Introduction

Intestinal ultrasound (IUS) is a non-invasive method that is increasingly used to monitor disease activity in patients with inflammatory bowel disease.¹ There is currently no consensus on the appropriate implementation of IUS to assess post-surgical recurrence in Crohn’s disease (CD). ​

Aims & Methods

The aim of this study was to determine appropriate parameters for evaluating postoperative recurrence of CD using IUS after surgery. The modified RAND-University of California Los Angeles appropriateness method (RAM)² was implemented using an international panel of 16 experts, including gastroenterologists, surgeons, radiologists, and methodologists, to evaluate the appropriateness of statements related to using IUS for assessing postoperative recurrence of CD. This exercise specifically focused on assessing the anastomosis, neoterminal ileum after ileocecal resection, and primary anastomosis in CD. To inform statement generation for the RAM, a systematic review was performed to identify parameters described in the literature for the sonographic evaluation of postoperative disease recurrence in patients with CD. Statements were developed focusing on when, where, and how sonographic parameters should be assessed after surgery. Panellists voted anonymously in 2 rounds of surveys containing up to 122 statements, rating each statement for appropriateness on a 9-point Likert scale (1=highly inappropriate; 5=uncertain; 9=highly appropriate). Median appropriateness ratings were summarised, and interquartile ranges were calculated. The statement list and survey results were discussed in moderated videoconferences prior to voting. The panellists met in person to discuss the results and ratify the final statements.

Results

After 2 rounds of voting, 80% of the statements were rated as appropriate with agreement. IUS findings in the neoterminal ileum and the inlet of the neoterminal ileum were considered likely to reflect clinically meaningful disease. Recognising that immediate postoperative changes related to surgical healing may mimic CD, IUS should not be performed within 4 weeks of resection in the context of evaluating postoperative recurrence. Defining the entire component of the anastomosis as consisting of colonic blind side, ileal blind side, neoterminal inlet, and neoterminal ileum, if any were visible/present, was considered appropriate by the panellists. However, there was uncertainty with describing and measuring thickening within the blind loops and whether those segments represent postoperative recurrence. Use of bowel wall thickness, bowel wall stratification, bowel wall vascularity on Doppler, mesenteric inflammatory fat, lymphadenopathy, submucosal layer thickness, muscularis propria layer thickness, small bowel peristalsis, free fluid, abscess, inflammatory mass, fistula/sinus tract, anastomotic or neoterminal ileal stricture, luminal narrowing, pre-stenotic dilation, and stricture length were considered appropriate to assess postoperative CD recurrence, and parameters for each component were identified.

Conclusion

This first set of internationally guided recommendations (Table) for using IUS to assess postoperative recurrence of CD has been developed to facilitate standardisation of a non-invasive method of monitoring patients following surgical bowel resection.

References

¹ Dolinger MT, Kayal M. Intestinal ultrasound as a non-invasive tool to monitor inflammatory bowel disease activity and guide clinical decision making. World J Gastroenterol. 2023;29(15):2272-2282. Doi: 10.3748/wjg.v29.i15.2272
² Fitch K, Bernstein SJ, Aguilar MD, et al. The RAND/UCLA Appropriateness Method User’s Manual. Santa Monica, CA: RAND Corporation, 2001.

