Received: 28 May 2020 - DOI: 10.1177/2050640620951905 REVIEW ARTICLE Accepted: 27 July 2020 European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations Stephan Miehlke1,2 | Danila Guagnozzi3,4,5,6 | Yamile Zabana6,7 | Gian E. Tontini8 | Anne‐Marie Kanstrup Fiehn9 | Signe Wildt10,11 | Johan Bohr12 | Ole Bonderup13 | Gerd Bouma14 | Mauro D'Amato15 | Peter J. Heiberg Engel16 | Fernando Fernandez‐Banares6,7 | Gilles Macaigne17 | Henrik Hjortswang18,19 | Elisabeth Hultgren‐Hörnquist20 | Anastasios Koulaouzidis21 | Jouzas Kupcinskas22 | Stefania Landolfi23 | Giovanni Latella24 | Alfredo Lucendo25 | Ivan Lyutakov26 | Ahmed Madisch27 | Fernando Magro28 | Wojciech Marlicz29 | Emese Mihaly30 | Lars K. Munck10,11 | Ann‐Elisabeth Ostvik31,32 | Árpád V. Patai33,34 | Plamen Penchev26 | Karolina Skonieczna‐Żydecka35 | Bas Verhaegh36 | Andreas Münch18,19 1 Center for Digestive Diseases, Internal Medicine Center Eppendorf, Hamburg, Germany 2 Center for Esophageal Disorders, University Hospital Eppendorf, Hamburg, Germany 3 Neuro‐Immuno‐Gastroenterology Group, Digestive Physiology and Pathophysiology Unit, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain 4 Digestive System Department, Vall d'Hebron University Hospital, Barcelona, Spain 5 Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, Spain 6 Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain 7 Department of Gastroenterology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Barcelona, Spain 8 Department of Pathophysiology and Organ Transplantation, University of Milan and Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy 9 Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Denmark 10 Department of Gastroenterology, Zealand University Hospital, Koege, Denmark 11 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark 12 Department of Medicine, Örebro University Hospital, Örebro University, Örebro, Sweden 13 Diagnostik Center, Hospitalenhed Midt, Regionshospitalet Silkeborg, Silkeborg, Denmark 14 Department of Gastroenterology and Hepatology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 15 School of Biological Sciences, Monash University, Clayton, Australia 16 Department of Pathology, Zealand University Hospital, Roskilde, Denmark 17 Hepatogastroenterology Unit, Centre Hospitalier de Marne‐la‐Vallee, Jossigny, France 18 Department of Gastroenterology and Hepatology in Linköping, Linköping University, Linköping, Sweden 19 Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden 20 School of Medical Sciences, Örebro University, Örebro, Sweden - This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology. United European Gastroenterol J. 2021;9:13–37. wileyonlinelibrary.com/journal/ueg2 13 14 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 21 The Royal Infirmary of Edinburgh, Endoscopy Unit, Edinburgh, UK 22 Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania 23 Department of Pathology, Hospital Universitari Vall d'Hebron, CIBERONC, Barcelona, Spain 24 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy 25 Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain 26 Department of Gastroenterology, Medical University of Sofia, University Hospital Tsaritsa Yoanna—ISUL, Sofia, Bulgaria 27 Department of Gastroenterology, CRH Clinic Siloah, Hannover, Germany 28 Department of Pharmacology, Hospital de Sao Joao, Porto, Portugal 29 Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland 30 Department of Internal Medicine, Semmelweis University, Budapest, Hungary 31 Department of Clinical and Molecular Medicine, NTNU: Norwegian University of Science and Technology, Trondheim, Norway 32 Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway 33 2nd Department of Medicine, Semmelweis University, Budapest, Hungary 34 Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA 35 Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Szczecin, Poland 36 Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands Correspondence Stephan Miehlke, Center for Digestive Abstract Diseases, Internal Medicine Center Introduction: Microscopic colitis is a chronic inflammatory bowel disease charac- Eppendorf, Center for Esophageal Disorders, University Hospital Eppendorf, Eppendorfer terised by normal or almost normal endoscopic appearance of the colon, chronic Landstraûe 42, 20249 Hamburg, Germany. watery, nonbloody diarrhoea and distinct histological abnormalities, which identify Email: miehlke@faz-eppendorf.de 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. Methods: 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. Results: 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 man- agement of microscopic colitis are provided based on evidence, expert opinion and best clinical practice. Conclusion: These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis. KEYWORDS budesonide, diarrhoea, inflammatory bowel disease, microscopic colitis MIEHLKE ET AL. - 15 INTRODUCTION diagnosis, monitoring; 5: treatment), each consisting of a working group leader and 5–7 group members. A steering committee was Microscopic colitis (MC) is an increasingly recognised inflammatory established consisting of the two coordinators (S.M., A.Mü.) and the bowel disease associated with significant symptom burden and an working group leaders (D.G., Y.Z., G.E.T., A.M.K.F., S.W). First, a list of impaired health‐related quality of life (HRQoL). The clinical course of topics and research questions to be covered by the guidelines was MC is variable, with chronic or recurrent mild to severe symptoms created by the steering committee based upon discussions with the persisting for months to years. The prevalence of MC varies sub- working group members on their relevance and their potential stantially between geographical regions. The two major histological impact on clinical practice. The final list of research questions was subtypes are collagenous colitis (CC) and lymphocytic colitis (LC), formatted into the patient, intervention, control, outcome frame- but incomplete forms may occur (incomplete MC [MCi]). The diag- work, when appropriate. nosis of MC relies on the histological examination of colonic biopsies and requires dedicated gastroenterologists, endoscopists and histopathologists. Literature search and assessment of evidence Several review articles have been published on various diagnostic and therapeutic aspects of MC.1–5 In 2012, the European Microscopic A formal systematic review of the literature was carried out for each Colitis Group (EMCG) proposed their first recommendations for the research question using MEDLINE (accessed via PubMed), EMBASE diagnosis and treatment of MC.6 In 2013, MC was included in the electronic databases and the Cochrane Database of Systematic Re- European consensus on the histopathology of inflammatory bowel views (Cochrane Library) and the Cochrane Central Register of disease published on behalf of the European Society of Pathology and Controlled Trials from inception until July 2019, with no restriction the European Crohn's and Colitis Organisation.7 According to this of languages and periodically updated. The search strategy and the particular guideline, MC is defined as a ‘clinical pathological entity process of study selection categorised per research question can be characterised by chronic watery (non‐bloody) diarrhoea, a normal or found in online Supporting Information Appendix a. A review of the almost normal endoscopic appearance of the colon, and a distinct citations to identify potentially relevant articles was also carried out. histologic pattern of collagenous colitis or lymphocytic colitis'. This This included systematic reviews and other documents offering a includes that other causes for chronic diarrhoea such as infections or critical synthesis of the scientific literature, as well as randomised other exogenous factors have been ruled out by clinical routine pro- clinical trials, whenever possible. cedures. More recently, the Spanish Microscopic Colitis Group and Data on epidemiology, pathogenesis, clinical manifestations, the American Gastroenterology Associations have published first diagnosis and treatment of MC were critically reviewed and meta‐ evidence‐based statements and recommendations using Grading of analyses conducted, when applicable. The working groups followed Recommendations Assessment, Development and Evaluation the GRADE methodology (https://www.gradeworkinggroup.org/) to (GRADE) methodology, which is now considered as the standard tool assess the quality of evidence of statements/recommendations, and for the development of clinical practice guides.8,9 classified the recommendations for the different clinical scenarios With persistent uncertainties and new developments in the into four final categories: strong recommendation for an intervention clinical management of MC, the United European Gastroenterology (implying to do it), weak recommendation for an intervention (implying (UEG) and EMCG identified the need to develop updated clinical to probably do it), weak against an intervention (implying to probably practical guidelines in order to increase awareness for MC and sup- not do it) and strong against an intervention (implying not to do it). The port clinicians to improve clinical care of MC patients in daily routine strength of recommendation (GR: strong or weak) using the GRADE practice. approach was only given for studies on the accuracy of diagnostic procedures and on the assessment of the treatment efficacy. The level of evidence (LE) was classified in four categories: high, METHODOLOGY moderate, low or very low quality, based on the strict assessment of the quality of the evidence. The quality of the evidence could be The guideline working group downgraded as a result of limitations in the study design or in its implementation, imprecision of estimates, variability in the results, All members of EMCG were asked to participate and an open invi- indirectness of the evidence or publication bias; or upgraded because tation was placed on the UEG website for several months prior to the of a very large magnitude of effects, a dose‐response gradient or if all first group meeting held in Vienna in October 2018. Finally, the the plausible biases would reduce an apparent treatment effect. entire group consisted of 32 physicians and researchers from 14 Moreover, the recommendations were also based on some other European countries, including gastroenterologists, pathologists and factors, such as desirable and undesirable consequences of alterna- basic scientists with expertise in scientific methodology, evidence‐ tive management strategies, variability in values and preferences and based medicine and clinical and therapeutic management of MC. the use of resources (costs). The results of data extraction and quality A total of five working groups were established (1: epidemiology, risk of the evidence assessments are summarised in Supporting Infor- factors; 2: pathogenesis; 3: clinical manifestation, quality of life; 4: mation Appendix B. 16 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL Evolution of statements/recommendations What is the prevalence of MC? Statement 1.2: The pooled overall prevalence of MC is estimated Based on the literature review and assessment of evidence, the to be 119 (95% CI: 73–166) per 100,000 persons, with an overall working groups drafted initial statements and recommendations, prevalence of 50.1 per 100,000 person‐year for CC and 61.7 per which subsequently underwent a voting process by the entire 100,000 persons for LC. guideline group using the Delphi method. The participants judged the LE: high; GR: NA; agreement: 94%, consensus. statement/recommendation based on a 5‐point Likert scale (1: Summary of evidence: Five population‐based studies from strongly disagree; 2: disagree; 3: neutral; 4: agree; 5: strongly agree), Spain,21,41 North America20,27 and Sweden30 have assessed the and suggested modifications or even new ones. Following this pro- prevalence of MC and provided a wide range from 47.5 to 219 cases cess, the statements and recommendations were revised by the per 100,000 persons. These studies were pooled to provide an working groups. They were modified if necessary and voted on again overall MC prevalence of 119.4 (95% CI: 72.9–165.9, I2 = 97.08%) during a final face‐to‐face consensus meeting held in Barcelona in cases per 100,000 persons. For CC, the pooled prevalence was October 2019. Statements and recommendations were approved if estimated to be 50.1 (95% CI: 13.69–76.5, I2 = 98.37%) cases per 75% or more of the participants agreed with it (Likert score of 4 or 5; 100,000 persons.20,21,27,30,33,41 The estimated pooled prevalence of 75%–94%: consensus, 95%–100%: strong consensus). Each state- LC was 61.7 (95% CI: 48.2–75.3, I2 = 80.56%) per 100,000 ment and recommendation is accompanied by the LE (high, moderate, persons.20,21,27,30,41 Some studies reported that increasing age was a low, very low), grade of recommendation, result of the vote (per- risk factor for developing MC,20,33,41 with a 5.25 (95% CI: 3.81–7.24) centage agreement) at the consensus meeting and discussion of the times higher probability of MC in people over 65 years of age.41 corresponding evidence. The guideline group formulated a total of 39 What is the frequency of MC in chronic diarrhoea? statements and recommendations (Table 1). Statement 1.3: The pooled frequency of MC in patients with unexplained chronic watery diarrhoea is 12.8% (95% CI: 10–16), with significant heterogeneity (I2 = 93.6%). Epidemiology and risk factors of MC LE: moderate; GR: NA; agreement: 100%, strong consensus. Summary of evidence: The frequency of MC in patients with What is the incidence of MC? chronic or intermittent watery diarrhoea and a macroscopically Statement 1.1: The pooled overall incidence rate of MC is esti- normal (or near normal) colon has been evaluated in several mated to be 11.4 (95% confidence interval [CI]: 9.2–13.6) cases per studies.17,18,21,26,27,42–72 Based on studies with a moderate or 100,000 person‐years. The incidence of CC and LC ranges from 0.6 high quality, and a sample size of ≥100 patients,17,18,21,26,27,42,43, 45–47,49,52,54,56,59,60 to 16.4 cases per 100,000 person‐years and from 0.6 to 16.0 cases the pooled overall frequency of MC was esti- per 100,000 person‐years, respectively. mated to be 12.8% (95% CI: 9.9–15.9, I2 = 93.6%). The pooled fre- LE: high; GR: not applicable; agreement: 100%, strong consensus. quency of CC and LC was 4.96% (95% CI: 3.6–6.5, Summary of evidence: Epidemiological studies have documented I2 = 85.2%)17,18,21,26,27,42,43,45,47,49,52,54,56,60 and 8.2% (95% CI: 6.0– an increasing incidence of MC in western countries. An overall pooled 10.8, I2 = 92.0%),17,18,21,26,27,42,43,45,47,49,52,54,56,60 respectively (see 2 incidence rate of 11.4 (95% CI: 9.2–13.6, I = 99.72%) cases of MC per also Supporting Information Appendix d). The data showed high 100,000 person‐years was calculated based on studies providing heterogeneity and are not directly comparable, considering the population‐based data.10–31 Several studies from North America20,27 different geographical and genetic background, different definitions and Europe14,16–18,25,26,29 reported variations in incidence rates over of chronic watery diarrhoea used, the lack of clearly described a 10‐years‐time period in the same region. They all showed an diagnostic criteria for MC and diagnostic work‐up before increasing incidence in the early years, which has reached a plateau.32 colonoscopy. The pooled incidence rate for CC10,11,13–24,26–31,33–36 was 4.9 (95% CI: Is smoking a risk factor for MC? 4.2–5.7, I2 = 98.3%) cases per 100,000 person‐years. The pooled LC Statement 1.4: Former, but especially current smoking is asso- incidence rate was 5.0 (95% CI: 4.0–6.1, I2 98.75%) cases per 100,000 ciated with an increased risk for both CC and LC. person‐years.10–31 Geographic variations in the incidence of MC have LE: moderate; GR: NA; agreement: 100%, strong consensus. been reported; however, the limited number of studies from Southern Summary of evidence: The prevalence of current smoking in MC Europe compared to Northern Europe and the lack of direct patients ranged from 15.3% to 40.7% (CC: 13.6%–37.1%, LC: 13.2%– comparative studies from different countries for the same time period 26.0%) compared to 5.0 28.2% in non‐MC control groups.28,43,73–82 In does hinder firm conclusions on this matter. a recent meta‐analysis,83 current smokers had a significantly The MC incidence is higher in the elderly. A previous meta‐ increased risk of MC compared with never smokers (odds ratio [OR]: analysis showed the median patients' age at the time of diagnosis was 2.99, 95% CI: 2.15–4.15).83 Current smoking was more strongly over 60 years old (CC: 64.9, CI: 57.03–72.78; LC: 62.2, CI: 54.0– associated with CC than LC (OR: 5.5, 95% CI: 3.4–8.9, OR: 2.96, 95% 70.4 years).32 