Summary
Background
Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and ...mortality in IBD have been associated with disease‐related inflammation and immune suppression, but data are limited due to their rare occurrence.
Aim
To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric‐onset IBD.
Methods
Information on paediatric‐onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42‐month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years.
Results
In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD‐therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T‐cell lymphoma were identified, all were biologic‐naïve but thiopurine‐exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T‐cell lymphoma).
Conclusions
We report the largest number of paediatric‐onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer‐associated mortality. Disease‐related adenocarcinomas were a commoner cause of death than lymphomas.
Non‐alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver ...disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts by 170% in NAFLD and 298% in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE with NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP, and LAP3, all of which are up‐regulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, plasma proteome profiling can identify potential biomarkers and drug targets in liver disease.
Synopsis
Applying Plasma Proteome Profiling to liver disease in different human cohorts associated PIGR and ALDOB and other proteins to non‐alcoholic fatty liver disease. Potential biomarkers were validated in a mouse model.
Plasma proteome profiling augmented by Boxcar acquisition identified potential biomarkers of human liver diseases.
PIGR and ALDOB are associated with NAFLD, among other novel proteins.
DPP4, ANPEP, PIGR, APOE, and TGFBI highly correlate with AST, ALT, GGT and ALP.
A mouse NAFLD model recapitulated many of the changes seen in humans.
Applying Plasma Proteome Profiling to liver disease in different human cohorts associated PIGR and ALDOB and other proteins to non‐alcoholic fatty liver disease. Potential biomarkers were validated in a mouse model.
The combination of the severity of pediatric-onset inflammatory bowel disease (IBD) phenotypes and the need for intense medical treatment may increase the risk of malignancy and mortality, but ...evidence regarding the extent of the problem is scarce. Therefore, the Porto Pediatric IBD working group of ESPGHAN conducted a multinational-based survey of cancer and mortality in pediatric IBD.
A survey among pediatric gastroenterologists of 20 European countries and Israel on cancer and/or mortality in the pediatric patient population with IBD was undertaken. One representative from each country repeatedly contacted all pediatric gastroenterologists from each country for reporting retrospectively cancer and/or mortality of pediatric patients with IBD after IBD onset, during 2006-2011.
We identified 18 cases of cancers and/or 31 deaths in 44 children (26 males) who were diagnosed with IBD (ulcerative colitis, n = 21) at a median age of 10.0 years (inter quartile range, 3.0-14.0). Causes of mortality were infectious (n = 14), cancer (n = 5), uncontrolled disease activity of IBD (n = 4), procedure-related (n = 3), other non-IBD related diseases (n = 3), and unknown (n = 2). The most common malignancies were hematopoietic tumors (n = 11), of which 3 were hepatosplenic T-cell lymphoma and 3 Ebstein-Barr virus-associated lymphomas.
Cancer and mortality in pediatric IBD are rare, but cumulative rates are not insignificant. Mortality is primarily related to infections, particularly in patients with 2 or more immunosuppressive agents, followed by cancer and uncontrolled disease. At least 6 lymphomas were likely treatment-associated by virtue of their phenotype.
Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not ...been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY
.
Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY
and (4) Ex-9/sitagliptin combined.
In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY
increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone.
Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY
, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.
Abstract
Background
Patients with pediatric-onset immune-mediated inflammatory diseases (pIMID) show more aggressive phenotypes compared to patients diagnosed as adults. Despite this, data on ...mortality is extrapolated from patients diagnosed in adulthood, which might underestimate the actual risk. We aim to estimate the effect of pIMID compared to reference individuals from the general population on the long-term risk of all-cause mortality.
Methods
A population-based cohort study using the nationwide Danish health care registers. We included all patients diagnosed with pIMID in Denmark from 1980 to 2018 and matched them to up to ten reference individuals from the general population (with no recorded IMID) based on sex, age at diagnosis, and area of residence. Exposure was pIMID, defined as ICD codes indicative of autoimmune hepatitis, primary sclerosing cholangitis, Crohn’s disease, ulcerative colitis, juvenile idiopathic arthritis, system lupus erythematosus, or vasculitis registered before age 18.
