Tim van den Heuvel

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.

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

Volatile Organic Compounds in Exhaled Air as Novel Marker for Disease Activity in Crohn's Disease: A Metabolomic Approach.

Background:Disappearance of macroscopic mucosal inflammation predicts long-term outcome in Crohn’s disease (CD). It can be assessed by ileocolonoscopy, which is, however, an invasive and expensive procedure. Disease activity indices do not correlate well with endoscopic activity and noninvasive markers have a low sensitivity in subgroups of patients. Volatile organic compounds (VOCs) in breath are of increasing interest as noninvasive markers. The aim of this study was to investigate whether VOCs can accurately differentiate between active CD and remission. Methods:Patients participated in a 1-year follow-up study and Harvey–Bradshaw index, blood, fecal, and breath samples were collected at regular intervals. Patients were stratified into 2 groups: active (fecal calprotectin >250 µg/g) or inactive (Harvey–Bradshaw index <4, C-reactive protein <5 mg/L, and fecal calprotectin <100 µg/g) disease. Breath samples were analyzed by gas chromatography–time-of-flight mass spectrometry. Random forest analyses were used to find the most discriminatory VOCs. Results:Eight hundred thirty-five breath-o-grams were measured, 140 samples were assigned as active, 135 as inactive disease, and 110 samples of healthy controls. A set of 10 discriminatory VOCs correctly predicted active CD in 81.5% and remission in 86.4% (sensitivity 0.81, specificity 0.80, AUC 0.80). These VOCs were combined into a single disease activity score that classified disease activity in more than 60% of the previously undetermined individuals. Conclusions:We showed that VOCs can separate healthy controls and patients with active CD and CD in remission in a real-life cohort. Analysis of exhaled air is an interesting new noninvasive application for monitoring mucosal inflammation in inflammatory bowel disease.

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.

Better survival of renal cell carcinoma in patients with inflammatory bowel disease

Background Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population. Methods A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991–2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes. Results 180 IBD patients with RCC were identified. Pancolitis (OR 1.8–2.5), penetrating Crohns disease (OR 2.8), IBD related surgery (OR 3.7–4.5), male gender (OR 3.2–5.0) and older age at IBD onset (OR 1.0–1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression. Conclusions IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.

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.

Pancreatitis-associated protein has no additional value as a marker of disease activity in a real-life cohort of IBD patients

Background and aim Monitoring of mucosal inflammation in inflammatory bowel disease (IBD) is of major importance. New noninvasive markers for intestinal inflammation are needed. Previous studies have reported that pancreatitis-associated protein (PAP) correlates with clinical activity in IBD subgroups. Our aim was to investigate the correlation of serum and fecal PAP with clinical and biochemical parameters of disease activity in a real-life IBD cohort. Patients and methods Two hundred and five consecutive IBD patients were enrolled. Clinical disease activity was scored by the Harvey–Bradshaw Index or the Simple Clinical Colitis Activity Index; also, C-reactive protein (CRP), erythrocyte sedimentation rate, and fecal calprotectin were determined. As surrogate for endoscopy, a combination score of clinical indices with CRP or calprotectin was used to define active disease. Fecal and serum PAP were measured by ELISA. Results The median serum and fecal PAP did not differ in Crohn’s disease (CD) or ulcerative colitis (UC) patients with active compared with inactive disease according to clinical activity indices. Defining active disease by a combination score of Harvey–Bradshaw Index of more than 4 and CRP of more than 5 mg/l or calprotectin more than 250 µg/g, serum PAP (P=0.01), but not fecal PAP (P=0.32), was significantly higher in active than inactive CD patients. Area under the curve of the corresponding receiver operating curve (ROC) was 0.64. No differences were found in serum or fecal PAP levels using the combination score for active disease in UC. Conclusion Serum but not fecal PAP was higher in active compared with nonactive CD and may reflect mucosal inflammation in CD, but not in UC. However, the accuracy of serum PAP for the diagnosis of active disease was poor, and therefore, serum PAP does not seem to have additional value compared with the current noninvasive markers.

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma

Background: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case–control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. Results: We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohns disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. Conclusions: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use.

Su1218 Concomitant Use of Immunomodulators Increases Long Term Response to Infliximab in Ulcerative Colitis - A Population-Based IBD-Sl Cohort Study

Background Infliximab is an effective treatment for steroid-refractory and steroid-dependent ulcerative colitis (UC). However, a subset of patients does not respond to infliximab and many patients lose response during follow up. Few studies have examined predictors of infliximab failure in UC and all available studies were performed in referral center cohorts. Since anti-TNF treatment is expensive and has potentially severe side effects, it is important to identify markers for response. This study evaluates the loss of response to infliximab in an unselected population-based cohort and aims to identify predictive markers for response. Methods Since 1991, all newly diagnosed IBD patients are included in our populationbased Inflammatory Bowel Disease South-Limburg (IBD-SL) cohort. Patients that ever used infliximab for UC were identified. Their medical records were reviewed with regard to indication for infliximab, reason of infliximab failure, age, gender, smoking status, comedication, disease location at diagnosis and at first infusion, and disease duration. A Cox proportional hazards regression model was used to assess markers for predicting primary and secondary response. Factors with a p-value ,0.1 were analyzed in a multivariate model. Associations were presented as Hazard ratios (HR). Results In our IBD-SL cohort, 109 out of 1464 UC patients (7.4%) were exposed to infliximab. Indication for starting infliximab was steroid-refractory disease (46.8%), steroid-dependent disease (41.3%) or intolerance to thiopurines (11.0%). Median follow-up was 45.5 (IQR 32.9-56.8) months after first infusion. Within 2 years 43.1% of the patients discontinued infliximab. Nine patients (8.3%) discontinued because of no response after 3 infusions. This number was too small to analyze predictive markers for non-response. In the group of primary responders (n=100), 38.0% discontinued infliximab within 2 years: 30 patients (79.0%) because of loss of response, 7 (18.4%) because of side effects and 1 patient (2.6%) for another reason. Predictive marker for loss of response was no concomitant use of immunosuppressive agents (HR 2.36; 95%CI 1.10-5.08). No predictive effects were found for disease duration (HR 0.99; 95%CI 0.99-1.00), and days of prednisone use before first infusion (HR 1.01; 95%CI 1.00-1.01), nor for any of the other factors in the univariate analyses. Conclusion In our population-based IBD cohort, almost half of the UC patients discontinue infliximab within 2 years after the first infusion. The majority of primary responders discontinue the drug because of loss of response. The UCSuccess trial showed higher short term response rates in patients on combination of infliximab and azathioprine. This study provides evidence that concomitant use of immunomodulators with infliximab also improves the long term response to infliximab in UC.