Collagenous colitis

Collagenous colitis is an inflammatory bowel disease of unknown cause with watery non-bloody diarrhea as the leading symptom ¹. Collagenous colitis is a type of microscopic colitis, a condition characterized by chronic watery non‐bloody diarrhea ². The other type of microscopic colitis is lymphocytic colitis. The types of microscopic colitis are defined based on their findings by biopsy. Clinical features of both collagenous colitis and  lymphocytic colitis are very similar. Patients will typically present with chronic, watery, non-bloody diarrhea with normal or near normal appearing colonic mucosa at endoscopy and characteristic microscopic features ³. People with collagenous colitis have a normal appearing bowel when assessed by an endoscope (a camera used to look at the bowel); but have microscopic inflammation of the bowel when assessed by a biopsy (a tissue sample taken during endoscopy) ². There have even been case reports of concurrent lymphocytic and collagenous colitis ⁴.

Collagenous colitis classically occurs in elderly women ⁵, with a peak incidence around 60–70 years of age but has been described in all age groups, including the pediatric population ⁶. Most patients receive their diagnosis around the age of 65, but approximately 25 percent of patients get diagnosed before 45 ⁷. Collagenous colitis can happen in children but is very rare ⁸. There is a female preponderance in both collagenous and lymphocytic colitis. The female to male ratio of collagenous colitis is 3.0 and is 1.9 in lymphocytic colitis ⁹.

Since the first description of a case of collagenous colitis was first described in 1976 when a thick subepithelial collagenous deposit in the colorectal mucosa was identified in a rectal biopsy from a patient with chronic diarrhea ¹⁰, microscopic colitis has been associated with celiac disease and other autoimmune disorders ¹¹ as well as with the use of certain medications, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) ¹². Unlike the other inflammatory bowel diseases, many aspects of the condition’s cause, pathogenesis, and natural history remain poorly understood. Prior to the introduction of budesonide, the wide range of medications prescribed reflects the lack of specific guidelines for the treatment of microscopic colitis. With few randomized trials available to guide management ¹³. Treatment was based predominantly on the individual preference and experience of the treating physician, taking into account the pattern and severity of symptoms and potential contraindications to the use of specific therapies ¹⁴. Collagenous colitis is more clearly defined than lymphocytic colitis, furthermore, non-specific colonic lymphocyte infiltration is frequently encountered.

The incidence of collagenous colitis ranges from 2.0 to 10.8 per 100,000, and lymphocytic colitis ranges from 2.3 to 16 per 100,000 ¹⁵. An incidence of 5–10 per 100,000 has been described in population-based studies with a prevalence of collagenous colitis in Olmsted County, MN, USA in 2010 of 90.4 per 100,000 and in Örebro, Sweden of 67.7 per 100,000 ¹⁶.

A recent meta-analysis of 25 studies by Tong et al ¹⁷ reports a pooled incidence rate of 4.14 per 100,000 person years with steadily increasing incidence rates until 2000, but since then stable rates have been observed in the USA, Spain, and Sweden. However, higher reports were reported in a 10 year Danish pathology study with annual incidence rates increasing from 2.9 to 14.9 per 10,000. This rise corresponded with an increase in biopsies taken and the authors conclude that this may represent increased diagnostic activity ¹⁸.

A Korean study of chronic diarrhea detected collagenous colitis in 4% of patients similar to rates recorded in the western world ¹⁹ and has been reported with lower prevalence rates in Indian and Malaysian studies ²⁰.

Treatment depends on the severity of symptoms. Your gastroenterologist may prescribe medications to help control symptoms. Medications are almost always effective in treating microscopic colitis. The gastroenterologist may recommend eating, diet, and nutrition changes. In rare cases, the gastroenterologist may recommend surgery.

The gastroenterologist may prescribe one or more of the following:

• antidiarrheal medications such as bismuth subsalicylate (Kaopectate, Pepto-Bismol), diphenoxylate/atropine (Lomotil), and loperamide
• corticosteroids such as budesonide (Entocort) and prednisone
• anti-inflammatory medications such as mesalamine and sulfasalazine (Azulfidine)
• cholestyramine resin (Locholest, Questran)—a medication that blocks bile acids
• antibiotics such as metronidazole (Flagyl) and erythromycin
• immunomodulators such as mercaptopurine (Purinethol), azathioprine (Azasan, Imuran), and methotrexate (Rheumatrex, Trexall)
• anti-TNF therapies such as infliximab (Remicade) and adalimumab (Humira)

Corticosteroids are medications that decrease inflammation and reduce the activity of the immune system. These medications can have many side effects. Scientists have shown that budesonide is safer, with fewer side effects, than prednisone. Most health care providers consider budesonide the best medication for treating microscopic colitis.