The primary outcome was all-cause mortality. The secondary outcome was cause-specific mortality. Cox survival analysis was used to estimate hazard ratios (HR) and Aalen survival analysis to estimate rate differences with corresponding 95% confidence intervals (CI) adjusted for the year of diagnosis and family income.
Denmark has universal free health care, and health care data can be accessed through the nationwide health registers, continuously updated since 1980.
Results
We included 11,581 individuals diagnosed with pIMID, and 99,665 matched reference individuals, accounting for 1,371,994 person-years of follow-up. Median age at pIMID diagnosis was 12.6 years (IQR: 7.9 – 15.9). During follow-up, 152 pIMID patients and 316 reference individuals died, resulting in an all-cause mortality adjusted HR (aHR) of 3.8 (95% confidence interval CI: 3.1-4.7) compared to reference individuals without pIMID. This corresponded to 7.8 (95%CI: 6.1-9.5) additional deaths per 10,000 person-years. The strongest associations were found for gastrointestinal disorders (aHR 22.8 95%CI: 9.6-64.1), gastrointestinal cancers (aHR 19.2 95%CI: 5.0-74.2), and lymphoproliferative diseases (aHR 6.8 95%CI: 2.8-16.8). The aHR of suicide was 2.9 (95%CI: 1.6-5.0).
Conclusion
Patients diagnosed with pIMID have a four-fold increased risk of mortality when followed into adulthood. This underlines the severe disease course of pIMID and highlights the need for lifelong multidisciplinary care.
Abstract
Background
The increasing incidence of inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), Crohn’s disease (CD), and unclassified IBD (IBD-U), in Denmark requires close ...surveillance. Therefore, we aimed to investigate their current incidence and initial disease presentation in a population-based inception cohort.
Methods
IBD Prognosis Study is an ongoing prospective population-based inception cohort of patients diagnosed with UC, CD, or IBD-U between May 1st, 2021, and May 1st, 2023, according to the Copenhagen IBD Criteria within the well-defined geographical uptake area of Hvidovre University Hospital and Herlev University Hospital. This area has a catchment population of 1,050,000, corresponding to ~20% of the Danish population. The incidence rate is defined as the number of new cases between May 1st, 2021, and October 31st, 2022, divided by the total number of 100,000 inhabitants covered in included sites per year during the same period. For the incidence calculations, pediatric-onset of IBD was defined as age < 19 years at diagnosis. However, for the clinical description, for the clinical presentation, the cut-off was <18 years.
Results
As of October 31, 2022, a total of 219, 134, and 24 patients with adult-onset UC, CD, and unclassified IBD (IBD-U), respectively, has been included, corresponding to incidence rates of 13.9, 8.5, and 1.5 per 100,000 adults per year. Further, 11, 16, and two patients with pediatric-onset UC, CD, and IBD-U were included, corresponding to 3.6, 6.3, and 0.7 per 100,000 pediatric cases per year. Demographics and initial disease presentation are presented in Tables 1-2, initial disease burden and treatment patterns in Tables 3-4.
Conclusion: The preliminary data from the ongoing prospective population-based cohort, IBD Prognosis Study, indicate that the incidence rates of adult-onset IBD appear stabilized, while that of pediatric-onset CD is increasing, when compared with data from before 2010.1,2
The study is ongoing and includes extensive and continuous examinations, including endoscopy, intestinal ultrasound investigations, magnetic resonance imaging of the small intestine and biliary and pancreatic ducts, patient-reported measures, and biobanking. As such, the cohort is expected to deliver essential knowledge on the mechanisms for the unpredictable course of IBD.3
References:
1. Vind I et al. Am J Gastroenterol. 2006; doi:10.1111/j.1572-0241.2006.00552.x
2. Jakobsen C et al. Inflamm Bowel Dis. 2011; doi:10.1002/ibd.21654
3. Attauabi M et al. BMJ Open. 2022; doi:10.1136/bmjopen-2021-055779
Abstract
Background
The rate of having a resection for patients with Crohn's disease (CD) have decreased over decades, while the rates of re-resections seem to have been stable around 1/3 in historic ...cohorts. Re-resection rates might be influenced by targeted therapies. We aimed to investigate the re-resection rates and risk of recurrence in a contemporary cohort and the effect of medical treatment on these parameters.
