Search
Close
Search
Advanced Search
Search Menu
AI Discovery Assistant

Abstract

Objective

Microscopic colitis [MC], encompassing collagenous colitis [CC] and lymphocytic colitis [LC], is an increasingly prevalent gastrointestinal disease with an unknown aetiology. Previous research has reported significant differences in the incidence of MC within Denmark, with the lowest incidence found in the most populated region [Capital Region of Denmark]. Our aim was to elucidate the causes of these regional differences.

Design

All incident MC patients [n = 14 302] with a recorded diagnosis of CC [n = 8437] or LC [n = 5865] entered in The Danish Pathology Register between 2001 and 2016 were matched to 10 reference individuals [n = 142 481]. Information regarding drug exposure, including proton pump inhibitors [PPIs], selective serotonin reuptake inhibitors [SSRIs], statins, and nonsteroidal anti-inflammatory drugs [NSAIDs], were retrieved from The Danish National Prescription Registry. Information regarding endoscopy rate, smoking-related diseases, and immune-mediated inflammatory diseases were acquired from The Danish National Patient Registry.

Results

Smoking, immune-mediated inflammatory diseases, exposure to PPIs, SSRIs, statins, and NSAIDs were significantly associated with MC in all Danish regions. The association between drug exposure and MC was weakest in the Capital Region of Denmark with an odds ratio of 1.8 (95% confidence interval [CI]: 1.61–2.01). The relative risk of undergoing a colonoscopy with biopsy was significantly increased in sex- and age-matched controls in all regions compared with controls from the Capital Region of Denmark, with the greatest risk found in the Region of Southern Denmark, 1.37 [95% CI: 1.26–1.50].

Conclusions

The cause of the regional differences in MC incidence in Denmark seems to be multifactorial, including variations in disease awareness and distribution of risk factors.

Microscopic colitis, collagenous colitis, lymphocytic colitis, risk factors, PPI, SSRI, NSAID, statin

1. Background

Microscopic colitis [MC], encompassing collagenous colitis [CC] and lymphocytic colitis [LC], is a chronic inflammatory disorder of the large intestine characterised by non-bloody watery diarrhoea.1 The diagnosis relies on a triad of clinical symptoms, a macroscopic normal to near-normal colon, combined with abnormal histological findings in the colonic mucosa.2 The cause of the disease remains largely unknown but may occur as a result of an inappropriate immune response to commensal bacteria or luminal antigens in genetically predisposed individuals.3 Risk factors associated with the disease include exposure to proton pump inhibitors [PPIs], selective serotonin reuptake inhibitors [SSRIs], statins, and nonsteroidal anti-inflammatory drugs [NSAIDs].4,5 Previous epidemiological findings have also identified that smoking, older age, female sex, and immune-mediated inflammatory diseases are associated with an increased risk of MC.6,7

Evidence exists of an association between MC and other inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.8–11 However, the relationship is not clear and whether the diseases are risk factors to another or just different manifestations of the same disease is yet to established.

The incidence of MC varies between countries, with a high incidence reported in Northern Europe and America,12–14 although reports suggest an equivalent prevalence in newly industrialised countries.15,16 Furthermore, the incidence of MC also seems to vary substantially within countries.17–20 A recent Danish study demonstrated striking differences in MC incidence between different regions of the country. The risk of developing MC was significantly increased, relative risk [RR] of 1.6 (95% confidence interval [CI]: 1.5–1.7), in the least populated area of Denmark, the North Denmark Region, compared with the most populated area of Denmark, the Capital Region of Denmark.21 A similar phenomenon has been observed in other gastrointestinal tract diseases, such as eosinophil oesophagitis, where an inverse association between population density and development of the disease has been reported.22

Because MC is a newly recognised disease with an increasing incidence, environmental factors, rather than genetic changes, are likely to explain the evolving epidemiology. Another possible cause of the rapidly increasing incidence and the differences observed between countries might be attributed to detection bias, including disease awareness and access to endoscopic prodecures.23 Information regarding the geographical differences in the development of MC may provide aetiological clues for the pathogenesis. Therefore, the aim of this study was to further understand the geographical variation and to investigate the association between selected risk factors, including smoking, exposure to SSRIs, statins, PPIs, NSAIDs, and immune-mediated inflammatory diseases and MC in the five regions of Denmark, in a case-control study design. Moreover, we aimed to investigate the risk of having endoscopies performed in the five regions among controls.

2. Materials and Methods

2.1. Design

The association between selected factors and the risk of obtaining a diagnosis of MC in the five regions of Denmark was studied in a case-control design with population-based cases and controls. All data on risk factors were collected from January 1995 to December 2016. In controls, we investigated the risk as well as incidence of sigmoidoscopy/colonoscopy and colonic biopsies performed in the five regions of Denmark, to establish if the observed difference in MC incidence could result from detection bias.

2.2. Study population

Danish residents receive a unique Civil Registration [CPR] number at birth or upon immigration, which can be linked to information from national public health registries.24 Since the health care sector in Denmark is financed by general taxes and therefore accessible, free of charge, for the entire population, the nationwide health registries offer reliable and robust cohorts, including the entire Danish population of more than 5.7 million people.25 The present study was based on data from The Danish Pathology Register, which contains detailed diagnostic pathology statements since 1990.26 The diagnoses occurring in the register are coded after a Danish version of the Systematized Nomenclature of Medicine [SNOMED].26 The codes representing either CC or LC were introduced in The Danish Pathology Register in 2001. All individuals older than 18 years with a SNOMED code representing either CC [S62536] or LC [S62533] between January 1, 2001 and December 31, 2016 in The Danish Pathology Register were included in the study. The index date was defined as the first-ever occurring record of either CC or LC. Patients having biopsies stating both LC and CC at the same event were included as patients with CC, as the thickened collagen layer characterising CC can appear discontinuous through the colon.27

For each case, ten controls matched by sex, age [±12 months], and place of residence at MC diagnosis were randomly selected from the background population.

The evaluation of the risk of sigmoidoscopy/colonoscopy/colonic biopsy in the five regions was performed in controls adjusted for sex, age, and time of diagnosis to MC cases.

2.3. Risk factors

2.3.1. Drug exposure

The newly published European guidelines on MC state that chronic and frequent use of PPIs, NSAIDs, and SSRIs are associated with an increased risk of MC.28 A previous Danish study has also reported an association between exposure to statins and MC development.5 To investigate the exposure to PPIs, NSAIDs, SSRIs, and statins, we retrieved data from The Danish National Prescription Registry using the appropriate Anatomical Therapeutic Chemical Classification [ATC] codes [Supplementary Table 1s, available as Supplementary data at ECCO-JCC online]. The Danish National Prescription Registry is an encrypted copy of The Register of Medicinal Products Statistics and contains information on all redeemed drug prescriptions of Danish residents since 1994, achieving complete nationwide coverage in 1995.29

Drug exposure was divided into ever or never use depending on redemption of prescriptions before the index date.

