Description of studies

A literature search conducted on August 11, 2016 identified 333 records. Two additional studies were identified through searching of conference and other sources. After duplicates were removed, a total of 248 trials remained for review of titles and abstracts. Twenty‐seven studies were selected for full text review (see Figure 1). Twenty studies were excluded (See: Characteristics of excluded studies). Seven reports of 5 studies (n = 149 patients) met the pre‐defined inclusion criteria and were included in the review (Fine 1999; Calabrese 2007; Miehlke 2009; Pardi 2009; Latella 2010). A search of clinical trials.gov identified two ongoing randomized trials (NCT00184171; NCT01209208). The NCT00184171 study plans to assess the treatment of lymphocytic colitis with budesonide (9 mg/day), bismuth or fiber. The NCT01209208 plans to assess treatment of lymphocytic colitis with budesonide (9 mg/day), mesalazine (3 g/day) or placebo. The results of these ongoing studies will be included in future updates of this review when the study results become available.

Figure 1

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Study flow diagram.

Fine 1999, which was published in abstract form only, was a randomized, double‐blind, placebo‐controlled trial that compared bismuth subsalicylate to placebo in 14 patients (11 females: 3 males; age range 35 to 78 years) with microscopic colitis. Of these, five patients had lymphocytic colitis and nine had collagenous colitis. Patients were treated with bismuth subsalicylate (n = 3; nine 262 mg chewable tablets daily in 3 divided doses) or an identical placebo (n = 2) for 8 weeks. Each patient underwent 48‐hour stool collection prior to treatment and on the last two days of treatment stool weight and consistency were evaluated using standardized criteria. All patients underwent flexible sigmoidoscopy with standardized biopsy prior to entry and after treatment. Patients were not to take antibiotics or anti‐inflammatory agents for a minimum of 6 weeks, and antidiarrheals for minimum of 2 weeks prior to entry. Clinically active lymphocytic colitis was defined as at least eight weeks of non‐bloody watery diarrhea with normal radiologic and endoscopic findings. Lymphocytic colitis was confirmed by histopathology consisting of excess mononuclear inflammatory cells in the lamina propria and surface epithelium without significant neutrophilic or eosinophilic inflammation, numerous crypt abscesses, or granuloma; the absence of a thickened subepithelial collagen band; and no other evidence of Crohn's disease. The histological score ranged from 0 to 10 and was based on the following five parameters: surface epithelium (microulceration, cell flattening and mucin depletion ‐ scored 0 to 2); crypts; lamina propria cellularity; numbers of intraepithelial lymphocytes within the surface epithelium and the number of intra epithelial lymphocytes within the crypt epithelium. A clinical response was defined as the improvement of diarrhea to the passage of two or less formed or semi formed stools per day. A histological response was defined as a reduction in the histopathology score by greater than 50%. Adverse events were also documented.

Calabrese 2007 was a randomized, open‐label trial comparing mesalazine to mesalazine plus cholestyramine for the treatment of patients with active microscopic colitis. The study included 23 patients with collagenous colitis and 41 with lymphocytic colitis. Patients were randomized via a computer generated list to oral mesalazine 800 mg three times daily (n = 20) or oral mesalazine 800 mg three times daily plus cholestyramine 4 g once daily (n = 21) for 6 months of treatment. The diagnosis of lymphocytic colitis was based on clinical and histological criteria. Clinically active lymphocytic colitis was defined as chronic or recurrent non‐bloody diarrhea. Histological criteria included increased chronic inflammatory infiltrate (plasma cells, lymphocytes, eosinophils) in the lamina propria; increased number of intraepithelial lymphocytes, damage to surface epithelium, with flattening of epithelial cells or epithelial loss or both and detachment and minimal crypt architecture distortion. In addition, the number of intraepithelial lymphocytes had to be greater than 20 per 100 epithelial cells in the absence of a thickened subepithelial collagen layer to diagnose lymphocytic colitis. Patients with a clear correlation between symptoms and consumption of drugs (e.g. nonsteroidal anti‐inflammatory drugs (NSAIDS), ticlopidine, or proton pump inhibitors) were excluded. All patients underwent a colonoscopy pre‐treatment and 20 patients also underwent a colonoscopy at the end of 6 months. Outcomes included complete and partial clinical response and histological response. Complete response was defined as complete resolution of diarrhea. Partial clinical response was defined as improvement but not resolution of diarrhea. Histological response was defined as normalization of histologic pattern at the end of six months. Adverse events were also reported.

