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Björkqvist, O., Repsilber, D., Seifert, M., Brislawn, C., Jansson, J., Engstrand, L., . . . Halfvarson, J. (2019). Alterations in the relative abundance of Faecalibacterium prausnitzii correlate with changes in fecal calprotectin in patients with ileal Crohn's disease: a longitudinal study. Scandinavian Journal of Gastroenterology
Open this publication in new window or tab >>Alterations in the relative abundance of Faecalibacterium prausnitzii correlate with changes in fecal calprotectin in patients with ileal Crohn's disease: a longitudinal study
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2019 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objectives: Crohn's disease is characterized by a gut dysbiosis with decreased abundance of butyrate producers such as Faecalibacterium prausnitzii. Although F. prausnitzii secretes anti-inflammatory molecules, few studies have addressed the importance of F. prausnitzii in a longitudinal setting. We aimed to examine the relationship between temporal profiles of F. prausnitzii, the C. leptum group, overall butyrate production, and inflammatory activity.

Material and methods: Fecal samples (n = 59) were collected every third month from nine patients with ileal Crohn's disease. The abundance of F. prausnitzii and C. leptum was quantified relative to the total amount of bacteria using quantitative-PCR. To assess butyrate production of gut microbiota, gene copy numbers of the butyryl-CoA:acetate-CoA transferase (BCoAT) gene were quantified by qPCR. The inflammatory activity was defined by fecal (f)-calprotectin.

Results: No correlation between the relative abundance of F. prausnitzii, the C. leptum group, or copy numbers of the BCoAT gene, and f-calprotectin was observed in the total sample set. By analyzing alterations between consecutive samples, a negative correlation between changes in the relative abundance of F. prausnitzii and f-calprotectin was observed (R = -0.39; p = .009). Changes in C. leptum (R = -0.18, p = .23) and number of copies of the BCoAT gene (R = -0.12; p = .42) did not correlate with f-calprotectin.

Conclusions: There was an inverse correlation between temporal changes in the relative abundance of F. prausnitzii, but not overall butyrate producing capacity, and changes in inflammatory activity in ileal Crohn's disease. These findings indicate that F. prausnitzii may play a role in gut homeostasis, even though causality is still to be demonstrated.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Faecalibacterium prausnitzii, Crohn's disease, calprotectin, butyrate, dysbiosis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-74541 (URN)10.1080/00365521.2019.1599417 (DOI)000468702300001 ()31104514 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RB13-0160
Available from: 2019-06-03 Created: 2019-06-03 Last updated: 2019-06-03Bibliographically approved
Visuri, I., Eriksson, C., Mårdberg, E., Grip, O., Gustavsson, A., Hjortswang, H., . . . Halfvarson, J. (2019). Anti-TNF agent drug survival in patients with IBD: real-world comparisons of individual anti-TNF agents based on the Swedish National Quality Registry for IBD (SWIBREG). Journal of Crohn's & Colitis, 13(Suppl. 1), S443-S444
Open this publication in new window or tab >>Anti-TNF agent drug survival in patients with IBD: real-world comparisons of individual anti-TNF agents based on the Swedish National Quality Registry for IBD (SWIBREG)
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2019 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 13, no Suppl. 1, p. S443-S444Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-73336 (URN)10.1093/ecco-jcc/jjy222.773 (DOI)000460544502205 ()
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26Bibliographically approved
Weimers, P., Halfvarson, J., Sachs, M. C., Ludvigsson, J. F., Peter, I., Olén, O. & Burisch, J. (2019). Association between inflammatory bowel disease and Parkinson's disease: seek and you shall find? [Letter to the editor]. Gut, 68(1), 175-176
Open this publication in new window or tab >>Association between inflammatory bowel disease and Parkinson's disease: seek and you shall find?
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2019 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 1, p. 175-176Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
Epidemiology, inflammatory bowel disease
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-71215 (URN)10.1136/gutjnl-2018-316937 (DOI)000455727900023 ()30021791 (PubMedID)2-s2.0-85050249090 (Scopus ID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-02-04Bibliographically approved
Butwicka, A., Olén, O., Larsson, H., Halfvarson, J., Almqvist, C., Lichtenstein, P., . . . Ludvigsson, J. F. (2019). Association of Childhood-Onset Inflammatory Bowel Disease With Risk of Psychiatric Disorders and Suicide Attempt. JAMA pediatrics
Open this publication in new window or tab >>Association of Childhood-Onset Inflammatory Bowel Disease With Risk of Psychiatric Disorders and Suicide Attempt
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2019 (English)In: JAMA pediatrics, ISSN 2168-6203, E-ISSN 2168-6211Article in journal (Refereed) Epub ahead of print
Abstract [en]

Importance: Inflammatory bowel disease (IBD) has been associated with psychiatric morbidity in adults, although previous studies have not accounted for familial confounding. In children, IBD has an even more severe course, but the association between childhood-onset IBD and psychiatric morbidity remains unclear.

