Introduction

We lack reliable biomarkers to identify patients with inflammatory bowel disease (IBD) at a greater risk of severe disease course. With emerging evidence that early step-down treatment in severe patients leads to better disease outcomes, alongside worries about overtreatment of mild patients, there is a clinical need to identify such biomarkers.

Aims & Methods

In this study, we explore genetic variants associated with severe disease course for ulcerative colitis (UC) in a nationwide cohort of 4491 patients from Denmark.
We genotyped 4491 patients with UC (4153 from Danish birth blood spot archive; 338 from NorDIBD regional cohort), linking them with registry data capturing medical interactions throughout patients’ lifetimes. Patients who required 2+ IBD-related hospitalizations, 2+ IBD-related major surgeries, 1 IBD-related hospitalization and 1 IBD-related major surgery or use of systemic corticosteroids (≥5000 mg) in the first 3 years of diagnosis were defined as severe. We conducted a genome-wide association study comparing severe patients (N=1203) to those with a less severe disease course (N=3288).

Results

The GWAS identified a signal within the HLA region, with the HLA-DRB1*01:03 allele driving the association (OR=3.30 [2.23-4.87], P=2.08×10^-9, UC carriage rate=2.8%). We did not observe an association with CD severity in a similarly ascertained cohort of 3688 individuals (P=0.79).
Remarkably, carriage of DRB1*01:03 was associated with a seven-fold increase of major surgery risk (OR=7.05 [4.55-10.91], P=2.31×10^-16) (Table 1). At the point of diagnosis, carriage of DRB1*01:03 was associated with higher CRP levels (β=2.68, P=1.70×10^-7), f-cal levels (β=1.92, P=4.42×10^-3) and a higher rate of hospitalization at diagnosis (OR=1.64, P=0.014), suggesting that the effect on severity is not limited to disease progression.

Conclusion

In this large-scale, unselected nationwide cohort study, we find that HLA-DRB1*01:03 is a biomarker of UC disease course that is associated with a more severe presentation at diagnosis, as well as higher subsequent risk of surgery and hospitalization. Demonstrating the association at a genome-wide significance level for the first time, this study revitalizes findings from smaller studies at the beginning of the genetic era which explicitly recruited severe patients and made estimating carriage effects difficult.
While HLA-DRB1*01:03 is a low-frequency allele, patients who carry it are at a much higher risk of severe UC. As the cost of typing a single HLA allele is low (under 50 EUR) and several pharmacogenetic variants are beginning to be tested at diagnosis, we argue that it is a valuable addition to the arsenal of personalized healthcare tools.

Introduction

Ozanimod (OZA) is approved for the treatment of moderately to severely active ulcerative colitis (UC). Approximately 30% of patients (pts) were clinical nonresponders after 10 wk of OZA treatment in the phase 3 True North (TN) study (NCT02435992), but ~50% of these OZA nonresponders achieved symptomatic response after 5–10 wk of additional OZA treatment during the open-label extension (OLE) study (NCT02531126).

Aims & Methods

This analysis evaluated the impact of TN baseline (BL) endoscopic disease activity on the durability of OZA response in Week (W) 10 OZA clinical nonresponders after extended induction during the OLE up to 4 years (OLE W190). Pts were categorized by BL Mayo endoscopy subscore (MES) as moderate (MES=2) or severe (MES=3). Symptomatic, clinical, and mucosal efficacy were assessed through OLE W190 using observed case (OC) and nonresponder imputation (NRI) analyses.

Results

Of the 226 W10 OZA clinical nonresponders who entered the OLE, 67 had moderate and 159 had severe endoscopic disease at BL. Pt characteristics were generally similar between groups, but more pts with severe vs moderate endoscopic activity had prior immunomodulator (52.8% vs 34.3%), anti–tumor necrosis factor (TNF; 45.9% vs 25.4%), or non–anti-TNF biologic (36.5% vs 19.4%) exposure. Some symptomatic response was observed in OZA W10 clinical nonresponders from BL to W10/OLE entry, which was greater in pts with moderate disease and further improved with extended OZA exposure by OLE W5 (moderate: 36.9% at W10 and 66.2% by OLE W5; severe: 23.8% at W10 and 47.9% by OLE W5). Similar patterns were observed with symptomatic remission but overall rates were lower (moderate: 6.2% at W10 and 26.2% by OLE W5; severe: 1.3% at W10 and 13.0% by OLE W5). Symptomatic response and remission rates after OLE W5 were generally similar in moderate and severe endoscopic activity groups, and rates were maintained throughout the OLE. Likewise, clinical and mucosal efficacy were durable and rates were generally similar between subgroups through OLE W190 (Table). Notably, higher endoscopic improvement rates were achieved through OLE W190 in pts with BL moderate endoscopic activity despite ~50% of these pts progressing to severe by TN W10. Similar data trends were observed in the NRI analysis.