However, up to 25% of patients diagnosed with CC CI: 2.0–4.3, respectively).83 Former smoking was also associated with were less than 45 years33 and cases of CC have even been described an increased risk (OR: 1.6, 95% CI: 1.4–1.9).83 However, interstudy 37–40 in children. heterogeneity was high or moderate for all analyses. Smoking status TABLE 1 Summary of UEG/EMCG statements and recommendations for MC Section and number Statement/recommendation Level of evidence Grade of recommendation Voting MIEHLKE Section 1 Epidemiology and risk factors ET AL. Section 1.1 The pooled overall incidence rate of MC is estimated to be 11.4 (95% CI: 9.2–13.6) cases High NA 100% per 100,000 person‐years. The incidence of CC and LC ranges from 0.6 to 16.4 cases per 100,000 person‐years and from 0.6 to 16.0 cases per 100,000 person‐years, respectively. Section 1.2 The pooled overall prevalence of MC is estimated to be 119 (95% CI: 73–66) per 100,000 High NA 94% persons, with an overall prevalence of 50.1 per 100,000 person‐year for CC and 61.7 per 100,000 persons for LC. Section 1.3 The pooled frequency of MC in patients with chronic watery diarrhoea is 12.8% (95% CI: Moderate NA 100% 10–16), with significant heterogeneity (I2 = 93.6%). Section 1.4 Former, but especially current smoking is associated with an increased risk of both CC and Moderate NA 100% LC. Section 1.5 The risk of developing CC or LC is higher in women than in men. High NA 100% Section 1.6 There is insufficient evidence to evaluate the influence of smoking cessation on the disease Low NA 78% course. Section 1.7 Chronic or frequent use of PPI, NSAID or SSRI is associated with an increased risk of MC. Low NA 94% However, this does not imply a causal relationship. Section 1.8 We suggest to consider withdrawal of any drugs with a suspected chronological Very low Weak in favour 97% relationship between drug introduction and onset of diarrhoea. Section 1.9 MC does not increase the risk of colorectal cancer or adenoma. A special surveillance Low Strong in favour 100% colonoscopy program is not recommended. Section 2 Pathogenesis Section 2.1 Pathogenesis of MC is complex and multifactorial. It may include luminal factors, immune Low NA 100% dysregulation and genetic predisposition. Section 3 Clinical manifestation Section 3.1 The most common symptom of MC is chronic watery, nonbloody diarrhoea, which is Moderate NA 97% frequently associated with concomitant symptoms including faecal urgency, nocturnal stools and faecal incontinence. nocturnal stools and faecal incontinence. Section 3.2 MC diagnosis should be ruled out in patients fulfilling the criteria for functional bowel Moderate NA 93% disease, especially in presence of MC risk factors and/or in absence of IBS‐therapy response. Section 3.3 Health‐related quality of life is impaired in patients with MC, depending on the activity and Moderate NA 100% severity of the disease and concomitant comorbidities. - 17 18 - Section and number Statement/recommendation Level of evidence Grade of recommendation Voting Section 3.4 In the absence of a formally validated metric of disease activity, disease activity and clinical Moderate NA 100% remission in MC should be assessed by the Hjortswang criteria (clinical remission: mean of <3 stools/day and a mean <1 water stool/day during a 1‐week registration). Section 4 Diagnosis Section 4.1 Endoscopic findings are recognised with increased frequency in patients with MC, however Low NA 95% they are nonspecific. Section 4.2 The histopathologic criteria of CC are a thickened subepithelial collagenous band ≥10 μm Moderate NA 89% combined with an increased inflammatory infiltrate in lamina propria. The criteria apply to haematoxylin and eosin‐stained slides. Section 4.3 The histopathologic criteria of LC are an increased number of intraepithelial lymphocytes Moderate NA 100% ≥20 per 100 surface epithelial cells combined with an increased inflammatory infiltrate in lamina propria and a not significantly thickened collagenous band (<10 μm). The criteria apply to haematoxylin and eosin‐stained slides. Section 4.4 Incomplete MC comprises incomplete CC (defined by a thickened subepithelial collagenous Low NA 95% band >5 μm but <10 μm) and incomplete LC (defined by >10 IELs but <20 IELs and a normal collagenous band). Both types show a mild inflammatory infiltrate in the lamina propria. The criteria apply to haematoxylin and eosin‐stained slides. Section 4.5 We recommend ileocolonoscopy with biopsies from at least the right and left colon. High Strong in favour 100% Section 4.6 We recommend against histological monitoring in patients with MC. Very low Strong in favour 100% Section 4.7 Faecal calprotectin is not useful to exclude or monitor MC. Moderate NA 100% Section 4.8 We recommend screening for coeliac disease in patients with MC. High Strong in favour 100% Section 4.9 Testing for bile acid diarrhoea is not part of routine diagnostic workup in MC. Low NA 83% Section 4.10 Testing for bile acid diarrhoea can be considered in patients who experience nonresponse Low Strong in favour 82% to budesonide treatment. Section 5 Treatment Section 5.1.1 We recommend using oral budesonide to induce remission in patients with CC. Moderate Strong in favour 100% Section 5.1.2 We recommend using oral budesonide to induce remission in patients with LC. Low Strong in favour 100% Section 5.2.1 Oral budesonide is effective to maintain remission in patients with CC. Moderate Strong in favour 94% Section 5.2.2 We suggest using oral budesonide to maintain remission in patients with LC. Very low Weak in favour 84% Section 5.3.1 There is no increased risk of serious adverse events with budesonide in MC. Low NA 100% Section 5.3.2 The risk of osteoporotic bone fractures seems not be increased in budesonide treated MC Low NA 97% patients, although prolonged use might be associated with a decrease of bone mineral density. UNITED EUROPEAN GASTROENTEROLOGY JOURNAL MIEHLKE ET AL. TABLE 1 (Continued) Section and number Statement/recommendation Level of evidence Grade of recommendation Voting Section 5.4 We recommend against treatment with mesalazine in patients with MC for induction of Low Strong against 94% remission. There are no studies for maintenance. Section 5.5 There is not enough evidence to recommend bismuth subsalicylate in patients with MC. Very low Strong against 92% Section 5.6 There is not enough evidence to recommend the use of loperamide in MC. Given the Very low Strong in favour 100% documented effect in patients with chronic diarrhoea, the expert's opinion favours the use of this drug in mild disease. Section 5.7 In patients with MC and bile acid diarrhoea we suggest treatment with bile acid binders. Very low Weak in favour 100% Section 5.8 There is not enough evidence to recommend antibiotics for treatment of MC. Very low Strong against 100% Section 5.9 We recommend against use of probiotics for treatment of MC. Low Strong against 100% Section 5.10 We recommend against the use of prednisolone or other corticoste roids than budesonide Low Strong against 100% for the treatment of MC. Section 5.11 We recommend treatment with thiopurines, anti‐TNF drugs or vedolizumab in selected Low Strong in favour 97% patients with MC who fail to respond to budesonide to induce and maintain clinical remission. We recommend against the use of methotrexate in patients with MC. Section 5.12 Surgery can be considered in selected MC patients as last option if all medical therapy fails. Very low Weak in favour 100% Abbreviations: CC, collagenous colitis; CI, confidence interval; EMCG, European Microscopic Colitis Group; LC, lymphocytic colitis; IELs, intraepithelial lymphocytes; IBS, irritable bowel syndrome; MC, microscopic colitis; PPI, proton pump inhibitor; TNF, tumour necrosis factor; NSAID, nonsteroidal anti‐inflammatory drugs; SSRI, selective serotonin reuptake inhibitor; NA, not applicable; UEG, United European Gastroenterology. - 19 20 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL was often assessed by self‐administered questionnaires or review of associated with MC (OR: 2.95, 95% CI: 1.82–4.80, 2 54,81,82,91–96,98–100 medical records, and a homogeneous definition of smoking was I = 99%), especially when used continuously for lacking. 4–12 months (OR: 4.69, 95% CI: 3.58–6.13).98 Exposure to NSAIDs Is female gender a risk factor for MC? was also associated with an increased risk of MC (OR: 2.40, 95% CI: Statement 1.5: The risk of developing CC or LC is higher in 1.99–2.89, I2 = 88%).54,82,91–95,97–99 The combined use with PPIs women than in men. might further increase this risk.98 MC was also associated with SSRI LE: high; GR: NA; agreement: 100%, strong consensus. exposure (OR: 2.98, 95% CI: 2.35–3.78, I2 = 90%)54,81,82,91– 93,95,96,98,99 Summary of evidence: The incidence of MC is higher in women (see also Supporting Information Appendix D). It should than in men, as reported in a previous meta‐analysis published in be stressed that different criteria for ‘drug exposure' were applied 2015.32 Actually, subgroup analyses on the incidence of MC by sex and different reference populations were considered. Moreover, the were possible in 19 studies.10,12–24,26–30 Female sex was significantly studies lack information on the evolution of clinical symptoms after associated with MC (pooled OR: 2.52, 95% CI: 2.28–2.79, I2 = 89%), drug exposure, withdrawal or re‐challenge, hindering assessment of with no differences between studies from Northern Europe (pooled causality. 2 OR: 2.48, 95% CI: 2.22–2.78, I = 90%), Southern Europe (pooled OR: Should any drug, potentially related to MC onset, been withdrawn? 2.53, 95% CI: 1.63–3.94, I2 = 62%) and North America (pooled OR: Recommendation 1.8: We suggest to consider withdrawal of any 2.77, 95% CI: 2.02–3.81, I2 = 37%). Subgroup analyses of CC (n = 18 drugs with a suspected chronological relationship between drug studies)10,12–19,23,26–30,33,35,36 and LC (n = 15 studies)10,12–19,23,26–30 introduction and onset of diarrhoea. reproduced these results, with a pooled OR of 3.24 (95% CI: 3.03– LE: very low; GR: weak in favour; agreement: 97%, strong 2 2 3.47, I = 35%) in CC and 2.06 (95% CI: 1.84–2.31, I = 78%) in LC consensus. (see also Supporting Information Appendix D). The proportion of Summary of evidence: In total, 62 case reports and 13 case‐ females among MC populations have been described in the range of control studies97,101–159 describing drug‐induced MC were analysed 52%–86% (see Supporting Information Material, p. 28). In the three to calculate the so‐called ‘imputability score' describing the likelihood 12 14 29 largest studies from Sweden, Denmark and the Netherlands, of a causal relationship between drug exposure and MC. PPIs were the average proportion of females was approximately 72%. the most reported drugs in relation to MC. Resolution of diarrhoea Does smoking cessation influence the disease course of MC? and histological normalisation after PPI withdrawal has been re- Statement 1.6: There is insufficient evidence to evaluate the in- ported in four cases using omeprazole,156,157 in 16 cases using lan- fluence of smoking cessation on the disease course. soprazole111–113,119,123,124,129,138,141,142,146,150,153,154,160 and in one LE: low; GR: NA; agreement: 78%, consensus. case using esomeprazole.157 For rabeprazole, only one case of clinical Summary of evidence: No studies directly evaluated the effect of improvement without histological control has been published.139 In smoking cessation on the disease course. In one study, the risk of 10 cases111,112,138,153,154,156,157,160 switch to another PPI did not developing MC declined significantly over time (p = 0.017), leading to result in recurrence of diarrhoea, which contradicts the presumption an attenuated risk after 5 years after smoking cessation.73 However, of a class effect of PPI. One case‐control study clearly demonstrated compared to smokers, former smokers do not have a significantly that current and recent use of NSAIDs and PPIs were associated with lower risk of MC (OR: 1.44, 95% CI: 0.76–2.72).73–76,78,80,82 In two an increased risk of MC, when compared to never and past use, studies, current smokers developed MC more than one decade especially in the case of continuous exposure for 4–12 months98 This 77,84 earlier than former or never smokers. The majority of the studies observation underlines the clinical relevance of a suspected chro- showed no differences in terms of clinical presentation response to nological relationship between drug use an onset of MC. treatment, spontaneous remission rates and disease recurrence or Do MC patients require a special program for colonoscopy surveil- need for maintenance treatment73,75,77,78,81,84–89 (see also Suporting lance to rule out colorectal cancer (CRC) compared to general population? Information Appendix D). Only in a post‐hoc analysis of pooled data Recommendation 1.9: MC does not increase the risk of CRC or from two randomised controlled trials (RCTs) was current smoking adenoma. A special surveillance colonoscopy program is not associated with a decreased ability to achieve clinical remission with recommended. corticosteroid treatment (OR: 0.31, 95% CI: 0.10–0.98).90 LE: low; GR: strong in favour; agreement: 100%, strong Is drug use associated with a significant increased risk of MC? consensus. Statement 1.7: Chronic or frequent use of proton pump in- Summary of evidence: Only a few studies examined whether hibitors (PPIs), nonsteroidal anti‐inflammatory drugs (NSAIDs) or persistent chronic inflammation in MC is associated with an selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of CRC or adenomas.60,71,80,161–169 The meta‐analysis increased risk of MC. However, this does not imply a causal of five case‐control studies showed that MC was associated with a relationship. reduced risk for CRC or adenoma compared to controls (pooled OR: LE: low; GR: NA; agreement: 94%, consensus. 0.65, 95% CI: 0.33–1.28, I2 = 19% and OR: 0.49, 95% CI: 0.30–0.81, Summary of evidence: Drug‐induced MC was addressed by I2 = 92%, respectively). In a larger retrospective cohort of 547 MC retrospective case‐control studies54,81,82,91–100 showing an associa- patients (171 CC and 376 LC), CRC was detected in five CC (2.82%) tion with the use of NSAIDs, PPIs and SSRIs. PPI use was strongly and five LC patients (1.33%).163 MC was negatively associated with MIEHLKE ET AL. - 21 the risk for CRC and adenoma (OR: 0.34, 95% CI: 0.16–0.73, reported in 9% (95% CI: 4.5%–14.9%) among patients exhibiting p = 0.006 and OR: 0.52, 95% CI: 0.50–0.76, p < 0.001, respectively), diarrhoea‐predominant functional disorders.176,178 However, not all 163 during a mean follow‐up of 4.63 years studies employed the currently accepted diagnostic criteria for MC, and different criteria for defining functional bowel disorders were used, contributing to the high heterogeneity of the results. Pathogenesis of MC Is the patient's HRQoL impaired by MC? Statement 3.3: HRQoL is impaired in patients with MC, Statement 2.1: Pathogenesis of MC is complex and multifactorial. It depending on the activity and severity of the disease and concomi- may include luminal factors, immune dysregulation and genetic tant comorbidities. predisposition. LE: moderate; GR: NA; agreement: 100%, strong consensus. LE: low; GR: NA; agreement: 100%, strong consensus. Summary of evidence: MC can severely impact HRQoL, with Summary of evidence: The mechanisms involved in the devel- baseline HRQoL being lower than that of patients with other intes- opment of MC are poorly understood and the LE is scarce. It is not in tinal and proctological disorders.180 Impaired HRQoL was demon- the scope of this guideline to provide in‐depth information on this strated in both active CC and LC, including impact on function in daily subject. The current knowledge of the factors involved is briefly living, disease‐related worry and well‐being.2,8,181–183 However, summarised in Supporting Information Appendix C. HRQoL can also be impaired in patients with MC achieving clinical remission.89,184,185 In a population‐based study, 116 patients with active CC had an Clinical manifestation and quality of life impaired HRQoL compared with a background population, whereas patients in remission scored similar.186 HRQoL was impaired in those What are the most common symptoms in MC? with a mean of ≥3 stools/day or a mean of ≥1 watery stool/day. Statement 3.1: The most common symptom in MC is chronic Therefore, it was proposed that remission in CC should be defined as watery, nonbloody diarrhoea, which is frequently associated with a mean of less than 3 stools/day and a mean less than 1 watery stool/ concomitant symptoms including faecal urgency, nocturnal stools and day during a 1‐week registration.187 faecal incontinence. In a case‐control study including 212 MC patients, all four LE: moderate; GR: NA; agreement: 97%, strong