Update on managing inflammatory bowel disease and intestinal lymphoma in cats (Proceedings)

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.

Treatment

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 1 to 2.2 mg/kg 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 2.2 to 4.4 mg/kg 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 1 to 2.2 mg/kg 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.

Budesonide is a glucocorticoid that represents a new alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management; or that are intolerant of the corticosteroids discussed above. Budesonide is a new and recently approved corticosteroid for use in humans. It is one of a group of novel corticosteroids that have been in development for use in humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. Others include fluticasone propionate, tixocortol pivalate, and beclomethasone dipropionate.

Budesonide undergoes high first pass metabolism in the liver and 90% is converted into metabolites with low corticosteroid activity. It has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a "locally acting" corticosteroid.

Therapeutic results with budesonide have been promising in humans with Crohn's disease, collagenous colitis and lymphocytic colitis, ulcerative colitis, either when administered as a retention enema or in oral form, and primary biliary cirrhosis.

Budesonide has been used by some veterinary clinicians in recent years to treat IBD in dogs and cats. Dose recommendations vary. In humans, a range of 6 mg to 9 mg per day has been used during initial therapy. The following general recommendations have been made for dogs and cats. In general, budesonide is administered to cats and small dogs at 1 mg administered once per day. Budesonide is supplied as a 3 mg capsule (Entocort, AstraZenica). Compounding is necessary for accurate dosing for cats and small dogs (to a 1 mg prep).

Budesonide can be used in combination with other drugs. Since cats tolerate corticosteroids very well, there is little indication to use budesonide as initial therapy for IBD. However, this may be a very attractive option for use in diabetic cats that also have IBD, or in patients where conventional therapies have not been sufficiently effective.

Potential adverse effects include PU/PD, when budesonide is used at the high end of the dose range, and GI ulceration. These reactions have been observed in some human patients. These problems would be more likely to occur in dogs than in cats. It appears to be very safe when used at the levels listed above.

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 10 to 20 mg/kg 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 prednisolone 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 0.3 mg/kg (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.

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.

Another immunosuppressive drug that is used in some cats with severe IBD is chlorambucil (Leukeran). Some clinicians use chlorambucil as an alternative to azathioprine (they are not used in conjunction). Chlorambucil is an alkylating agent. Alkylating agents alter DNA synthesis and inhibit rapidly proliferating cells. Chlorambucil is administered initially at 0.01 to 0.2 mg/kg/day in conjunction with prednisolone at 2.2 mg/kg/day. The small pill size of chlorambucil (2 mg) allows for easy dosing. Most cats receive one-half tablet (1 mg) per day. Various dosage schedules for cats have been published. An alternate schedule is 0.15 to 0.3 mg/kg every 72 hours. Toxicities are uncommon in cats but may include anorexia, vomiting, and diarrhea, but these problems generally resolve rapidly when chlorambucil is reduced from daily to every other day administration. Bone marrow suppression is possible but uncommon, and is mild and rapidly reversible when it does occur. Once the desired clinical response is achieved, chlorambucil is gradually tapered over several months while prednisolone is continued as the primary maintenance drug.

Cobalamin therapy in cats: Significant tissue level cobalamin deficiency is present in some animals with GI disease. This is usually secondary to reduced cobalamin absorptive capacity. Therapy involves administering injectable cobalamin at the following schedule for cats: 250 ug subcutaneously once a week for 6 weeks, then every 2 weeks for the next 6 doses, then dose monthly. Most generic cobalamin preparations contain 1 mg/ml (1000 ug/ml). It is important to note that multi-vitamin and B-complex injectable formulations contain significantly lower concentrations of cobalamin and they also cause pain when injected. Therefore, it is recommended that these preparations not be used for cobalamin supplementation. Unless the intestinal disease is totally resolved, long-term and perhaps lifelong supplementation with cobalamin may be necessary. The frequency of injections on a long-term basis is determined by regular measurement of serum cobalamin concentration.

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.

Poor responses to treatment of cats with IBD usually result from:

1. Inadequate initial or long-term maintenance corticosteroid dosage (and consider using prednisolone rather than prednisone).

2. Failure to use ancillary medications (metronidazole, azathioprine, chlorambucil) in cases where disease is moderate to severe.

3. Failure to recognize and treat a concurrent condition (e.g., gastric hypomotility disorder that may either be secondary to IBD or idiopathic in nature, hyperthyroidism, parasitism [e.g., Giardia, Cryptosporidium], Clostridiumperfringens enterotoxicosis).

4. 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.

5. Failure to recognize and treat low body cobalamin levels (measure serum cobalamin).

6. Failure to identify an effective diet.

7. Poor client compliance

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, nor 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!