2.3.2. Immune-mediated inflammatory diseases

We identified the following immune-mediated inflammatory diseases: multiple sclerosis, psoriasis, psoriatic arthritis, pyoderma gangrenosum, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, coeliac disease, primary sclerosing cholangitis, primary biliary cholangitis, type 1 diabetes, asthma, sarcoidosis, Graves’ disease, Crohn’s disease, ulcerative colitis, and iridocyclitis before the index date. The diseases were identified as at least one diagnostic listing by International Classification of Diseases Version 10 [ICD-10] codes in The Danish National Patient Registry,30 as described in Supplementary Table 2s, available as Supplementary data at ECCO-JCC online. The Danish National Patient Registry contains all hospital admissions in Denmark since 1977, and by 1995 additional data regarding outpatient and emergency visits were also included.30

2.3.3. Smoking

As smoking history is not available in the Danish health registries, we used a proxy of ICD-10 codes associated with smoking to obtain this information; see Supplementary Table 3s, available as Supplementary data at ECCO-JCC online. These ICD codes have been established as a proxy for smoking in previous studies.31,32

2.4. Danish regions

The five regions of Denmark—Capital Region of Denmark, Region Zealand, Region of Southern Denmark, Central Denmark Region, and North Denmark Region—were created as administrative entities in 2007. Population density per km2 in 201633 and incidence of MC in 201621 in the five regions are included in Figure 1. We have chosen to categorise subjects included before 2007 into the respective region based on the present geographical division.

Population density per square kilometre and incidence [95% confidence intervals, CIs] of microscopic colitis in Regions of Denmark in 2016. The figure is licensed under the Creative Commons Attribution-Share Alike 2.5 Generic, 2.0 Generic, and 1.0 Generic license. Originally Jarke, modified by Petra Weimers, derived from [https://commons.wikimedia.org/wiki/File:Denmark_regions.svg].
Figure 1.

Population density per square kilometre and incidence [95% confidence intervals, CIs] of microscopic colitis in Regions of Denmark in 2016. The figure is licensed under the Creative Commons Attribution-Share Alike 2.5 Generic, 2.0 Generic, and 1.0 Generic license. Originally Jarke, modified by Petra Weimers, derived from [https://commons.wikimedia.org/wiki/File:Denmark_regions.svg].

Open in new tabDownload slide

2.5. Endoscopy definition

Information on the number of endoscopies performed for the control group in each region was obtained by assessing procedure codes (according to the Danish version of the Nordic Medico-Statistical Committee [NOMESCO] classification, representing sigmoidoscopy and colonoscopy) listed in The Danish National Patient Registry [Supplementary Table 4s, available as Supplementary data at ECCO-JCC online]. To include endoscopies performed at private hospitals/practices, we included pathology codes representing colon biopsies in The Danish Pathology Register, see Supplementary Table 5s, available as Supplementary data at ECCO-JCC online.

2.6. Statistics

The case-control study was analysed using a conditional logistic regression model. This was adjusted by sex and age to estimate the odds ratios [OR] for the association between smoking, drug exposure, and immune-mediated inflammatory diseases and MC, CC, and LC, in Denmark overall and in the five regions. In this analysis, all risk factors occurring, from January 1, 1995 until the first MC diagnosis, or the corresponding index date, were counted.

Exposure to each of the four specified types of drugs, SSRIs, PPIs, NSAIDS, and statins, was also considered independently. The 95% confidence intervals [CIs] calculation was based on a standard normal approximation on the log scale.

To see the distribution and use of ICD-10 codes associated with smoking in the regions, we investigated the crude incidence and relative risk [RR] in controls calculated with Poisson regression adjusted for sex, age, and year.

The endoscopy rates in controls were calculated by crude incidence rates per 100 000 person-years. In the analyses calculating the RR of endoscopy in the controls, Poisson regression was used, correcting for sex, age, year, and region. Follow-up started at the time of the index date as defined for the controls.

When investigating the RR of pathology codes representing colonic endoscopies, subjects with several colonic biopsies performed at the same date were counted as one event.

We used R statistical software [version 3.6.1] and SAS statistical software [version 9.4] for the statistical analyses. We computed 95% CIs by inverting likelihood ratio test statistics.

The study was approved by the Danish Data Protection Agency [Jr. no. VD-2018–194]. According to Danish law, neither individual informed consent nor approval by the ethics review board of Denmark is necessary when conducting a registry-based study.

3. Results

3.1. Population description

From 2001 to 2016, we identified 14 302 subjects with a CC or LC diagnosis in The Danish Pathology Register. Corresponding to the cohort, 142 481 matched controls were identified. Characteristics of the study population are presented in Table 1.

Table 1.
Open in new tab

Demographic information of Danish patients diagnosed with microscopic colitis and their matched controls.

Microscopic colitis, allCollagenous colitisLymphocytic colitisMatched controls
Total143028437 [59.0%]5865 [41.0%]142481
Sex
Female10127 [70.8%] 6362 [75.4%]3765 [64.2%]100837 [70.8%]
Age
Age at first MC diagnosis mean [SD]65 [14]67 [13]63 [15]66 [14]
Age at first MC diagnosis median [IQR]67 [57‐75]68 [58‐76]65 [55‐74]67 [57–76]
Region
Central Denmark Region2774 [194%]1799 [21.3%]975 [16.6%]27613 [19.4%]
North Denmark Region2054 [14.4%]1291 [15.3%]763 [13.0%]20465 [14.4%]
Region Zealand2634 [18.4%]1555 [18.4%]1079 [18.4%]26227 [18.4%]
Region of Southern Denmark3372 [23.6%]1743 [207%]1629 [27.8%]33589 [23.6%]
Capital Region of Denmark3468 [24.3%]2049 [24.3%]1419 [25.2%]34587 [24.3%]
Microscopic colitis, allCollagenous colitisLymphocytic colitisMatched controls
Total143028437 [59.0%]5865 [41.0%]142481
Sex
Female10127 [70.8%] 6362 [75.4%]3765 [64.2%]100837 [70.8%]
Age
Age at first MC diagnosis mean [SD]65 [14]67 [13]63 [15]66 [14]
Age at first MC diagnosis median [IQR]67 [57‐75]68 [58‐76]65 [55‐74]67 [57–76]
Region
Central Denmark Region2774 [194%]1799 [21.3%]975 [16.6%]27613 [19.4%]
North Denmark Region2054 [14.4%]1291 [15.3%]763 [13.0%]20465 [14.4%]
Region Zealand2634 [18.4%]1555 [18.4%]1079 [18.4%]26227 [18.4%]
Region of Southern Denmark3372 [23.6%]1743 [207%]1629 [27.8%]33589 [23.6%]
Capital Region of Denmark3468 [24.3%]2049 [24.3%]1419 [25.2%]34587 [24.3%]

MC, microscopic colitis; SD, standard deviation; IQR, interquartile range;

Table 1.
Open in new tab

Demographic information of Danish patients diagnosed with microscopic colitis and their matched controls.