Disclosure

KLN has received consulting fees from AbbVie, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Pendopharm, Pfizer, and Takeda, with speaker's fees from AbbVie, Fresenius Kabi, Janssen, Pfizer and Takeda; and research support from Pfizer, and the Helmsley Trust.
SA has received speaker/honoraria fees from AbbVie, Fresenius Kabi, Janssen, Pfizer, and Takeda; and received research grants from A.I Vali and ATGen.
MA received consulting fee from Nikkiso Europe, Mundipharma, Janssen, AbbVie, Ferring, Galapagos, Alfasigma, Lilly, Sandoz, and Pfizer.
AdBvO has received speaker fees from Amgen, Takeda, and Janssen Pharmaceuticals.
PGK is a speaker and consultant for AbbVie, Celltrion, Johnson & Johnson, Pfizer and Takeda. He received scientific grants from Pfizer and Takeda, and is involved in clinical research for Ventyx, Roche, and Takeda.
CL has received advisory/consulting fees from AbbVie, Agomab, Celltrion, JnJ, Lilly, Pfizer, Takeda, Fresenius Kabi, Pendopharm, and Ferring.
CM received lecture and/or consulting fee from AbbVie, Alfasigma, Biocon Biologics, Bristol Myers Squibb, Ferring, Galapagos, Gilead, Lilly, J&J, Pfizer, and Takeda.
GM has received lectures or consulting fees from AbbVie, Janssen, Samsung, Galapagos, and Fresenius-Kabi.
RP reports being a Consultant for Abbott, AbbVie, Abbivax, Alimentiv Inc. (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; reports Speaker’s Fees for: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and reports Advisory Boards for: AbbVie, Alimentiv Inc. (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
MR reports receiving consulting/advisory fees from AbbVie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), Celltrion, and Roche.
JR has received lectures fees from AbbVie and Takeda; is or has been advisor for Gilead, Takeda, Agomab, Janssen, Boehringer Ingelheim, Lumen, Ferring, and Bracco; and has received consultant fees from Alimentiv Inc. He received scientific grants from Takeda and AbbVie.
AS has received consulting fees from Stryker and Johnson and Johnson.
SAT reports grant support from Takeda; consultancy with AstraZeneca; and shareholder of Motilent.
RW reports speaker or consultancy fees by Alimentiv Inc, Pfizer, Takeda, J&J, and Nautilus Scientific.
WAB reports no competing interests.
NKC reports being a Consultant for Samsung and Speaker for Bristol-Myers Squibb.
KBG has received grants from AbbVie, Pfizer Inc., Celltrion and Galapagos; consultancy fees from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen Pharmaceuticals, Pfizer Inc., Samsung Bioepis, and Takeda; and speaker’s honoraria from AbbVie, Celltrion, Eli Lilly, Ferring, Janssen Pharmaceuticals, Pfizer Inc, Takeda, and Tillotts.
SA, SK, and LJC are employees of Alimentiv Inc.
CM has received consulting fees from AbbVie, Alimentiv Inc., Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, and Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv Inc., Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, and Takeda; royalties from Springer Publishing; and research support from AbbVie, Ferring, and Pfizer.

Introduction

Primary thromboprophylaxis is used in the post-partum and the post-surgical period. 2014 Canadian Association of Gastroenterology guidelines and a 2021 Nature Reviews consensus recommend outpatient thromboprophylaxis only for those ambulatory inflammatory bowel disease (IBD) patients at high risk of thromboembolic events.

Aims & Methods

We aimed to analyse our inpatient burden and our rate of post-discharge thromboembolic (TEEs) in those with primary and secondary diagnoses pertaining to IBD. We also aimed to identify associated risk factors.
Our hospital inpatient and radiology databases were queried for discharges with primary and secondary diagnoses pertaining to IBD and scans pertaining to TEEs respectively.

Results

1,601 discharges pertaining to 954 individual patients were identified over the 13-years ended 2024. 54% (n=870) were female. Median age was 44 (IQR:32-59). 58% (n=932) pertained to Crohn’s disease.
Investigations for TEEs were performed during 117 admissions (7.3%). 10 patients had inpatient TEEs (0.6%). Age ≥ 50 years was significantly associated with inpatient TEE (Odds ratio [OR]: 1.89; 95% confidence intervals [CI]: 1.13-3.16; p=0.01). Male gender (OR: 0.92; 95% CI: 0.59-1.44; p=0.72), ulcerative colitis subtype (OR: 1.51; 95% CI: 0.95-2.41; p=0.08) and inpatient surgical intervention (OR: 1.39; 95% CIs: 0.89-2.17; p=0.15) were not significant associated factors.
63 discharges (3.9%) had imaging querying TEEs performed within 180 days. Six patients (0.4%) had TEEs within this time frame. No significant associations were identified for age ≥50 years (OR: 1.16; 95% CIs: 0.68-1.99; p=0.59), male gender (OR: 0.84; 95% CIs: 0.48-2.17; p=1.47, p=0.55), ulcerative colitis subtype (OR: 1.12; 95% CIs: 0.65-1.91; p=0.68), inpatient surgical intervention (OR: 1.37; 95% CIs: 0.79-2.35; p=0.26) or prior VTE (OR not calculable) in relation to post-discharge TEEs.

