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Canadian Cyclosporin treatment of perianal fistulas in dogs
Karol A. Mathews, Sara A. Ayres Cheryl A. Tano, Steve M. Riley,
Hanif R. Sukhiani, Catherine Adams
Perianal fistula (PAF) is a well-documented. painful, chronic, progressive inflammatory disease involving the anal and perianal area of dogs (1-4). Medical management has proved to be unsuccessful in achieving resolution of lesions (4.5), and current treatment options are of various surgical techniques (4-7). A recent review of current surgical methods for PAF indicates good to poor outcome and low to high recurrence rates (1). All the methods are invasive, frequently requiring multiple treatments and postoperative management by the owner. Similarities in the clinical appearance of canine PAF and PAF in humans with Crohn's disease have been reported (2). In both instances, the etiology is yet unknown. However, in Crohn's disease, the immune system is thought to play an important role (8). In dogs. an abnormality in immune function has been suggested:
however, no mechanism has been, elucidated (9). A recent study demonstrating the efficacv of cyclosporin in the treatment of anal fistulas in human patients with Crohn's disease (10) was the impetus for cyclosporin treatment in dogs with PAF in this report.
Eight German shepherds (GSD) and 1 Border collie were examined at the Veterinary Teaching Hospital (VTH) of the Ontario Veterinary College and 1 GSD was examined at the Saint John Animal Hospital, Saint John. .New Brunswick, between July 1994 and August 1995 for assessment of PAF. Seven of the dogs had received surgical treatment for this disease previously, and the owners felt strongly about not subjecting their dogs to this method of treatment again. In 3 dogs, this was the first occurrence of PAF and the owner declined surgical treatment. Physical examination confirmed the presence of PAF.
There was no evidence of anal sac involvement in any of the dogs in which prior anal sacculectomy had not been performed. Otherwise, all dogs were healthy.
Department of Clinical Studies, Ontario Veterinary College,
University of Guelph, Guelph, Ontario NlG 2W1
(Mathews.Ayres. Sukhiani, Tano, Riley)
Saint John Animal Hospital Ltd.,
1700 Manawagonish Road, Saint John, New Brunswick,E2M 3Y5
(Adams)
We are indebted to the generosity of Sandoz Canada Inc. for the donation of Sandimmun.
Can Vet J Volume 38, January 1997 PAGE 1 of 3
Table 1. Demographic and clinical data of each dog with perianal fistula (PAF) receiving cyclosporin therapy
8-wk therapy
10. 5-year-old. 3 mo Antibiotic flushes 90°
-360°
, up 8 wk >11 mo
spayed. female to 0.5 cm deep
Border collie
GSD=German Shepard Dog
Ontario). 0.05 mg/kg BW, IV, and acepromazine
(Atravet, Wyeth-Ayerst Don Mills. Ontario), 0.025mg/kg BW, IV, were used.
The age, signalment, any treatment for the anal furunculosis prior to cyclosporin therapy, and the extent of lesion involvement for each case upon presentation are shown in Table 1. Self-mutilation was reported in all dogs. except cases 5, 6, and 7; dyschezia was reported in all dogs, except cases 8 and 10. Loose or frequent bowel movements were reported in cases 1, 2, 3, and 7. Intermittent fecal incontinence was reported in case 3, after surgical treatment but prior to cyclosporin treatment. On rectal examination, firm, thickened rectal mucosa with varying degree of stricture was present in cases 1,2,5,7 and 9. Anal sacs were still present in all dogs, except in cases 2, 6, and 7, which had had anal sacculectomy performed with previous surgical treatment for anal furunculosis. In addition to the cyclosporin therapy, cases 1 and 3 received trimethoprimsulphamethoxazole and cases 4, 5, 7, 8, 9, and 10 received cephalexin. Cephalexin was discontinued after 2 and 3 d in cases 4 and 5 because of vomiting. The vomiting resolved after the cephalexin was discontinued.
