Cause of Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) may be defined using clinical, histologic, immunologic, pathophysiologic, and genetic criteria.
Clinical criteria Inflammatory bowel disease has been defined clinically as a spectrum of gastrointestinal disorders of an unknown cause that is associated with chronic inflammation of the stomach, intestine, or colon. A clinical diagnosis of inflammatory bowel disease is considered only if affected animals have: (1) persistent (> 3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucosy 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 inflammatory bowel disease have been reported in both dogs and cats, although large bowel inflammatory bowel disease appears to be more prevalent in the dog.
Histologic criteria Inflammatory bowel disease has been defined histologically by the type of inflammatory infiltrate (neutrophilic, eosinophilic, lymphocytic, plasmacytic, granulomatous), associated mucosal pathology (villus atrophy, fusion, crypt collapse), distribution of the lesion (focal or generalized, superficial or deep), severity (mild, moderate, severe), mucosal thickness (mild, moderate, severe), and topography (gastric fundus, gastric antrum, duodenum, jejunum, ileum, cecum, ascending colon, descending colon). As with small intestinal inflammatory bowel disease, subjective interpretation of large intestinal inflammatory bowel disease lesions has made it difficult to compare tissue findings between pathologists. Subjectivity in histologic assessments has led to the development of several inflammatory bowel disease grading systems.
Immunologic criteria Inflammatory bowel disease (IBD) has been denned immunologically by the innate and adaptive response of the mucosa to gastrointestinal antigens. Although the precise immunologic events of canine and feline inflammatory bowel disease remain to be determined, a prevailing hypothesis for the development of inflammatory bowel disease is the loss of immunologic tolerance to the normal bacterial flora or food antigens, leading to abnormal T cell immune reactivity in the gut microenvironment. Genetically engineered animal models (e. g., IL-2, IL-10, T cell receptor knockouts) that develop inflammatory bowel disease involve alterations in T cell development, function, or both, suggesting that T cell populations are responsible for the homeostatic regulation of mucosal immune responses. Immunohistochemical studies of canine inflammatory bowel disease have demonstrated an increase in the T cell population of the lamina propria, including CD3+ cells and CD4+ cells, macrophages, neutrophils, and IgA-containing plasma cells. Many of the immunologic features of canine inflammatory bowel disease can be explained as an indirect consequence of mucosal T cell activation. Enterocytes are also likely involved in the immunopathogenesis of inflammatory bowel disease. Enterocytes are capable of behaving as antigen-presenting cells, and interleukins (e. g., IL-7, IL-15) produced by enterocytes during acute inflammation activate mucosal lymphocytes. Up-regulation of Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expression contribute to the innate immune response of the colon. Thus the pathogenesis and pathophysiology of inflammatory bowel disease appears to involve the activation of a subset of CD4+ T cells within the intestinal epithelium that overproduce inflammatory cytokines with concomitant loss of a subset of CD4+ T cells and their associated cytokines, which normally regulate the inflammatory response and protect the gut from injury. Enterocytes, behaving as antigen-presenting cells, contribute to the pathogenesis of this disease.
Pathophysiologic criteria Inflammatory bowel disease (IBD) may be defined patho-physiologically in terms of changes in transport, blood flow, and motility. The clinical signs of inflammatory bowel disease, whether small or large bowel, have long been attributed to the pathophysiology of malabsorption and hypersecretion, but experimental models of canine inflammatory bowel disease have instead related clinical signs to the emergence of abnormality motility patterns.
Genetic criteria Inflammatory bowel disease (IBD) may be defined by genetic criteria in several animal species. Crohn’s disease and ulcerative colitis are more common in certain human genotypes, and a mutation in the NOD2 gene (nucleotide-binding oligomerization domain2) has been found in a subgroup of patients with Crohn’s disease. Genetic influences have not yet been identified in canine or feline inflammatory bowel disease, but certain breeds (e. g., German shepherds, boxers) appear to be at increased risk for the dis-
Inflammatory Bowel Disease: Pathophysiology
The pathophysiology of large intestinal inflammatory bowel disease is explained by at least two interdependent mechanisms: (1) the mucosal immune response and (2) accompanying changes in motility.