Microscopic colitis, allCollagenous colitisLymphocytic colitisMatched controls
Total143028437 [59.0%]5865 [41.0%]142481
Sex
Female10127 [70.8%] 6362 [75.4%]3765 [64.2%]100837 [70.8%]
Age
Age at first MC diagnosis mean [SD]65 [14]67 [13]63 [15]66 [14]
Age at first MC diagnosis median [IQR]67 [57‐75]68 [58‐76]65 [55‐74]67 [57–76]
Region
Central Denmark Region2774 [194%]1799 [21.3%]975 [16.6%]27613 [19.4%]
North Denmark Region2054 [14.4%]1291 [15.3%]763 [13.0%]20465 [14.4%]
Region Zealand2634 [18.4%]1555 [18.4%]1079 [18.4%]26227 [18.4%]
Region of Southern Denmark3372 [23.6%]1743 [207%]1629 [27.8%]33589 [23.6%]
Capital Region of Denmark3468 [24.3%]2049 [24.3%]1419 [25.2%]34587 [24.3%]
Microscopic colitis, allCollagenous colitisLymphocytic colitisMatched controls
Total143028437 [59.0%]5865 [41.0%]142481
Sex
Female10127 [70.8%] 6362 [75.4%]3765 [64.2%]100837 [70.8%]
Age
Age at first MC diagnosis mean [SD]65 [14]67 [13]63 [15]66 [14]
Age at first MC diagnosis median [IQR]67 [57‐75]68 [58‐76]65 [55‐74]67 [57–76]
Region
Central Denmark Region2774 [194%]1799 [21.3%]975 [16.6%]27613 [19.4%]
North Denmark Region2054 [14.4%]1291 [15.3%]763 [13.0%]20465 [14.4%]
Region Zealand2634 [18.4%]1555 [18.4%]1079 [18.4%]26227 [18.4%]
Region of Southern Denmark3372 [23.6%]1743 [207%]1629 [27.8%]33589 [23.6%]
Capital Region of Denmark3468 [24.3%]2049 [24.3%]1419 [25.2%]34587 [24.3%]

MC, microscopic colitis; SD, standard deviation; IQR, interquartile range;

3.2. Drug exposure

The association between an ever use of SSRIs, PPIs, NSAIDs, and statins and later MC was significant in Denmark as a whole unit and across all individual regions. The lowest OR for the association between MC and previous use of PPIs, NSAIDs, and statins were found in the Capital Region of Denmark, and for SSRIs in Region Zealand, see Table 2.

Table 2.
Open in new tab

Odds ratio [95% confidence intervals, CIs] of SSRIs, PPIs, NSAIDs and statin use preceding index date, MC case vs control, stratified by region.

Region SSRIsPPIsNSAIDsStatins
Central Denmark Region1.53 [1.46–1.60]1.84 [1.75–1.93]1.52 [1.40–1.65]1.35 [1.28–1.42]
North Denmark Region1.46 [1.38–1.55]1.99 [1.87–2.11]1.61 [1.45–1.78]1.29 [1.21–1.37]
Region Zealand1.42 [1.35–1.49]1.94[1.85–2.05]1.59 [1.46–1.73]1.26 [1.20–1.33]
Region of Southern Denmark1.49 [1.42–1.55]1.99 [1.90–2.09]1.66 [1.54–1.80]1.24 [1.18–1.30]
Capital Region of Denmark1.45 [1.39–1.52]1.69 [1.61–1.77]1.52 [1.42–1.63]1.23 [1.17–1.28]
All Denmark1.47 [1.44–1.50]1.87 [1.83–1.92]1.58 [1.52–1.63]1.27 [1.24–1.30]
Region SSRIsPPIsNSAIDsStatins
Central Denmark Region1.53 [1.46–1.60]1.84 [1.75–1.93]1.52 [1.40–1.65]1.35 [1.28–1.42]
North Denmark Region1.46 [1.38–1.55]1.99 [1.87–2.11]1.61 [1.45–1.78]1.29 [1.21–1.37]
Region Zealand1.42 [1.35–1.49]1.94[1.85–2.05]1.59 [1.46–1.73]1.26 [1.20–1.33]
Region of Southern Denmark1.49 [1.42–1.55]1.99 [1.90–2.09]1.66 [1.54–1.80]1.24 [1.18–1.30]
Capital Region of Denmark1.45 [1.39–1.52]1.69 [1.61–1.77]1.52 [1.42–1.63]1.23 [1.17–1.28]
All Denmark1.47 [1.44–1.50]1.87 [1.83–1.92]1.58 [1.52–1.63]1.27 [1.24–1.30]

MC, microscopic colitis; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.

Table 2.
Open in new tab

Odds ratio [95% confidence intervals, CIs] of SSRIs, PPIs, NSAIDs and statin use preceding index date, MC case vs control, stratified by region.

Region SSRIsPPIsNSAIDsStatins
Central Denmark Region1.53 [1.46–1.60]1.84 [1.75–1.93]1.52 [1.40–1.65]1.35 [1.28–1.42]
North Denmark Region1.46 [1.38–1.55]1.99 [1.87–2.11]1.61 [1.45–1.78]1.29 [1.21–1.37]
Region Zealand1.42 [1.35–1.49]1.94[1.85–2.05]1.59 [1.46–1.73]1.26 [1.20–1.33]
Region of Southern Denmark1.49 [1.42–1.55]1.99 [1.90–2.09]1.66 [1.54–1.80]1.24 [1.18–1.30]
Capital Region of Denmark1.45 [1.39–1.52]1.69 [1.61–1.77]1.52 [1.42–1.63]1.23 [1.17–1.28]
All Denmark1.47 [1.44–1.50]1.87 [1.83–1.92]1.58 [1.52–1.63]1.27 [1.24–1.30]
Region SSRIsPPIsNSAIDsStatins
Central Denmark Region1.53 [1.46–1.60]1.84 [1.75–1.93]1.52 [1.40–1.65]1.35 [1.28–1.42]
North Denmark Region1.46 [1.38–1.55]1.99 [1.87–2.11]1.61 [1.45–1.78]1.29 [1.21–1.37]
Region Zealand1.42 [1.35–1.49]1.94[1.85–2.05]1.59 [1.46–1.73]1.26 [1.20–1.33]
Region of Southern Denmark1.49 [1.42–1.55]1.99 [1.90–2.09]1.66 [1.54–1.80]1.24 [1.18–1.30]
Capital Region of Denmark1.45 [1.39–1.52]1.69 [1.61–1.77]1.52 [1.42–1.63]1.23 [1.17–1.28]
All Denmark1.47 [1.44–1.50]1.87 [1.83–1.92]1.58 [1.52–1.63]1.27 [1.24–1.30]

MC, microscopic colitis; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.

Although there was a significant association between the use of SSRIs, PPIs, NSAIDs, and statins and later MC, a large proportion of MC cases were not exposed to the drugs before diagnosis, as seen in Table 3.

Table 3.
Open in new tab

Percentage of MC cases without prior exposure to SSRIs, PPIs, NSAIDs, or statins.

RegionSSRIsPPIsNSAIDsStatins
Central Denmark Region61.2%34.6%8.4%57.3%
North Denmark Region66.9%29.5%7.0%58.3%
Region Zealand66.5%29.5%7.2%61.5%
Region of Southern Denmark62.4%29.3%7.1%59.4%
Capital Region of Denmark65.0%36.4%9.2%64.5%
RegionSSRIsPPIsNSAIDsStatins
Central Denmark Region61.2%34.6%8.4%57.3%
North Denmark Region66.9%29.5%7.0%58.3%
Region Zealand66.5%29.5%7.2%61.5%
Region of Southern Denmark62.4%29.3%7.1%59.4%
Capital Region of Denmark65.0%36.4%9.2%64.5%

MC, microscopic colitis; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.

Table 3.
Open in new tab

Percentage of MC cases without prior exposure to SSRIs, PPIs, NSAIDs, or statins.

