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Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.
Zheng, T, Roda, G, Zabana, Y, Escudero-Hernández, C, Liu, X, Chen, Y, Camargo Tavares, L, Bonfiglio, F, Mellander, MR, Janczewska, I, et al
Journal of Crohn's & colitis. 2024;(3):349-359
Abstract
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.
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Prevalence and Implications of Frailty in Older Adults With Incident Inflammatory Bowel Diseases: A Nationwide Cohort Study.
Kochar, B, Jylhävä, J, Söderling, J, Ritchie, CS, , , Ludvigsson, JF, Khalili, H, Olén, O
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022;(10):2358-2365.e11
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BACKGROUND AND AIMS We aimed to compare the risk of frailty in older adults with incident inflammatory bowel disease (IBD) and matched non-IBD comparators and assess the association between frailty and future hospitalizations and mortality. METHODS In a cohort of patients with incident IBD ≥60 years of age from 2007 to 2016 in Sweden identified using nationwide registers, we defined frailty using Hospital Frailty Risk Score. We compared prevalence of frailty in patients with IBD with age, sex, place of residency- and calendar year-matched population comparators. In the IBD cohort, we used Cox proportional hazards modeling to examine the associations between frailty risk and hospitalizations or mortality. RESULTS We identified 10,590 patients with IBD, 52% female with a mean age of 71 years of age, matched to 103,398 population-based comparators. Among patients with IBD, 39% had no risk for frailty, 49% had low risk for frailty, and 12% had higher risk for frailty. Mean Hospital Frailty Risk Score was 1.9 in IBD and 0.9 in matched comparators (P < .01). Older adults with IBD at higher risk for frailty had a 20% greater risk for mortality at 3 years compared with those who were not frail. Compared with nonfrail older patients with IBD, patients at higher risk for frailty had increased mortality (hazard ratio [HR], 3.22, 95% confidence interval [CI], 2.86-3.61), all-cause hospitalization (HR, 2.42; 95% CI, 2.24-2.61), and IBD-related hospitalization (HR, 1.50; 95% CI, 1.35-1.66). These associations were not attenuated after adjusting for comorbidities. CONCLUSIONS Frailty is more prevalent in older adults with IBD than in matched comparators. Among older patients with IBD, frailty is associated with increased risk for hospitalizations and mortality.
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Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies.
Chan, SSM, Chen, Y, Casey, K, Olen, O, Ludvigsson, JF, Carbonnel, F, Oldenburg, B, Gunter, MJ, Tjønneland, A, Grip, O, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022;(5):1048-1058
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BACKGROUND AND AIMS It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. CONCLUSIONS In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.
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Microscopic colitis.
Burke, KE, D'Amato, M, Ng, SC, Pardi, DS, Ludvigsson, JF, Khalili, H
Nature reviews. Disease primers. 2021;(1):39
Abstract
Microscopic colitis (MC) is an inflammatory disease of the large intestine associated with urgent watery diarrhoea. MC may occur in people of all ages, although the disease primarily affects older women. Once believed to be rare, MC is now known to be a common cause of chronic watery diarrhoea in high-income countries, affecting 1 in 115 women and 1 in 286 men during their lifetime in Swedish population-based estimates. An inappropriate immune response to disturbances in the gut microenvironment is implicated in the pathogenesis of MC. Evidence also supports an underlying genetic basis for disease. The diagnosis of MC relies on clinical symptoms and microscopic assessment of colonic biopsy samples. MC is categorized histologically into collagenous colitis, lymphocytic colitis and their incomplete forms. The mainstay of treatment includes the use of budesonide, with or without adjunctive therapies, and withdrawal of offending drugs. Emerging studies suggest a role for biologicals and immunosuppressive therapies for the management of budesonide-refractory or budesonide-dependent disease. MC can have a substantial negative effect on patient quality of life. The outlook for MC includes a better understanding of the immune response, genetics and the microbiome in disease pathogenesis along with progress in disease management through robust clinical trials.
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Decrease in primary but not in secondary abdominal surgery for Crohn's disease: nationwide cohort study, 1990-2014.
