Microscopic colitis (MC) is a common inflammatory bowel condition that is characterised by watery diarrhoea. It can have a chronic, intermittent or chronic-recurrent course. Associated symptoms are weight loss (seen in 42% of patients), abdominal pain (41%) and nocturnal diarrhoea (27%), and quality of life (QoL) may be significantly impaired [1]. MC is present in around 10% of people with diarrhoea-predominant irritable bowel syndrome and 7.5–10% of those with chronic diarrhoea [2,3]. Most people with MC can be successfully treated with anti-diarrhoeal agents or budesonide, which induces remission in 80% of patients [3]. However, symptom relapse occurs in up to 70% of patients after treatment is stopped, which leads to continued maintenance therapy [4]. Causes of non-response include incorrect initial diagnosis, poor drug adherence, risk factors not considered and other disease-influencing symptoms. A small proportion of patients (around 1%) are truly refractory to or highly dependent on budesonide [5]. The following steps provide a practical approach to managing these patients. 


Step 1: Review The Diagnosis  

An incorrect diagnosis of MC might explain why budesonide therapy fails. Although established diagnostic criteria exist for MC, occasionally histological evaluation is challenging [6]. Infectious colitis, classic inflammatory bowel diseases, radiation-induced injury and amyloidosis can all show histological features reminiscent of MC [6]. If there is any doubt regarding the histological diagnosis, repeat evaluation by a specialist pathologist should be undertaken and a repeat biopsy considered.  


Step 2: Review Modifiable Risk-factors 

Numerous medications have been associated with MC. Proton-pump inhibitors and serotonin-specific-receptor inhibitors have odds ratios of 2.68 and 2.41, respectively [7]. Other drugs to consider are non-steroidal anti-inflammatory drugs, statins and ranitidine [7,8]. Cessation of these drugs should be considered in all MC patients if possible.  

Whether smoking cessation influences the symptoms of MC is unclear, but MC develops a mean of more than 10 years earlier in active smokers than in non-smokers [9]. As smoking is a recognised risk factor and has a deleterious effect on other organs, we advocate smoking cessation in all patients with MC.  


Step 3: Consider Alternative Causes of Diarrhoea 

Other causes for persistent diarrhoea (more than three stools per day) should be considered when budesonide treatment fails. A systematic approach to undertaking further investigations should be adopted. The current BSG guidelines on chronic diarrhoea provide a potential framework [4]. Bile-acid diarrhoea, lactose malabsorption and coeliac disease require particular consideration as they have an increased prevalence in people with MC; the prevalence of coeliac disease is up to 50 times higher than that expected in the general population [4,10,11]. Appropriate investigations are a SeHCAT (23-seleno-25-homotaurocholic acid, selenium homocholic acid taurine) scan, coeliac serology (with or without duodenal biopsy) and a lactose hydrogen breath test. Owing to the association of MC with various autoimmune diseases, testing for thyroid disease and type 1 diabetes should be considered if not previously performed.  


Step 4: Managing Refractory Microscopic Colitis  

There is a paucity of evidence and a lack of randomised controlled data regarding second-line therapies. Immunomodulators (azathioprine, 6-mercaptopurine and methotrexate) and tumour necrosis factor inhibitors have shown efficacy in case series [12–16]. In a small study from the USA that involved nine patients, azathioprine induced partial or complete remission in eight (89%) at a median follow-up of 26 months [14]. In a retrospective study of 46 patients from Spain, Sweden and Denmark, 19 (41%) responded to thiopurines, although azathioprine was accompanied with frequent side-effects necessitating therapy withdrawal in 13 patients [15].  

The data supporting methotrexate therapy for MC are more uncertain. Sixteen (84%) of 19 patients with collagenous colitis reported a good or partial clinical response within 2–3 weeks of starting oral methotrexate (median dose 7.5–10 mg per week) [17]. By contrast, in a later study of 15–25 mg subcutaneous methotrexate per week in nine patients, none showed any improvement [18].  Vedolizumab, a monoclonal antibody targeting integrin α4β7, induced clinical remission in five of 11 patients refractory to budesonide [5]. Of these responders, 75% had evidence of histological normalisation. Further research is needed to establish the most clinical and cost-effective ways of delivering second-line therapies to MC patients within the NHS.      

Surgical intervention in MC is regarded as a last-resort treatment [3]. Diverting ileostomy, subtotal colectomy and ileoanal pouch anastomosis have all been used with success [3], but are performed rarely due to advances in medical therapies.  



Most patients with MC respond to budesonide or anti-diarrhoeal agents. Non-responders generally have other causes for their symptoms and are unlikely to be truly refractory. A structured approach to this group of patients is paramount and can improve symptoms. Further research is needed to determine the optimum way of providing second-line therapies. 


Matthew Kurien, Senior Clinical Lecturer and Honorary Consultant Gastroenterologisti  

Suneil A Raju, Academic Clinical Fellowii

Learning points 

  • Microscopic colitis is a common disease that impacts quality of life  

  • Most patients respond to budesonide or anti-diarrhoeal agents 

  • Second-line therapies include immunomodulators, tumour necrosis factor inhibitors, monoclonal antibodies and surgery 

  • Randomised controlled trials are required to establish the most effective second-line therapy