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Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies., Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied., Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC., Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Extra-intestinal manifestations are frequently reported in inflammatory bowel diseases. However, data comparing the effect of vedolizumab and ustekinumab on articular extra-intestinal manifestations are limited. The aim here was to evaluate differences in new-onset and the evolution of pre-existing joint extra-intestinal manifestations during both treatments., Methods: An international multicentre retrospective study was performed on inflammatory bowel disease patients who started vedolizumab or ustekinumab between May 2010 and December 2020. Extra-intestinal manifestations were assessed at baseline and joint extra-intestinal manifestations were evaluated throughout the 2-year follow-up. Arthropathy was defined by joint inflammation [arthritis/sacroiliitis], diagnosed by a rheumatologist, and arthralgia as articular pain without confirmed inflammation. Additionally, skin, ocular and hepatic extra-intestinal manifestations were assessed at baseline. Uni- and multivariate analyses were performed., Results: In total, 911 patients [vedolizumab: 584; ustekinumab: 327] were included. Deterioration of pre-existing arthropathy and rate of new-onset arthropathy were not significantly associated with vedolizumab over ustekinumab. Arthropathy was used as reason to stop treatment in six vedolizumab and two ustekinumab patients. The odds of developing new arthralgia within 6 months was higher in patients who took vedolizumab compared to ustekinumab (adjusted odds ratio [aOR]: 2.28 [1.01-5.15], p = 0.047). However, this effect was not sustained during the 2-year follow-up (aOR: 1.35 [0.80-2.29], p = 0.259). Deterioration of pre-existing arthralgia was comparable between ustekinumab and vedolizumab-treated patients. In two vedolizumab-treated patients arthralgia was given as the reason to stop treatment., Conclusions: Vedolizumab and ustekinumab can be used safely in patients with articular extra-intestinal manifestations. Only a temporary increased risk for developing arthralgia has been observed under vedolizumab., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Crohn's disease [CD] can develop penetrating complications at any time during the disease course. Enterocutaneous fistulae [ECF] are disease-related complications with an important impact on quality of life. Our aim was to describe the outcomes of this complication, including its medical and/or surgical management and their temporal trends. The primary endpoint was fistula closure, defined as the absence of drainage, with no new abscess or surgery, over the preceding 6 months., Methods: Clinical information from all adult patients with CD and at least one ECF-excluding perianal fistulae-were identified from the prospectively-maintained ENEIDA registry. All additional information regarding treatment for this complication was retrospectively reviewed., Results: A total of 301 ECF in 286 patients [January 1970-September 2020] were analysed out of 30 088 records. These lesions were mostly located in the ileum [67%] and they had a median of one external opening [range 1-10]. After a median follow-up of 146 months (interquartile range [IQR], 69-233), 69% of patients underwent surgery. Fistula closure was achieved in 84%, mostly after surgery, and fistula recurrence was uncommon [13%]. Spontaneous and low-output fistulae were associated with higher closure rates (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.17-1.93, p = 0.001, and HR 1.49, 95% CI 1.07-2.06, p = 0.03, respectively); this was obtained more frequently with medical therapy since biologics have been available., Conclusions: ECF complicating CD are rare but entail a high burden of medical and surgical resources. Closure rates are high, usually after surgery, and fistula recurrence is uncommon. A significant proportion of patients receiving medical therapy can achieve fistula closure., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Patient-reported outcome measures [PROMs] aim to measure patients' perception of how their disorder influences everyday functioning. The objective of this study was to develop a PROM to assess disease activity in microscopic colitis [MC] fulfilling the requirements of the Food and Drug Administration [FDA]., Methods: The European Microscopic Colitis Activity Index [E-MCAI] was developed in four steps. [1] A list of symptoms associated with active MC was created by a group of experts in the field. [2] Content validity of the symptoms was performed by experts [n = 14] and patients [n = 79] using the Content Validity Index. [3] Questions and response alternatives were created for each symptom, and validity of the E-MCAI was evaluated with cognitive interviews with patients [n = 7] and by the experts. [4] A pilot postal survey was performed to ensure usability., Results: Seven of the symptoms related to active MC fulfilled the criteria for content validity and were included in the E-MCAI: stool consistency, stool frequency, stools at night, feel a need to pass more stools shortly after a bowel movement, urgent need to empty the bowel, leakage of stool and abdominal pain. The development and validation process resulted in the current version of the E-MCAI consisting of six questions related to MC., Conclusions: The E-MCAI was developed using the methods advocated by the FDA. The evaluation indicates good content validity. Further evaluation will be performed to achieve construct validity, reliability and responsiveness in future cross-sectional and longitudinal studies., (© 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: journals.permissions@oup.com.)