Miehlke 2009 was a randomized, double‐blind, placebo‐controlled trial that compared oral budesonide to placebo in patients with lymphocytic colitis. Forty‐two patients (28 females;14 males; median age 61) with lymphocytic colitis were randomized in a 1:1 ratio via a centralized randomization list in blocks of four to receive oral budesonide (9 mg/day, n = 21) or placebo (n = 20) for 6 weeks of treatment. Non‐responders at week six were treated with open‐label budesonide (9 mg/day) for an additional 6 weeks. Clinically active lymphocytic colitis was defined as more than three watery or loose stools per day on average, for at least 4 weeks. The diagnosis of lymphocytic colitis was based on histology and confirmed by the central pathologist. The number of intraepithelial lymphocytes had to be greater than 20/100 epithelial cells, with inflammation of the lamina propria. The primary outcome measure was clinical remission at 6 weeks which was defined as no more than 3 non‐watery stools per day on average, and a reduction in more than stool compared with screening. Complete colonoscopy including histology was assessed at entry and after 6 weeks, and was used to determine rates of histological remission and histological response. Histological remission was defined as a reduction in the number of intraepithelial lymphocytes to less than 20/100 epithelial cells, plus a reduction in lamina propria inflammation. Histological response was defined as a greater than 50% reduction in the number of intraepithelial lymphocytes compared to baseline or a reduction in lamina propria inflammation or both. Other outcome measures included clinical remission from lymphocytic colitis after 3 weeks, quality of life, which was assessed at entry and after 6 weeks with the validated SF‐36 instrument (a 36 item questionnaire measuring both physical and mental components of quality of life), and the occurrence of adverse events.

Pardi 2009 was a double‐blind, randomized controlled trial comparing controlled ileal‐release budesonide to placebo for the treatment of patients with diarrhea and microscopically confirmed lymphocytic colitis (the criteria were not described). Patients with possible drug‐induced lymphocytic colitis were excluded, unless symptoms persisted despite discontinuation of the offending medication. The study included 15 patients who were randomized to receive either 9 mg/day of budesonide (3 x 3 mg; n = 11) or three placebo capsules (n = 4). Symptoms were self‐recorded daily then averaged for each week of the study. The primary outcome was global assessment of improvement in diarrhea as assessed by the patient. This was defined as at least a 50% improvement in the frequency of bowel movements in at least three of the last four weeks of the study, compared to baseline. Clinical histologic features were graded on a four‐point scale which accounted for features such as intraepithelial lymphocyte infiltration and lamina propria cellularity. Colon biopsies were taken before study entry, and follow‐up sigmoidoscopy and biopsy was requested from each subject at the end of the study. No definitions were provided for either complete or partial clinical remission, or histologic remission. As such, all results were described in terms of either improvement or worsening of the patient's condition. In our analysis, we defined clinical response as an improvement in global assessment score and histologic response as an improvement in the histologic score. Secondary outcomes included improvement in number of bowel movements per day, consistency of stool, abdominal discomfort, histology and adverse events.

Latella 2010, which was published in abstract form only, was a randomized, open‐label trial comparing beclometasone dipropionate to mesalazine for the treatment of patients with lymphocytic colitis. The study included 46 patients with lymphocytic colitis. The diagnosis of lymphocytic colitis was based on clinical and histological criteria. Clinically active lymphocytic colitis was defined as greater than 3 watery or loose stools per day on average per week and a history of diarrhea lasting for more than four weeks. Histologic criteria included a complete colonoscopy with colonic biopsies within four weeks of entry, and a histologically confirmed diagnosis of active lymphocytic colitis. Patients were randomized to receive beclometasone dipropionate 5 mg/day (n = 18), beclometasone dipropionate 10 mg/day (n = 13) or mesalazine 2.4 g/day (n = 15) for 8 weeks. Outcomes included clinical remission at 8 weeks, defined as less than or equal to 3 soft or solid stools per day during the last week of treatment, and relapse at 6 and 12 months after treatment, defined as greater than three stools per day on four or more consecutive days.

Risk of bias in included studies

The overall results of the risk of bias analysis are reported in Figure 2.