Patients with microscopic colitis generally achieve relief through treatment with medications, although relapses can occur. Some patients may need long-term treatment if they continue to have relapses.

What is microscopic colitis?

Microscopic colitis is an inflammation of the colon that a health care provider can see only with a microscope. Inflammation is the body’s normal response to injury, irritation, or infection of tissues. Microscopic colitis is a type of inflammatory bowel disease—the general name for diseases that cause irritation and inflammation in the intestines.

The two types of microscopic colitis are collagenous colitis and lymphocytic colitis. Health care providers often use the term microscopic colitis to describe both types because their symptoms and treatments are the same. Some scientists believe that collagenous colitis and lymphocytic colitis may be different phases of the same condition rather than separate conditions.

In both types of microscopic colitis, an increase in the number of lymphocytes, a type of white blood cell, can be seen in the epithelium—the layer of cells that lines the colon. An increase in the number of white blood cells is a sign of inflammation. The two types of colitis affect the colon tissue in slightly different ways:

• Lymphocytic colitis. The number of lymphocytes is higher, and the tissues and lining of the colon are of normal thickness.
• Collagenous colitis. The layer of collagen, a threadlike protein, underneath the epithelium builds up and becomes thicker than normal.

When looking through a microscope, the health care provider may find variations in lymphocyte numbers and collagen thickness in different parts of the colon. These variations may indicate an overlap of the two types of microscopic colitis.

Does microscopic colitis increase the risk of colon cancer?

No. Unlike the other inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, microscopic colitis does not increase a person’s risk of getting colon cancer.

Collagenous colitis causes

The exact cause of microscopic colitis is unknown. Collagenous colitis is a multifactorial disease, likely the result of an abnormal immune reaction to luminal antigens or bacteria in predisposed individuals, with subsequent epithelial barrier dysfunction in the colonic mucosa ²¹.

Scientists have proposed other causes, including:

• autoimmune diseases
• medications
• infections
• genetic factors
• bile acid malabsorption

There have been two possible causes of microscopic colitis theorized and a genetic component that predisposes to the condition, including medications and smoking tobacco ¹⁵. Medications that have links as causative or that lead to flares include nonsteroidal anti-inflammatory drugs (NSAIDs) ²². While this currently has the strongest link, other drugs also demonstrate correlations as potential causes including proton pump inhibitors, especially lansoprazole, statins, selective serotonin reuptake inhibitors, and pembrolizumab which is a humanized antibody used in cancer immunotherapy ²³.

Smoking may play a role in microscopic colitis, as it has been linked to multiple other inflammatory conditions as well. It has been linked to an increased risk of microscopic colitis and can lead to the development of microscopic colitis more than ten years earlier than in non-smokers ²⁴.

Celiac disease is another inflammatory bowel condition that primarily affects the upper gastrointestinal system. This syndrome is associated with HLA-DR3-DQ2 haplotype, which also correlates with microscopic colitis, similarly to celiac disease; the inflammatory process is similar between the two syndromes ²⁵.

An aberrant T lymphocyte response is thought to drive chronic gut inflammation and a Th1 cytokine profile predominates with elevated levels of interferon-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-1β ²⁶. The mechanism of diarrhea has been attributed to reduced Na+ and Cl− absorption accompanied by active Cl− secretion. Watery stools in collagenous colitis are driven by a combination of osmotic and secretory components as well as impaired barrier function ²⁷.

Unlike Crohn’s disease and ulcerative colitis there is little data to suggest genetic inheritance, however, there are reports of familial cases of collagenous colitis. Two families are described, in each two first degree relatives develop collagenous colitis and in all four patients the human leukocyte A2 antigen was detected ²⁸.

Variations in matrix metalloproteinase-9 and TNFα gene expression have been described ²⁹.

Others postulate that collagenous colitis occurs as a sequela to infectious colitis with the reports of development after Yersinia enterocolitica and Clostridium difficile infections ³⁰. Furthermore, resolution of symptoms following treatment for Helicobacter pylori has been reported ³¹.

The development of a thickened collagen band is attributed to abnormal collagen metabolism. Subepithelial matrix deposition is driven by increased expression of fibrogenic gene procollagen I and metalloproteinase inhibitor and promyofibroblastic cells as well as impaired fibrinolysis ³².

Increased levels of eosinophils transforming growth factor beta expression have been demonstrated in patients with collagenous colitis, and this is thought to drive tissue collagen accumulation ³³. Increased expression of nitric oxide synthase driven by upregulation of nuclear transcription factor beta results in increased colonic nitric oxide production, which in turn may cause a secretory diarrhea ³⁴.

Autoimmune diseases

Sometimes people with microscopic colitis also have autoimmune diseases—disorders in which the body’s immune system attacks the body’s own cells and organs. Autoimmune diseases associated with microscopic colitis include:

• Celiac disease—a condition in which people cannot tolerate gluten because it damages the lining of the small intestine and prevents absorption of nutrients. Gluten is a protein found in wheat, rye, and barley.
• Thyroid diseases such as:
  • Hashimoto’s disease—a form of chronic, or long lasting, inflammation of the thyroid.
  • Graves’ disease—a disease that causes hyperthyroidism. Hyperthyroidism is a disorder that occurs when the thyroid gland makes more thyroid hormone than the body needs.
• Rheumatoid arthritis—a disease that causes pain, swelling, stiffness, and loss of function in the joints when the immune system attacks the membrane lining the joints.
• Psoriasis—a skin disease that causes thick, red skin with flaky, silver-white patches called scales.

Medications

Researchers have not found that medications cause microscopic colitis. However, they have found links between microscopic colitis and certain medications, most commonly:

• nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen
• lansoprazole (Prevacid)
• acarbose (Prandase, Precose)
• ranitidine (Tritec, Zantac)
• sertraline (Zoloft)
• ticlopidine (Ticlid)

Other medications linked to microscopic colitis include:

• carbamazepine
• clozapine (Clozaril, FazaClo)
• dexlansoprazole (Kapidex, Dexilant)
• entacapone (Comtan)
• esomeprazole (Nexium)
• flutamide (Eulexin)
• lisinopril (Prinivil, Zestril)
• omeprazole (Prilosec)
• pantoprazole (Protonix)
• paroxetine (Paxil, Pexeva)
• rabeprazole (AcipHex)
• simvastatin (Zocor)
• vinorelbine (Navelbine)

Infections

• Bacteria. Some people get microscopic colitis after an infection with certain harmful bacteria. Harmful bacteria may produce toxins that irritate the lining of the colon.
• Viruses. Some scientists believe that viral infections that cause inflammation in the alimentary tract may play a role in causing microscopic colitis.

Genetic factors

Some scientists believe that genetic factors may play a role in microscopic colitis. Although researchers have not yet found a gene unique to microscopic colitis, scientists have linked dozens of genes to other types of inflammatory bowel disease, including

• Crohn’s disease—a disorder that causes inflammation and irritation of any part of the alimentary tract
• ulcerative colitis—a chronic disease that causes inflammation and ulcers in the inner lining of the large intestine

Bile acid malabsorption

Some scientists believe that bile acid malabsorption plays a role in microscopic colitis. Bile acid malabsorption is the intestines’ inability to completely reabsorb bile acids—acids made by the liver that work with bile to break down fats. Bile is a fluid made by the liver that carries toxins and waste products out of the body and helps the body digest fats. Bile acids that reach the colon can lead to diarrhea.

Risk factors for developing collagenous colitis

Traditionally, microscopic colitis was considered a condition of middle-aged women using aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) but now many classes of drugs including selective seratonin reuptake inhibitors, statins, proton pump inhibitors, topirimate, venotonic agents, and histamine antagonists have been associated with medication related colitides ³⁵. However, evidence supporting cause and effect is lacking, in fact, many of these medications list diarrhea as a side effect.

Smoking is consistently reported as an environmental risk factor in the development of collagenous colitis ³⁶. This may be related to impaired colonic circulatory changes. The smokers developed their disease >10 years earlier than nonsmokers, but smoking does not influence the subsequent disease course ³⁷.

Experts recommends obtaining a detailed medication, diet, and smoking history to identify factors that may exacerbate symptoms, furthermore, coexisting causes of diarrhea (celiac disease or bile-salt diarrhea) should be considered.

Clinical characteristics, treatment and outcomes of microscopic colitis in 222 patients was studied and a history of concomitant autoimmune disorders was recorded in 62 patients (28%). Twenty-six patients (11%) had either a known diagnosis of celiac disease or were diagnosed at the same time as their lower gastrointestinal examination ³⁸. This underlines the particular importance of colonic biopsy in patients whose celiac disease remains symptomatic despite adherence to a gluten-free diet. Recently, data from a Canadian population study ³⁹ report a strong association between microscopic colitis and celiac disease with concomitance being ~50 times that expected in the general population. A Spanish case-control study ³⁶ recently showed that autoimmune diseases were independently associated with the risk of microscopic colitis development.