Immune responses A generic inflammatory response involving cellular elements (B and T lymphocytes, plasma cells, macrophages, and dendritic cells), secretomotor neurons (e. g., vasoactive intestinal polypeptide, substance P, cholinergic neurons), cytokines and interleukins, and inflammatory mediators (e. g., leukotrienes, prostanoids, reactive oxygen metabolites, nitric oxide (NO], 5-HT, IFN-γ, TNF-α, platelet-activating factor) is typical of canine and feline inflammatory bowel disease. Many similarities exist between the inflammatory response of the small and large intestine, but recent immunologic studies suggest that inflammatory bowel disease of the canine small intestine is a mixed Th 1 and Th2 response, whereas inflammatory bowel disease of the canine colon may be more of a Th 1 type response with elaboration of IL-2, IL-12, INF-γ, and TNF-α. Other studies of canine colonic inflammatory bowel disease have demonstrated increased numbers of mucosal IgA- and IgG-containing cells, nitrate, CD3+ T cells, NO, and inducible nitric oxide synthase (iNOS) in the inflamed colonic mucosa (Table Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease). Increases in the CD3+ positive T cell population of the inflamed colon are consistent with changes reported in the inflamed canine intestine. Thus important similarities exist, as do differences between small and large bowel inflammatory bowel disease.
Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease
|Histolocic Findings||Immunologic Abnormalities|
|Lymphocytic-plasmacytic colitis||Increased nitric oxide and IgG in colonic lavage fluid|
|Lymphocytic-plasmacytic colitis||Increased expression of inducible nitric oxide synthase mRNA|
|Lymphocytic-plasmacytic colitis||Increases in T cells and B cells in lamina propria|
|Lymphocytic-plasmacytic colitis||Increases in CD3+ T cells and in lgA+ and lgC+ plasma cells|
|Lymphocytic-plasmacytic colitis||Increased IL-2 and TNF-α mRNA expression|
|Tissue / Cell Type||Motility Abnormalities|
|Colon||Loss of spontaneous phasic contractions|
|Decreased frequency of migrating motor complexes (MMCs)|
|Increased frequency of giant migrating contractions (CMCs)|
|Colonic circular smooth muscle cells||Decreased amplitude and duration of the slow wave plateau potential|
|Shift from the M3 to M2 muscarinic receptor subtype|
|Reduced calcium influx through L-type calcium channel|
|Reduced L-type calcium channel expression|
|Decreased open probability of KCa channels|
|Down-regulation of PKC α, β, ξ expression and activation|
|Reduced phospholipase A2 expression|
|Increased NF-κB expression and activation|
|Colonic enteric neurons||Sensitization to substance P during colonic inflammation|
|Colonic interstitial cells of Cajal||Reduced density of interstitial cells|
|Cytoplasmic vacuolation and damage to cellular processes|
IgG, Immunoglobulin G; IgA, immunoglobulin A; IL-2, interleukin-2; TNF-α, tumor necrosis factor alpha; PKC, protein kinase C; M, muscarinic; NF-κB, nuclear factor-icB; KCa, calcium-activated potassium channel.
Motility changes Experimental studies of canine large intestinal inflammatory bowel disease have shown that many of the clinical signs (diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and urgency of defecation) are related to motor abnormalities of the colon. Ethanol and acetic acid perfusion of the canine colon induces a large bowel form of inflammatory bowel disease syndrome indistinguishable from the natural condition. I Inflammation in this model suppresses the normal phasic contractions of the colon, including the migrating motility complex, and triggers the emergence of giant migrating contractions. The appearance of these giant migrating contractions in association with inflammation is a major factor in producing diarrhea, abdominal cramping, and urgency of defecation. Giant migrating contractions are powerful lumen-occluding contractions that rapidly propel pancreatic, biliary, and intestinal secretions in the fasting state (and undigested food in the fed state) to the colon to increase its osmotic load. Malabsorption results from direct injury to the epithelial cells and from ultrarapid propulsion of intestinal contents by giant migrating contractions so that sufficient mucosal contact time is not allowed for digestion and absorption to take place.
