Inflammatory Bowel Disease in Dogs

Todd R. Tams, DVM, DACVIM
W. Los Angeles, CA

It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Although treatment principles for cats and dogs with IBD are similar, drug selection and dosage regimens vary between these two species in some situations.

Specific treatment recommendations for dogs with inflammatory bowel disease (IBD) are as follows. Corticosteroids are the initial treatment of choice for lymphocytic-plasmacytic and eosinophilic enteritis in most cases. Mild to moderate cases (as determined by clinical signs, normal protein levels, and degree of inflammatory cell infiltrate on biopsy) often respond to prednisone at a dose of 0.25 to 0.75 mg/lb divided twice daily for two to four weeks followed by a gradual decrease in 50% increments at two-week intervals. Alternate day or every third day treatment can often be reached by two to three months. Occasionally treatment can be discontinued altogether by three to six months.

Moderate to severe cases and any case in which the total protein is less than 5.5 g/dl should be treated more aggressively using an initial prednisone dose of 1 mg/lb per day for two to four weeks before an attempt is made to decrease the dose. Dogs in this category often require long-term therapy (months to years) on an every other day or every third day basis to maintain remission. Use of combination drug therapy (prednisone and metronidazole) in these cases at the outset is recommended in order to improve chances of controlling clinical signs more quickly and to prevent progression of the disease.

If significantly bothersome side effects are caused by prednisone (e.g., severe polyuria/polydipsia, panting, lethargy, etc.), oral dexamethasone can be used instead. In some dogs dexamethasone is much better tolerated and side effects are minimal or nonexistent. If prednisone side effects are judged to be severe it is generally discontinued for 12 to 36 hours in order to allow for adequate metabolism and clearance. Prednisone may then be reintroduced at 25 to 50 percent of the previous dose or alternatively dexamethasone can be instituted at a conservative level (0.005 to 0.01 mg/lb/day orally).

Metronidazole has both an antibacterial and antiinflammatory effect. It is useful in treatment of IBD in dogs as well as in cats. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated responses, and anaerobic antibacterial activity. Metronidazole is administered at 5 to 10 mg/lb two times daily. A major advantage of using combination therapy is that the corticosteroid dose can usually be decreased from the high initial dose in a timely manner, thus decreasing the likelihood of significant corticosteroid-related side effects. Also, I have successfully managed on a long-term basis canine patients with mild to moderate lymphocytic-plasmacytic enteritis that were intolerant to corticosteroids or metronidazole alone.

When prednisone and metronidazole are used in combination the dosage level of each drug is generally gradually decreased as the animal's condition improves and laboratory parameters (especially protein levels and white blood cell count) return to normal. Corticosteroids are decreased gradually for several months before any reduction is made on the metronidazole dose. If there has been an excellent response it is possible that metronidazole can be discontinued after several months. Alternatively, if chronic therapy is required, metronidazole can often be administered on a once daily and eventually on an every other day basis. If it is not possible to discontinue medication altogether due to recurrence of symptoms when no medication is given control can be maintained with prednisone and/or metronidazole given on an alternate day basis. If both drugs are used, I often recommend giving prednisone on one day and metronidazole on the alternate day. Occasionally in dogs with moderate to severe IBD or in a case where both IBD and chronic bacterial overgrowth are present it is necessary to continue metronidazole on a long-term (months to years) basis (5 to 10 mg/lb twice daily). I have observed no instances of significant complications when this protocol has been used.

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. There are reports of humans with Crohn's disease who have been treated with high doses of metronidazole for prolonged periods of time and who subsequently developed breast or oral cancer. A cause and effect relationship has not been established. To date I am aware of no cases of GI or mammary cancer that have occurred in dogs or cats in conjunction with metronidazole use. I consider it to be a safe drug for prolonged use (months to years) in patients with chronic disorders for which long-term therapy is required.

