Long-term prospective evaluation of topically applied 0.1% tacrolimus ointment for treatment of perianal sinuses in dogs

Bryden J. Stanley Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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 DVM, MVetSc, DACVS
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Joe G. Hauptman Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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 DVM, MS, DACVS

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Abstract

Objective—To evaluate effectiveness of a combination of topically applied tacrolimus, orally administered prednisone, and a novel-protein diet for treatment of perianal sinuses in dogs and to monitor clinical progress and owner management of the condition for 2 years.

Design—Noncontrolled clinical trial.

Animals—19 dogs with perianal sinuses.

Procedures—Perianal sinuses were diagnosed during physical examination, and dogs were placed on a 16-week treatment protocol consisting of topically applied 0.1% tacrolimus ointment, orally administered prednisone (tapering dose), and a novel-protein diet. Metronidazole was orally administered for the first 2 weeks. Anal sacculectomy was recommended whenever anal sacs were involved. Dogs were evaluated every month for the first 4 months and then every 6 to 12 weeks for 2 years.

Results—Perianal sinuses resolved completely in 15 of 19 dogs during the 16 weeks. In the remaining 4 dogs, the lesions markedly improved but failed to completely resolve. Three of these had anal sac involvement, and the owner of 1 dog had complied poorly with treatment instructions. During the 2 years following treatment, all dogs were maintained on intermittently applied tacrolimus ointment, 4 dogs also received prednisone every other day, and 11 dogs remained on the novel-protein diet. At the conclusion of the study, 13 of the 15 dogs that survived to that point were free of perianal disease.

Conclusions and Clinical Relevance—The described protocol was effective and economical for resolving perianal sinuses. Dogs maintained on intermittent medications were unlikely to redevelop lesions. When the anal sacs were involved, anal sacculectomy appeared to improve the outcome.

Abstract

Objective—To evaluate effectiveness of a combination of topically applied tacrolimus, orally administered prednisone, and a novel-protein diet for treatment of perianal sinuses in dogs and to monitor clinical progress and owner management of the condition for 2 years.

Design—Noncontrolled clinical trial.

Animals—19 dogs with perianal sinuses.

Procedures—Perianal sinuses were diagnosed during physical examination, and dogs were placed on a 16-week treatment protocol consisting of topically applied 0.1% tacrolimus ointment, orally administered prednisone (tapering dose), and a novel-protein diet. Metronidazole was orally administered for the first 2 weeks. Anal sacculectomy was recommended whenever anal sacs were involved. Dogs were evaluated every month for the first 4 months and then every 6 to 12 weeks for 2 years.

Results—Perianal sinuses resolved completely in 15 of 19 dogs during the 16 weeks. In the remaining 4 dogs, the lesions markedly improved but failed to completely resolve. Three of these had anal sac involvement, and the owner of 1 dog had complied poorly with treatment instructions. During the 2 years following treatment, all dogs were maintained on intermittently applied tacrolimus ointment, 4 dogs also received prednisone every other day, and 11 dogs remained on the novel-protein diet. At the conclusion of the study, 13 of the 15 dogs that survived to that point were free of perianal disease.

Conclusions and Clinical Relevance—The described protocol was effective and economical for resolving perianal sinuses. Dogs maintained on intermittent medications were unlikely to redevelop lesions. When the anal sacs were involved, anal sacculectomy appeared to improve the outcome.

The condition of perianal sinuses (also known as anal furunculosis, perianal fistulae, pararectal fistulae, anusitis, or fistulae-in-ano) is an insidiously progressive, chronic inflammatory disease of the perianal and perirectal tissues in dogs, most commonly German Shepherd Dogs.1,2 The disease is characterized by deep suppurative ulcers and abscesses of the perianal region.3,4 Clinical signs usually include tenesmus, dyschezia, licking of the perineum, bleeding from the anal area, and malodorous, mucopurulent discharge. Bowel movements are often loose or frequent, but constipation may also develop.2,5,6 Affected dogs may have no clinical signs, but generally this disease is debilitating for the affected dogs and distressing for their owners.

Several hypotheses have been tested regarding the etiology of the disease and the predisposition of German Shepherd Dogs, generally without yielding much insight. Studies1,3,4,6–14 have been conducted to assess tail conformation, anal anatomy, bacterial involvement, histologic changes in anal tissues, thyroid gland function, concurrent colitis, and various immune dysregulations in affected dogs. Whereas local environment may play a role in the perpetuation and exacerbation of perianal sinuses, identification of a specific primary cause remained elusive for many years. However, results of recent studies7,8,13,15–22 suggest that an inappropriate T-cell–mediated inflammatory response is involved and that the predisposition in German Shepherd Dogs reflects a probable genetic component.23

As usual with a disease that is difficult to cure, various methods have been used to manage perianal sinuses. Local cleansing and topical and systemic antimicrobial treatment are palliative only, and historically, surgery was performed after this approach failed. Radical excision of the lesions (with and without anal sacculectomy), anal resection with rectal pull-through, deroofing and electrofulguration, chemical cauterization, cryotherapy, caudectomy, and laser excision are all surgical approaches to treatment. Although satisfactory short-term results are often achieved through surgical intervention (up to 80% of dogs improve), lesions redevelop in a high proportion (50% to 90%) of affected dogs, with complications including fecal incontinence or rectal stricture.24–39

