PURINA Pro Club German Shepherd Dog Update Vol. 7, No. 1 ■ June 2008 Research Focuses on Genetic Basis of Perianal Fistula arolyn Lavengood found the perfect canine companion in her first German Shepherd Dog, Kinderheim’s Kandi-Ana Angel, CGC. She and “Kandi” became good friends at puppy socialization classes and later at canine obedience training. Though Lavengood had no intention of showing Kandi in conformation, the shepherd’s sire was a conformation champion, and the dam came from a police canine line. When Kandi was 2 ½ years old, Lavengood noticed she frequently licked her bottom and struggled to defecate. At first, she thought it could be related to impacted anal glands; Kandi went monthly to the veterinarian to have the glands expressed. Then, Lavengood noticed a near-perfect circle of tiny pin holes around Kandi’s rear end. As it turned out, Kandi was diagnosed with anal furunculosis, more commonly known as perianal fistula (PAF). A chronic, progressive, inflammatory condition, perianal fistulas occur in several breeds, but German Shepherd Dogs make up about 90 percent to 95 percent of cases. Though the majority of affected dogs are 7 years old or older, the condition has been reported in puppies as young as 6 to 8 months old. Perianal fistulas also occur in humans with Crohn’s disease. A painful disease, PAF can become inflamed and raw from dogs constantly licking. Infection oozes from tiny pin holes, which actually are fistulous tracts, or tubelike structures that the body creates for the infection to drain. The thick, bushy tail of the German Shepherd Dog is believed to aggravate the condition by keeping the area moist. Adding to owners’ frustrations, dogs emanate a constant odor. Sadly, some owners have had to euthanize affected dogs due to chronic problems. In 1993, when Kandi was diagnosed with perianal fistulas, Lavengood, who lives in Lexington, Ky., learned about an experimental treatment involving prednisone, a steroid, developed by veterinarians at Michigan State University. She was eager to try it, so her veterinarian contacted the Michigan State veterinarians to learn the pro- C tocol. At first, Lavengood could not believe the required dosage. The first two weeks of treatment were the most intense. Dogs were given one milligram of prednisone per pound of body weight. Kandi, who weighed 80 pounds, received 80 milligrams. The dosage was reduced to half over the next four weeks. Eventually a Signs of Perianal Fistula erman Shepherd Dogs account for 90 percent to 95 percent of reported cases of perianal fistula, although the condition has been identified in many other breeds. Owners should be aware of signs of this condition as early diagnosis and treatment can help to improve a dog’s prognosis. Among common signs are: • Licking and biting the anal area; • Difficulty defecating; • Behavioral changes, such as lethargy and anorexia; • Anorexia, or prolonged loss of appetite; • Depression; and • Diarrhea. G maintenance level was determined. “We were never able to get the prednisone down to an acceptable level,” Lavengood recalls. “When the level became too low, the fistulas began festering again. All along Kandi experienced terrible side effects. She thought she was starving to death and was always thirsty. She developed puppy mange and had bare spots on her coat. She experienced a staph infection, muscle wasting and was depressed. She totally was not herself.” After 10 months of prednisone treatment, Lavengood decided to take Kandi off the steroid and try surgery. Though the surgery was not guaranteed to work, it offered hope. The twoand-a-half-hour procedure involved the veterinarian excising the diseased tissue and cauterizing the fistulous tracts. Risks included possible scar tissue, damage to the sphincter muscle that could lead to incontinence, and stenosis, or narrowing of the anus. Following surgery, “the veterinarian told me if Kandi made it six months without perianal fistulas, she had a good chance they would not recur,” says Lavengood. With her bottom full of surgical staples, Kandi went home, where she received optimal care from Lavengood. Indeed, the PAF did not return. In fact, after her anal glands were removed a few months later, Kandi never had another surgery the rest of her life. She died in June 2004 at age 13 ½. The lessons learned from the experience prompted Lavengood in 1998 to organize an online support group to help others. She serves as moderator of the PAF chat room that today has 458 members worldwide. Study Involves Genome Scan One investigator has a keen interest in discovering the genetic aspects of perianal fistulas. Lorna Kennedy, Ph.D., senior scientist at the University of Manchester Centre for Integrated Genomic Medical Research in the United Kingdom, has received an AKC Canine Health Foundation grant to examine genes potentially associated with PAF. She is conducting a genomewide scan looking for variations in the DNA sequence that are potentially associated with perianal fistula. “The prevalence of this disease in German Shepherd Dogs suggests a genetic predisposition,” Kennedy says. “Their high risk for PAF is almost certainly due to the presence of a particular gene or several genes acting together at high frequency,” she says. “Because cyclosporine, an immunosuppressant, is effective in treating this disease, we believe an immunemediated pathogenesis exists.” The research team has studied canine major histocompatibility complex (MHC) immune response genes in 107 German Shepherd Dogs with perianal fistulas and 196 unaffected German Shepherd Dogs. They also looked at a second smaller group of Continued on page 2 Perianal Fistula PAF Support Group & Web Site Available continued from page 1 German Shepherd Dogs from Finland consisting of 12 diagnosed with PAF and 15 with various other diagnoses. A breakthrough came when the investigators discovered a strong association between one particular gene variant in the major histocompatibility complex and perianal fistula. The MHC is known to play a part in determining