RegionSSRIsPPIsNSAIDsStatins
Central Denmark Region61.2%34.6%8.4%57.3%
North Denmark Region66.9%29.5%7.0%58.3%
Region Zealand66.5%29.5%7.2%61.5%
Region of Southern Denmark62.4%29.3%7.1%59.4%
Capital Region of Denmark65.0%36.4%9.2%64.5%
RegionSSRIsPPIsNSAIDsStatins
Central Denmark Region61.2%34.6%8.4%57.3%
North Denmark Region66.9%29.5%7.0%58.3%
Region Zealand66.5%29.5%7.2%61.5%
Region of Southern Denmark62.4%29.3%7.1%59.4%
Capital Region of Denmark65.0%36.4%9.2%64.5%

MC, microscopic colitis; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.

Data covering the total sales of PPIs, NSAIDs, SSRIs, and statins in the Danish regions between 2007 [the start of the regions] and 2016 are presented in Figure 2.34

The volume of PPIs, NSAIDs, statins, and SSRIs sold at the pharmacy per 1000 inhabitants in the five regions of Denmark. PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.
Figure 2.

The volume of PPIs, NSAIDs, statins, and SSRIs sold at the pharmacy per 1000 inhabitants in the five regions of Denmark. PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.

Open in new tabDownload slide

When investigating the exposure to any of the four medications and later MC, the weakest association was found in the Capital Region of Denmark (OR 1.80 [95% CI: 1.61–2.01]) and the strongest in the Region of Southern Denmark (OR 2.38 [95% CI: 2.05–2.77]). When investigating CC and LC separately, drug exposure was slightly more strongly associated with CC compared with LC, with an OR of 2.10 [95% CI: 1.93–2.30] and 1.96 [95% CI: 1.79–2.14], respectively [Supplementary Tables 6s and 7s, available as Supplementary data at ECCO-JCC online].

3.3. Smoking

The crude incidence of smoking-associated ICD-10 codes in controls was highest in Region Zealand, with 1414.5 per 100 000 person-years, and the RR was slightly increased, with 1.07 [95% CI: 1.00–1.14] as compared with controls in the Capital Region of Denmark. Also, the RR of smoking was significantly lower in controls living in the Region of Southern Denmark, North Denmark Region, and Central Denmark Region than controls in the Capital Region of Denmark.

The association of smoking and MC was significant in all regions of Denmark, with the strongest association observed in the North Denmark Region (OR 1.29 [95% CI: 1.18–1.40]) and lowest in Central Denmark Region (OR 1.13 [95% CI: 1.03–1.23]).

Smoking was equally associated with CC and LC with an OR of 1.22 [95% CI:1.17–1.28] and 1.26 [95% CI:1.20–1.33], respectively.

3.4. Immune-mediated inflammatory diseases

The occurrence of immune-mediated inflammatory diseases ranged from 15.3% to 18.4% among patients with MC and 7.1% to 8.2% among controls in the five regions of Denmark, as seen in Table 4.

Table 4.
Open in new tab

Percentage of patients with MC with 0, 1, 2 or > 2 immune-mediated inflammatory diseases prior to index date

Number of concomitant immune-mediated inflammatory diseases
Region012>2
Central Denmark Region81.6%13.9%3.11%1.4%
North Denmark Region84.7%11.4%2.2%1.8%
Region Zealand83.7%11.0%3.5%1.8%
Region of Southern Denmark81.6%13.1%3.7%1.7%
Capital Region of Denmark82.6%12.3%3.7%1.4%
All Denmark82.7%12.4%3.3%1.6%
Number of concomitant immune-mediated inflammatory diseases
Region012>2
Central Denmark Region81.6%13.9%3.11%1.4%
North Denmark Region84.7%11.4%2.2%1.8%
Region Zealand83.7%11.0%3.5%1.8%
Region of Southern Denmark81.6%13.1%3.7%1.7%
Capital Region of Denmark82.6%12.3%3.7%1.4%
All Denmark82.7%12.4%3.3%1.6%
Table 4.
Open in new tab

Percentage of patients with MC with 0, 1, 2 or > 2 immune-mediated inflammatory diseases prior to index date

Number of concomitant immune-mediated inflammatory diseases
Region012>2
Central Denmark Region81.6%13.9%3.11%1.4%
North Denmark Region84.7%11.4%2.2%1.8%
Region Zealand83.7%11.0%3.5%1.8%
Region of Southern Denmark81.6%13.1%3.7%1.7%
Capital Region of Denmark82.6%12.3%3.7%1.4%
All Denmark82.7%12.4%3.3%1.6%
Number of concomitant immune-mediated inflammatory diseases
Region012>2
Central Denmark Region81.6%13.9%3.11%1.4%
North Denmark Region84.7%11.4%2.2%1.8%
Region Zealand83.7%11.0%3.5%1.8%
Region of Southern Denmark81.6%13.1%3.7%1.7%
Capital Region of Denmark82.6%12.3%3.7%1.4%
All Denmark82.7%12.4%3.3%1.6%

The observed association between the presence of at least one immune-mediated inflammatory disease and MC was similar in all regions, with the strongest association found in Region of Southern Denmark. When analysing the OR of CC or LC in subjects with immune-mediated inflammatory diseases, the OR of CC was 1.64 [95% CI: 1.58–1.70] and of LC 1.52 [95% CI:1.45–1.59], see Supplementary Tables s6 and s7.

3.5. Endoscopy rate

The RR of sigmoidoscopies with colonic biopsies in controls were significantly higher in Region Zealand compared with the Capital Region of Denmark, 1.21 [95% CI: 1.02–1.43]. The RR of colonoscopy with biopsy, which is the preferred method of diagnosing MC, was significantly increased in all four regions compared with the Capital Region of Denmark, see Table 5.

Table 5.
Open in new tab

The relative risk of MC, the odds ratio of drug exposure [SSRI, PPI, NSAID, and statin], smoking, and immune-mediated inflammatory diseases before index date [MC case vs control] as well as the relative risk of undergoing colonoscopy/sigmoidoscopy/colonic biopsy among controls. All risk estimates are including 95% confidence intervals [CIs].