Perianal sinuses reportedly respond to immunosuppressive treatment protocols, which supports the hypothesis that the disease is immune mediated.7,8,13,15–22 Administration of prednisone at a high dose (2 mg/kg [0.91 mg/lb], PO, q 24 h for 2 weeks, followed by 1 mg/kg [0.45 mg/lb], PO, q 24 h for 4 weeks) and feeding of a novel-protein diet (ie, diet including protein to which dogs had not previously been exposed) resulted in short-term improvement or cure in 67% of dogs with perianal sinuses and concurrent colitis in 1 study.13 Oral administration of cyclosporine, an immunosuppressive drug that inhibits T-cell activation and suppresses cell-mediated immune responses,40 yields even more remarkable short-term results than prednisone (up to 100% of affected dogs have an improvement in clinical signs, and 80% to 90% have resolution of lesions) but less successful long-term results (lesions redevelop in 30% to 50% of affected dogs).15–18,20,21

The main concern with treatment protocols that include cyclosporine is the high cost to owners. Other factors that may discourage use include logistic difficulties in measuring 12-hour trough (lowest) blood concentrations of cyclosporine and occasional adverse effects (eg, vomiting, diarrhea, oral growths, coat shedding, and hirsutism).15,17,40,41 To reduce the dose of cyclosporine without loss of efficacy, ketoconazole, which inhibits the hepatic metabolism of cyclosporine, can be concurrently administered.22,42–44 This approach may reduce cost to owners, although the cost and systemic effects of ketoconazole can be substantial. To further reduce treatment costs, protocols involving short-term administration of immunosuppressive drugs immediately prior to surgical intervention or administration of azathioprine have also been used but appear to be less effective.17,19,45–47

Tacrolimus (FK506) is a nonsteroidal immunomodulator with a mechanism of action that is similar to but much more potent than cyclosporine, although tacrolimus is structurally quite different. Tacrolimus is more efficacious when applied topically than cyclosporine, probably because of its much smaller molecular weight.48–50 Topical application of tacrolimus ointment yields considerable benefits in humans with psoriasis, atopic dermatitis, pyoderma gangrenosum, oral and perineal Crohn's disease, and vulvar lichen sclerosis.51–58 It is also safe when applied topically for up to 1 year in humans, with minimal adverse effects and no evidence of systemic accumulation.59 Tacrolimus ointment is commercially available in 2 strengths, 0.1% and 0.03% (pediatric), and contains a base of mineral oil, paraffin, propylene carbonate, white petrolatum, and white wax.a The product is sold via prescription in 30-, 60-, and 100-g tubes.a

The effect of topical application of 0.1% tacrolimus ointment as the sole treatment for perianal sinuses was evaluated in 10 dogs that were treated for 16 weeks.60 In that study, 5 dogs had complete resolution of lesions, 4 dogs had a partial response, and 1 dog did not improve. To our knowledge, there have been no additional reports of studies involving topical application of tacrolimus ointment in dogs with perianal sinuses. Lack of long-term follow-up in most studies makes it difficult to evaluate the long-term outcome of treatments for perianal sinuses.

The purpose of the study reported here was to evaluate responses to a 16-week treatment protocol consisting of twice-daily topical application of 0.1% tacrolimus ointment, a tapering dose of orally administered prednisone, a novel-protein diet, and short-term oral administration of metronidazole in dogs with perianal sinuses. We also sought to obtain information on the dogs' lesion status at regular intervals for an additional 2 years. We hypothesized that results equivalent or superior to those of cyclosporine-based treatment protocols would be obtained, with minimal morbidity and considerable cost savings to owners.

Materials and Methods

Animals—Dogs with perianal sinuses evaluated at the Veterinary Teaching Hospital of the College of Veterinary Medicine, Michigan State University, from October 2002 through December 2005, were eligible for inclusion. Owner consent was obtained prior to enrollment, and participating owners agreed to allow regular and long-term follow-up of their dog's lesion status for 2 years. Enrolled dogs were taken off all medication for perianal sinuses 2 weeks before the study began to allow any systemic medications to leave the bloodstream.

The following information was obtained for enrolled dogs: breed, age, sex, body weight, body condition score (9-point scale, with 1 indicating emaciation and 9 indicating obesity), history of weight loss, history of perianal sinuses, and presence of clinical signs of licking at the perineum, tenesmus or dyschezia, bleeding from the anal area, constipation, and diarrhea. Any previous treatments were recorded. A complete physical examination, CBC, and serum biochemical analysis were performed for each dog at the time of initial evaluation. Urinalyses were also performed. Dogs < 10 years of age routinely underwent 3-view thoracic radiography.

Evaluation of perianal sinuses—After initial evaluation, dogs were sedated with either acepromazine maleate (0.05 mg/kg [0.023 mg/lb], IV) and hydromorphone (0.07 mg/kg [0.032 mg/lb], IV) or medetomidine (10 to 40 μg/kg [4.5 to 18.2 μg/lb], IM). The perineum of each dog was clipped, cleansed with 0.05% chlorhexidine diacetate solution, and carefully examined with a probe. The anal sacs, external anal sphincter, and anorectal mucosa were closely inspected, and a digital rectal examination was performed to assess sphincter function and degree of thickening in the distal aspect of the rectum and anus. The perianal sinuses were assessed for maximal depth of the lesions and degrees of circumferential, anal sac, and rectal involvement. Degree of circumferential involvement was categorized as 0° to 90°, 90° to 180°, 180° to 270°, or 270° to 360°. Maximum depth was categorized as mild (< 1 cm), moderate (1 to 2 cm), or severe (> 2 cm). All perianal sinuses were photographed with a high-resolution digital camera.b

Treatment protocol and assessment—All dogs were treated in accordance with a 16-week protocol consisting of the following treatments: topical application of 0.1% tacrolimus ointment on the perianal region, twice per day; oral administration of prednisone (2 mg/kg, q 24 h for 2 weeks; 1 mg/kg, q 24 h for 4 weeks; and then 1 mg/kg, q 48 h for 10 weeks); oral administration of metronidazole (10 mg/kg, q 12 h for 2 weeks); and fecal softener (eg, psyllium-based product or canned pumpkin) as needed. During the 16-week period, the diet of all dogs was restricted to a novel-protein diet (eg, venison or fish and potato). The only allowable snacks were potatoes, apples, and carrots, and heartworm medication could not include meat flavoring.

Owners were asked to notice and record the time (in days) of any change in clinical signs and time (in days) of any change in lesion appearance. Dogs were reexamined every 4 weeks, lesions were photographed, and lesion changes were recorded. For those dogs with anal sac involvement, anal sacculectomy was recommended at that time. If approved by the owner, involved anal sacs were excised via an open technique61 and submitted for histologic evaluation. After the 16-week treatment concluded, owners were contacted for information on their dog's status every 6 to 12 weeks by telephone or in person during a follow-up appointment. When the 2-year period ended, the perineum of each dog was reexamined.

Results

Animals—Nineteen dogs were enrolled in the study. The mean age was 7.2 years (range, 1.5 to 12 years), and mean body weight was 36.4 kg (80 lb; range, 30 to 42.8 kg [66 to 94 lb]). The mean body condition score was 3.8 (range, 2 to 6), and 9 dogs had a history of weight loss associated with the onset of signs of perianal sinuses. Seventeen dogs were German Shepherd Dogs, 1 was a Chesapeake Bay Retriever, and 1 was an Irish Setter. Over the same period as this study, 4% of dogs admitted to the teaching hospital were German Shepherd Dogs. Ten of the study dogs were castrated males, 5 were spayed females, 2 were sexually intact males, and 2 were sexually intact females. For all dogs evaluated at the hospital during the study period, the ratio of castrated male to castrated female dogs was 0.9:1 and 32% were sexually intact.

Most of the 19 dogs had undergone treatment for perianal sinuses with various combinations of the following treatments: antimicrobial other than sulfasalazine (n = 10 dogs), prednisone or prednisolone (7), hypoallergenic diet (6), cyclosporine (3; 1 dog received an inadequate dose), sulfasalazine (2), surgery (2), and topically applied antimicrobial ointment (1) or antiseptic solution (1). In addition, once-daily topical application of 0.1% tacrolimus ointment (an inadequate dosing interval) had been prescribed for 1 dog treated with no other medication. Owners were all seeking treatment for their dog's condition because of a lack of response to these previous treatments. No dogs had received medication for perianal sinuses in the 2 weeks immediately before the study began. Dogs had a history of perianal sinuses that ranged from 1 month to 7 years.

No dog was free of clinical signs of perianal sinuses when initially evaluated at the hospital. Clinical signs at that time included licking at the anus (n = 17 dogs), tenesmus or dyschezia (13), bleeding from the anus (8), constipation (7), and diarrhea (7). In addition, 2 dogs were coprophagic, 1 dog ran while defecating, and another dog defecated inappropriately in secluded areas of the house. In 5 dogs, the only clinical sign was licking. Physical examination findings and clinical signs not associated with perianal sinuses included chronic superficial keratitis (pannus; 4), other ocular disease (5), dental tartar (1), lipomata (1), degenerative myelopathy (1), and arthritis (1). Five dogs had dry or scaly skin, a history of pruritic episodes, and alopecia.

Results of a CBC were unremarkable in 11 of 19 dogs; the remainder had a mild, mature neutrophilia (> 7.8 × 103/PL), with variable mild monocytosis (> 0.7 × 103/PL). Results of serum biochemical analyses were within reference ranges for 9 dogs; 8 dogs had a serum globulin concentration that slightly exceeded the upper reference limit of 4.1 g/dL. A urinalysis was performed for 16 dogs, and results were all within reference limits. The 3 dogs for which a urinalysis was not performed were < 4 years of age.

Results of initial evaluation—Results of digital rectal examinations at the initial evaluation, after 16 weeks of treatment, and 2 years later were summarized (Table 1). No rectocutaneous fistulae were detected during the initial digital rectal examination of any dog. One dog had roughened mucosa on the ventral rectum, and 3 dogs had a functional anal stenosis (swelling of the anal sphincter and perianal tissues without fibrosis). Sixteen of the 19 dogs resented rectal examination. Overall, 1 or both anal sacs were involved in the perianal sinuses in 9 dogs.

Table 1—

Characteristics of perianal sinuses in 19 dogs at initial evaluation, after treatment in accordance with a 16-week protocol,* and after subsequent long-term (2-year) treatment with variations on the protocol.

DogAnal sac affectedCircum (°)Maximum depth (cm)Status at 16 weeksStatus at 2 yearsTreatments received during 2-year period
Dosage of tacrolimusDosage of prednisoneNovel diet
ANone3601–2CRDeadNANANA
BBoth2701–2CRCR2–3 times/wkYes
CNone2701–2CRCR2–3 times/wkNo
DNone90< 1CRCR1–2 times/wkYes
ENone360< 1CRCR1–2 times/wkYes
FRight1801–2CRCR2–3 times/wk5 mg, q 48 hYes
GNone3601–2CRCRq 24 h§10 mg, q 48 hYes
HRight1801–2PRRight PPFq 24 h10 mg, q 28 hYes
IBoth360> 2PRLostNANANA
JNone2701–2CRCR2–3 times/wkNo
KNone360> 2CRCR2–3 times/wkNo
LNone270> 2PRDeadNANANA
MBoth360> 2PRBilateral PPFq 24 h5 mg, q 48 hYes
NNone2701–2CRCR2–3 times/wkYes
OBoth1801–2CRDeadNANANA
PRight3601–2CRCR2–3 times/wkNo
QBoth1801–2CRCR2–3 times/wkYes
RNone90< 1CRCR1–2 times/wkYes
SRight270> 2CRCRIntermittentIntermittentYes

The treatment protocol included twice daily topical application of 0.1% tacrolimus on the perianal region, a tapering dose of orally administered prednisone, a novel-protein diet, and short-term (2 weeks) oral administration of metronidazole.

The cause of death was not related to perianal sinuses.

Dog had both anal sacs surgically removed 4 weeks after the initial evaluation.

Perianal sinuses would redevelop at 3 o'clock and 9 o'clock positions whenever the owner ceased applying the tacrolimus ointment.

Owner admitted poor compliance with protocol.

Dog had intermittent anal erythema and, when the erythema was evident, received twice-daily topical application of 0.1% tacrolimus ointment and 10 mg of prednisone every other day until the erythema subsided.

Circum = Circumference. CR = Completely resolved. NA = Not available. PR = Partially resolved. PPF = Pinpoint fistulae. — = Drug not administered.

Evaluation after the 16-week treatment—All dogs completed the 16-week treatment protocol. Owners reported mean interval to improvement in clinical signs of 7 days (range, 4 to 14 days); 1 owner was unsure of the interval. The mean interval to improvement in lesion appearance was 13 days (range, 7 to 21 days). All owners reported improvement in clinical signs and lesion appearance; none reported deterioration in clinical signs or exacerbation of the lesions. A marked reduction in the frequency of coprophagia or inappropriate defecation was also reported for both coprophagic dogs as well as the inappropriately defecating dog.

Direct inspection and digital rectal examination revealed that perianal sinuses had completely resolved in 15 dogs, including the 5 dogs that underwent anal sacculectomy (Figure 1). Histologic evaluation of the anal sac tissue obtained from the dogs that underwent anal sacculectomy revealed evidence of moderate to marked chronic inflammatory responses, multifocal epithelial or subepithelial degeneration associated with mononuclear inflammatory cells, and varying degrees of fibrosis. In 4 dogs, perianal sinuses had partially resolved (Figure 2). Of these dogs, 3 had anal sac involvement but owners had declined anal sacculectomy for their dog because of considerable improvement in lesions and complete resolution of clinical signs. For the remaining dog with partially resolved lesions, the owner admitted poor compliance with the treatment protocol because of the nature of the dog. All 4 dogs with partially resolved lesions were fed the same commercial diet,c and owners claimed complete compliance with the dietary component of the treatment protocol.

Figure 1—
Figure 1—

Photographs of the perianal region of a representative dog with perianal sinuses before (A) and after (B) institution of a 16-week treatment protocol. The protocol included twice-daily topical application of 0.1% tacrolimus ointment on the perianal region, a tapering dose of orally administered prednisone, a novel-protein diet, and short-term (2 weeks) oral administration of metronidazole. Lesions in this dog completely resolved by the end of treatment.

Citation: Journal of the American Veterinary Medical Association 235, 4; 10.2460/javma.235.4.397

Figure 2—
Figure 2—

Photographs of the perianal region of a representative dog with perianal sinuses before (A) and after (B) institution of a 16-week treatment protocol, in which lesions only partially resolved by the end of treatment. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 235, 4; 10.2460/javma.235.4.397

None of the adverse treatment effects reported by owners appeared to be associated with the tacrolimus ointment. Several owners reported signs that were consistent with and attributed to the high dose of oral prednisone during the first month of the protocol. These reported signs consisted of polyphagia, polydipsia, polyuria, and restlessness, all of which attenuated as the dose of prednisone was reduced. Owners reported that one 30-g tube of 0.1% tacrolimus ointment would last for approximately 5 weeks with twice-daily application to the affected area. At our hospital, the cost of this medication to the owner for the 16-week period (4 tubes) was $484.

Assessment at 2 years—Three dogs died from causes unrelated to the perianal sinuses before the end of the 2-year follow-up period, and 1 dog was lost to follow-up. Of the 15 dogs available for follow-up at 2 years, all were free of clinical signs of perianal sinuses. Thirteen of the 15 were still free of perianal sinuses lesions. The remaining 2 dogs still had tiny (pinpoint) fistulae over the anal sacs. Both owners had persistently declined anal sacculectomy because of the absence of any clinical signs.

The study recommendation was to discontinue all medications other than the novel-protein diet when the 16-week treatment concluded. Owners were not compliant with this recommendation and continued to medicate their dogs intermittently with 0.1% tacrolimus ointment (n = 11) and prednisone (4; Table 1). Of the 4 dogs that continued to receive prednisone, 2 still had tiny fistulae over the anal sacs, 1 was prone to recurrence of small lesions over the anal sacs (these lesions would resolve when 0.1% tacrolimus ointment was applied daily and 10 mg/kg prednisone was administered every other day), and 1 had firmer feces and ate better when receiving 5 mg of prednisone every other day, as reported by the owner. One dog was not maintained on the protocol medication; the dog's lesions had resolved completely during the 16-week treatment period, but it continued to have intermittent episodes of anal erythema. When these episodes happened, the owner would treat the dog with application of 0.1% tacrolimus ointment twice daily and 10 mg of prednisone every other day until the erythema subsided.

Eleven dogs continued to be fed a novel-protein diet during the 2-year period, whereas the remaining dogs returned to regular commercial pet food. The 2 dogs with residual pinpoint fistulae over the anal sacs had remained on a novel-protein diet,c although complete owner compliance with respect to snacks could not be assured with one of the owners. Of the initial 9 dogs with a history of weight loss associated with the onset of perianal sinuses, 6 were available for the 2-year assessment. All 6 dogs had returned to what the owners considered a normal body weight.

Discussion

Distributions of breed, age, and sex in the present study of dogs with perianal sinuses were consistent with those of other reports,3,4,13,16,20–22,24,39,43 with German Shepherd Dogs being overrepresented and male sex predominating. The distribution of sexually intact dogs with perianal sinuses was slightly lower than that of our general hospital population during the same period; however, because of the limited number of dogs in the study, no conclusions can be made about this finding. Clinical signs, history, and physical examination findings associated with the perianal sinuses were consistent with those of other reports,24,28,39,62 including the weight loss that was evident in almost half (9/19) of the study dogs.

As our understanding of perianal sinuses grows, it is clear that immunosuppressive medication, specifically that which suppresses T-lymphocyte activation, should be the major component of any treatment protocol.3,6–9,23 Topical application of tacrolimus ointment reportedly inhibits T-lymphocyte activation and cytokine elaboration in the skin and draining lymph nodes.63 Unlike cyclosporine, which is most effective when administered orally, tacrolimus is effective topically, minimizing the risk of systemic adverse effects.50

Dogs with perianal sinuses may also have colitis.6,13 Clinical signs associated with colitis and perianal sinuses are similar (tenesmus, dyschezia, and hematochezia), and without histologic evaluation of colonic biopsy specimens, it was impossible to be certain whether clinical signs were compounded by the existence of concurrent colitis. Our intent was to develop a protocol to treat perianal sinuses and presumed concurrent colitis. The protocol developed was identical to the longstanding cyclosporine protocol used in our hospital, but in place of oral administration of cyclosporine, we substituted topical application of 0.1% tacrolimus ointment. The purpose of the tacrolimus was to inhibit T-lymphocyte activation, and that of the prednisone was to provide initial systemic immunosuppression; both drugs were intended to ameliorate lesions and signs associated with perianal sinuses. The 16-week protocol used also included metronidazole for the first 2 weeks. Metronidazole is an effective against anaerobic bacteria and protozoa and has some inhibitory action on cell-mediated immunity; it is commonly used to treat colitis in dogs. Finally, a strict novel-protein diet was included with the intent of allergen avoidance in the event that any concurrent colitis or the perianal sinuses may have been caused or exacerbated by a dietary antigen.

The rapid amelioration of clinical signs and improved appearance of perianal sinuses lesions in all dogs in the present study were encouraging. The combination of the tacrolimus ointment and prednisone appeared to control discomfort associated with defecation early during the treatment period. It is also possible that metronidazole treatment aided in reducing colonic irritation during the first 2 weeks. Adverse effects were transient (within the first month of the protocol) and were attributed to the high dose of prednisone because they resolved as the dose of prednisone was reduced.

