Budesonide is accepted as first-choice therapy for microscopic colitis (MC); however, symptoms often recur and some patients may be dependent, intolerant, or even fail budesonide. We performed a systematic review and meta-analysis to determine the effectiveness of non-budesonide therapies (thiopurines, bismuth subsalicylate [BSS], bile acid sequestrants [BAS], loperamide and biologics) for MC suggested by international guidelines.

We searched the CENTRAL, MEDLINE, and EMBASE databases from their inception to 18 April 2023 for the above-mentioned therapeutics in MC. We pooled the response and remission rates by medication using a random-effects model.

Twenty-five studies comprising 1475 patients were included in the meta-analysis. Treatment with BSS showed the highest response rate of 75% (95% confidence interval [CI] 0.65-0.83; I² = 70.12%), with 50% achieving remission of symptoms (95% CI 0.35-0.65; I² = 71.06%). Treatment with tumor necrosis factor (TNF) inhibitors (infliximab and adalimumab) demonstrated a response rate of 73% (95% CI 0.63-0.83; I² = 0.00%), with a remission rate of 44% (95% CI 0.32-0.56; I² = 0.00%). The response rate for those treated with vedolizumab was similar; 73% responded to treatment (95% CI 0.57-0.87; I² = 35.93%), with a remission rate of 56% (95% CI 0.36-0.75; I² = 46.30%). Loperamide was associated with response and remission rates of 62% (95% CI 0.43-0.80; I² = 92.99%) and 14% (95% CI 0.07-0.25), respectively, whereas BAS use was associated with response and remission rates of 60% (95% CI 0.51-0.68; I² = 61.65%) and 29% (95% CI 0.12-0.55), respectively. Finally, the outcomes for thiopurine use were 49% (95% CI 0.27-0.71; I² = 81.45%) and 38% (95% CI 0.23-0.54; I² = 50.05%), respectively DISCUSSION: The present systematic review and meta-analysis provides rates of effectiveness of non-budesonide therapies for MC based on available data in the field. Studies in the meta-analysis showed a large amount of heterogeneity due to the variability in assessing the clinical effects of intervention between the studies caused by differences in the definitions of response or remission rates between the studies included. This may likely result in overestimating the benefit of a treatment. Furthermore, the number of participants and drug dosages varied, and only a few studies applied disease-specific activity indices. Only one randomized controlled trial (RCT) was identified. All other 24 included studies were either case series or (retrospective) cohort studies, which complicated efforts to perform further sensitivity analyses to adjust for potential confounders and risk of bias. In addition, the overall evidence on the effect of these treatment options was judged as low, mostly due to comparability bias and the observational nature of the available studies, which limited statistically robust comparisons of rates of effectiveness of the different non-budesonide agents ranked against each other. However, our observational findings may inform clinicians regarding the most rational selection of non-budesonide therapies to patients with MC.

PROSPERO protocol #CRD42020218649.

Microscopic colitis (comprising lymphocytic and collagenous colitis, albeit an incomplete variant is gaining recognition as well) is a chronic, immune-mediated inflammatory state of the lower gastrointestinal tract (colon). The diagnosis requires diagnostic colonoscopy with characteristic histopathological findings. They have a propensity to present in senior populations (above 60 years of age), particularly women - who are approximately 2.5-3 times more likely to develop microscopic colitis. Preexisting other immune-inflammatory diseases are also shown to predispose patients for the development of microscopic colitis. The classic presentation is profuse watery diarrhea, often during the night or early morning hours. Fecal incontinence and abdominal pain are frequent as well. Thus, the disease impacts patients' quality of life and well-being. The first described cases date back to the seventies and eighties of the twentieth century, thereby they can be considered fairly recently discovered disease states. Our understanding of the disease and its pathophysiology is still incomplete. Although there is a lack of unified recommendation for treatment, most clinicians prefer the use of budesonide, and most published guidelines regard this locally acting glucocorticoid as the therapy of choice. In our article, we aimed for a brief, noncomprehensive overview of the clinical significance, diagnosis, and management of microscopic colitis.

Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, nonbloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder.

Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method.

These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice.

These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.

Collagenous colitis (CC) is an increasingly recognized cause of chronic inflammatory bowel disease characterized by watery non-bloody diarrhea. As a lesser studied inflammatory bowel disease, many aspects of the CC's natural history are poorly understood. This review discusses strategies to optimally manage CC. The goal of therapy is to induce clinical remission, <3 stools a day or <1 watery stool a day with subsequent improved quality of life (QOL). Antidiarrheal can be used as monotherapy or with other medications to control diarrhea. Budesonide therapy has revolutionized treatment and is superior to prednisone, however, the treatment is associated with high-relapse rates and the management of refractory disease is challenging. Ongoing trials will address the safety and efficacy of low-dose maintenance therapy. For those with refractory disease, case reports and case series support the role of biologic agents. Diversion of the fecal stream normalizes colonic mucosal changes and ileostomy may be considered where anti-tumor necrosis factor (TNF)-α agents are contraindicated. Underlying celiac disease, bile salt diarrhea, and associated thyroid dysfunction should be ruled out. The author recommends smoking cessation as well as avoidance of nonsteroidal anti-inflammatories as well as other associated medications.