Collagenous colitis symptoms

The hallmark of collagenous colitis is chronic watery diarrhea; other symptoms include abdominal pain, urgency fecal incontinence, abdominal pain, fatigue, and weight loss ⁴⁰. Episodes of diarrhea can last for weeks, months, or even years. However, many people with microscopic colitis may have long periods without diarrhea. The symptoms of microscopic colitis can come and go frequently. Sometimes, the symptoms go away without treatment.

Collagenous colitis is rarely associated with serious complications, however, cases of spontaneous and post colonoscopy perforation have been reported ⁴¹ and Bohr et al ⁴² propose a connection between mucosal tears and colonic perforation in collagenous colitis. Unlike chronic inflammation seen in ulcerative and Crohn’s colitis, no increased risk of colorectal cancer has been attributed to collagenous colitis, furthermore, it may be protective against colorectal cancer. In a study of 305 patients undergoing colonoscopy for evaluation of chronic non-bloody diarrhea, 16% had microscopic colitis, and patients with microscopic colitis were negatively associated with the risk of neoplastic polyps ⁴³.

The clinical symptoms may be misdiagnosed as irritable bowel syndrome (IBS). A total of 247 who were diagnosed with diarrhea predominant irritable bowel underwent colonoscopy and 6% were subsequently diagnosed with microscopic colitis (13 lymphocytic colitis, 2 collagenous colitis) ⁴⁴. Interestingly, colonoscopies performed in patients who fulfilled diagnostic criteria for IBS were significantly more likely to find organic gastrointestinal pathology in those with diarrhea predominant symptoms, with microscopic colitis diagnosed in 2.2% of patients ⁴⁵. Additionally, there is considerable symptomatic overlap between both disorders ⁴⁶.

Quality of life was severely impaired in Swedish patients, particularly when the colitis is active compared to the background population ⁴⁷. A Swedish case-control study subsequently demonstrated that abdominal pain, fatigue, arthralgia, myalgia, fecal incontinence, and nocturnal defecation were significantly more prevalent in collagenous colitis patients compared with controls ⁴⁸.

Collagenous colitis complications

Currently, there are no known complications of disease progression itself outside of recurrent symptoms. The primary concern would be complications of therapy with budesonide as this is a steroid with multiple complications associated with long term use ⁴⁹.

Collagenous colitis diagnosis

There are no reliable biomarkers, no specific laboratory tests, stool cultures are sterile and radiological findings are normal.

Fecal lactoferrin and calprotectin, which can be used as non-invasive markers of inflammation in ulcerative colitis and Crohn’s disease are not reliable in the diagnosis or assessment of collagenous colitis ⁵⁰.

Endoscopic evaluation of the colon can be normal, however, erythema, edema, change in vascularity, mucosal tears, and nodularity have been described ⁵¹.

The diagnosis is made based on characteristic histological findings in colonic mucosal biopsies. The key histological feature of collagenous colitis is a thickened collagen band under the surface epithelium ⁵². The European consensus guidelines on diagnosis state that the thickness of the collagen band should exceed 10 μm (normal <3 μm) in well-oriented biopsies (cut perpendicularly to the mucosal surface) ⁵². The band can appear thicker (up to 70 μm) and band thickness greater than 15mm is usually associated with diarrhea ⁵³, but there is no direct correlation between band thickness and symptoms.

Hematoxylin and eosin staining is sufficient for diagnosis in most cases. In questionable cases special collagen stains (blue trichrome, Goldner, and Sirius red) or immunohistochemistry with anti-tenascin antibodies are required for diagnosis ⁵⁴.

Findings can be patchy in nature, with colonic segments affected to varying extents ⁵³. The subepithelial collagen band tends to be less thick in the distal colon, in particular the rectum and sigmoid colon ⁵⁵. Carpenter et al ⁵⁶ demonstrated that in patients with proximal inflammation left-sided biopsies alone would have missed 40% of cases. Therefore, rectal and left-sided biopsies alone are insufficient for diagnosis. The best approach to diagnosis is obtaining multiple biopsies throughout the colon submitted as individual pathology specimens ⁵⁷.

