Liekele E. Oostenbrug

Association between Toll-like receptor 4 and inflammatory bowel disease.

Background: The human Toll‐like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family‐based controls. Methods: In 781 IBD cases and 315 controls, genotyping was performed for Asp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohns disease (CD). Results: The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset ≥40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found. Conclusions: Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.

Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases.

Background : Azathioprine is widely used in Crohns disease. A major drawback is the occurrence of side‐effects, especially acute pancreatitis. Acute pancreatitis is rarely seen when azathioprine is used for other diseases than Crohns disease.

Clinical outcome of Crohn's disease according to the Vienna classification: disease location is a useful predictor of disease course.

Objectives Crohns disease (CD) is a complex genetic disease with multiple clinical patterns. Clinical classifications may help to identify subgroups of patients that have a distinct pattern of disease, and they are also a prerequisite for the conduction of genetic and therapeutic studies. The aim of this study was to determine the usefulness of the Vienna classification in patient care and clinical studies. Methods The clinical data of patients were carefully reviewed retrospectively. The behaviour and location of the disease were determined according to the Vienna classification and additional clinical characteristics including surgical data, vitamin B12 status and medication were also assessed. Results Data according to the Vienna classification of 292 CD cases were available. The mean age at diagnosis was 31.4 years. The operation rate was higher in patients with ileocolonic localization (P<0.05) and stricturing and penetrating disease behaviour (P<0.001). The incidence of vitamin B12 deficiency was 41.9% in cases with ileal involvement and 20.7% in cases with disease confined to the colon. In 187 cases (64.0%) an operation was performed because of CD-related complications, in a majority (126, 67.4%) this took place within 5 years after diagnosis. Intolerance of azathioprine occurred in 36 cases (22.0%). Conclusions Ileocolonic disease localization is associated with a complicated course of disease. Vitamin B12 deficiency occurs frequently, also in patients with disease apparently confined to the colon. We propose that location parameters can be used for the prediction of disease course in clinical settings and in interventional studies.

Disease Outcome of Ulcerative Colitis in an Era of Changing Treatment Strategies: Results from the Dutch Population-based IBDSL Cohort

BACKGROUND AND AIMS In the past decades, treatment options and strategies for ulcerative colitis [UC] have radically changed. Whether these developments have altered the disease outcome at population level is yet unknown. Therefore, we evaluated the disease outcome of UC over the past two decades in the South-Limburg area of The Netherlands. METHODS In the Dutch population-based IBDSL cohort, three time cohorts were defined: cohort 1991-1997 [cohort A], cohort 1998-2005 [cohort B], and cohort 2006-2010 [cohort C]. The colectomy and hospitalisation rates were compared between cohorts by Kaplan-Meier survival analyses. Hazard ratios [HR] for early colectomy [within 6 months after diagnosis], late colectomy [beyond 6 months after diagnosis], and hospitalisation were calculated using Cox regression models. RESULTS In total, 476 UC patients were included in cohort A, 587 patients in cohort B, and 598 patients in cohort C. Over time, an increase in the use of immunomodulators [8.1%, 22.8% and 21.7%, respectively, p < 0.01] and biological agents [0%, 4.3% and 10.6%, respectively, p < 0.01] was observed. The early colectomy rate decreased from 1.5% in cohort A to 0.5% in cohort B [HR 0.14; 95% confidence interval 0.04-0.47], with no further decrease in cohort C [0.3%, HR 0.98; 95% confidence interval 0.20-4.85]. Late colectomy rate remained unchanged over time [4.0% vs 5.2% vs 3.6%, respectively, p = 0.54]. Hospitalisation rate was also similar among cohorts [22.3% vs 19.5% vs 18.3%, respectively, p = 0.10]. CONCLUSION Over the past two decades, a reduction in early colectomy rate was observed, with no further reduction in the most recent era. Late colectomy rate and hospitalisation rate remained unchanged over time.

Improvements in the Long-Term Outcome of Crohn's Disease Over the Past Two Decades and the Relation to Changes in Medical Management: Results from the Population-Based IBDSL Cohort

Objectives:Medical treatment options and strategies for Crohn’s disease (CD) have changed over the past decades. To assess its impact, we studied the evolution of the long-term disease outcome in the Dutch Inflammatory Bowel Disease South Limburg (IBDSL) cohort.Methods:In total, 1,162 CD patients were included. Three eras were distinguished: 1991–1998 (n=316), 1999–2005 (n=387), and 2006–2011 (n=459), and patients were followed until 2014. Medication exposure and the rates of hospitalization, surgery, and phenotype progression were estimated using Kaplan–Meier survival analyses and compared between eras by multivariable Cox regression models. Second, propensity score matching was used to assess the relation between medication use and the long-term outcome.Results:Over time, the immunomodulator exposure rate increased from 30.6% in the era 1991–1998 to 70.8% in the era 2006–2011 at 5 years. Similar, biological exposure increased from 3.1% (era 1991–1998) to 41.2% (era 2006–2011). In parallel, the hospitalization rate attenuated from 65.9% to 44.2% and the surgery rate from 42.9% to 17.4% at 5 years, respectively (both P<0.01). Progression to a complicated phenotype has not changed over time (21.2% in the era 1991–1998 vs. 21.3% in the era 2006–2011, P=0.93). Immunomodulator users had a similar risk of hospitalization, surgery, or phenotype progression as propensity score-matched nonusers (P>0.05 for all analyses). Similar results were found for biological users (P>0.05 for all analyses).Conclusions:Between 1991 and 2014, the hospitalization and surgery rates decreased, whereas progression to complicated disease is still common in CD. These improvements were not significantly related to the use of immunomodulators and biologicals.

