Introduction

Immunomodulators and biologicals play an essential role in current IBD management, but are associated with increased risk of infections. In light of the growing number of treatment options, the benefit-risk balance of drugs is becoming increasingly important in clinical decision making. Post-marketing surveillance studies are pivotal to assess infection risk, yet mainly focus on severe infections. As a result, data on mild and moderate infections are scarce. However, mild and moderate infections take longer to clear in immunosuppressed patients, have been reported to be the most burdensome adverse drug reaction according to patients, and can negatively influence drug adherence.

Aims & Methods

Aim: To assess the incidence of all infections and identify risk factors for the development of infections in IBD patients.
Methods: We previously developed and validated a Patient-Reported Infections Questionnaire (PRIQ), with excellent diagnostic accuracy, covering 15 infection categories with a 3-month recall period. [1] The current prospective, multicentre, observational cohort study was performed between Jun, 1 2020 and Jul, 1 2021, enrolling consecutive IBD patients and using the PRIQ which was implemented in myIBDcoach, an established telemedicine platform. Infection severity was defined as mild (self-limiting or topical treatment), moderate (oral antibiotics, antivirals or antifungals) or severe (hospitalization or IV treatment). Incidence rates (IR) were calculated for all infections, stratified for severity and subtype. Multivariable logistic regression, adjusting for relevant confounders, was performed to identify risk factors for infections.

Results

In total, 629 IBD patients (n=346 CD, n=283 UC, 58.3% female, mean age at cohort entry 48.3 years [SD 14.8], mean disease duration 12.4 years [SD 10.8]) were included which completed 2391 PRIQs during 572 person-years (PY) of follow-up. This resulted in 990 reported infections, corresponding to IRs of 17.3, 11.8, 5.1, and 0.4 per 10PY for all, mild, moderate, and severe infections, respectively. Upper respiratory tract (IR 26.9/100PY) and urinary tract infections (IR 14.8/100PY) were the most commonly reported mild and moderate infections types, respectively (Table 1). Compared to patients without treatment, patients on immunosuppressive treatment more frequently experienced infections of any severity (mild vs. no treatment: IR ratio (IRR) 1.57 [95%CI 1.21-2.06] p<0.001, moderate vs. no treatment: IRR 1.42 [95%CI 1.20-1.69] p<0.001). On multivariable logistic regression, female sex (mild adjusted odds ratio [aOR] 1.96 [95%CI 1.38-2.79]; moderate aOR 1.71 [95%CI 1.15-2.54]), smoking status (mild aOR 1.66 [95%CI 1.15-2.41]; moderate aOR 1.86 [95%CI 1.05-3.28]), higher BMI (moderate aOR 1.05 [95%CI 1.02-2.00]), and more comorbidities (mild aOR 2.41 [95%CI 1.46-3.98]; moderate aOR 1.82 [95%CI 1.07-3.11]) were all significantly associated with the development of mild and moderate infections.

Conclusion

​In this real-world prospective study, immune suppressive therapy was associated with mild and moderate infections of any kind in IBD patients. These infections particularly occur in females, smokers, patients with higher BMI and more comorbidities. This information should be considered in personalised treatment selection.

References

[1] Rezazadeh Ardabili A, van Esser D, Wintjens D, et al. Development and validation of a remote monitoring tool for assessment of mild, moderate, and severe infections in Inflammatory Bowel Disease [published online ahead of print, 2023 Feb 16]. J Crohns Colitis. 2023;jjad023. doi:10.1093/ecco-jcc/jjad023

Disclosure

M.P. reports grants and non-financial support from Falk Pharma, grants from European commission, grants from ZonMw (Dutch national research fund), grants and non-financial support from Takeda, grants and non-financial support from Johnson and Johnson, grants and non-financial support from Abbvie, non-financial support from Ferring, non-financial support from Immunodiagnostics, non-financial support from MSD, all outside the submitted work. D.J. reports grants from Top Knowledge Institute (Well on Wheat), grants from Horizon 2020 DISCOvERIE, grants from NWO-CCC Partnership program (Carbokinetics), all outside the submitted work. Z.M. reports grants form MLDS, Niels Stensen Fellowship and Galapagos. A.v.B. has served as speaker, adviser and/or principal investigator for AbbVie, Arandal, Arena, Celgene, Ferring, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, TEVA, and received research grants from Pfizer, TEVA, Eurostars funding, ZonMw, all outside the submitted work.
The other authors have nothing to disclose relevant to this publication.

