Introduction

Irritable bowel syndrome (IBS) is a bothersome condition with long term pain and bowel symptoms and the most common cause of referral to gastroenterologists in the United Kingdom. Despite this, IBS is poorly understood as a clinical entity. Furthermore, IBS has numerous comorbidities but the full spectrum of these and how they relate to IBS has not been studied.

Aims & Methods

Using clustering analysis on the UK Biobank dataset, an adult cohort (age > 40 years), we aimed to define the top co-morbidities associated with IBS and develop a machine learning model to predict IBS. Co-morbidities in patients based on ICD-10 Summary Diagnosis codes 2 years prior to and 2 years following diagnosis with IBS were assessed and clusters defined. These were compared with a control group of non-IBS patients. Several machine learning algorithms (K-Means, Linear Discriminant Analysis, Gaussian Mixture Models) were compared for accuracy.

Results

Amongst 18000 total adults (aged over 40), 8168 patients coded for IBS, 75% of whom were female. The top ten comorbidities (Table 1) found in IBS patients included diverticular disease, hypertension, hernia, haemorrhoids, osteoarthritis, asthma, gastro-oesophageal reflux disease without oesophagitis, history of psychoactive substance abuse, hypercholesterolaemia, and cholelithiasis. K-Means achieved the highest accuracy (83%) for predicting IBS based on the co-morbidity profile.

Conclusion

Most clusters identified contained obesity, hypercholesterolemia, and hypertension, indicating a possible link with metabolic syndrome. Asthma and allergies suggest a possible cohort of IBS patients with atopy. Further research is needed to establish these links. In clinical practice, this could help both in predicting development of IBS, and also identify the cohorts of IBS on which certain therapies are more likely to work.

References

Drossman, D. A., Camilleri, M., Mayer, E. A., & Whitehead, W. E. (2002). AGA technical review on irritable bowel syndrome. Gastroenterology, 123(6), 2108-2131. doi:10.1053/gast.2002.37095
Snyder, N. (2023, 10 Feb 2023). Irritable bowel syndrome. BMJ Best Practice. Retrieved from https://bestpractice.bmj.com/topics/en-gb/122
Staller, K., Olén, O., Söderling, J., Roelstraete, B., Törnblom, H., Khalili, H., . . . Ludvigsson, J. F. (2021). Diagnostic yield of endoscopy in irritable bowel syndrome: A nationwide prevalence study 1987-2016. Eur J Intern Med, 94, 85-92. doi:10.1016/j.ejim.2021.08.001

Introduction

The randomized controlled OPTIC trial reported that optimised mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at one year in ulcerative colitis (UC) patients failing 5-aminosalicylates after receiving induction treatment with corticosteroids.

Aims & Methods

We aimed to assess cost-effectiveness and cost-utility of therapeutic drug monitoring (TDM)-guided mercaptopurine treatment in UC. Data were collected during the OPTIC trial to perform a health economic evaluation for mercaptopurine treatment versus placebo in UC patients. The economic evaluation was performed from a health care and societal perspective using a cost-effectiveness and cost-utility analysis with a time horizon of one year. Volumes and costs of in-hospital care, out-of-hospital care, out-of-pocket expenses and productivity loss were assessed. Main outcomes were the costs per patient who achieved combined corticosteroid-free clinical remission and endoscopic improvement at one year and the costs per quality-adjusted life-year (QALY).

Results

In total, 59 patients were randomized to the intervention (n = 29) and control (n = 30) group. Patients on mercaptopurine treatment showed a non-significant gain in QALYs of 0.047 (-0.024 to 0.117) (P=0.184) corrected for baseline health utility. Non-significant differences in costs were €63 (-€1267 to €1434; P=0.927) in favour of placebo from a health care perspective and -€742 (-€3683 to €2016; P=0.644) in favour of mercaptopurine from a societal perspective, including patients’ out-of-pocket expenses and employers’ productivity loss. The probability of optimised mercaptopurine treatment being cost-effective was 0.80 at a willingness to pay per additional QALY of €20,000.

Conclusion

Optimised mercaptopurine treatment in UC patients failing 5-aminosalicylates is a cost-effective strategy from a societal perspective.

References

1. de Boer NKH, Peyrin-Biroulet L, Jharap B, et al. Thiopurines in inflammatory bowel disease: new findings and perspectives. J Crohns Colitis 2018;12:610–20.
2. Löwenberg, M., Volkers, A., van Gennep, S., Mookhoek, A., Montazeri, N., Clasquin, E., Duijvestein, M., van Bodegraven, A., Rietdijk, S., Jansen, J., van Asseldonk, D., van der Zanden, E., Dijkgraaf, M., West, R., de Boer, N., & D'Haens, G. (2023). Mercaptopurine for the Treatment of Ulcerative Colitis: A Randomized Placebo-Controlled Trial. Journal of Crohn's & Colitis, 17(7), 1055–1065.

Disclosure

NA

Introduction

Biliary stenting by endoscopic retrograde cholangiopancreatography (ERCP) is a common palliative endoscopic procedure for unresectable malignant biliary obstruction or for patients unfit for surgery.

Aims & Methods

We conducted a multicentre retrospective cohort study in 3 centres in Portugal, involving patients submitted to first palliative biliary drainage for malignant biliary obstruction by ERCP, between 2015 and 2022. This study aimed to identify predictive factors of 90-day mortality after endobiliary drainage and propose a predictive model. We have analysed data from 217 patients. Statistical analysis was performed using SPSS v.29.

Results

In our cohort, 51,2% (N=111) of patients were female and the mean age was 74 years. 52,5% (N=114) had stage IV disease and in 88% (N=191) the biliary obstruction resulted from primary tumour involvement. The most frequent tumour was primary pancreatic cancer (53,5%, N=116), followed by cholangiocarcinoma (26,7%, N=58). Metallic stents were used in 53,9% (N=117) of the patients, mainly with fully uncovered self-expandable metallic stents (66,7%, N=78). In the multivariate regression model, the independent predictors for 90-day mortality after first ERCP-guided stent placement were primary tumour size <3 cm (p = 0,014; OR 0,394; 95% CI, 0,187-0,830), stage IV malignant disease (p = 0,005; OR 3,776; 95% CI, 1,507-9,465), intrahepatic biliary obstruction (p = 0,004; OR 3,727; 95% CI, 1,518-9,150) and palliative chemotherapy after ERCP biliary drainage (p <0,0001; OR 0,44; 95% CI, 0,015-0,132). Using these variables, we developed a prediction model for the risk of mortality within 90 days after biliary drainage (Hosmer-Lemeshow X² = 2,907, p = 0,893) with R² of 44,1% in our cohort. The AUROC for our prediction model was 0,833 (p <0,0001; 95% CI, 0,774-0,892). By the Youden’s J statistic, the optimal cut-off value for was 0,4, with a sensitivity of 73,9% and specificity of 76,3%. Patients with a score < 0,2 had a low likelihood of death, whereas a score ≥ 0,9 had a high likelihood of death.

Conclusion

The present study was able to identify statistically significant predictive factors of 90-day mortality after ERCP-guided biliary stenting in unresectable malignant biliary obstruction, which may help to stratify the risk of death within 90 days post-stent placement. Since all these predictive factors can be determined before ERCP, this risk stratification could help in the definition of the proper palliative strategy for each patient.

References

Termsinsuk, P., Charatcharoenwitthaya, P., & Pausawasdi, N. (2022). Development and validation of a 90-day mortality prediction model following endobiliary drainage in patients with unresectable malignant biliary obstruction. Frontiers in oncology, 12, 922386. https://doi.org/10.3389/fonc.2022.922386;
Sripongpun, P., Attasaranya, S., Chamroonkul, N., Sookpaisal, T., Khow-Ean, U., Siripun, A., Kongkamol, C., Piratvisuth, T., & Ovartlarnporn, B. (2018). Simple Clinical Score to Predict 24-Week Survival Times in Patients with Inoperable Malignant Distal Biliary Obstruction as a Tool for Selecting Palliative Metallic or Plastic Stents. Journal of gastrointestinal cancer, 49(2), 138–143. https://doi.org/10.1007/s12029-017-9918-9;
Afshar, M., Khanom, K., Ma, Y. T., & Punia, P. (2014). Biliary stenting in advanced malignancy: an analysis of predictive factors for survival. Cancer management and research, 6, 475–479. https://doi.org/10.2147/CMAR.S71111.