Association of interleukin-1 receptor-associated kinase M (IRAK-M) and inflammatory bowel diseases

Objective. Inflammatory bowel diseases (IBD) have a complex genetic background. The interleukin receptor associated kinase-M (IRAK-M) is a NF-κB-mediated, negative regulator of Toll-like receptor (TLR) signaling. A functional mutation in a negative regulator might induce impaired endotoxin tolerance and increased inflammatory responses. IRAK-M is situated on chromosome 12q14, a susceptibility locus for IBD, which makes it a good candidate gene. The objective of the study was to analyze a large cohort of IBD patients for the association between IBD and IRAK-M. Material and methods. A total of 542 patients with IBD (309 Crohns disease (CD), 233 ulcerative colitis (UC)) and 305 controls were studied. Two single nucleotide polymorphisms (V147I and V270I) and six microsatellite markers were evaluated using association analysis and the haplotype sharing statistic. Results were stratified for CARD15 mutations R702W, G908R and 1007fsinsC. Results. No significant differences in IRAK-M allele frequencies were observed between IBD, UC, CD or subgroups of CD or UC and controls. Five out of 36 UC patients (13.9%) with an IBD-associated CARD15 mutation were carriers versus 2/167 (1.2%) in non-carriers (OR 13.1, 95% CI 1.0–164.5). No interaction was observed for CD. Conclusions. No evidence was found to suggest an association between IBD, CD, UC or subsets of CD and UC and IRAK-M. However, an interaction was found between IRAK-M and CARD15 in UC patients. In CARD15 mutant patients, the production of IRAK-M upon stimulation might be impaired. Further studies are needed to determine whether an impaired negative regulation of the TLR-signaling pathway might be partly responsible for the development of IBD.

Cohort Profile: The Inflammatory Bowel Disease South Limburg Cohort (IBDSL)

Cohort Profile: The Inflammatory Bowel Disease South Limburg Cohort (IBDSL) Tim RA van den Heuvel,* Daisy M Jonkers, Steven FG Jeuring, Marielle JL Romberg-Camps, Liekele E Oostenbrug, Maurice P Zeegers, Ad A Masclee and Marie J Pierik Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centreþ, Maastricht, The Netherlands, Department of Gastroenterology and Hepatology, Orbis Medical Centre, Sittard-Geleen, The Netherlands and Department of Gastroenterology and Hepatology, Atrium Medical Centre, Heerlen, The Netherlands

Inflammatory bowel disease, cancer and medication: Cancer risk in the Dutch population-based IBDSL cohort.

The management of inflammatory bowel disease (IBD) has changed since the mid‐1990s (e.g., use of thiopurines/anti‐TNFα agents, improved surveillance programs), possibly affecting cancer risk. To establish current cancer risk in IBD, updates are warranted from cohorts covering this time span, and detailed enough to study associations with phenotype and medication. We studied intestinal‐, extra‐intestinal‐ and overall cancer risk in the Dutch population‐based IBDSL cohort. In total, 1,157 Crohns disease (CD) and 1,644 ulcerative colitis (UC) patients were diagnosed between 1991 and 2011, and followed until 2013. Standardized incidence ratios (SIRs) were calculated for CD and UC separately, as well as for gender‐, phenotype‐, disease duration‐, diagnosis era‐ and medication groups. We found an increased risk for colorectal cancer in CD patients with colon involvement (SIR 2.97; 95% CI 1.08–6.46), but not in the total CD or UC population. In addition, CD patients were at increased risk for hematologic‐ (2.41; 1.04–4.76), overall skin‐ (1.55; 1.06–2.19), skin squamous cell‐ (SCC; 3.83; 1.83–7.04) and overall cancer (1.28; 1.01–1.60), whereas UC patients had no increased risk for extra‐intestinal‐ and overall cancer. Finally, in a medication analysis on CD and UC together, long‐term immunosuppression exposure (>12 months) was associated with an increased risk for hematologic cancer, non‐Hodgkin lymphoma, SCC and overall cancer, and this increase was mainly attributed to thiopurines. IBD patients with long‐term immunosuppression exposure can be considered as having a higher cancer risk, and our data support the advice in recent IBD guidelines to consider skin cancer screening in these patients.