Figure 2

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Effects of interventions

See: Summary of findings for the main comparison Bismuth subsalicylate versus placebo for treating lymphocytic colitis; Summary of findings 2 Budesonide versus mesalazine for treating lymphocytic colitis; Summary of findings 3 Mesalazine versus mesalazine + cholestyramine for treating lymphocytic colitis; Summary of findings 4 Beclometasone dipropionate versus mesalazine for treating lymphocytic colitis

Bismuth subsalicylate versus placebo

Clinical response

In the Fine 1999 study, all 3 patients in the bismuth subsalicylate group achieved a clinical response after 8 weeks of treatment, while those 2 patients assigned to placebo did not (RR 5.25, 95% CI 0.41 to 67.73). A GRADE analysis rated the overall quality of the evidence supporting this outcome as very low due to unclear risk of bias (allocation concealment) and very serious imprecision (3 events; See summary of findings Table for the main comparison).

Histological response

In Fine 1999, 2 of 3 patients in the bismuth subsalicylate group achieved a histological response after 8 weeks of treatment, compared to 1 of the 2 patients treated with placebo (RR 1.33, 95% CI 0.27 to 6.61). A GRADE analysis rated the overall quality of the evidence supporting this outcome as very low due to unclear risk of bias (allocation concealment) and very serious imprecision (3 events; See summary of findings Table for the main comparison).

Quality of life

Fine 1999 did not report on quality of life as an outcome measure.

Adverse events

Fine 1999 reported no adverse events in either the bismuth subsalicylate or placebo groups.

Budesonide versus placebo

Clinical response

In Miehlke 2009, 18 of 21 patients in the budesonide group achieved a clinical response after 6 weeks of treatment, compared to 10 of 21 patients in the placebo group (RR 1.80, 95% CI 1.11 to 2.91). The number needed to treat to achieve a clinical response with budesonide was 3 patients.

In Pardi 2009, 10 of 11 patients in the budesonide group achieved a clinical response after 8 weeks of treatment, compared to 1 of 4 patients in the placebo group (RR 3.64, 95% CI 0.66 to 20.06).

The pooled analysis for clinical response showed a statistically significant benefit for budesonide over placebo. Clinical response was noted in 88% of budesonide patients compared to 38% of placebo patients (2 studies; 56 participants; RR 2.03, 95% CI 1.25 to 3.33; I² = 0%). The number needed to treat to achieve a clinical response with budesonide was two. A GRADE analysis rated the overall quality of the evidence supporting this outcome as low due to unclear risk of bias for blinding and sparse data (39 events; See summary of findings Table 2).

Histological response

In Miehlke 2009, 11 of 15 patients in the budesonide group who underwent a follow‐up colonoscopy achieved a histological response after 6 weeks of treatment, compared to 4 of 13 patients in the placebo group who underwent a follow‐up colonoscopy (RR 2.81, 95% CI 1.00 to 5.69). The number needed to treat to achieve a histological response with budesonide was 3 patients.

In Pardi 2009, 7 of 8 patients in the budesonide group who underwent follow‐up sigmoidoscopy achieved a histological response after 8 weeks of treatment, compared to 1 of 3 patients ) in the placebo group (RR 2.63 95% CI 0.52 to 13.29).

The pooled analysis for histological response showed a statistically significant benefit for budesonide over placebo. Histological response was noted in 78% of budesonide patients compared to 33% of placebo patients (2 studies; 39 participants; RR 2.44, 95% CI 1.13 to 5.28; I² = 0%). The number needed to treat to achieve a histological response with budesonide was three. A GRADE analysis rated the overall quality of the evidence supporting this outcome as low due to very sparse data (23 events; See summary of findings Table 2).

Quality of life

SF‐36 scores at baseline were reduced compared to normal values for both the physical and mental domains. In the budesonide group, the mean physical sum score increased from 42.0 at baseline to 49.7 after 6 weeks of treatment, while the mean mental sum score was unchanged, with a value of 46.5 at baseline and 46.9 after 6 weeks (Miehlke 2009). In the placebo group, the mean physical sum score increased from 44.1 at baseline to 48.0 after 6 weeks of treatment, while the mean mental sum score was unchanged, with a value of 49.0 at baseline and 49.1 after 6 weeks (Miehlke 2009).

