Treatments for lymphocytic colitis

What is lymphocytic colitis?

Lymphocytic colitis is a type of microscopic colitis, a condition characterized by chronic non-bloody watery diarrhea. People with lymphocytic colitis have a normal appearing bowel when assessed by an endoscope (a camera used to look at the bowel) or an X-ray; but have microscopic (histological) inflammation of the bowel when assessed by a biopsy (a tissue sample taken during endoscopy). The cause of this disorder is unknown. This review is an update of a previously published Cochrane review.

What treatments have been tried for lymphocytic colitis?

Budesonide, mesalazine with or without cholestyramine, beclometasone dipropionate and bismuth subsalicylate (i.e. Pepto-Bismol®) have been tried as treatment for lymphocytic colitis. Budesonide is an immunosuppressive steroid drug that is quickly metabolized by the liver resulting in reduced steroid-related side-effects. It is taken by mouth. Beclometasone dipropionate is also a steroid drug. Steroid drugs are used to treat inflammation. Mesalazine (also known as 5-ASA) is an anti-inflammatory drug which is often taken by mouth. Cholestyramine is a drug that helps the body remove bile acids. Pepto-Bismol®, is an antacid medication used to treat temporary discomforts of the stomach and gastrointestinal tract.

What did the researchers investigate?

The researchers investigated whether these drugs improve the symptoms of lymphocytic colitis (e.g. diarrhea) or microscopic inflammation and whether any side effects result from treatment. The researchers searched the medical literature extensively up to 11 August 2016.

What did the researchers find?

Five studies including 149 participants were identified. These studies assessed budesonide versus placebo (e.g. a sugar pill), mesalazine versus mesalazine plus cholestyramine and beclometasone dipropionate versus mesalazine and Pepto-Bismol® versus placebo. The study which compared mesalazine to mesalazine plus cholestyramine and the study which compared beclometasone dipropionate to mesalazine were judged to be of low quality. The study which compared Pepto-Bismol® bismuth subsalicylate to a placebo was judged as low quality due to a very small sample size (5 participants) and limited data. The other three studies were judged to be high quality.

A pooled analysis of two studies (57 participants) showed that budesonide (9 mg/day for 6 to 8 weeks) was superior to placebo for improvement of diarrhea and improvement of microscopic inflammation of the bowel. Improvement in diarrhea was noted in 88% of budesonide participants compared to 38% of placebo participants. Improvement in microscopic inflammation was reported in 78% of budesonide participants compared to 33% of placebo participants. Forty-one participants were enrolled in the study that compared mesalazine (2.4. g/day) to mesalazine plus cholestyramine (4 g/day). Improvement in diarrhea was noted in 85% of participants in the mesalazine group compared to 86% of participants in the mesalazine plus cholestyramine group. Five patients were enrolled in the trial studying Pepto-Bismol® (nine 262 mg tablets daily for 8 weeks versus placebo). There were no differences in improvement of diarrhea or in improvement of microscopic inflammation of the bowel. Forty-six participants were enrolled in the trial studying beclometasone dipropionate (5 mg/day or 10 mg/day) versus mesalazine (2.4 g/day). Although participants receiving beclometasone dipropionate (84%) and mesalazine (86%) had improved diarrhea at 8 weeks, this improvement was not maintained at 12 months (26% and 20%, respectively). Side effects reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, excessive sweating and headache. Side effects reported in the mesalazine plus cholestyramine study included nausea and skin rash. Side effects in the beclometasone dipropionate trial included nausea, sleepiness and change of mood. No side effects were reported in the Pepto-Bismol® study.

Low quality evidence suggests that budesonide may be an effective therapy for the treatment of lymphocytic colitis. Low quality evidence also suggests that mesalazine with or without cholestyramine and beclometasone dipropionate may be effective for treatment of lymphocytic colitis. No conclusions can be made regarding bismuth subsalicylate due to the very small number of participants in the study. In the future, researchers should consider further large placebo-controlled trials of budesonide to confirm the suggested benefit and safety of this therapy. Bismuth subsalicylate, which has less potential for toxicity than budesonide, also warrants further study. The effectiveness and safety of mesalazine with or without cholestyramine, and beclometasone dipropionate need to be investigated in a large placebo-controlled studies.