Introduction

Chronic fatigue is a debilitating symptom and has major impacts on the quality of life of patients with chronic inflammatory conditions. In IBD, an estimated 50% of patients suffer from persistent fatigue despite successful treatment of intestinal inflammation. During active disease flares, this number jumps to 80% (Borren et al. 2018). Tryptophan metabolites are not only associated with disease activity in UC and CD, but also with chronic fatigue (Kavyani et al. 2022). Thus, our aims are (1) to characterize the relationship between fatigue and tryptophan derivatives and (2) to understand the metabolic dynamics arising when fatigue symptoms improve following therapeutic intervention.

Aims & Methods

In a prospective open label cohort of patients with moderate-to-severe Crohn’s disease (CD, n = 71) and ulcerative colitis (UC, n = 94) assigned to biologics therapy or JAK inhibitors, fatigue was assessed by the fatigue subscale of the Functional Assessment of the Chronic Illness Therapy – Fatigue (FACIT-F) questionnaire at therapy induction and 2 and 14 weeks thereafter. A FACIT-F score of <30.1 was considered severe fatigue while a score of >40 was considered no relevant fatigue. Clinical response at week 14 was defined as Crohn’s Disease Activity Index (CDAI) <150 and reduction of Partial Mayo Clinical Score (PMCS) >50% vs. baseline, respectively. We used targeted mass spectrometry to quantify the levels of 13 tryptophan derivatives and neopterin in a subset of patient serum in the weeks following therapy induction (at 0, 2, and 14 weeks, n = 120 individuals).

Results

Half of the recruited patients had severe fatigue at baseline (50.3%). Of the 120 patients who reached week 14 and had FACIT-F scores available, severe fatigue was experienced by 45.9% of the patients who did not respond to therapy and the rate was reduced to 13.2% in therapy responders. We found 8 metabolites positively associated with FACIT-F: tryptophan, kynurenic acid, kynurenine, picolinic acid, xanthurenic acid, serotonin, indole-3-proprionic acid, and quinaldic acid, while neopterin was negatively associated (FDR < 0.05). Four of these metabolites changed dynamically as a function of the extent of fatigue improvement: tryptophan, kynurenine, xanthurenic acid, and serotonin (FDR < 0.05). In all cases, the rate of change of these metabolites increased as a function of fatigue improvement.

Conclusion

Fatigue is linked to a diverse array of tryptophan metabolites. Notably, all of the significantly associated tryptophan derivatives were positively associated with FACIT-F, meaning that as fatigue symptoms improve, tryptophan metabolite levels increase. Many of these metabolites have previously been linked to symptom severity in IBD: for example, tryptophan, kynurenic acid and xanthurenic acid all tend to increase with symptom alleviation (Nikolaus et al. 2017, Michaudel et al. 2022). While the kynurenine-to-tryptophan ratio is elevated in active IBD (Nikolaus et al. 2017), this ratio did not convey a specific, fatigue-related signature. Considering that some patients continue to suffer from persistent fatigue even during disease quiescence, further work is needed to disentangle the impact of tryptophan metabolism on therapy response from its role on fatigue improvement.

Disclosure

F. Tran receives scientific funding from Sanofi, received consulting fee's from LEK Consulting and speaker's fees from Lilly, Janssen, Falk, Abbvie, Celltrion, onkowissen.de, CED Service GmbH. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk.

Clinical Case Summary

A 40-year-old male came to our emergency department referring worsening jaundice, mental status deterioration, epigastric pain and anorexia over the past week. Four weeks earlier he presented odynophagia, myalgias, and hand pruritus but didn’t seek medical attention.
Patient’s clinical background included cognitive impairment due to peripartum anoxia and type 2 Diabetes Mellitus. At admission, he had elevated liver enzymes (R value=2,7), coagulopathy (INR 1.3), pancreatic enzymes >3 times the upper normal level and hyperbilirubinemia (mostly conjugated).
The CT-scan revealed pancreatic tail globosity, diffuse abdominal and retroperitoneal peri-centimetric lymph nodes and excluded biliary lithiasis.
After common causes of acute hepatitis and pancreatitis were ruled out, and since patient was at risk of acute liver failure despite supportive treatment, a liver biopsy was performed. Autoimmune hepatitis, drug-induced liver injury or lymphoproliferative disease were held as potential differentials. Hepatitis E Virus (HEV) RNA was then found and genotyped in the serum (genotype 3). HEV infection was assumed as the cause for both hepatitis and pancreatitis. Histological pattern was inconclusive and epidemiological source wasn’t found.