Conclusion

Our incidences of inpatient and post-discharge TEEs were low over 13-years. In agreement with international guidelines, we recommend against the need for routine primary prophylaxis in the post-discharge ambulatory period.

References

1. Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology. 2014;146(3):835-848.e6. doi:10.1053/j.gastro.2014.01.042
2. Olivera PA, Zuily S, Kotze PG, et al. International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(12):857-873. doi:10.1038/s41575-021-00492-8

Introduction

Biologic agents have emerged as the most important therapeutic weapon in the treatment of Crohn's disease, but there are few data in the literature comparing the efficacy and safety between different molecules. The aim of this study is to describe the population of patients who received different molecules as first-line therapy and their persistence on first-line therapy.

Aims & Methods

622 patients from 6 Gastroenterology departments from Bucharest, Iasi and Cluj treated between 2006 and 2024 were included in the study. 75 (14%) were excluded because they received only Mesalazine. 535 were included in the final analysis. The main outcomes were: clinical response at 12 weeks of treatment (complete response = clinical remission, partial response= decrease of CDAI ≥ 25% of the initial value without remission or primary non-response), persistence on therapy and serious adverse events leading to therapy discontinuation.

Results

The main characteristics of the studied patients are shown in the table 1. There are significant differences between the 3 groups of patients: regarding age, extension of the disease, disease phenotype, proportion of individuals with perianal fistulas, clinical severity of the disease, proportion of operated patients. Median therapy duration was 48 months (3÷330). 45% of patients received Adalimumab, 40% were treated with Infliximab, and in 13% Ustekinumab was given. The 3 biologics studied (Adalimumab/Infliximab/Ustekinumab) had a similar rate of complete response 80%, the non-response rate was also similar: 6.5% but persistence on therapy at 2 years was better for Ustekinumab (64%) compared to Adalimumab and Infliximab (45%) (p=0.03). Serious adverse events leading to therapy discontinuation were more frequent in those treated with Infliximab (10%) compared to Adalimumab (3%) and Ustekinumab (6%) (p=NS).

Conclusion

Patients that received anti-TNF alpha antibodies had more severe forms of Crohn’s disease. All three biological agents used in real life for Crohn’s disease therapy show similar efficacy, with a complete response rate of aprox. 80% and a nonresponse rate of 6.5%, but persistence on therapy at 2 years was significantly better for Ustekinumab (64%) compared to Adalimumab and Infliximab (45%) (p=0.03). Serious adverse events leading to therapy discontinuation were more frequent in patients treated with Infliximab (10%) compared to those who received Ustekinumab (6%) or Adalimumab (3%).

Clinical Case Summary

Background: Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome in which the symptomatology of intestinal obstruction occurs without any mechanical cause. This syndrome may reveal or complicate celiac disease during follow-up.
Cases presentation: We report two cases of 40 and 24-year-old women. The first is followed since the age of 8 for celiac disease on a poorly followed gluten-free diet and consulted for repeated pseudo-occlusive syndromes. the second was admitted to the surgery department for a recurrent occlusive syndrome which resolves after gastric aspiration, then referred to our service for exploration of chronic diarrhea. For both, no mechanical obstruction was found. Ionic disorders and lymphoma were also ruled out. The diagnostic of CIPO was retained. The intestinal mucosal biopsy was characteristic of celiac disease. The evolution was favorable under a gluten-free diet. Symptoms of CIPO never recurred.
Conclusion: Our observations highlight that CIPO may be a rare and severe complication of celiac disease, which should always be suspected since the gluten-free diet can improve symptoms and prevent recurrences.

