Treatment Options for Microscopic Colitis

Arthur M. Barrie, MD, PhD

Disclosures

March 18, 2016

Case Discussion

Oral budesonide has proven to be the most effective treatment for MC, and it is the recommended first-line medical therapy for symptomatic MC in the recently published American Gastroenterological Association (AGA) Institute guidelines for the medical management of MC.[2] Prior Cochrane systematic reviews concluded the same for budesonide in the treatment of collagenous colitis, and probably for lymphocytic colitis as well.[3,4]

Oral budesonide is a corticosteroid that suppresses inflammation topically in the gastrointestinal tract. Ninety percent of the drug is metabolized by the liver upon absorption, thereby limiting its systemic activity, including potential corticosteroid related adverse effects, such as adrenal suppression and osteoporosis.

Two formulations of oral budesonide are used to treat inflammatory bowel disease in the United States: Entocort® EC (AstraZeneca) and Uceris® (Salix Pharmaceuticals). Entocort EC is designed to release budesonide in the terminal ileum and ascending colon, is approved to treat Crohn disease, and has been the principal formulation of budesonide used in clinical trials and practice to treat MC. Uceris delivers budesonide to the entire colon and is approved to treat ulcerative colitis.

Budesonide was significantly more effective than placebo at inducing short- and long-term clinical response and histologic improvement in a meta-analysis of seven randomized, controlled trials.[5] Budesonide-treated patients were three times more likely to experience short-term clinical improvement than patients who received placebo (risk ratio, 3.07; 95% confidence interval [CI], 2.06-4.57).

The recommended starting dose of budesonide to induce clinical remission of MC is 9 mg/day, with most patients experiencing improvement in their diarrhea in 2-4 weeks. Budesonide induction therapy is typically continued for 4 weeks, and if the patient's disease is in remission at that time, the medication is tapered down by 3 mg every 2 weeks, and then discontinued. Budesonide induction therapy may be continued for 8-12 weeks if clinical remission is not achieved by 4 weeks.

Patients who are responsive to budesonide are at high risk for relapse when the medications are stopped; disease will remain in remission in only one third of patients.[2] The median time to relapse is 2 weeks after treatment cessation, with patients younger than 60 years at a greater risk for relapse. Patients with relapse may be retreated with either intermittent or low-dose maintenance budesonide therapy.

The AGA guideline[2] recommends maintenance budesonide therapy for patients with recurrent symptoms after discontinuation of induction therapy. Studies have shown that maintenance budesonide therapy at 6 mg/day is three times more effective than placebo at maintaining remission for up to 6 months (RR, 3.22; 95% CI, 1.05-9.89).[5] For budesonide-dependent patients with MC who again achieve remission using budesonide 6 mg/day, Pardi and Kelly[6] recommend reducing the budesonide dosage to 3 mg/day, and to 3 mg every other day if possible, and then attempting discontinuation of maintenance therapy after 6-12 months. If patients experience relapse when off maintenance therapy, budesonide treatment may be resumed and continued indefinitely at the lowest effective dose and frequency.

Budesonide induction and maintenance therapy appear to be safe, given the low systemic activity of the drug; the meta-analysis found no significant difference in adverse effects between budesonide recipients and placebo recipients.[5] However, budesonide-dependent patients should still be monitored for potential corticosteroid-related adverse effects, such as osteoporosis.

According to the AGA guideline,[2] mesalamine may be considered as second-line medical therapy for MC if patients cannot tolerate or afford budesonide. Historically, mesalamine was frequently prescribed for treatment, but it has recently fallen out of favor because studies have failed to show that it effectively treats MC. Specifically, mesalamine (3 g/day) was found to be ineffective or inferior to budesonide (9 mg/day) compared with placebo for the short-term treatment of collagenous colitis in a randomized, double-blind. multicenter trial.[7] Eighty percent of budesonide treated patients (n = 30) achieved clinical remission after 8 weeks of treatment, compared with only 44% of mesalamine-treated patients (n = 25) and 37.8% of placebo recipients (n = 37; budesonide vs placebo, P < .001).

Regarding cholestyramine, the AGA guideline[2] recommends against adding cholestyramine to mesalamine monotherapy and does not discuss cholestyramine monotherapy owing to the lack of clinical trials. It is this author's opinion that cholestyramine can sometimes be a helpful adjunctive treatment for MC, especially for patients who also have postcholecystectomy diarrhea. Bile acids and bile acid malabsorption have been implicated in the pathogenesis of MC,[6] and cholestyramine has been reported to induce clinical remission in patients with concomitant MC and bile acid malabsorption.[8]

Azathioprine may be considered as a rescue therapy for cases of refractory MC that do not respond to budesonide or second-line therapies once other causes of diarrhea are ruled out, including celiac disease, which is strongly associated with MC. The reported experience of azathioprine therapy for refractory MC is limited to two small case series involving primarily corticosteroid-dependent patients; azathioprine induced a clinical response in 89% (8 of 9) of patients in one of the studies[9] and 41% (19 of 46) of patients in the other study.[10] Azathioprine therapy was complicated in these case series by frequent adverse effects for the majority of patients, including nausea and hepatitis.

Accordingly, given the relative low toxicity of budesonide compared with azathioprine, budesonide is preferred over azathioprine for maintenance therapy of corticosteroid-dependent patients with MC.

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