Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki
Finland
Introduction
Based on reports of the WSAVA gastrointestinal standardization group, inflammatory bowel disease (IBD) is defined as an idiopathic chronic inflammation of the stomach, small intestine and/or large intestine. The clinical diagnosis of IBD is only justified when following four criteria can be applied:
Persistent gastrointestinal signs (>3 weeks in duration) such as anorexia, weight loss, diarrhea, hematochezia, mucoid feces.
Failure to respond to symptomatic therapies such as anti-parasitics, antibiotics, gastrointestinal protectants.
Failure to document other causes of gastroenterocolitis by thorough diagnostic work up (e.g., infectious or neoplastic primary gastrointestinal diseases, primary intestinal lymphangiectasia, and hepatic, pancreatic, renal or endocrine disorders with secondary involvement of the gastrointestinal tract).
Histologic diagnosis of benign intestinal inflammation.1
This definition differentiates IBD from antibiotic or tylosin responsive diarrhea (ARD/TRD).2 However, ARD is suggested to lead to IBD due to prolonged bacterial stimulation of the intestinal immune system.3
Canine IBD is histologically differentiated. Lymphoplasmacytic enteritis (LPE) is the most common form followed by eosinophilic (gastritis)-enteritis-(colitis) (EGE). Rare IBD forms include immunoproliferative enteropathy of basenjis and granulomatous (regional) enteritis.3
Histiocytic ulcerative colitis of boxers is not an idiopathic IBD anymore. It has been discovered that adherent and invasive E. coli play a major role in the pathogenesis of the disease. Giving affected patients enrofloxacin (5 mg/kg/day for 6-8 weeks) leads to a long term treatment success. However, the pathophysiology of histiocytic boxer-colitis gives, similar to ARD, evidence that IBD may be the result of an abnormally exuberant immune response to intestinal microbiota in genetically susceptible individuals.4
It is unlikely that idiopathic IBD is a single condition. It rather summarizes different inflammatory gastrointestinal disorders with poorly understood etiology and pathogenesis. It is to be expected that the increasing use of more sophisticated diagnostic methods will reveal a spectrum of disorders that are currently still included in the diagnosis 'idiopathic IBD'. Until then the treatment of IBD is based on the assessment of the disease severity in an affected animal.5-9
Assessment of Disease Severity
The assessment of disease severity can be used for treatment decisions based on a differentiation between (a) uncomplicated IBD and (b) complicated IBD with systemic effects. Different scoring systems have been developed to assess the severity of IBD. The most commonly used clinical scoring is the canine IBD activity index (CIBDAI).5-9 The CIBDAI is the summation of the score of 6 different clinical signs including attitude/activity, appetite, vomiting, stool consistency, stool frequency, and weight loss.5 Recently a canine chronic enteropathy clinical activity index (CCECAI) has been introduced adding the scoring of serum-albumin concentration, peripheral edema and ascites, and severity of pruritus to the CIBDAI. The CCECAI allows a better estimation of the possible therapeutic success. High scores are associated with a high risk for negative outcome.9 Another laboratory parameter closely linked to the outcome is serum cobalamine. Low cobalamine concentrations correlate with a poorer prognosis.9,10
Interestingly, there are contradictory results concerning endoscopic scores. Some authors documented a correlation between disease severity and therapeutic outcome8 and others not.9 Histologic scoring systems have failed so far to predict the therapeutic outcome.6-9 However, since per definition the diagnosis of idiopathic IBD is based on the histologic evidence of benign intestinal inflammation, endoscopy or laparotomy with intestinal biopsy remains to be strongly recommended.
Treatment of Uncomplicated Canine IBD
Canine idiopathic IBD can be regarded as uncomplicated when the clinical signs are solely associated to the gastrointestinal tract and the patient does not show clinical or laboratory evidence of systemic complications. According to the WSAVA definition, antiparasites, GI-protectants and antibiotics have failed to resolve the signs. Furthermore, endoscopy has been performed that revealed benign inflammation of any degree from mild to severe.1 It has been documented that clinical CIBDAI score and histological score do not correlate in patients with IBD and that patients with food responsive (uncomplicated) enteropathy cannot be histologically differentiated from dogs with corticoid responsive (complicated) IBD.6,9
Concerning the treatment, uncomplicated IBD responds in most cases favorably to dietary management. Since dietary components especially proteins are suspected to play a role in the pathophysiology of chronic inflammation, it has always been recommended that diet change is a fundamental step in managing IBD. For small intestinal IBD, highly digestible, gluten-free diets with a novel protein sources or hypoallergenic, hydrolyzed diets have shown to be of benefit. In most cases with uncomplicated IBD, diet change can be the only necessary treatment regardless of the initial clinical score.6, 9-11 For IBD colitis, the use of moderately fermentable fiber (psyllium, beet pulp) has been shown to improve clinical signs due to binding of colonic irritants and normalization of colonic peristalsis. Additionally, the fermentable fibers support as 'prebiotics' the development of beneficial intestinal microbiota. The resulting increased bacteriological production of short chain fatty acids is beneficial for colonic function. The use of probiotics for the treatment of canine IBD is under research. There is some evidence that they are beneficial in mild IBD.11
Dietary management alone is seen as successful when the initial clinical signs clearly improve or resolve within 10-14 days.9,10 The diet should be given for 14 weeks.9 In most cases, the gradual reintroduction of previous food sources will not cause a relapse except in patients that suffer from food intolerance or allergy. They will need continuation of the newly introduced diet.
