8 Aug 2016
Kit Sturgess discusses some of the causes of this intestinal disease and how using probiotics and dietary therapy are among the best available approaches to treatment.
Kit Sturgess
Job Title
Figure 3. Amber, a nine-year-old neutered female Welsh springer spaniel, with a chronic history of weight loss, diarrhoea and hypoalbuminaemia.
Inflammatory bowel disease (IBD) is not a diagnosis, but a description of a histopathological picture with a variety of different forms that have a multifactorial aetiology. Even the name may be misleading in terms of whether inflammation has a central role in the disease process.
Unravelling the picture and understanding the relative contribution of genetics, environment, trigger factors and disease in an individual case is an almost impossible task with current technologies. Research into the aetiology of IBD in man has been extensive, but no unifying theory has emerged.
In a few cases, such as histiocytic ulcerative colitis in a boxer caused by enteroinvasive Escherichia coli, underlying aetiology in dogs and cats is similarly elusive. Like man, clear genetic and environmental factors exist that affect the likelihood of a particular cat or dog developing IBD.
The microbiota of the gut is also likely to have a key role in the development and/or persistence of IBD, with some individuals responding well to faecal matter transplantation from a healthy individual. This points to the fact IBD is likely the end result of a variety of initiating factors, culminating in the presence of increased numbers of inflammatory cells in the lamina propria of the gastrointestinal tract (GIT).
This “inflammatory infiltrate” is often accompanied by a variety of other histologic changes, including ulceration, villous blunting, crypt necrosis, lacteal dilation and protein exudation (Figure 1). The inflammatory infiltrate can be variable typically lymphoplasmacytic, but, in some individuals, neutrophilic and eosinophilic components exist.
Whether these represent differing aetiologies is uncertain – suggestions have been made that larger numbers of eosinophils tend to point towards dietary hypersensitivity, whereas neutrophils reflect a process driven by the intestinal microflora. This multiple aetiology, leading to a stereotypic intestinal histological appearance, has led to a number of clinicians using the term “chronic inflammatory enteropathy”.
Two further complications in diagnosis and treatment that need to be considered, particularly in cats, are:
Despite IBD being the most common cause of chronic GIT disease in cats and dogs, relatively few studies have been published looking at best therapy or how to best benchmark response to therapy.
Resolution of clinical signs is most widely used, either individually or combined with other data to produce a canine IBD activity index or feline chronic enteropathy activity index.
This is due partly because repeat diagnostic testing is not required and repeat biopsy often fails to demonstrate a significant change in the number of inflammatory cells in the lamina propria, despite demonstrable improvement in clinical signs. This finding suggests, in many cases, the drivers are ongoing and, therefore, in established cases, it is important to make sure the owner is aware his or her pet’s disease is being managed rather than cured.
It also tends to reflect the fact the intestinal tract has a massive reserve capacity, in that significant compromise of function is required before clinical signs become apparent and therapy is only required to drive a small improvement in function for the clinical signs to resolve and the patient appear “better”.
This also likely explains the waxing and waning nature of IBD clinical signs and that, for many individuals, a variety of dietary and drug therapies result in unsustained improvement. It would also suggest the need for ongoing therapy, even when signs have resolved, to re-establish as much GIT reserve as possible so the inevitable minor changes in disease status do not result in overt clinical signs (Figures 2 and 3).
A suggested approach to a known/strongly suspected IBD case would be:
Prior to any treatment for IBD, full faecal analysis should have been performed to exclude infectious causes, vitamin B12 and folate levels assessed, and trypsin-like immunoreactivity measured if signs would be consistent with exocrine pancreatic insufficiency (Figure 4).
Management options can be broadly grouped into:
Antacids, mucosal protectants, prokinetics and antiemetics will often result in significant improvement in a patient’s clinical signs and are useful adjunctive treatments. They will not, however, lead to sustained improvement.