Dogs with marked hypoproteinemia (total protein less than 4.5 g/dl) caused by lymphocytic-plasmacytic enteritis often respond well when an aggressive therapeutic course is undertaken (prednisone, metronidazole, and azathioprine used in combination). This aggressive approach has led to control of clinical signs and return to a total protein level of greater than 6.0 g/dl (by 2 to 4 months) in a number of cases. One exception to this approach, in my experience, is that animals with hypoproteinemia resulting from eosinophilic enteritis often respond well to corticosteroids alone.

Combination drug therapy is used early in severe cases or if a side effect to one drug requires that it be used at a lower dose. If corticosteroids are poorly tolerated (e.g., excessive polyuria/polydipsia, listlessness, panting, inappetence associated with steroid hepatopathy) or if corticosteroids and metronidazole are unable to achieve remission, then azathioprine should be added to the regimen. Azathioprine is started early in the course for cases of lymphocytic-plasmacytic enteritis that cause a protein-losing enteropathy with a total protein level less than 4.5 g/dl. The canine dose is 1 to 1.25 mg/lb once daily (note significant difference in dose between cats [0.15 mg/lb once every other day] and dogs). If azathioprine is used at the outset, the prednisone dose is decreased by 50% from 1mg/lb per day after three to four weeks or based on clinical improvement (i.e., remission of signs and increase in protein levels) and degree of tolerance of this dose of prednisone. Subsequent decreases in the prednisone dose can usually be made at monthly intervals until an alternate day schedule is reached. If azathioprine is started in any type of IBD case because of significant corticosteroid side effects, the prednisone is initially decreased by 50% to 75% but is not stopped completely unless absolutely necessary because loss of remission might result. Azathioprine is generally used for three to nine months in dogs. Once adequate control is achieved, the daily dose is decreased by 50%, and subsequently alternate day therapy is used. Side effects are uncommon in dogs but may include anorexia, jaundice (hepatic damage), poor hair growth, and bone marrow suppression. In addition, it is suspected that azathioprine has the potential to induce pancreatitis. This is an uncommon occurrence, however, in my experience. A complete blood count should be run to monitor for evidence of anemia or leukopenia at three week intervals for the first two months and then once every several months. Routine monitoring also includes periodic (once every 4 to 6 weeks initially) evaluation of hepatic enzyme levels (increases may be due to corticosteroids and occasionally azathioprine) and protein levels.

IBD that is initially graded as moderate to severe usually can be managed quite successfully and can be maintained in remission but not often cured. Sometimes follow-up biopsies in severe cases reveal only slight to moderate histologic resolution of inflammatory infiltrates despite excellent clinical control even on lower drug doses. Alternatively, dramatic histologic resolution has been noted in other cases. Treatment decisions (e.g., can treatment be discontinued completely?) ideally are based on a thorough review of clinical response to date (control of clinical signs, levels of medication required, and resolution of hypoproteinemia if it was initially present) and follow-up endoscopic biopsy information. As a general clinical rule of thumb an attempt can be made to discontinue therapy after two to three months of successful control on twice weekly medication. If signs recur then medication is resumed on a daily basis for 7 to 14 days before a gradual reduction program is started. In some dogs with severe lymphocytic-plasmacytic enteropathy and marked hypoproteinemia, therapy can be successfully discontinued as early as six months to one year. In others, lifelong treatment is required.

Dietary Management

In some animals with mild lymphocytic-plasmacytic enteritis or eosinophilic enteritis dietary modification may lead to partial or complete resolution of clinical signs and even improvement in histologic lesions. In others dietary therapy may be an important adjunct to pharmacotherapy in the control of clinical signs related to chronic IBD. It is also possible that dietary management used on a long-term basis will effectively help maintain control once drug therapy is discontinued. Potential benefits of dietary therapy include reduction of hypersensitivity reactions to dietary antigens, alteration of bowel motility, and effects on composition of the bowel flora and mucosal morphology and function.