Kalman, TD, Everhov, ÅH, Nordenvall, C, Sachs, MC, Halfvarson, J, Ekbom, A, Ludvigsson, JF, Myrelid, P, Olén, O
The British journal of surgery. 2020;(11):1529-1538
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BACKGROUND Treatment of patients with Crohn's disease has evolved in recent decades, with increasing use of immunomodulatory medication since 1990 and biologicals since 1998. In parallel, there has been increased use of active disease monitoring. To what extent these changes have influenced the incidence of primary and repeat surgical resection remains debated. METHODS In this nationwide cohort study, incident patients of all ages with Crohn's disease, identified in Swedish National Patient Registry between 1990 and 2014, were divided into five calendar periods of diagnosis: 1990-1995 and 1996-2000 with use of inpatient registries, 2001, and 2002-2008 and 2009-2014 with use of inpatient and outpatient registries. The cumulative incidence of first and repeat abdominal surgery (except closure of stomas), by category of surgical procedure, was estimated using the Kaplan-Meier method. RESULTS Among 21 273 patients with Crohn's disease, the cumulative incidence of first abdominal surgery within 5 years of Crohn's disease diagnosis decreased continuously from 54·8 per cent in 1990-1995 to 40·4 per cent in 1996-2000 (P < 0·001), and again from 19·8 per cent in 2002-2008 to 17·3 per cent in 2009-2014 (P < 0·001). Repeat 5-year surgery rates decreased from 18·9 per cent in 1990-1995 to 16·0 per cent in 1996-2000 (P = 0·009). After 2000, no further significant decreases were observed. CONCLUSION The 5-year rate of surgical intervention for Crohn's disease has decreased significantly, but the rate of repeat surgery has remained stable despite the introduction of biological therapy.
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The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register.
Shrestha, S, Olén, O, Eriksson, C, Everhov, ÅH, Myrelid, P, Visuri, I, Ludvigsson, JF, Schoultz, I, Montgomery, S, Sachs, MC, et al
Scandinavian journal of gastroenterology. 2020;(4):430-435
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Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown.Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals.Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis.Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.
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Changes in inflammatory bowel disease subtype during follow-up and over time in 44,302 patients.
Everhov, ÅH, Sachs, MC, Malmborg, P, Nordenvall, C, Myrelid, P, Khalili, H, Elmberg, M, Ekbom, A, Askling, J, Jakobsson, G, et al
Scandinavian journal of gastroenterology. 2019;(1):55-63
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AIM: To investigate inflammatory bowel disease (IBD) register-based subtype classifications over a patient's disease course and over time. METHODS We examined International Classification of Diseases coding in patients with ≥2 IBD diagnostic listings in the National Patient Register 2002-2014 (n = 44,302). RESULTS 18% of the patients changed diagnosis (17% of adults, 29% of children) during a median follow-up of 3.8 years. Of visits with diagnoses of Crohn's disease (CD) or ulcerative colitis (UC), 97% were followed by the same diagnosis, whereas 67% of visits with diagnosis IBD-unclassified (IBD-U) were followed by another IBD-U diagnosis. Patients with any diagnostic change changed mostly once (47%) or twice (31%), 39% from UC to CD, 33% from CD to UC and 30% to or from IBD-U. Using a classification algorithm based on the first two diagnoses ('incident classification'), suited for prospective cohort studies, the proportion adult patients with CD, UC, and IBD-U 2002-2014 were 29%, 62%, and 10% (43%, 45%, and 12% in children). A classification model incorporating additional information from surgeries and giving weight to the last 5 years of visits ('prevalent classification'), suited for description of a study population at end of follow-up, classified 31% of adult cases as CD, 58% as UC and 11% as IBD-U (44%, 38%, and 18% in children). CONCLUSIONS IBD subtype changed in 18% during follow-up. The proportion with CD increased and UC decreased from definition at start to end of follow-up. IBD-U was more common in children.
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Work Loss Before and After Diagnosis of Crohn's Disease.
Everhov, ÅH, Khalili, H, Askling, J, Myrelid, P, Ludvigsson, JF, Halfvarson, J, Nordenvall, C, Neovius, M, Söderling, J, Olén, O
Inflammatory bowel diseases. 2019;(7):1237-1247
Abstract
BACKGROUND The aim of this study was to examine work loss in patients with Crohn's disease. METHODS Using nationwide registers, we identified incident patients with Crohn's disease (2007-2010) and population comparator subjects without inflammatory bowel disease, matched by age, sex, calendar year, health care region, and education level. We assessed the number of lost workdays due to sick leave and disability pension from 5 years before to 5 years after first diagnosis of Crohn's disease or end of follow-up (September 30, 2015). RESULTS Among the 2015 incident Crohn's disease patients (median age, 35 years; 50% women), both the proportion with work loss and the mean annual number of lost workdays were larger 5 years before diagnosis (25%; mean, 45 days) than in the 10,067 comparators (17%; mean, 29 days). Increased work loss was seen during the year of diagnosis, after which it declined to levels similar to before diagnosis. Of all patients, 75% had no work loss 24-12 months before diagnosis. Of them, 84% had full work ability also 12-24 months after diagnosis. In patients with total work loss (8.3% of all) before diagnosis, 83% did not work after. Among those with full work ability before diagnosis, the absolute risk of having total work loss after diagnosis was 1.4% (0.43% in the comparators). Our results were consistent across several sensitivity analyses using alternative definitions for date of diagnosis. CONCLUSIONS Patients with Crohn's disease had increased work loss several years before diagnosis, possibly explained by comorbidity or by diagnostic delay.