Patients that do not respond to diet change alone but show mild to moderate clinical signs without systemic effects can receive long term oral antibiotic treatment, if not done already before the endoscopic examination. The drugs of choice are tylosin (15 mg/kg BID) and metronidazole (5-10 mg/kg BID) for about 4-6 weeks. Tylosin is thought to be immunomodulatory by supporting the development of enterococci with probiotic effects.11 Metronidazole affects anaerobic bacteria and protozoa, and is supposed to have immunomodulatory effects by inhibiting cell mediated immunity and leukocyte--endothelial cell adhesion.12
In patients with IBD colitis, 5-aminosalicylic acid (e.g., sulfasalazine: oral induction: 20-40 mg/kg, BID; maintenance: 10-15 mg/kg BID) has shown to be highly effective probably due to a decrease of pro-inflammatory leukotriene production in the colonic mucosa.12 However, dogs should be monitored for tear secretion at regular intervals since the drug can induce an irreversible keratoconjunctivitis sicca as a reported negative side effect.13,14
Patients that have failed to respond to dietary change with added antibiotic and immunomodulatory treatment should be considered to suffer from complicated IBD and undergo immunosuppressive treatment.
Treatment of Complicated Canine IBD
Complicated IBD has to be suspected when patients do not respond to treatment for uncomplicated IBD or when clinical signs and/or laboratory results show evidence of systemic disease. Clinical signs considered of negative prognostic value are pruritus, edema, and ascites/hydrothorax especially in connection with panhypoproteinemia. Low serum albumin values can occur rather due to enteric protein loss than malabsorption, when liver failure and protein loosing nephropathy have been excluded. Low serum cobalamine has also been reported to be a negative prognostic factor. 9,10
Patients that show systemic effects of IBD need a more aggressive therapeutic approach adding immunomodulatory/immunosuppressive drugs to the dietary change already at an early stage of the medical management. Induction and maintenance regimes are mainly influenced by rapidity of clinical remission, severity of side effects, compliance, and drug costs.2,10
Prednisone/prednisolone has been used as single agent or in combination with other medications to successfully control clinical signs of IBD. Even when controlled clinical studies are missing there is enough empirical evidence to justify the use of glucocorticoids for the treatment of IBD.15 It is generally recommended to start the treatment with an immunosuppressive dosage (2 mg/kg per day) until clinical improvement. This is followed by gradual reduction of the corticoid dose over several weeks to months. To avoid long term side effects on the pituitary-adrenal axis, maintenance treatment should be given every other day. Some patients need lifelong glucocorticoid treatment. Others can be gradually taken off the medication and stay clear of clinical signs without further immunosuppression. There is no other predictive parameter than repeated clinical review of the patients (e.g., every 2-6 weeks) during the induction phase and the phase of gradual dose reduction for maintenance.
In case of severe side effects of glucocorticoids (polyuria, polydipsia, apathy, depression), reduction of prednisolone can be achieved by combining the glucocorticoid with metronidazole or azathioprine (2 mg/kg per day until remission, than reduction to 1 mg/kg every other day). It is necessary to check patients receiving azathioprine at least every 2 weeks for the development of an agranulocytosis as a reversible negative side effect. The use of budesonide, a poorly absorbed glucocorticoid with reduced systemic toxicity remains anecdotic or theoretical due to its high costs.
In case of relapse during glucocorticoid reduction, it is advised to start again with the immunosuppressive dose and taper down until reaching the dose that is shown to be still effective.
Dogs with complicated IBD, hypoproteinemia and severe histological changes should immediately receive a combined treatment of prednisolone and azathioprine because they do have the worst prognosis for a positive treatment response.16 If the patient does not respond to the immunosuppressive therapy any more, a rescue protocol for steroid-refractory IBD with cyclosporine (5 mg/kg per day, 10 weeks) has been reported to be of benefit in some cases.17
Cobalamin supplementation (250-1000 µg/dog, weekly for 4 weeks, thereafter monthly) has been recommended for dogs with hypocobalaminemia.18 However, studies are missing that prove a positive effect on the outcome.15
References
1. Washabau RJ. Proceedings, 17th ECVIM-CA Congress, Budapest 2007: 162-4
2. Westermarck, et al. J Vet Intern Med. 2005;19(2):177-86
3. Hall EJ. Proceedings of the 22nd ACVIM--Forum, Minneapolis, 2004
4. Mansfield CJ. Proceedings of the 32nd WSAVA World Congress, Sydney, 2007
5. Jergens AE, et al. J Vet Intern Med 2003; 17 (3): 291-7
6. Allenspach K, et al. Am J Vet Res 2006; 67 (3): 479-83
7. Munster M, et al. Berl Munch Tierarztl Wochenschr 2006; 119(11-12): 493-505
8. Garcia-Sancho M, et al. J Vet Intern Med 2007; 21:11-7
9. Allenspach K, et al. J Vet Intern Med 2007; 21:700-8
10. Lenhard T. Doctoral thesis. Justus-Liebig-University, Giessen, Germany, 2007
11. Harmoinen, et al. Proceedings of the 31st WSAVA World Congress, Prague, 2006
12. Webster CRL. Quick look: Clinical Pharmacology, Teton New Media, 2001: 105
13. Sansom J, et al. Vet Rec 1985;116:391-3.
14. Barnett KC, Joseph EC. Hum Toxicol 1987, 6:377-83
15. Jergens AE. Proceedings, 17th ECVIM-CA Congress, Budapest 2007: 165-7
16. Spillmann T, Hewiger-Trautwein M. Waltham Focus 2005, 15: 20-6
17. Allenspach K, et al. J Vet Intern Med 2006; 20:239-44
18. Ruaux CG. Proceedings of the 20th ACVIM Forum, 2002