Home > Knowledge Hub > Web Education > Management of difficult microscopic colitis after failure of budesonide therapy

Management of difficult microscopic colitis after failure of budesonide therapy

Updated on: 21 Sep 2020   First published on 13 Dec 2019


Dr Matthew Kurien
Dr Suneil Raju


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.

About the Authors

Dr Matthew Kurien is a Senior Clinical Lecturer at the University of Sheffield and Honorary Consultant Gastroenterologist at Sheffield Teaching Hospitals NHS Foundation Trust. He has research interests in small bowel disease and clinical nutrition. In 2016 he was recipient of the Julie Wallace Award from the Nutrition Society.

Dr Sunny Raju is an Academical Clinical Fellow in Gastroenterology who has an interest in microscopic colitis, coeliac disease and novel endoscopic techniques. He is the current Vice President of the Sheffield Clinical Academic Society and practices in South Yorkshire. Sunny joined the Sheffield Gastroenterology team in 2015 as a Clinical Academic Foundation Trainee after graduating with a first class honours BMedSci and MBChB.

[i] Academic Unit of Gastroenterology, Departments of Infection and Immunity and Cardiovascular Science, University of Sheffield, Medical School, Beech Hill Road, Sheffield, South Yorkshire, S10 2RX

[ii] Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF


  1. Bohr J, Tysk C, Eriksson S et al. Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients. Gut 1996;39:846–851.
  2. Guagnozzi D, Arias A, Lucendo AJ. Systematic review with meta-analysis: diagnostic overlap of microscopic colitis and functional bowel disorders. Aliment Pharmacol Ther 2016;43:851–862.
  3. Munch A, Aust D, Bohr J et al. Microscopic colitis: current status, present and future challenges: statements of the European Microscopic Colitis Group. J Crohns Colitis 2012;6:932–945.
  4. Arasaradnam RP, Brown S, Forbes A et al. Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition. Gut 2018;67:1380–1399.
  5. Riviere P, Munch A, Michetti P et al. Vedolizumab in refractory microscopic colitis: an international case series. J Crohns Colitis 2018;13:337–340.
  6. Langner C, Aust D, Ensari A et al. Histology of microscopic colitis-review with a practical approach for pathologists. Histopathology 2015;66:613–626.
  7. Tong J, Zheng Q, Zhang C et al. Incidence, prevalence, and temporal trends of microscopic colitis: a systematic review and meta-analysis. Am J Gastroenterol 2015;110:265–276; quiz 277.
  8. Beaugerie L, Pardi DS. Review article: drug-induced microscopic colitis – proposal for a scoring system and review of the literature. Aliment Pharmacol Ther 2005;22:277–284.
  9. Fernandez-Banares F, de Sousa MR, Salas A, et al. Impact of current smoking on the clinical course of microscopic colitis. Inflamm Bowel Dis 2013;19:1470–1476.
  10. Stewart M, Andrews CN, Urbanski S, et al. The association of coeliac disease and microscopic colitis: a large population-based study. Aliment Pharmacol Ther 2011;33:1340–1349.
  11. Fernandez-Banares F, Esteve M, Salas A, et al. Bile acid malabsorption in microscopic colitis and in previously unexplained functional chronic diarrhea. Dig Dis Sci 2001;46:2231–2238.
  12. Esteve M, Mahadevan U, Sainz E et al. Efficacy of anti-TNF therapies in refractory severe microscopic colitis. J Crohns Colitis 2011;5:612–618.
  13. Munch A, Ignatova S, Strom M. Adalimumab in budesonide and methotrexate refractory collagenous colitis. Scand J Gastroenterol 2012;47:59–63.
  14. Pardi DS, Loftus EV, Jr, Tremaine WJ et al. Treatment of refractory microscopic colitis with azathioprine and 6-mercaptopurine. Gastroenterology 2001;120:1483–1484.
  15. Munch A, Fernandez-Banares F, Munck LK. Azathioprine and mercaptopurine in the management of patients with chronic, active microscopic colitis. Aliment Pharmacol Ther 2013;37:795–798.
  16. Cotter TG, Kamboj AK, Hicks SB et al. Immune modulator therapy for microscopic colitis in a case series of 73 patients. Aliment Pharmacol Ther 2017;46:169–174.
  17. Riddell J, Hillman L, Chiragakis L et al. Collagenous colitis: oral low-dose methotrexate for patients with difficult symptoms: long-term outcomes. J Gastroenterol Hepatol 2007;22:1589–1593.
  18. Munch A, Bohr J, Vigren L et al. Lack of effect of methotrexate in budesonide-refractory collagenous colitis. Clin Exp Gastroenterol 2013;6:149–152.


Login to your BSG member account to read and post comments on this page