Overview

Inflammatory bowel (IBD) is a chronic gastrointestinal tract disorder of unknown cause and ill-defined pathogenesis. Interactions between the mucosal immune system, host genetic susceptibility, and environmental factors (e.g., normal microflora) have been implicated as causing intestinal inflammation. Two general hypotheses have been proposed: 1) inflammation is due to an abnormal immune response (e.g., host hypersensitivity caused by increased intestinal permeability, defective suppressor function of GALT, and/or other primary immunologic events) and, 2) inflammation is initiated by an appropriate immune response to a normal luminal constituent (dietary antigen or resident enteric flora). With either paradigm, both cellular components (activated intestinal B and T lymphocytes) and molecular elements (complement, prostanoids, leukotrienes, proinflammatory cytokines, leukocyte proteases, nitric oxide, and reactive oxygen species) likely contribute to mucosal inflammation. Clinical signs are attributed to mucosal cellular infiltrates and inflammatory mediators.

Relevant Diagnostic Testing

A diagnosis of IBD is one of exclusion and requires ruling-out of many other diseases which may cause intestinal inflammation. Systemic diseases, chronic parasitism, dietary sensitivity (e.g., food allergy or intolerance), infectious diseases, and alimentary lymphosarcoma are the major differential diagnoses for IBD. Objective criteria for diagnosis of canine and feline IBD have been described. It is essential that clinical signs be correlated with histologic evidence of gastroenteritis, and that other causes for chronic mucosal inflammation be eliminated by appropriate diagnostic testing. Therapeutic trials using anthelmintics or hypoallergenic diets may be effective in animals having parasitic or dietary causes, respectively, for enterocolitis. One recent study indicates that up to 30% of cats with idiopathic gastrointestinal problems may have food sensitivities.

Clinical Staging of IBD

The clinical course of IBD is generally characterized by spontaneous exacerbations and remissions, making accurate assessment of disease burden difficult. Determination of degree of illness (e.g., disease activity) is desirable since it serves to gauge initial IBD severity and helps guide therapeutic strategies. There is a paucity of data defining any clinical scoring systems for either canine or feline IBD. We have recently developed a simple numerical scoring system, termed the canine IBD disease activity index (CDAI), which produces very reproducible scores from one clinician to the next. Using this system, six salient gastrointestinal signs are scored 0-3, based upon the magnitude of their alteration from normal in a given IBD patient. Use of this disease activity index has been recently evaluated in a large prospective study. In this investigation, it was shown that the CDAI correlated positively with both histology scores and laboratory markers of intestinal inflammation (e.g., serum haptoglobin and C-reactive protein). Lastly, this same study showed that the CDAI could provide valuable prognostic information when assessing therapeutic responses.

Histologic Grading Criteria

Histologic evaluation of tissue specimens is required for definitive diagnosis of IBD. Unfortunately, no standard microscopic grading system for assessment of biopsy specimens has been established. Biopsy interpretation is notoriously subjective from one pathologist to the next, and is further hampered by the technical constraints of specimen size and procurement or processing artifacts inherent in evaluation of endoscopic specimens. We propose utilization of a grading system based upon the extent of architectural disruption and mucosal epithelial changes. "Mild" IBD lesions are those in which there is no mucosal architectural disruption, glandular necrosis, immaturity or fibrosis in the lamina propria. "Severe" IBD is manifest by architectural distortion of the mucosa as seen with extensive ulceration, necrosis, villus atrophy, glandular loss/hyperplasia, or fibrosis of the lamina propria. Note that in this grading scheme, no attempt is made to quantitate the number of inflammatory cells within the lamina propria. Greater confidence may be placed in a histologic diagnosis of mild IBD when concurrent cytologic lesions of benign mucosal inflammation are observed. Endoscopic exfoliative cytology has been shown to be a useful adjunct to mucosal biopsy for the diagnosis of IBD in the dog and cat.

Treatment of IBD

Dietary Therapy. Patients with IBD may be nutritionally deficient due to decreased food intake, impaired nutrient absorption, and/or increased exudation as seen with protein-losing enteropathy. The most convenient means for dietary manipulation in veterinary patients is with controlled (hypoallergenic) diets. These diets should be formulated with ingredients which the animal has not been fed before (e.g., novel protein source such as venison, rabbit, lamb, whitefish or turkey) or that are unlikely to evoke allergic responses (e.g., potatoes). Controlled diets may have to be fed for several (6-8) weeks to assess their efficacy. Altering the dietary ratio of omega-6 (n=6) to n=3 polyunsaturated fatty acids may affect the inflammatory response of IBD. Diets enriched in n=3 fatty acids are incorporated into biologic membranes resulting in decreased concentrations of pro-inflammatory n=6 fatty acid metabolites (e.g., leukotriene B₄ [LTB₄], prostaglandins, and interleukin-1). Therapeutic trials assessing the efficacy of dietary fatty acid modification in dogs or cats with IBD have not been published. Fiber-enriched diets are recommended to mitigate signs of large bowel diarrhea and tenesmus. Dietary fiber may increase fecal consistency, bind potential colonic irritants, improve abnormal colonic motility, and produce beneficial short chain fatty acids (e.g., butyrate) which positively influence large bowel structure and function.Commercial high fiber diets or hypoallergenic diets supplemented with moderately fermentable fiber (e.g., psyllium or oat bran) may be fed.

