Microscopic colitis : An approach to treatment

Division of Gastroenterology, The University of Western Ontario, London, Ontario Correspondence: Dr Nilesh Chande, Mailbox 55, London Health Sciences Centre – South Street Hospital, 375 South Street, London, Ontario N6A 4G5. Telephone 519-667-6582, fax 519-667-6820, e-mail nchande2@uwo.ca Received and accepted for publication May 24, 2008 N Chande. Microscopic colitis: An approach to treatment. Can J Gastroenterol 2008;22(8):686-688.

C ollagenous colitis and lymphocytic colitis, the two sub- types of microscopic colitis, typically cause diarrhea in middle-aged or older individuals.They share many epidemiological and clinical features, but are distinguished by their histological features.Collagenous colitis is defined by a thickened subepithelial collagen band (thicker than 10 μm), with minimal lymphocytic infiltration.A diagnosis of lymphocytic colitis requires an increased number of intraepithelial lymphocytes (more than 20 lymphocytes per 100 epithelial cells), without a significantly thickened collagen band.
Various therapies have been reported to be effective for treating patients with microscopic colitis, but most randomized, controlled trials have included patients with collagenous colitis only.However, in practice, it seems that treatments for collagenous colitis can be used for lymphocytic colitis as well, with similar benefit.Because microscopic colitis generally is a benign disorder that does not lead to serious consequences such as weight loss or malnutrition, an approach to treatment must consider the severity of the symptoms, particularly when using therapies with potential toxicities.The present review aims to provide a logical approach to treating patients with microscopic colitis, summarizing key evidence for therapy and placing various treatment options into a rational, clinical context.

MEDICATION REVIEW
Although the etiology of microscopic colitis is not clear in most cases, certain medications have been associated with the onset of symptoms.Those most strongly implicated include acarbose, acetylsalicylic acid, Cyclo 3 Fort (Pierre Fabre Medicament, France), lansoprazole, nonsteroidal antiinflammatory drugs, ranitidine, sertraline and ticlopidine (1).A careful review of a patient's medication history is the first step in managing a patient with microscopic colitis, because stopping treatment with an offending drug may lead to resolution of the symptoms.

RULE OUT CELIAC DISEASE
Celiac disease is a common comorbidity in patients with microscopic colitis, occurring in 15% to 20% of patients (2,3).Patients with microscopic colitis should be screened for celiac disease using serology.A small bowel biopsy is required to confirm the diagnosis.Those patients determined to have celiac disease should be treated with a gluten-free diet.Because there is a considerable overlap of symptoms between celiac disease and microscopic colitis, a gluten-free diet often leads to improvement in diarrhea and other symptoms shared by the two disorders.

MEDICAL THERAPY
Initial and subsequent medical therapies should take into account the severity of the patient's symptoms, the response to previous treatments and the potential toxicity of the prescribed medication.Many patients can be managed with intermittent courses of therapy when their disease is most active; relatively few patients require long-term continuous medical treatment (Table 1).

Antidiarrheals
Antidiarrheal therapy with loperamide or similar medications is usually the first-line medical therapy for patients with microscopic colitis.Many patients will have treated themselves with these types of therapies before presentation to their physician.However, the doses used by self-treating patients may be suboptimal, and high-dose antidiarrheal therapy should not be excluded as a therapeutic manoeuvre when initially managing patients with microscopic colitis.Symptomatic benefit may be seen in a substantial portion of patients when antidiarrheals are used alone, or these therapies can be used in conjunction with others when treating more refractory cases (4,5).

Bismuth subsalicylate
Bismuth subsalicylate is an over-the-counter agent used for various gastrointestinal complaints.It has been studied for the treatment of microscopic colitis, and been found to improve both clinical and histological activity of the disease over the short term, without significant adverse events (6,7).The longterm benefits of this medication are unproven, but it likely can be used effectively to treat patients with relapsing disease.There is a theoretical potential for bismuth toxicity with continuous use, so a regimen of intermittent use is preferred (8).