Lab tests may include:

• blood tests
• stool tests

Blood tests. A blood test involves drawing blood at a health care provider’s office or a commercial facility and sending the sample to a lab for analysis. A health care provider may use blood tests to help look for changes in red and white blood cell counts.

• Red blood cells. When red blood cells are fewer or smaller than normal, a person may have anemia—a condition that prevents the body’s cells from getting enough oxygen.
• White blood cells. When the white blood cell count is higher than normal, a person may have inflammation or infection somewhere in the body.

Collagenous colitis and lymphocytic colitis histopathology

In general, both collagenous colitis and lymphocytic colitis present with inflammation within the mucosa. Specifically, in the lamina propria, there is mononuclear cell predominance, with few neutrophils and eosinophils. There are, however, other histological differences that are worth noting between the two types of microscopic colitis.

• Collagenous colitis – A collagen band greater than 10 micrometers in diameter in the subepithelial layer defines this type of microscopic colitis ⁵⁸.
• Lymphocytic colitis – 20 or more intraepithelial lymphocytes per 100 epithelial cells, typically without crypt distortion, defines lymphocytic colitis ⁵⁹.
• Microscopic colitis not otherwise specified – This terminology is used to describe a subgroup of patients with typical symptoms such as diarrhea, increased cellular infiltrate, and either an abnormal collagenous layer or increased intraepithelial lymphocytes that do not match the above criteria ⁶⁰.

Collagenous colitis treatment

No curative therapy currently exists for microscopic colitis. 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. Prior to the introduction of budesonide, choice of treatment relied largely on the experience of the individual physician or institution and was based on observational data, with few randomized trials available to guide management ¹³; the few controlled trials that exist have mainly evaluated budesonide.

The main treatment for microscopic colitis is medication. In many cases, your doctor will start treatment with an antidiarrheal medication such as Pepto-Bismol® or Imodium® .

Other medications the doctor can prescribe include:

• Corticosteroids, man-made drugs that closely resemble cortisol (a hormone that your adrenal glands produce). Steroids work by decreasing inflammation and reducing the activity of the immune system. The two steroids most often prescribed for microscopic colitis are budesonide (Entocort®) and prednisone. Budesonide is believed to be the safest and most effective medication for treating microscopic colitis.
• Cholestyramine resin (Locholest®, Questran®), which blocks bile acids
• Antibiotics
• Mesalamine (Apriso®, Asacol®) and sulfasalazine (Azulfidine®) to reduce swelling
• Medications that work on the immune system, such as mercaptopurine (Purinethol®), azathioprine (Azasan®, Imuran®), and methotrexate (Rheumatrex®, Trexall®)
• Tumor Necrosis Factor (TNF) inhibitors such as infliximab (Remicade®) and adalimumab (Humira®)

Your doctor may also recommend that you avoid certain foods, such as caffeine or artificial sugars.

As a last resort when medications are not working, the doctor may recommend surgery to remove part or all of the colon.

Hjortswang et al ⁶¹ studied the impact of colonic symptoms on health-related quality of life in collagenous colitis and based on these defined criteria for remission and disease activity. Quality of life was impaired in those with a mean of ≥3 stools/day or a mean of ≥1 watery stool/day, therefore, the Hjortswang-Criteria propose that clinical remission in collagenous colitis is defined as a mean of <3 stools/day and a mean of <1 watery stool per day and disease activity to be a daily mean of ≥3 stools or a mean of ≥1 watery stool.

Initial management of symptoms includes antidiarrheal agents such as loperamide ⁶². These medications alone may be enough to control symptoms, but other medicines may be necessary for control. When using these medications, it is essential to complete an infectious workup first, as they can worsen symptoms of Clostridium difficile infection. If the patient continues to have three or more stools daily with at least one being watery, the addition of a glucocorticoid such as budesonide is a recommended therapy. With budesonide, 6 to 8 weeks of therapy is typically necessary for complete resolution ⁶³. After this duration of therapy, the drug must be tapered. A typical dose starts at 9mg daily. Prednisone is another glucocorticoid that is an option for therapy; however, current research indicates that budesonide is more effective.

If patient symptoms continue despite the above therapy, additional agents may be needed. Cholestyramine at a dose of 4g four times per day may help until diarrhea resolves. Cholestyramine is a bile acid binding resin utilized for diarrhea with concurrent bile acid malabsorption, which can occur. If diarrhea continues to persist after 2 weeks, bismuth subsalicylate can be given at a dose of 524mg (3 tabs) 3 times daily ⁶⁴.