HEV infection paradigm has changed and is now considered an endemic zoonotic infection in most high-income countries (Portuguese seroprevalence is 16.3%)¹. Infection occurs due to ingestion of undercooked pig or boar meat and should be suspected in every acute hepatitis, mostly with a cholestatic pattern.
The setting of acute HEV hepatitis complicated with acute pancreatitis (AP) is uncommon². AP usually starts after a median of 10 days of jaundice onset³. Literature only reports association between AP and HEV caused by genotype 1 from Southeast Asia^{3 4}, and genotype 3 was only related to gallstone-related pancreatitis, according to current knowledge⁵. This might be the first form of HEV genotype 3 infection with hepatitis and pancreatitis.

References

1. Nascimento MSJ, Pereira SS, Teixeira J, et al. A nationwide serosurvey of hepatitis E virus antibodies in the general population of Portugal. Eur J Public Health 2018;28(4):720-24. doi: 10.1093/eurpub/ckx213 [published Online First: 2017/12/14]
2. Debnath P, Datta AK, Chakraborty U, et al. Acute viral hepatitis E complicated with acute pancreatitis in an immunocompetent adult. BMJ Case Rep 2021;14(2) doi: 10.1136/bcr-2020-239684 [published Online First: 2021/02/06]
3. Haffar S, Bazerbachi F, Garg S, et al. Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review. Pancreatology 2015;15(4):321-6. doi: 10.1016/j.pan.2015.05.460 [published Online First: 2015/06/08]
4. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018;68(6):1256-71. doi: 10.1016/j.jhep.2018.03.005 [published Online First: 2018/04/04]
5. Karlsson M, Norder H, Bergstrom M, et al. Hepatitis E virus genotype 3 is associated with gallstone-related disease. Scand J Gastroenterol 2019;54(10):1269-73. doi: 10.1080/00365521.2019.1666163 [published Online First: 20190925]

Introduction

The degree of fibrosis during colorectal ESD varies and sometimes makes the procedure itself difficult. Preoperative prediction of fibrosis is expected to help develop a reliable strategy.

Aims & Methods

Of 1309 colorectal ESD lesions performed at our hospital between April 2012 and September 2022, 953 lesions larger than 20 mm were included after excluding post-treatment recurrence, SMT, and other conditions. Intraoperative fibrosis was classified into F0 (none), F1 (mild), and F2 (severe).

Results

Fibrosis was observed in 192 (20.1%) patients (F1; 143, F2; 49). The tumor diameter (median, range) was 23 (20-135), 30 (20-210), and 35 (20-115) mm in F0, F1, and F2 groups, respectively. The rate of the cecum (%) was 13.3 : 29.4 : 16.3, which was higher in F1. Overall, bleeding was observed in 17 patients (1.8%) and perforation in 3 patients (0.3%), and the frequency was similar in each group. The curative resection rate (%) was 98.4:91.6:59.2, with F2 being significantly inferior. The long treatment time (≥120 minutes) (%) was 1.7 : 9.1 : 46.9, showing a significant difference between F0 vs F1 and F1 vs F2, and the dissection speed (mean±SD, mm²/min) was 25.9±14.5 : 23.2±13.6 : 15.3±10.6, which was significantly slower in F2. The predictive factors of F1 and F2: straddling the folds, prior biopsy, lesion diameter, site, and morphology, were included in the study, and multivariate analysis showed that the predictive factors of F1 were straddling folds (OR;2.07,95%CI;1.39-3.11), lesion diameter ≥50mm (OR;4.68,95%CI;2.45-8.94), biopsy (OR;6.44,95%CI;3.32-12.5), NGPD (OR;4.31,95%CI;2.37-7.83), and cecum(OR;3.73,95%CI;2.35-5.92). The predictive factors of F2 were straddling folds (OR;2.34,95%CI;1.21-4.51), lesion diameter ≥50 mm (OR;7.29,95%CI;3.03-17.5), biopsy (OR;5.07,95%CI;1.81-14.1), and protruded type (OR;6.44,95%CI;3.23-12.8).