consensus. HRQoL dimensions (symptom burden, social function, disease‐related Summary of evidence: The predominant symptom of MC is worry, general well‐being) were impaired in patients with active CC chronic watery, nonbloody diarrhoea, which was reported by 84%– and LC.184 In a cross‐sectional survey of 151 MC patients, 52 (34.4%) 100% of patients in 22 studies. In one third of the cases, the onset of reported IBS‐type symptoms and had higher levels of anxiety, diarrhoea was acute in nature,170–173 and according to a European depression and somatisation and impaired quality of life.179 In prospective registry174 it persists for 6 months before diagnosis in another cross‐sectional survey of 129 patients with a new diagnosis 43%. Symptoms such as stool frequency, stool consistency and of MC, fatigue severity resulted to be associated with IBS‐type overall duration of diarrhoea are reported in a number of the studies, symptoms, psychological comorbidity and impaired quality of life, including a large Danish study of 539 patients,13 in which an average with a negative correlation in HRQoL measures.188 In a cross‐ of 6–7 bowel movements per day was reported. Common concomi- sectional study including 158 female MC patients, those with coex- tant symptoms included faecal urgency (55%), nocturnal stools isting IBS‐like symptoms (55%) experienced worse psychological (35.3%) and faecal incontinence (26.3%). Less frequent complaints well‐being than those without. Also, smoking and PPI were associ- with varying prevalences among studies are abdominal pain, weight ated with gastrointestinal symptoms and impaired psychological well‐ loss and bloating.172,173,175 A Swedish study from 2004 involving 199 being in MC patients.89 HRQoL was evaluated in five RCTs including 173 patients with LC reported a median weight loss of 5 (4–8) kg; CC patients189–194 and in two RCTs including LC patients.192–195 In however, early studies might have included a selected population, as all seven RCTs, HRQoL was markedly altered at baseline in both CC the awareness for MC was lower. and LC patients, and improved after budesonide treatment.196–198 Should MC be ruled out in patients fulfilling the criteria for functional Are there established metrics to measure disease activity and clinical bowel disease with diarrhoea predominant subtype? remission in MC? Statement 3.2: MC diagnosis should be ruled out in patients Statement 3.4: In the absence of a formally validated metric of fulfilling the criteria for functional bowel disease, especially in pres- disease activity, disease activity and clinical remission in MC should ence of MC risk factors and/or in absence of irritable bowel syn- be assessed by the Hjortswang criteria (clinical remission: mean of drome (IBS)‐therapy response. less than 3 stools/day and a mean less than 1 water stool/day during LE: moderate; GR: NA; agreement: 93%, consensus. a 1‐week registration). Summary of available evidence: MC shares similar symptoms and LE: moderate; GR: NA; agreement: 100%, strong consensus. endoscopic results with functional bowel disorders, especially in Summary of evidence: In the absence of a reliable biomarker, the diarrhoea‐dominant IBS and chronic functional diarrhoea.176–179 In definition of disease activity is based on clinical disease activity. two meta‐analyses, the identification of underlying MC diagnosis was Various definitions for relapse or clinical remission have been used in 22 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL clinical trials on MC, mainly based on stool frequency191,199–204 and endoscopic findings (and which) may be more common in one or the 200,202 stool weight. A reduction of the mucosal inflammation or other histological subtype. thinning of the collagen layer has also been used to assess histo- What are the criteria for the histological diagnosis of CC? pathological response in trials,195,199–201,203 but the correlation be- Statement 4.2: The histopathologic criteria of CC are a thickened tween histology and clinical symptoms is weak.205 subepithelial collagenous band ≥10 mm combined with an increased In a Swedish population‐based survey, CC patients with a mean inflammatory infiltrate in the lamina propria. The criteria apply to of less than 3 stools/day and a mean of less than 1 watery stool/day haematoxylin and eosin (HE)‐stained slides. during a 1‐week symptom registration had no or only mild impact on LE: moderate; GR: NA; agreement: 89%, consensus. their HRQoL and were, hence, defined as being in remission.187 Summary of evidence: The original histological criteria of CC In contrast, CC patients with either ≥3 stools/day or ≥1 watery have not been contested but elaborated by few others.209 The most stool/day had a significant impact on their HRQoL and were, thus, characteristic feature is a thickened subepithelial collagenous band defined as having active disease. This definition is often referred to as exceeding 10 mm.210–214 The band often has an irregular deeper the ‘Hjortswang criteria' for disease activity. edge and may contain entrapped capillaries, red blood cells and in- An MC Disease Activity Index (MCDAI) has been proposed based flammatory cells. Focal damage of the surface epithelium, including on the same methodological principles as was once used for the detachment from the basement membrane, flattening and development of the Crohn's Disease Activity Index.206 A total of mucindepletion,205,210,212,215–220 as well as an increased number of 162 MC patients completed a symptom questionnaire and the intraepithelial lymphocytes (IELs) is seen.210,211,215–233 This should HRQoL questionnaire Inflammatory Bowel Disease Questionnaire be combined with an inflammatory infiltrate in lamina propria of mild 180 (IBDQ). A single investigator scored a physician global assessment to moderate degree, dominated by plasma cells and lymphocytes, but (PGA) of disease severity on a 10‐point scale based on the patients' also includes eosinophils,205,210,213–217,219,223–225 mast cells213 and, survey results. Multiple linear regressions identified the following more rarely, neutrophils.212,214–216,219–221,224,226 Paneth cell meta- symptoms to best predict the PGA: number ofunformed stools daily, plasia205,210,221,224 and occasionally cryptitis can be 212,216,220,221,224,227 presence of nocturnal stools, abdominal pain, weight loss, faecal urgency seen. The biopsies should be orientated vertically, and faecal incontinence. These symptoms were then combined in a since tangential sectioning can simulate a thickened collagenous weighted formula to create the MCDAI. The MCDAI was moderately band.228 associated with the IBDQ (r = ‐0.62, p < 0.001). The histologic criteria are based on HE‐stained sections. Sup- Neither the ‘Hjortswang criteria' nor the MCDAI have undergone plementary stains, such as Van Gieson, Masson Trichrome or Sirius formal prospective validation and they do not fulfil the new re- red,219,220,229 might be helpful since the collagenous band is high- quirements from the Food and Drug Administration for a patient lighted. The interobserver reproducibility of the histological diagnose reported outcome in clinical trials.207 However, the ‘Hjortswang of CC is good.230,231 criteria' has been used in seven published clinical studies, of which What are the criteria for the histological diagnosis of LC? three were RCTs,193,195,203 which represents a real‐life external and Statement 4.3: The histopathologic criteria of LC are an prospective validation of the score in clinical practice. increased number of IELs ≥20 per 100 surface epithelial cells com- bined with an increased inflammatory infiltrate in the lamina propria and a not significantly thickened collagenous band (<10 mm). The Diagnosis of MC criteria apply to HE‐stained slides. LE: moderate; GR: NA; agreement: 100%, strong consensus. What is the endoscopic appearance of MC? Summary of evidence: LC was originally named in 1989,217 Statement 4.1: Endoscopic findings are recognised with although described under the name MC in 1980.232 The criteria were increased frequency in patients with MC; however, they are based on HE‐stained slides.217 The most characteristic feature of LC nonspecific. is an increased number of IELs in the surface epithelium ≥20 per 100 LE: low; GR: NA; agreement: 95%, strong consensus. epithelial cells.1,3,4,7,233–244 Counting should be performed in the Summary of evidence: Overall, 80 informative articles including surface epithelium, and areas in close relation to lymphoid aggre- 1582 patients on endoscopic findings in MC were identified, including gates in the lamina propria should be avoided.1 Focal and mild 756 patients with CC, 779 patients with LC and 47 patients with damage of the surface epithelium, including flattening, mucin deple- MC.19,23,166,208 Macroscopically visible lesions or alterations were tion and vacuolisation, is seen, although not as prominently as in reported in 38.8% of patients in various parts of the colon, including CC.1,3,167,218,220,236,237,240,242,245–248 This should be combined with isolated linear ulcerations, pseudomembranes, irregular vascular an inflammatory infiltrate in lamina propria of a mild to moderate patterns, mucosal lacerations, erythema, oedema, nodularity and degree, dominated by plasma cells and surface textural alterations. lymphocytes,3,4,167,217,218,220,233,236,238,239,241,242,246–254 but might Although a larger number of publications exist for CC, the also include fewer eosinophils and neutrophils.3,217,220,248,250,254,255 number of published CC and LC patients is very similar.208 Therefore, occasionally, cryptitis217,220,221,249,252,256 or Paneth cells metaplasia no conclusive statement can be made as to whether or not is seen.221,236,241,250,252 MIEHLKE ET AL. - 23 Supplementary immunohistochemical staining might be helpful, participating in this guideline tended towards separate containers, especially in borderline cases, since highlighting the lymphocytes although there is no firm evidence to support this. makes counting easier.1,3,6,244,257 This might lead to over diagnosing Is histological monitoring necessary in patients with MC? and it has been suggested to use higher cut‐off values when counting Recommendation 4.6: We recommend against histological is performed on CD3‐stained slides.258 monitoring in patients with MC. What are the criteria for the histological diagnosis of MCi? LE: very low; GR: strong in favour; agreement: 100%, strong Statement 4.4: MCi comprises incomplete CC (CCi; defined by a consensus. thickened subepithelial collagenous band >5 μm but <10 μm) and Summary of evidence: Histology of postdiagnostic disease ac- incomplete LC (LCi; defined by >10 IELs but <20 IELs and a normal tivity has been described, but histological assessment of remission collagenous band). Both types show a mild inflammatory infiltrate in and relapse is not standardised171,195,199,203,215,241,247,263,272–276 and the lamina propria. The criteria apply to HE‐stained slides. correlation between clinical disease activity and histologic features is LE: low; GR: NA; agreement: 95%, strong consensus. only weak.171,195,199,203,215,241,247,263,272–276 Summary of evidence: Patients with symptoms of MC not Conversion between CC and LC occurs in some studies.263,273,275 completely fulfilling the histological criteria of CC or LC can be In a study of 283 patients, histological features persisted in post- classified as CCi or LCi.1,6,237 Different terms have been used, diagnostic biopsies for up to 1 year in 77% with CC, 64% with LC and including MC not otherwise specified,224,259,260 MC type undesig- 45% in MCi, of whom 6%, 9% and 18% converted to a different nated,261 borderline LC217 and paucicellular LC.251,262 Although the subtype, respectively. Histological features normalised in approxi- clinical characteristics of MC and MCi seem indistinguish- mately 10% and persisted beyond the first year in a significant 13,263,264 able, one study reports that a greater proportion of patients number of patients, including those in whom diarrhoea had resolved with MCi experience spontaneous remission.263 In CCi, the sub- and not recurred.263 epithelial collagenous band is more than 5 mm but less than 10 mm. Is faecal calprotectin useful in MC? In LCi, greater than 10 but less than 20 IELs are required. The in- Statement 4.7: Faecal calprotectin is not useful to exclude or flammatory infiltrate in lamina propria is usually mild but comprises monitor MC. identical cell types, as in CC and LC. LE: moderate; GR: NA; agreement: 100%, strong consensus. In borderline cases, it is recommended to use a supplementary Summary of evidence: Small studies have demonstrated that special stain or an immunohistochemical staining procedure in addi- faecal calprotectin was slightly, although significantly, higher in those tion to HE stains.265 with MC as compared to patients without organic cause of diar- Where should biopsies be taken in patients with suspected MC? rhoea277 and IBS.278 The predictive value was low due to a large Recommendation 4.5: We recommend ileocolonoscopy with bi- overlap. Wildt et al.279 demonstrated that faecal calprotectin was opsies from at least the right and left side of the colon. increased in some but not all 21 patients with active CC and over- LE: high; GR: strong in favour; agreement: 100%, strong lapped between patients with active and quiescent disease and consensus. normal controls. Further studies demonstrated overlapping values of Summary of evidence: Studies including a high number of pa- other faecal biomarkers, including faecal eosinophil protein and tients with simultaneous biopsies taken from the right and left colon eosinophil cationic protein,63 faecal lactoferrin,279,280 alpha‐1‐anti- show characteristic histological changes of MC in both sides in 95%– tryptin,281 and tryptase, eosinophil protein X and myeloperox- 13,23,263 98%. Similarly, smaller studies have found high idase.282 More studies on faecal biomarkers in MC including 18,45,46,205,211,266–270 concordance. Studies without a strict biopsy calprotectin are clearly needed. protocol reported a lower number of diagnostic biopsies from the left Should patients with MC be tested for coeliac disease? colon.214,219,229,243 Biopsies exclusively from the rectum are not Recommendation 4.8: We recommend screening for coeliac dis- 10,214,215,219,220 sufficient. ease in patients with MC. However, since a full ileocolonoscopy is indicated for virtually all LE: high; GR: strong in favour; agreement: 100%, strong patients with chronic diarrhoea, it is recommended to take biopsies consensus. from the right and left side of the colon. Summary of evidence: One large prospective study demon- It may be advisable to send these in separately labelled con- strated an incidence of celiac disease in 3.3% of patients with MC tainers as the number of inflammatory cells in normal surface versus 0.4% in controls.283 Incidence rates were between 2% and 4% epithelium and lamina propria is higher in the right colon.233,271 in large cohort studies,13,284 a case‐control study76 and one pathol- Similarly, the normal collagenous band has been reported to be ogy registry including 3456 MC patients having undergone both 226,227 thicker in the sigmoid colon and rectum. Especially in border- gastroscopy and lower endoscopy with biopsy.285 These estimates line cases, this may help the pathologists know that the biopsies are are larger than in the background populations, although lower than from, for example, the left side where the cellularity is usually lower, reported in numerous retrospective studies, mostly older case series because this would support the diagnosis if the pathologist is in and incomplete cohorts.28,88,163,166,170,172,173,286–290 Coeliac disease doubt. For these reasons, expert opinion among the pathologists was mainly diagnosed by biochemical testing rather than histology 24 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL and most studies screened only approximately half of the patients. stool/day). The inclusion of this study in the meta‐analysis using 291 Development of MC was not associated with intake of gluten. these data resulted in a pooled clinical remission rate of 81% (62/77) Should patients with MC be tested for bile acid diarrhoea? for budesonide compared to 26% (22/84) with placebo (RR: 3.10, Statement 4.9: Testing for bile acid diarrhoea is not part of 95% CI: 1.8–5.3; random effects). There was no significant hetero- routine diagnostic work‐up in patients with MC. geneity (p = 0.186, I2 = 37.7%; Supporting Information Appendix D). LE: low; GR: NA; agreement: 83%, consensus. Recommendation 4.10: Testing for bile acid diarrhoea can be considered in patients who experience nonresponse to budesonide Histological response treatment. LE: low; GR: strong in favour; agreement: 82%, consensus. The pooled analysis of histological response of the four studies197 Summary of evidence: Symptoms of MC and bile acid diarrhoea included a total of 161 patients with histological remission occurring are indistinguishable, and the two conditions coexist.13,292,293 The in 60/77 (78%) and 27/84 (32%) of patients receiving budesonide and diagnosis of bile acid diarrhoea relies on radiolabelled75 selenium placebo, respectively (RR: 2.68, 95% CI: 1.37–5.24), which did homotaurocholic acid taurine (SeHCAT) testing. SeHCAT for was demonstrate a statistically significant response. performed in 181 of 539 patients included in a large incidence cohort, and retention (<10%) was reduced in 125.13 Small case series reporting a high incidence of bile acid diarrhoea were probably Quality of life biased by referral.292,293 Active CC was associated with a reduced ileal bile acid reuptake and normalisation of disease activity In one study,201 the validated Gastrointestinal Quality of Life Index 294 increased retention and normalised bile acid synthesis. Whether (GIQLI) was used to measure quality of life at baseline and after 6 this bile acid diarrhoea is a consequence of inflammation in the right weeks of treatment with budesonide or placebo. A complete quality colon or even terminal ileum or merely a coexisting disease per se of life assessment was calculated for 29 trial participants (budeso- remains to be explored. Expression of the main bile acid receptor was nide: n = 17; placebo: n = 12). The mean baseline GIQLI score was 67 reduced in biopsies from the colon of patients with MC.295 MC was in the budesonide group and 86 in the placebo group. After 6 weeks not associated with prior cholecystectomy.296 of treatment, the mean GIQLI score remained unchanged in the placebo group (86–88) but increased significantly in the budesonide group (67–92; p < 0.001). Treatment Is oral budesonide effective in inducing remission of LC? Recommendation 5.1.2: We recommend using oral budesonide to Is oral budesonide effective in inducing remission of CC? induce remission in patients with LC. Recommendation 5.1.1: We recommend using oral budesonide to LE: low; GR: strong in favour; agreement: 100%, strong induce remission in patients with CC. consensus. LE: moderate; GR: strong in favour; agreement: 100%, strong Summary of evidence: consensus. Summary of evidence: Clinical response Clinical response A pooled analysis for clinical response in three studies192,195,297 shows a statistically significant benefit for budesonide over placebo. 