Authors' conclusions: 

Low quality evidence suggests that budesonide may be effective for the treatment of active lymphocytic colitis. This benefit needs to be confirmed by a large placebo -controlled trial. Low quality evidence also suggests that mesalazine with or without cholestyramine and beclometasone dipropionate may be effective for the treatment of lymphocytic colitis, however this needs to be confirmed by large placebo-controlled studies. No conclusions can be made regarding bismuth subsalicylate due to the very small number of patients in the study, Further trials studying interventions for lymphocytic colitis are warranted.

Read the full abstract...
Background: 

Lymphocytic colitis is a cause of chronic diarrhea. It is a subtype of microscopic colitis characterized by chronic, watery, non-bloody diarrhea and normal endoscopic and radiologic findings. The etiology of this disorder is unknown.Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review is an update of a previously published Cochrane review.

Objectives: 

To evaluate the efficacy and safety of treatments for clinically active lymphocytic colitis.

Search strategy: 

The MEDLINE, PUBMED and EMBASE databases were searched from inception to 11 August 2016 to identify relevant papers. Manual searches from the references of included studies and relevant review articles were performed.

Abstracts from major gastroenterological meetings were also searched to identify research submitted in abstract form only. The trial registry web site www.ClinicalTrials.gov was searched to identify registered but unpublished trials. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies.

Selection criteria: 

Randomized controlled trials assessing medical therapy for patients with biopsy-proven lymphocytic colitis were considered for inclusion

Data collection and analysis: 

Data was independently extracted by at least two authors. Any disagreements were resolved by consensus. Data were analyzed on an intention-to-treat (ITT) basis. The primary outcome was clinical response as defined by the included studies. Secondary outcome measures included histological response as defined by the included studies, quality of life as measured by a validated instrument and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Data were combined for analysis if they assessed the same treatments. Dichotomous data were combined using a pooled RR along with corresponding 95% CI. A fixed-effect model was used for the pooled analysis.

Main results: 

Five RCTs (149 participants) met the inclusion criteria. These studies assessed bismuth subsalicylate versus placebo, budesonide versus placebo, mesalazine versus mesalazine plus cholestyramine and beclometasone dipropionate versus mesalazine. The study which assessed mesalazine versus mesalazine plus cholestyramine and the study which assessed beclometasone dipropionate versus mesalazine were judged to be at high risk of bias due to lack of blinding. The study which compared bismuth subsalicylate versus us placebo was judged as low quality due to a very small sample size and limited data. The other 3 studies were judged to be at low risk of bias. Budesonide (9 mg/day for 6 to 8 weeks) was significantly more effective than placebo for induction of clinical and histological response. Clinical response was noted in 88% of budesonide patients compared to 38% of placebo patients (2 studies; 57 participants; RR 2.03, 95% CI 1.25 to 3.33; GRADE = low). Histological response was noted in 78% of budesonide patients compared to 33% of placebo patients (2 studies; 39 patients; RR 2.44, 95% CI 1.13 to 5.28; GRADE = low). Forty-one patients were enrolled in the study assessing mesalazine (2.4 g/day) versus mesalazine plus cholestyramine (4 g/day). Clinical response was noted in 85% of patients in the mesalazine group compared to 86% of patients in the mesalazine plus cholestyramine group (RR 0.99, 95% CI 0.77 to 1.28; GRADE = low). Five patients were enrolled in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks versus placebo). There were no differences in clinical (P=0.10) or histological responses (P=0.71) in patients treated with bismuth subsalicylate compared with placebo (GRADE = very low). Forty-six patients were enrolled in the trial studying beclometasone dipropionate (5 mg/day or 10 mg/day) versus mesalazine (2.4 g/day). There were no differences in clinical remission at 8 weeks (RR 0.97; 95% CI 0.75 to 1.24; GRADE = low) and 12 months of treatment (RR 1.29; 95% CI 0.40 to 4.18; GRADE = very low). Although patients receiving beclometasone dipropionate (84%) and mesalazine (86%) achieved clinical remission at 8 weeks, it was not maintained at 12 months (26% and 20%, respectively). Adverse events reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, hyperhidrosis and headache. Nausea and skin rash were reported as adverse events in the mesalazine study. Adverse events in the beclometasone dipropionate trial include nausea, sleepiness and change of mood. No adverse events were reported in the bismuth subsalicylate study.

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