Canine inflammatory bowel disease: The 8 components of therapy (Proceedings)

IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic inflammation of the stomach, intestine and/or colon of unknown etiology. A clinical diagnosis of IBD is considered only if affected animals have: (1) persistent (>3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucousy feces), (2) failure to respond to symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, (3) failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and (4) histologic diagnosis of benign intestinal inflammation. Small bowel and large bowel forms of IBD have been reported in both dogs and cats, although large bowel IBD appears to be more prevalent in the dog.

Treatment – Management of IBD consists of 1) dietary therapy, 2) exercise, 3) antibiotics, 4) probiotics, 5) anti-diarrheal agents, 6) restoration of normal motility, 7) anti-inflammatory or immunosuppressive therapy, and 8) behavioral modification.

1. Dietary Therapy

The precise immunologic mechanisms of canine and feline IBD have not yet been determined, but a prevailing hypothesis for the development of IBD is the loss of immunologic tolerance to the normal bacterial flora or food antigens. Accordingly, dietary modification may prove useful in the management of canine and feline IBD. Several nutritional strategies have been proposed including novel proteins, hydrolyzed diets, anti-oxidant diets, medium chain triglyceride supplementation, low fat diets, modifications in the omega-6/omega-3 (ω-6/ω-3) fatty acid ratio, and fiber supplementation. Of these strategies, some evidence-based medicine has emerged for the use of novel protein, hydrolyzed, and fiber-supplemented diets.

Food sensitivity reactions were suspected or documented in 49% of cats presented because of gastroenterologic problems (with or without concurrent dermatologic problems) in a prospective study of adverse food reactions in cats. Beef, wheat, and corn gluten were the primary ingredients responsible for food sensitivity reactions in that study, and most of the cats responded to the feeding of a chicken- or venison-based selected-protein diet for a minimum of 4 weeks. The authors concluded that adverse reactions to dietary staples are common in cats with chronic gastrointestinal problems and that they can be successfully managed by feeded selected-protein diets. Further support for this concept comes from studies in which gastroenterologic or dermatologic clinical signs were significantly improved by the feeding of novel proteins.

Evidence is accruing that hydrolyzed diets may be useful in the nutritional management of canine IBD. The conceptual basis of the hydrolyzed diet is that oligopeptides are of insufficient size and structure to induce antigen recognition or presentation. In one preliminary study, dogs with inflammatory bowel disease showed significant improvement following the feeding of a hydrolyzed diet although they had failed to respond to the feeding of a novel protein. Clinical improvement could not be solely attributed to the hydrolyzed nature of the protein source because the test diet had other modified features, i.e., high digestibility, cornstarch rather than intact grains, medium chain triglycerides, and an altered ratio of ω-6 to ω-3 polyunsaturated fatty acids. Additional studies will be required to ascertain the efficacy of this nutritional strategy in the management of IBD.

Fiber-supplemented diets may be useful in the management of irritable bowel syndrome (IBS) in the dog. IBS is a poorly defined syndrome in the dog that may or may not bear resemblance to IBS in humans. Canine IBS has been defined as a chronic large-bowel type diarrhea without known cause and without evidence of colonic inflammation on colonoscopy or biopsy. Dogs fulfilling these criteria were successfully managed with soluble fiber (psyllium hydrophilic mucilloid) supplementation of a highly digestible diet.

2. Exercise

Experimental IBD in the dog is accompanied by significant abnormalities in the normal colonic motility patterns. Physical exercise has been shown to disrupt the colonic MMCs and to increase the total duration of contractions that are organized as non-migrating motor complexes during the fed state. Exercise also induces GMCs, defecation, and mass movement in both the fasted and fed states. The increased motor activity of the colon and extra GMCs that result from physical exercise may aid in normal colonic motor function.

3. Antibiotics

Some IBD cases are initiated by true enteric pathogens, while others are complicated by small intestinal bacterial overgrowth. Some IBD cases may show short term responsiveness to one or more antibiotics, e.g., tylosin, metronidazole, or oxytetracycline.

