Inflammatory Bowel Disease and Intestinal Lymphoma in Cats
Todd R. Tams, DVM, Dipl. ACVIM
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) currently is recognized as a common and important medical problem in cats. Three general types of clinical presentations have been identified in cats with idiopathic IBD: (1) a clinical course characterized primarily by vomiting, (2) a clinical course characterized primarily by diarrhea, and (3) a clinical course that includes both vomiting and diarrhea as primary signs. Associated clinical signs can include change in appetite (anorexia, inappetence, or ravenousness), weight loss, and lethargy. In some cats, the clinical signs are cyclic; they seem to flare up and then abate in a predictable pattern.
Vomiting, one of the most frequent clinical signs of IBD in cats, is most often recognized as an intermittent occurrence for weeks, months, or years Affected cats are frequently misdiagnosed as having hairballs as the primary problem. As the disorder progresses, an increased frequency of vomiting often leads the owner to seek veterinary attention. In addition to vomiting, diarrhea is a common sign observed in feline IBD and most likely is due to derangement of normal mechanisms of absorption and motility caused by mucosal inflammation. In most cases, diarrhea is intermittent early in the course of the disorder, and there may be a transient response (weeks to several months) to dietary manipulation or any of a variety of medications. Later, the diarrhea becomes persistent and usually responds only to specific treatment, which is determined after a definitive diagnosis is made. Signs of small bowel diarrhea predominate, but signs of large bowel diarrhea may be evident as well if there is generalized intestinal tract involvement.
Appetite changes in cats with idiopathic IBD vary from decreased appetite to complete anorexia to ravenousness. Inappetence seems to occur more commonly in cats that have vomiting as the primary clinical sign and usually occurs during exacerbation of clinical signs, and vomiting or diarrhea is not observed until later or not at all. The three leading differential diagnoses for a cat with a ravenous appetite, diarrhea, and weight loss are IBD, hyperthyroidism, and exocrine pancreatic insufficiency (uncommon).
A definitive diagnosis of IBD can be made based only on intestinal biopsy. Further tests are run to evaluate the overall health status of the patient and to rule out other disorders. Recommended baseline tests include a complete blood count, biochemical profile, urinalysis, fecal exams for parasites, serum thyroxine test, and a feline leukemia virus test. Testing for feline immunodeficiency virus should be considered in cats with chronic wasting disease.
It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Corticosteroids are the cornerstone of treatment for idiopathic inflammatory bowel disorders. Mild to moderate cases often respond to prednisone or prednisolone at a starting dose of 0.5 to 1 mg/lb divided twice daily for two to four weeks followed by a gradual decline in 50% increments at two week intervals. Cats with inflammatory changes graded as mild usually respond quite well to the lower dose and alternate day or every third day treatment can often be achieved by two to three months. Occasionally treatment can be discontinued altogether by three to six months.
If biopsies reveal disease that is moderate to severe a prednisolone dose of 1 to 2 mg/lb divided twice daily is used for the first 2 to 8 weeks or until clinical signs resolve. I do prefer to use prednisolone over prednisone in cats with inflammatory disorders of a moderate to severe nature, as there may be improved bioavailability in some cats with prednisolone. This dose of corticosteroid is usually well tolerated in cats. In these cases a dose of 0.5 to 1 mg/lb per day may be necessary long term (months to years) to maintain clinical remission. Use of combination drug therapy may also be required at the outset to control clinical signs and prevent progression of the disease. Cats with hypoproteinemia and histologic changes graded as severe often respond quite well when an aggressive therapeutic course is undertaken.
When combination therapy is indicated metronidazole (Flagyl) is usually the first choice to be used in conjunction with prednisone. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated immune responses, and anaerobic antibacterial activity. A dosage of 5 to 10 mg/lb two times daily is used for IBD. Ideally, at least several months of metronidazole therapy is given once it is started. In some cats with severe disease long term consecutive use or one to two month cycles of treatment may be required. Side effects to metronidazole at this low dose are uncommon in cats. Occasionally nausea or vomiting may be seen.
Methylprednisolone acetate (Depo-Medrol, Upjohn) can be used as sole treatment for cats with mild to moderate IBD or as adjunctive therapy when oral prednisone and/or metronidazole are used as the primary treatment and flare-ups of clinical signs occur. Consistent control of clinical signs in cats with moderate to severe IBD is more difficult to maintain when methylprednisolone acetate is used alone, however. It is recommended that sole use of methylprednisolone acetate be reserved for situations in which the owner is unable to consistently administer tablet or liquid (Prednidrops) prednisone preparations. Initially 20 mg is given subcutaneously or intramuscularly and is repeated at 2-week intervals for 2 to 3 doses. Injections are then given every 2 to 4 weeks or as needed for control.