The aim of this study was to assess the activity of eosinophils, neutrophils, and CD4+ as well as CD8+ T-cells in 11 patients with active collagenous colitis (CC) before and after 8 weeks of budesonide treatment (9 mg once daily) compared to 10 healthy individuals.

Clinical symptoms were recorded and intestinal biopsy samples were taken and analyzed by flow cytometry. Eosinophils with a high surface expression of CD44 and low CD9 expression were classified as activated. Neutrophil activity was assessed by their expression of CD66b, and CD69 was used as an activation marker for T-cells.

All patients responded to the treatment. The eosinophils in active CC showed increased activity compared to controls. The activity was back to control levels after treatment. Neutrophils were not activated in CC patients before or after treatment. CD8+ T-cells from untreated CC patients had a lower activity than controls, and a tendency of lower activity was observed on CD4+ T-cells. After treatment, the activity was increased on both types of T-cells and was not different from controls.

In the present study we demonstrated that the inflammation in CC is characterized by activated eosinophils but there is no neutrophil activity. CD4+ and CD8+ T-cells are increased in numbers in active CC but, surprisingly, they had a lower grade of activity than in control subjects. The major finding of this study is that budesonide treatment restores the normal activation of eosinophils and T-cells, accompanied by clinical remission.

Collagenous colitis is a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.

To determine effective treatments for patients with collagenous colitis.

Relevant papers published between 1970 and December 2007 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies.

Ten randomized trials were identified. Seven of these compared active treatment to placebo for treating active disease. Of these, 1 trial studied bismuth subsalicylate, 1 trial studied Boswellia serrata extract, 3 trials studies budesonide, 1 trial studied prednisolone, and 1 trial studied probiotics. One trial compared mesalamine to mesalamine + cholestyramine for treating active disease. Two trials compared budesonide to placebo in maintaining response induced by budesonide.

Data were extracted independently by each author onto 2x2 tables (treatment versus comparator and response versus no response). For therapies assessed in one trial only, P-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.

In treating active disease, there were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Clinical response occurred in 100% of patients who received bismuth subsalicylate compared to 0% of patients who received placebo (P = 0.03). Thirty-one patients were enrolled in the trial studying Boswellia serrata extract (three 400 mg capsules daily for 8 weeks). Clinical response occurred in 44% of patients who received Boswellia serrata extract compared to 27% of patients who received placebo (P = 0.32). A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). Clinical response occurred in 81% of patients who received budesonide compared to 17% of patients who received placebo (P < 0.00001). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53 to 27.46), with a number needed to treat of 2 patients. Statistically significant histological response occurred with treatment in all 3 trials studying budesonide therapy. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). Clinical response occurred in 63% of patients who received prednisolone compared to 0% who received placebo (P = 0.15). Twenty-nine patients were enrolled in the trial studying probiotics (2 capsules containing 0.5 x 10(10) CFU each of L. acidophilus LA-5 and B. animalis subsp. lactis strain BB-12 twice daily for 12 weeks). Clinical response occurred in 29% of patients who received probiotics compared to 13% of patients who received placebo (P = 0.38). Twenty-three patients were enrolled in the trial studying mesalamine (800 mg three times daily) with or without cholestyramine (4 g daily) for 6 months. Clinical response occurred in 73% of patients who received mesalamine alone compared to 100% of patients who received mesalamine + cholestyramine (P = 0.14). In maintaining response, 80 patients who had responded to open-label budesonide were enrolled in 2 trials studying budesonide (6 mg daily for 6 months). Clinical response was maintained in 83% of patients who received budesonide compared to 28% of patients who received placebo (P = 0.0002). The pooled odds ratio for maintenance of clinical response to treatment with budesonide was 8.40 (95% CI 2.73 to 25.81), with a number needed to treat of 2 patients. Histological response was maintained in 48% of patients who received budesonide compared to 15% of patients who received placebo (P = 0.002).

Budesonide is effective for inducing and maintaining clinical and histological response in patients with collagenous colitis. The evidence for benefit with bismuth subsalicylate and for mesalamine with or without cholestyramine is weak. There is no evidence for the effectiveness of Boswellia serrata extract, prednisolone, or probiotics. These agents and other therapies require further study.

As the diagnosis of microscopic colitis (MC) is made on the basis of histologic criteria, it is crucial to render an accurate microscopic interpretation. Features include 20 or more lymphocytes per 100 epithelial cells, mixed lamina propria inflammatory infiltrate, and preservation of crypt architecture for both lymphocytic and collagenous colitis (CC). CC is further characterized by a collagen band at least 10 mum thick. Although the pathogenesis of MC is poorly understood, medication-induced toxicity to the colonic mucosa is important to recognize, as medication cessation leads to prompt improvement. If MC is mild, symptomatic treatment is all that is needed, because some cases are self-limiting. Budesonide, 9 mg daily for at least 8 weeks, is the best documented treatment of choice for more severe or protracted cases. A 75% response rate has been reported; however, when treatment is discontinued, relapse is common, and longer-term tapering dose therapy often is necessary. There are disadvantages and no advantage to other forms of steroid therapy. Cholestyramine, bismuth, and 5-aminosalicylate derivatives appear to be less efficacious but are reasonable therapeutic options for less severe cases. Use of immunosuppressant therapy such as azathioprine or 6-mercaptopurine should be highly restricted because MC is a benign condition that does not result in other complications. Probiotic therapy with Lactobacillus acidophilus and Bifidobacterium animalis has not been shown to be effective in reducing bowel frequency. Surgical diversion of the fecal stream can control diarrhea and improve histology but is very rarely indicated and should be reserved for highly selected cases of severely symptomatic steroid-refractory MC.

Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory diseases of the colon with a benign and sometimes relapsing course. Frequency among patients with chronic diarrhea and normal looking colonoscopy is around 10-15%. To date, treatment of CC and LC is not well defined. Data about these conditions are mostly derived from retrospective studies. The aim of the present study was to evaluate the response to treatment and the clinical course of CC and LC in a large group of patients prospectively diagnosed.

A total of 819 patients underwent a colonoscopy because of chronic watery diarrhea and among them we found 41 patients with LC and 23 with CC. These patients were later randomized and assigned to treatment with mesalazine or mesalazine + cholestyramine for 6 months. Fifty-four patients (84.37%) had resolved diarrhea in less than 2 weeks. After 6 months a colonoscopy with biopsies was repeated. Clinical and histological remission was achieved in 85.36% of patients with LC and in 91.3% with CC, with a better result in patients with CC treated with mesalazine + cholestyramine. During a mean period of 44.9 months, 13% of patients relapsed; four with LC and three with CC. They were retreated for another 6 months. At the end of this period one patient with CC was still symptomatic and persistence of CC was confirmed at histology.

Treatment with mesalazine seems to be an effective therapeutic option for LC to date, while mesalazine + cholestyramine seems to be more useful in the treatment of CC.

Approximately 10% of patients with chronic diarrhea carry a diagnosis of microscopic colitis. The endoscopic appearance of both collagenous colitis and lymphocytic colitis may be normal; however, biopsies confirm the diagnosis. Available treatments include antidiarrheals, bismuth salicylate, and budesonide. Although most patients with fecal diversion may have endoscopic evidence of colitis, a much smaller percentage of patients are symptomatic. Some cases of diversion colitis respond to treatment with short-chain fatty acid enemas; however, return of the fecal stream is the most successful therapy. A variety of oral, intravenous, and per rectum chemicals may cause colitis; symptoms usually abate when chemical exposure is discontinued.

Collagenous colitis is a disorder that is recognized as a cause of chronic diarrhea. Treatment has been based mainly on anecdotal evidence. This review was performed to identify therapies for collagenous colitis that have been proven in randomized trials.

To determine effective treatments for patients with clinically active collagenous colitis.

Relevant papers published between 1970 and June 2006 were identified via the MEDLINE and PUBMED databases. Manual searches from the references of identified papers, as well as review papers on collagenous or microscopic colitis were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Finally, the Cochrane Controlled Trials Register and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies.

Seven randomized trials were identified. One trial studied bismuth subsalicylate (published in abstract form only), one trial studied Boswellia serrata extract (published in abstract form only), one trial studied probiotics, one trial studied prednisolone, and 3 trials studied budesonide for the therapy of collagenous colitis.

Data were extracted independently by each author onto 2x2 tables (treatment versus placebo and response versus no response). For therapies assessed in one trial only, p-values were derived using the chi-square test. For therapies assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. Data were combined for analysis only if the outcomes were sufficiently similar in definition.

There were 9 patients with collagenous colitis in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks). Those randomized to active drug were more likely to have clinical (p = 0.003) and histological (p = 0.003) improvement than those assigned to placebo. Eleven patients were enrolled in the trial studying prednisolone (50 mg daily for 2 weeks). There was a trend towards clinical response in patients on active medication compared to placebo (p = 0.064). The effect of prednisolone on histologic improvement was not studied. Thirty-one patients were enrolled in the Boswellia serrata extract trial. Clinical improvement was noted in 44% of patients who received active treatment compared to 27% of patients who received placebo (p = 0.32). Twenty-nine patients were enrolled in the probiotics trial. Clinical improvement was noted in 29% of patients who received probiotics compared to 13% of patients who received placebo (p = 0.635). A total of 94 patients were enrolled in 3 trials studying budesonide (9 mg daily or in a tapering schedule for 6 to 8 weeks). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI 5.53-27.46), with a number needed to treat of 2 patients. There was significant histological improvement with treatment in all 3 trials studying budesonide therapy. Budesonide also appears to improve patients' quality of life.

Budesonide is effective for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate is weaker. The effectiveness of prednisolone, Boswellia serrata extract, probiotics and other therapies for induction or maintenance of remission of collagenous colitis is unknown and requires further study.