Conclusion

Delayed response to OZA was observed in pts who did not achieve clinical response after 10 wk of OZA therapy, regardless of BL endoscopic activity. W10 nonresponders with moderate endoscopic activity responded faster with additional OZA exposure, whereas those with severe endoscopic activity needed longer exposure to OZA to achieve similar efficacy rates that were durable with continuous OZA exposure. These results suggest that some pts may require a longer induction on OZA but ultimately maintain durable OZA response.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Traci Stuve, MA, and Julie Ko, PharmD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.
PI: received lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, Sandoz, Sapphire Medical, Shire, Takeda, Tillotts, and Warner Chilcott; received financial support for research from Celltrion, MSD, Pfizer, and Takeda; received advisory fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Hospira, Janssen, MSD, Pfizer, Pharmacosmos, Prometheus Biosciences, Roche, Samsung Bioepis, Sandoz, Takeda, TopiVert, VH2, Vifor, and Warner Chilcott.
RKC: consulted for AbbVie, Bristol Myers Squibb, Fresenius Kabi, Fzata, Janssen, Magellan Health, Option Care, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, Sebela, and Takeda; scientific co-director of the CorEvitas Registry and executive committee member of the IBD Education Group; received financial support for research from Janssen.
TR: served on advisory boards for AbbVie, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Genentech, Intercept Health, Janssen, Merck, Pfizer, and Takeda; speaker for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda.
AS: declares no competing financial or nonfinancial interests.
PH: consultant and speaker for Boston Scientific, FujiFilm, MedWork, and Viatris.
SC: consultant for AbbVie, Bristol Myers Squibb, Janssen, and Pfizer.
ST, HW, MTO, and AJ: employees and/or shareholders of Bristol Myers Squibb.
DCW: received research funding from AbbVie, Amgen, Arena/Pfizer, Celgene/Bristol Myers Squibb, Genentech, and Janssen; lectured for AbbVie, Bristol Myers Squibb, Janssen, and Takeda; consulted for AbbVie, Arena/Pfizer, Celgene/Bristol Myers Squibb, Eli Lilly, Janssen, and Takeda.

Introduction

Celiac disease (CD) is an immune-mediated systemic disease, triggered by the ingestion of gluten, which only develops in genetically predisposed individuals. The main characteristics of the disease are the gluten-dependent small intestinal mucosal lesion, villous atrophy and crypt hyperplasia, and the production of the specific serum autoantibodies. The gold standard for diagnosis has been based on the biopsy findings. In 2012, new ESPGHAN diagnostic guidelines removed the necessity of duodenal biopsy in symptomatic children showing a high serum transglutaminase 2 titers (TG2-IgA) together with the presence of endomysial antibodies (EmA) and HLA DQ2 and/or DQ8.

Aims & Methods

Our aim was to assess the clinical outcome of the diagnostic change in children by comparing new serology-based diagnosed patients to the biopsy-based ones.
We conducted a retrospective analysis of data collected from the medical charts of the patients diagnosed during a four-year period, from 2010 to 2014, being a time overlapping the guideline change. From a total of 63 patients, 30 were biopsy-diagnosed and 33 diagnoses were based on serology only. Clinical data and laboratory parameters were compared between the groups at diagnosis and at follow-ups at 1 year, 2 years and at their latest follow-up visit during the gluten-free diet (GFD) treatment, median time 8.7 years for the serology-based group and 10 years for the biopsy-based group.

Results

Our results show clear improvement upon GFD in gastrointestinal symptoms in both groups. However, there was a general trend for better treatment outcomes in the biopsy-based group compared to the serology-based group at 1 and 2 years of follow-up. Body mass index Z score was in the biopsy group at baseline -1.5, at 1 year on GFD -0.2 and at 2 years -0.2. The corresponding results in the serology group was -1.51, -0.8 (p=0-056), and -1.35 (p=0.023). Anemia was observed in the serology group at one year as frequently (25%) as at baseline (26.7%) but in the biopsy group improvement from baseline was seen, 27.4% to 7.1 % of patients. At two years, anemia was present in 16.6% of patients. Ferritin values were significantly lower in the serology group at one year (27.5 µg/L vs 59, p=0.040) but not anymore at 2 years. After two years on GFD both TG2-IgA and EmA were often still above the cut-off for positivity in both diagnostic groups (serology group 58.3 % and 50% respectively and in the biopsy group somewhat less, 50% and 28.6% respectively). At long term, no anemia was present anymore. However, 4 children from serology group and 8 from the biopsy group showed antibodies above cut-off even after 8.7 and 10 years of treatment, respectively. Upon long-term follow-up the patients from the biopsy-proven group seemed to be more compliant with the follow-up visits and more adherent to the gluten-free diet.