If remission cannot be maintained with use of corticosteroids and metronidazole then azathioprine (Imuran) should be used. Azathioprine is an immunosuppressive drug with a nonspecific effect. Replication of rapidly dividing cells, including immunoblasts, is inhibited. Azathioprine is usually used in cats only when the previously discussed therapeutic measures fail to control the disease. The most important side effect of azathioprine in cats is bone marrow suppression. I use a maximum starting dose in cats of 0.15 mg/lb once every other day. At this low dose side effects are extremely uncommon. Alternatively if clinical signs of IBD do not resolve on the initial azathioprine dose the dose can be increased slightly if there is no evidence of bone marrow suppression. Because of a lag effect, beneficial therapeutic results from azathioprine often are not apparent until 2 to 3 weeks after treatment is started. Azathioprine is generally used for 3 to 9 months in cats. A majority of cats with IBD do not require azathioprine treatment.
A complete blood count should be run to monitor for anemia and leukopenia at 3 to 4 week intervals for the first 2 months and then once monthly. Significant side effects are most often identified during the first 3 to 6 weeks of treatment with azathioprine. There is usually no physical evidence of early azathioprine toxicity in cats. Mild leukopenia (e.g., 3000 - 4000 cells/mm) is usually the first abnormality that is identified. Azathioprine is currently only available as 50 mg tablets. The low dosage used in cats requires that the tablet be broken into small fragments (i.e., 1/30 - 1/50 tablet depending on body weight). Since this is a very inaccurate and potentially dangerous way of administering azathioprine to cats, this drug must be administered in suspension form.
I have used a preparation which allows for accurate dosing of azathioprine and less chance of accidental toxicity. A 50 mg tablet is pulverized and mixed in 15 ml of V.A.L. Syrup (Ft. Dodge Laboratories). This is a flavored vitamin preparation which is quite palatable to most cats. Powdered medication mixes well with the syrup and does not seem to precipitate out appreciably. The dosage in ml is then calculated based on the cat's body weight (e.g., 0.33 ml once every 48 hours for an 8 pound cat). The client is instructed to shake the medication well before administering it. Alternatively, a suspension preparation can be made by a compounding pharmacy service. A major advantage of administering azathioprine in this manner is that any required increase in dosage can be done very accurately. If azathioprine is well tolerated and there has been inadequate clinical improvement the dosage can be increased form 0.15 mg/lb to 0.2 to 0.25 mg/lb once every 48 hours.
Poor responses to treatment of cats with IBD usually result from (1) inadequate initial corticosteroid dosage, (2) poor client compliance, or more commonly (3) treatment for only small intestinal inflammatory disease when colitis is present as well. Some cats with concurrent IBD and colitis may show minimal or no clinical signs of colitis.
Because dietary allergens may play a role in the cause if IBD, specific dietary therapy may be beneficial. Often, moderate to severe degrees of IBD are either temporarily responsive or only minimally responsive to careful dietary manipulations. However, long term control of IBD with as minimal a drug administration schedule as possible may be aided by specific dietary management. This should be started as soon as a diagnosis is made and continued as drug therapy is decreased later. Chicken, duck, lamb, or venison based diets are often tried initially. A gradual change to commercial diets that are low in additives and that are formulated with chicken or lamb as their primary ingredient is then attempted. Diets such as IVD Select Care Neutral or IVD Limited Ingredient Diets, Iams Feline, Hill's Prescription Diet c/d or w/d, or Waltham select protein diets are generally recommended.
Treatment of Intestinal Lymphoma in Cats
Lymphoma is the most common feline neoplasm. It is also the most common form of gastrointestinal neoplasia in cats. Gastrointestinal lymphoma is often referred to as either well differentiated (low grade or lymphocytic), poorly differentiated (high grade, lymphoblastic, or immunoblastic), and intermediate (or mixed). Endoscopy has been shown to be a very useful modality for diagnosis of intestinal lymphoma in cats, especially when multiple biopsies are obtained using proper technique and instruments that can procure adequate size tissue samples. Full thickness intestinal biopsies may be required in a very limited number of cases in order to establish the correct diagnosis.
Many cats respond favorably to treatment for intestinal lymphoma, especially with the low grade or chronic lymphocytic type. Clinical signs can be very similar to cats with IBD. Therefore, it is strongly recommended that cats with chronic GI signs undergo a biopsy procedure as early as possible, so that the correct diagnosis can be established and the best course of therapy be made available for each individual cat.
Multi-agent chemotherapy is recommended for all cats with GI lymphoma. Surgery is done only if there is an isolated mass that is causing some degree of luminal obstruction. Survival times in excess of 12 to 18 months are not unusual. In some cats the response is somewhat shorter (three to six months). The prognosis for longer survival time is much better if the diagnosis is made before clinical signs become chronic and debilitation results.