Lymphocytic colitis and collagenous colitis represent two conditions that fall under the category of microscopic abnormalities within the lamina propria of the colon. Patients are predominantly women in the sixth decade of life who present with non-bloody watery diarrhea. Few other symptoms exist. Diagnosis is based upon finding characteristic abnormalities in the colonic mucosa, more likely to be found on the right side of the colon than the left. Treatment is symptomatic, although some newer therapies suggest regression of the lesion. Other autoimmune associations have been described, including celiac disease, and appropriate work-up for this condition should be considered for the patient who has seemingly refractory colitis. The natural history is benign, and most patients experience resolution of their symptoms.

To conduct a systematic review to determine effective treatments for patients with clinically active collagenous colitis.

Relevant articles were identified via the MEDLINE, PUBMED, and Cochrane Collaboration databases, manual searches of the references of identified articles, and review articles on collagenous or microscopic colitis, as well as searches of abstracts from major gastroenterological meetings.

Five randomized trials assessing treatments for collagenous colitis were identified. One trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 wk) included 9 patients. Patients who received the bismuth preparation were more likely to have clinical (p= 0.003) and histological (p= 0.003) improvement than those who received placebo. In a trial comparing prednisolone (50 mg daily for 2 wk) to a placebo in 11 patients, a trend toward clinical response in patients on prednisone was reported (p= 0.064). The effect of prednisolone on histological improvement was not studied. A total of 94 patients were enrolled in three trials studying budesonide (9 mg daily or in a tapering schedule for 6-8 wk). The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% CI: 5.53-27.46). The NNT (number of patients needed to treat with budesonide to achieve 1 improved patient) was 2 patients. This therapy was well tolerated. There was significant histological improvement with treatment in all three trials studying budesonide therapy.

There is strong evidence that budesonide is effective and well tolerated for the treatment of collagenous colitis. The evidence for benefit with bismuth subsalicylate or prednisolone is weaker. It is not clear that any of these agents produce actual remission, as opposed to clinical and histological improvement of the disease.

Microscopic colitis is a condition that is clinically underrecognized as a cause of chronic or intermittent diarrhea and can be diagnosed only by mucosal biopsy. Microscopic colitis is more common in middle-age to elderly women, appears to be induced by some medications, particularly nonsteroidal antiinflammatory drugs, and has been associated with autoimmune conditions and sprue. Symptomatic treatment includes cholestyramine and antidiarrheal medications. Bismuth subsalicylate, and 5-amniosalicylates are therapeutic options; however, budesonide is more effective in achieving clinical and histologic improvement and/or remission and has been studied in more randomized trials. Use of immune modulators should be restricted to more severe cases that are steroid refractory or steroid dependent. Surgical intervention should be reserved for a very highly select group of refractory cases. Diverting ileostomy or colectomy appear to be equally effective surgical alternatives for microscopic colitis, which is not a risk factor for carcinoma.

Data on collagenous colitis (CC) and lymphocytic colitis (LC) have been based on retrospective studies of registries of patients from multiple hospitals. Such studies may induce a selection of patients with severe forms of the disease, and conclusions about the clinical spectrum of the disease and treatment efficacy are difficult to be drawn. The aim of this study was to compare the clinical features, response to treatment, and long-term follow-up of CC and LC in a large group of patients prospectively diagnosed in a single center.

A specific program was undertaken to prospectively diagnose all patients with microscopic colitis from those referred for a full colonoscopy because of recurrent or chronic diarrhea. Detailed clinical and histological features, response to treatment, and long-term follow-up were compared in patients with confirmed CC and LC.

Thirty-seven patients with CC and 44 with LC were included. Patients with CC were significantly younger and had a significantly longer duration of diarrhea before diagnosis than those with LC. Otherwise, clinical presentation was similar. Drug-induced disease was suspected for ticlopidine, flutamide, gold salts, and bentazepam in LC. Complete resolution of diarrhea was achieved in all patients, spontaneously occurring in nearly 20% of them. Response to salicylates (mainly, mesalazine) was significantly better in LC than in CC (86% vs 42%, p = 0.005). Cholestyramine was highly effective in patients of both groups with concomitant bile acid malabsorption. Patients with CC required prednisone more often than those with LC (30% vs 4.5%, p = 0.005). Both prednisone and budesonide controlled ileal release were highly effective in patients with CC (82% and 89% efficacy). After cessation of diarrhea, 25% of patients with LC and 30% of those with CC relapsed after a mean follow-up of around 3 yr.

CC and LC share a similar clinical picture and have a benign course with long-term cessation of diarrhea in more than 70% of patients. Mesalazine and budesonide seem to be good options as first-line treatment in LC and CC, respectively. Cholestyramine may be a good alternative in patients with concomitant bile acid malabsorption.

The aims were to determine whether a wide variation exists between hospitals in the diagnosis of microscopic colitis and to assimilate clinical data.

Retrospective study of 90 patients with microscopic colitis aged between 16 and 92 years from 11 hospitals in south-east England.

A questionnaire was designed to collect relevant data from all patients in whom a new diagnosis of microscopic colitis had been made at the source hospital between January 1990 and December 1996. The inclusion criteria were presentation with watery diarrhoea, a normal endoscopy and a histological report of microscopic colitis. Histology slides were then requested and reviewed. Clinical data were analysed with reference to the confirmed diagnosis.