Adverse events

In Miehlke 2009, 6 adverse events occurred in 2 patients (10%) in the budesonide group, compared to 9 adverse events in 3 patients (15%) in the placebo group (RR 0.63, 95% CI 0.12 to 3.41). A GRADE analysis rated the overall quality of the evidence supporting this outcome as low due to very sparse data (5 events; See summary of findings Table 2). All adverse events were graded as mild or moderate in intensity. The most common adverse event were headaches. One patient in the budesonide group withdrew due to adverse events (nausea and headache) and one patient in the placebo group withdrew due to adverse events. Serious adverse events were reported in two placebo patients (nausea, abdominal pain, and hyperhidrosis in one patient; and headache, neck pain, and abdominal discomfort in the other patient).

Pardi 2009 reported no adverse events in either budesonide or placebo treatment groups.

Mesalazine versus mesalazine + cholestyramine

Clinical response

In Calabrese 2007, 17 of 20 patients in the mesalazine alone group achieved a clinical response after 6 months of treatment, compared to 18 of 21 patients in the mesalazine + cholestyramine group (RR 0.99; 95% CI 0.77 to 1.28). A GRADE analysis rated the overall quality of the evidence supporting this outcome as low due to high risk of bias (blinding), unclear allocation concealment and sparse data (35 events; See summary of findings Table 3).

Histological response

In Calabrese 2007, all patients with lymphocytic colitis who had a clinical response showed a normalization of histological features, specifically normalization of intraepithelial lymphocytes. Seventeen of 20 patients in the mesalazine group had a histological response compared to 18 of 21 patients in the combined mesalazine + cholestyramine group (RR 0.99; 95% CI 0.77 to 1.28). A GRADE analysis rated the overall quality of the evidence supporting this outcome as low due to high risk of bias (blinding), unclear allocation concealment and sparse data (35 events; See summary of findings Table 3).

Quality of life

In Calabrese 2007, quality of life was not reported as an outcome measure.

Adverse events

In Calabrese 2007, 2 of 21 patients (10%) in the mesalazine + cholestyramine group reported nausea as an adverse event. This was considered a mild event and did not lead to study withdrawal. No events were reported in the mesalazine alone group.

Beclometasone dipropionate versus mesalazine

Clinical response

In Latella 2010, 15 of 18 patients in the 5 mg/day beclometasone dipropionate group achieved a clinical remission after 8 weeks of treatment, compared to 11 of 13 in the 10 mg/day beclometasone dipropionate group, and 13 of 15 in the mesalazine group. There was no statistically significant difference in the proportion of patients who achieved clinical remission. Eighty‐four per cent (26/31) of patients in the beclometasone dipropionate group achieved remission compared to 86% (13/15) of mesalazine patients (RR 0.97, 95% CI 0.75 to 1.29). A GRADE analysis rated the overall quality of the evidence supporting this outcome as low due to high risk of bias (blinding) and sparse data (39 events; See summary of findings Table 4).

At 12 months, 5 of 18 patients (28%; 95% CI 12% to 51%) in the beclometasone dipropionate group maintained clinical remission compared to 3 of 13 patients (23%; 95% CI 8% to 50%) in the 10 mg/day beclometasone dipropionate group and 3 of 15 patients (20%; 95% CI 7% ‐ 45%) in the mesalazine group. There was no statistically significant difference in the proportion of patients who maintained clinical remission. Twenty‐six per cent (8/31) of patients in the beclometasone dipropionate group maintained remission at 12 months compared to 20% (3/15) of mesalazine patients (RR 1.29, 95% CI 0.40 to 4.18). A GRADE analysis rated the overall quality of the evidence supporting this outcome as very low due to high risk of bias (blinding) and very sparse data (11 events; See summary of findings Table 4).

Histological response

Latella 2010 did not report on histological response as an outcome measure.

Quality of life

Latella 2010 did not report on quality of life as an outcome measure.

Adverse events

In the Latella 2010 study, 3 of 46 patients discontinued treatment prematurely because of adverse events; one from each of the three groups. Adverse events reported in the beclometasone dipropionate group were nausea,sleepiness and change of mood in the 5 mg/day and 10 mg/day groups, respectively. In the mesalazine group, one patient discontinued treatment due to a skin rash.