One study has reported excellent results in cats with chronic lymphocytic lymphoma using a protocol of prednisone (10 mg PO per cat per day) and chlorambucil (Leukeran) at a dosage of 15 mg/m2 PO, once every day for 4 days, repeated every 3 weeks. Sixty-nine percent of the cats with lymphocytic lymphoma treated with this regimen achieved a complete remission. The median disease free interval for cats that achieved complete remission was 20.5 months (range, 5.8-49 months). The median survival for all cats with lymphocytic lymphoma treated with chemotherapy was 17 months (range, 0.33-50 months). Cyclophosphamide (Cytoxan) was used for rescue in some of the cats that were entered in this protocol (225 mg/m2, PO, every 3 weeks). For further reference on this protocol, see Richter,K: Feline gastrointestinal lymphoma, ACVIM Proceedings 2001, p. 547-549.
The protocol that I have used most often was originally published by Cotter in 1983. Dosage levels have been modified slightly since that time. This protocol utilizes cyclophosphamide, oncovin, and prednisone or prednisolone (COP). This protocol can be easily managed in any practice setting. Vincristine is administered intravenously at a dose of 0.5-0.75 mg/m2 once weekly for 4 consecutive weeks and then once every 3 weeks. The initial doses are often decreased by approximately 25 percent for cats that are inappetent or debilitated. If well tolerated the dose can then be gradually increased. Care is taken to ensure that none of the vincristine is given extravascularly. The average volume that is administered is quite low (0.1 to 0.15 ml for many cats, using a vincristine concentration of 1 mg/ml). Cyclophosphamide is given orally at a single dose of 225 mg/m2 every 3 weeks (50 mg tablets are used with dosage adjusted to the nearest 25 mg on the low side of the calculated dose). Prednisone or prednisolone (preferred) is given orally at 10 mg per cat per day. Although cyclophosphamide and vincristine can be given on the same day I often prefer to have the owner administer the cyclophosphamide 2 to 3 days after the oncovin. A CBC is done several times during the first month and then every 3 weeks to be sure that adequate granulocytes are present before treatment. At least 3,000 granulocytes/ul must be present before cyclophosphamide is given. If the granulocyte count drops to less than 1,000/ul 5 to 7 days after cyclophosphamide, the dose for subsequent treatments is reduced by 25 percent. The highest non-toxic dose is most likely to result in the greatest tumor cell kill.
The COP protocol is generally well tolerated, although side effects may occur and dosage or interval adjustments may be necessary. Side effects of COP in cats may include anorexia, vomiting, lethargy, and severe tissue irritation if any vincristine is given extravascularly. Also, the haircoat may become thinner, but complete hair loss does not occur. Cats do tend to lose whiskers. Cats should be carefully observed for sepsis especially during the induction phase. Prophylactic antibiotics are not indicated, but any infections that occur should be treated aggressively. Advantages of this protocol include hospital visits at only 3 week intervals after the first 4 weeks, lower cost to the owner, and a treatment interval that allows recovery of normal cells between treatments. I would like to emphasize that with careful monitoring and use of a dosage schedule that is tailored to each individual cat few problems are encountered It is my general practice to encourage owners of most cats with GI lymphoma to pursue treatment that includes chemotherapy.
Nutritional and metabolic support are also important. If inappetence is a problem cyproheptadine can be administered as an appetite stimulant (1 to 2 mg PO every 12 to 24 hours) on an as needed basis (long-term if necessary). If there is concurrent renal disease with azotemia or if dehydration is a problem owners are taught how to administer subcutaneous fluids at home (e.g., lactated Ringer's 100 to 150 ml every 24 hours to 48 hours, based on each individual cat's needs). Injections of B complex vitamins are sometimes helpful as well.
Rarely chemotherapy can be discontinued after one year. This is done only if follow-up endoscopic intestinal biopsies indicate that there is no remaining lymphoma. Most cats remain on treatment for the remainder of their lives. If chemotherapy is poorly tolerated and reduced dosages and increased intervals between treatment times are unsuccessful in adequately decreasing side effects chemotherapy should be suspended. Prednisone should be continued however because it may help maintain remission for a period of time. L-asparaginase can also be used if cyclophosphamide and vincristine are poorly tolerated. Doxorubicin (Adriamycin) can also be used in cats.
For clinicians who are inexperienced in administering chemotherapy, or who have not treated many cats with intestinal lymphoma, it is recommended that a veterinary oncologist or internist be consulted for guidance on protocol selection and ongoing management. Many cats with intestinal lymphoma can be managed successfully for some period of time!