Introduction

​​​​​Concerns regarding colorectal cancer in short bowel syndrome (SBS) patients receiving teduglutide (TED) treatment have led to the recommendation of colonoscopy for screening and surveillance.^1,2 While there are reports of new small bowel polyps in TED patients, data on small bowel cancer risk and surveillance are lacking.^3,4 This study aims to evaluate the feasibility and effectiveness of using double-balloon enteroscopy (DBE) for surveillance in SBS patients undergoing TED treatment.

Aims & Methods

Data from patients with SBS in TED treatment who underwent DBE within a year of starting TED at a tertiary referral center for enteroscopy between December 2019 and October 2023 were collected. The primary endpoints were technical success, adverse events, and total enteroscopy rates. Secondary endpoints included the incidence of small bowel polyps and residual small bowel length measurement.

Results

Nine patients (7 female, median age 65.5, IQR 58-79) with SBS (22% type 1, 55.6% type 2, 22.2% type 3-SBS) underwent DBE (10 anterograde, 2 retrograde) under procedural sedation. Crohn’s disease (33.3%) and post-surgical complications (33.3%) were the most frequent causes of SBS. The median interval from TED prescription to DBE surveillance was 9.1 months (IQR 3.2-32.9). The median depth of maximal insertion was 85 cm (IQR 50-187). No adverse events occurred during all the procedures. The total enteroscopy rate was 75% (80% [8/10] of anterograde DBEs, 50% [1/2] of retrograde DBEs). Panenteric DBE allowed the estimation of small bowel residual length in all cases (2/2) where this important clinical information was unknown and revealed a different residual small bowel length compared to surgery in 44% of patients. No small bowel malignancies were detected during the study period.

Conclusion

DBE surveillance for small bowel malignancy in SBS patients undergoing TED treatment is feasible and effective. Total enteroscopy can be frequently achieved with a single endoscopy in these patients, allowing easy oncologic surveillance.

References

1. Revestive (teduglutide). Summary of product characteristics. Takeda; August 2022. Accessed 23 March 2024. https://www. medicines.org.uk/emc/product/3382/smpc
2. Pironi L, Allard JP, Joly F, et al. Use of teduglutide in adults with short bowel syndrome-associated intestinal failure. Nutr Clin Pract 2024;39:141-153.
3. Pevny S, Pape UF, Elezkurtaj S, et al. De Novo Development of Distal Jejunal and Duodenal Adenomas After 41 Months of Teduglutide Treatment in a Patient With Short-Bowel Syndrome: A Case Report. JPEN J Parenter Enteral Nutr 2021;45:652-656.
4. Ukleja A, Alkhairi B, Bejarano P, et al. De Novo Development of Hamartomatous Duodenal Polyps in a Patient With Short Bowel Syndrome During Teduglutide Therapy: A Case Report. JPEN J Parenter Enteral Nutr 2018;42:658-660.

Introduction

With the implementation of the new nomenclature on steatotic liver disease (SLD), three main subgroups consisting of metabolic dysfunction-associated liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD) have been defined. However, the risk of SLD for all-cause mortality and adverse outcomes as well as the different risks between MASLD, MetALD, and ALD needs further clarification.

Aims & Methods

Data from 13,599 participants without cancer of the population-based Gutenberg Health Study (baseline enrollment between 2007 and 2012) were cross-sectionally and prospectively analysed. The fatty liver index (FLI) with a score of ≥60 was used to define SLD. The subgroups of SLD (MASLD, MetALD, and ALD) were defined according to the new nomenclature based on five cardiometabolic criteria and alcohol consumption. The fibrosis-4 score (FIB-4) was calculated to determine patients at risk of fibrosis (≥1.3). All-cause mortality (10-year follow-up) and several adverse outcomes (hepatic decompensation, major adverse cardiac events (MACE), extrahepatic cancer) were analysed and compared across the subgroups of SLD. Cox regression models were used to estimate adjusted hazard ratios (aHR) and their 95% confidence intervals (CIs). Adjustments were made for age, sex, socioeconomic status, education, and smoking.

Results

The overall prevalence of SLD was 37.3% (n=5,074), whereas the prevalence of MASLD, MetALD, and ALD were 30.5% (n=4,154), 5.3% (n=717) and 1.5% (n=202), respectively. Almost half of the population were women (48.9%, n=6,644), and the mean age was 54.3 (±11.0) years. An elevated FIB-4 ≥1.3 was present in 20.2% (n=1,021) with SLD compared to 13.9% (n=1,184) without SLD (p<0.0001). The cumulative incidence of all-cause mortality was higher in SLD and all its subgroups MASLD, MetALD, and ALD compared to no SLD (p<0.0001). Stratification by FIB-4 ≥1.3 revealed a higher risk of all-cause mortality across all investigated SLD subgroups compared to FIB-4 <1.3 (p<0.0001). Each subgroup of SLD was associated with a higher risk of all-cause mortality: MASLD (aHR 1.6, 95% CI 1.4-1.9, p<0.0001), MetALD (aHR 1.6, 95% CI 1.3-2.1, p=0.00024) and ALD (aHR 1.6 95% CI 1.0-2.5, p=0.033). The risk of adverse outcomes was increased in MASLD (hepatic decompensation: aHR 1.2, 95% CI 1.0-1.5, p=0.0045; MACE: aHR 1.5, 95% CI 1.2-1.8, p<0.0001; extrahepatic cancer: aHR 1.2, 95% CI 1.1-1.4, p=0.0086), whereas no differences were seen for MetALD and ALD.