197 A meta‐analysis conducted in 2017 included four randomised Clinical remission was noted in 84% (43/51) of budesonide patients placebo‐controlled trials with a total of 161 CC patients.199–201,203 and 43% (19/44) of placebo patients (RR: 1.89, 95% CI: 1.3–2.7), After 6–8 weeks of treatment, pooled analysis revealed 81% (62/77) without heterogeneity (I2 = 0%) (see also Supporting Information of patients treated with budesonide 9 mg/day achieved a clinical Appendix D). response compared to 36% (30/84) of patients treated with placebo (relative risk [RR]: 2.98, 95% CI: 1.14–7.75; random‐effects). This analysis was statistically significant for heterogeneity (p = 0.001, Histological response I2 = 81%). After excluding an outlier with an unusually high response rate to placebo,203 the I2 statistic decreased to 0% and the respective The pooled analysis for histological response showed a statistically clinical response rates were 81% (38/47) and 17% (8/47) (RR: 4.56, significant benefit for budesonide over placebo. Histological response 95% CI: 2.43–8.55). Secondary end points in that study203 included was noted in 78% of budesonide patients compared to 33% of pla- assessing clinical remission at 8 weeks according to the Hjortswang cebo patients (two studies; 39 participants; RR: 2.44, 95% CI: 1.13– criteria of disease activity (mean <3 stools/day, with <1 watery 5.28, I2 = 0%).196 MIEHLKE ET AL. - 25 Quality of life CI: 1.44–6.95). This was not significant for heterogeneity (p = 0.60, I2 = 0%).197 The 36‐item Short Form Health Survey scores at baseline were Is oral budesonide effective for maintaining remission of LC? reduced compared to normal values for both the physical and mental Recommendation 5.2.2: We suggest using oral budesonide to domains. In the budesonide group, the mean physical sum score maintain remission in patients with LC. increased from 42.0 at baseline to 49.7 after 6 weeks of treatment, LE: very low; GR: weak in favour; agreement: 84%, consensus. while the mean mental sum score was unchanged, with a value of Summary of evidence: There is no RCT assessing the efficacy 46.5 at baseline and 46.9 after 6 weeks192 In the placebo group, the of budesonide to maintain remission in LC. However, given the mean physical sum score increased from 44.1 at baseline to 48.0 similarity of this disease with CC, budesonide has been used to after 6 weeks of treatment, while the mean mental sum score was maintain remission in LC in clinical practice. The opinion of the unchanged, with a value of 49.0 at baseline and 49.1 after 6 experts favours the use of this drug in the maintenance of clinical weeks.192 remission in LC. Is oral budesonide effective for maintaining remission of CC? Is budesonide a safe drug in the treatment of MC? Recommendation 5.2.1: We recommend using oral budesonide to Statement 5.3.1: There is no increased risk of serious adverse maintain remission in patients with CC. events with budesonide in MC. LE: moderate; GR: strong in favour; agreement: 94%, consensus. LE: low; GR: NA; agreement: 100%, strong consensus. Summary of evidence: Summary of evidence: Five of seven RCTs of CC reported the proportion of patients experiencing at least one adverse 191,193,201,203,272 event. Pooled adverse event data, regardless of Maintenance of clinical response whether the study was an induction or maintenance trial, showed no statistically significant difference in adverse event rates between In three studies,191,193,272 patients with CC who had achieved a budesonide and placebo.197 Forty‐nine percent (68/140) of patients clinical response with open‐label budesonide were randomised to given budesonide and 42% (63/150) of patients given placebo continuous treatment with budesonide or placebo. A pooled analysis experienced at least one adverse event (five studies, 290 patients; of the three studies showed that 68% (57/84) of patients receiving RR: 1.18, 95% CI: 0.92–1.51). Seven percent (10/140) and 7% (11/ budesonide maintained remission at their respective study endpoints, 150) of patients administered budesonide and placebo, respectively, whereas only 20% (18/88) of patients receiving placebo maintained withdrew due to adverse events (five studies, 290 patients; RR: 0.97, remission (RR: 3.30, 95% CI: 2.13–5.09).197 At the end of 6 months, 95% CI: 0.43–2.17). Serious adverse events were rare, with 1% (1/84) more patients assigned to budesonide than placebo had maintained of patients receiving budesonide and 1% (1/91) of patients receiving their clinical response (75% vs. 25%). Results from two randomised placebo experiencing one (four studies, 175 patients; RR: 1.11, 95% clinical trials showed that maintenance therapy with budesonide CI: 0.15–8.01). 6 mg daily over 6 months resulted in a lower risk of clinical relapse Adverse events were reported in two RCTs of LC.192,195 In one 197 (RR: 0.34, 95% CI: 0.19–0.6). A lower dose of budesonide (3 mg study, six adverse events occurred in two patients (10%) in the daily alternating with 6 mg daily) over 12 months showed similar budesonide group, compared to nine adverse events in three patients efficacy in maintaining clinical response (see also Supporting Infor- (15%) in the placebo group (RR: 0.63, 95% CI: 0.12–3.41).192 In mation Appendix D). In a retrospective study on 75 patients with CC, another RCT, 47.4% (9/19) in the budesonide group and 42.1% (8/19) only 20% required budesonide doses of 6 mg/day or more to main- in the placebo group presented adverse events.195 85 tain clinical remission. Is prolonged use of oral budesonide in MC associated with an increased risk of osteoporosis? Statement 5.3.2: The risk of osteoporotic bone fractures seems Maintenance of histological response not be increased in budesonide‐treated MC patients, although pro- longed use might be associated with a decrease of bone mineral In two studies,191,272 25 patients assigned to budesonide with a density. maintained clinical response underwent a follow‐up colonoscopy or LE: low; GR: NA; agreement: 97%, strong consensus. sigmoidoscopy at the end of 6 months of treatment. Of these, 19 Summary of evidence: Data on the effect of longterm budesonide patients had also maintained their histological response, representing on bone mineral density mainly come from its use in other diseases. A 48% (19/40) of the initial patient cohort randomised to budesonide. mean dose of budesonide of 8.5 mg/day (range: 6 9 mg/day) for 2 In comparison, 19 patients assigned to placebo with a maintained years induced more alterations in bone mineral density (loss >2% per clinical response also underwent a follow‐up colonoscopy or year) than not receiving corticosteroid treatment in patients with sigmoidoscopy at the end of 6 months of treatment. Six of these Crohn's disease in remission.298 However, in a case‐control study, patients, representing 15% (6/40) of the initial patient cohort rand- treatment with budesonide at a dose of around 3 mg/day was not omised to placebo, had a maintained histological response. The associated with an increased risk of fracture.299 Oral budesonide pooled RR for maintenance of histological response was 3.17 (95% (6 mg/day for 3 years) plus ursodeoxycholic acid to treat patients 26 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL with primary biliary cirrhosis was also associated with a decrease in LE: very low; GR: strong in favour; agreement: 100%, strong 300 bone mass density, with no relation to the stage of liver disease. consensus. One study in MC patients (n = 50) showed no significant dif- Summary of evidence: Two large retrospective case series re- ferences in bone mineral density compared to a control group ported response or remission in 49 of 69 patients with CC173 and in (n = 49) of similar age and sex: 58% osteoporosis and osteopenia in 47 of 67 patients with LC.170 A large retrospective cohort of 539 79 MC versus 39% in the control group. However, the sample size was patients with MC reported a subjective effect of loperamide in 46/ insufficient and the statistical power low. The cumulative dose of 77 with MC.13 Several cohorts or smaller series reported complete budesonide was associated with lower bone mineral density and T‐ or near complete relief of diarrhoea in 18 57% patients with MC score in the hip, with a cut‐off of 2500 mg of budesonide to predict treated with loperamide.288,304 Loperamide has proven efficacious osteopenia. The markers of bone formation pro‐N‐terminal peptide and safe in several randomised, placebo‐controlled trials in patients procollagen type 1 and bone alkaline phosphatase were lower in with chronic diarrhoea, in particular abolishing faecal inconti- patients with MC than in controls, suggesting an osteoblast nence.306–309 dysfunction due to the systemic effect of budesonide or to the dis- Are bile acid binding agents effective in MC? 301 ease itself. In a recent case‐control study, there was no increase in Recommendation 5.7: In patients with MC and bile acid diar- osteoporotic fractures in general, but a modest isolated effect of rhoea we suggest treatment with bile acid binders. budesonide on the risk of spinal fractures was observed, mainly in LE: very low; GR: weak in favour; agreement: 100%, strong younger patients. consensus. Is mesalazine effective in MC? Summary of evidence: A large, prospective cohort study Recommendation 5.4: We recommend against treatment with demonstrated that bile acid diarrhoea diagnosed with SeHCAT co- mesalazine in patients with MC for induction of remission. There are exists with MC with an estimated prevalence of approximately 14%, no studies for maintenance. and 84 of 167 patients treated with cholestyramine reported sub- LE: low; GR: strong against; agreement: 94%, consensus. jective cessation of diarrhoea.13 This concurs with two large case Summary of evidence: Mesalazine has been shown in placebo‐ series reporting the effect of cholestyramine in 26 of 44 patients with controlled, randomised studies to lack efficacy and to be inferior to CC170 and in 26 of 46 patients with LC.173 An open‐label controlled 203 195 treatment with budesonide in CC and LC. Remission rates were trial demonstrated a very high response rate to cholestyramine,305 as 80%, 44% and 38% after 8 weeks of treatment with budesonide, did Ung et al.293 in CC patients both with and without concurrent bile 203 mesalazine and placebo, respectively, in patients with CC, and acid diarrhoea. An effect of cholestyramine was also reported in 79%, 63% and 42%, respectively, in patients with LC.195 These find- further small case series.273,288,302 Thus, the available data indicates ings are supported by real‐life experience in larger cohorts reporting that bile acid diarrhoea coexists with MC in a substantial number of clinical response to mesalazine in 4/28 with CC, 1/9 with LC and 1/6 patients, and that cholestyramine could be efficacious in patients 13 170 173 with MCi in 15 of 33 with LC and in 12 of 31 with CC. Others with coexisting MC and bile acid diarrhoea. case series reported response to mesalazine in about half of patients Is there a role for antibiotics in MC? with CC and LC.272,302–304 By contrast, mesalazine was effective in Recommendation 5.9: There is not enough evidence to recom- almost all patients in an open‐label mesalazine ±cholestyramine mend antibiotics for treatment of MC. trial.305 LE: very low; GR: strong against; agreement: 100%, strong Is there a role for bismuth subsalicylate in MC? consensus. Recommendation 5.5: There is not enough evidence to recom- Summary of evidence: Antibiotics for inducing and maintaining mend bismuth subsalicylate in patients with MC. remission in MC have not been investigated in controlled trials. Only LE: very low; GR: strong against; agreement: 92%, consensus. a few retrospective case series have reported the outcomes of MC Summary of evidence: The effect of treatment with bismuth after antibiotic treatment. In a retrospective series of 161 CC pa- subsalicylate for 8 weeks was studied in one open‐label study with 13 tients, various antibiotics (metronidazole, erythromycin and peni- patients with LC or CC.274 Clinical remission was reported in 11 and cillin) showed response rates of up to 60%.170 In another histological abnormalities resolved in nine of 13. An effect of bismuth retrospective cohort series of 199 patients with LC, 14/23 and 2/5 in 10 of 55 patients with LC (45.5%) and in 21 of 76 patients with CC responded to metronidazole and norfloxacin.173 In both studies, no 302 (63.6%) was reported in a retrospectively collected case series. A information about response definition, concomitant treatment, total of 23% of 22 patients with LC identified retrospectively re- dosing or relapse rate were reported. Finally, in a large consecutive ported cessation of diarrhoea,288 but the histological criteria were 10 cohort of 539 patients with MC, 6/33 patients had response to an- IELs per 100 epithelial cells. tibiotics; however, effect measurement was not defined, and treat- Is there a role for loperamide in MC? ment duration and antibiotics of choice not reported.13 Recommendation 5.6: There is not enough evidence to recom- Is there a role for probiotics in MC? mend the use of loperamide in MC. Given the documented effect in Recommendation 5.10: We recommend against use of probiotics patients with chronic diarrhoea, the expert's opinion favours the use for treatment of MC. of this drug in mild disease. LE: low; GR: strong against; agreement: 100%, strong consensus. MIEHLKE ET AL. - 27 Summary of evidence: Only one placebo‐controlled trial exam- Biologics ining probiotics against placebo has been published. In an induction study with sample size = 29, Lactobacillus acidophilus and Bifido- Anti‐TNF agents in MC have been studied in small case series320,321 194 bacterium animalis subs Lactis were not superior to placebo. In and single cases.322–324 In four MC patients with severe symptoms another randomised but open‐labelled trial, the effect of the pro- refractory to standard medical therapies, infliximab or adalimumab biotic VSL#3 versus mesalazine was examined. Twenty‐four patients lead to long‐term clinical remission in three cases (two with adali- fulfilled the study. In the VSL#3 group, a significant reduction in stool mumab and one with infliximab). One patient on adalimumab had an weight at 8 weeks was demonstrated (p = 0.03) but no change was