Methods
This population-based cohort included all CD patients undergoing primary intestinal resection between 2010 and 2020 in Eastern Denmark, with a background population of 2,730,000 (46% of the Danish population). Individual clinical characteristics, medication, surgical procedures, and complications, as well as imaging, and endoscopy results were collected. Disease recurrence was defined as a colonoscopy with SES-CD≥3, Rutgeerts score ≥2i, inflammation or stenosis on imaging (MRI, CTA, or IUS), fecal calprotectin ≥ 250 mg/kg, starting corticosteroids after resection or re-resection due to disease activity. We characterized the cohort using nonparametric statistics (median, IQR, percentages) and survival analysis. A Cox regression analysis with propensity score incorporating Montreal classification, age, gender, smoking, and types of resection (colon, ileocecal, or small bowel) was conducted to assess the effect of initiating prophylactic biologic treatment within the first year from resection.
Results
A total of 631 patients had a primary resection due to disease activity, with a median follow-up from time from diagnosis of 118 months (IQR: 69-170) (Table 1). Prior to the first resection 337 (53%) patients received immunomodulators and 249 (39%) biologics; the same numbers post-surgery were 314 (50%) and 264 (42%), respectively. A total of 256 (41%) patients were resected within two years from diagnosis while this proportion increased to 424 (67%) and 533 (84 %) after 5 and 10 years, respectively. Re-resection rates due to disease activity 5 and 10 years after primary resection were 5% and 10%. The median time from primary resection to disease recurrence was 11,3 months (IQR: 4.7-24.8) (Figure 1). Median time from first to second and second to third resection were 37 months (IQR: 15-64) and 38 months (IQR: 26-55), respectively. We found no significant difference regarding prophylactic biologic therapy within the first year of resection (n 45) based on recurrence or re-resection compared to patients not starting biologics within the first year (HR 0.40, 95%CI(0.12-1.34), p=0.14).
Conclusion
Most patients undergoing primary resection face post-surgery disease recurrence, yet 1 in 4 remain relapse-free for decades. Despite extensive biologic therapy, 15% still require further resections due to disease activity.
Gastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S cells in response to low luminal ...pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the postoperative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.
A specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after, and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin, and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation.
Plasma postprandial secretin was more than doubled in humans after RYGB (P < 0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased the secretion of secretin in a sodium-glucose cotransporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P < 0.05) from the perfused rat pancreas but affected neither insulin (P = 0.2) nor glucagon (P = 0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P = 0.04), while blood glucose peak time was delayed (from 15 to 45 min) and gastric emptying time prolonged (P = 0.004).
Glucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S cells warrants further studies.
Abstract
Background
The disease course of inflammatory bowel disease (IBD) is heterogeneous and highly unpredictable. Intestinal Ultrasound (IUS) is a non-invasive modality capable of assessing ...disease activity in IBD. IUS is reliable, patient-friendly, and allows frequent monitoring of disease activity. However, the evidence for IUS as a predictor of disease course is still limited. Here we present novel data on the predictive value of IUS performed at the time of IBD diagnosis.
Methods
Patients with new-onset IBD are currently being included in the ongoing multicentre prospective inception cohort study, the IBD Prognosis Study. During the first five years following diagnosis, patients undergo regular clinical, biochemical, endoscopic, and imaging assessments. IBD treatment and disease events are prospectively recorded. IUS is performed at diagnosis, after three months, and hereafter annually. Patients with proctitis do not undergo assessment with IUS. The newly developed IUS score, the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS), is calculated for the most inflamed segment, with a high score indicating severe disease activity. The score incorporates bowel wall thickness (BWT), bowel wall stratification, colour Doppler signal, and inflammatory fat. In this abstract, we report our preliminary results after including patients for six months.