Because of the underlying dysbiosis, the use of antibacterial agents has been advocated. Their true benefit is unknown, as the most commonly used – metronidazole and doxycycline/oxytetracycline – are also thought to have immunomodulatory activity as well. Other antibacterial agents should not be used, as there is a significant risk their negative effects on disrupting the intestinal flora outweigh any positive effects they might have on managing the patient’s enteric dysbiosis.
Undoubtedly, there is also a group of dogs that present with chronic GIT signs with little or no evidence of inflammation on biopsy, but are “antibacterial-responsive”. Other antibacterial agents also worth consideration include tylosin and sulfasalazine.
Low vitamin B12 reduces the effectiveness of other treatments in managing clinical signs (Simpson et al, 2001). Traditionally for dogs and cats with low serum B12, injectable therapy has been given at 20µg/kg SC and has proven effective. A typical regime would be weekly for four doses, followed by fortnightly for four doses, then monthly for four doses before stopping. Periodic measurement of B12 is required. This regime also assumes GI absorption is improved with other treatments that allow levels to be maintained by absorption of dietary vitamin B12.
Using oral supplementation has been suggested, although the injectable route is still recommended. Suggested dose rates are 250µg/cat every 24 hours and 250µg/dog to 1,500µg/dog every 24 hours depending on size, such as 250µg for dogs below 5kg, 500µg for 15kg dogs, 1,000µg for 30kg dogs and 1,500µg for dogs more than 50kg.
Dysbiosis is seen as an important part of IBD. The enteric microbiome may have an important role in susceptibility to developing IBD.
In established disease, alterations in bacterial numbers and species will likely affect clinical signs, effectiveness and durability of response to treatment. Returning the microbiome to a “healthy” balance may serve as valuable therapeutic option. Probiotics, both alive and dead, have been shown to alter the intestinal and systemic cytokine environment having a beneficial effect on the immunoregulatory environment.
Clinically, probiotics may also result in symptomatic relief, with a study (Rossi et al, 2014) suggesting similar levels of clinical response in a small group of patients fed probiotics compared to a group treated with metronidazole and prednisolone. As yet, it is unclear on the length of treatment likely to be required to achieve these effects, but evidence would suggest weeks (Rossi et al, 2014). It is also important to remember a number of probiotic supplements also contain clays, which can affect absorption of other drugs, so timing of dosing needs to be considered.
Week 1 to 3: 1mg/kg PO q12hr with dietary therapy.
Week 4 to 6: 1mg/kg PO q24hr with dietary therapy.
Week 7 to 9: 0.5mg/kg PO q24hr with dietary therapy.
Week 10 to 12: 0.5mg/kg PO q48hr with dietary therapy.
Week 13 onwards: dietary therapy alone.
For most patients, prednisolone is an appropriate first choice medication initially at 1mg/kg PO every 12 hours. At this dose, side effects are common, but should reduce as the dose rate is lowered.
Starting therapy at doses higher than 2mg/kg/day is of uncertain value and side effects usually outweigh any likely benefits; in these cases, a better approach is to introduce a second immunosuppressive agent.
Prednisolone can, however, cause excessive catabolism in some already cachexic patients, leading to significant muscle loss. A dose rate in mg/kg is also inappropriate for larger dogs, and for dogs weighing more than 30kg, the author will use 20kg/m2 to 25kg/m2 body surface area every 12 hours. For some patients/owners, the side effects of prednisolone treatment are unacceptable and steroid sparing therapies are required. A reducing dose schedule is initiated (Panel 1).
Alternatively, a glucocorticoid with a strong first pass metabolism that primarily works locally in the GIT, such as budesonide, can be considered and has been shown to be as effective as prednisolone (Dye et al, 2013). The dose rate for budesonide is poorly established, with suggested dose rates ranging from 0.05mg/kg/day to 1mg/kg/day in dogs (not exceeding 3mg/dog every 8 hours) and up to 1mg every 8 hours in cats.