Conclusion

The prevalence of SLD and especially MASLD is high in the general population. Patients with SLD and any of its three main subgroups show a higher risk of all-cause mortality, whereas the risk for adverse outcomes is particularly increased in those with MASLD. These results highlight the importance of screening for SLD and related risk factors to improve outcomes.

Clinical Case Summary

Defects in the PERCC1 gene have recently been identified as a cause of congenital diarrhoea and enteropathy with intestinal failure (IF) resulting from congenital enteroendocrine cell maldevelopment/dysfunction^1,2. Patients present within the first few weeks of life with watery diarrhoea and hyponatraemia and require long term parenteral nutrition (PN). No effective pharmacological treatments are available in these patients and health-care related quality of life is compromised by home PN and symptoms of malabsorptive diarrhoea. Here we report the first known functional characterization of enteric hormones in a 14-year-old patient (previously described as Patient A²) with IF due to a homozygous stop-gain point mutation in PERCC1. We observed widespread enteroendocrine hormone deficiency; specifically, negligible or undetectable fasting and post-prandial levels of gastrin, pancreatic polypeptide, ghrelin, PYY(1-36), PYY(3-36) and glucagon-like peptide-2 (GLP-2). At baseline, our patient was hyperphagic, passing 5-7 watery, steatorrhoeal stools per day and reliant on PN to provide 32% of his calculated weekly calorie requirement. Hormone replacement therapy with the GLP-2 analogue teduglutide resulted in prompt cessation of PN, resolution of hyperphagia, markedly improved weight gain and 10-fold reduction in fat malabsorption.
We report successful achievement of enteral autonomy in a patient with PERCC1-associated enteropathy and IF using the GLP-2 analogue teduglutide. These results have important implications for the pathogenesis and treatment of IF in patients with PERCC1-associated enteropathy and have therapeutic applicability to patients with enteroendocrine hormone deficiency from other congenital or acquired causes.

Article in press, Annals of Internal Medicine

References

1. Oz-Levi D, Olender T, Bar-Joseph I, et al. Noncoding deletions reveal a gene that is critical for intestinal function. Nature 2019;571:107-11.
2. Marek-Yagel D, Stenke E, Pode-Shakked B, et al. Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy. Hum Genet 2023;142:691-6.

Introduction

Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking agent, was approved in Europe and the USA for the treatment of moderate-to-severe Crohn’s disease (CD) in 2014. Real-world evidence is essential for understanding the effectiveness and benefit–risk profile of VDZ for CD outside clinical trial settings. A systematic literature review and meta-analysis published in 2018 confirmed the real-world effectiveness and positive benefit–risk profile of VDZ treatment for up to 12 months in patients with inflammatory bowel disease.¹ However, there are limited real-world evidence on the long-term (> 12 months) effectiveness of VDZ in patients with CD.

Aims & Methods

A systematic literature review was performed using MEDLINE, MEDLINE In-Process, Embase, Cochrane Library, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform to identify relevant studies published from May 2014 to July 2022. In addition, if the congress abstracts were not indexed in Embase, key congresses from 2015 to July 2022 were hand-searched. Data from adults (aged ≥ 18 years) with CD treated with VDZ in a real-world setting were extracted for meta-analysis. Depending on data availability, the analysis was conducted using the DerSimonian-Laird random-effects model to obtain weighted mean rates (percentage of patients) and the corresponding 95% confidence interval (CI) for each outcome of interest, as per the 2018 meta-analysis.¹ The aims of the current analysis were to evaluate the rates of treatment persistence at 12 and 24 months and mucosal healing at 12 months (overall and stratified by biologic-naïve versus biologic-experienced patients) to address the paucity of long-term data available on these outcomes.

Results

Overall, data from 78 studies of 30 158 patients with CD had at least one outcome of interest for analysis. Using the reported number of patients as the weight, the baseline weighted mean age was 39.3 years (standard error [SE] 2.7; 15 studies), weighted mean disease duration was 12.5 years (SE 0.5; 8 studies), weighted mean CD activity index score was 177 (SE 4.3; 3 studies), and weighted mean Harvey-Bradshaw index score was 7.9 (SE 0.7; 5 studies). In the 32 and 13 studies that assessed treatment persistence at 12 and 24 months, respectively, the rates of treatment persistence were 62.8% (95% CI 56.6–68.9) and 54.9% (95% CI 44.3–65.4), and were higher in biologic-naïve patients than biologic-experienced patients at both time points (Table). The rate of mucosal healing at 12 months (assessed in 20 studies) was 38.4% (95% CI 30.2–46.5) and was higher in biologic-naïve patients than biologic-experienced patients at both time points (Table).

Conclusion

This meta-analysis of real-world studies of VDZ demonstrated high rates of robust, long-term treatment persistence and mucosal healing in patients with CD, particularly in biologic-naïve versus biologic-experienced patients. Over a third of patients achieved mucosal healing at 12 months, confirming the effectiveness of VDZ for achieving this important treatment outcome.

References

1. Schreiber S et al. J Gastroenterol 2018;53:1048–64.

Disclosure

This study was funded by Takeda Pharmaceuticals International AG. Medical writing services were provided by Matthew Reynolds, of Oxford PharmaGenesis, and funded by Takeda Pharmaceuticals International AG.
SS: Personal fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, ProventionBio, Takeda and Theravance Biopharma.
PB: Employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
RJB: Employee of PHMR Ltd., who received funding for this study from Takeda Pharmaceuticals International AG.
MN: Employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
SW: Employee and stockholder of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
AA Advisory board/lecture fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda.