week if there was beneficial response. Dosage was not changed more frequently than once every four weeks. The rationale behind this is that some dogs may be maintained on a dosage somewhere between daily and alternate day therapy and one of the authors (PF) uses this approach. Another RCT reported that ultimately 50 per cent of cases required every other day therapy, 25 per cent twice weekly and 25 per cent daily therapy (Steffan and others 2003).
Reduction in the dosage is based on the clinical response to therapy rather than the measurement of serum levels of ciclosporin. In people serum ciclosporin levels are measured routinely in organ transplantation cases. In dogs the methodology is available to undertake routine monitoring and can be performed by a variety of different techniques. Those most commonly used include high-pressure liquid chromatography, fluorescent polarisation immunoassay and radioimmunoassay (Guaguère and others 2004). However, the interpretation of serum levels of ciclosporin in cases of canine AD is difficult because of the lack of clinical data correlating concentrations with response to therapy. Nevertheless, because the dosages of ciclosporin required in canine AD are much lower than the anti-rejection levels used in humans and because the safety margin is much greater in dogs, routine monitoring does not seem to be justified in general practice (Steffan and others 2004b). Blood levels measurement may, however, be useful when animals have failed to respond to appropriate levels of medication or if there is concern about toxicity when ciclosporin has been given over a prolonged period with another drug that is known to enhance bioavailability.
A blinded, prednisolone RCT (Olivry and others 2002a) looking at the reduction of pruritus produced by ciclosporin, at a dose of 5 mg/kg orally once daily, compared to prednisolone, at a dose of 0.5 mg/kg orally once daily, showed no significant difference in the reduction in pruritus in both groups. This suggested that the excellent reduction in pruritus score achieved within three weeks of starting ciclosporin therapy should make it a valuable alternative to glucocorticoid therapy in dogs with AD. However, as many dogs with AD exhibit severe pruritus accompanying self-inflicted trauma, more recent work has focussed on combinations of drugs, especially using glucocorticoids with ciclosporin, to try and improve its speed of action. Concurrent administration of ciclosporin with methylprednisolone has been shown in people to have variable effects. Some studies have shown a decrease in blood concentrations of ciclosporin, others have shown no change (Campana and others 1996). In dogs methylprednisolone was given at a dose of 1 mg/kg daily with ciclosporin at a high dose rate of 20 mg/kg daily without resulting in any interaction or adverse effects (Guaguère and others 2004). Concurrent administration of prednisolone with ciclosporin has been investigated as a means of accelerating the reduction in pruritus (Dip and others 2013). In a comparison of therapeutic response in two groups of atopic dogs given either ciclosporin alone at a dose of 5 mg/kg orally once daily or with prednisolone at a dose of 1 mg/kg orally once daily for 14 days then on an alternate day basis both owners and investigators agreed that concurrent therapy with prednisolone resulted in a quicker improvement in the dogs' overall skin condition and reduction in pruritus.
Longer term remission of clinical signs of dogs with non-seasonal AD has been recorded in animals treated with both glucocorticoids and ciclosporin. In a comparative study using methylprednisolone and ciclosporin (Steffan and others 2004a), workers demonstrated that although 87 per cent of dogs treated with methylprednisolone relapsed within two months of cessation of therapy only 62 per cent of dogs treated with ciclosporin showed a similar deterioration. Similarly, in a retrospective study of long-term management of canine AD with ciclosporin (Radowicz and Power 2005), in 12 out of 51 cases (24 per cent) it was possible to reduce and ultimately withdraw ciclosporin therapy without recurrence of clinical signs. These dogs remained in remission for a mean duration of 12 months following treatment withdrawal.
Use with allergen-specific immunotherapy
Allergen-specific immunotherapy (ASIT) offers an alternative to either glucocorticoids or ciclosporin therapy where either the cost or side effects of medication are a problem. Identification of putative allergens is required for the formulation of ASIT and ciclosporin has been shown to have no statistically significant effects on either intradermal or serum IgE allergy tests when administered at therapeutic dose rates of 5 mg/kg orally once daily for 30 days (Goldman and others 2010). It has therefore proved to be a useful drug to use for short-term control of AD to facilitate glucocorticoid withdrawal, allergy testing and the institution of ASIT. No work has been undertaken on the effect of ciclosporin on ASIT. However, many veterinary dermatologists routinely use ciclosporin during the induction and maintenance phase of ASIT without any apparent reduction in efficacy. Successful ASIT in dogs has been shown to be linked to an increase in the T regulatory cell population (Keppel and others 2008). In atopic humans, low dose ciclosporin therapy has been shown to significantly increase the T regulatory cell populations (Brandt and others 2009) suggesting that ciclosporin therapy may be synergistic with ASIT. Obviously this link needs further investigation.