Background: Whereas the exact aetiology of microscopic colitis [MC] remains unknown, a dysregulated immune response to luminal factors or medications is the most accepted pathogenesis hypothesis., Methods: We conducted a systematic review of the pathogenesis of MC. We applied the Joanna Briggs Institute methodologies and the PRISMA statement for the reporting of systematic reviews [PROSPERO Trial Identifier: CRD42020145008]. Populations, Exposure of interest, and Outcome [PEO] questions were used to explore the following topics in MC: 1] intestinal luminal factors; 2] autoimmunity; 3] innate immunity; 4] adaptive immunity; 5] extracellular matrix; 6] genetic risk factors; and 7] mechanism of diarrhoea. A search was done in PubMed, Embase, and Web of Science up to February 2020. A narrative description was performed explaining the findings for each aspect of MC aetiopathogenesis., Results: Thirty-eight documents provided evidence for PEO1, 100 for PEO2, 72 for PEO3 and 4, 38 for PEO5, 20 for PEO6, and 23 for PEO7. The majority of documents were cohorts, case reports, and case series, with a few case-control and some experimental studies. Consistency among data provided by different studies was considered to support pathogenetic hypotheses. MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea., Conclusions: This is the first systematic review on the aetiology of MC supporting the notion that MC is a multifactorial disease. However, high-profile studies are lacking, and most evidence derives from small heterogeneous studies., (© 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: journals.permissions@oup.com.)

Background and Aims: The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life., Methods: Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16., Results: A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection., Conclusions: Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab., (© 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: journals.permissions@oup.com.)

Background and Aims: There is controversy as to whether the risk of relevant infection in IBD is related to immunosuppressants or the disease itself. The aims of this study were to evaluate: [1] the life-long prevalence and types of relevant infections in patients with IBD related to immunosuppressive treatment, and [2] the relationship of both infection and patient comorbidity to mortality., Methods: Observational multicentre retrospective study of IBD patients that presented a relevant infection. For each case, four periods of infection exposure were analysed: P1: pre-IBD diagnosis, P2: from IBD diagnosis to immunosuppressant initiation, P3: during immunosuppressant therapy, and P4: after treatment withdrawal., Results: The life-long prevalence of relevant infection in the total cohort of patients [6914] was 3%, and 5% in immunosuppressed patients [4202]. 366 relevant infections were found in 212 patients [P1: 9, P2: 17, P3: 334, and P4: 6]. Differences between periods were significant [p < 0.0001]. The most frequent types of infection were respiratory, intestinal and urinary. The most frequent opportunistic infections were tuberculosis [prevalence: 2.6/1000] and herpes zoster [prevalence: 3.9/1000]. Herpes zoster infection was associated with thiopurines alone or in combination with anti-TNF in 75% of the cases, whereas tuberculosis was associated with anti-TNF in 94% of patients. The overall mortality was 4.2%. Infection-related mortality was 2.8% and it was not influenced by comorbidity., Conclusions: Relevant infections in IBD patients are rare and appear to be related to immunosuppression. Relevant infection is a major cause of death in IBD., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: There is very limited information regarding region-specific immunological response in human intestine. We aimed to determine differences in immune compartmentalisation between ileum and colon in healthy and inflamed mucosa., Methods: T cell profile and its apoptosis were measured by flow cytometry, Th1, Th17, Treg [CD4(+)CD25(+)FOXP3(+)], double positive [DP, CD3(+)CD4(+)CD8(+)] and double negative T cells [DN, CD3(+)CD4(-)CD8(-)], immunohistochemistry [FOXP3, caspase-3], and real-time polymerase chain reaction [PCR] [IFN-γ, IL-17-A, and FOXP3] on biopsies from different regions of healthy intestine and of intestine in inflammatory bowel diseases., Results: Healthy colon showed higher percentages of Treg, Th17, and DN, and lower numbers of DP T cells compared with ileum [p < 0.05]. Some but not all region-specific differences were lost in inflammatory conditions. Disease-specific patterns were found: a Th1/Th17 pattern and a Th17 pattern in Crohn's disease and ulcerative colitis respectively, whereas a reduction in Th1/Th17 was found in microscopic colitis. In colonic Crohn's disease and microscopic colitis, DN T cells had a pattern inverse to that of Th1/Th17 (increase in microscopic colitis [p < 0.05] and decrease in Crohn's disease [p < 0.005]). Higher levels of lymphocyte apoptosis were found in healthy colon compared with the ileal counterparts [p = 0.001]. All forms of colonic inflammation presented a dramatic decrease in apoptosis compared with healthy colon. By contrast ileal Crohn's disease showed higher levels of cleaved-Caspase(+) CD3(+) cells., Conclusions: Immunological differences exist in healthy gastrointestinal tract. Inflammatory processes overwhelm some location-specific differences, whereas others are maintained. Care has to be taken when analysing immune response in intestinal inflammation, as location-specific differences may be relevant., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Lymphocytic (LC) and collagenous (CC) colitis are the two major forms of microscopic colitis (MC). The aim of this study was to identify similarities and differences in their mucosal immune characteristics., Methods: Colonic biopsies from 15 CC, 8 LC, and 10 healthy controls were collected. Mucosal lymphocytes were assessed by flow cytometry. Tissue gene expression and protein levels were determined by real-time PCR and ELISA, respectively., Results: LC patients had lower numbers of CD4(+) and double-positive CD4(+)CD8(+)mucosal T lymphocytes, and higher numbers of CD8(+) and CD4(+)TCRγδ(+) mucosal T cells, compared with controls and CC patients. Regulatory Treg (CD4(+)CD25(+)FOXP3(+)) and double-negative (CD3(+)CD4(-)CD8(-)) T cell percentages were higher in both CC and LC compared with controls, coupled with higher levels of the anti-inflammatory IL-10, both at mRNA and protein levels. By contrast, Th1 and Th17 cells were lower in both CC and LC, although gene expression of Th1/Th17 cytokines was higher in both., Conclusion: CC and LC share some regulatory and effector mechanisms, but not others. Higher IL-10 levels and higher Treg and double-negative T cell percentages, found in both CC and LC, could be responsible for the lack of progression of structural damage and the blockade of proinflammatory cytokine production. However, CC and LC are revealed as separate, independent entities, as they show clearly different mucosal lymphocyte profiles, which could be caused by different luminal triggers of the two diseases. Hence, CC and LC are two closely related but independent intestinal disorders., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Few studies have assessed the prevalence of microscopic colitis (MC) and the natural history of this disease is not well known. The aim of this study was to evaluate the prevalence rate of MC, the burden of disease in terms of loss of health and the long-term natural history of MC in a population-based cohort study., Methods: Cases were obtained from the pathology department registry Hospital Universitari Mutua Terrassa. Belonging to the catchment area, maintaining residence in that area, and being alive on August 31, 2014 were confirmed for each case. Adjusted prevalence rates were calculated. Current active drugs for MC and diarrhoea persistence in every patient were recorded., Results: The prevalence rate of MC was 107 per 10(5) inhabitants. The rate of patients with active disease, i.e. those representing the true burden of the disease in terms of loss of health, was 31 per 10(5) inhabitants. After a follow-up of 7.8±0.38 years from diagnosis, 75% of the patients experienced prolonged disease remission, defined as clinical remission without requiring drugs for 1 year or more. The only variable associated with prolonged MC remission was how clinical remission was achieved (spontaneous 93.3%, drug-induced, 60.5%; odds ratio 8.4, 95% confidence interval 2.7-26)., Conclusions: The rate of patients with MC and active disease, which represents the true disease burden in terms of loss of health, is low. Most patients with MC experience prolonged disease remission, with key differences between spontaneous and drug-induced clinical remission., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Assess IBD patients starting anti-TNF for the impact of preventive measures in HBV and/or HCV, and the predictive response factors to HBV vaccination., Methods: Multicenter prospective study including 389 IBD patients. Four interventions were established: I-1) anti-HBs <100IU/L: HBV vaccination with double doses at 0-1-2months, and revaccination if titres <100IU/L (seroprotection defined as anti-HBs10-100IU/L and effective vaccination anti-HBs >100IU/L); I-2) anti-HBs >100IU/L (previous effective vaccination): monitoring levels; I-3) anti-HBc and/or HCV+: analysis every two months; I-4) HBsAg+: start anti-virals., Results: I-1 and I-2) For first vaccination, effective vaccination and seroprotection were obtained in 26.4% and 43.5%, and for revaccination 31.3% and 44.4%, respectively. Predictive factors of effective vaccination were age ≤30years (OR=2.2) and being vaccinated simultaneously with anti-TNF (OR=5.2) instead of late vaccination, whereas age ≤30years (OR=2.6) and anti-TNF monotherapy (OR=2.4) were predictive for seroprotection. 