Results
IBUS-SAS at diagnosis was available in 60 patients. 32 patients were diagnosed with Crohn’s disease (ilieal: 7, colonic: 19, ileocolonic: 6) and 28 patients were diagnosed with ulcerative colitis (UC) or unclassified IBD (proctitis: 1, left-sided colitis: 8, extensive colitis: 19). The mean IBUS-SAS at diagnosis was 51.1, with a mean BWT of 5.2 mm. Major clinical outcomes were initiation of biologic therapy, n=12 (20.0%), IBD-related bowel resection, n=5 (8.3%), IBD-related hospitalisation, n=19 (31.7%). The mean IBUS-SAS at diagnosis was 66.2 among patients with the combined endpoint of any of these disease outcomes during follow-up vs. 34.7 for no major outcomes (p<0.001), see Figure 1. Additionally, we found that all patients with an IBUS-SAS above 80 at diagnosis had been hospitalised and started on systemic steroids. So far, 20 patients had an IUS follow-up scan after three months showing a mean IBUS-SAS reduction by 17.0 points (p=0.008).
Conclusion
We present data on the predictive value of early IUS in new-onset IBD. IUS activity at diagnosis of IBD seems to have the capability to predict short term disease outcome. At diagnosis, high IBUS-SAS is associated with major disease events such as starting biological therapy, IBD-related bowel resection, and IBD-related hospitalisation. Furthermore, response to treatment is reflected by a decrease in IBUS-SAS after three months.
Abstract
Background
Denmark has one of the highest occurrences of inflammatory bowel disease (IBD) in the world, with reported incidence rates of 7.2 and 6.2 in paediatric ulcerative colitis (pUC) ...and 10 and 9.4 per 105 for girls and boys in Crohn’s disease (pCD). Incidence rates in adult patients have been reported to be 9.1 and 18.6 per 105 for ulcerative colitis (UC) and Crohn’s disease (CD), respectively. We aimed to evaluate the incidence and initial disease presentation of newly diagnosed paediatric and adult IBD patients in the Hvidovre and Herlev Hospital uptake areas, covering approximately 1.050.000 inhabitants, corresponding to ~20% of the Danish population.
Methods
During a 2-year inclusion period, all incident paediatric (≤18 years of age, pIBD) and adult IBD patients residing in the uptake area at the time of diagnosis are included in a prospective, multicentre, population-based inception cohort (IBD Prognosis Study). The study was initiated on May 1st, 2021. Patients are prospectively followed with regular intestinal biopsies, stool-, serum-, and whole blood samples to analyze biomarkers, microbiome and genetic profiles at predefined time points. Demographics and disease-related characteristics were collected at diagnosis. Incidence was defined as the number of new IBD cases during May 1st – October 31st divided by the total inhabitants covered in included sites during the same period.
Results
A total of 125 IBD patients were included during the initial six months (table 1). For paediatric patients, the incidence rates were 8.2 and 16.4 per 105 for pUC and pCD. Adult incidence rates were 19.4, 17.0, and 2.4 per 105 for UC, CD and IBD-unclassified (IBD-U), respectively. At diagnosis, extraintestinal manifestations were present in 15% of paediatric and 36% of adult patients. In paediatric patients, 20% and 0% of pUC and pCD had moderate to severe disease activity at diagnosis, based on PUCAI- and PCDAI scores. In adults, 33%, 50% and 50% of UC, CD and IBD-U patients had moderate to severe disease activity at disease onset based on SCCAI- and HBI scores. More extensive disease and increased faecal calprotectin were associated with more severe disease activity in adult UC. CRP correlated positively, while haemoglobin and albumin correlated negatively with UC disease extension.
Conclusion
The IBD incidence rates in paediatric and adult patients continuously increase in Denmark, thus constituting a substantial burden for the Danish health care system. A large proportion of patients presented with significant symptoms and future findings of this cohort will potentially bring us a better understanding of the heterogeneous course of IBD, including the differential need for, and response to, treatment.
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