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Incidence and Treatment of Patients Diagnosed With Inflammatory Bowel Diseases at 60 Years or Older in Sweden.
Everhov, ÅH, Halfvarson, J, Myrelid, P, Sachs, MC, Nordenvall, C, Söderling, J, Ekbom, A, Neovius, M, Ludvigsson, JF, Askling, J, et al
Gastroenterology. 2018;(3):518-528.e15
Abstract
BACKGROUND & AIMS Diagnosis of inflammatory bowel diseases (IBD) is increasing among elderly persons (60 years or older). We performed a nationwide population-based study to estimate incidence and treatment of IBD. METHODS We identified all incident IBD cases in Sweden from 2006 through 2013 using national registers and up to 10 matched population comparator subjects. We collected data on the patients' health care contacts and estimated incidence rates, health service burden, pharmacologic treatments, extra-intestinal manifestations, and surgeries in relation to age of IBD onset (pediatric, <18 years; adults, 18-59 years; elderly, ≥60 years). RESULTS Of 27,834 persons diagnosed with incident IBD, 6443 (23%) had a first diagnosis of IBD at 60 years or older, corresponding to an incidence rate of 35/100,000 person-years (10/100,000 person-years for Crohn's disease, 19/100,000 person-years for ulcerative colitis, and 5/100,000 person-years for IBD unclassified). During a median follow-up period of 4.2 years (range, 0-9 years), elderly patients had less IBD-specific outpatient health care but more IBD-related hospitalizations and overall health care use than adult patients with IBD. Compared with patients with pediatric or adult-onset IBD, elderly patients used fewer biologics and immunomodulators but more systemic corticosteroids. Occurrence of extra-intestinal manifestations was similar in elderly and adult patients, but bowel surgery was more common in the elderly (13% after 5 years vs 10% in adults) (P < .001). The absolute risk of bowel surgery was higher in the elderly than in the general population, but in relative terms, the risk increase was larger in younger age groups. CONCLUSIONS In a nationwide cohort study in Sweden, we associated diagnosis of IBD at age 60 years or older with a lower use of biologics and immunomodulators but higher absolute risk of bowel surgery, compared with diagnosis at a younger age. The large differences in pharmacologic treatment of adults and elderly patients are not necessarily because of a milder course of disease and warrant further investigation.
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Intestinal failure after necrotising enterocolitis: incidence and risk factors in a Swedish population-based longitudinal study.
Sjoberg Bexelius, T, Ahle, M, Elfvin, A, Björling, O, Ludvigsson, JF, Andersson, RE
BMJ paediatrics open. 2018;(1):e000316
Abstract
BACKGROUND AND OBJECTIVE Paediatric intestinal failure (IF) is a disease entity characterised by gut insufficiency often related to short bowel syndrome. It is commonly caused by surgical removal of a large section of the small intestine in association with necrotising enterocolitis (NEC), which usually affects premature infants. This study investigated the incidence and risk of IF in preterm infants with or without NEC. DESIGN A matched cohort study to investigate the incidence and risk factors for IF in a population-based setting in Sweden from 1987 to 2009 using the Swedish Patient Register. PARTICIPANTS Infants with a diagnosis of NEC (n=720) were matched for gestational age and year of birth with reference individuals without NEC (n=3656). The study cohort was censored at death, IF or at end of follow-up (2 years of age). We calculated HRs with 95%CIs for IF using Cox regression, adjusting for pertinent perinatal factors. RESULTS IF was 15 times more common in the infants with NEC compared with the reference infants (HR=7.2, with 95% CI 3.7 to 14.0). Other risk factors for IF were small for gestational age, extreme preterm birth and abdominal surgery. Neonatal mortality in infants with NEC decreased from 20.6% in 1987-1993 to 10.4% in 2007-2009. CONCLUSION IF was more common in the infants with NEC but was also linked to extreme preterm birth, a history of abdominal surgery and small for gestational age. IF was more common at the end of the study period, indicating that it increases when more preterm infants with NEC survive the neonatal period.