80.8% of patients previously vaccinated maintained titres at 29months follow-up. The only factor related to maintaining titres was previous vaccination versus achieving effective vaccination during anti-TNF (HR=2.49); I-3 and I-4) HBV-DNA + without reactivation was detected in 7% of 29 anti-HBc. No reactivation was found in the remaining HCV (n=5) or HBsAg (n=4) patients., Conclusions: 1) Response to vaccination/revaccination is low in patients with anti-TNF. Young patients vaccinated at the beginning of anti-TNF and receiving it as a monotheraphy showed better response. 2) Long-lasting effective vaccination is greatest in patients previously vaccinated. 3) Following-up the established surveillance and/or preventive anti-viral therapy seems to be safe in HBV and HCV patients., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Active smoking has been associated with a higher risk of developing Crohn's disease (CD). However, its impact on clinical outcomes has been controversial among studies., Aims: To evaluate the influence of active smoking on initial manifestations of CD, the development of disease-related complications, and therapeutic requirements., Methods: Patients diagnosed with CD within a ten-year period (1994-2003) were identified. Clinical and therapeutic features until October 2008 or loss of follow-up were recorded. Smoking status was assessed at each major disease-related event (e.g. penetrating and stricturing complications, perianal disease, intestinal resection, introduction of immunomodulators or biological agents)., Results: A total of 259 patients were included in the study with a median follow-up period of 91 months. At diagnosis, 50.5% were active smokers and only 12% of them quit smoking during follow-up, mostly after a major disease-related event occurred. Smoking at diagnosis was not associated with a particular CD presentation. Active smoking did not influence the development of strictures, intraabdominal and perianal penetrating complications, or increased resectional surgery, biological therapy or immunomodulators requirements., Conclusions: Patients who develop CD while smoking seem to have a similar disease course to those who never smoked., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Patients with ulcerative colitis (UC) and concomitant perianal disease (PAD) are occasionally seen, but the impact of PAD on UC outcome has been scarcely assessed., Aims: To evaluate the prevalence, clinical features and outcomes of PAD among UC patients., Methods: Patients with an initial diagnosis of UC who ever developed PAD were identified from three IBD hospital databases. Each case was matched by age, disease extent at diagnosis, and year of diagnosis, with two UC patients who never developed PAD., Results: Thirty-seven UC patients (5% of the whole series) developed PAD (complex in about a half of them), being more frequent among men (62%), with distal (50%) or extense (34%) disease. Proximal spread of UC occurred in 19% of cases. No differences in demographic features, rate of proximal spread or colectomy during follow-up were found as compared to controls, but greater requirements of steroids (P=0.019) were detected in UC-PAD patients. A change in disease diagnosis occurred in 6 patients mainly because of transmural involvement in colectomy specimen, small intestinal involvement, and/or endoscopic appearance., Conclusions: PAD may occur in up to 5% of UC patients. When complex it leads to a change in disease diagnosis in one third of cases. UC-related therapeutic requirements are not increased in these patients, except for steroids., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Systemic amyloidosis is a rare but life-threatening complication of inflammatory bowel disease (IBD), most cases being reported among Crohn's disease (CD) patients. The only two available retrospective studies showed a prevalence ranging from 0.9% to 3% among CD patients., Aims: To evaluate the prevalence of secondary systemic amyloidosis in a large IBD cohort of a referral centre, and to describe its clinical characteristics and outcome., Methods: Patients diagnosed with amyloidosis were identified among 1006 IBD patients included in the IBD database of our centre, and their medical records were carefully reviewed., Results: Among a total of 1006 IBD patients, 5 cases of amyloidosis were identified, all of them with CD, resulting in a prevalence of 0.5% for IBD and 1% for CD. Two patients died after developing renal failure. Two patients were treated with anti-TNF agents, showing a clinical improvement of their amyloidosis., Conclusions: Secondary amyloidosis occurs mainly in long-lasting, complicated, Crohn's disease and seems to be as prevalent among IBD patients as previously reported., (Copyright © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)