early loss of response and was referred for colectomy.320 Münch 310 seen in stool frequency. et al.321 reported three CC patients receiving adalimumab as a third‐ Is there a role for prednisolone in MC? line therapy. Two achieved clinical remission at Week 6, while one Recommendation 5.11: We recommend against the use of had to discontinue due to side effects, despite clinical response. The prednisolone or other corticosteroids than budesonide for the largest series included 18 patients (16 CC, two LC) treated with treatment of MC. adalimumab or infliximab.323 At Week 12, nine patients achieved LE: low; GR: strong against; agreement: 100%, strong consensus. remission and six were responders. Summary of evidence: Only one placebo‐controlled trial with Vedolizumab has been studied in an international case series of prednisolone exists. Treatment duration was very short, sample size 11 patients (five LC, six CC) who failed to respond to other therapies low (12 patients) and prednisolone was without significant effect.202 including anti‐TNF agents.325 After three infusions, clinical remission In one open small trial and in several retrospective cohort studies, a was observed in five patients (two LC and three CC), of whom three positive effect of prednisolone has been reported; however, relapse remained well with maintenance therapy during a median duration of rates were high.170,173,288,311,312 An open‐label retrospective study 13 months. Other case series reported successful use of vedolizumab investigated beclomethasone dipropionate as a synthetic cortico- to induce remission of MC.326–328 steroid with topical colonic release in 30 patients with MC showing a Is there a role for surgery in MC? 313 response rate of 80% and remission rate of 67%. Recommendation 5.13: Surgery can be considered in selected Is there a role for immunomodulators and biologics in the treatment patients as last option if all medical therapy fails. of patients with MC? LE: very low; GR: weak; agreement: 100%, strong consensus. Recommendation 5.12: We recommend treatment with thio- Summary of evidence: Scientific evidence on surgical treatment purines, anti‐tumour necosis factor (TNF) drugs or vedolizumab in in MC comes only from a few case reports.329–332 One case series selected patients with MC who fail to respond to budesonide to published in 1995 reported on nine female CC patients who failed to induce and maintain clinical remission. We recommend against the respond to medical therapies (none of them received budesonide, use of methotrexate in patients with MC. immunomodulators or biologics). An ileostomy was performed in LE: low; GR: strong; agreement: 97%, strong consensus. eight patients and a sigmoidostomy in one patient. Postoperatively, Summary of evidence: Azathioprine/6‐mercaptopurine. The ef- diarrhoea ceased in all patients; however, clinical symptoms recurred fect of thiopurines in MC has been evaluated in several retrospective after restoration of intestinal continuity. case series including from 9 to 49 MC patients who usually were A case report in 2000 described a CC patient who was treated steroid‐dependent or ‐refractory. The reported long‐term response successfully by total proctocolectomy and ileal pouch anal anasto- rates allowing corticosteroid discontinuation ranged from 28% to mosis.332 In two case reports of CC patients not responding to 89%.314–316 budesonide331 or adalimumab,330 symptoms improved after tempo- A retrospective analysis of 49 patients (43 on azathioprine and rary loop ileostomy, but recurred after restoration of bowel conti- six on mercaptopurine) demonstrated complete or partial response in nuity. One case report described a CC patient undergoing colectomy 43% and 22%, respectively, whereas cessation of therapy because of after adalimumab failure, but no outcome has been reported.320 317 adverse events occurred in 17 patients (35%). Therapeutic management of MC Methotrexate Based upon the available evidence and expert opinion, a therapeutic Methotrexate was evaluated in a retrospective analysis including algorithm for MC is proposed (Figure 1). This algorithm is supported 19 MC patients, of whom 16 (84%) showed complete or partial by a high level of agreement among the guideline group (strongly 318 clinical response. Another series of 12 patients reported complete agree 64.3%, agree 35.7%). For patients with active MC oral bude- response in seven, partial response in two patients and no response sonide, which is currently the only licenced drug for treatment of MC, in three patients.317 Only one study has prospectively evaluated the should be the medical therapy of choice. In case of chronic active effect of methotrexate in patients intolerant or refractory to bude- disease, long‐term treatment with oral budesonide with the lowest sonide. Here, none of the nine included patients achieved clinical possible dose for as long as needed is advised. The question of remission.319 budesonide withdrawal should be discussed with the patient and 28 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL Active micrscopic colitis Avoid risk factors* Induction: Budesonide 9 mg daily, 6 to 8 weeks Intolerance, patient’s preference Clinical remission Clinical non-response Loperamide, Cholestyramine Clinical relapse Other causes for Treat diarrhea identified by accordingly new clinical work-up** No relapse Induction: Budesonide 9 mg/d No Chronic active disease maintenance therapy Maintenance: Budesonide Consider alternatives: low-dose (3-6 mg/d) Loperamide, cholestyramine +/- lopermide (or in combination) adalimumab, infliximab, azathioprine/6-MP, Chronic active disease despite vedolizumab, surgery budesonide ≥6 mg/d, intolerance *smoking, NSAID, PPI **i.e. bile acid diarrhoea, coeliac disease F I G U R E 1 Therapeutic algorithm for microscopic colitis in clinical practice. *Smoking, NSAID, PPI; **for example bile acid diarrhoea, coeliac disease. NSAID, nonsteroidal anti‐inflammatory drugs; PPI, proton pump inhibitor decided on an individual basis. In case of long‐term budesonide A CK NO W L E D GM E N T S treatment, supplementation with calcium/vitamin D and monitoring The steering committee (S. M., A. Mü., D. G., Y. Z., G. E. T., A. M. K., S. of bone mineral density may be considered on an individual basis, W.) organised the working groups and designed the preliminary list of especially in patients with additional risk factors for osteoporosis. topics to be covered. All authors systematically reviewed the litera- Loperamide may be used on demand if needed. In budesonide‐re- ture and drafted the statements and recommendations and provided fractory patients and in patients requiring budesonide more than Grading of Recommendations Assessment, Development and Evalu- 6 mg/day to maintain clinical remission, alternative medical therapies ation evaluations. All authors and members of the consensus group including immunomodulators or biologics should be considered. voted on the statements and recommendations. The steering com- mittee then drafted the initial manuscript, which was reviewed, revised and approved by all authors and members of the consensus CONCLUSIONS AND FUTURE PERSPECTIVES group. Subsequently it was made available to all members for final comments prior to submission for publication. Collaborators: Nadine These EMCG/UEG guidelines provide evidenced‐based statements Steubesand and Franziska Dambon, Clinical Guideline Services, Kiel, and recommendations for essential aspects of the clinical manage- Germany. These guidelines have been developed with reasonable ment of MC. The main objective and potential of these guidelines is care and with the best of knowledge available to the authors at the to increase awareness for a presumably under‐recognised medical time of preparation. They are intended to assist healthcare pro- condition and to improve medical care and patient outcomes. fessionals and allied healthcare professionals as an educational tool Extensive dissemination of these guidelines is needed to facilitate to provide information that may support them in providing care to widespread use and implementation in clinical practice. Several un- patients. Patients or other community members using these guide- met needs have been identified, including a better understanding of lines shall do so only after consultation with a health professional and the natural course and pathophysiological mechanisms of disease, shall not mistake these guidelines as professional medical advice. reliable noninvasive biomarkers, validated instruments for assess- These guidelines must not substitute seeking professional medical ment of disease activity and new treatment modalities. These gaps and health advice from a health professional. These guidelines may should be addressed by high‐quality basic research and well‐designed not apply to all situations and should be interpreted in the light of clinical trials. specific clinical situations and resource availability. It is up to every MIEHLKE ET AL. - 29 clinician to adapt these guidelines to local regulations and to each 3. Munch A, Langner C. Microscopic colitis: clinical and pathologic patient's individual circumstances and needs. The information in perspectives. Clin Gastroenterol Hepatol. 2015;13:228–36. 4. Pardi DS. Diagnosis and management of microscopic colitis. Am J these guidelines shall not be relied upon as being complete, current Gastroenterol. 2017;112:78–85. or accurate, nor shall it be considered as inclusive of all proper 5. Pardi DS, Kelly CP. Microscopic colitis. Gastroenterology. treatments or methods of care or as a legal standard of care. United 2011;140:1155–65. European Gastroenterology (UEG) makes no warranty, express or 6. Munch A, Aust D, Bohr J, et al. Microscopic colitis: current status, present and future challenges: statements of the European implied, in respect of these guidelines and cannot be held liable for Microscopic Colitis Group. J Crohns Colitis. 2012;6:932–45. any damages resulting from the application of these guidelines, in 7. Magro F, Langner C, Driessen A, et al. European consensus on the particular for any loss or damage (whether direct or indirect) histopathology of inflammatory bowel disease. J Crohns Colitis. resulting from a treatment based on the guidance given herein. UEG 2013;7:827–51. 8. Fernandez‐Banares F, Casanova MJ, Arguedas Y, et al. Current shall not be held liable to the utmost extent permissible according to concepts on microscopic colitis: evidence‐based statements and the applicable laws for any content available on such external web- recommendations of the Spanish Microscopic Colitis Group. sites, which can be accessed by using the links included herein. These Aliment Pharmacol Ther. 2016;43:400–26. guidelines were developed with the support of a UEG Activity Grant. 9. Pardi DS, Tremaine WJ, Carrasco‐Labra A. American Gastroen- The European Microscopic Colitis Group administered all aspects of terological Association Institute technical review on the medical management of microscopic colitis. Gastroenterology. the meetings without other external funding sources. 2016;150:247–74. 10. Agnarsdottir M, Gunnlaugsson O, Orvar KB, et al. Collagenous and C O N F LI C T O F I N T E R ES T S lymphocytic colitis in Iceland. Dig Dis Sci. 2002;47:1122–8. There are no industry or government relationships to report: Johan 11. Andrews CN, Beck PL, Wilsack L, et al. Evaluation of endoscopist and pathologist factors affecting the incidence of microscopic co- Bohr, Mauro D'Amato, JE, Anne‐Marie Kanstrup Fiehn, Jouzas litis. Can J Gastroenterol. 2012;26:515–20. Kupcinskas, Giovanni Latella, Ivan Lyutakov, Gilles Macaigne, 12. Bergman D, Clements MS, Khalili H, et al. A nation‐wide cohort Fernando Magro, Emese Mihaly, Lars Kristian Munck, Árpád V. Patai, study of the incidence of microscopic colitis in Sweden. Aliment Karolina Skonieczna‐Zydecka, Bas Verhaegh. Advisory boards, Pharmacol Ther. 2019;49:1395–400. 13. Bjornbak C, Engel PJ, Nielsen PL, et al. Microscopic colitis: clinical consulting: Stephan Miehlke: Dr Falk Pharma, Tillotts; Yamile findings, topography and persistence of histopathological sub- Zabana: Tillotts, Janssen, FAES; Fernando Fernandez‐Banares: groups. Aliment Pharmacol Ther. 2011;34:1225–34. Tillotts, Thermofisher; Henrik Hjortswang: Abbvie, Janssen, Pfizer, 14. Bonderup OK, Wigh T, Nielsen GL, et al. The epidemiology of Takeda, Tillotts; Anastasios Koulaouzidis: Tillotts, Dr Falk Pharma; microscopic colitis: a 10‐year pathology‐based nationwide Danish cohort study. Scand J Gastroenterol. 2015;50:393–8. Wojciech Marlicz Sanprobi; Ahmed Madisch: Dr Falk Pharma; Ole 15. Daferera N, Almer S, Münch A. P634 incidence of microscopic Bonderup: Tillotts; Gian E. Tontini: Aorta SRL, CapsoVision Inc; colitis 2008–2011 in central Ostergotland, Sweden. Evidence for Andreas Münch: Ferring, Tillotts, Dr Falk Pharma; Signe Wildt: an increase?. J Crohns Colitis. 2013;7:S265. Tillotts, Takeda. Research grants/clinical trial funding: Ole Bonderup: 16. Davidson S, Sjoberg K, Engel PJH, et al. Microscopic colitis in Denmark and Sweden: incidence, putative risk factors, histological Tillotts; Fernando Fernandez‐Banares: Dr Falk Pharma; Henrik assessment and endoscopic activity. Scand J Gastroenterol. Hjortswang: Abbvie, Ferring, Tillotts, Biomedal; Andreas Münch: 2018;53:818–24. Ferring. Speaker's bureau: Stephan Miehlke: Dr Falk Pharma/Falk 17. Fernandez‐Banares F, Salas A, Esteve M, et al. Evolution of the Foundation; Yamile Zabana: Abbvie, MSD, Ferring; Danila Guagnozzi: incidence of collagenous colitis and lymphocytic colitis in Terrassa, Allergan; Ole Bonderup: Dr Falk Pharma/Falk Foundation, Tillotts; Spain: a population‐based study. Inflamm Bowel Dis. 2011;17:1015–20. Henrik Hjortswang: Abbvie, Tillotts; Anastasios Koulaouzidis: Dr Falk 18. Fernandez‐Banares F, Salas A, Forne M, et al. Incidence of collag- Pharma; Ahmed Madisch: Dr Falk Pharma/Falk Foundation; Wojciech enous and lymphocytic colitis: a 5‐year population‐based study. Marlicz: Alfasigma; Andreas Münch: Tillotts. Am J Gastroenterol. 1999;94:418–23. 19. Fumery M, Kohut M, Gower‐Rousseau C, et al. Incidence, clinical presentation, and associated factors of microscopic colitis in O R C ID northern France: a population‐based study. Dig Dis Sci. Stefania Landolfi https://orcid.org/0000-0002-1059-635X 2017;62:1571–9. Alfredo Lucendo https://orcid.org/0000-0003-1183-1072 20. Gentile NM, Khanna S, Loftus EV Jr, et al. The epidemiology of Ivan Lyutakov https://orcid.org/0000-0001-8883-1121 microscopic colitis in Olmsted County from 2002 to 2010: a population‐based study. Clin Gastroenterol Hepatol. 2014;12:838– Wojciech Marlicz https://orcid.org/0000-0002-2649-5967 42. Árpád V. Patai https://orcid.org/0000-0003-1863-5971 21. Guagnozzi D, Lucendo AJ, Angueira‐Lapena T, et al. Prevalence and incidence of microscopic colitis in patients with diarrhoea of un- R E F ER E N C E S known aetiology in a region in central Spain. Dig Liver Dis. 1. Langner C, Aust D, Ensari A, et al. Histology of microscopic colitis‐ 2012;44:384–8. review with a practical approach for pathologists. Histopathology. 22. Heron T, Walsh S, Mowat C. Microscopic colitis in Tayside: clinical 2015;66:613–26. features, associations, and behaviour. Gut. 2005;54:A84. 2. Miehlke S, Verhaegh B, Tontini GE, et al. Microscopic colitis: 23. Kane JS, Rotimi O, Ford AC. Macroscopic findings, incidence and pathophysiology and clinical management. Lancet Gastroenterol characteristics of microscopic colitis in a large cohort of patients Hepatol. 2019;4:305–14. from the United Kingdom. Scand J Gastroenterol. 2017;52:988–94. 30 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 24. Lewis NR, Archer T, Kaye P. PWE–061 epidemiology of micro- 45. Erdem L, Yildirim S, Akbayir N, et al. Prevalence of microscopic scopic colitis in Nottingham: a contemporary cohort study. Gut. colitis in patients with diarrhea of unknown etiology in Turkey. 2017;66:A156. World J Gastroenterol. 2008;14:4319–23. 25. Moore M, Coleman HG, Allen PB, et al. Microscopic colitis: a 46. Fine KD, Seidel RH, Do K. The prevalence, anatomic distribution, population‐based case series over a 9‐year period in Northern and diagnosis of colonic causes of chronic diarrhea. Gastrointest Ireland. Colorectal Dis. 2018;20:1020–7. Endosc. 2000;51:318–26. 26. Olesen M, Eriksson S, Bohr J, et al. Microscopic colitis: a common 47. Gado AS, Ebeid BA, El Hindawi AA, et al. Prevalence of microscopic diarrhoeal disease. An epidemiological study in Orebro, Sweden, colitis in patients with chronic diarrhea in Egypt: a single‐center 1993–1998. Gut. 2004;53:346–50. study. Saudi J Gastroenterol. 2011;17:383–6. 27. Pardi DS, Loftus EV Jr., Smyrk TC, et al. The epidemiology of 48. Garg PK, Singh J, Dhali GK, et al. Microscopic colitis is a cause of microscopic colitis: a population based study in Olmsted County, large bowel diarrhea in Northern India. J Clin Gastroenterol. Minnesota. Gut. 2007;56:504‐8. 