Idiopathic inflammatory bowel disease (IBD) is a common cause of signs of chronic gastrointestinal disease in the dog.[1-5] Idiopathic IBD is differentiated from food responsive and antibiotic responsive causes of chronic enteropathy by lack of response to dietary or antibiotic therapies alone. The definitive cause of idiopathic IBD is unknown. However, current evidence suggests that affected individuals have an altered interaction between the mucosal immune system and intestinal microbes with aggressive host immune responses resulting in chronic intestinal inflammation.[5-10] Treatment for idiopathic IBD typically requires immunosuppressive drugs. Many dogs are treated with a combination of therapies.[3, 11]
Corticosteroids are commonly prescribed for the treatment of IBD in dogs.[1, 3, 9] In a retrospective study of 80 dogs with IBD, prednisolone was the most frequently prescribed medication having been administered alone or in combination to 61% of animals. Several studies have shown prednisone to be beneficial in the treatment of IBD in dogs.[3, 8, 11] In humans with IBD (Crohn's disease and ulcerative colitis), corticosteroids are also a mainstay of therapy.[3, 9, 13-16]
Unfortunately, systemic corticosteroids are often associated with adverse effects.[1, 9, 14-18] Commonly reported adverse effects of systemic corticosteroids in dogs include polyphagia, polyuria, polydipsia, restlessness, panting, and behavior changes. Long-term effects of corticosteroids can include obesity, vacuolar hepatopathy, muscle atrophy and weakness, ligament rupture, urinary tract infection, pyoderma, and development of diabetes mellitus. These adverse effects can negatively affect quality of life for animals even if clinical signs of IBD are controlled.[9, 17, 18]
Budesonide is a nonhalogenated glucocorticoid that was developed for use in human patients with IBD to limit systemic adverse effects. In humans, budesonide has a high ratio of topical to systemic activity because of high first pass metabolism in the liver and is therefore associated with fewer adverse effects than systemic corticosteroids.[9, 13, 14, 17, 19] Many studies in humans have shown budesonide to be as effective as prednisone for induction therapy of IBD.[9, 13, 15-17, 19-21]
Budesonide has been used in veterinary medicine to treat animals with IBD but no controlled studies have been published to evaluate efficacy of this treatment. A recent uncontrolled study evaluated the use of budesonide for induction therapy of IBD in a small population of dogs and found budesonide therapy to be effective with no adverse effects. Two previous studies have evaluated the effects of budesonide on the pituitary adrenocortical axis. Both studies showed pituitary adrenal axis suppression, but neither study showed other subjective or objective systemic effects.[9, 17]
The goal of this study was to compare the efficacy of budesonide therapy to conventional prednisone therapy for induction therapy of histopathologically confirmed IBD using IBDAI scores. Additionally, the incidence and severity of owner-observed corticosteroid related adverse effects were compared between treatment groups.
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- Materials and Methods
Budesonide has been used in dogs for treatment of allergic dermatitis (topically), chronic inflammatory airway disease (aerosol), and IBD, but there are no controlled studies evaluating the efficacy of oral budesonide therapy for IBD in dogs.[17, 18, 22, 23] This study demonstrates that budesonide is effective for the treatment of IBD and is generally well tolerated although the incidence of adverse effects was not lower for dogs receiving budesonide as compared to dogs receiving prednisone.
Budesonide is a very potent glucocorticoid, being 15 times more potent than prednisolone. It has a good distribution to mucosal surfaces because it is highly water soluble. It penetrates well into local tissue cells where it is converted into a highly lipophilic ester which is gradually hydrolyzed releasing active budesonide; this allows for a prolonged local anti-inflammatory effect. The active form of budesonide has high affinity for intracellular glucocorticoid receptors.[9, 18, 24, 25]
We used a pure powder-based formulation of budesonide in this study. Because dogs often have involvement of the upper portion of the gastrointestinal tract contributing to clinical signs of IBD, the sustained release product might not be as desirable in dogs as in humans. Additionally, the pure powder-based formulation is significantly more cost effective than the commercially available micronized formulation. The micronized formulation is only commercially available in 3 mg capsules3 so compounding is required for smaller veterinary patients regardless of which formulation is used.
The budesonide dosage used in this study was empirical. Various dosages for oral budesonide have been reported in the veterinary literature with the most commonly reported dosage being 3 mg/m2.[17, 18, 25] Other studies have used 9 mg/dog or 2 mg for dogs less than 18 kg and 3 mg for dogs greater than 18 kg. Because there have not been other controlled studies evaluating the efficacy of budesonide in treating inflammatory bowel disease, the most appropriate dosage in dogs is still unknown.