Relative risk of MC21Odds ratio, MC case vs controlRelative risk, controls
Region Drug exposureSmokingImmune-mediated inflammatory diseaseSigmoidoscopy with biopsy [public hospital]Colonoscopy with biopsy
[public hospital]		Colonic biopsy
[public and private hospital]
Central Denmark Region1.07 [1.01–1.12]1.99 [1.72–2.29]1.13 [1.03–1.23]1.63 [1.53–1.74]0.73 [0.61–0.88]1.29 [1.17–1.42]0.91 [0.85–0.97]
North Denmark Region1.57 [1.49‐1.66]2.09 [1.75–2.49]1.29 [1.18–1.40]1.54 [1.43–1.66]0.82 [0.68–1.00]1.11 [1.00–1.24]0.91 [0.85–0.98]
Region Zealand1.39 [1.32‐1.46]2.10 [1.81–2.44]1.26 [1.17–1.35]1.58 [1.48–1.68]1.21 [1.02–1.43]1.32 [1.20–1.46]0.99 [0.93–1.06]
Region of Southern Denmark1.26 [1.20–1.32]2.38 [2.05–2.77]1.24 [1.16–1.33]1.64 [1.55–1.73]1.08 [0.92–1.27]1.37 [1.26–1.50]1.00 [0.94–1.07]
Capital Region of Denmark1 [ref.]1.80 [1.61–2.01]1.27 [1.19–1.35]1.54 [1.46–1.63]1 [ref.]1 [ref.]1 [ref.]
All DenmarkN/A2.03 [1.91–2.17]1.24 [1.20–1.28]1.59 [1.54–1.63]N/AN/AN/A
Relative risk of MC21Odds ratio, MC case vs controlRelative risk, controls
Region Drug exposureSmokingImmune-mediated inflammatory diseaseSigmoidoscopy with biopsy [public hospital]Colonoscopy with biopsy
[public hospital]		Colonic biopsy
[public and private hospital]
Central Denmark Region1.07 [1.01–1.12]1.99 [1.72–2.29]1.13 [1.03–1.23]1.63 [1.53–1.74]0.73 [0.61–0.88]1.29 [1.17–1.42]0.91 [0.85–0.97]
North Denmark Region1.57 [1.49‐1.66]2.09 [1.75–2.49]1.29 [1.18–1.40]1.54 [1.43–1.66]0.82 [0.68–1.00]1.11 [1.00–1.24]0.91 [0.85–0.98]
Region Zealand1.39 [1.32‐1.46]2.10 [1.81–2.44]1.26 [1.17–1.35]1.58 [1.48–1.68]1.21 [1.02–1.43]1.32 [1.20–1.46]0.99 [0.93–1.06]
Region of Southern Denmark1.26 [1.20–1.32]2.38 [2.05–2.77]1.24 [1.16–1.33]1.64 [1.55–1.73]1.08 [0.92–1.27]1.37 [1.26–1.50]1.00 [0.94–1.07]
Capital Region of Denmark1 [ref.]1.80 [1.61–2.01]1.27 [1.19–1.35]1.54 [1.46–1.63]1 [ref.]1 [ref.]1 [ref.]
All DenmarkN/A2.03 [1.91–2.17]1.24 [1.20–1.28]1.59 [1.54–1.63]N/AN/AN/A

MC, microscopic colitis; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor; N/A, not available; ref., reference value.

Table 5.
Open in new tab

The relative risk of MC, the odds ratio of drug exposure [SSRI, PPI, NSAID, and statin], smoking, and immune-mediated inflammatory diseases before index date [MC case vs control] as well as the relative risk of undergoing colonoscopy/sigmoidoscopy/colonic biopsy among controls. All risk estimates are including 95% confidence intervals [CIs].

Relative risk of MC21Odds ratio, MC case vs controlRelative risk, controls
Region Drug exposureSmokingImmune-mediated inflammatory diseaseSigmoidoscopy with biopsy [public hospital]Colonoscopy with biopsy
[public hospital]		Colonic biopsy
[public and private hospital]
Central Denmark Region1.07 [1.01–1.12]1.99 [1.72–2.29]1.13 [1.03–1.23]1.63 [1.53–1.74]0.73 [0.61–0.88]1.29 [1.17–1.42]0.91 [0.85–0.97]
North Denmark Region1.57 [1.49‐1.66]2.09 [1.75–2.49]1.29 [1.18–1.40]1.54 [1.43–1.66]0.82 [0.68–1.00]1.11 [1.00–1.24]0.91 [0.85–0.98]
Region Zealand1.39 [1.32‐1.46]2.10 [1.81–2.44]1.26 [1.17–1.35]1.58 [1.48–1.68]1.21 [1.02–1.43]1.32 [1.20–1.46]0.99 [0.93–1.06]
Region of Southern Denmark1.26 [1.20–1.32]2.38 [2.05–2.77]1.24 [1.16–1.33]1.64 [1.55–1.73]1.08 [0.92–1.27]1.37 [1.26–1.50]1.00 [0.94–1.07]
Capital Region of Denmark1 [ref.]1.80 [1.61–2.01]1.27 [1.19–1.35]1.54 [1.46–1.63]1 [ref.]1 [ref.]1 [ref.]
All DenmarkN/A2.03 [1.91–2.17]1.24 [1.20–1.28]1.59 [1.54–1.63]N/AN/AN/A
Relative risk of MC21Odds ratio, MC case vs controlRelative risk, controls
Region Drug exposureSmokingImmune-mediated inflammatory diseaseSigmoidoscopy with biopsy [public hospital]Colonoscopy with biopsy
[public hospital]		Colonic biopsy
[public and private hospital]
Central Denmark Region1.07 [1.01–1.12]1.99 [1.72–2.29]1.13 [1.03–1.23]1.63 [1.53–1.74]0.73 [0.61–0.88]1.29 [1.17–1.42]0.91 [0.85–0.97]
North Denmark Region1.57 [1.49‐1.66]2.09 [1.75–2.49]1.29 [1.18–1.40]1.54 [1.43–1.66]0.82 [0.68–1.00]1.11 [1.00–1.24]0.91 [0.85–0.98]
Region Zealand1.39 [1.32‐1.46]2.10 [1.81–2.44]1.26 [1.17–1.35]1.58 [1.48–1.68]1.21 [1.02–1.43]1.32 [1.20–1.46]0.99 [0.93–1.06]
Region of Southern Denmark1.26 [1.20–1.32]2.38 [2.05–2.77]1.24 [1.16–1.33]1.64 [1.55–1.73]1.08 [0.92–1.27]1.37 [1.26–1.50]1.00 [0.94–1.07]
Capital Region of Denmark1 [ref.]1.80 [1.61–2.01]1.27 [1.19–1.35]1.54 [1.46–1.63]1 [ref.]1 [ref.]1 [ref.]
All DenmarkN/A2.03 [1.91–2.17]1.24 [1.20–1.28]1.59 [1.54–1.63]N/AN/AN/A

MC, microscopic colitis; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor; N/A, not available; ref., reference value.

The crude incidence rate of colonoscopy with biopsy was lowest in the Capital Region of Denmark with 465.1 per 100 000 person-years, and highest in the Region of Southern Denmark with 646.6 per 100 000 person-years, from 1995 to 2016.

The risk of colonic biopsies performed was similar across all regions of Denmark, although significantly lower in the Central Denmark Region and North Denmark Region compared with the Capital Region of Denmark, with an RR of 0.91 [95% CI: 0.85–0.97] and 0.91 [95% CI: 0.85–0.98], respectively.

A summary of the RR of MC,21 the association between drug exposure, smoking, and immune-mediated inflammatory diseases and MC, and the RR for controls to undergo colonoscopy/sigmoidoscopy/colonic biopsy are listed in Table 5.

4. Discussion

4.1. Main findings

This nationwide study, including more than 14 000 MC patients and 140 000 matched controls from the background population, demonstrated that immune-mediated inflammatory diseases, smoking, and exposure to NSAIDS, PPIs, SSRIs, and statins were associated with an increased risk of developing MC. The total sales of NSAIDs, PPIs, SSRIs, and statins were lower in the Capital Region of Denmark, where the incidence of MC was the lowest, compared with the North Denmark Region where the incidence was the highest. Whereas the association between smoking and MC was equally strong in all regions of Denmark, the association between drug exposure was weakest in the Capital Region of Denmark. Moreover, the RR of colonoscopy in controls was significantly higher in all four regions compared with controls with a place of residence in the Capital Region of Denmark, indicating a lower frequency of performed colonoscopies with biopsy.

4.2. Comparison with previous studies

Intestinal bacterial infection, smoking, autoimmune diseases, and exposure to NSAIDs, PPIs, SSRIs, and statins have previously been identified as possible risk factors associated with MC.5,6,35–37 Environmental factors, such as lifestyle, diet, and air pollution, have also been investigated as possible risk factors, without concluding any firm association.38,39 Only one study has, to our knowledge, investigated potential causes of differences in MC incidence across two regions in two comparable high-incidence countries.19 No clear explanation was found, but the potential influencing factors presented were awareness of MC and accessibility to colonoscopy.

