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Management of difficult microscopic colitis after failure of budesonide therapy

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

Authors

Dr Matthew Kurien
Dr Suneil Raju

Introduction

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.

Conclusions

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


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