Inflammation impairs the regulation of the colonic motility patterns at several levels (i. e., enteric neurons, interstitial cells of Cajal, circular smooth muscle cells; summarized in Table Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease). Inflammation-induced changes in the amplitude and duration of the smooth muscle slow wave plateau potentials contribute to the suppression of rhythmic phasic contractions. These alterations likely have their origin in structural and functional damage to the interstitial cells of Cajal. At the same time that inflammation suppresses the rhythmic phasic contractions, inflammation sensitizes the colon to the stimulation of giant migrating contractions by the neurotransmitter substance P. These findings suggest that SP increases the frequency of giant migrating contractions during inflammation and that selective inhibition of giant migrating contractions during inflammation may minimize the symptoms of diarrhea, abdominal discomfort, and urgency of defecation associated with these contractions.
Inflammation suppresses the generation of tone and phasic contractions in the circular smooth muscle cells through multiple molecular mechanisms (see Table Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease). Inflammation shifts muscarinic receptor expression in circular smooth muscles from the M3 to the M2 subtype. This shift has the effect of reducing the overall contractility of the smooth muscle cell. Inflammation also impairs calcium influx” and down-regulates the expression of the L-type calcium channel, which may be important in suppressing phasic contractions and tone while concurrently stimulating giant migrating contractions in the inflamed colon. Changes in the open-state probability of the large conductance calcium-activated potassium channels (Kc) partially attenuate this effect. Inflammation also modifies the signal transduction pathways of circular smooth muscle cells. Phospholipase A2 and protein kinase C. (PKC) expression and activation are significantly altered by colonic inflammation, and this may partially account for the suppression of tone and phasic contractions. PKC α, β and ξ isoenzyme expression is down-regulated, PKC i and X isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. The L-type calcium channel, already reduced in its expression, is one of the molecular targets of PKC. Inflammation also activates the transcription factor NF-κB that further suppresses cell contractility.
Clinical Examination The clinical signs of large intestinal inflammatory bowel disease are those of a large bowel-type diarrhea (i. e., marked increased frequency, reduced fecal volume per defecation, blood pigments and mucous in feces, and tenesmus). Anorexia, weight loss, and vomiting are occasionally reported in animals with severe inflammatory bowel disease of the colon or concurrent inflammatory bowel disease of the stomach, small intestine, or both. Clinical signs usually wax and wane in their severity. A transient response to symptomatic therapy may occur during the initial stages of inflammatory bowel disease. As the condition progresses, diarrhea gradually increases in its frequency and intensity and may become continuous. In some cases the first bowel movement of the day may be normal or nearlv normal, whereas successive bowel movements are reduced in volume and progressively more urgent and painful. During severe episodes, mild fever, depression, and anorexia may occur.
There does not appear to be any sex predilection, but age may be a risk factor, with inflammatory bowel disease appearing more frequently in middle-aged animals (mean age approximately 6 years with a range of 6 months to 20 years). German shepherd and boxer dogs are at increased risk for inflammatory bowel disease, and pure-breed cats appear to be at greater risk. Cats more often have an upper gastrointestinal form of inflammatory bowel disease, whereas dogs are at risk for both small and large bowel inflammatory bowel disease.
Physical examination is unremarkable in most cases. Thickened bowel loops may be detected during abdominal palpation if the small bowel is concurrently involved. Digital examination of the anorectum may evoke pain or reveal irregular mucosa, and blood pigments and mucous may be evident on the examination glove.