In our study, the RR of colonoscopy with biopsy was significantly higher in all regions when compared with the Capital Region of Denmark. The risk of colonic biopsies was similar across all regions of Denmark, although significantly decreased in the North Denmark Region compared with the Capital Region of Denmark, which contradicts the consideration of a higher detection rate in the North Denmark Region. The finding might also indicate a that substantial part of the performed endoscopies with biopsies are performed in private hospitals/practices rather than in a public setting in the Capital Region of Denmark. As The Danish Pathology Register does not hold information on whether the colonic biopsies were taken during a proctoscopy, sigmoidoscopy, colonoscopy, or other procedure/surgery at private hospitals/practices, we cannot depend on The Danish Pathology Register as a representation for colonoscopy with biopsy, which is the preferred method of diagnosing MC. Therefore, the finding of a higher RR of colonic biopsies in the Capital Region of Denmark might be of lesser significance.

A recent study investigating the incidence of MC in Region Zealand [Denmark] and Region Skåne [Sweden] concluded that the incidence of MC and cases per colonic biopsy were higher in Region Zealand. Uninvestigated but possible factors contributing to this difference were inter-regional differences in awareness among clinicians and endoscopists, waiting times, access to colonoscopy, and indications for biopsy taking.19 Exploratory factors that might also be applied to the differences observed within Denmark.

Exposures to PPIs, NSAIDs, SSRIs, and statins have in previous reports been suggested to be associated with the development of MC.4–6 Several suggestions regarding the potential underlying mechanism have been made, proposing that PPIs inhibit colonic proton pumps, induce intra-epithelial lymphocytosis, increase the intestinal permeability, and alter intestinal microbiota.40–43 Few suggestions have been proposed regarding NSAIDs, possibly causing an increased intestinal permeability.44 As the association between drug exposure and MC is still unclear, future studies are needed to establish the underlying mechanisms.

In our cohort, the association between PPIs and MC was the strongest and the association between statins and MC the weakest, which is in line with previous research.5 The weakest association between drug exposure and MC was found in the Capital Region of Denmark. As the volume sold per inhabitant was lower for all drug classes in the Capital Region of Denmark than in the North Denmark Region, this finding may partly explain the observed difference in MC incidence.

Smoking is not only a well-known risk factor associated with the development of MC; it has also been associated with a worse clinical outcome.35,37,45 A recent systematic review and meta-analysis found current smokers to have an OR of developing MC of 2.99 [95% CI: 2.15–4.15] relative to never-smokers, and former smokers having an OR of developing MC of 1.63 [95% CI: 1.37–1.94] relative to never-smokers.7 In our cohort, we only had access to ICD-10 codes of diseases/procedures associated with smoking, such as chronic obstructive pulmonary disease, lung cancer, and nicotine dependency. However, an association between smoking and MC was present in all regions of Denmark, with the strongest association being in the least populated region of Denmark, the North Denmark Region.

We observed that 18% of the MC patients included in our cohort were diagnosed with one or more immune-mediated inflammatory disease before their MC diagnosis. Similar numbers have been found in other high-incidence countries like Spain, France, and Sweden.46–48 Also, a newly published study suggested a shared genetic risk between CC, coeliac disease, Crohn’s disease, and ulcerative colitis.8 The OR of the association of autoimmune diseases and MC was similar across Denmark’s regions, although the weakest associations were found in both the Capital Region of Denmark and North Denmark Region. Therefore, immune-mediated inflammatory diseases are unlikely to explain the difference in MC incidence between the two regions.

Risk estimates of diagnostic procedures and factors associated with MC varied across the regions of Denmark, and no clear pattern could be established and linked to the previously observed regional incidence rates of MC. These findings reflect the complexity of the aetiology of MC and highlight the need for future studies investigating other and unexplored risk factors of MC.

4.3. Strengths and limitations

The present study has several strengths: the large number and representability of patients and controls included as well as the complete records of MC, endoscopies; and drug consumption in the regions.

Our study also holds some limitations. As data on smoking history and habits were not available, we used ICD-10 codes associated with smoking and nicotine dependency as a proxy. Therefore, patients with pulmonary diseases not related to smoking might have been included. Also, the availability and access of smoking cessation courses and the use of ICD codes related to this might vary between regions.

NSAIDs and PPIs are in Denmark obtainable both via prescription and over the counter. Therefore, The Danish National Prescription Registry does not provide complete information regarding exposure to NSAIDs and PPIs and their use might therefore be underestimated in this study. Moreover, we did not have access to data regarding diet or weight that might differ across regions, and as obesity or weight gain during adulthood is linked to a decreased risk of MC, this might influence the MC incidence.49

4.4. Conclusion

The difference in incidence of MC observed across the regions of Denmark is multifactorial and may be due to uneven awareness and access to colonic endoscopic procedures. Another possible explanation is differences in exposures to risk factors such as NSAIDS, SSRIs, PPIs, and statins, which were lower in the Capital Region of Denmark compared with the high-incidence region, North Denmark Region. However, the relationships between the prevalence of risk factors and the incidence of MC in the regions of Denmark were inconsistent, highlighting the need for future studies to explore potential other causes of the differences in incidence, such as lifestyle and altered microbiota.

Funding

This study was partly funded by research grants from Tillotts Pharma AG, Lizzi og Mogens Staal Fonden [grant number 2019-0388], and Nordsjælland Hospital. None of the funding organisations had any role in the design or conduct of the study, in the collection, management, and analysis of the data, or in the preparation, review, and approval of the manuscript.

Conflict of Interest

PW has received consulting fees from Vifor Pharma Nordiska AB and grants from Ferring Lægemidler and Tillotts Pharma AG, as well as non-financial support from Janssen-Cilag A/S, Calpro AS, Pharmacosmos A/S, and Vifor Pharma Nordiska AB. DVA has received grants from Ferring Pharmaceuticals and non-financial support from Calpro AS. SL has worked as a consultant for LEO Pharma, Novo Nordisk, and Contura. OB has received speaker fees from Tillotts and Dr Falk Pharma, was a member of the advisory board for Tillotts, and received unrestricted grants from Tillotts. AM has received consulting fees from Ferring, Vifor, Falk Pharma, and Tillotts, lecture fees from Ferring, Vifor, Janssen, and Tillotts, and has received an unrestricted grant from Ferring and Tillotts. PM has received consulting fees from Tillotts, Janssen-Cilag, Abbvie, and Ferring, lecture fees from AbbVie, Pfizer, MSD, Coloplast, Pharmacosmos, Calpro, and Takeda, and has received unrestricted grants from Takeda, Tillotts, Ferring, and Calpro. JB has received consulting fees from Celgene, Janssen-Cilag, Abbvie, and Ferring, lecture fees from AbbVie, Pfizer, MSD, Coloplast, and Takeda, and has received an unrestricted grant from Takeda and Tillots Pharma.

Author Contributions

PW, JB, PM, EL planned and designed the study. PW was responsible for acquisition of data. PW, JB, SL, and PM analysed the data. PW drafted the manuscript. All authors interpreted the data, contributed to critical revisions of the manuscript for important intellectual content, approved the final version, and agreed to be accountable for all aspects of the work. JB is the guarantor of the article.

References

1.