Some patient will continue to have symptoms despite the above treatment. It is important to realize that approximately 10 to 20 percent o patients are non-responders ⁶⁵. Other therapies then need to be pursued. Anti-tumor necrosis factor and immunomodulators currently have limited evidence from case series and need further research. Surgery is a mode of therapy reserved for patients that are refractory and intolerant to symptoms.

Currently, maintenance therapy is not recommended secondary to side effects with budesonide. However, if this is necessary, the lowest dose possible should be utilized, and the dose should not exceed 6mg daily. Patients can be treated intermittently with budesonide to induce remission as well.

Avoidance of environmental triggers

Smoking cessation is recommended as well as withdrawal of medications associated with collagenous colitis where possible. Experts recommends a detailed medication history and where possible cessation of potentially provocative agents ⁶⁶.

Symptomatic management of diarrhea

For control of symptoms, loperamide is an effective treatment. Antidiarrheals can be used as monotherapy or with other medications to control diarrhea ⁶⁷. Although these have not formally been subject to randomized placebo-controlled trials, they are considered first-line therapy in patients with mild symptoms for symptomatic response.

In patients with associated bile-acid malabsorption cholestyramine may be considered as cholestyramine may adhere to bacterial toxins that have been implicated in collagenous colitis pathogenesis.

Budesonide

Budesonide remains the first-line therapy, significantly improving symptoms and quality of life. It is a locally active corticosteroid that undergoes first-pass metabolism in the liver with subsequent low systemic exposure.

A systematic review of 10 randomized controlled trials concluded that budesonide was safe, effective, and well tolerated for induction and maintenance of clinical and histological remission; evidence for bismuth, prednisone, probiotics, mesalamine, and cholestyramine was weaker ⁶⁸.

When symptoms persist despite antidiarrheals some experts suggest treatment with budesonide. A suggested approach is 9 mg daily for 6–8 weeks. If symptoms persist or recur budesonide 9 mg can be used for 12 weeks and then tapered accordingly. Budesonide short-term therapy is safe and effective and can improve quality of life ⁶⁸. A meta-analysis of eight randomized trials ⁶⁹ that included 248 patients randomized to budesonide or placebo demonstrated that short-term clinical response rates were significantly higher with budesonide, as compared with placebo.

In a Phase 3 placebo-controlled, multicenter study, Miehlke et al ⁷⁰ studied budesonide and mesalamine as short-term therapies for collagenous colitis. In a double-blind, double-dummy manner patients with active disease were treated with 9 mg once daily budesonide (n=30), 3 g once daily mesalamine (n=25), or placebo (n=37) for 8 weeks. The primary endpoint was clinical remission (<3 bowel motions a day).

After 8 weeks therapy, 84.8% of patients on budesonide were in clinical remission (<3 bowel motions a day) compared to 60.6% receiving placebo, using the Hjortswang-Criteria for clinical remission 80% of patients receiving budesonide therapy entered clinical remission compared to 37.8% of patients treated with placebo. Of those patients given mesalamine 44% achieved clinical remission, but superior outcomes were seen with budesonide. Furthermore, budesonide therapy was shown to improve histological scores, stool consistency and abdominal pain. There were no differences in adverse effects noted between treatment groups.

Budesonide has been shown to significantly reduce the histological inflammatory changes in collagenous colitis with no change in the collagen thickness band, but a significant decrease in the lamina propria infiltrate ⁷¹.

Using the Gastrointestinal Quality of Life Index tool, quality of life in patients with collagenous colitis randomized to budesonide or placebo was assessed and found that quality of life scores are low in patients with collagenous colitis, after 6 weeks of treatment with budesonide scores improved significantly compared to those receiving placebo ⁷².

Corticosteroids

The use of prednisone in the management of collagenous colitis is limited given inferior efficacy and increased side effect profile compared to budesonide.

Compared to budesonide, prednisone is associated with a lower response rate, more side effects, and a higher risk of relapse when therapy is withdrawn.

The clinical pathological effect of prednisolone was studied prospectively in six patients with collagenous colitis. Prednisolone resulted in a transient decrease in stool frequency, with a trend toward decreased inflammatory changes in posttreatment biopsies but without resolution of the collagen band (except in one patient) ⁷³.