Canine perianal fistulae
Canine perianal fistulae (PAF) is a chronic, progressive disease characterised by the development of cutaneous and retrocutaneous fistulae with associated ulceration around the perianal tissues. The condition is mainly confined to German shepherd dogs but can affect other breeds as well. Clinical signs include perineal pain, dyschezia, tenesmus, constipation and perineal discharge. The condition is painful and debilitating. An immune-mediated cause is suspected (Kennedy and others 2008) and for this reason ciclosporin has been used to treat this disease. A literature search revealed eight studies describing the use of ciclosporin to treat PAF (Table 3). Two of these studies were RCTs and the remainder were open trials or case series. Drug doses, outcome measures and follow up vary considerably between studies. Drug doses in particular vary from 1.5 mg/kg sid to 7.5 mg/kg twice a day (bid) and so comparison between studies and pooling of data is not possible. Several studies used a combination of ciclosporin with ketoconazole to reduce cost. Overall, ciclosporin has been shown to be effective for the management of PAF and one RCT showed resolution of lesions in six of 10 cases treated with ciclosporin at a dosage of 5 mg/kg sid (House and others 2006). Higher dosages seem to result in more rapid resolution of signs (Griffiths and others 1999). Follow-up periods vary but some cases do appear to go into long-term remission. Even in those cases where signs recur, repeat treatment is often successful (Patricelli and others 2002). In conclusion, ciclosporin appears to be effective for the management of PAF but further controlled studies on the use of ciclosporin to treat PAF are required to elucidate the optimum dosage and duration of therapy.
Sebaceous adenitis is an uncommon, scaling skin disease with variable alopecia and pruritus and is characterised by follicular cast formation. The standard poodle, English springer spaniel, Japanese akita, samoyed and Hungarian viszla are predisposed. Histologically, there is progressive destruction of sebaceous glands and an associated nodular granulomatous to pyogranulomatous inflammation consisting of histiocytes, lymphocytes and neutrophils. The pathogenesis is unknown but lipid abnormalities, a structural glandular or ductal defect and autoimmunity (Rybnicek and others 1998) have all been postulated as possible causes. Ciclosporin has been used to treat sebaceous adenitis because of its immunomodulatory properties and also because it initiates anagen and thus stimulates hair growth. In an uncontrolled open trial (Linek and others 2005) (Table 4), 12 dogs were treated with ciclosporin at a dosage of 2.3 mg/kg bid. After four months there was a significant improvement in clinical scores and subjectively, both the extent of alopecia and the severity of scaling improved in all dogs, resulting in a markedly improved hair coat quality. However, sebaceous adenitis is usually treated with topical therapy including keratolytic shampoos and moisturisers such as propylene glycol, and a controlled study compared the use of ciclosporin alone, ciclosporin with topical therapy, and topical therapy alone for the management of sebaceous adenitis (Lortz and others 2010). There was no difference between the groups with respect to improvement in alopecia scores but there was a marked reduction in scaling with the use of topical therapy in addition to ciclosporin and the group treated with a placebo and topical therapy responded better than the group treated with ciclosporin alone, underlining the importance of topical therapy for sebaceous adenitis.
In addition to its use in canine AD, perianal fistulation and sebaceous adenitis, ciclosporin has also been used for many other presumed immune-mediated and autoimmune diseases (Table 5). Most of these are single case reports of relatively uncommon to rare diseases so the level of evidence for efficacy is low. Nevertheless, the majority of these reports are of a successful outcome and are the best evidence available at the present time. It is worth pointing out however, that ciclosporin is reported to be ineffective for the treatment of epithelioptrophic cutaneous lymphoma (Rosenkrantz and others 1989).
Chronic pododermatitis is a common presentation in many breeds. In most cases a specific underlying cause can be identified such as demodicosis, deep pyoderma, poor confirmation or AD. However, in some cases, despite a thorough work up, a specific cause remains elusive. One study reported success in using ciclosporin to treat idiopathic pododermatitis in seven dogs (Breathnach and others 2005).
Chronic proliferative otitis externa
Chronic proliferative otitis externa (CPOE) is also a common clinical presentation, particularly in the cocker spaniel (Angus and others 2002). Underlying primary causes of inflammation may be identified, but addressing these is unlikely to resolve the proliferative disease and most cases require total ear canal ablation. One small pilot study found that ciclosporin was useful in the management of CPOE and while lesions and infection persisted, the dogs' quality of life greatly improved with therapy and this is worth considering where surgical therapy is not an option for whatever reason.
Pemphigus foliaceus is a pustular and crusting autoimmune disease, usually treated using systemic immunosuppressive therapy with glucocorticoids with or without additional immunosuppressive agents (Rosenkrantz 2004). In one small pilot study, ciclosporin as a sole agent was ineffective in controlling skin lesions (Olivry and others 2003a), but in another study lesion remission was induced in all cases when ciclosporin was administered along with prednisolone. It was possible to reduce maintenance dosage of prednisolone to 0.5 mg/kg every other day suggesting a possible glucocorticoid sparing effect of ciclosporin (Maeda and others 2008). Furthermore, it was possible to withdraw glucocorticoid therapy and maintain remission in three refractory cases of canine pemphigus foliaceus that had not responded to a combination of azathioprine and prednisolone following the addition of ciclosporin (Rosenkrantz and Aniya 2007).
Over the past 10 years, ciclosporin, a calcineurin inhibitor, has proven to be a very safe and effective therapy for the management of a variety of dermatological conditions in dogs. In particular, its use in the treatment of canine AD is well documented. Its relatively slow onset of action can be ameliorated by the additional use of glucocorticoid therapy for the first two to three weeks of therapy. Once maximal therapeutic effect has been achieved, a very slow reduction in dosage is advisable to identify those cases that can be managed on treatment levels somewhere between daily and alternate day, or alternate day and twice weekly administration.
There is also variable evidence that ciclosporin is useful in the management of many other immune-mediated skin diseases.
Provenance: not commissioned; externally peer reviewed
Conflict of interests Peter Forsythe has received consultancy and lecture fees from Novartis Animal Health.
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