There was a progressive improvement in each dog's demeanor and behavior on defecation, as well as resolution of the perianal inflammation and self-mutilation, after 1 wk of cyclosporin therapy.
During the first 2 weeks of cyclosporin therapy, diarrhea and dyschezia resolved in all dogs, and the frequency of bowel movements decreased in those that had previously been reported as excessive or frequent. The duration of cyclosporin therapy and the time to reduction in size of the perianal fistulas and total resolution was variable, depending on the size of the lesion, but occurred over a 2- to 20-week period, see (Table 1). All fistulas in all dogs resolved during cyclosporin therapy. There were no problems associated with cyclosporin therapy. No infections were seen in anv of the dogs and in fact, in those dogs not receiving antibiotics, the mucopurulent discharge associated with the fistulas resolved. The initial dosing of cyclosporin at 10 mg/kg BW, ql2h, proved to exceed the 400-600 ng/mL trough target level and was reduced to7.5 mg/kg BW, ql2h. The dose was reduced further to 5 mg/kg BW, ql2h, in those dogs maintaining trough levels above 600 ng/mL. Originally, antibiotic therapy was prescribed for 8 dogs; it had to be discontinued in 2 dogs because of vomiting; therefore, only 6 dogs received a course of antibiotics with cyclosporin (cases 1,3,7,8,9 and 10) In those cases in which fistulas recurred, the treatment period was only 8 wk (Table 1) although cyclosporin therapy was discontinued when the fistulas were resolved after 2consecutive examinations. 4 wk apart. One dog required surgical excision of a fistulous tract (case 3). The fistula in question recurred repeatedly at the same site and a specific nidus was considered to be the cause. Unfortunately, the excised tissue was not submitted for histolotical examination. This tract was not associated with the anal sac. The presence or absence of anal sacs did not affect the final outcome in this study. The thickened rectal mucosa and functional stricture resolved in all dogs. No dog maintained or acquired fecal incontinence after cyclosporin therapy. Complete blood cell counts were not performed upon completion of cyclosporin therapy, as vcl osporin does not cause myelosuppression. At final writing of this report, all dogs, except case 2, are in remission. Remission times are recorded in Table I.
A recent report of the pathology of surgically resected tissue from dogs with PAF identified plasma cells, lymphoid infiltrates, and neutrophils indicated that a simple reason could not be offered for the breed predilection in GSDs (2). Similar cellular infiltrates are present in PAF associated with Crohn's disease in humans and the condition is routinely managed with standard steroid and sulfasalzine therapy (10). A group of 16 patients refractory to this standard therapy were treated with cyclosporin, which resulted in a moderate improvement in their condition (10). Dogs with PAF in this study also appeared responsive to cyclosporin treatment.
Cyclosporin is a potent immunosuppressive drug, which is used widely in organ transplantation, although its use is not restricted to this field. Due to its suppressive effects on the T- cell mediated arm of the immune system, its utility is being recotnized in several immune-mediated diseases (11). Based on this action of cyclosporin and the response to its administration in the dogs in this report, we consider that an immune-mediated cause for perianal fisrulas seems likely. An' immunological basis has been suspected in PAF of GSDs; however, a recent study conc~ded that a simple immunological defect did not underlie the predisposition of GSDs to anal furunculosis (3). A clinical update on the treatment of perianal fistulas in dogs cites a study using prednisolone at 2.0 mg/kg BW, q24h, for 2 wk and 1.0 mg/kg BW, q24h, for an additional 4 wk, resultint in resolution of inflammatory bowel disease and coexisting perianal fistulas in 9 of 30 GSDs (5).
Acknowledgments
We thank Dr. Gerard Murphy, Senior Medical Advisor. Sandoz Canada Inc, Dorval, Quebec for his interest and invaluable advice on the use of Sandimmun. cvj
References> 1. Matushek KJ Rosin E. Perianal fistulas in dogs. Compend Contin Educ Pract Vet 1991:13: 2. Day MJ. Weaver BMQ. Pathology of surgically resected tissue from 5.El1ison GW. Clinical update: Treatment of perianal fistulas in dogs. J Am Vet Med Assoc 1995: 206: 1680-1682.
6. Elkins AD. Hobson HP. Management of perianal fistulae. A retrospective Study of 23 cases. Vet Surg 1982:11:110-114.
7. Houlton JEF. Anal furunculosis: A review of seventy cases. J Small Anim Pract 1980: 21: 575-584. 8.MacDermott RP. Stenson WF. The role of the immune system in inflammatory bowel disease. Immunol Allergy Clin North Am 1988:8: 521-541.
9. Ki11ingsworth CR, Walshaw R. Reiman KA. Rosser EJ Jr. Thyroid and immunologica1 status of dogs with perianal fistula. Am J Vet Res 1988:49: 1742-1746.
10. Present DH. Lichtiger S. Efficacy of cyclosoorine in treatment of fistula of Crohn's Disease. Dig Dis Sci 1994:39: 374-380.
11. Bennett WM. Norman DJ, Action and toxicity of cyclosporine. Ann Rev Med 1986: 37: 215-214. 12.Mathews KA. Holmberg DL. Johnston K. Renal allograft survival in outbred mongrel dogs utilizing combination immunosuppressive drug therapy and donor bone marrow. Vet Surg 1994: 23: 347-357.
Randomized controlled trial of cyclosporine for treatment of perianal fistulas in dogs
Karol A. Mathews, DVM, DVSc, and Hanif R. Sukhiani, DVM, DVSc
Objective - To evaluate efficacy of cyclosporine for treatment of perianal fistulas in dogs.
Design - Randomized, controlled trial.
Animals - 20 German Shepherd Dogs with naturally developing perianal fistulas.
Procedure - 10 dogs were treated with cyclosporine; the other 10 dogs were given a placebo. Overall improvement and change in total surface area of involvement and depth of the deepest fistula were determined after 4 weeks. Thereafter, cyclosporine-group dogs were treated for an additional 12 weeks and control-group dogs were treated with cyclosporine for 16 weeks.
Results - All cyclosporine-group dogs, but none of the control-group dogs, were subjectively improved after 4 weeks. Mean total surface area and mean fistula depth decreased 78 and 62%, respectively, in the cyclosporine-group dogs but increased 29 and 11%, respectively, in the control-group dogs. After 16 weeks of cyclosporine treatment, fistulas had healed in 17 (85%) dogs. However, fistulas recurred in 7 of 17 dogs, and additional cyclosporine treatment or anal sacculectomy and surgical excision of fistulas was necessary.
Clinical Implications - Cyclosporine appeared to be effective in dogs with perianal fistulas. Even in dogs which fistulas were not completely healed, cyclosporine administration appeared to be beneficial, because the surgical procedures that were required were less extensive than those that would have been necessary if cyclosporine had not been given. (J Am Vet Med Assoc 1997;211:1249-1253)
The term "perianal fistulas" refers to a chronic, progressive, debilitating disease affecting medium to large breed dogs, particularly German Shepherd Dogs, and is characterized by formation of abscesses in the perianal skin that progress to chronic sinuses and ulcers.1-3 Clinical signs commonly associated with perianal fistulas include tenesmus, dyschezia, constipation, malodorous mucopurulent discharge from the ulcerated tissues, low tail carriage, weight loss, and lethargy. 2
Treatment of perianal fistulas can be frustrating. Medical treatment, consisting of administration of antibiotics and local hygiene, is only palliative.1,2 Surgical treatment may include chemical cauterization, cryosurgery, laser surgery, deep excision, deroofing and fulguration, or tail amputation.1,2,4,11 Success rates as high as 97% have been reported; however, recurrence rates as high as 70% have also been reported, and complications, such as anal stricture and fecal incontinence, are common.1, 2, 10
The etiopathogenesis of perianal fistulas is still unclear, although many theories have been proposed. An immunologic defect is suspected. 3,2,13 and an association between colitis and perianal fistulas in German Shepherd Dogs has recently been reported.14 Perianal fistulas can develop in people with regional enteritis (Crohn's disease), and cyclosporine has proven effective for treatment of perianal fistulas in these patients.15 Thus, it seems reasonable that cyclosporine might be useful in dogs with perianal fistulas. Cyclosporine has been used for treatment of perianal fistulas in dogs.16 The purpose of the study reported here was to more carefully evaluate efficacy of cyclosporine for treatment of perianal fistulas in dogs by use of a randomized, controlled trial.
Materials and Methods
Dogs – Twenty German Shepherd Dogs with naturally developing perianal fistulas, representing consecutive cases referred to a veterinary teaching hospital, were included in the study. A sample size of 20 dogs was chosen on the basis of a power analysis of expected outcomes.16 All dogs with clinical evidence of perianal fistulas12 were eligible for inclusion regardless of the severity of the lesion or previous surgical or medical treatment. Owners of all dogs provided informed consent.
Experimental procedure – A complete physical examination, CBC, and serum biochemical analyses were performed at the time of enrollment in the study. Dogs were sedated with acepromazine maleate (0.05mg/kg [0.02 mg/lb] of body weight, IV), and oxymorphone hydrochloride (0.05 mg/kg [0.02mg/lb], IV), and the perianal area was carefully examined and photographed. For each dog, the depth of the fistulas was determined with a blunt probe, and the surface dimensions of the fistulated area were measured and charted. Total surface area involved was calculated mathematically from the measured surface dimensions.
Owners were asked to grade their dogs on a scale from 1 to 7 in each of the following areas; activity and playfulness; affection toward the owner; appetite; body weight; consistency of feces; appropriateness of location of defecation fecal continence; vocalization during defecation; straining during defecation; fecal continence; frequency of licking; chewing; and biting at the perianal area; quality of coat; quality of day-to-day life.
A computer-generated protocol was used to randomly assign dogs to the treatment or control group. Dogs in the treatment group received cyclosporine2 at an initial dosage of approximately 5 mg/kg (2.3 mg/lb), PO, every 12 hours; dogs in the control group received identical-looking capsules containing only the lipid vehicle, PO, every 12 hours. In addition, all dogs were treated with cephalexin (20 mg/kg [9 mg/lb], PO, q 8 h) for 10 days. Other systemic or topical treatment was not administered. Only 1 of the investigators was aware of the group assignment.
Blood samples were collected in EDTA tubes from each dog weekly for the first 3 weeks and, thereafter, after any adjustment to the drug dosage. Trough blood cyclosporine concentrations (ie, concentrations 12 hours after administration of cyclosporine) were determined by use of a monoclonal radioimmunoassay6 in dogs receiving cyclosporine. If the trough concentration was not between 400 and 600 ng/ml, the owner was contacted and the cyclosporine dosage was adjusted. In addition, the placebo dosage was adjusted for one of the control-group dogs.
Assessment of efficacy and follow-up evaluation – After 4 weeks, dogs were reevaluated by an investigator who was not aware of the group assignment. The investigator assigned an overall subjective assessment of whether the fistulas were improved and measured total surface area and depth of the fistulas. Owners were asked to again grade their dogs' attitude and behavior. The group assignment code was then broken. Dogs in the treatment group were treated with cyclosporine for an additional 12 weeks, and dogs in the control group were treated with cyclosporine for 16 weeks. Serum creatinine concentration was measured before the end of treatment. Dogs were reexamined every other month for a minimum of 6 months after administration of cyclosporine was discontinued. Further follow-up information was obtained from owners by telephone.