Dietary therapy for IBD may involve use of a strict elimination diet or a balanced commercial diet that contains minimal additives. In most cases, diets that are highly digestible and low-residue work best for small intestinal disease. If a decision is made to initially manage an animal with dietary therapy alone the dietary trial should be conducted for a minimum of three to four weeks. Some animals require six weeks or more before clinical improvement occurs. If biopsies reveal moderate to severe IBD and/or if there is any degree of patient compromise pharmacotherapy should be included in the treatment regimen along with dietary management. In my experience, animals with this degree of disease rarely respond to dietary manipulation alone.

Diets that often work well include those that supply a single source of protein to which the animal has not previously been exposed (i.e., "novel" proteins). These may include lamb, rabbit, venison, duck, or low-fat cottage cheese. A single digestible carbohydrate such as boiled rice should be added to home prepared diets. Many of the premium commercial diets now include optimum levels of omega-6 and omega-3 fatty acids. These agents may be useful in reducing inflammation in the intestine. Baby food or boiled chicken are often well tolerated in cats that will not eat commercial foods. Dividing feedings into two to three meals per day will help maximize dietary assimilation.

Chronic Enteropathy In Shar Peis

Shar Peis with chronic diarrhea frequently have moderate to severe inflammatory bowel disease and intestinal bacterial overgrowth. Typical signs in Shar Peis often include persistent diarrhea weeks to months in duration, weight loss, and an increased to ravenous appetite. There is almost always evidence of small bowel diarrhea, but in some dogs large intestinal signs such as hematochezia, mucoid feces, and dyschezia are evident as well. Energy level often remains normal or nearly normal until the disease is severe. There is also intermittent vomiting in some dogs. The prognosis for successful clinical control of symptoms is excellent, as long as a definitive diagnosis is made before the disease becomes too severe. Clinicians are reminded that although a great majority of Shar Peis with chronic diarrhea have IBD and IBO an occasional case of intestinal lymphoma, histoplasmosis, etc. may still be found in this breed. Clinical signs and baseline laboratory parameters may be similar in all of these disorders. Therefore, it is always best to make every effort to establish a definitive diagnosis, rather than simply assuming that the most common problem is indeed present and subsequently administering empirical therapy. This issue should be thoroughly discussed with clients who may initially be reluctant to support the diagnostic testing that is necessary to make a diagnosis.

The most consistent laboratory parameters are panhypoproteinemia (usually ranging from 2.8 to 5.0 g/dl), indicating significant small intestinal involvement, and low cobalamin (vitamin B12) levels, which is most consistent with intestinal bacterial overgrowth. Folate levels are usually either normal or mildly elevated (increased folate is also consistent with bacterial overgrowth). There may be leukocytosis (often 20,000 to 40,000 cells/ul) with mature neutrophilia, and mild anemia (most consistent with anemia of chronic disease, and rarely blood loss). Eosinophilia is occasionally present. Despite the fact that the triad of signs of chronic diarrhea, weight loss, and ravenous appetite is strongly suggestive of exocrine pancreatic insufficiency, I have found this disease to be quite uncommon in Shar Peis (based on trypsin-like immunoreactivity assays).

In addition to a complete blood count, serum biochemical profile, fecal examinations for parasites, fecal cytology, fecal analysis for Clostridium perfringens enterotoxin, TLI assay for exocrine pancreatic insufficiency, and cobalamin and folate assays for intestinal bacterial overgrowth, Shar Peis with chronic diarrhea should undergo upper and lower GI endoscopy in order to obtain biopsies from the stomach, duodenum, jejunum (if it can be reached) ileum, and colon. Even if there are no clinical signs consistent with large bowel disease colonoscopy is still done because it is important that biopsies be obtained from the ileum. Usually there is diffuse involvement of the small intestine. However, occasionally histologic lesions will be found only in the lower small intestine (this highlights the importance of doing both upper and lower GI endoscopy). Other findings may include esophagitis (grossly evident at endoscopy), gastric hypomotility, and colitis.