In humans, high dosages of budesonide are typically used for induction of remission in both adults and children with standard induction dosage being 9 mg/d.[9, 13, 19-21] In 1 study, a dosage of 3 mg/d in adult humans with Crohn's disease was not effective in inducing remission.[9, 19] This might suggest that current veterinary dosages are too low given that pharmacokinetics of budesonide appear similar between humans and dogs.[18, 23]
When calculated on a mg/kg body weight basis, the budesonide dosage in this study ranged between 0.11 and 0.27 mg/kg with a mean and median dosage of 0.16 mg/kg. Given that budesonide is 15 times as potent as prednisone, this budesonide dosage equates to a prednisone dosage of 2.4 mg/kg/d. Based on this data, dogs in the budesonide group received similar corticosteroid dosages as dogs in the prednisone group for the first 3 weeks of the study but approximately 2.4 times as much corticosteroid in the second half of the study. This is an important consideration in that budesonide appeared to be well tolerated at this dosage but was providing a relatively higher amount of corticosteroid. Unfortunately, the relatively higher corticosteroid dosage did not result in a significantly higher efficacy for budesonide than prednisone but it is possible that a larger trial or trial of longer duration might demonstrate a difference.
Previous studies evaluating oral budesonide in dogs have demonstrated suppression of the hypothalamic-pituitary-adrenal axis.[9, 17] Interestingly, none of the previous studies evaluating oral budesonide in dogs have demonstrated elevations in liver enzymes or glucocorticoid associated adverse effects whereas both were noted in our study.[9, 17, 18] The previous studies involved use of both the pure powder and the controlled release formulation and both normal healthy dogs and dogs with IBD so it is unlikely that the use of the powder formulation or use in a study population with inflammatory bowel disease contributed to these findings.[9, 17, 18] Additionally, in humans the absorption of budesonide was not shown to be affected by the severity of inflammatory bowel disease, so it would not seem likely that dogs with IBD would have more adverse effects that normal dogs. However, further comparisons may be warranted as more rapid absorption of budesonide was noted in a study of dogs with IBD than in a study in which budesonide was administered to healthy dogs. The 2 studies did use different dosages of budesonide.[18, 26]
It is possible that reporting of adverse effects by owners in this study population was biased since owners were aware that their pet was being treated with a steroid medication although blinded as to which steroid. It is interesting to note that many pet owners reported polydipsia and polyuria as an adverse effect but there was no change in urine specific gravity for patients in either group between baseline and 6 weeks.
Although the overall incidence of adverse effects was similar between the 2 treatment groups, it is important to note that severe adverse effects were only reported within the prednisone group with none of the dogs in the budesonide group reported as having severe adverse effects; however, this difference was not statistically significant. It may be that a larger population of dogs would be necessary to demonstrate a significant difference in adverse effect severity.
Two dogs were withdrawn from the prednisone group by their owners solely because of glucocorticoid-related adverse effects (polydipsia, polyuria, lethargy, and weakness, and in 1 dog reflex dyssynergia). A 3rd dog was withdrawn because of severe steroid adverse effects and hepatopathy. Unfortunately, the owners of this dog declined work-up for the hepatopathy but it did resolve with discontinuation of prednisone and administration of antibiotics, SAM-e, ursodiol, and vitamin E. This dog's IBD was later successfully treated with budesonide.
This study did have several limitations. Although the dogs had undergone food and antibiotic trial therapies before entry into the study, these trial therapies were not standardized. Many of the dogs had undergone trial therapies at the referring veterinarian before being referred for endoscopy, and medical records were often incomplete so it was difficult to assess the adequacy of the trials. However, all dogs were continued on their previous diet throughout the study and additional therapies besides the study drug were not allowed. Therefore, it is not likely that the lack of standardized trial therapies influenced the outcomes between treatment groups.
This study was limited to a duration of 6 weeks. A study of longer duration would be needed to assess the efficacy of budesonide as a maintenance treatment. Corticosteroid related adverse effects often become more apparent and less tolerable with a longer duration of treatment. After induction therapy for IBD with prednisone, gradual dosage tapering is generally recommended to limit adverse effects, but some animals relapse as the dosage is decreased. It is possible that budesonide may be more or less tolerated with long term use than prednisone.
The biggest limitation of this study is the small number of enrolled dogs, which limits the power of the statistical analysis. There were also a larger number of dogs with eosinophillic inflammation in the prednisone group, which could have affected response to the treatment, and the dogs in the prednisone group had higher white blood counts and neutrophil counts than dogs in the budesonide group, which could indicate that they were a sicker population of dogs. However, CIBDAI scores were similar at baseline between groups, and remission rates for both group are similar to those reported for previous studies involving treatment of idiopathic IBD.[2, 3, 8]
In conclusion, this study demonstrates that budesonide may be an effective alternative to prednisone for induction therapy of IBD but may not necessarily be associated with fewer glucocorticoid adverse effects. Larger trials would be recommended to further evaluate the use of budesonide for induction and maintenance therapy of IBD and to best determine the most appropriate dosage and formulation of budesonide for animals. Further evaluation of the incidence and severity of adverse effects through the use of more objective parameters would also be recommended.