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Case Studies: Ketotifen Treatment of Active Colitis in Patients with
5-Aminosalicylate Intolerance
John K. Marshall MD FRCPC1
1Research Fellow and 2Associate Professor, Division of Gastroenterology,
Department of Medicine, McMaster University, Hamilton, Ontario.
Address correspondence to:
Abstract
Introduction
Pretreatment with mast cell stabilizers has been found to attenuate the development of experimental colitis in a number of animal models.6,7 We report our experience with the administration of ketotifen, a potent mast cell stabilizer, to three patients with symptomatic colitis (Case 1: Crohn's disease; Case 2: ulcerative colitis; and Case 3: collagenous colitis) who were allergic to, or intolerant of, 5-aminosalicylic acid (5-ASA).
Case 1
In February 1997, while on no medical therapy, the patient presented again with increased stool frequency and moderate lower abdominal cramping. Flexible sigmoidoscopy to 45 cm from the anal verge revealed a diffusely granular mucosa with micro-ulceration, loss of vascular pattern and purulent exudate. Mucosal biopsies revealed marked architectural distortion with deep plasma cells but no eosinophils, and a peripheral blood count showed no eosinophilia. A tapering course of prednisone was initiated with gradual improvement in her symptoms. However, repeated attempts over the following four months to reduce the dose below 15 mg/day resulted in recurrence of her symptoms. In June 1997, oral ketotifen was initiated at a dose of 1 mg b.i.d. for one week and then increased to 2 mg b.i.d. Within three weeks the patient's bowel habit had normalized. Ketotifen was maintained at 1 mg b.i.d., and the dose of prednisone was gradually reduced.
After two months of ketotifen, the patient remained in clinical remission despite reduction of her prednisone dose to 7.5 mg daily. A flexible sigmoidoscopy to 60 cm showed improvement, with granular and friable mucosa, but no visible ulceration. After five months of ketotifen, prednisone was withdrawn, without clinical relapse.
Case 2
In June 1992, the patient presented with an exacerbation of diarrhea while on no medical therapy, but refused treatment with corticosteroids. Ketotifen was introduced at a dose of 1 mg b.i.d., and continued until September 1994. During that period she had only one symptomatic episode lasting six weeks, which resolved with a short course of tapering corticosteroids. Since 1994, she has gone on to develop a perianal fistula and has suffered one flare of colitis in 1996 requiring systemic corticosteroids. A colonoscopy at that time confirmed the diagnosis of Crohn's colitis, with no excess of eosinophils noted in mucosal biopsies.
Case 3
In 1992, the patient developed a flare of her disease, with increased stool frequency and looser stool consistency. A trial of oral metronidazole (500 mg t.i.d.) produced no benefit, but her symptoms resolved while on a tapering course of oral corticosteroids. However, within five weeks of discontinuing prednisone the symptoms recurred, and a second tapering course of systemic corticosteroids was prescribed in June 1992. In an attempt to reduce her steroid requirement, a six-month course of oral ketotifen (1 mg b.i.d.) was initiated.
While on ketotifen, the patient remained well. However, within two weeks of discontinuing her ketotifen in December 1992, she again observed an increase in stool frequency, which improved when the ketotifen was reintroduced. In May 1993, another course of corticosteroids was required, and tapered gradually over four months. The ketotifen was finally discontinued at the patient's request in January 1994. She has since remained well, and has required no further medical therapy.
Discussion
Ketotifen is a benzocycloheptathiophene derivative administered as a prophylactic agent in the management of bronchial asthma and allergic disorders. Although widely promoted as an inhibitor of mast cell degranulation, its true mode of action in asthma remains obscure, and may also include direct histamine antagonism, impaired release of inflammatory mediators by basophils, inhibition of activated eosinophils and suppression of T-cell recruitment.8
The known actions of ketotifen in colonic mucosa are also diverse. Ketotifen has been shown in vitro to reduce the accumulation of mucosal prostaglandin E2, leukotriene B4 and leukotriene C4 by 33-60%.9 Ketotifen has also been reported to alter the expression of inducible nitric oxide synthase, an important regulator of colonic inflammation, in colonic mucosal explants.10 Furthermore, a noncholinergic, nonhistaminergic myocontractile effect has been observed when isolated segments of rodent intestine are exposed to ketotifen,11 and doxantrazole, another "mast cell stabilizer," has been reported to block TNBS-induced changes in the smooth muscle adrenoreceptors of guinea pig intestine.12
Ketotifen has been used successfully to treat a number of allergic disorders, including eosinophilic gastroenteritis, recurrent idiopathic anaphylaxis and chronic urticaria.13 It is of interest that two of our patients professed an allergy to penicillin, and that one had suffered a prior episode of eosinophilic pneumonia. Although the colonic biopsies were not specifically assessed for mast cell numbers or products of mast cell degranulation, none of our patients showed evidence of peripheral or mucosal eosinophilia when ketotifen was initiated, and none had other systemic manifestations of allergy. It is unclear, however, whether their symptomatic improvement was a result of an anti-inflammatory effect of ketotifen, or treatment of an unrecognized concomitant allergic disorder.
Each of our patients demonstrated intolerance to 5-aminosalicylates, which prompted our search for alternative therapeutic agents. Case 1 developed reversible diarrhea requiring drug withdrawal, a relatively common adverse event acknowledged in the literature. Reversible pulmonary eosinophilia, as observed in Case 2, is an increasingly recognized complication of 5-aminosalicylate therapy.14 Case 3 appeared to develop a hypersensitivity to mesalamine, characterized by a skin rash and fever which resolved upon drug withdrawal. While hypersensitivity reactions are more often associated with sulfasalazine, they can also occur following the administration of derivatives of 5-aminosalicylic acid.15 A trial of ketotifen, with its antiallergic effects, may be particularly appropriate in colitic patients who, like ours, develop adverse reactions to conventional drugs.
The benefit our patients appeared to derive from treatment with the mast cell stabilizer ketotifen provides the first evidence of a new class of therapeutic agents for patients with symptomatic colitis and 5-ASA intolerance or allergy. Although these results are clearly anecdotal, they serve to highlight the potential role of mast cells and their mediators in the pathogenesis and progression of colonic inflammation. Further research is thus warranted to better define the mode of action of ketotifen, and to evaluate more rigorously its efficacy in patients with active inflammatory bowel disease.
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