Statistical analysis – For each dog, change in total surface area of involvement and the depth of the deepest fistula after 4 weeks was expressed as a fraction of the total surface area and depth prior to treatment (ie, change in surface area = [surface area at week 4 – surface area at week 0] /surface area at week 0). Independent t-tests were then used to compare mean change in surface area and depth between groups. Fisher's exact test was used to determine whether treatment group was associated with subjective assessment of improvement after 4 weeks. c
2 Analyses were used to determine whether owners' perception of improvement in their dogs attitude and behavior was associated with treatment group. For all analyses, a value of P< 0.05 was considered significant.
Results
Dogs – Ten dogs (7 male [3 castrated], 3 female [1 spayed]} were assigned to the cyclosporine group, and the other 10 [7 male [3 castrated], 3 female [2 spayed]) were assigned to the control group. All 20 dogs had previously been treated with antibiotics. In addition, 4 cyclosporine-group dogs and 2 control-group dogs had undergone surgery; 2 cyclosporine-group dogs and 1 control-group dog had been treated with corticosteroids. Cyclosporine-group dogs were neither significantly older (mean, 70 months; range, 7 to 127 months) than control-group dogs (mean, 45 months; range, 18 to 60 months) nor had they had perianal fistulas (mean duration, 11 months; range, 1 to 36 months) for a significantly longer time than control-group dogs (mean duration, 6 months; range, 1 to 18 months).
Four-week evaluation – The percentage of cyclosporine-group dogs (10/10) that were subjectively improved after 4 weeks was significantly greater than the percentage of control-group dogs (0/10). Three control-group dogs were considered unchanged and 7 were worse. Mean change in surface area of the fistulas after four weeks for the cyclosporine-group dogs (mean ± SD, -78 ± 20%) was significantly different from mean change for the control-group dogs (29 ± 47%; Table1). Similarly, mean change in depth of the deepest fistula after 4 weeks for the cyclosporine-group dogs (-62 ± 23%) was significantly different from the mean change in depth for the control-group dogs (11 ± 38%).
There is a constant inter- and intrapatient variabilitv in the rate of absorption and metabolism of cyclosponn in dogs (12), which requires monitoring to ensure blood levels within therapeutic range. Based on the 100% response rate to cyclosporin, the poor response to antibiotic therapy prior to cyclosporin treatment, and the fact that 4 dogs did not receive a course of antibiotic therapy whilst receiving cyclosporin in this study, it would appear that antibiotics are not essential in managing this disease. Because the PAF was resolved without the risk of incontinence or stricture formation. without pain or discomfort. and without the need for intensive management, all owners preferred cyclosporin over surgical treatment for their dogs.
Where surgical intervention was necessary due to a persistent fistula (case 3), the preceding treatment with cyclosporin reduced the lesion to a point where only minor surgical excision was required, which, in this instance, was acceptable to the owner. In those cases in which the condition recurred, the original cyclosporin therapy was only for 8 wk. This suggests that a minimum period for cyclosporin therapy longer than 8 wk is necessary. Whether permanent remission can be attained with cyclosporin in some dogs is unknown at this time. Remission times with surgical treatment can be short, as 7 dogs in this study had surgical treatment prior to cyclosporin therapy (1 three times, 3 twice and 3 once) (Table 1). The dogs in this report have been free of perianal fistulas for up to 19 mo.
We conclude, from this study that perianal fistulas in dogs are responsive to cyclosporin therapy and the remission times at writing are superior to those obtained with surgical intervention. Surgical treatment can be reserved for those cases where cyclosporin therapy does not completely resolve the fistulas.
3. Day MJ. Immunopathology of anal furunculosis in the dog. J Small Anim Pract 1993: 34: 381-388.>
4. Matthieson DT. Maretta SM. Diseases of the anus and
rectum. In:Slatter D, ed. Textbook of Small Animal Surgery.
2nd ed. Philadelphia: WB Saunders, 1993: 627-645.>
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