The protocol used in the present study was effective at resolving or reducing perianal sinuses and associated clinical signs in all dogs, with most having complete resolution of their lesions. These results were similar to or better than responses obtained in other studies,15–18,20,21 in which orally administered cyclosporine was used as the sole treatment modality. In those studies, the proportion of dogs in which lesions resolved ranged from 69% to 100%. We could not determine whether the tacrolimus ointment, prednisone, or novel-protein diet was responsible for continued improvement during the 16-week study period. However, in another study,13 only 33% of dogs had complete resolution of their perianal sinuses when they received a high dose of prednisone and an alternative protein diet alone. This implies that the tacrolimus ointment was a critical component of the protocol in the present study. Only 1 study60 has been reported in which topically applied 0.1% tacrolimus ointment was used for the treatment of perianal sinuses in dogs. In that study, the lesions of 9 of 10 dogs noticeably improved, with those of 5 dogs healing fully.

Involvement of the anal sacs appeared to impede complete resolution of perianal sinuses in the dogs in the present study. Lesions in the 5 dogs with anal sac involvement that underwent anal sacculectomy all healed completely during the 16-week treatment period. Of the 4 dogs with anal sac involvement that did not have an anal sacculectomy, only 1 had complete resolution during the same period. These findings underscore the importance of thorough examination of the affected anal area at the time of initial examination and recommendation of anal sacculectomy should anal sacs be involved in the perianal sinuses.19,35 The anal sacs of German Shepherd Dogs are located deeper within the perianal tissue, and they extend further cranially into the external anal sphincter than in other breeds.10 Therefore, a meticulous technique and good anatomic knowledge are needed to ensure complete anal sacculectomy in German Shepherd Dogs, with minimal adverse sequelae.

In humans with oral and perineal Crohn's disease, a mild stinging sensation after topical application of tracrolimus ointment is possible.53,54,57,59 None of the dog owners in the present study reported a behavior in their dog that could be attributed to irritation when the ointment was applied, but it should be mentioned that our protocol does require that the dog's nature tolerate twice-daily topical application to the sensitive anal area. Discomfort associated with the perianal sinuses appeared to improve in the first week of treatment, and this relief of discomfort should facilitate topical application to the perineum.

A major advantage of the treatment protocol reported here is the considerable cost savings, compared with a similar protocol that includes cyclosporine. At our hospital, the cost of the 0.1% tacrolimide ointment for the 16-week treatment period (four 30-g tubes) was $484. On the other hand, the cost of cyclosporine (at 5 mg/kg [2.3 mg/lb], PO, q 12 h) for the 16-week protocol is between $2,326 and $2,417, depending on the weight of the dog. This does not take into account the cost of blood collection and laboratory fees that would be incurred during determination of the optimal dose of cyclosporine.

When cyclosporine is used as the immunomodulating agent in a treatment protocol, perianal sinsuses can reportedly redevelop after treatment ceases, requiring additional cyclosporine treatment and often anal sacculectomy.15,17,21 We were unable to make conclusions about redevelopment of lesions in the dogs in our study because treatment was continued in all dogs with a reduced frequency of topical application of the tacrolimus ointment, with or without a low dose of prednisone and a novel-protein diet. The role of a specific novel-protein diet or the effect of increased dietary fish oils could not be ascertained because different diets were used and only 15 dogs were available for long-term assessment.

The 16-week treatment protocol used in the study reported here appeared effective at resolving perianal sinuses in dogs. Continuing treatment with 0.1% tacrolimus ointment at a lower frequency of application and with prednisone at a lower dose and frequency of administration appeared to control the disease for at least 2 years. No adverse effects associated with the tacrolimus ointment were reported during the whole study period. Anal sac involvement appeared to impede healing of the lesions, and anal sacculectomy should be considered for these situations. A substantial cost saving to owners can be achieved with this protocol, compared with the cost of protocols that involve cyclosporine. Additional prospective studies of perianal sinuses should be undertaken to compare the effects of protocols involving orally administered cyclosporine and topically applied tacrolimus ointment, ascertain the importance of specific novel-protein diets in these protocols, evaluate the potential role of dietary fish oils, and evaluate the effects of other T-cell inhibitors such as pimecrolimus.64

a.

Protopic, Astellas Pharma Mfg Inc, Grand Island, NY.

b.

Nikon Coolpix 4500, Nikon ring flash, Nikon Inc, Melville, NY.

c.

Fish and Potato Canine Dry Formula, The Iams Co, Dayton, Ohio.

References

  • 1.

    Harvey CE. Perianal fistula in the dog. Vet Rec 1972;91:2533.

  • 2.

    van Ee RT. Perianal fistulas. In: Bojrab MJ, ed. Disease mechanisms in small animal surgery. 2nd ed. Philadelphia: Lea & Febiger, 1993;285286.

    • Search Google Scholar
    • Export Citation
  • 3.

    Day MJ, Weaver BMQ. Pathology of surgically resected tissue from 305 cases of anal furunculosis in the dog. J Small Anim Pract 1992;33:583589.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Killingsworth CR, Walshaw R, Dunstan RW, et al. Bacterial population and histologic changes in dogs with perianal fistula. Am J Vet Res 1988;49:17361741.

    • Search Google Scholar
    • Export Citation
  • 5.

    Matushek KJ, Rosin E. Perianal fistulas in dogs. Compend Contin Educ Pract Vet 1991;13:621627.

  • 6.