The number of patients diagnosed at each hospital ranged between zero and 30, with a median of six. Sixty-eight patients had histological slides reviewed. The numbers of patients with a final reviewed diagnosis of collagenous colitis, lymphocytic colitis and microscopic colitis, type undesignated, were 37, 18 and seven respectively. In thirty-one patients (34%) there was a recent history of the use of non-steroidal anti-inflammatory drugs.

These data confirm that there is wide hospital variation in the diagnosis of microscopic colitis. Furthermore, the small group with the undesignated type may be associated with the use of non-steroidal anti-inflammatory drugs.

Collagenous colitis is an idiopathic microscopic colitis characterized by chronic watery diarrhea, a typical subepithelial collagen layer, and lymphoplasmacellular infiltration. We investigated the effect of budesonide on symptoms and histology in patients with collagenous colitis in a randomized, double-blind, placebo-controlled multicenter trial.

Patients with chronic diarrhea and histologically proven collagenous colitis were randomized to receive either oral budesonide (Entocort capsules; AstraZeneca, Sodertalje, Sweden) 9 mg/day for 6 weeks or placebo. Complete colonoscopy was performed before and after treatment. Histopathology was assessed by a single pathologist blinded to the patients' treatment. Clinical symptoms were assessed by standardized questionnaires.

Fifty-one patients were randomized; 45 patients were available for per protocol analysis. The rate of clinical remission was significantly higher (P < 0.001) in the budesonide group than in the placebo group (per protocol 86.9% vs. 13.6%, respectively; intention-to-treat 76.9% vs. 12.0%, respectively). Histologic improvement was observed in 14 patients of the budesonide group (60.9%) and in 1 patient of the placebo group (4.5%; P < 0.001). Two patients in the budesonide group (7.7%) and 1 patient in the placebo group (4.0%) discontinued treatment prematurely because of side effects.

Oral budesonide (Entocort capsules) is an effective and safe treatment modality for patients with collagenous colitis. Long-term follow-up of these patients is necessary to investigate whether clinical and histologic remission is sustained.

Microscopic colitis is an umbrella term used to include two idiopathic inflammatory bowel disorders that present with chronic watery diarrhea, normal endoscopic findings and characteristic inflammatory changes on histology. Collagenous colitis and lymphocytic colitis are distinguished by the presence of a thickened subepithelial collagen table. It is likely that they are a spectrum of one disease, but this is yet to be proven. The majority of cases tend to undergo spontaneous remission within a few years of onset, and their clinical course is benign, with no increase in risk of colorectal cancer. Sufficient evidence exists to suggest that microscopic colitis occurs as a response to one or more luminal antigens. A variety of medications have been reported in the treatment of this condition, but only colloidal bismuth and budesonide have thus far been shown to be effective in randomized controlled trials.

In the nearly 20 yr since collagenous colitis was first recognized, the results of therapies have not been systematically described in substantial numbers of patients. We have therefore conducted a retrospective analysis of 26 patients treated in this institution during the years 1991-1994.

Twenty-nine cases of collagenous colitis were obtained by review of biopsy specimens collected between 1991 and 1994 at The Mount Sinai Hospital. Each chart was reviewed for patient demographics, symptoms, coexisting conditions, specific therapies, and therapeutic outcomes. Additional data were obtained from telephone calls to patients when deemed necessary. Three patients were exeluded from the study because of lack of follow-up. Therapeutic outcomes were defined as follows: Complete Remission (CR): normalization of bowel function; Partial Remission (PR): 50% reduction in frequency of bowel movements; Failure: <50% reduction in frequency of bowel movements; or Relapse: return of symptoms after cessation of treatment. Median follow-up was 58 wk from time of diagnosis, with a range of 22-376 wk.

The 26 patients (25 women, one man) had a mean age of 62 yr (range, 22-85 yr) at diagnosis. Of 26 patients, 22 responded to some form of therapy and one had spontaneous remission. Six of the responders ultimately remained in CR with no therapy. Twelve are maintained on 5-aminosalicylic acid (5-ASA) and or antidiarrheals to control symptoms. An additional six required prednisone throughout the follow-up period to remain in CR or PR. Two patients failed all therapy.

Collagenous colitis is a treatable condition in most patients. We recommend initial therapy with antidiarrheals, followed by a trial of 5-ASA agent. A trial of 5-ASA in combination with prednisone should be attempted in patients refractory to 5-ASA alone, with subsequent attempts in the responders to taper prednisone and maintain remission with no therapy, if possible, or with 5-ASA and/or antidiarrheal agents if necessary.

Celiac sprue is associated with specific HLA-DQ genes (mainly DQ2). Because there are epidemiological and histopathological similarities between celiac sprue and microscopic colitis, we hypothesized that these syndrome may share an HLA genetic predisposition and pathogenesis.

The HLA-DQ genes of 25 patients with celiac sprue, 53 patients with the microscopic colitis syndrome, and 429 normal controls were typed and compared. Serum was analyzed for antigliadin and antiendomysial antibodies. Small intestinal biopsies were analyzed for signs of histopathology.