4. Probiotics

Probiotics are living organisms with low or no pathogenicity that exert beneficial effects (e.g., stimulation of innate and acquired immunity) on the health of the host. The Gram-positive commensal lactic acid bacteria (e.g., Lactobacilli) have many beneficial health effects, including enhanced lymphocyte proliferation, innate and acquired immunity, and anti-inflammatory cytokine production. Lactobacillus rhamnosus GG, a bacterium used in the production of yogurt, is effective in preventing and treating diarrhea, recurrent Clostridia difficile infection, primary rotavirus infection, and atopic dermatitis in humans. Lactobacillus rhamnosus GG has been safely colonized in the canine gastrointestinal tract, although probiotic effects in the canine intestine have not been firmly established. The probiotic organism, Enterococcus faecium (SF68), has been safely colonized in the canine gastrointestinal tract, and it has been shown to increase fecal IgA content and circulating mature B (CD21+/MHC class II+) cells in young puppies. It has been suggested that this probiotic may be useful in the prevention or treatment of canine gastrointestinal disease. This organism may, however, enhance Campylobacter jejuni adhesion and colonization of the dog intestine, perhaps conferring carrier status on colonized dogs.

Two recent studies have shown that many commercial veterinary probiotic preparations are not accurately represented by label claims. Quality control appears to be deficient for many of these formulations. Until these products are more tightly regulated, veterinarians should probably view product claims with some skepticism.

5. Anti-Diarrheal Agents

     Prostaglandin Synthetase Inhibitors

          - Sulfasalazine - 10-25 mg/kg TID-QID, PO

          - 5-aminosalicylate - 5-10 mg/kg PO, TID-QID (dog)

     µ,d-Opioid Agonists – These drugs stimulate circular smooth muscle contraction and, therefore,intestinal segmentation. It has been shown more recently that these drugs also stimulate absorption, and inhibit secretion of, fluid and electrolytes.

          - Loperamide 0.08 mg/kg TID, PO-preferred drug

          - Diphenoxylate 0.05-0.10 mg/kg TID-QID, PO-available in Lomotil

     5-HT3 Serotonin Antagonists - Antagonists of the neuronal 5-HT3 receptor inhibit Cl- and H2O secretion from intestinal epithelial cells.

          - Ondansetron (Zofran, Glaxo) - 0.5-1.0 mg/kg BID, PO

          - Granisetron (Kytril, SmithKline Beecham) - 0.5-1.0 mg/kg BID, PO

     α2-Adrenergic Antagonists - These drugs must be used carefully as they can activate α2-adrenergic receptors in the chemoreceptor trigger zone and cause vomiting.

          - Clonidine 5-10 µg/kg BID-TID, SQ/PO

6. Restoration of Normal Motility

The mixed µ,δ-opioid agonist, loperamide, stimulates colonic fluid and electrolyte absorption while inhibiting colonic propulsive motility. Loperamide (0.08 mg/kg PO TID-QID) may be beneficial in the treatment of difficult or refractory cases of large bowel-type IBD.

7. Anti-Inflammatory/Immunosuppressive Therapy

Sulfasalazine – Sulfasalazine is a highly effective prostaglandin synthetase inhibitor that has proven efficacy in the therapy of large bowel IBD in the dog. Sulfasalazine is a compound molecule of 5-aminosalicylate (meselamine) and sulfapyridine linked in an azo chemical bond. Following oral dosing, most of the sulfasalazine is transported to the distal gastrointestinal tract where cecal and colonic bacteria metabolize the drug to its component parts. Sulfapyridine is largely absorbed by the colonic mucosa but much of the 5-aminosalicylate remains in the colonic lumen where it inhibits mucosal lipoxygenase and the inflammatory cascade. Sulfasalazine has been recommended for the treatment of canine large bowel IBD at doses of 10-25 mg/kg PO TID for 4-6 weeks. With resolution of clinical signs, sulfasalazine dosages are gradually decreased by 25 per cent at 2-week intervals and eventually discontinued while maintaining dietary management. Salicylates are readily absorbed and induce toxicity in cats, therefore this drug classification should be used with great caution in cats. If used in cats, some authors have recommended using half of the recommended dog dose (i.e., 5-12.5 mg/kg PO TID. Sulfasalazine usage has been associated with the development of keratoconjunctivitis sicca in the dog, so tear production should be assessed subjectively (by the pet owner) and objectively (by the veterinarian) during usage.