    Jamieson PM, Simpson JW, Kirby BM, et al. Association between anal furunculosis and colitis in the dog: preliminary observations. J Small Anim Pract 2002;43:109114.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    House AK, Catchpole B, Gregory SP. Matrix metalloproteinase mRNA expression in canine anal furunculosis lesions. Vet Immunol Immunopathol 2007;115:6875.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    House A, Gregory SP, Catchpole B. Expression of cytokine mRNA in canine anal furunculosis lesions. Vet Rec 2003;153:354358.

  • 9.

    Day MJ. Immunopathology of anal furunculosis in the dog. J Small Anim Pract 1993;34:381388.

  • 10.

    Budsberg SC, Spurgeon TL, Liggitt HD. Anatomic predisposition to perianal fistulae formation in the German Shepherd Dog. Am J Vet Res 1985;46:14681472.

    • Search Google Scholar
    • Export Citation
  • 11.

    Killingsworth CR, Walshaw R, Reimann KA, et al. Thyroid and immunologic status of dogs with perianal fistula. Am J Vet Res 1988;49:17421746.

    • Search Google Scholar
    • Export Citation
  • 12.

    Shearer DH, Day MJ. Aspects of the humoral immune response to Staphylococcus intermedius in dogs with superficial pyoderma, deep pyoderma and anal furunculosis. Vet Immunol Immunopathol 1997;58:107120.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Harkin KR, Walshaw R, Mullaney TP. Association of perianal fistula and colitis in the German shepherd dog: response to high-dose prednisone and dietary therapy. J Am Anim Hosp Assoc 1996;32:515520.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Day MJ, Penhale WJ. Serum immunoglobulin A concentrations in normal and diseased dogs. Res Vet Sci 1988;45:360363.

  • 15.

    Doust R, Griffiths LG, Sullivan M. Evaluation of once daily treatment with cyclosporine for anal furunculosis in dogs. Vet Rec 2003;152:225229.

  • 16.

    Griffiths LG, Sullivan M, Borland WW. Cyclosporin as the sole treatment for anal furunculosis: preliminary results. J Small Anim Pract 1999;40:569572.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Hardie RJ, Gregory SP, Tomlin J, et al. Cyclosporine treatment of anal furunculosis in 26 dogs. J Small Anim Pract 2005;46:39.

  • 18.

    House AK, Guitian J, Gregory SP, et al. Evaluation of the effect of two dose rates of cyclosporine on the severity of perianal fistulae lesions and associated clinical signs in dogs. Vet Surg 2006;35:543549.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Klein A, Deneuche A, Fayolle P, et al. Preoperative immunosuppressive therapy and surgery as a treatment for anal furunculosis. Vet Surg 2006;35:759768.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Mathews KA, Ayres SA, Tano CA, et al. Cyclosporin treatment of perianal fistulas in dogs. Can Vet J 1997;38:3941.

  • 21.

    Mathews KA, Sukhiani HR. Randomized controlled trial of cyclosporine for treatment of perianal fistulas in dogs. J Am Vet Med Assoc 1997;211:12491253.

    • Search Google Scholar
    • Export Citation
  • 22.

    O'Neill T, Edwards GA, Holloway S. Efficacy of combined cyclosporine A and ketoconazole treatment of anal furunculosis. J Small Anim Pract 2004;45:238243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Kennedy LJ, O'Neill T, House A, et al. Risk of anal furunculosis in German shepherd dogs is associated with the major histocompatibility complex. Tissue Antigens 2008;71:5156.

    • Search Google Scholar
    • Export Citation
  • 24.

    Goring RL, Bright RM, Stancil ML. Perianal fistulas in the dog: retrospective evaluation of surgical treatment by deroofing and fulguration. Vet Surg 1986;15:392398.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    van Ee RT, Palminteri A. Tail amputation for treatment of perianal fistulas in dogs. J Am Anim Hosp Assoc 1987;23:95100.

  • 26.

    Anson LW, Betts CW, Stone EA. A retrospective evaluation of the rectal pull-through technique. Procedure and postoperative complications. Vet Surg 1988;17:141146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Budsberg SC, Robinette JD, Farrell RK. Cryotherapy performed on perianal fistulas in dogs. (Washington State University 1976–1980). Vet Med Small Anim Clin 1981;76:667669.

    • Search Google Scholar
    • Export Citation
  • 28.

    Ellison GW, Bellah JR, Stubbs WP, et al. Treatment of perianal fistulas with ND:YAG laser—results in twenty cases. Vet Surg 1995;24:140147.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Greiner TP. Surgical treatment of canine perianal fistulas. Vet Med Small Anim Clin 1981;76:663664.

  • 30.

    Holt P. Anal and perianal surgery in dogs and cats. In Pract 1985;7:8289.

  • 31.

    Houlton JE. Canine anal furunculosis: a modified approach. J Small Anim Pract 1980;21:585593.

  • 32.

    Houlton JE. Anal furunculosis: a review of seventy cases. J Small Anim Pract 1980;21:575584.

  • 33.

    Lane JG, Burch DG. The cryosurgical treatment of canine anal furunculosis. J Small Anim Pract 1975;16:387392.

  • 34.

    Liska WD. Anorectal and perianal cryosurgery. Vet Clin North Am Small Anim Pract 1980;10:803820.

  • 35.