Gentile et al ⁷⁴ compared clinical outcomes in 80 patients with microscopic colitis (40 collagenous colitis, 40 lymphocytic colitis) treated with corticosteroids. Among samples, 17 were treated with prednisone (21.2%) and 63 with budesonide (78.8%). Significantly higher rates of clinical response were observed in the budesonide treatment group (82.5% vs 52.9%) with lower rates of recurrence after treatment discontinuation. Furthermore, a randomized, double-blind trial of short-term prednisolone 50 mg or placebo demonstrated incomplete remission in nine patients ⁷⁵. Therefore, prednisone therapy is not recommended as a first-line treatment for collagenous colitis.

Recurrent symptoms and maintenance therapy

Recurrence after budesonide treatment is common and can be retreated with budesonide as intermittent therapy or as continuous maintenance therapy ideally at the lowest dose that maintains clinical remission ⁶⁹. However, low-dose maintenance treatment is controversial, mainly due to risk of steroid-related side effects.

Risk factors for relapse after budesonide withdrawal were assessed in 123 patients who achieved clinical remission with budesonide therapy for collagenous colitis in controlled trials ⁷⁶. The rate of relapse was 61%. Risk factors associated with relapse included high-stool frequency at baseline and a long duration of diarrhea. Time to relapse was shorter in those with a baseline stool frequency of >5 per day and in those with a >12 month history of diarrhea. Budesonide maintenance therapy was a protective factor against recurring symptoms and maintenance therapy delayed time from relapse from 56 to 207 days.

In a randomized controlled trial assessing long-term outcomes of budesonide therapy clinical relapse occurred in 61% of patients after a median of 2 weeks and relapse occurred significantly more often in patients over the age of 60 years ⁷⁶.

A meta-analysis on the short- and long-term efficacy of corticosteroids in the treatment of microscopic colitis of 248 patients from eight trials randomized to corticosteroids revealed that short- and long-term treatment with budesonide is effective and well tolerated for microscopic colitis and was associated with clinical and histological response ⁶⁹. Again, this confirmed high rates of symptom relapse (46%–80%) of patients within 6 months of treatment discontinuation.

A prospective randomized, placebo-controlled trial of low-dose budesonide (mean dose 4.5 mg a day) for the maintenance of clinical remission in collagenous colitis demonstrated that budesonide maintained clinical remission for at least 1 year in 61.4% (27/44 patients) compared to 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favor of budesonide) ⁷⁷. There was a high-relapse rate after discontinuation 82.1% (23/28 patients). Overall treatment was well tolerated with no serious adverse events, and the authors conclude that treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high-relapse rate after budesonide discontinuation.

Refractory collagenous colitis

Ten to 20 percent of patients do not respond to budesonide therapy ⁷⁸ and there is a paucity of data to guide therapy in those with refractory collagenous colitis.

In those not responding to antidiarrheals and budesonide one should assess for other causes of chronic diarrhea, particularly celiac disease and thyroid dysfunction given the higher incidence of autoimmune diseases in the patient population. Persistent use of NSAIDS needs to be ruled out as well as IBS and bile salt diarrhea ⁷⁹.

An approach to those with mild symptoms who do not respond to budesonide is to use a combination treatment with loperamide and cholestyramine. If symptoms persist despite this strategy Bismuth subsalicylate could be considered, but availability is limited and use is limited by nephrotoxicity ⁸⁰.

Cholestyramine

Bile acid diarrhea is commonly associated with collagenous colitis and in those patients with concomitant bile acid malabsorption cholestryramine is an effective therapy ⁸¹.

Rates of bile acid malabsorption and the effect of bile acid sequestration were studied in 28 patients with collagenous colitis, 12 (44%) had evidence of bile acid malabsorption. Bile acid treatment resulted in rapid resolution of symptoms in 11/12 patients with concomitant bile acid malabsorption compared with 10/15 (67%) without ⁸². The authors conclude that bile acid malabsorption commonly occurs in collagenous colitis patients and may contribute to the pathogenesis of colonic inflammation, bile acid therapy should be considered given higher response rates and no serious side effects.

Forty-one patients with lymphocytic colitis and 23 with collagenous colitis were randomized to mesalazine with or without cholestyramine for 6 months. Diarrhea was resolved within 2 weeks in 54 patients (84.37%).

In those with collagenous colitis clinical and histological remission was achieved in 91.3% of patients, with better results seen in those randomized to both mesalazine and cholestyramine ⁸³.

Furthermore, budesonide treatment has been shown to increase bile acid absorption in patients with collagenous colitis and this reduction in colonic bile load may in part explain its efficacy ⁸⁴.

Amino salicylates

Previously, there was only anecdotal evidence to support the use of sulfasalazine and mesalazine therapy, but recently they have been studied in controlled trials.