Other 5-Aminosalicylates – This drug classification was developed to reduce the toxicity of the sulfapyridine portion of the parent molecule (sulfasalazine) and to enhance the efficacy of the 5-aminosalicylate portion. Meselamine (Dipentum, Asachol) and dimeselamine (Olsalazine) are available for use in the treatment of canine large bowel IBD. Olsalazine has been used at a dosage of 5-10 mg/kg PO TID in the dog. Despite the formulation of sulfa-free 5-aminosalicylate preparations, instances of keratoconjunctivitis sicca have still been reported in the dog.

Metronidazole – Metronidazole (10-20 mg/kg PO BID-TID) has been used in the treatment of mild to moderate cases of large bowel IBD in both dogs and cats. Metronidazole has been used either as a single agent or in conjunction with 5-aminosalicylates or glucocorticoids. Metronidazole is believed to have several beneficial properties, including anti-bacterial, anti-protozoal, and immunomodulatory effects. Side effects include anorexia, hypersalivation, and vomiting at recommended doses and neurotoxicity (ataxia, nystagmus, head title, and seizures) at higher doses. Side effects usually resolve with discontinuation of therapy but diazepam may accelerate recovery of individual patients.

Glucocorticoids – Anti-inflammatory doses of prednisone or prednisolone (1-2 mg/kg PO SID) may be used to treat IBD in dogs that have failed to respond to dietary management, sulfasalazine, or metronidazole, and as adjunctive therapy to dietary modification in feline IBD. Prednisone or prednisolone is used most frequently, as both have short durations of action, are cost-effective, and are widely available. Equipotent doses of dexamethasone are equally effective but may have more deleterious effects on brush border enzyme activity. Prednisone should be used for 2-4 weeks depending upon the severity of the clinical signs. Higher doses of prednisone (e.g., 2-4 mg/kg PO SID) may be needed to control severe forms of eosinophilic colitis or hypereosinophilic syndrome in cats. Combination therapy with sulfasalazine, metronidazole, or azothioprine may reduce the overall dosage of prednisone needed to achieve remission of clinical signs. As with sulfasalazine, the dose of glucocorticoid may be reduced by 25% at 1-2 week intervals while hopefully maintaining remission with dietary modification.

Because of steroid side effects and suppression of the hypothalamic-pituitary-adrenal axis, several alternative glucocorticoids have been developed that have excellent topical (i.e., mucosal) anti-inflammatory activity but are significantly metabolized during first pass hepatic metabolism. Budesonide has been used for many years as an inhaled medication for asthma, and an enteric-coated form of the drug is now available for treatment of IBD in humans (and animals). There is little evidence-based medicine in support of the use of this medication in canine or feline IBD, but doses of 1 mg/cat or 1 mg/dog per day have been used with some success in anecdotal cases.

Azathioprine – Azathioprine is a purine analog that, following DNA incorporation, inhibits lymphocyte activation and proliferation. It is rarely effective as a single agent, and it should instead be used as adjunctive therapy with glucocorticoids. Azathioprine may have a significant steroid-sparing effect in IBD. Doses of 2 mg/kg PO q 24 hours in dogs and 0.3 mg/kg PO q 48 hours in cats have been used with some success in IBD. It may take several weeks or months of therapy for azathioprine to become maximally effective. Cats particularly should be monitored for side effects, including myelosuppression, hepatic disease, and acute pancreatic necrosis.

Cyclosporine – Cyclosporine has been used in the renal transplantation patient for its inhibitory effect on T cell function. In more recent times, cyclosporine has been used in a number of immune-mediated disorders, including keratoconjunctivitis sicca, perianal fistula (anal furunculosis), and IMHA. Anecdotal reports suggest that cyclosporine (3-7 mg/kg PO BID) may be useful in the treatment of some cases of refractory IBD. Evidence-based medicine studies will be needed to establish efficacy, but anecdotal experience would suggest that cyclosporine may be useful in some of the more difficult or refractory cases of IBD.

Chlorambucil – Chlorambucil (2 mg/m2 PO every other day) has been used in place of azathioprine in some difficult or refractory cases of feline IBD.

8. Behavioral Modification

Inflammatory bowel disease and irritable bowel syndrome very likely have underlying behavioral components. Abnormal personality traits and potential environmental stress factors were identified in 38% of dogs in one study. Multiple factors were present in affected households, including travel, re-location, house construction, separation anxiety, submissive urination, noise sensitivity, and aggression. The role of behavior in the pathogenesis and therapy of canine and feline gastrointestinal disorders remains largely unexplored.

References available upon request