Diagnosis of Inflammatory Bowel Disease
CBCs, serum chemistries, and urinalyses are often normal in mild cases of large bowel inflammatory bowel disease. Chronic cases may have one or more subtle abnormalities. One review of canine and feline inflammatory bowel disease reported several hematologic abnormalities including mild anemia, leukocytosis, neutrophilia with and without a left shift, eosinophilia, eosinopenia, lymphocytopenia, monocytosis, and basophilia. The same study reported several biochemical abnormalities including increased activities of serum alanine aminotransferase and alkaline phosphatase, hypoalbuminemia, hypoproteinemia, hyperamylasemia, hyperglobulinemia, hypokalemia, hypocholesterolemia, and hyperglvcemia. No consistent abnormality in the complete blood count or serum chemistry has been identified.
A scoring index for disease activity in canine inflammatory bowel disease was recently developed that relates severity of clinical signs to serum acute-phase protein (C-reactive protein (CRP], serum amyloid A) concentrations. The canine inflammatory bowel disease activity index (CIBDAI) assigns levels of severity to each of several gastroen-terologic signs (e. g., anorexia, vomiting, weight loss, diarrhea), and it appears to be a reliable index of mucosal inflammation in canine inflammatory bowel disease. Interestingly, both the activity index and serum concentrations of C-reactive protein improve with successful treatment, suggesting that serum C-reactive protein is suitable for the laboratory evaluation of therapy in canine inflammatory bowel disease. Other acute-phase proteins were less specific than C-reactive protein. One important caveat that should be emphasized is that altered CRP is not prima facie evidence of gastrointestinal inflammation. Concurrent infections or other inflammatory conditions could cause an acute-phase response, including C-reactive protein, in affected patients.
Treatment of Inflammatory Bowel Disease
Dietary therapy The precise immunologic mechanisms of canine and feline inflammatory bowel disease have not yet been determined, but a prevailing hypothesis for the development of inflammatory bowel disease 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 inflammatory bowel disease. Several nutritional strategies have been proposed including novel proteins, hydrolyzed diets, antioxidant diets, medium chain triglyceride supplementation, low-fat diets, modifications in the omega-6 (ω-6) and omega-3 (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 com 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 feeding selected protein diets. Further support for this concept comes from studies in which gastroenterologic or dermatologic clinical signs were significandy improved by the feeding of novel proteins.
Evidence is accruing that hydrolyzed diets may be useful in the nutritional management of canine inflammatory bowel disease. 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 after 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, an altered ratio of ω-6 to ω-3 polyunsatu-rated fatty acids). Additional studies will be required to ascertain the efficacy of this nutritional strategy in the management of inflammatory bowel disease.
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 irritable bowel syndrome 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.
Exercise Experimental inflammatory bowel disease (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 nonmigrating motor complexes during the fed state. Exercise also induces giant migrating contractions, defecation, and mass movement in both the fasted and fed states. The increased motor activity of the colon and extra giant migrating contractions that result from physical exercise may aid in normal colonic motor function.
Pharmacologic therapy Animals with mild to moderate forms of large bowel inflammatory bowel disease generally respond favorably to dietary modification alone, but pharmacologic therapy will be required with more severe forms of large bowel inflammatory bowel disease. Medical therapy includes anti-inflammatory (sulfasalazine and other 5-aminosalicylates, metronidazole, prednisone, budesonide), immunosuppressive (azathioprine, cyclosporine, chlorambucil), and motility-modifying (loperamide) drugs (Table Drug Index — Large Bowel Diarrhea).