1996;22:11–5. 28. Thorn M, Sjoberg D, Ekbom A, et al. Microscopic colitis in Uppsala 49. Gu HX, Zhi FC, Huang Y, et al. Microscopic colitis in patients with health region, a population‐based prospective study 2005–2009. chronic diarrhea and normal colonoscopic findings in Southern Scand J Gastroenterol. 2013;48:825‐30. China. Int J Colorectal Dis. 2012;27:1167–73. 29. Verhaegh BP, Jonkers DM, Driessen A, et al. Incidence of 50. Hatemi AI, Senates E, Dobrucali A, et al. Collagenous colitis: a microscopic colitis in the Netherlands. A nationwide population‐ retrospective survey of patients with chronic diarrhea. Hep- based study from 2000 to 2012. Dig Liver Dis. 2015;47: atogastroenterology. 2011;58:1963–7. 30–6. 51. Hotouras A, Collins P, Speake W, et al. Diagnostic yield and eco- 30. Wickbom A, Bohr J, Eriksson S, et al. Stable incidence of collage- nomic implications of endoscopic colonic biopsies in patients with nous colitis and lymphocytic colitis in Orebro, Sweden, 1999–2008: chronic diarrhoea. Colorectal Dis. 2012;14:985–8. a continuous epidemiologic study. Inflamm Bowel Dis. 52. Kagueyama FM, Nicoli FM, Bonatto MW, et al. Importance of bi- 2013;19:2387–93. opsies and histological evaluation in patients with chronic diarrhea 31. Williams JJ, Kaplan GG, Makhija S, et al. Microscopic colitis‐ and normal colonoscopies. Arq Bras Cir Dig. 2014;27:184–7. defining incidence rates and risk factors: a population‐based study. 53. Larsson JK, Sjoberg K, Vigren L, et al. Chronic non‐bloody diar- Clin Gastroenterol Hepatol. 2008;6:35–40. rhoea: a prospective study in Malmo, Sweden, with focus on 32. Tong J, Zheng Q, Zhang C, et al. Incidence, prevalence, and tem- microscopic colitis. BMC Res Notes. 2014;7:236. poral trends of microscopic colitis: a systematic review and meta‐ 54. Macaigne G, Lahmek P, Locher C, et al. Microscopic colitis or analysis. Am J Gastroenterol. 2015;110:265–76. functional bowel disease with diarrhea: a French prospective 33. Bohr J, Tysk C, Eriksson S, et al. Collagenous colitis in Orebro, multicenter study. Am J Gastroenterol. 2014;109:1461–70. Sweden, an epidemiological study 1984–1993. Gut. 1995;37:394‐7. 55. Miraglia S, Luigiano C, Siringo S, et al. P.12.14 the paucicellular 34. Raclot G, Queneau P, Ottignon Y. Incidence of collagenous colitis— lymphocytic colitis is the most frequent type of microscopic colitis a retrospective study in the east of France. Gastroenterology. in a city of southern Italy: preliminary results of a 6‐month pilot 1994;106:A23. study. Dig Liver Dis. 2013;45:S177. 35. Rajan J, Noble C, Anderson C. The epidemiology and clinical fea- 56. Misra V, Misra SP, Dwivedi M, et al. Microscopic colitis in patients tures of collagenous colitis in Lothian. Gut. 2005;54:A99–100. presenting with chronic diarrhea. Indian J Pathol Microbiol. 36. Vigren L, Olesen M, Benoni C, et al. An epidemiological study of 2010;53:15–9. collagenous colitis in southern Sweden from 2001–2010. World J 57. Shah RJ, Fenoglio‐Preiser C, Bleau BL, et al. Usefulness of colo- Gastroenterol. 2012;18:2821–6. noscopy with biopsy in the evaluation of patients with chronic 37. El‐Matary W, Girgis S, Huynh H, et al. Microscopic colitis in chil- diarrhea. Am J Gastroenterol. 2001;96:1091–5. dren. Dig Dis Sci. 2010;55:1996–2001. 58. Shaw A, Hall J, Ravi S. Random colonic biopsies for chronic 38. Gremse DA, Boudreaux CW, Manci EA. Collagenous colitis in diarrhoea—a numbers needed to investigate approach. Int J Surg. children. Gastroenterology. 1993;104:906–9. 2016;36:S61. 39. Liu X, Xiao SY, Plesec TP, et al. Collagenous colitis in children and 59. Sidhu PS, Khan F, Hebden J, et al. PWE‐187 colonic biopsies to adolescents: study of 7 cases and literature review. Mod Pathol. detect microscopic colitis in patients with diarrhoea and “normal” 2013;26:881–7. colonoscopy: worth the effort? Gut 2012;61:A372. 40. Vanderhoof JA, Goble K, Young RJ. Collagenous colitis in a 4‐year‐ 60. Tontini GE, Pastorelli L, Spina L, et al. Microscopic colitis and old child: response to budesonide. J Pediatr Gastroenterol Nutr. colorectal neoplastic lesion rate in chronic nonbloody diarrhea: a 2010;50:688–90. prospective, multicenter study. Inflamm Bowel Dis. 2014;20:882– 41. Fernandez‐Banares F, Zabana Y, Aceituno M, et al. Prevalence and 91. natural history of microscopic colitis: a population‐based study 61. Trembling PM, Nicol F, Hoare J. PTU‐259 routine biopsy during with long‐term clinical follow‐up in Terrassa, Spain. J Crohns Co- lower gi endoscopy is of diagnostic value for patients with chronic litis. 2016;10:805–11. diarrhoea. Gut 2015;64:A175–76. 42. Batista L, Ruiz L, Zabana Y, et al. P240 microscopic colitis is the 62. Villafuerte‐Galvez J, Sotelo‐Olivera MI, Cok J, et al. Colonoscopic most frequent diagnosis of patients with watery chronic diarrhoea findings in Peruvian patients with chronic diarrhea. PLoS One. and macroscopically normal colonoscopy in a context of clinical 2012;7:e46690. practice. J Crohns Colitis. 2018;12:S221. 63. Wagner M, Sjoberg K, Vigren L, et al. Elevated fecal levels of 43. Cotter TG, Binder M, Smyrk T, et al. Sa1410 optimization of a eosinophil granule proteins predict collagenous colitis in patients scoring system to predict microscopic colitis in a cohort of patients referred to colonoscopy due to chronic non‐bloody diarrhea. Scand with chronic diarrhea. Gastroenterology. 2016;150:S308. J Gastroenterol. 2016;51:835–41. 44. da Silva JG, De Brito T, Cintra Damiao AO, et al. Histologic study of 64. Arcana Lopez R, Frisancho Velarde O, Chacaltana A. Etiology of colonic mucosa in patients with chronic diarrhea and normal chronic diarrhea in the elderly in hospital Edgardo Rebagliati, Lima‐ colonoscopic findings. J Clin Gastroenterol. 2006;40:44–8. Peru. Rev Gastroenterol Peru. 2012;32:366–70. MIEHLKE ET AL. - 31 65. Carmona‐Sanchez R, Tostado‐Fernandez F, Esmer‐Sanchez D. 86. Gentile NM, Khanna S, Kammer PP, et al. Outcomes of microscopic Usefulness of colonoscopy with biopsy for the study of patients colitis and smoking: a population‐based study. Gastroenterology. with chronic diarrhea. Revista de Gastroenterologıa de Mexico. 2013;144:S439. 2007;72:349–54. 87. Munch A, Tysk C, Bohr J, et al. Smoking status influences 66. Channaiah D, Mohammad K, Kini R, et al. Yield of colonoscopy with clinical outcome in collagenous colitis. J Crohns Colitis. biopsy in the evaluation of chronic diarrhea. Indian J Gastro- 2016;10:449–54. enterol. 2017;36:A76. 88. O'Toole A, Coss A, Holleran G, et al. Microscopic colitis: clinical 67. Essid M, Kallel S, Brahim EB, et al. Prevalence of microscopic colitis characteristics, treatment and outcomes in an Irish population. Int to the course of the chronic diarrhea: about 150 cases. Tunis Med. J Colorectal Dis. 2014;29:799–803. 2005;83:284–7. 89. Roth B, Bengtsson M, Ohlsson B. Diarrhoea is not the only symp- 68. Gonzalez N, Guerra L, Sanguinetti A, et al. Prevalence of micro- tom that needs to be treated in patients with microscopic colitis. scopic colitis in a group of patients from Montevideo, Uruguay. Eur J Intern Med. 2013;24:573–8. Acta Gastroenterol Latinoam. 2019;40:216–20. 90. Miehlke S, Hansen JB, Madisch A, et al. Risk factors for symptom 69. Marshall J, Singh R, Diaz‐Arias A. Chronic, unexplained diarrhea: relapse in collagenous colitis after withdrawal of short‐term are biopsies necessary if colonoscopy is normal?. Am J Gastro- budesonide therapy. Inflamm Bowel Dis. 2013;19:2763–7. enterol. 1995;90:372–6. 91. Bonderup OK, Fenger‐Gron M, Wigh T, et al. Drug exposure and 70. Matsubara Y, Ohta T, Maemoto A. Abnormal colonic biopsy find- risk of microscopic colitis: a nationwide Danish case‐control study ings in chronic diarrhea patients with almost normal endoscopic with 5751 cases. Inflamm Bowel Dis. 2014;20:1702–7. findings. Gastroenterol Endosc. 2014;56:1563–9. 92. Bonderup OK, Nielsen GL, Dall M, et al. Significant association 71. Sethi S. Outcomes in patients undergoing colonoscopy to investi- between the use of different proton pump inhibitors and micro- gate chronic diarrhea. J Gastroenterol Hepatol. 2012;27:43. scopic colitis: a nationwide Danish case‐control study. Aliment 72. Valle Mansilla JL, Leon Barua R, Recavarren Arce S, et al. Micro- Pharmacol Ther. 2018;48:618–25. scopic colitis in patients with chronic diarrhea. Rev Gastroenterol 93. Fernandez‐Banares F, Esteve M, Espinos JC, et al. Drug con- Peru. 2002;22:275–8. sumption and the risk of microscopic colitis. Am J Gastroenterol. 73. Burke KE, Ananthakrishnan AN, Lochhead P, et al. Smoking is 2007;102:324–30. associated with an increased risk of microscopic colitis: results 94. Keszthelyi D, Jansen SV, Schouten GA, et al. Proton pump inhibitor from two large prospective cohort studies of US women. J Crohns use is associated with an increased risk for microscopic colitis: a Colitis. 2018;12:559–67. case‐control study. Aliment Pharmacol Ther. 2010;32:1124–8. 74. Larsson JK, Sonestedt E, Ohlsson B, et al. The association between 95. Masclee GM, Coloma PM, Kuipers EJ, et al. Increased risk of the intake of specific dietary components and lifestyle factors and microscopic colitis with use of proton pump inhibitors and non‐ microscopic colitis. Eur J Clin Nutr. 2016;70:1309–17. steroidal anti‐inflammatory drugs. Am J Gastroenterol. 75. Roth B, Gustafsson RJ, Jeppsson B, et al. Smoking‐ and alcohol 2015;110:749–59. habits in relation to the clinical picture of women with micro- 96. Pascua MF, Kedia P, Weiner MG, et al. Microscopic colitis and scopic colitis compared to controls. BMC Wom Health. medication use. Clin Med Insights Gastroenterol. 2010;2010:11–9. 2014;14:16. 97. Riddell RH, Tanaka M, Mazzoleni G. Non‐steroidal anti‐ 76. Verhaegh BPM, Pierik MJ, Goudkade D, et al. Early life exposure, inflammatory drugs as a possible cause of collagenous colitis: a lifestyle, and comorbidity as risk factors for microscopic colitis: a case‐control study. Gut. 1992;33:683–6. case‐control study. Inflamm Bowel Dis. 2017;23:1040–6. 98. Verhaegh BP, de Vries F, Masclee AA, et al. High risk of drug‐ 77. Vigren L, Sjoberg K, Benoni C, et al. Is smoking a risk factor for induced microscopic colitis with concomitant use of NSAIDs and collagenous colitis?. Scand J Gastroenterol. 2011;46:1334–9. proton pump inhibitors. Aliment Pharmacol Ther. 2016;43:1004– 78. Wickbom A, Nyhlin N, Montgomery SM, et al. Family history, co- 13. morbidity, smoking and other risk factors in microscopic colitis: a 99. Yen EF, Yoo J, Ture A, et al. Medication exposure and the risk of case‐control study. Eur J Gastroenterol Hepatol. 2017;29:587–94. microscopic colitis: results from a prospective US trial. Gastroen- 79. Wildt S, Munck LK, Becker S, et al. Risk of osteoporosis in micro- terology. 2017;152:S194. scopic colitis. Postgrad Med. 2018;130:348–54. 100. Harma C, Havelet M, Dean T, et al. Lymphocytic colitis and proton 80. Yen EF, Pokhrel B, Du H, et al. Current and past cigarette smoking pump inhibitor use: a case‐control study. J Gastroenterol Hepatol. significantly increase risk for microscopic colitis. Inflamm Bowel 2011;26:68–83. Dis. 2012;18:1835–41. 101. Al‐Ghamdi MY, Malatjalian DA, Veldhuyzen van Zanten S. Causa- 81. Fernandez‐Banares F, de Sousa MR, Salas A, et al. Epidemiological tion: recurrent collagenous colitis following repeated use of risk factors in microscopic colitis: a prospective case‐control study. NSAIDs. Can J Gastroenterol. 2002;16:861–2. Inflamm Bowel Dis. 2013;19:411–7. 102. Beaugerie L, Luboinski J, Brousse N, et al. Drug induced lympho- 82. Guagnozzi D, Lucendo AJ, Angueira T, et al. Drug consumption and cytic colitis. Gut. 1994;35:426–8. additional risk factors associated with microscopic colitis: case‐ 103. Beaugerie L, Pardi DS. Review article: drug‐induced microscopic control study. Rev Esp Enferm Dig. 2015;107:347–53. colitis—proposal for a scoring system and review of the literature. 83. Jaruvongvanich V, Poonsombudlert K, Ungprasert P. Smoking and Aliment Pharmacol Ther. 2005;22:277–84. risk of microscopic colitis: a systematic review and meta‐analysis. 104. Beaugerie L, Patey N, Ranitidine BN. Diarrhoea, and lymphocytic Inflamm Bowel Dis. 2019;25:672–8. colitis. Gut. 1995;37:708–11. 84. Fernandez‐Banares F, de Sousa MR, Salas A, et al. Impact of cur- 105. Begaud B, Evreux J, Jouglard J, et al. Imputation of the unexpected rent smoking on the clinical course of microscopic colitis. Inflamm or toxic effects of drugs. Actualization of the method used in Bowel Dis. 2013;19:1470–6. France. Therapie. 1985;40:111–8. 85. Fernandez‐Banares F, Piqueras M, Guagnozzi D, et al. Collagenous 106. Berrebi D, Sautet A, Flejou JF, et al. Ticlopidine induced colitis: a colitis: requirement for high‐dose budesonide as maintenance histopathological study including apoptosis. J Clin Pathol. treatment. Dig Liver Dis. 2017;49:973–7. 1998;51:280–3. 32 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 107. Bouaniche M, Chassagne P, Landrin I, et al. Colite lymphocytaire au 132. Maroy B. Lymphocytic colitis probably due to etifoxine. A case with Cyclo 3 Fort®. La Revue de Medecine Interne. 1996;17:776–8. relapse after reintroduction. Therapie. 2009;64:137–8. 108. Bouchet‐Laneuw F, Deplaix P, Dumollard JM, et al. Chronic diar- 133. Maroy B. Acute lymphocytic colitis due to carbamazepine. Gas- rhea following ingestion of Tardyferon associated with lymphocytic troenterol Clin Biol. 2010;34:155–6. colitis. Gastroenterol Clin Biol. 1997;21:83–4. 134. Mennecier D, Saloum T, Roycourt AM, et al. Chronic diarrhea and 109. Bouvet C, Bellaiche G, Slama R, et al. Lymphocytic colitis and lymphocytic colitis associated with Daflon therapy. Gastroenterol villous atrophy after treatment with ticlopidine. Gastroenterol Clin Clin Biol. 1999;23:1101–2. Biol. 1998;22:1117‐8. 135. Mennecier D, Thiolet C, Bredin C, et al. Lymphocytic colitis after 110. Brigot C, Courillon‐Mallet A, Roucayrol AM, et al. Lymphocytic ingestion of Rustacea flavonoid extract. Presse Med. colitis and ticlopidine. Gastroenterol Clin Biol. 1998;22:361–2. 2001;30:1063. 111. Capurso G, Marignani M, Attilia F, et al. Lansoprazole‐induced 136. Menon R, Ng C. Sertraline‐induced microscopic colitis. Psychoso- microscopic colitis: an increasing problem? Results of a prospective matics. 2015;56:316–7. case‐series and systematic review of the literature. Dig Liver Dis. 137. Milman N, Kraag G. NSAID‐induced collagenous colitis. J Rheu- 2011;43:380–5. matol. 2010;37:2432–3. 112. Chande N, Driman DK. Microscopic colitis associated with lanso- 138. Mukherjee S. Diarrhea associated with lansoprazole. J Gastro- prazole: report of two cases and a review of the literature. Scand J enterol Hepatol. 2003;18:602–3. Gastroenterol. 2007;42:530–3. 139. Murasawa M, Sakurada T, Oishi D, et al. Collagenous colitis asso- 113. Chiba M, Sugawara T, Tozawa H, et al. Lansoprazole‐associated ciated with rabeprazole in a peritoneal dialysis patient. Perit Dial collagenous colitis: diffuse mucosal cloudi‐ness mimicking ulcera- Int. 2015;35:588–90. tive colitis. World J Gastroenterol. 2009;15:2166–9. 140. Nielsen JA, Steephen A, Lewin M. Angiotensin‐II inhibitor (olme- 114. Dharancy S, Dapvril V, Dupont‐Evrard F, et al. Colite lymphocy- sartan)‐induced collagenous sprue with resolution following taire et atrophie villositaire ileale secondaires a` la prise de Cyclo 3 discontinuation of drug. World J Gastroenterol 2013 19:6928–30. Fort. Gastroenterol Clin Biol. 2000:24–134. 141. Nomura E, Kagaya H, Uchimi K, et al. Linear mucosal defects: a 115. Duncan HD, Talbot IC, Silk DB. Collagenous colitis and cimetidine. characteristic endoscopic finding of lansoprazole‐associated Eur J Gastroenterol Hepatol. 1997;9:819–20. collagenous colitis. Endoscopy 2010; 42(Suppl 2):E9–E10. 116. Fathallah N, Chatti S, Azouz MM. Lymphocytic colitis associated 142. OzekiT, OgasawaraN, IzawaS, et al. Protein‐losing enteropathy with oxetorone consumption. Gastroenterol Clin Biol. associated with collagenous colitis cured by withdrawal of a proton 2010;34:154–5. pump inhibitor. Intern Med. 2013;52:1183–7. 117. Feurle GE, Bartz KO, Schmitt‐Graff A. Lymphocytic colitis, induced 143. Pelizza L, Melegari M. Clozapine‐induced microscopic colitis: a case by ticlopidine. Z Gastroenterol. 1999;37:1105–8. report and review of the literature. J Clin Psychopharmacol. 118. Fuste L, Arevalo D, Gomez M, et al. Lymphocytic colitis during 2007;27:571–4. treatment with ticlopidine. Gastroenterol Hepatol. 2000;23:363–4. 144. Piche T, Raimondi V, Schneider S, et al. Acarbose and lymphhoctiic 119. Ghilain JM, Schapira M, Maisin JM, et al. Lymphocytic colitis colitis. Lancet. 2000;356:1246. associated with lansoprazole treatment. Gastroenterol Clin Biol. 145. Pierrugues R, Saingra B. Lymphocytic colitis and Cyclo 3 fort: 4 2000;24:960–2. new cases. Gastroenterol Clin Biol. 1996;20:916–7. 