Time trends in the epidemiology and outcome of perianal fistulizing Crohn’s disease in a population-based cohort

Objective Perianal disease is a debilitating condition that frequently occurs in Crohn’s disease (CD) patients. It is currently unknown whether its incidence has changed in the era of frequent immunomodulator use and biological availability. We studied the incidence and outcome of perianal and rectovaginal fistulas over the past two decades in our population-based Inflammatory Bowel Disease South-Limburg cohort. Patients and methods All 1162 CD patients registered in the Inflammatory Bowel Disease South-Limburg registry were included. The cumulative probabilities of developing a perianal and rectovaginal fistula were compared between three eras distinguished by the year of CD diagnosis: 1991–1998, 1999–2005 and 2006–2011. Second, clinical risk factors and the risk of fistula recurrence were determined. Results The cumulative 5-year perianal fistula rate was 14.1% in the 1991–1998 era, 10.4% in the 1999–2005 era and 10.3% in the 2006–2011 era, P=0.70. Colonic disease was associated with an increased risk of developing perianal disease, whereas older age was associated with a decreased risk (both P<0.01). Over time, more patients were exposed to immunomodulators or biologicals before fistula diagnosis (18.5 vs. 32.1 vs. 52.1%, respectively, P=0.02) and started biological therapy thereafter (18.6 vs. 34.1 vs. 54.0%, respectively, P<0.01). The cumulative 5-year perianal fistula recurrence rate was not significantly different between eras (19.5 vs. 25.5 vs. 33.1%, P=0.28). In contrast, the cumulative 5-year rectovaginal rate attenuated from 5.7% (the 1991–2005 era) to 1.7% (the 2006–2011 era), P=0.01. Conclusion Over the past two decades, the risk of developing a perianal fistula was stable, as well as its recurrence rate, underlining the lasting need for improving treatment strategies for this invalidating condition.OBJECTIVE Perianal disease is a debilitating condition that frequently occurs in Crohns disease (CD) patients. It is currently unknown whether its incidence has changed in the era of frequent immunomodulator use and biological availability. We studied the incidence and outcome of perianal and rectovaginal fistulas over the past two decades in our population-based Inflammatory Bowel Disease South-Limburg cohort. PATIENTS AND METHODS All 1162 CD patients registered in the Inflammatory Bowel Disease South-Limburg registry were included. The cumulative probabilities of developing a perianal and rectovaginal fistula were compared between three eras distinguished by the year of CD diagnosis: 1991-1998, 1999-2005 and 2006-2011. Second, clinical risk factors and the risk of fistula recurrence were determined. RESULTS The cumulative 5-year perianal fistula rate was 14.1% in the 1991-1998 era, 10.4% in the 1999-2005 era and 10.3% in the 2006-2011 era, P=0.70. Colonic disease was associated with an increased risk of developing perianal disease, whereas older age was associated with a decreased risk (both P<0.01). Over time, more patients were exposed to immunomodulators or biologicals before fistula diagnosis (18.5 vs. 32.1 vs. 52.1%, respectively, P=0.02) and started biological therapy thereafter (18.6 vs. 34.1 vs. 54.0%, respectively, P<0.01). The cumulative 5-year perianal fistula recurrence rate was not significantly different between eras (19.5 vs. 25.5 vs. 33.1%, P=0.28). In contrast, the cumulative 5-year rectovaginal rate attenuated from 5.7% (the 1991-2005 era) to 1.7% (the 2006-2011 era), P=0.01. CONCLUSION Over the past two decades, the risk of developing a perianal fistula was stable, as well as its recurrence rate, underlining the lasting need for improving treatment strategies for this invalidating condition.

A 20-Year Temporal Change Analysis in Incidence, Presenting Phenotype and Mortality, in the Dutch IBDSL Cohort—Can Diagnostic Factors Explain the Increase in IBD Incidence?

Background The aim was to study temporal changes in incidence, disease phenotype at diagnosis, and mortality of adult inflammatory bowel disease [IBD] patients in South Limburg, The Netherlands, diagnosed between 1991 and 2010. In addition, the 2010 IBD prevalence was estimated. Methods A multi-faceted approach including hospital administrations, the national pathology registry [PALGA], and general practitioners led to the identification of 1162 patients with Crohns disease [CD], 1663 with ulcerative colitis [UC], and 84 with unclassified IBD [IBD-U]. Temporal changes in incidence, disease phenotype, and mortality were studied using linear, multinomial regression analyses, and standardised mortality rates [SMR], respectively. Results The annual incidences increased from 17.90/100000 in 1991 to 40.36/100000 in 2010 for IBD, from 5.84/100000 to 17.49/100000 for CD, and from 11.67/100000 to 21.47/100000 for UC [p < 0.01 for all]. A shift towards milder disease at diagnosis was observed over time [eg decrease of complicated disease in CD, increase of proctitis in UC]. IBD mortality was similar to that in the general population (SMR 0.92; 95% confidence interval [CI] 0.81-1.05), and did not change over time. The estimated IBD prevalence was 830/100000. Conclusions The IBD incidence in South Limburg increased significantly between 1991 and 2010. The shift towards milder disease at diagnosis in parallel with the improved diagnostics and ability to detect low-grade inflammation was suggestive of an important role of diagnostic factors in this increase. Environmental factors probably played a role as well. The mortality was low and, together with the increasing incidence, led to the high prevalence of IBD in South Limburg.