Mesalamine
Mesalamine, commonly used to treat inflammatory bowel disease, has also been studied for the treatment of microscopic colitis.An open-label, randomized trial (9) demonstrated high clinical and histological responses to mesalamine treatment, with a maintained response over six months and minimal adverse events.The addition of cholestyramine may have some further benefit for patients with collagenous colitis (9).Mesalamine should be considered early in the treatment algorithm, and can likely be used for both induction and maintenance of response for patients with microscopic colitis.

Cholestyramine
Bile acid malabsorption may contribute to the diarrhea seen in some patients with microscopic colitis.Cholestyramine may be effective as monotherapy or when used in conjunction with mesalamine for patients with microscopic colitis (9)(10)(11).

Budesonide
Budesonide, a steroid with extensive first-pass metabolism, has the strongest evidence from clinical trials for treating patients with microscopic colitis.Three randomized, placebo-controlled trials (12)(13)(14) in patients with collagenous colitis demonstrated that this medication is effective for treating active disease over six to eight weeks, with a pooled response rate of 81% in a metaanalysis (15) (compared with 17% with placebo), a pooled OR of 12.32 and a number needed to treat of two patients.Budesonide was well tolerated, and also improved histology and quality of life (12)(13)(14)(15)(16).It was also shown to be effective for maintaining a clinical response in two trials (17,18) of patients with collagenous colitis over a six-month period, with a pooled response rate of 83% (compared with 28% with placebo), a pooled OR with budesonide therapy of 8.40, and a number needed to treat of two patients.A maintained histological response to budesonide was also found (17,18).
A single randomized, placebo-controlled trial (19) of budesonide in patients with active lymphocytic colitis was also positive, with a response rate to budesonide of 86% (and 40% with placebo), and a number needed to treat of three patients.Budesonide has not been studied for maintaining response in patients with lymphocytic colitis, but it probably can be effectively used for this purpose.
Despite the best evidence for efficacy, budesonide should not necessarily be the first-line therapy for all patients with microscopic colitis.It is a corticosteroid; therefore, there is a potential for significant adverse events.Cost and drug coverage issues may also be a limiting factor for some patients.As a result, budesonide is often reserved for patients with severe symptoms or those who fail more benign treatments.

Prednisone
Prednisone has been studied in one small, randomized, placebo-controlled trial (as the active form, prednisolone) (20).This study demonstrated a trend toward benefit with prednisolone.However, the trial was small (it enrolled 11 patients with collagenous colitis and one patient with lymphocytic colitis) and lacked the power to detect a significant difference.Adverse events with prednisone are common;  therefore, it should be used only for patients with disease refractory to budesonide therapy.

Immunosuppressive therapy
Patients who fail to respond to systemic steroids, or relapse when tapering or discontinuing them are candidates for immunosuppressive therapy.Azathioprine or 6-mercaptopurine, and methotrexate are probably the most appropriate choices.However, there are also reports of cyclosporine use (21)(22)(23)(24)(25). Dosages should be similar to those used for inflammatory bowel disease, although an oral route rather than a parenteral route for methotrexate is probably sufficient.

SURGICAL THERAPY
Surgical intervention is rarely required for patients with microscopic colitis, and should be reserved for those who fail all medical therapies.Most patients can be managed with a diverting ileostomy without removing the colon.Fecal stream diversion will often lead to histological improvement in the colon.Re-establishing the fecal stream will lead to recurrence of the microscopic colitis, and is not recommended.A proctocolectomy with ileal J-pouch anal anastomosis can be used for selected patients who do not want a permanent ostomy (26)(27)(28)(29)(30).

CONCLUSIONS
Collagenous colitis and lymphocytic colitis should be considered as diagnostic possibilities in patients presenting with watery diarrhea, and are diagnosed by a colonoscopy or sigmoidoscopy with biopsies.A positive diagnosis should lead to a review of current and previous medication use, as well as a screening test for celiac disease.The choice of initial medical therapy will depend on symptom severity.Budesonide has the best evidence for efficacy.However, more benign and inexpensive treatments, including antidiarrheals, bismuth subsalicylate, mesalamine and cholestyramine, may suffice.Most patients can manage with intermittent therapy when their symptoms are most severe.Refractory cases will require corticosteroid or immunosuppressive treatments, or even surgical intervention.A logical and stepwise approach to managing patients with microscopic colitis will lead to optimal patient outcomes.

TABLE 1
Medical therapies for patients with microscopic colitis