Objective: To examine the risk of psychiatric morbidity in individuals with childhood-onset IBD, controlling for potential confounding shared between siblings.

Design, Setting, and Participants: A population-based cohort study was conducted using data from the Swedish national health care and population registers of all children younger than 18 years born from 1973 to 2013. The study included 6464 individuals with a diagnosis of childhood-onset IBD (3228 with ulcerative colitis, 2536 with Crohn disease, and 700 with IBD unclassified) who were compared with 323 200 matched reference individuals from the general population and 6999 siblings of patients with IBD. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% CIs. Statistical analysis was performed from January 1, 1973, to December 1, 2013.

Main Outcomes and Measures: The primary outcome was any psychiatric disorder and suicide attempt. Secondary outcomes were the following specific psychiatric disorders: psychotic, mood, anxiety, eating, personality, and behavioral disorders; substance misuse; attention-deficit/hyperactivity disorder; autism spectrum disorders; and intellectual disability.

Results: The study included 6464 individuals with a diagnosis of childhood-onset IBD (2831 girls and 3633 boys; mean [SD] age at diagnosis of IBD, 13 [4] years). During a median follow-up time of 9 years, 1117 individuals with IBD (17.3%) received a diagnosis of any psychiatric disorder (incidence rate, 17.1 per 1000 person-years), compared with 38 044 of 323 200 individuals (11.8%) in the general population (incidence rate, 11.2 per 1000 person-years), corresponding to an HR of 1.6 (95% CI, 1.5-1.7), equaling 1 extra case of any psychiatric disorder per 170 person-years. Inflammatory bowel disease was significantly associated with suicide attempt (HR, 1.4; 95% CI, 1.2-1.7) as well as mood disorders (HR, 1.6; 95% CI, 1.4-1.7), anxiety disorders (HR, 1.9; 95% CI, 1.7-2.0) eating disorders (HR, 1.6; 95% CI, 1.3-2.0), personality disorders (HR, 1.4; 95% CI, 1.1-1.8), attention-deficit/hyperactivity disorder (HR, 1.2; 95% CI, 1.1-1.4), and autism spectrum disorders (HR, 1.4; 95% CI, 1.1-1.7) Results were similar for boys and girls. Hazard ratios for any psychiatric disorder were highest in the first year of follow-up but remained statistically significant after more than 5 years. Psychiatric disorders were particularly common for patients with very early-onset IBD (<6 years) and for patients with a parental psychiatric history. Results were largely confirmed by sibling comparison, with similar estimates noted for any psychiatric disorder (HR, 1.6; 95% CI, 1.5-1.8) and suicide attempt (HR, 1.7; 95% CI, 1.2-2.3).

Conclusions and Relevance: Overall, childhood-onset IBD was associated with psychiatric morbidity, confirmed by between-sibling results. Particularly concerning is the increased risk of suicide attempt, suggesting that long-term psychological support be considered for patients with childhood-onset IBD.

Place, publisher, year, edition, pages
American Medical Association, 2019
National Category
Psychiatry Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-75913 (URN)10.1001/jamapediatrics.2019.2662 (DOI)31424531 (PubMedID)
Available from: 2019-08-26 Created: 2019-08-26 Last updated: 2019-08-26Bibliographically approved
Walker, G. J., Harrison, J. W., Heap, G. A., Voskuil, M. D., Andersen, V., Anderson, C. A., . . . Ahmad, T. (2019). Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease. Journal of the American Medical Association (JAMA), 321(8), 773-785
Open this publication in new window or tab >>Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease
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2019 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, no 8, p. 773-785Article in journal (Refereed) Published
Abstract [en]

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).

Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).

Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.

Exposures: Genetic variants associated with TIM.

Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.

Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.

Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Place, publisher, year, edition, pages
American Medical Association, 2019
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-72877 (URN)10.1001/jama.2019.0709 (DOI)000460191400019 ()30806694 (PubMedID)2-s2.0-85062067665 (Scopus ID)
Note

Funding Agencies:

International Serious Adverse Events Consortium  

Crohn's Colitis UK  

Wellcome Trust  WT097835MF 

National Institutes of Health  P01DK046763 

Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-06-19Bibliographically approved
Everhov, Å. H., Sachs, M. C., Malmborg, P., Nordenvall, C., Myrelid, P., Khalili, H., . . . Olén, O. (2019). Changes in inflammatory bowel disease subtype during follow-up and over time in 44,302 patients. Scandinavian Journal of Gastroenterology, 54(1), 55-63
Open this publication in new window or tab >>Changes in inflammatory bowel disease subtype during follow-up and over time in 44,302 patients
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2019 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, no 1, p. 55-63Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Crohn’s disease, IBD-U, Inflammatory bowel disease, indeterminate colitis, inflammatory bowel disease unclassified, register-based definition, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-72038 (URN)10.1080/00365521.2018.1564361 (DOI)000462902700008 ()30700170 (PubMedID)2-s2.0-85060872917 (Scopus ID)
Funder
The Swedish Medical AssociationSwedish Research CouncilSwedish Cancer SocietyThe Karolinska Institutet's Research FoundationStockholm County Council
Note

Funding Agencies:

Bengt Ihre foundation  

Mag-tarmfonden 

Karolinska Institutet (ALF)

Available from: 2019-02-12 Created: 2019-02-12 Last updated: 2019-06-19Bibliographically approved
Romagnoni, A., Halfvarson, J. & Whittaker, P. (2019). Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data. Scientific Reports, 9, Article ID 10351.
Open this publication in new window or tab >>Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10351Article in journal (Refereed) Published
Abstract [en]

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:oru:diva-75724 (URN)10.1038/s41598-019-46649-z (DOI)000475832500026 ()31316157 (PubMedID)2-s2.0-85069470428 (Scopus ID)
Note

Funding Agencies:

Fondation pour la Recherche Medical  DEI20151234405 

Investissements d'Avenir programme  ANR-11-IDEX-0005-02 

Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-09-17Bibliographically approved
Burisch, J., Vardi, H., Schwartz, D., Krznaric, Z., Lakatos, P. L., Fumery, M., . . . Odes, S. (2019). Cost analysis in a prospective European population-based inception cohort: is there a cost-saving effect of biological therapy?. Journal of Crohn's & Colitis, 13(Suppl. 1), S9-S10
Open this publication in new window or tab >>Cost analysis in a prospective European population-based inception cohort: is there a cost-saving effect of biological therapy?
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2019 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 13, no Suppl. 1, p. S9-S10Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-73332 (URN)10.1093/ecco-jcc/jjy222.014 (DOI)000460544500016 ()
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26Bibliographically approved
Burisch, J., Chetcuti Zammit, S., Ellul, P., Turcan, S., Duricova, D., Bortlik, M., . . . Epi-IBD, g. (2019). Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: an Epi-IBD study. Journal of Gastroenterology and Hepatology, 34(6), 996-1003
Open this publication in new window or tab >>Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: an Epi-IBD study
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2019 (English)In: Journal of Gastroenterology and Hepatology, ISSN 0815-9319, E-ISSN 1440-1746, Vol. 34, no 6, p. 996-1003Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following five years.

METHODS: The Epi-IBD study is a prospective population-based cohort of 1,289 IBD patients diagnosed in centres across Europe. Clinical data were captured prospectively throughout the follow-up period.

RESULTS: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n=20, 71%) or CD (n=8, 29%) after a median of six months (IQR: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n=6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n=107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU.

CONCLUSIONS: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after five years of follow-up. One in four patients with IBDU eventually were classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
Inflammatory bowel disease unclassified, prognosis, treatment
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-70825 (URN)10.1111/jgh.14563 (DOI)000470791800010 ()30562421 (PubMedID)2-s2.0-85060325984 (Scopus ID)
Note

Funding Agencies:

Kirsten og Freddy Johansens Fond  

Nordsjaellands Hospital Forskningsrad  

Available from: 2018-12-21 Created: 2018-12-21 Last updated: 2019-07-23Bibliographically approved
Yzet, C., Ungaro, R., Bossuyt, P., Baert, F., Vanasek, T., D'Haens, G., . . . Colombel, J.-F. -. (2019). Endoscopic and deep remission at 1 year prevents disease progression in early Crohn's disease: long-term data from CALM. Journal of Crohn's & Colitis, 13(Suppl. 1), S24-S25
Open this publication in new window or tab >>Endoscopic and deep remission at 1 year prevents disease progression in early Crohn's disease: long-term data from CALM
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2019 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 13, no Suppl. 1, p. S24-S25Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-73337 (URN)10.1093/ecco-jcc/jjy222.032 (DOI)000460544500034 ()
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26Bibliographically approved
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