Pharmacologic Therapy. Dietary management alone for moderate-to-severe IBD is seldom successful and most animals will require pharmacologic therapy.

Corticosteroids. Prednisone or prednisolone are reasonable first-choice agents for induction therapy of IBD in some dogs and most cats. Beneficial responses are usually observed when dosages of 1-2 mg/kg body weight/day are used in conjunction with dietary therapy. Induction therapy of 2-4 weeks (depending on severity of signs and type of histologic lesion) is generally recommended. Combination drug therapy (e.g., steroids combined with metronidazole, azathioprine, or sulfasalazine) allows a reduced steroid dose for maintenance therapy. Alternative glucocorticoid preparations characterized by high topical anti-inflammatory activity and first pass hepatic metabolism have been recently used in human IBD. They were developed to attain maximal therapeutic effect of conventional steroids while minimizing deleterious systemic effects. These medications are administered rectally (tixcortal pivilate, beclomethasone dipropionate) or orally (budesonide). The efficacy (and potential toxicity) of these new preparations in dogs and cats remains to be proven; although, anecdotal evidence suggests budesonide may be of value in some dogs with lymphocytic-plasmacytic colitis.

Sulfasalazine. Sulfasalazine (SASA) is considered by many clinicians to be the first-choice drug for canine colitis. The recommended dosage range for SASA in dogs is 20-50 mg/kg up to a maximum of 1.0 gm q8h in refractory patients or those having severe disease. I use an initial dosage of 12.5 mg/kg q8h. It is important to continue induction therapy for a minimum of 4 weeks before modifying drug dosage. With resolution of signs, SASA dosages are gradually decreased by 25% at 2 week intervals and eventually discontinued while maintaining dietary management. Caution is advised in using SASA in cats because of their sensitivity to salicylates.

Newer 5-ASA Preparations. Topical and oral 5-ASA preparations are now used for treatment of human IBD.Two oral preparations of potential use in dogs include olsalazine and mesalamine. Olsalazine (Dipentum) consists of two molecules of mesalamine linked by an azo bond. Various enteric-coated preparations of mesalamine (Pentasa, Asacol) release active drug (5-ASA) in the distal small intestine and colon, respectively.The use of these agents for treatment of canine and feline IBD has not been critically evaluated, but there are substantial anecdotal reports of their efficacy. The proposed dose is approximately one-half that of SASA.

Metronidazole. Anecdotal reports suggest that metronidazole has beneficial effects in the therapy of canine and feline IBD. Its mechanisms of action might include antiprotozoal action, inhibition of cellular immunity, and bacteriocidal spectrum of activity against anaerobes (e.g., Bacteroides spp). The recommended dosage of metronidazole used in dogs and cats for IBD is 10-20mg/kg q8-12h. Metronidazole is most often combined with corticosteroids or sulfasalazine in patients having moderate-to-severe clinical signs or histologic lesions. It is also effective as a sole agent in animals having mild intestinal inflammation.

Azathioprine. Azathioprine (AZA) is a potent cytotoxic drug occasionally used as adjunctive therapy in severe and refractory IBD. This drug is metabolized in the body to 6-mercaptopurine (6-MP), it's active metabolite, which functions to interfere with antigenic triggering of lymphocytes.Controversy exists concerning the efficacy and safety of AZA and 6-MP in treatment of human IBD. The suggested dosage is 2 mg/kg q24h in dogs and 0.3 mg/kg q48h in cats. A lag time of 3-5 weeks is expected before clinical improvement may be observed.

Miscellaneous Immunomodulating Drugs. A variety of other drugs (e.g., cyclophosphamide, cyclosporin, tylosin) are occasionally of value in treating refractory IBD. Cyclosporin acts primarily by inhibiting interleukin-2 release from helper T-cells, which prevents T-cell recruitment/amplification and inhibits the release of gamma-interferon. Preliminary observations in humans with IBD suggest that cyclosporine may act synergistically with corticosteroids and produce a more rapid response than classic immunosuppressants. The use of 5-lipoxygenase inhibitor drugs, such as Zileuton, may offer a new type of treatment for IBD.

Summary of Drug Therapy. Most drug therapies interrupt the amplification sequence of inflammation in IBD, explaining why maintenance therapy (via diet and/or drugs) is important. Anecdotal evidence supports the use of oral corticosteroids, sulfasalazine or similar drugs, and metronidazole in therapy of small animal IBD. The added therapeutic benefit of combination drug therapy in dogs and cats has not been established. However, combination drug therapy appears warranted in animals with severe disease, multiorgan involvement, and to reduce systemic effects of corticosteroids.

References

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2.  Wilcox B. Endoscopic biopsy interpretation in canine or feline enterocolitis. Semin Vet Med Surg 1992; 7:162-171.

3.  Jergens AE. Inflammatory bowel disease: Current perspectives. Vet Clin North Am Small Anim Pract 1999; 29:501-521.

4.  Jergens AE, Andreasen CB, Hagemoser WA, et al. Cytologic examination of exfoliative specimens obtained during endoscopy for diagnosis of gastrointestinal tract disease in dogs ans cats. J Am Vet Med Assoc 1998; 213:1755-1759.