Treatment

Treatment of Shar Peis usually includes management of IBD and IBO (prednisone, metronidazole, and amoxicillin which is administered for one month if there is laboratory evidence of IBO). In severe cases of IBD it may be necessary to use azathioprine (see guidelines described earlier). It may be useful to administer tylosin powder if the diarrhea is poorly responsive to initial therapy (reasons for poor response may include persistent bacterial overgrowth or Clostridium perfringens Enterotoxicosis that did not respond to metronidazole and/or amoxicillin). Esophagitis is managed with a restricted fat diet, H2-blocker therapy (e.g., famotidine once daily 30 minutes before food), and metoclopramide. Treatment for gastric hypomotility includes a restricted fat diet provided in divided feedings two to three times daily and a promotility drug (metoclopramide or cisapride). Colitis is managed with metronidazole and in some cases sulfasalazine is used as well. Anemia often resolves as the inflammatory disease comes under control. Dietary therapy guidelines previously described for IBD are followed.

Most Shar Peis can be managed on a long-term basis, once remission has been achieved, with maintenance doses of prednisone (every two to three days) and metronidazole (once daily to every other day). In some cases medication can be discontinued altogether after 6 to 24 months. Hematologic parameters and overall clinical condition should be consistently back to normal before all medication is stopped. Dogs with gastric motility disease (hypomotility) may require lifelong promotility therapy. If there are periodic flare-ups of large intestinal signs sulfasalazine is used as needed, generally for 7 to 21 days at a time (dose and frequency of administration depends on severity of clinical signs).

Lymphocytic-Plasmacytic Enteritis of Basenjis

Lymphocytic-plasmacytic enteritis (LPE) of Basenjis is an immunoproliferative process involving primarily the small intestine. This is a potentially severe form of IBD that is thought to result from a genetic disorder of immune regulation. There is an intense infiltration of lymphocytes and plasma cells in the intestinal mucosa. Other changes often include gastric rugal hypertrophy, lymphocytic gastritis and/or gastric mucosal atrophy, blunting and widening of intestinal villi, and mild dilation of lacteals.

LPE of Basenjis is often progressive in nature. Clinical signs may tend to be intermittent for a period of time before they worsen and become more persistent. Gastrointestinal signs may be exacerbated by episodes of "stress" such as traveling, boarding, or other medical disorders. Clinical signs usually include small intestinal diarrhea which may become intractable, vomiting, and/or inappetence. Weight loss can become significant as the disease progresses. Ulcerative dermatitis of the pinnae occasionally occurs in conjunction with this disease. Most affected Basenjis demonstrate clinical signs by 3 to 4 years of age.

Basenji enteropathy is commonly associated with hypoalbuminemia and hyperglobulinemia, especially in advanced cases. Neutrophilic leukocytosis and mild non-regenerative anemia are commonly present as well. Early in the disease course Basenji enteropathy may mimic other forms of IBD (mild symptoms, no significant laboratory abnormalities, etc.). As the disease becomes more advanced signs and laboratory parameters are characteristic, however, clinicians should be aware that other forms of intestinal disease such as lymphoma, lymphangiectasia, or histoplasmosis may be present and the symptoms of any of these diseases can mimic Basenji enteropathy. Therefore, it is always best to confirm the diagnosis by doing intestinal biopsies before instituting aggressive immunosuppressive therapy.

Treatment of Basenji enteropathy is based on control of the inflammatory bowel component (see guidelines for treatment of IBD in dogs described earlier in this chapter), management of intestinal bacterial overgrowth if it is present, and feeding a controlled or hypoallergenic diet. Since the disease is often progressive Basenjis with this disorder should be carefully monitored. Over time treatment may need to include combination immunosuppressive drugs and use of long-term antibiotics (e.g., metronidazole, tylosin). If there is evidence of gastric hypomotility, a promotility drug (metoclopramide or cisapride) is also used. Most Basenjis die within 2 to 3 years of diagnosis, while some affected dogs can be maintained for a period of years with careful monitoring and ongoing therapy. Affected dogs should not be bred.