HLA-DQ2 or DQ1,3 (the latter as DQ1,7,DQ1,8, or DQ1,9) were seen more frequently in both patient groups relative to controls. In patients with the microscopic colitis syndrome, serological tests for celiac sprue were weakly positive in 17%; mild inflammation of the small intestine without villous atrophy was present in 43%, and inflammation plus partial or subtotal villous atrophy was present in 27%.

A shared set of predisposing HLA-DQ genes account for the epidemiological overlap of celiac sprue and microscopic colitis. Mild to moderate mononuclear cell inflammation of the small intestine, often accompanied by partial or subtotal villous atrophy, is frequent in patients with the microscopic colitis syndrome. Although further studies will be necessary to determine if this enteropathy is induced by dietary gluten, we speculate that the small intestinal but not colonic histopathology in patients with microscopic colitis is caused by immunological gluten sensitivity.

Collagenous colitis is a chronic watery diarrhea disorder characterized by a subepithelial collagen layer and a lymphoplasmacytic infiltration within the lamina propria. However, no standard treatment has been introduced by controlled clinical trials. Aim of the present pilot trial was to investigate the clinical effects of orally administered budesonide (3 mg t.i.d.) in 7 patients with collagenous colitis. In addition, the histomorphological changes after budesonide treatment were described in a group of 3 patients.

The study was performed as an open label pilot trial. Study end point was the clinical remission of collagenous colitis defined by stool frequency and stool consistency.

The results indicate a rapid and sustained clinical response in all patients. Stool frequency significantly decreased (p < 0.001) from 10.43 +/- 5.56 per day (4-20 per day) to 3.3 +/- 1.2 (1-5 per day) after 10 days and to 1.86 +/- 0.69 per day (1-3 per day) after 10 wk. Moreover stool consistency changed from watery (6 patients) or soft (1 patient) to soft (1 patient) or solid (6 patients). Clinical improvement was achieved within the first 10 days in all patients and maintained after dose reduction. In 3 patients no diarrhea recurred within 7, 12, or 15 months after treatment with budesonide was terminated. In these patients control biopsies were taken and showed a marked regression of both characteristics, the collagen band and the lymphoplasmacytic infiltration.

With respect to the preliminary data from this pilot trial, budesonide with its high topical and low systemic effects seems to be of therapeutic clinical benefit in collagenous colitis. A therapeutic effect could be demonstrated for both therapeutic goals, the clinical response and morphological changes. Further studies on the effects of budesonide on mucosal collagen metabolism and long-term follow-up are warranted.

When possible, patients taking nonsteroidal anti-inflammatory medications should discontinue them when the diagnosis of microscopic colitis is made. Although there is no direct evidence of its efficacy, a trial of elimination of caffeine or lactose or both should be undertaken. Nonspecific antidiarrheal agents (eg, loperamide, diphenoxylate) may be administered, but appear to be largely ineffective in this population. An aminosalicylate should be initiated at full therapeutic dose (2 to 4 g daily) as the first-line therapy. Because sulfasalazine appears to be associated with a high incidence of adverse effects in patients with microscopic colitis, other derivatives of 5-aminosalicylate (5-ASA) are preferred. Bile salt-binding agents such as cholestyramine or colestipol appear to be effective alternatives for patients who are either unresponsive to or intolerant of aminosalicylates. Systemic corticosteroids are an effective treatment for microscopic colitis, but may offer only transient improvement in symptoms. Given their potential adverse effects, corticosteroids should be reserved for patients with refractory disease in whom aminosalicylates and bile salt-binding agents have failed. Other agents that may be effective include antibiotics, bismuth subsalicylate, budesonide, pentoxifylline, octreotide, and methotrexate. Although these agents can be considered in unusual cases, the cumulative clinical experience with them in this setting is relatively limited. Surgical intervention, with either fecal stream diversion or subtotal colectomy, shows promise as an intervention of last resort. In refractory cases of microscopic colitis, strong consideration should be given to excluding a concomitant diagnosis of celiac disease, bacterial overgrowth, or chronic infection.

The aetiology of the chronic inflammatory bowel diseases-ulcerative colitis and Crohn's disease-as well as 'microscopic colitis'-both collagenous (COC) and lymphocytic colitis (LC)-remains unknown. Autoimmune mechanisms, cytokine polymorphism, commensal bacteria, infectious agents and vascular impairment have all been proposed as playing important roles in the pathogenesis of this spectrum of diseases. A variety of proinflammatory mediators, including tumour necrosis factor alpha, interleukin-1beta, interferon gamma, leukotriene B4 and platelet activating factor, promote the adherence of phagocytes to the venular endothelium and extravasation of these cells into the colonic mucosa. In addition to large amounts of nitric oxide (NO), injurious peroxynitrite may be formed in the epithelium by the inducible nitric oxide synthase (iNOS), which is considered to elicit cytotoxicity by the generation of superoxide with reduced L-arginine availability. In active ulcerative colitis, and to a lesser extent in Crohn's disease, a greatly increased production of NO has been demonstrated by indirect and direct measurements. Surprisingly, even higher rates of production have been observed in COC-a condition which is never associated with injurious inflammation. The latter observation favours the notion that NO promotes mucosal integrity. Further evidence for a protective role of NO in chronic inflammatory bowel disorders is provided by the observation of increased susceptibility to the induction of experi mental colitis in 'knock-out' mice deficient in iNOS. Selective inhibitors of iNOS activity, as well as topical L-arginine, may therefore prove beneficial in inflammatory bowel disease by reducing the production of superoxide by iNOS, while only the former option may be expected to reduce diarrhoea in chronic inflammatory bowel disorders. Clearly, further experimental work needs to be done before testing topical L-arginine in human inflammatory bowel disease.