120. Giardiello FM, Hansen FC 3rd, Lazenby AJ, et al. Collagenous 146. Rammer M, Kirchgatterer A, Hobling W, et al. Lansoprazole‐ colitis in setting of nonsteroidal anti‐inflammatory drugs and an- associated collagenous colitis: a case report. Z Gastroenterol. tibiotics. Dig Dis Sci. 1990:257–60. 2005;43:657–60. 121. Gugenberger C, Donner P, Naami A, et al. Persistent diarrhea and 147. Rassiat E, Michiels C, Sgro C, et al. Lymphocytic colitis due to loss of weight during therapy with leflunomide. Dtsch Med Modopar. Gastroenterol Clin Biol. 2000;24:852–3. Wochenschr. 2008;133:1730–2. 148. Rosa I, Nahon S, Cohen C, et al. Ticlopidine‐induced lymphocytic 122. Gwillim EC, Bowyer BA. Duloxetine‐induced lymphocytic colitis. J colitis. Ann Med Interne. 1999;150:437–9. Clin Gastroenterol. 2012;46:717–8. 149. Salter TG, Williams MD. Antidepressant‐associated microscopic 123. Hilmer SN, Heap TR, Eckstein RP, et al. Microscopic colitis asso- colitis: a case report and literature review. Psychosomatics. ciated with exposure to lansoprazole. Med J Aust. 2006;184:185– 2017;58:307–12. 6. 150. Sawada K, Fujiya M, Itabashi K, et al. Collagenous colitis appeared 124. Kitagawa T, Sato K, Yokouchi Y, et al. A case of lansoprazole‐ after 6‐year administration of lansoprazole. Clin J Gastroenterol. associated collagenous colitis with longitudinal ulcer. J Gastro- 2010;3:18–21. intestin Liver Dis. 2013;22:9. 151. Swine C, Cornette P, Van Pee D, et al. Ticlopidine, diarrhea and 125. Kusnik B, Stolte M. Lymphocytic colitis under treatment with lymphocytic colitis. Gastroenterol Clin Biol. 1998;22:475–6. duloxetine. Z Gastroenterol. 2010;48:693–5. 152. Thiolet C, Bredin C, Rimlinger H, et al. Lymphocytic colitis follo- 126. Larzilliere I, Gargot D, Zleik T, et al. Microscopic colitis and ticlid. wing administration of Cyclo 3 fort. Presse Med. 2003;32: Gastroenterol Clin Biol. 1999;23:795–6. 1323–4. 127. Lim C, Macaigne G, Boivin JF, et al. Stalevo‐associated lymphocytic 153. Thomson RD, Lestina LS, Bensen SP, et al. Lansoprazole‐associated colitis. Gastroenterol Clin Biol. 2008;32:698–9. microscopic colitis: a case series. Am J Gastroenterol. 128. Linares Torres P, Fidalgo Lopez I, Castanon Lopez A, et al. Lym- 2002;97:2908–13. phocytic colitis as a cause of chronic diarrhea: possible association 154. Umeno J, Esaki M, Nuki Y, et al. Letter: lansoprazole consumption with carbamazepine. Atención Primaria. 2000;25:366–7. is more common in Japanese patients with collagenous colitis. 129. Macaigne G, Boivin JF, Simon P, et al. Lansoprazole‐associated Aliment Pharmacol Ther. 2013;38:208–9. collagenous colitis. Gastroenterol Clin Biol. 2001;25:1030. 155. Verschueren P, Vandooren AK, Westhovens R. Debilitating diar- 130. Macaigne G, Boivin JF, Chayette C, et al. Oxetorone‐associated rhoea and weight loss due to colitis in two RA patients treated with lymphocytic colitis. Gastroenterol Clin Biol. 2002;26:537. leflunomide. Clin Rheumatol. 2005;24:87–90. 131. Macaigne G, Ozon N, Dikov D, et al. Colite lymphocytaire associée 156. Wilcox GM, Mattia A. Collagenous colitis associated with lanso- à la prise de Piasclédine®. Gastroenterol Clin Biol. 2004;28:412–3. prazole. J Clin Gastroenterol. 2002;34:164–6. MIEHLKE ET AL. - 33 157. Wilcox GM, Mattia AR. Microscopic colitis associated with omep- 179. Kane JS, Irvine AJ, Derwa Y, et al. High prevalence of irritable razole and esomeprazole exposure. J Clin Gastroenterol. bowel syndrome‐type symptoms in microscopic colitis: implications 2009;43:551–3. for treatment. Therap Adv Gastroenterol. 2018;11:175628 158. Yagi K, Nakamura A, Sekine A, et al. Nonsteroidal anti‐ 4818783600. inflammatory drug‐associated colitis with a histology of collage- 180. Cotter TG, Binder M, Loftus EV Jr., et al. Development of a nous colitis. Endoscopy. 2001;33:629–32. microscopic colitis disease activity Index: a prospective cohort 159. Chauveau E, Prignet JM, Carloz E, et al. Lymphocytic colitis likely study. Gut. 2018;67:441–6. attributable to use of vinburnine (Cervoxan). Gastroenterol Clin 181. Gentile N, Yen EF. Prevalence, pathogenesis, diagnosis, and man- Biol. 1998;22:362. agement of microscopic colitis. Gut Liver. 2018;12:227–35. 160. Simsek Z, Alagozlu H, Tuncer C, et al. Lymphocytic colitis associ- 182. O'Toole A. Optimal management of collagenous colitis: a review. ated with lansoprazole treatment. Curr Ther Res Clin Exp. Clin Exp Gastroenterol. 2016;9:31–9. 2007;68:360–6. 183. Bohr J, Wickbom A, Hegedus A, et al. Diagnosis and management 161. Coyne JD. Microscopic colitis occurring in association with hy- of microscopic colitis: current perspectives. Clin Exp Gastroenterol. perplastic polyps and tubulovillous adenomas: observations in 10 2014;7:273–84. cases. J Clin Pathol. 2014;67:919–20. 184. Nyhlin N, Wickbom A, Montgomery SM, et al. Long‐term prognosis 162. Fernàndez‐Bañares F, Salas A, Zabana A, et al. Risk of colorectal of clinical symptoms and health‐related quality of life in micro- adenomas in patients with microscopic colitis: a case‐control study. scopic colitis: a case‐control study. Aliment Pharmacol Ther. United European Gastroenterol J. 2016;4:A434. 2014;39:963–72. 163. Kao KT, Pedraza BA, McClune AC, et al. Microscopic colitis: a large 185. Roth B, Ohlsson B. Gastrointestinal symptoms and psychological retrospective analysis from a health maintenance organization well‐being in patients with microscopic colitis. Scand J Gastro- experience. World J Gastroenterol. 2009;15:3122–7. enterol. 2013;48:27–34. 164. Levy A, Borren NZ, Maxner B, et al. Cancer risk in microscopic 186. Hjortswang H, Tysk C, Bohr J, et al. Health‐related quality of life is colitis: a retrospective cohort study. BMC Gastroenterol. impaired in active collagenous colitis. Dig Liver Dis. 2011;43:102– 2019;19:1. 9. 165. McPhaul C, Sonnenberg A, Genta R. Low prevalence of colon 187. Hjortswang H, Tysk C, Bohr J, et al. Defining clinical criteria for polyps in patients with diarrhea and microscopic colitis. Am J clinical remission and disease activity in collagenous colitis. Gastroenterol. 2013;108:S164. Inflamm Bowel Dis. 2009;15:1875–81. 166. Mellander MR, Ekbom A, Hultcrantz R, et al. Microscopic colitis: a 188. Kane JS, Irvine AJ, Derwa Y, et al. Fatigue and its associated factors descriptive clinical cohort study of 795 patients with collagenous in microscopic colitis. Therap Adv Gastroenterol. 2018;11: and lymphocytic colitis. Scand J Gastroenterol. 2016;51:556–62. 1756284818799599. 167. Mills LR, Schuman BM, Thompson WO. Lymphocytic colitis. A 189. Madisch A, Heymer P, Voss C, et al. Oral budesonide therapy im- definable clinical and histologi‐cal diagnosis. Dig Dis Sci. proves quality of life in patients with collagenous colitis. Int J 1993;38:1147–51. Colorectal Dis. 2005;20:312–6. 168. Sonnenberg A, Genta RM. Low prevalence of colon polyps in 190. Madisch A, Miehlke S, Eichele O, et al. Boswellia serrata extract for chronic inflammatory conditions of the colon. Am J Gastroenterol. the treatment of collagenous colitis. A double‐blind, randomized, 2015;110:1056–61. placebo‐controlled, multi‐center trial. Int J Colorectal Dis. 169. Chan JL, Tersmette AC, Offerhaus GJ, et al. Cancer risk in collag- 2007;22:1445–51. enous colitis. Inflamm Bowel Dis. 1999;5:40–3. 191. Miehlke S, Madisch A, Bethke B, et al. Oral budesonide for mainte- 170. Bohr J, Tysk C, Eriksson S, et al. Collagenous colitis: a retrospective nance treatment of collagenous colitis: a randomized, double‐blind, study of clinical presentation and treatment in 163 patients. Gut. placebo‐controlled trial. Gastroenterology. 2008;135:1510–6. 1996;39:846–51. 192. Miehlke S, Madisch A, Karimi D, et al. Budesonide is effective in 171. Calabrese C, Gionchetti P, Liguori G, et al. Clinical course of treating lymphocytic colitis: a randomized double‐blind placebo‐ microscopic colitis in a single‐center cohort study. J Crohns Colitis. controlled study. Gastroenterology. 2009;136:2092–100. 2011;5:218–21. 193. Munch A, Bohr J, Miehlke S, et al. Low‐dose budesonide for 172. Koskela RM, Niemela SE, Karttunen TJ, et al. Clinical characteris- maintenance of clinical remission in collagenous colitis: a rando- tics of collagenous and lymphocytic colitis. Scand J Gastroenterol. mised, placebo‐controlled, 12‐month trial. Gut. 2016;65:47–56. 2004;39:837–45. 194. Wildt S, Munck LK, Vinter‐Jensen L, et al. Probiotic treatment of 173. Olesen M, Eriksson S, Bohr J, et al. Lymphocytic colitis: a retrospec- collagenous colitis: a randomized, double‐blind, placebo‐controlled tive clinical study of 199 Swedish patients. Gut. 2004;53:536–41. trial with Lactobacillus acidophilus and Bifidobacterium animalis 174. Verhaegh B, Münch B, Cebula W, et al. Demographic and prognosis subsp. Lactis. Inflamm Bowel Dis. 2006;12:395–401. of incident patients with microscopic colitis‐first results of the 195. Miehlke S, Aust D, Mihaly E, et al. Efficacy and safety of budeso- European pro‐MC collaboration, a Link Award project. United nide, vs mesalazine or placebo, as induction therapy for lympho- European Gastroenterol J. 2017;5 (8):1138–50. cytic colitis. Gastroenterology. 2018;155:1795–804. 175. Chande N, Driman DK, Reynolds RP. Collagenous colitis and lym- 196. Chande N, Al Yatama N, Bhanji T, et al. Interventions for treating phocytic colitis: patient characteristics and clinical presentation. lymphocytic colitis. Cochrane Database Syst Rev. 2017;7: Scand J Gastroenterol. 2005;40:343–7. CD006096. 176. Guagnozzi D, Arias A, Lucendo AJ. Systematic review with meta‐ 197. Kafil TS, Nguyen TM, Patton PH, et al. Interventions for treating analysis: diagnostic overlap of microscopic colitis and functional collagenous colitis. Cochrane Database Syst Rev. 2017;11: bowel disorders. Aliment Pharmacol Ther. 2016;43:851–62. CD003575. 177. Hilpusch F, Johnsen PH, Goll R, et al. Microscopic colitis: a missed 198. Sebastian S, Wilhelm A, Jessica L, et al. Budesonide treatment for diagnosis among patients with moderate to severe irritable bowel microscopic colitis: systematic review and meta‐analysis. Eur J syndrome. Scand J Gastroenterol. 2017;52:173–7. Gastroenterol Hepatol. 2019;31:919–27. 178. Kamp EJ, Kane JS, Ford AC. Irritable bowel syndrome and micro- 199. Baert F, Schmit A, D'Haens G, et al. Budesonide in collagenous scopic colitis: a systematic review and meta‐analysis. Clin Gastro- colitis: a double‐blind placebo‐controlled trial with histologic enterol Hepatol. 2016;14:659–68. follow‐up. Gastroenterology. 2002;122:20–5. 34 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 200. Bonderup OK, Hansen JB, Birket‐Smith L, et al. Budesonide 222. Goranzon C, Kumawat AK, Hultgren‐Hornqvist E, et al. Immuno- treatment of collagenous colitis: a randomised, double blind, pla- histochemical characterization of lymphocytes in microscopic co- cebo controlled trial with morphometric analysis. Gut. litis. J Crohns Colitis. 2013;7:e434–442. 2003;52:248–51. 223. Levy AM, Yamazaki K, Van Keulen VP, et al. Increased eosin- 201. Miehlke S, Heymer P, Bethke B, et al. Budesonide treatment for ophil infiltration and degranulation in colonic tissue from pa- collagenous colitis: a randomized, double‐blind, placebo‐controlled, tients with collagenous colitis. Am J Gastroenterol. multicenter trial. Gastroenterology. 2002;123:978–84. 2001;96:1522–8. 202. Munck LK, Kjeldsen J, Philipsen E, et al. Incomplete remission with 224. Falodia S, Makharia GK, Sateesh J, et al. Spectrum of microscopic short‐term prednisolone treatment in collagenous colitis: a ran- colitis in a tertiary care centre in India. Trop Gastroenterol. domized study. Scand J Gastroenterol. 2003;38:606–10. 2007;28:121–5. 203. Miehlke S, Madisch A, Kupcinskas L, et al. Budesonide is more 225. Foerster A, Fausa O. Collagenous colitis. Pathol Res Pract. effective than mesalamine or placebo in short‐term treatment of 1985;180:99–106. collagenous colitis. Gastroenterology. 2014;146:1222–30. 226. Lee E, Schiller LR, Vendrell D, et al. Subepithelial collagen table 204. Miehlke S, Madisch A, Voss C, et al. Long‐term follow‐up of thickness in colon specimens from patients with microscopic collagenous colitis after induction of clinical remission with bude- colitis and collagenous colitis. Gastroenterology. 1992;103: sonide. Aliment Pharmacol Ther. 2005;22:1115–9. 1790–6. 205. Goff JS, Barnett JL, Pelke T, et al. Collagenous colitis: histopa- 227. Wang HH, Owings DV, Antonioli DA, et al. Increased subepithelial thology and clinical course. Am J Gastroenterol. 1997;92:57–60. collagen deposition is not specific for collagenous colitis. Mod 206. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and Pathol. 1988;1:329–35. reliable measure of therapeutic efficacy in the treatment of in- 228. Lazenby AJ, Yardley JH, Giardiello FM, et al. Pitfalls in the diag- flammatory bowel disease. Canadian Crohn's Relapse Prevention nosis of collagenous colitis: experience with 75 cases from a reg- Trial Study Group. Gastroenterology. 1994;106:287–96. istry of collagenous colitis at the Johns Hopkins hospital. Hum 207. Minsk ABJ and Cohen DR. FDA issues final guidance on patient‐re- Pathol. 1990;21:905–10. ported outcome measures used to support labeling claims.Silver Spring: 229. Narabayashi K, Murano M, Egashira Y, et al. Endoscopic and his- US Department of Health and Human Services; 2010. topathological evaluation of collagenous colitis. Digestion. 208. Marlicz W, Skonieczna‐Zydecka K, Yung DE, et al. Endoscopic 2012;85:136–40. findings and colonic perforation in microscopic colitis: a systematic 230. Fiehn AM, Bjornbak C, Warnecke M, et al. Observer variability in review. Dig Liver Dis. 2017;49:1073–85. the histopathologic diagnosis of microscopic colitis and subgroups. 209. Lindstrom CG. ‘Collagenous colitis' with watery diarrhoea–a new Hum Pathol. 2013;44:2461–6. entity?. Pathol Eur. 1976;11:87–9. 231. Limsui D, Pardi DS, Smyrk TC, et al. Observer variability in the 210. Abdo A, Raboud J, Freeman HJ, et al. Clinical and histological histologic diagnosis of microscopic colitis. Inflamm Bowel Dis. predictors of response to medical therapy in collagenous colitis. 2009;15:35–8. Am J Gastroenterol. 2002;97:1164–8. 232. Read NW, Krejs GJ, Read MG, et al. Chronic diarrhea of unknown 211. Armes J, Gee DC, Macrae FA, et al. Collagenous colitis: jejunal and origin. Gastroenterology. 1980;78:264–71. colorectal pathology. J Clin Pathol. 1992;45:784–7. 233. Carmack SW, Lash RH, Gulizia JM, et al. Lymphocytic disorders of 212. Baert F, Wouters K, D'Haens G, et al. Lymphocytic colitis: a distinct the gastrointestinal tract: a review for the practicing pathologist. clinical entity? A clinicopathological confrontation of lymphocytic Adv Anat Pathol. 2009;16:290–306. and collagenous colitis. Gut. 1999;45:375–81. 234. Chetty R, Govender D. Lymphocytic and collagenous colitis: an 213. Rubio CA. A simple method to evaluate the thickness of collagen in overview of so‐called microscopic colitis. Nat Rev Gastroenterol collagenous colitis. Scand J Gastroenterol. 2000;35:223–4. Hepatol. 2012;9:209–18. 214. Tanaka M, Mazzoleni G, Riddell RH. Distribution of collagenous 235. Fernandez‐Banares F, Salas A, Esteve M. Pitfalls and errors in the colitis: utility of flexible sigmoidoscopy. Gut. 1992;33:65–70. diagnosis of collagenous and lymphocytic colitis. J Crohns Colitis. 215. Carpenter HA, Tremaine WJ, Batts KP, et al. Sequential histologic 2008;2:343–7. evaluations in collagenous colitis. Correlations with disease 236. Geboes K. Lymphocytic, collagenous and other microscopic coli- behavior and sampling strate‐gy. Dig Dis Sci. 1992;37:1903–9. tides: pathology and the relationship with idiopathic inflammatory 216. Jessurun J, Yardley JH, Giardiello FM, et al. Chronic colitis with bowel diseases. Gastroenterol Clin Biol. 2008;32:689–94. thickening of the subepithelial collagen layer (collagenous colitis): 237. Guagnozzi D, Landolfi S, Vicario M. Towards a new paradigm of histopathologic findings in 15 patients. Hum Pathol. 1987;18:839– microscopic colitis: incomplete and variant forms. World J Gas- 48. troenterol. 2016;22:8459–71. 217. azenby AJ, Yardley JH, Giardiello FM, et al. Lymphocytic (“micro- 238. Langner C. Colorectal normal histology and histopathologic find- scopic”) colitis: a comparative histopathologic study with particular ings in patients with chronic diarrhea. Gastroenterol Clin N Am. reference to collagenous colitis. Hum Pathol. 1989;20:18–28. 2012;41:561–80. 218. Mosnier JF, Larvol L, Barge J, et al. Lymphocytic and collagenous 239. Liszka L, Woszczyk D, Pajak J. Histopathological diagnosis of colitis: an immunohistochemical study. Am J Gastroenterol. microscopic colitis. J Gastroenterol Hepatol. 2006;21:792–7. 1996;91:709–13. 240. Mahajan D, Goldblum JR, Xiao SY, et al. Lymphocytic colitis 219. Offner FA, Jao RV, Lewin KJ, et al. Collagenous colitis: a study of and collagenous colitis: a review of clinicopathologic features the distribution of morphological abnormalities and their histo- and immunologic abnormalities. Adv Anat Pathol. 