Introduction

Advances in medical management of Crohn’s disease (CD) have improved disease outcomes; however, significant gaps remain. Approximately 30% of patients experience primary non-response to induction therapy with biologics, and over 40% will experience loss of response. There is an urgent need to identify new adjunct therapies, including diet, that can alter the disease course. Dietary patterns characterized by increased intakes of fibre, fruit, vegetables and decreased intakes of processed foods, sugar and omega-6 fatty acids are linked to a reduced prevalence of CD and decreased biomarkers of intestinal and systemic inflammation; however, the effects upon mucosal inflammation are unknown in patients who have lost response to usual medical treatments. We developed the CD Therapeutic Dietary Intervention (CD-TDI), a novel dietary approach incorporating best practices and current evidence to determine its therapeutic potential in reducing inflammation in patients with active CD who have lost response to their usual therapies.

Aims & Methods

This 13-week RCT aimed to explore the efficacy of the CD-TDI compared with conventional management (CM) to reduce clinical disease activity (Harvey-Bradshaw Index (HBI) <5) and reduce mucosal inflammation, as measured by fecal calprotectin (FCP) in mild-to-moderately active luminal CD. Patients with mild to moderately active disease, determined by endoscopic, cross-sectional imaging or FCP >100 ug/g, on stable medical therapy 8 weeks prior to recruitment were eligible to participate (n=28). Upon randomization, the CD-TDI group (n=16) met virtually with a registered dietitian trained in the CD-TDI protocol weekly for 13 weeks. Participants assigned to CM (n=12) followed their habitual diet and met with the same registered dietitian as participants in the CD-TDI group at week 0 (W0) and week 13 (W13) to capture their dietary recall. FCP, HBI, and C-reactive protein (CRP) were assessed at W0 and W13.

Results

Twenty-eight participants (53% females, age 40 years (IQR:31-55); BMI 27 kg/m² (IQR:24-31)) were enrolled. Medical therapy did not differ between groups, with 54% (15/28) of participants receiving no drug therapy, 29% (8/28) 5-ASA monotherapy, 21% (6/28) biologic therapy, 11% (3/28) corticosteroids or 14% (4/28) immunomodulators. At W0, the FCP, HBI and CRP did not differ significantly between groups. In the CD-TDI group, FCP decreased significantly from 130 ug/g (IQR: 38-411) at W0 to 72 ug/g (IQR:3-153) at W13 (p= 0.01) and significantly differed between the CM group at W13 (p=0.04). In a sub-group analysis (n=11) of participants with FCP >250 ug/g at W0, at W13 the FCP decreased significantly from 632 ug/g (IQR: 356-1013) to 166 ug/g, (IQR:52-701) (p=0.06) within the CD-TDI group, however, this same trend was not observed in the CM (W0:337 ug/g IQR:324-1013 vs. W13:431 ug/g, IQR:46-1770, p=0.69). At W13, between-group differences in the CRP were found between the CD-TDI group (1.0 mg/L, IQR:0.6-2.4) and the CM group (4.5 mg/L, IQR:2.6-13.0) (p=0.002). The CD-TDI group experienced a significant decrease in HBI from W0 to W13 (W0: 3.0, IQR:1.0-5.3; W13: 2.0, IQR:0-3.0; p=0.05), however, this was not observed in the CM group.

Conclusion

At W13, the CD-TDI significantly decreased clinical and biochemical markers of inflammation in patients with mild-to-moderately active CD. This preliminary analysis suggests that CD-TDI could be a potential adjunct management strategy for reducing inflammation in CD. We hope to confirm these promising results with an adequately powered sample.

Clinical Case Summary

Introduction: Superior Mesenteric Vein (SMV) Thrombosis accounts for only 5% of all cases of intestinal ischemia. As opposed to acute mesenteric ischemia secondary to an arterial thrombus which has a more drastic presentation, SMV thrombus typically presents with non-specific signs and symptoms. Rarely, when venous congestion leads to bowel wall edema which can consequently head to intestinal obstruction.
Case presentation: We present the case of a 47-year-old male presenting with severe generalized abdominal pain and vomiting. Abdominal CT findings were suggestive of small bowel obstruction and venous thrombosis. CT angiogram confirmed SMV thrombus which was visualized as severe narrowing of the SMV at the midabdomen a few centimeters above the umbilicus, with consequent congestion and decreased contrast enhancement proximal to the area of narrowing. The patient was initially managed conservatively with anticoagulation, however the patient did not improve clinically. Since there were no signs of infarction or peritonitis that would warrant immediate surgical intervention, an alternative approach using endovascular technique was attempted. The patient underwent SMV stenting which subsequently relieved the obstruction.