The pathogenesis of the microscopic colitis syndrome is unknown but may involve bacteria, an intestinal luminal antigen, and/or autoimmunity. It was hypothesized that bismuth subsalicylate would resolve both diarrhea and colonic inflammation in microscopic colitis because it possesses antidiarrheal, antibacterial, and anti-inflammatory properties.

Thirteen patients with microscopic colitis (7 with subepithelial collagen deposition and 6 without) were treated with eight chewable 262-mg bismuth subsalicylate tablets per day for 8 weeks. Patients recorded the frequency of bowel movements daily. Forty-eight-hour stool collections and flexible sigmoidoscopy with 24 biopsies were performed before and after treatment in each patient.

Twelve patients completed the trial. Eleven patients had a resolution of diarrhea and a reduction in fecal weight. The average time to respond was 2 weeks. In 9 patients, colitis resolved. When present before treatment, subepithelial collagen thickening disappeared. Those completing the trial experienced no side effects. Posttreatment follow-up for 7-28 months shows that 9 patients remain well having undergone no further treatment, 2 are well but required retreatment, and 1 has continued diarrhea.

Bismuth subsalicylate treatment for 8 weeks is safe and well tolerated. This regimen appears to be efficacious for the treatment of microscopic colitis and is worthy of further study in a controlled trial.

Data on collagenous colitis have been based on a limited number of patients.

To obtain more information on this disease from a register set up at Orebro Medical Center Hospital.

Twenty five Swedish hospitals have contributed to this patient register, which comprises 163 histopathologically verified cases. Clinical data were retrospectively analysed.

Collagenous colitis followed a chronic intermittent course in most cases (85%) with a sudden onset in 42%. Symptoms were chronic watery diarrhoea, often nocturnal (27%), abdominal pain (41%), and weight loss (42%). Sixty six patients (40%) had one or more associated diseases. Routine laboratory data were mostly normal. The median age at diagnosis was 55 (range 16-86) years, but 25% of the patients were younger than 45 years. Seven patients died of unrelated diseases. The response rate for sulphasalazine was 59%, and 50% and 40% for mesalazine and olsalazine. Prednisolone was most effective with a response rate of 82%, but the required dose was often high and the effect was not sustained after withdrawal. Antibiotics were efficient in 63%. Cholestyramine and loperamide had response rates of 59% and 71% respectively.

Collagenous colitis follows a chronic continuous course. Symptoms can be socially disabling, but the disease does not seem to have a malignant potential. A plan for the treatment of a newly diagnosed patient with collagenous colitis is proposed.

The aetiology and pathogenesis of collagenous colitis are unknown. Autoimmunity has been suggested, but no serological findings have supported such a theory.

Serum from 38 collagenous colitis patients and 38 matched healthy controls was analysed for autoantibodies--that is, antinuclear antibodies, antineutrophil cytoplasmic antibodies, smooth muscle and mitochondrial antibodies, rheumatoid factor and antibodies to thyroglobulin and microsomal antigen, together with antibodies to endomysium, gliadin, and cardiolipin. The serum values of IgA, IgG, IgM, and IgG-subclasses, and complement factors C3 and C4 were also determined.

In patients with collagenous colitis the mean value of IgM was significantly increased 2.5 g/l (95% CI; 1.9, 3.2) compared with 1.4 g/l (95% CI; 1.2, 1.7) in controls (p = 0.002). Antinuclear antibodies occurred in nine of 38 patients compared with three of 38 controls, this difference was not statistically significant (p = 0.11). The results of all other immunoglobulins, complement factors, and specific antibodies showed no statistical difference between patients and controls.

No firm evidence for an autoimmune genesis in collagenous colitis is found in this study, although the findings of a positive ANA-titre in some patients and an increased IgM level might give some support for this hypothesis.

Collagenous colitis is a rare disease of unknown etiology that primarily affects middle-aged women. It presents with chronic watery diarrhea and thickening of the subepithelial collagen layer of the colonic mucosa in the absence of endoscopic abnormalities.

This study was undertaken to review the current literature on clinical course, pathology, diagnosis, and current management of collagenous colitis.

Collagenous colitis is an inflammatory disease of the colon, clinically characterized by a waxing and waning course of watery diarrhea, an inflammatory infiltration of the colonic mucosa, and a thickening of the subepithelial collagen layer. Its pathogenesis remains unclear, but there is evidence for an inflammatory process triggered possibly by an uncommon luminal agent. Diagnosis is established by colonic biopsies; in the setting of normal colonic mucosa, the disorder is primarily managed medically with virtually no role for surgery.