2012;19: logical detection. Hum Pathol. 1999;30:451–7. 28–38. 220. Veress B, Lofberg R, Bergman L. Microscopic colitis syndrome. Gut. 241. Shaz BH, Reddy SI, Ayata G, et al. Sequential clinical and histo- 1995;36:880–6. pathological changes in collagenous and lymphocytic colitis over 221. Ayata G, Ithamukkala S, Sapp H, et al. Prevalence and significance time. Mod Pathol. 2004;17:395–401. of inflammatory bowel disease‐like morphologic features in 242. Stoicescu A, Becheanu G, Dumbrava M, et al. Microscopic colitis—a collagenous and lymphocytic colitis. Am J Surg Pathol. missed diagnosis in diarrhea‐predominant irritable bowel syn- 2002;26:1414–23. drome. Maedica (Buchar). 2012;7:3–9. MIEHLKE ET AL. - 35 243. Thijs WJ, van Baarlen J, Kleibeuker JH, et al. Microscopic colitis: 265. Fiehn AM, Engel U, Holck S, et al. CD3 immunohistochemical prevalence and distribution throughout the colon in patients with staining in diagnosis of lymphocytic colitis. Hum Pathol. chronic diarrhoea. Neth J Med. 2005;63:137–40. 2016;48:25–31. 244. Zabana Y, Ferrer C, Aceituno M, et al. Advances for improved 266. Macaigne G, Lahmek P, Locher C, et al. Over 90% of cases of diagnosis of microscopic colitis in patients with chronic diarrhoea. microscopic colitis can be diagnosed by performing a short colo- Gastroenterol Hepatol. 2017;40:107–16. noscopy. Clin Res Hepatol Gastroenterol. 2017;41:333–40. 245. Jaskiewicz K, Rzepko R, Adrych K, et al. Microscopic colitis in 267. Matteoni CA, Wang N, Goldblum JR, et al. Flexible sigmoidoscopy routine colonoscopies. Dig Dis Sci. 2006;51:241–4. for the detection of microscopic colitis. Am J Med. 2000;108:416– 246. Mohamed N, Marais M, Bezuidenhout J. Microscopic colitis as a 8. missed cause of chronic diarrhea. World J Gastroenterol. 268. Prior A, Lessells AM, Whorwell PJ. Is biopsy necessary if colo- 2011;17:1996–2002. noscopy is normal?. Dig Dis Sci. 1987;32:673–6. 247. Mullhaupt B, Guller U, Anabitarte M, et al. Lymphocytic colitis: 269. Shale MJ, Walters JR, Westaby D. Adequacy of flexible sigmoid- clinical presentation and long term course. Gut. 1998;43:629–33. oscopy with biopsy for diarrhea in patients under age 50 without 248. Setia N, Alpert L, van der Sloot KW, et al. Lymphocytic colitis: features of proximal disease. Gastrointest Endosc. 2011;73:757– pathologic predictors of response to therapy. Hum Pathol. 64. 2018;78:1–7. 270. Zins BJ, Tremaine WJ, Carpenter HA. Collagenous colitis: mucosal 249. Bo‐Linn GW, Vendrell DD, Lee E, et al. An evaluation of the sig- biopsies and association with fecal leukocytes. Mayo Clin Proc. nificance of microscopic colitis in patients with chronic diarrhea. J 1995;70:430–3. Clin Invest. 1985;75:1559–69. 271. Paski SC, Wightman R, Robert ME, et al. The importance of 250. Fasoli R, Talbot I, Reid M, et al. Microscopic colitis: can it be recognizing increased cecal inflammation in health and avoiding qualitatively and quantitatively characterized?. Ital J Gastro- the misdiagnosis of nonspecific colitis. Am J Gastroenterol. enterol. 1992;24:393–6. 2007;102:2294–9. 251. Goldstein NS, Bhanot P. Paucicellular and asymp‐tomatic lympho- 272. Bonderup OK, Hansen JB, Teglbjaerg PS, et al. Long‐term bude- cytic colitis: expanding the clinicopathologic spectrum of lympho- sonide treatment of collagenous colitis: a randomised, double‐ cytic colitis. Am J Clin Pathol. 2004;122:405–11. blind, placebo‐controlled trial. Gut. 2009;58:68–72. 252. Patil DT, Odze RD. Biopsy diagnosis of colitis: an algorithmic 273. Fernandez‐Banares F, Salas A, Esteve M, et al. Collagenous and approach. Virchows Arch. 2018;472:67–80. lymphocytic colitis. evaluation of clinical and histological features, 253. Rahman MA, Raihan AS, Ahamed DS, et al. Symptomatic overlap in response to treatment, and long‐term follow‐up. Am J Gastro- patients with diarrhea predominant irritable bowel syndrome and enterol. 2003;98:340–7. microscopic colitis in a sub group of Bangladeshi population. 274. Fine KD, Lee EL. Efficacy of open‐label bismuth subsalicylate for Bangladesh Med Res Counc Bull. 2012;38:33–8. the treatment of microscopic colitis. Gastroenterology. 254. Singh P, Das P, Jain AK, et al. Microscopic colitis in children 1998;114:29–36. with chronic diarrhea. J Pediatr Gastroenterol Nutr. 2013;57: 275. Vigren L, Olesen M, Benoni C, et al. Are collagenous and lympho- 240–4. cytic colitis different aspects of the same disease?. Scand J Gas- 255. Fine KD, Lee EL, Meyer RL. Colonic histopathology in untreated troenterol. 2012;47:1448–53. celiac sprue or refractory sprue: is it lymphocytic colitis or colonic 276. Yagi K, Endo S, Nakamura A, et al. Clinical course of drug‐induced lymphocytosis?. Hum Pathol. 1998;29:1433–40. collagenous colitis and histological changes after drug withdrawal 256. Wang N, Dumot JA, Achkar E, et al. Colonic epithelial lymphocy- in a Japanese case series. Eur J Gastroenterol Hepatol. tosis without a thickened subepithelial collagen table: a clinico- 2012;24:1105–9. pathologic study of 40 cases supporting a heterogeneous entity. 277. Batista L, Ruiz L, Ferrer C, et al. Usefulness of fecal calprotectin as Am J Surg Pathol. 1999;23:1068–74. a biomarker of microscopic colitis in a cohort of patients with 257. Chang F, Deere H, Vu C. Atypical forms of microscopic colitis: chronic watery diarrhoea of functional characteristics. Dig Liver morphological features and review of the literature. Adv Anat Dis. 2019;51:1646–51. Pathol. 2005;12:203–11. 278. von Arnim U, Wex T, Ganzert C, et al. Fecal calprotectin: a marker 258. Fiehn AK, Clausen LN, Engel U, et al. Is revision of cutoff values for clinical differentiation of microscopic colitis and irritable bowel needed when using CD3 immunohistochemical staining in histo- syndrome. Clin Exp Gastroenterol. 2016;9:97–103. pathologic diagnosis of lymphocytic colitis?. Hum Pathol. 279. Wildt S, Nordgaard‐Lassen I, Bendtsen F, et al. Metabolic and in- 2019;84:115–23. flammatory faecal markers in collagenous colitis. Eur J Gastro- 259. Fraser AG, Warren BF, Chandrapala R, et al. Microscopic colitis: a enterol Hepatol. 2007;19:567–74. clinical and pathological review. Scand J Gastroenterol. 280. Fine KD, Ogunji F, George J, et al. Utility of a rapid fecal latex 2002;37:1241–5. agglutination test detecting the neutrophil protein, lactoferrin, for 260. Warren BF, Edwards CM, Travis SP. ‘Microscopic colitis': classifi- diagnosing inflammatory causes of chronic diarrhea. Am J Gas- cation and terminology. Histopathology. 2002;40:374–6. troenterol. 1998;93:1300–5. 261. Kitchen PA, Levi AJ, Domizio P, et al. Microscopic colitis: the tip of 281. Strygler B, Nicar MJ, Santangelo WC, et al. a1‐Anti‐trypsin the iceberg?. Eur J Gastroenterol Hepatol. 2002;14:1199–204. excretion in stool in normal subjects and in patients with gastro- 262. Fernandez‐Banares F, Casalots J, Salas A, et al. Paucicellular lym- intestinal disorders. Gastroenterology. 1990;99:1380–7. phocytic colitis: is it a minor form of lymphocytic colitis? A clinical 282. Lettesjo H, Hansson T, Peterson C, et al. Detection of inflammatory pathological and immunological study. Am J Gastroenterol. markers in stools from patients with irritable bowel syndrome and 2009;104:1189–98. collagenous colitis. Scand J Gastroenterol. 2006;41:54–9. 263. Rasmussen J, Engel PJ, Wildt S, et al. The temporal evolution of 283. Green HD, Beaumont RN, Thomas A, et al. Genome‐wide associ- histological abnormalities in microscopic colitis. J Crohns Colitis. ation study of microscopic colitis in the UK biobank confirms im- 2016;10:262–8. mune‐related pathogenesis. J Crohns Colitis. 2019;13:1578–82. 264. Sonnenberg A, Genta RM. Lymphocytic and collagenous colitis: 284. Stewart M, Andrews CN, Urbanski S, et al. The association of epidemiologic differences and similarities. Dig Dis Sci. coeliac disease and microscopic colitis: a large population‐based 2013;58:2970–5. study. Aliment Pharmacol Ther. 2011;33:1340–9. 36 - UNITED EUROPEAN GASTROENTEROLOGY JOURNAL 285. Sonnenberg A, Turner KO, Genta RM. Associations of microscopic 305. Calabrese C, Fabbri A, Areni A, et al. Mesalazine with or without colitis with other lymphocytic disorders of the gastrointestinal cholestyramine in the treatment of microscopic colitis: randomized tract. Clin Gastroenterol Hepatol. 2018;16:1762–7. controlled trial. J Gastroenterol Hepatol. 2007;22:809–14. 286. Fernandez‐Banares F, Esteve M, Farre C, et al. Predisposing HLA‐ 306. Allison MC, Sercombe J, Pounder RE. A double‐blind crossover DQ2 and HLA‐DQ8 haplotypes of coeliac disease and associated comparison of lidamidine, loperamide and placebo for the enteropathy in microscopic colitis. Eur J Gastroenterol Hepatol. control of chronic diarrhoea. Aliment Pharmacol Ther. 1988;2: 2005;17:1333–8. 347–51. 287. Matteoni CA, Goldblum JR, Wang N, et al. Celiac disease is highly 307. Barbezat GO, Clain JE, Halter F. A double‐blind trial of loperamide prevalent in lymphocytic colitis. J Clin Gastroenterol. in the treatment of chronic diarrhoea. S Afr Med J. 1979;55:502–3. 2001;32:225–7. 308. Mainguet P, Fiasse R. Double‐blind placebo‐controlled study of 288. Pardi DS, Ramnath VR, Loftus EV Jr., et al. Lymphocytic colitis: loperamide (Imodium) in chronic diarrhoea caused by ileocolic clinical features, treatment, and outcomes. Am J Gastroenterol. disease or resection. Gut. 1977;18:575–9. 2002;97:2829–33. 309. Sun WM, Read NW, Verlinden M. Effects of loperamide oxide on 289. Svensson M, Bergman D, Olen O, et al. Validating microscopic gastrointestinal transit time and anorectal function in patients with colitis (MC) in Swedish pathology registers. Scand J Gastroenterol. chronic diarrhoea and faecal incontinence. Scand J Gastroenterol. 2018;53:1469–75. 1997;32:34–8. 290. Vigren L, Tysk C, Strom M, et al. Celiac disease and other auto- 310. Rohatgi S, Ahuja V, Makharia GK, et al. VSL#3 induces and main- immune diseases in patients with collagenous colitis. Scand J tains short‐term clinical response in patients with active micro- Gastroenterol. 2013;48:944–50. scopic colitis: a two‐phase randomised clinical trial. BMJ Open 291. Liu PH, Lebwohl B, Burke KE, et al. Correction: dietary gluten Gastroenterol. 2015;2:e000018. intake and risk of microscopic colitis among US women without 311. Gentile NM, Abdalla AA, Khanna S, et al. Outcomes of patients with celiac disease: a prospective cohort study. Am J Gastroenterol. microscopic colitis treated with corticosteroids: a population‐ 2019;114:837. based study. Am J Gastroenterol. 2013;108:256–9. 292. Femandez‐Banares F, Esteve M, Espinos JC, et al. Bile acid 312. Sloth H, Bisgaard C, Grove A. Collagenous colitis: a prospective malabsorption (BAM) in patients with functional chronic diarrhea: trial of prednisolone in six patients. J Intern Med. 1991;229:443–6. response to cholestyramine. Gastroenterology. 2000;118:A885. 313. Corte T, Janssens E, D'Hondt A, et al. Beclomethasone dipropio- 293. Ung KA, Gillberg R, Kilander A, et al. Role of bile acids and bile acid nate in microscopic colitis: results of an exploratory open‐label binding agents in patients with collagenous colitis. Gut. multicentre study (COLCO). United European Gastroenterol J. 2000;46:170–5. 2019;7:1183–8. 294. Bajor A, Kilander A, Galman C, et al. Budesonide treatment is 314. Vennamaneni SR, Bonner GF. Use of azathioprine or 6‐mercapto- associated with increased bile acid absorption in collagenous coli- purine for treatment of steroid‐dependent lymphocytic and tis. Aliment Pharmacol Ther. 2006;24:1643–9. collagenous colitis. Am J Gastroenterol. 2001;96:2798–9. 295. Torres J, Palmela C, Gomes de Sena P, et al. Farnesoid X receptor 315. Munch A, Fernandez‐Banares F, Munck LK. Azathioprine and expression in microscopic colitis: a potential role in disease etio- mercaptopurine in the management of patients with chronic, pathogenesis. GE Port J Gastroenterol. 2018;25:30–7. active microscopic colitis. Aliment Pharmacol Ther. 296. Laing AW, Pardi DS, Loftus EV Jr., et al. Microscopic colitis is not 2013;37:795–8. associated with cholecystectomy or appendectomy. Inflamm Bowel 316. Pardi DS, Loftus EV Jr, Tremaine WJ, et al. Treatment of refractory Dis. 2006;12:708–11. microscopic colitis with azathioprine and 6‐mercaptopurine. 297. Pardi DS, Loftus EV, Tremaine WJ, et al. T1193 a randomized, Gastroenterology. 2001;120:1483–4. double‐blind, placebo‐controlled trial of budesonide for the treat- 317. Cotter TG, Kamboj AK, Hicks SB, et al. Immune modulator therapy ment of active lymphocytic colitis. Gastroenterology. 2009;136: for microscopic colitis in a case series of 73 patients. Aliment A519–A520. Pharmacol Ther. 2017;46:169–74. 298. Cino M, Greenberg GR. Bone mineral density in Crohn's disease: a 318. Riddell J, Hillman L, Chiragakis L, et al. Collagenous colitis: oral longitudinal study of budesonide, prednisone, and nonsteroid low‐dose methotrexate for patients with difficult symptoms: long‐ therapy. Am J Gastroenterol. 2002;97:915–21. term outcomes. J Gastroenterol Hepatol. 2007;22:1589–93. 299. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated 319. Munch A, Bohr J, Vigren L, et al. Lack of effect of methotrexate in with different types of oral corticosteroids and effect of termina- budesonide‐refractory collagenous colitis. Clin Exp Gastroenterol. tion of corticosteroids on the risk of fractures. Calcif Tissue Int. 2013;6:149–52. 2008;82:249–57. 320. Esteve M, Mahadevan U, Sainz E, et al. Efficacy of anti‐TNF ther- 300. Rautiainen H, Farkkila M, Neuvonen M, et al. Pharmacokinetics and apies in refractory severe microscopic colitis. J Crohns Colitis. bone effects of budesonide in primary biliary cirrhosis. Aliment 2011;5:612–8. Pharmacol Ther. 2006;24:1545–52. 321. Münch A, Ignatova S, Strom M. Adalimumab in budesonide and 301. Reilev M, Hallas J, Thomsen Ernst M, et al. Long‐term oral bude- methotrexate refractory collagenous colitis. Scand J Gastroenterol. sonide treatment and risk of osteoporotic fractures in patients 2012;47:59–63. with microscopic colitis. Aliment Pharmacol Ther. 2020;51:644–51. 322. Anderson RJ, Makins R. Successful use of adalimu‐mab in patient 302. Colussi D, Salari B, Stewart KO, et al. Clinical characteristics with treatment‐refractory microscopic colitis. BMJ Case Rep. and patterns and predictors of response to therapy in collage- 2016;2016:bcr2016215639. nous and lymphocytic colitis. Scand J Gastroenterol. 323. Daferera N, Hjortswang H, Ignatova S, et al. Single‐centre experi- 2015;50:1382–8. ence with anti‐tumour necrosis factor treatment in budesonide‐ 303. Fiedler LM, George J, Sachar DB, et al. Treatment responses in refractory microscopic colitis patients. United European Gastro- collagenous colitis. Am J Gastroenterol. 2001;96:818–21. enterol J. 2019;7:1234–40. 304. Jobse P, Flens MJ, Loffeld RJ. Collagenous colitis: description of a 324. Pola S, Fahmy M, Evans E, et al. Successful use of infliximab in the single centre series of 83 patients. Eur J Intern Med. 2009;20:499– treatment of corticosteroid dependent collagenous colitis. Am J 502. Gastroenterol. 2013;108:857–8. MIEHLKE ET AL. - 37 325. Riviere P, Munch A, Michetti P, et al. Vedolizumab in refractory 332. Williams RA, Gelfand DV. Total proctocolectomy and ileal pouch microscopic colitis: an international case series. J Crohns Colitis. anal anastomosis to successfully treat a patient with collagenous 2019;13:337–40. colitis. Am J Gastroenterol. 2000;95:2147. 326. Casper M, Zimmer V, Hubschen U, et al. Vedolizumab for re- fractory collagenous colitis: another piece of the puzzle. Dig Liver Dis. 2018;50:1099–100. 327. Cushing KC, Mino‐Kenudson M, Garber J, et al. Vedolizumab as a S U P P O R T I N G I N F O RM A T I O N novel treatment for refractory collagenous colitis: a case report. Additional supporting information may be found online in the Sup- Am J Gastroenterol. 2018;113:632–3. porting Information section at the end of this article. 328. Jennings JJ, Charabaty A. Vedolizumab‐induced remission in 3 patients with refractory microscopic colitis: a tertiary care center case series. Inflamm Bowel Dis. 2019;25:e97. How to cite this article: Miehlke S, Guagnozzi D, Zabana Y, 329. Daferera N, Kumawat AK, Hultgren‐Hornquist E, et al. Fecal stream diversion and mucosal cytokine levels in collagenous colitis: et al. European guidelines on microscopic colitis: United a case report. World J Gastroenterol. 2015;21:6065–71. European Gastroenterology and European Microscopic Colitis 330. Jarnerot G, Tysk C, Bohr J, et al. Collagenous colitis and fecal Group statements and recommendations. United European stream diversion. Gastroenterology. 1995;109:449–55. Gastroenterol J. 2021;9:13–37. https://doi.org/10.1177/ 331. Munch A, Soderholm JD, Wallon C, et al. Dynamics of mucosal permeability and inflammation in collagenous colitis before, during, 2050640620951905 and after loop ileostomy. Gut. 2005;54:1126–8.