Drug Index — Large Bowel Diarrhea
|Drug Classification And Examples||Dose||Indication|
|Albendazole||25 mg / kg PO SID x 2 days||Ciardia infection|
|Febantel||10 mg / kg PO SID x 3 days — adult dogs||Trichuris infection|
|15 mg / kg PO SID x 3 days — puppies||Trichuris infection|
|Fenbendazole||50 mg / kg PO SID x 3 days||Trichuris, Ancylostoma, Ciardia infection|
|Ivermectin||200 μg / kg SQ once||Larvicidal for Trichuris canis|
|Mebendazole||22 mg / kg PO SID x 3 days||Trichuris infection|
|Metronidazole||25 mg / kg PO BID x 5 days||Ciardia infection|
|Milbemycin oxime||0.5 mg / kg PO once per month||Trichuris preventive|
|Praziquantel||44 mg / kg PO once||Heterobilharzia|
|Pyrantel pamoate||5 mg / kg PO dog, 20 mg / kg cat||Ancylostoma, Toxocara|
|Ampicillin||22mg / kg PO IV TID||Salmonella, E. coli, Clostridium perfringens|
|Cefadroxil||22 mg / kg PO BID||Salmonella, E. coli|
|Chloramphenicol||44 mg / kg PO TID — dogs||Campylobacter|
|11 mg / kg PO BID — cats||Campylobacter|
|Enrofloxacin||5 mg / kg PO IM SQ BID||Salmonella, E. coli|
|Erythromycin||15-20 mg / kg PO TID||Campylobacter, C. perfringens|
|Metronidazole||10-20 mg / kg PO BID-TID||C. perfringens|
|Orbifloxacin||2.5-7.5 mg / kg PO SID||Salmonella, E. coli|
|Trimethoprim sulfonamide||30 mg / kg PO IM SQ BID||Salmonella|
|Tylosin||40-80 mg / kg PO SID||Inflammatory bowel disease, C. perfringens|
|Amphotericin B||2-3 mg / kg IV QOD administered to a cumulative dose of 24-27 mg / kg||Histoplasmosis, pythiosis, protothecosis|
|Itraconazole||5 mg / kg PO BID for several months||Histoplasmosis, pythiosis, protothecosis|
|Ketoconazole||10-15 mg / kg PO BID several months||Histoplasmosis, pythiosis. protothecosis|
|Budesonide||1 mg / cat or 1 mg / dog PO SID||Inflammatory bowel disease|
|Meselamine||10 mg / kg PO TID||IBD|
|Metronidazole||10-20 mg / kg PO BID-TID for 4-6 weeks||Inflammatory bowel disease|
|Olsalazine||5-10 mg / kg PO TID for 4-6 weeks||IBD|
|Prednisolone||4.0-6.0 mg / kg PO SID for 4-6 weeks||Feline eosinophilic colitis|
|Prednisone||1.0-2.0 mg / kg PO SID for 4-6 weeks||IBD|
|Sulfasalazine||10-25 mg / kg PO TID for 4-6 weeks — dogs||inflammatory bowel disease, ulcerative colitis|
|5-12.5 mg / kg PO TID for 2-4 weeks — cats||Refractory IBD|
|Azathioprine||2 mg / kg PO SID for 4-6 weeks — dogs||Inflammatory bowel disease|
|Chlorambucil||2 mg / m PO every other day for 4-6 weeks||IBD|
|Cyclosporine||3-7 mgAg PO BID for 4-6 weeks||IBD|
|Loperamide||0.08 mgAg PO TID-QID||IBD, IBS|
|Propantheline||0.25 mg / kg PO BID-TID||Irritable bowel syndrome|
|Aminopentamide||0.01-0.03 mg / kg PO BID-TID||IBS|
|Enterococcus faecium (SF68)||5 x 10 colony-forming units / day||IBD|
|Lactobacillus rhamnosus GC||1 x 10 to 5 x 10 colony-forming units / day||Inflammatory bowel disease|
PO, per os; SID, once per day; IV, intravenous; TID, three times per day; BID, twice per day; QOD, every other day.
Sulfasalazine Sulfasalazine is a highly effective prostaglandin synthetase inhibitor that has proven efficacy in the therapy of large bowel inflammatory bowel disease in the dog. Sulfasalazine is a compound molecule of 5-aminosalicylate (meselamine) and sulfapyridine linked in an azochemical bond. After 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 cyclooxygenase and the inflammatory cascade. Sulfasalazine has been recommended for the treatment of canine large bowel inflammatory bowel disease at doses of 10 to 25 mg / kg orally, three times a day for 4 to 6 weeks. With resolution of clinical signs, sulfasalazine doses are gradually decreased by 25% 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 to 12.5 mg / kg orally, three times a day). Sulfasalazine use 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 use.