Conclusion

Colorectal ESD for fibrotic lesions was safe, but the curative resection rate was low in F2. F1-specific predictors were cecum and NGPD, and F2-specific predictors were protruded type, suggesting that the choice of surgeon and strategy should depend on the expected degree of fibrosis.

Introduction

Crohn’s disease (CD) clinical trials have evolved from evaluating symptoms to including endoscopic outcomes as coprimary endpoints, as was done in clinical trials of upadacitinib (UPA), an oral, reversible Janus kinase inhibitor, and ustekinumab (UST), an anti-interleukin 12/23. Endoscopic healing has been recommended as a long-term treatment target by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative.

Aims & Methods

The objective of this study is to conduct a placebo (PBO)-anchored matching-adjusted indirect comparison (MAIC) of endoscopic outcomes between UPA and UST among patients with moderately to severely active CD. Data from phase 3 UPA trials (NCT: 03105128, 03104413, 03105102) and an UST endoscopy substudy (NCT: 01369329, 01369342, 01369355) from the phase 3 UNITI/IM-UNITI program were used. For induction, patients (pts) received UPA 45mg once daily (QD) for 12 weeks (wks), UST 6mg/kg intravenously, or PBO. For maintenance, pts received UPA 15mg or 30mg QD, subcutaneous UST 90mg every 8 (Q8W) or 12 wks (Q12W), or PBO. Individual pt level data from the UPA trials included pts with baseline (BL) CD Activity Index between 220-450 and excluded pts with prior UST or vedolizumab exposure or missing data due to COVID. Induction BL characteristics identified as treatment-effect modifiers, including disease duration, location, and phenotype, median c-reactive protein, prior biologic failure, and mean Simple Endoscopic Score for CD (SES-CD), were weighted to match those reported in the UST endoscopy substudy for both induction and maintenance. Endoscopic outcomes were evaluated after induction (Wk 12 UPA, Wk 8 UST) and maintenance (Wk 52 UPA, Wk 44 UST). Endoscopic outcomes included endoscopic response (reduction of ≥50% from induction BL in SES-CD) and remission (total SES-CD ≤2), mucosal healing (present with ulceration in at least 1 ileocolonic segment at induction BL) and change in SES-CD score from induction BL.

Results

The effective sample sizes for induction MAICs were 207 UPA and 155 UST pts and ranged from 16–53 (UPA) and 17–46 (UST) for maintenance MAICs. A significantly (P<0.05) greater proportion of UPA vs UST pts achieved endoscopic response and remission, mucosal healing, and had a larger reduction from BL in mean SES-CD score at the end of induction; PBO-adjusted treatment differences were 26.3%, 9.9%, 13.0%, and –3.7 points, respectively. Endoscopic remission rates at the end of maintenance were numerically higher for UPA 30mg vs UST 90mg (Q8W+Q12W). PBO-adjusted rate differences in endoscopic response and mucosal healing between UPA 30mg and UST Q12W were significant (35.5% and 39.0%, respectively; p<0.05); other outcomes (UPA 15mg vs UST) were comparable.

Conclusion

Greater proportions of pts on UPA vs UST achieved endoscopic outcomes at the end of induction for pts with moderately to severely active CD. Although sample sizes during maintenance were limited, these MAICs show endoscopic outcomes are achieved in a numerically higher proportion of pts treated with UPA 30mg vs. UST, while outcomes are comparable with UPA 15mg vs UST.

Disclosure

C Ma has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Tillotts; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; research support from Ferring, Pfizer.
MC Dubinsky has received consulting fees from AbbVie, Abivax, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Prometheus Biosciences, Prometheus Labs, Takeda
JE Axelrad reports receiving research grants from BioFire Diagnostics; consultancy fees or honorarium from BioFire Diagnostics, Janssen, Pfizer, Abbvie, and BMS; and holds US Patent 2012/0052124A1 and no other conflicts of interest.
J Griffith, S Anyanwu, and N Joshi are employees of AbbVie and may own stock.
J Tran is a funded PhD student at the University of Washington and a contractor for AbbVie.