the susceptibility of dogs to several immune-mediated diseases, such as rheumatoid arthritis, hemolytic anemia, lymphocytic thyroiditis, and even diabetes. “The association confirms there is a partly genetic basis for this disease that is likely to have an autoimmune component,” says Kennedy. “However, since not all German Shepherd Dogs carrying this particular variant devel- “THE ASSOCIATION CONFIRMS THERE IS A PARTLY GENETIC BASIS FOR THIS DISEASE THAT IS LIKELY TO HAVE AN AUTOIMMUNE COMPONENT. NOT ALL HOWEVER, SINCE GERMAN SHEPHERD DOGS CARRYING THIS PARTICULAR VARIANT DEVELOP PERIANAL FISTULAS, THE LIKELIHOOD IS THAT THERE ARE OTHER GENES INVOLVED IN DISEASE DEVELOPMENT, AS WELL AS A POSSIBLE ENVIRONMENTAL TRIGGER.” LORNA KENNEDY, PH.D., SENIOR SCIENTIST AT THE UNIVERSITY OF MANCHESTER CENTRE FOR INTEGRATED GENOMIC MEDICAL RESEARCH IN THE UNITED KINGDOM op perianal fistulas, the likelihood is that there are other genes involved in disease development, as well as a possible environmental trigger. Thus, a dog will have to carry particular variants at several different genes in order to develop the disease.” The results of the whole genome scan currently are being analyzed. The investigators are optimistic that the scan will indicate several areas of the genome that are associated with the disease. These areas will then be targeted for further research to identify the genes that may contribute to the disease development. Meanwhile, Kennedy advises breeders to avoid breeding dogs with the condition, especially dogs that develop the disease at an early age. If a genetic basis could be found for perianal fistulas and a genetic test developed, breeders could potentially selectively breed dogs that would not produce affected offspring. wners whose dogs have been diagnosed with perianal fistula (PAF) can visit http://groups. yahoo. com to find an online support group. Carolyn Lavengood, whose German Shepherd Dog “Kandi” was diagnosed with PAF in 1993, moderates the chat room. Additional information on PAF can be found at this Web address: http://members.tripod.com/~perianal-fistulas/MainIndex.html. O Disease Management Until a test is available, veterinarians continue to work to improve treatment and surgical options for affected dogs. Since Kandi received treatment for PAF in 1993, cyclosporine has been discovered as an effective, although expensive, treatment option. This medication was known to help humans with Crohn’s disease who develop perianal fistulas and was likewise found to benefit dogs. Researchers at the University of Wisconsin School of Veterinary Medicine found that cyclosporine effectively resolved or reduced perianal fistula in 25 of 26 dogs they studied. Robert Hardie, D.V.M., assistant professor of surgery at the University of Wisconsin, says, “We now largely treat canine perianal fistula with a combination of cyclosporine and ketoconazole, a drug given to slow down the metabolism of cyclosporine. Our approach to treating this disease has changed dramatically over the last several years with the success of cyclosporine therapy, and we rarely recommend surgery as a ‘first line of treatment.’ “Unfortunately, recurrence of PAF after an initial course of cyclosporine treatment is still relatively high, and many dogs require long-term or maintenance therapy to control the disease,” Hardie says. “For these dogs, the goal of treatment is to minimize the clinical signs and extent of the lesions with the least amount of cyclosporine possible, similar to how humans with Crohn’s disease are managed throughout their lives.” Rod Rosychuk, D.V.M., associate professor of dermatology at Colorado State University College of Veterinary Medicine, agrees. “Surgery is seldom used today,” he says. “This is because medical management using cyclosporine largely has been more successful than surgery.” A wide variety of cyclosporine dosages and dosage regimens are used. “We typically begin at a higher level and then reduce the dosage gradually once the maximal degree of benefit is achieved,” Rosychuk says. “Once individuals go into remission, the drug can eventually be stopped in some individuals. In others, perianal fistulas recur as the cyclosporine is reduced, and the dog must be returned to a higher dose to control the problem. Long-term maintenance therapy may be required.” Besides the cauterization surgery that Kandi received, other surgical techniques include electrosurgery, 2 laser surgery and surgical excision. “All have potential postoperative complications such as PAF recurrence, anal stricture formation, fecal incontinence, and difficulty defecating,” says Hardie. “In other words, all of these surgical procedures involve some risk that is generally avoided with cyclosporine therapy.” Kandi was one of the lucky German Shepherd Dogs whose surgery did successfully manage PAF and who went on to live a long life. Lavengood has continued to stay involved as moderator of the online PAF chat room. She now lives with two German Shepherd Dogs, neither having experienced perianal fistulas. Lavengood is optimistic that Kennedy and the United Kingdom research team will eventually unravel the genetic mystery about the disease. “Perianal fistula is a horrible condition to go through with your dog,” Lavengood says. “Kandi and I were handed a bunch of lemons, and we tried to make lemonade. I think we are on the brink of some major discoveries that will help breeders and owners everywhere.” ■ Purina appreciates the support of the American German Shepherd Dog Charitable Foundation and particularly Ginny Altman, AGSDCF health liaison and immediate past president of the German Shepherd Dog Club of America Inc., in helping to identify topics for the Purina Pro Club German Shepherd Dog Update newsletter. Want to Reach the Editor? Have comments about Purina Pro Club Update? Send them to us at: Purina Pro Club Update, c/o Editor, Nestlé Purina PetCare, 2T Checkerboard Square, St. Louis, MO 63164 or via e-mail at today’[email protected]. 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