Update on managing IBD in dogs (Proceedings)

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).

Budesonide is a new and recently approved corticosteroid for use in humans. Budesonide is a glucocorticoid that also represents a new alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management; or that are intolerant of the corticosteroids discussed above. It is one of a group of novel corticosteroids that have been in development for use in humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. Others include fluticasone propionate, tixocortol pivalate, and beclomethasone dipropionate.

Budesonide undergoes high first pass metabolism in the liver and 90% is converted into metabolites with low corticosteroid activity. It has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a "locally acting" corticosteroid.

Therapeutic results with budesonide have been promising in humans with Crohn's disease, collagenous colitis and lymphocytic colitis, ulcerative colitis, either when administered as a retention enema or in oral form, and primary biliary cirrhosis. Budesonide has been used by some veterinary clinicians in recent years to treat IBD in dogs and cats. Dose recommendations vary. In humans, a range of 6 mg to 9 mg per day has been used during initial therapy. The following general recommendations have been made for dogs and cats. In general, budesonide is administered to cats and small dogs at 1 mg administered once per day. It has been used at higher doses (3 mg per small dog or cat per day), but the lower dose is frequently effective. Large dogs receive 3 mg twice daily initially, and the dose is later tapered to 3 mg once daily, and then to alternate day administration for longer term use.

When a patient is either poorly responsive to corticosteroids when used as outlined above, or if there is poor tolerance, the next best options are to try either budesonide or cyclosporine. Cyclosporine is described further below. Budesonide can be used in combination with other drugs. Potential adverse effects include PU/PD, when budesonide is used at the high end of the dose range, and GI ulceration. These reactions have been observed in some human patients. These problems would be more likely to occur in dogs than in cats. It appears to be very safe when used at the levels listed above.

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.

Cyclosporine

Cyclosporine A (cyA) has been shown to be effective in steroid-resistant IBD in humans and also perianal fistula management in both humans and dogs. Other uses in dogs have included management of atopic dermatitis and sebaceous adenitis. A study was undertaken to evaluate the pharmacokinetics and clinical efficacy of oral cyA treatment in 14 dogs with steroid-refractory IBD (Allenspach K, et al, JVIM 2006). Patient assessment included determination of a clinical activity score to assess severity of clinical signs before and after treatment. The total number of infiltrating lymphocytes and T cells in duodenal biopsies obtained via endoscopy were also assessed before and after treatment. Improvement was noted in 12/14 dogs. There was a significant improvement in clinical activity score and a decrease in T cell numbers, implying that T cell lysis is a possible mechanism of action. Results from this study suggest that cyA is an effective option for managing some dogs with steroid refractory IBD.

The anti-inflammatory effect of cyA in human IBD is believed to be due to suppression of activated T cells infiltrating the mucosa, thereby decreasing the amount of proinflammatory cytokines, and ultimately, the clinical signs of disease. The cyA dose used in the study of 14 dogs was 5 mg/kg (2.3 mg/lb) SID. The sole therapy was cyA. Previous therapy had included immunosuppressive doses of steroids in all dogs (starting dose of prednisolone was 1 mg/lb/day, administered for a range of 6 to 14 weeks before the dose was decreased). Other drugs tried in most of the dogs included metronidazole (range of 2 to 38 weeks).

There were transient adverse effects observed in 5 dogs, most of which occurred in the first 1-2 weeks of therapy, after which time they abated. Adverse reactions included vomiting and inappetence (4/14 dogs), and gingival ulceration and alopecia followed by hypertrichosis in 1 dog. A lag phase of 7 to 10 days has been seen in humans before there are obvious signs of clinical improvement, and a similar finding was observed in the dogs in the study reported here.

The clinical efficacy study showed that cyA was effective in 11/14 of the dogs (78%). Nine dogs were considered complete responders after 10 weeks of treatment, 3 were partial responders, and 2 were nonresponders that had to be euthanized during the study because no clinical improvement was observed. Eight out of the 9 dogs that responded well initially were still doing well after 6 months to 2 years follow-up. One dog responded well for 14 weeks but then relapsed and declined with severe vomiting and was euthanized. Eight dolgs were discontinued from cyA after 10 weeks of therapy. Three dogs were kept on therapy for 4, 6, and 36 months. These dogs had all shown significant improvement in clinical score but the owners elected to keep their dogs on therapy.

Further clinical experience is needed with cyA in dogs with IBD, but the results from the study as well as some anecdotal reports of positive responses indicate that cyA can be an effective form of therapy in dogs with steroid refractory IBD.

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 of IBD

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.