Miehlke
S
,
Verhaegh
B
,
Tontini
GE
,
Madisch
A
,
Langner
C
,
Münch
A
.
Microscopic colitis: pathophysiology and clinical management
.
Lancet Gastroenterol Hepatol
2019
;
4
:
305
–
14
.

Google Scholar

Crossref
Search ADS
PubMed

 
2.

Magro
F
,
Langner
C
,
Driessen
A
, et al. ;
European Society of Pathology [ESP]; European Crohn’s and Colitis Organisation [ECCO]
.
European consensus on the histopathology of inflammatory bowel disease
.
J Crohns Colitis
2013
;
7
:
827
–
51
.

Google Scholar

Crossref
Search ADS
PubMed

 
3.

Pisani
LF
,
Tontini
GE
,
Vecchi
M
,
Pastorelli
L
.
Microscopic colitis: what do we know about pathogenesis?
Inflamm Bowel Dis
2016
;
22
:
450
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
4.

Verhaegh
BP
,
de Vries
F
,
Masclee
AA
, et al.
High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors
.
Aliment Pharmacol Ther
2016
;
43
:
1004
–
13
.

Google Scholar

Crossref
Search ADS
PubMed

 
5.

Bonderup
OK
,
Fenger-Grøn
M
,
Wigh
T
,
Pedersen
L
,
Nielsen
GL
.
Drug exposure and risk of microscopic colitis: a nationwide Danish case-control study with 5751 cases
.
Inflamm Bowel Dis
2014
;
20
:
1702
–
7
.

Google Scholar

Crossref
Search ADS
PubMed

 
6.

Fernández-Bañares
F
,
De Sousa
MR
,
Salas
A
, et al.
Epidemiological risk factors in microscopic colitis: a prospective case-control study
.
Inflamm Bowel Dis
2013
;
19
:
411
–
7
.

Google Scholar

Crossref
Search ADS
PubMed

 
7.

Jaruvongvanich
V
,
Poonsombudlert
K
,
Ungprasert
P
.
Smoking and risk of microscopic colitis: a systematic review and meta-analysis
.
Inflamm Bowel Dis
2019
;
25
:
672
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
8.

Stahl
E
,
Roda
G
,
Dobbyn
A
, et al.
Collagenous colitis is associated with HLA signature and shares genetic risks with other immune-mediated diseases
.
Gastroenterology
2020
;
159
:
549
–
61.e8
.

Google Scholar

Crossref
Search ADS
PubMed

 
9.

Khalili
H
,
Burke
KE
,
Roelstraete
B
,
Sachs
MC
,
Olén
O
,
Ludvigsson
JF
.
Microscopic colitis and risk of inflammatory bowel disease in a nationwide cohort study
.
Gastroenterology
2020
;
158
:
1574
–
83.e2
.

Google Scholar

Crossref
Search ADS
PubMed

 
10.

Wickbom
A
,
Bohr
J
,
Nyhlin
N
, et al. ;
Swedish Organisation for the Study of Inflammatory Bowel Disease [SOIBD]
.
Microscopic colitis in patients with ulcerative colitis or Crohn’s disease: a retrospective observational study and review of the literature
.
Scand J Gastroenterol
2018
;
53
:
410
–
6
.

Google Scholar

Crossref
Search ADS
PubMed

 
11.

Carstens
A
,
Dicksved
J
,
Nelson
R
, et al.
The gut microbiota in collagenous colitis shares characteristics with inflammatory bowel disease-associated dysbiosis
.
Clin Transl Gastroenterol
2019
;
10
:
e00065
.

Google Scholar

Crossref
Search ADS
PubMed

 
12.

Bonderup
OK
,
Wigh
T
,
Nielsen
GL
,
Pedersen
L
,
Fenger-Grøn
M
.
The epidemiology of microscopic colitis: a 10-year pathology-based nationwide Danish cohort study
.
Scand J Gastroenterol
2015
;
50
:
393
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
13.

Bergman
D
,
Clements
MS
,
Khalili
H
,
Agréus
L
,
Hultcrantz
R
,
Ludvigsson
JF
.
A nationwide cohort study of the incidence of microscopic colitis in Sweden
.
Aliment Pharmacol Ther
2019
;
49
:
1395
–
400
.

Google Scholar

Crossref
Search ADS
PubMed

 
14.

Gentile
NM
,
Khanna
S
,
Loftus
EV
, et al.
The epidemiology of microscopic colitis in Olmsted county from 2002 to 2010: a population-based study
.
Clin Gastroenterol Hepatol
2014
;
12
:
838
–
42
.

Google Scholar

Crossref
Search ADS
PubMed

 
15.

Park
YS
,
Baek
DH
,
Kim
WH
, et al.
Clinical characteristics of microscopic colitis in Korea: prospective multicenter study by KASID
.
Gut Liver
2011
;
5
:
181
–
6
.

Google Scholar

Crossref
Search ADS
PubMed

 
16.

Gado
AS
,
Ebeid
BA
,
El Hindawi
AA
,
Akl
MM
,
Axon
AT
.
Prevalence of microscopic colitis in patients with chronic diarrhea in Egypt: a single-center study
.
Saudi J Gastroenterol
2011
;
17
:
383
–
6
.

Google Scholar

Crossref
Search ADS
PubMed

 
17.

Fernández-Bañares
F
,
Zabana
Y
,
Aceituno
M
,
Ruiz
L
,
Salas
A
,
Esteve
M
.
Prevalence and natural history of microscopic colitis: a population-based study with long-term clinical follow-up in Terrassa, Spain
.
J Crohns Colitis
2016
;
10
:
805
–
11
.

Google Scholar

Crossref
Search ADS
PubMed

 
18.

Tong
J
,
Zheng
Q
,
Zhang
C
,
Lo
R
,
Shen
J
,
Ran
Z
.
Incidence, prevalence, and temporal trends of microscopic colitis: a systematic review and meta-analysis
.
Am J Gastroenterol
2015
;
110
:
265
–
76
.

Google Scholar

Crossref
Search ADS
PubMed

 
19.

Davidson
S
,
Sjöberg
K
,
Engel
PJH
, et al.
Microscopic colitis in Denmark and Sweden: incidence, putative risk factors, histological assessment and endoscopic activity
.
Scand J Gastroenterol
2018
;
53
:
818
–
24
.

Google Scholar

Crossref
Search ADS
PubMed

 
20.

Guagnozzi
D
,
Lucendo
AJ
,
Angueira-Lapeña
T
,
González-Castillo
S
,
Tenias Burillo
JM
.
Prevalence and incidence of microscopic colitis in patients with diarrhoea of unknown aetiology in a region in central Spain
.
Dig Liver Dis
2012
;
44
:
384
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
21.

Weimers
P
,
Ankersen
DV
,
Lophaven
S
, et al.
Incidence and prevalence of microscopic colitis between 2001 and 2016: a Danish nationwide cohort study
.
J Crohns Colitis
2021
;
14
:
1717
–
23
.

Google Scholar

Crossref
Search ADS

 
22.

Jensen
ET
,
Hoffman
K
,
Mpa
M
,
Shaheen
NJ
,
Genta
RM
,
Dellon
ES
.
Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database HHS Public Access
.
Am J Gastroenterol
2014
;
109
:
668
–
75
.

Google Scholar

Crossref
Search ADS
PubMed

 
23.