Conclusion

Both clinical and laboratory results show slow recovery upon gluten-free diet. High percentage of autoantibody positivity still at 2 years on GFD indicates substantial amounts of gluten in the diet. Biopsy-proven patients seemed to have a faster recovery than the serology-diagnosed. Serological diagnosis also appears to negatively influence the adherence and compliance to treatment and follow-up. Novel (drug/vaccine) treatments adjunctive to GFD are an unmet need also in children. Duodenal mucosal recovery results on long-term GFD are warranted.

Introduction

Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease. Diagnosis can be made by simple tests available in primary care setting, particularly abdominal ultrasound and FIB4 index. More accurate assessment of fibrosis and specialized follow-up may be necessary to prevent progression to cirrhosis or hepatocellular carcinoma.

Aims & Methods

The aim of our study was to define the prevalence of hepatic steatosis and MASLD in a hospital cohort, to analyze the factors associated with MASLD in our population, and to select patients who need more accurate fibrosis assessment and closer follow up. A prospective descriptive and analytical study was conducted over a 7 months period. After consenting to participate to the study, patients consulting our department for gastroenterological or proctological complaints were included, excluding those followed up for known chronic liver disease. Epidemiologic and clinical data were collected, followed by abdominal ultrasonography. We first divided our population into 2 groups according to the presence of steatosis on ultrasound. FIB4 index were then calculated for patients with steatosis. Statistical analysis was performed with IBM SPSS Statistics 20.0 software.

Results

Among the 450 patients included, the prevalence of hepatic steatosis was 24.88 %. The mean age was 50.6 (16 - 98 years). Older age (p = 0.005), obesity (p = 0.02) and diabetes (p < 0.001) were significantly associated with the presence of steatosis. In the steatotic population, 37.5% were diabetic (88.09% of type 2 diabetes), and 20.5% hypertensive. All these patients were overweight or obese, with a mean BMI of 29.01 kg/m² and a mean waist circumference of 92.7 cm. Seven point forteen percent were drinking alcohol, with an average intake of 25 g/week. Twenty-two patients (29.34%) were found to have a Fib4 > 1.3. Comparing these two steatotic subgroups, we found a significant difference in diabetes and obesity, which were significantly more prevalent in the Fib4>1.3 group (p<0.001 and p=0.02, respectively).

Conclusion

Our study confirms the high prevalence of hepatic steatosis, especially MASLD, which becomes a major public health problem. Advanced age, diabetes and obesity were the main risk factors associated with MASLD in our study. These data highlight the importance of systematic screening for fibrosis in these populations, as well as specialized follow-up.

Introduction

The etiology and pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC) are complex and the mechanisms that lead to the development of these diseases remain unclear. Extracellular vesicles (EVs) are small particles covered with a cell membrane, originating from the emitting cell, excreted into the extracellular medium, and subsequently captured by receptor cells. EVs have a role in multiple diseases and they could also have a function in IBD pathogenesis. Therefore, the analysis of EVs isolated from the serum of newly diagnosed IBD patients (before starting any treatment) may represent an appropriate experimental approach to elucidate their role in IBD pathogenesis.

Aims & Methods

We aimed to evaluate EVs’ composition and potential effects in the pathogenesis of IBD. To assay this, EVs were isolated by size exclusion chromatography from the 500 µl of serum from 100 patients with IBD (50 patients with CD and 50 patients with UC) recently diagnosed and 50 healthy controls (HC). Then, the protein loaded in the EVs was characterized by proteomics and their size and concentration in serum by Nanoparticle tracking analysis (NTA). The biological function of EVs and alterations in signaling pathways related to IBD were determined using Ingenuity Pathways Analysis (IPA) to analyze the OMICs results.

Results

A total of 1,100 proteins have been identified, of which 105 proteins were differentially expressed by patients with CD versus HC, 111 proteins by patients with UC versus HC, and 32 proteins by patients with UC versus CD. IPA analysis revealed that proteins carried in EVs are involved in the dysregulation of immune pathways such as the acute phase response, LXR/RXR activation pathway, and the complement pathway. These pathways were regulated differentially in IBD patients compared with HC, but also when the CU group was compared with the CD group being upregulated nuclear receptors signaling and cytotoxicity pathways.

Conclusion

EVs carry proteins that can be involved in the dysregulation of the immune system in IBD; this effect would be different in UC and CD since their EVs show a differential profile. Consequently, EVs may play role in IBD pathogenesis and source of strong biomarkers candidates for diagnosis in UC and CD. Further studies on their specific function during IBD are warranted.