References

1. Treatment of superior mesenteric and portal vein thrombosis with direct thrombolytic infusion via an operatively placed mesenteric catheter; https://pubmed.ncbi.nlm.nih.gov/1527918
2. A systematic review of the management of acute superior mesenteric vein thrombosis in adults https://mednexus.org/doi/full/10.1097/JP9.0000000000000051
3. Naffouj S, Al-Shammari M, Salgia R. Treatment of colonic varices with a superior mesenteric venous stent: a case report describing a unique approach. Gastroenterol Rep (Oxf). 2021 Feb 4;9(6):597-600. doi: 10.1093/gastro/goab003. PMID: 34925858; PMCID: PMC8677559
4. Vekariya P, Daneti D, Senthamizhselvan K, et al. (June 14, 2021) Acute Intestinal Obstruction as an Initial Presentation of Mesenteric Venous Thrombosis. Cureus 13(6): e15652. doi:10.7759/cureus.15652

Disclosure

None

Introduction

Chronic pancreatitis is a progressive inflammatory disease characterized by irreversible damage to the pancreas. The etiology of the disease is heterogenous and includes alcohol abuse, smoking, genetic risk factors and autoimmune diseases. Several clinical classification and severity scoring systems have been proposed, but none have been globally accepted or reached broad clinical use. Identifying patients at a higher risk of death is crucial for improving patient care and management.

Aims & Methods

This study aimed to develop a prediction model based on promoter hypermethylation of specific genes and clinical factors to differentiate patients with chronic pancreatitis who are at a higher risk of mortality. Clinical variables such as age, sex, smoking status, alcohol consumption, exocrine insufficiency, and endocrine insufficiency, as well as the methylation status of 16 genes, were analyzed using a backward stepwise Cox regression model. The methylation status was determined by a specialized bisulfite based PCR technique. The final model's performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), and used to determine a risk score for each patients. The “cutpt” package in Stata was used to determine an optimal cut-off, in order to stratify patients into low and high-risk groups. Kaplan-Meier survival curves, and cox regression, and AUC were used to determine the accuracy of the risk groups.

Results

Ninety-seven patients with chronic pancreatitis were included in the study. The final prediction model included age, sex, exocrine insufficiency, endocrine insufficiency, and the methylation status of 5 genes: SFRP2, HIC1, MLH1, RASSF1A, and CDKN2B. The AUC of the model was 0.84, indicating high reliability. The model was superior to a model including only clinical variables (AUC = 0.76), indicating added value of the methylation markers. The optimal cut-off value for the risk score was 7.76. According to this, 67 patients were in the low-risk group, and 30 in the high-risk group. The 5-year survival in the high-risk group was 53% compared to 94% in the low-risk group. Being in the high-risk group was significantly associated with an increased HR of death of 10.2 (95% CI; 4.9-21.1), demonstrating the model's strong prognostic value.

Conclusion

The developed prediction model, which combines clinical factors and gene promoter hypermethylation status, could be a valuable tool for identifying patients with chronic pancreatitis who are at a higher risk of death. This study serves as proof-of-concept of the unexplored potential of methylation analysis in cell-free DNA in chronic pancreatitis. This model can potentially enhance patient care by enabling targeted interventions and monitoring for high-risk individuals, ultimately improving their prognosis and quality of life.

Disclosure

S.D.H., P.H.M., O.T.-U., and H.B.K. declare that they have a patent on a diagnostic panel including the promoter hypermethylation status of 8 genes. Application No. 16161073.8 – 1403 Pancreatic Cancer methylation Markers (18.03.2016)