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 inflammatory bowel disease. Olsalazine has been used at a dose of 5 to 10 mg / kg orally, three times a day 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 to 20 mg / kg orally, twice a day to three times a day) has been used in the treatment of mild to moderate cases of large bowel inflammatory bowel disease in both dogs and cats. Metronidazole has been used either as a single agent or in conjunction with 5-aminosalicylates or glucocorti-coids. Metronidazole is believed to have several beneficial properties, including antibacterial, antiprotozoal, 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 to 2 mg / kg orally, once a day) may be used to treat inflammatory bowel disease in dogs that have failed to respond to dietary management, sulfasalazine, or metronidazole, and as adjunctive therapy to dietary modification in feline inflammatory bowel disease. Prednisone or prednisolone are used most frequendy, because 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 to 4 weeks depending upon the severity of the clinical signs. Higher doses of prednisone (e. g., 2 to 4 mg / kg orally, once a day) may be needed to control severe forms of eosinophilic colitis or hypereosinophilic syndrome in cats.
Combination therapy with sulfasalazine, metronidazole, or azathioprine may reduce the overall dose of prednisone needed to achieve remission of clinical signs. As with sulfasalazine, the dose of glucocorticoid may be reduced by 25% at 1- to 2-week intervals while (it is hoped) 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 inflammatory bowel disease in humans (and animals). Little clinical evidence supports of the use of this medication in canine or feline inflammatory bowel disease, 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, after DNA incorporation, inhibits lymphocyte activation and proliferation. It is rarely effective as a single agent and should instead be used as adjunctive therapy with glucocorticoids. Azathioprine may have a significant steroid-sparing effect in inflammatory bowel disease. Doses of 2 mg / kg orally, every 24 hours in dogs and 0.3 mg / kg orally every 48 hours in cats have been used with some success in inflammatory bowel disease. 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. Evidence-based medicine studies will be needed to establish efficacy, but anecdotal experience would suggest that cyclosporine (3 to 7 mg / kg orally, twice a day) may be useful in some of the more difficult or refractory cases of inflammatory bowel disease.
Chlorambucil Chlorambucil (2 mg / m orally, every other day) has been used in place of azathioprine in some difficult or refractory cases of feline inflammatory bowel disease.
Motility-modifying drugs The mixed μ, δ-opioid agonist, loperamide, stimulates colonic fluid and electrolyte absorption while inhibiting-colonic propulsive motility. Loperamide (0.08 mg / kg orally, three times a day to four times a day) may be beneficial in the treatment of difficult or refractory cases of large bowel-type inflammatory bowel disease.
Probiotic therapy Probiotics (see Table Drug Index — Large Bowel Diarrhea) 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 rhamnous GG and Lactobacillus acidophilus (strain DSM13241) have 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 11+) 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 Campybbacter 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.
Behavioral modification Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) 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, relocation, 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.
Prognosis of Inflammatory Bowel Disease
Most reports indicate that the short-term prognosis for control of inflammatory bowel disease is good to excellent. After completion of drug therapy, many animals are able to maintain remission of signs with dietary management alone. Treatment failures are uncommon and are usually due to (1) incorrect diagnosis (it is especially important to rule out alimentary lymphosarcoma), (2) presence of severe disease such as histiocytic ulcerative colitis and protein-losing enteropathy or irreversible mucosa lesions such as fibrosis, (3) poor client compliance with appropriate drug and dietary recommendations, (4) use of inappropriate drugs or nutritional therapy, and (5) presence of concurrent disease such as small intestinal bacterial overgrowth or hepatobiliary disease. The prognosis for cure of inflammatory bowel disease is poor, and relapses should be anticipated.