    Milner HR. The role of surgery in the management of canine anal furunculosis. A review of the literature and a retrospective evaluation of treatment by surgical resection in 51 dogs. N Z Vet J 2006;54:19.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Robins GM, Lane JG. The management of anal furunculosis. J Small Anim Pract 1973;14:333342.

  • 37.

    Schaffer A, Block IR. Pathology and surgical correction of perianal fistulous tracts in a dog. J Am Vet Med Assoc 1961;138:2223.

  • 38.

    Shelley BA. Use of the carbon dioxide laser for perianal and rectal surgery. Vet Clin North Am Small Anim Pract 2002;32:621637.

  • 39.

    Vasseur PB. Results of surgical excision of perianal fistulas in dogs. J Am Vet Med Assoc 1984;185:6062.

  • 40.

    Guaguëre E, Steffan J, Olivry T. Cyclosporin A: a new drug in the field of canine dermatology. Vet Dermatol 2004;15:6174.

  • 41.

    Blackwood L, German AJ, Stell AJ, et al. Multicentric lymphoma in a dog after cyclosporine therapy. J Small Anim Pract 2004;45:259262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Dahlinger J, Gregory C, Bea J. Effect of ketoconazole on cyclosporine dose in healthy dogs. Vet Surg 1998;27:6468.

  • 43.

    Mouatt JG. Cyclosporin and ketoconazole interaction for treatment of perianal fistulas in the dog. Aust Vet J 2002;80:207211.

  • 44.

    Patricelli AJ, Hardie RJ, McAnulty JE. Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs. J Am Vet Med Assoc 2002;220:10091016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Tisdall PL, Hunt GB, Beck JA, et al. Management of perianal fistulae in five dogs using azathioprine and metronidazole prior to surgery. Aust Vet J 1999;77:374378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    Lowry PW, Weaver AL, Tremaine WJ, et al. Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn's disease perianal fistulae. Inflamm Bowel Dis 1999;5:239245.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Harkin KR, Phillips D, Wilkerson M. Evaluation of azathioprine on lesion severity and lymphocyte blastogenesis in dogs with perianal fistulas. J Am Anim Hosp Assoc 2007;43:2126.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48.

    Meingassner JG, Stütz A. Immunosuppressive macrolides of the type FK 506: a novel class of topical agents for treatment of skin diseases? J Invest Dermatol 1992;98:851855.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Lauerma AI, Granlund H, Reitamo S. Use of the newer immunosuppressive agents in dermatology. BioDrugs 1997;8:96106.

  • 50.

    Lauerma AI, Surber C, Maibach HI. Absorption of topical tacrolimus (FK506) in vitro through human skin: comparison with cyclosporin A. Skin Pharmacol 1997;10:230234.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Assmann T, Becker-Wegerich P, Grewe M, et al. Tacrolimus ointment for the treatment of vulvar lichen sclerosus. J Am Acad Dermatol 2003;48:935937.

  • 52.

    Assmann T, Homey B, Ruzicka T. Applications of tacrolimus for the treatment of skin disorders. Immunopharmacology 2000;47:203213.

  • 53.

    Assmann T, Homey B, Ruzicka T. Topical tacrolimus for the treatment of inflammatory skin diseases. Expert Opin Pharmacother 2001;2:11671175.

  • 54.

    Casson DH, Eltumi M, Tomlin S, et al. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn's disease. Gut 2000;47:436440.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Ruzicka T, Assmann T, Homey B. Tacrolimus: the drug for the turn of the millennium? Arch Dermatol 1999;135:574580.

  • 56.

    Ruzicka T, Assmann T, Lebwohl M. Potential future dermatological indications for tacrolimus ointment. Eur J Dermatol 2003;13:331342.

  • 57.

    Ruzicka T, Bieber T, Schöpf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. N Engl J Med 1997;337:816821.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58.

    Schuppe HC, Homey B, Assmann T, et al. Topical tacrolimus for pyoderma gangrenosum. Lancet 1998;351:832.

  • 59.

    Reitamo S, Wollenberg A, Schöpf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol 2000;136:9991006.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 60.

    Misseghers BS, Binnington AG, Mathews KA. Clinical observations of the treatment of canine perianal fistulas with topical tacrolimus in 10 dogs. Can Vet J 2000;41:623627.

    • Search Google Scholar
    • Export Citation
  • 61.

    Marretta SM. Anal sac removal. In: Bojrab MJ, ed. Current techniques in small animal surgery. 3rd ed. Philadelphia: Lea & Febiger, 1990;270274.

    • Search Google Scholar
    • Export Citation
  • 62.

    Ellison GW. Treatment of perianal fistulas in dogs. J Am Vet Med Assoc 1995;206:16801682.

  • 63.

    Homey B, Assmann T, Vohr HW, et al. Topical FK506 suppresses cytokine and costimulatory molecule expression in epidermal and local draining lymph node cells during primary skin immune responses. J Immunol 1998;160:53315340.

    • Search Google Scholar
    • Export Citation
  • 64.

    Stuetz A, Baumann K, Grassberger M, et al. Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus. Int Arch Allergy Immunol 2006;141:199212.

    • Crossref
    • Search Google Scholar
    • Export Citation
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