Clinical Case Summary

A 74-year-old, female patient was referred to the study center for pancreatic cysts. Magnetic resonance imaging revealed multiple pancreatic cysts up to 15 mm in size distributed from the pancreatic head to the pancreatic tail and enlargement of the main pancreatic duct diameter to 8 mm. T1- and T2-weighted imaging demonstrated showed a 10 mm mass with iso-intensityin the main pancreatic duct in the pancreatic body with diffusion restriction on diffusion-weighted imaging. Endoscopic ultrasonography also demonstrated a mass located in the main pancreatic duct in the pancreatic body, but determining whether the tumor was located in the pancreatic duct or was an extension of the intraparenchymal lesion into the main pancreatic duct was difficult. On contrast-enhanced abdominal computed tomography, the mass was difficult to identify as a lesion because it showed the same contrast as the surrounding pancreatic parenchyma. Endoscopic retrograde choangiopancreatography revealed enlargement of the duodenal papillary entrance, mucus discharge, and a mass-like, translucent image with an irregular surface in the main pancreatic duct in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration led to the diagnosis of adenocarcinoma, and a distal pancreatectomy was performed on the assumption that the lesion derived from IPMN. Pathological analysis led to the diagnosis of IOPN consisting of papillary cells with an eosinophilic cytoplasm, positive immunostaining for MUC5AC and MUC6, and partially positive staining for MUC1 and HepPar-1. The mass was determined to be within the pancreatic parenchyma by comparing a resection specimen with preoperative images. Fusion gene analysis revealed the presence of ATP1B1-PRKACA, confirming the diagnosis of IOPN.
It is important always to bear in mind the possibility of IOPN if pancreatic cysts are observed. IOPN is relatively rare, and more cases are needed for a better understanding of this disease.

References

Aatur D. Singhi, Laura D.Wood, Emma Parks, Michael S.Torbenson, Matthaus Felsenstein. Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct : Gastroenterology. 2020 Feb ; 158(3) : 573-582.
Eriko Ikeda. Histological Classification of Intraductal Papillary Mucinous Neoplasms of the Pancreas : Journal of Biliary Tract & Pancreas. 2020 ; 41(1) : 27-31

Introduction

The incidence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are notably higher in individuals diagnosed with type 2 diabetes mellitus (T2DM). However, studies evaluating the progression of MASLD in patients with T2DM and normal serum aminotransferase (ALT) levels are limited.

Aims & Methods

This 5-year prospective cohort study aimed to evaluate the progression of MASLD in T2DM patients with normal ALT. People with type 2 diabetes who had MASLD (defined by controlled attenuation parameter (CAP) >250 dB/min) and ALT levels that stayed normal (defined by ALT ≤40 IU/L for at least two occasions spanning at least six months) at Rajavithi Hospital, Bangkok, from November 2016 to 2017 were included. We excluded patients with viral hepatitis and alcohol consumption exceeding moderate levels. Transient elastography (TE) and CAP measurements were performed at baseline and ≥5 years of follow-up. The cutoffs to define significant and advanced fibrosis were TE >8 kPa and TE >12 kPa, respectively. All patients were instructed to reduce their weight and abstain from herbal remedies; medications for comorbidities were prescribed without limitations, subject to the physician's assessment. (most patients were under endocrinologist care.)

Results

The study included 84 patients, 57% of whom were female and had a mean age of 58.5 years. Of these, 62% were obese, with a mean BMI of 28.6 kg/m2. At baseline, the median TE was 6.92±3.35 kPa; 57 (68%) had no significant fibrosis, 22 (26%) had significant fibrosis, and 5 (6%) had advanced fibrosis, and after a 5-year follow-up, the median TE was 6.54±3.57 kPa; 69 (82%) had no significant fibrosis, 15 (18%) had significant fibrosis, and 2 (2%) had advanced fibrosis. During the follow-up, fibrosis decreased in 45 (54%), remained stable in 6 (7%), and increased in 33 (39%) patients, while a small proportion of patients experienced changes in the stages of fibrosis: 1.2% progressed from significant to advanced fibrosis; 17.4% regressed from advanced to significant fibrosis or transitioned from significant to no fibrosis; 12.8% remained stable with significant and advanced fibrosis; and the majority (66.3%) remained without significant fibrosis. A significant factor associated with fibrosis progression was alcohol consumption (p=0.013), while the use of angiotensin receptor blockers (p=0.042) was associated with fibrosis regression. Significant factors associated with steatosis progression included high baseline BMI (p=0.013), an increase in BMI ≥ 5% (p=0.04), high fasting plasma glucose, and LDL cholesterol levels, while a decrease in BMI ≥ 5% (p=0.002) the use of calcium channel blockers (p=0.038) and coffee consumption >3 cups per day (p=0.031) were associated with steatosis regression. ALT elevation during the follow-up occurred in a small proportion of patients, and it was not significantly associated with fibrosis or steatosis progression.

Conclusion

The majority of MASLD patients with T2DM and normal ALT maintained a relatively stable liver disease during 5 years of follow-up. Obesity, weight gain, alcohol consumption, and inadequate metabolic control were all associated with the progression of MASLD, whereas weight loss, coffee consumption, angiotensin receptor blockers, and calcium channel blockers were all associated with the improvement of MASLD.

Disclosure

I have nothing to disclose