Budesonide is relatively expensive and only available in 3mg capsules containing enteric-coated beads, meaning recompounding is necessary and accurate dosing problematic. The effect or absorption by placing part of a capsule into a new gelatine capsule is unknown, but clinically appears efficacious. The author has had good success with using an initial dose rate of 3mg/dog every 12 hours in patients weighing 25kg to 30kg and pro rata for smaller individuals.
In cats, an initial dose rate of 1.5mg/cat every 24 hours has been successful. At higher dose rates, despite its pharmacology, some glucocorticoid side effects will be seen.
No published studies exist comparing the efficacy of different adjunctive immunosuppressive therapies, with limited studies on individual agents. The author would use ciclosporin as a first choice as it holds a veterinary licence in cats and dogs and published evidence of its efficacy in dogs (Allenspach et al, 2006). Suggested dose rates of adjunctive immunosuppressive agents are given in Table 1.
Although rarely a primary driver, exposure of dietary proteins in the environment of an inflamed GIT can evoke sensitivity and exaggerated host responses. By restricting antigen exposure (such as dietary proteins), drivers that perpetuate inflammation are reduced.
Further diets that are highly digestible and have high biological value will help ameliorate impaired nutrient absorption and reduce the amount of undigested nutrients passing through the GIT that can potentially lead to bacterial overgrowth. Other dietary management may also be required where there is a significant protein-losing enteropathy associated with moderate-to-severe mucosal inflammation.
The benefits of dietary therapy alone, or in combination with drug therapy, in the clinical management of canine and feline IBD are well documented. Several studies involving both controlled and elimination diets alone, or in combination with drug therapy, have suggested response in about three-quarters of cats (105) and two-thirds of dogs (253).
The optimal diet, in terms of one novel protein source versus another, or the advantage in feeding an intact protein elimination diet versus a hydrolysed protein elimination diet, has not been demonstrated. Characteristics of an ideal diet for IBD include the presence of a novel intact (such as white fish, duck and venison) or hydrolysed protein source, highly digestible carbohydrate (potato, sweet potato and rice), gluten-free, low in lactose and fat, nutritionally balanced and high palatability.
Modifying the dietary n3:n6 fatty acid ratio may also modulate inflammatory responses by reducing production of proinflammatory metabolites. Supplementation with parenteral cobalamin is necessary if serum concentrations are low.
A major challenge in managing IBD is how to decide treatment reduction is appropriate to minimise side effects and client costs, and if a reduction is contemplated by how much and how long is it appropriate to wait before another treatment change is made.
No objective criteria have been established that allow easy recognition that underlying disease activity is increasing/decreasing, allowing changes in treatment to be evidence based. Acute phase proteins, such as C-reactive protein (in dogs) and haptoglobin or α1-acid glycoprotein (in cats), may help, but decision-making parameters are not established.
The author tends to use a three-week rule; for example, make a single change in therapy or introduce a dietary component no more than once every three weeks, so if there is a change in clinical signs, it is likely to reflect the most recent change. Clinically, this approach appears to be reasonably robust in that changes in disease activity are slow in addition; any dietary hypersensitivity is type IV (delayed), so if a dietary component to which the patient is sensitive is reintroduced, it may take several weeks for clinical signs to become apparent.
IBD remains a challenging condition to characterise, as our understanding of its aetiology remains incomplete in the absence of an identified cause.
Management of IBD requires an individualised, usually multimodal, plan, with the likelihood of significant long-term client support being necessary. Adjunctive therapy beyond immunosuppression can have a profound effect on improving patient well-being, managing clinical signs and reducing drug use and side effects, and should be considered as part of the management of cats and dogs with IBD.
This does not mean all patients will be on lifelong medication, as many can be successfully managed with diet alone. In a significant number of patients, immune regulation and tolerance seems to re-establish and their diet can be gradually returned to a routine maintenance diet.