Calabrese et al ⁸³ randomized 64 patients with microscopic colitis to 6 months’ treatment with mesalazine 2.4 g/day or mesalazine 2.4 g/day and cholestyramine 4 g/day. The high-remission rate was seen in both treatment arms, and 85% of patients with lymphocytic colitis and 91% of patients with collagenous colitis were in remission at the end of the study. However, a placebo-controlled, randomized trial of mesalazine 3 g/day for 8 weeks as a short-term induction agent was no more efficacious than placebo ⁷⁰.

As mentioned in the study by Miehlke et al ⁷⁰, of patients with active collagenous colitis randomized to budesonide (9 mg), mesalazine (3 g), or placebo therapy, rates of remission with mesalamine and placebo were similar after 8 weeks (32% and 38%, respectively). An older study of 163 patients with collagenous colitis demonstrated remission rates of 40% with mesalamine or olsalazine ⁸⁵.

Antibiotics and probiotics

There are no controlled data to advocate the use of antibiotics, but metronidazole or erythromycin have previously been used.

Bismuth has anti-inflammatory, antidiarrheal, and anti-biotic properties but is not widely available due to concerns regarding nephrotoxicity ⁷⁷. In a small open label trial, bismuth therapy was shown to induce remission of symptoms and disappearance of the collagen band in patients with collagenous colitis ⁸⁶, treatment was well tolerated with no serious side effects.

Probiotic treatment and the role of the intestinal micro-biome requires further assessment ⁸⁷.

Madisch et al ⁸⁸ studied the effect of the Boswellia serrate extract (BSE) on symptoms, QOL, and histology in 31 patients with collagenous colitis and found that after 6 weeks, the proportion of patients in clinical remission was higher in the BSE group than in the placebo group (63.6% vs 26.7%). Larger trials are required to confirm the clinical efficacy of Boswellia serrate extract in microscopic colitis.

Immunomodulators

In the small number of patients with persistent symptoms despite budesonide and antidiarrheal agents, immunomodulator therapy may be considered ⁸⁹.

Azathioprine induced partial or complete remission in eight of nine patients with microscopic colitis in an open study ⁹⁰, further-more, a retrospective series, demonstrated an overall response rate to thiopurines of 41% (19 of 46), but azathioprine was poorly tolerated accompanied by a high frequency of side effects, leading to treatment cessation ⁹¹.

Methotrexate

An open case series of nine patients with budesonide refractory collagenous colitis demonstrated no clinical effect of methotrexate ⁹². Methotrexate therapy 15 mg subcutaneously was administered weekly for 6 weeks and increased to 25 mg thereafter if symptoms persisted. No patient experienced clinical remission or improved quality of life and four patients withdrew from the study due to adverse events.

Biologics

There are no randomized trials studying the role of biologics in the management of collagenous colitis, but recent case reports have suggested a role for anti-TNFα therapies (infliximab and adalimumab) in collagenous colitis refractory to budesonide and the author recommends considering biologic therapy before colectomy ⁹³.

Miscellaneous

Other agents have been studied including octreotide and verapamil, but with no consistent beneficial effect ⁹⁴.

Surgery

Surgery should only be considered in those refractory to medical management ⁹⁵. Diversion of the fecal stream has been shown to induce histopathological remission in collagenous colitis but upon restoration of flow the collagen band returned ⁹⁶. This implies that a luminal factor contributes to inflammation and for some patients with refractory disease ileostomy may be an appropriate therapeutic strategy. Surgical options include split ileostomy and subtotal colectomy and success has been reported with total proctocolectomy and ileal pouch anal anastomosis ⁹⁷. Considering advances in medical therapy the indication for surgery is limited.

Collagenous colitis diet

To help reduce symptoms, a health care provider may recommend the following dietary changes:

• avoid foods and drinks that contain caffeine or artificial sugars
• drink plenty of liquids to prevent dehydration during episodes of diarrhea
• eat a milk-free diet if the person is also lactose intolerant
• eat a gluten-free diet

People should talk with their health care provider or dietitian about what type of diet is right for them.

Collagenous colitis prognosis

Many patients with microscopic colitis will have a chronic, intermittent course of disease symptoms. Diarrhea can sometimes resolve without treatment or will often resolve with treatment within weeks. Relapses of symptomatology are frequent. It is currently unclear if one form is worse than the other. At present, there is no associated increased risk of colorectal cancer with microscopic colitis ¹⁵.

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