Pardi
DS
,
Loftus
EV
Jr,
Smyrk
TC
, et al.
The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota
.
Gut
2007
;
56
:
504
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
24.

Pedersen
CB
.
The Danish civil registration system
.
Scand J Public Health
2011
;
39
:
22
–
5
.

Google Scholar

Crossref
Search ADS
PubMed

 
25.

Statistics Denmark
.
FOLK1A: Population at the First Day of the Quarter by Region, Sex, Age And Marital Status
. https://www.statistikbanken.dk/statbank5a/default.asp?w=1280
Accessed April 1, 2020
.

26.

Bjerregaard
B
,
Larsen
OB
.
The Danish pathology register
.
Scand J Public Health
2011
;
39
:
72
–
4
.

Google Scholar

Crossref
Search ADS
PubMed

 
27.

Vigren
L
,
Olesen
M
,
Benoni
C
,
Sjöberg
K
.
Are collagenous and lymphocytic colitis different aspects of the same disease?
Scand J Gastroenterol
2012
;
47
:
1448
–
53
.

Google Scholar

Crossref
Search ADS
PubMed

 
28.

Miehlke
S
,
Guagnozzi
D
,
Zabana
Y
, et al.
European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations
.
United Eur Gastroenterol J
2021
;
9
:
13
–
37
.

Google Scholar

Crossref
Search ADS

 
29.

Wallach Kildemoes
H
,
Toft Sørensen
H
,
Hallas
J
.
The Danish national prescription registry
.
Scand J Public Health
2011
;
39
:
38
–
41
.

Google Scholar

Crossref
Search ADS
PubMed

 
30.

Schmidt
M
,
Schmidt
SA
,
Sandegaard
JL
,
Ehrenstein
V
,
Pedersen
L
,
Sørensen
HT
.
The Danish National Patient Registry: a review of content, data quality, and research potential
.
Clin Epidemiol
2015
;
7
:
449
–
90
.

Google Scholar

PubMed
OpenURL Placeholder Text

 
31.

Egeberg
A
,
Mallbris
L
,
Gislason
GH
,
Skov
L
,
Hansen
PR
.
Risk of multiple sclerosis in patients with psoriasis: a Danish Nationwide Cohort Study
.
J Invest Dermatol
2016
;
136
:
93
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
32.

Egeberg
A
,
Mallbris
L
,
Warren
RB
, et al.
Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study
.
Br J Dermatol
2016
;
175
:
487
–
92
.

Google Scholar

Crossref
Search ADS
PubMed

 
33.

Statista
.
Denmark: Density of Population by Region 2016. |
https://www.statista.com/statistics/588357/density-of-population-by-region-in-denmark/
Accessed January 23, 2021
.

34.

Danish Health Data Authority
. https://medstat.dk/
Accessed August 12, 2020
.

35.

Fernández-Bañares
F
,
de Sousa
MR
,
Salas
A
, et al. ;
RECOMINA Project, GETECCU [Grupo Español de Enfermedades de Crohn y Colitis Ulcerosa]
.
Impact of current smoking on the clinical course of microscopic colitis
.
Inflamm Bowel Dis
2013
;
19
:
1470
–
6
.

Google Scholar

Crossref
Search ADS
PubMed

 
36.

Nielsen
HL
,
Dalager-Pedersen
M
,
Nielsen
H
.
High risk of microscopic colitis after Campylobacter concisus infection: population-based cohort study
.
Gut
2020
;
69
:
1952
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
37.

Burke
KE
,
Ananthakrishnan
AN
,
Lochhead
P
, et al.
Smoking is associated with an increased risk of microscopic colitis: results from two large prospective cohort studies of US women
.
J Crohns Colitis
2018
;
12
:
559
–
67
.

Google Scholar

Crossref
Search ADS
PubMed

 
38.

Larsson
JK
,
Sonestedt
E
,
Ohlsson
B
,
Manjer
J
,
Sjöberg
K
.
The association between the intake of specific dietary components and lifestyle factors and microscopic colitis
.
Eur J Clin Nutr
2016
;
70
:
1309
–
17
.

Google Scholar

Crossref
Search ADS
PubMed

 
39.

Verhaegh
BPM
,
Bijnens
EM
,
van den Heuvel
TRA
, et al.
Ambient air quality as risk factor for microscopic colitis ‐ a geographic information system [GIS] study
.
Environ Res
2019
;
178
:
108710
.

Google Scholar

Crossref
Search ADS
PubMed

 
40.

Nakamura
M
,
Matsui
H
,
Serizawa
H
,
Tsuchimoto
K
.
Lansoprazole novel effector sites revealed by autoradiography: relation to helicobacter pylori, colon, esophagus and others
.
J Clin Biochem Nutr
2007
;
41
:
154
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
41.

Vesper
BJ
,
Jawdi
A
,
Altman
KW
,
Haines
GK
3rd,
Tao
L
,
Radosevich
JA
.
The effect of proton pump inhibitors on the human microbiota
.
Curr Drug Metab
2009
;
10
:
84
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
42.

Keszthelyi
D
,
Jansen
SV
,
Schouten
GA
, et al.
Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study
.
Aliment Pharmacol Ther
2010
;
32
:
1124
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
43.

Yu
YH
,
Han
DS
,
Choi
EY
, et al.
Is use of PPIs related to increased intraepithelial lymphocytes in the colon?
Dig Dis Sci
2012
;
57
:
2669
–
74
.

Google Scholar

Crossref
Search ADS
PubMed

 
44.

Lucendo
AJ
.
Drug exposure and the risk of microscopic colitis: a critical update
.
Drugs R D
2017
;
17
:
79
–
89
.

Google Scholar

Crossref
Search ADS
PubMed

 
45.

Münch
A
,
Tysk
C
,
Bohr
J
, et al.
Smoking status influences clinical outcome in collagenous colitis
.
J Crohns Colitis
2016
;
10
:
449
–
54
.

Google Scholar

Crossref
Search ADS
PubMed

 
46.

Sifuentes Giraldo
WA
,
Llop Vilaltella
M
,
Bouruncle Alaluna
C
, et al.
THU0571 Association of microscopic colitis with autoimmune diseases in a series of 97 cases
.
Ann Rheum Dis
2015
;
74
:
407
.

Google Scholar

OpenURL Placeholder Text

 
47.

Fumery
M
,
Kohut
M
,
Gower-Rousseau
C
, et al. ;
on behalf on the Somme MC group; EPIMAD group
.
Incidence, clinical presentation, and associated factors of microscopic colitis in northern France: a population-based study
.
Dig Dis Sci
2017
;
62
:
1571
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
48.

Vigren
L
,
Tysk
C
,
Ström
M
, et al.
Celiac disease and other autoimmune diseases in patients with collagenous colitis
.
Scand J Gastroenterol
2013
;
48
:
944
–
50
.

Google Scholar

Crossref
Search ADS
PubMed

 
49.

Liu
P-H
,
Burke
KE
,
Ananthakrishnan
AN
, et al.
Obesity and weight gain since early adulthood are associated with a lower risk of microscopic colitis
.
Clin Gastroenterol Hepatol
2019
;
17
:
2523
–
32
.

Google Scholar

Crossref
Search ADS
PubMed

 
© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: [email protected]
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://dbpia.nl.go.kr/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Topic:
Issue Section:
Original Articles
Download all slides
  • Supplementary data

    • Supplementary data

    jjab119_suppl_Supplementary_Material - docx file