Pathogenesis of collagenous colitis remains unclear. Current data favor an inflammatory etiology, possibly involving an initiating luminal insult. Guidelines for diagnosis are being established, and medical treatment options are variably effective in the majority of cases. Very unusual refractory cases may benefit from surgical management.

Collagenous colitis and lymphocytic colitis present with a similar clinical picture. Whether these conditions are separate entities or whether they represent different pathological stages of the same condition is an unresolved issue.

This is a case of collagenous colitis following a fulminant course in which a colectomy was necessary. In the operative specimen the thickened collagen plate, which had been present only two weeks preoperatively had been lost and the pathology was of a lymphocytic colitis. Six months postoperatively this patient developed a CREST syndrome and primary biliary cirrhosis.

This case shows the lability of the collagen plate and the common ground between collagenous and lymphocytic colitis, and presents evidence that these two conditions are different manifestations of the same disease. It also describes for the first time an association between collagenous colitis and CREST syndrome and primary biliary cirrhosis.

The incidence and prevalence of collagenous colitis are unknown. An epidemiological study was undertaken between 1984-93. All patients living in the immediate catchment area of Orebro Medical Center Hospital with the diagnosis collagenous colitis were identified. Biopsy specimens classified as unspecific intestinal fibrosis were re-examined to identify cases not correctly diagnosed at first. Medical records were scrutinised and colorectal biopsy specimens re-evaluated. Thirty patients with collagenous colitis were diagnosed during the study period. The female:male ratio was 9:1. The median age at diagnosis was 64 (28-78) years. The prevalence at 31 December 1993, was 15.7/10(5) inhabitants (95% CI; 9.8 to 21.6/10(5)). The mean annual incidence during the period 1984-93 was 1.8/10(5) inhabitants (95% CI; 1.2 to 2.4/10(5)). A peak incidence was found in women 70-79 years old. Collagenous colitis occurs mainly in middle aged women, and the frequency is higher than earlier anticipated. The prevalence and incidence is similar to primary biliary cirrhosis. In women 70-79 years of age, the incidence for collagenous colitis approaches the incidence for ulcerative colitis.

Collagenous colitis is associated with normal endoscopy examination and peculiar histopathological changes. The natural history and optimal treatment are not well defined. Our objectives were to analyze the symptomatology of collagenous colitis, determine the natural history, and response to treatment. All patients with collagenous colitis from 1978 to 1992 were studied. Demographic data, symptomatology, associated conditions, colonoscopic findings, and pathology specimens were reviewed. Clinical improvement was classified as none, partial, or complete. Nineteen patients were identified, mainly white females over age 50. Mean follow-up was 22.6 months. Symptom duration was 37 months (range 4 months to 15 years). Symptoms were intermittent diarrhea (19), with a predominant nocturnal component (13); abdominal pain (15); and mild weight loss and incontinence (8). Colonoscopy was normal in 12 patients. Segmental mucosal edema and loss of vasculature pattern were present in seven. Antiperistaltic agents were used in 17 patients with no improvement (15), partial resolution (1), and complete resolution (1). Eight nonresponders received sulfasalazine. Responses were none (6) or complete (2). Ten patients received steroids (10-20 mg/day). One failed to respond. Nine initially responded completely but two relapsed. Seven patients who did not respond to any type of treatment improved eventually, two partially and five completely. These patients were younger (54.3 vs 68.3 years, P = 0.04) and symptom duration was shorter (25.4 vs 44.5 months, P = 0.38) than the rest of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Collagenous and lymphocytic colitis are newly recognized causes of chronic watery diarrhea that typically affect middle-aged patients. Although endoscopic studies are normal, inflammatory changes and (in the case of collagenous colitis) collagen deposition occur histologically in the colonic mucosa. The pathogenesis of these disorders remains a mystery, but the possible causes are intriguing. Patients may experience spontaneous remissions and relapses, but treatment with sulfasalazine or prednisone is usually effective for patients with distressing symptoms.

Neutropenic colitis is a complication of the treatment of hematologic malignancies and, less commonly, of other disease entities. The septic, inflammatory process has a predilection for the terminal ileum and right colon. While the pathogenesis is not clear, mucosal injury caused by several different mechanisms and local opportunistic infection play significant roles. An association has been recognized between neutropenic colitis and sepsis caused by C. septicum. Patients present with fever, diarrhea, and acute abdominal pain and tenderness often localized in the right lower quadrant. Sonography and CT are helpful in demonstrating colonic wall thickening and pericolic fluid. Peritoneal lavage has been used to exclude perforation in these critically ill patients. Although there has been debate about whether medical or operative management is best, the optimal initial therapy includes supportive care with gastric decompression, fluid and blood product replacement, and broad-spectrum antibiotics. The indications for surgery include continued intestinal bleeding despite correction of coagulopathy and pancytopenia, free intraperitoneal air, and uncontrolled sepsis. At operation, a right colectomy with ileostomy and mucous fistula or, in selected patients, primary anastomosis is the procedure of choice. Timely return of functioning neutrophils and the eventual prognosis of the primary disease are crucial to the overall success or failure of treatment of neutropenic colitis.