Introduction

Total retocolectomy with ileal pouch anal anastomosis (IPAA) is the surgical procedure of choice for patients with ulcerative colitis (UC) refractory to clinical treatment and familial adenomatous polyposis (FAP) with many polyps in the rectum. Primary ileitis of the ileal pouch (IP) is one of the most common complications in UC, being rare in FAP. Previous studies have identified an increase in pro-inflammatory cytokines, as well as alterations in the apoptosis and macroautophagy pathways markers in the IP mucosa of UC patients, compared to those with FAP and normal distal ileum (controls). Since autophagy and apoptosis can be modulated by endoplasmic reticulum (ER) stress, we investigated this pathway in IP of UC compared to PAF and controls.

Aims & Methods

The aim was to evaluate the modulation of ER stress in the IP mucosa of UC and FAP patients who underwent IPAA, compared to controls. Thirty-two patients were included, ten in the UC group, twelve in FAP group and ten in the control group. Patients who had undergone ileostomy closure for less than one year and had clinical, histological, or endoscopic evidence of pouchitis were excluded. The patients underwent routine colonoscopy, and biopsies were performed from the IP. For the control group, biopsies were taken from the normal distal ileum. The local Ethics Committee approved the study. The biopsies were processed for RNA extraction and subsequent gene expression analysis using the quantitative PCR (qPCR) technique. The following transcripts were investigated: IRE1 (ERN), PERK (EIF2AK3), ATF6, GRP78 (HSPA5), GRP94 (HSP90B1), ATF3, STC2, DDIT3, DNAJC3, and CALR. Nonparametric tests were used for statistical analysis, with a significance level of p<0.05.

Results

The pouchitis disease activity index (PDAI) was applied to verify the absence of pouchitis, with all patients scoring lower than 7. There was no increase in the transcriptional level of the main ER stress pathway markers (ERE1, PERK, and ATF6) in the IP without pouchitis. However, there was a significantly lower expression of DDIT3 in the UC and FAP groups compared to the control (p≤0.05), which may suggest a deficiency in counterbalance the ER stress activation. On the other hand, concerning the UPR pathway markers, the levels of CALR and HSP90B1 were significantly higher in the IP of UC compared to the respective IP afferent loop (p≤0.05), supporting potential activation of the ER stress in the IP in the UC group. Additionally, the transcriptional level of ATF3 was significantly higher in the PAF group compared to the control (p≤0.05), which may indicate a counter-regulatory mechanism in response to tissue damage, which was not verified in the UC group.

Conclusion

Our findings demonstrated that markers of the unfolded protein response (UPR) signaling pathway, which is activated in response to ER stress, are modulated in the IP mucosa of UC patients, even in the absence of pouchitis. These results may explain the propensity to IP inflammation in UC patients. They may guide the identification of additional molecular pathways contributing to inflammation of the IP and the search for new therapeutic targets.

References

1. Negreiros LMV, Pascoal LB, Genaro LM, et al. Pouchitis: insight into the pathogenesis and clinical aspects. Am J Transl Res. 2022 Jul 15;14(7):4406-4425.
2. Rodrigues BL, Dotti I, Pascoal LB, et al. Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation. Mediators Inflamm. 2022 Feb 9;2022:6049500.
3. Paiva NM, Pascoal LB, Negreiros LMV, et al. Ileal pouch of ulcerative colitis and familial adenomatous polyposis patients exhibit modulation of autophagy markers. Sci Rep. 2018 Feb 8;8(1):2619.
4. Qiao D, Zhang Z, Zhang Y, Chen Q, Chen Y, Tang Y, et al. Regulation of Endoplasmic Reticulum Stress-Autophagy: A Potential Therapeutic Target for Ulcerative Colitis. Front Pharmacol. 2021;Volume 12-2021.

Clinical Case Summary

A 27-year-old woman is admitted to a tertiary hospital for a sudden painful wound on the inner side of her upper arm. The patient stated that she had been diagnosed with ulcerative colitis 6 years ago and had been treated with prednisone and mesalazine, but was currently in remission and discontinued treatment. She was treated twice in the surgical ward for similar ulcers 2-3 years ago. Physical examination revealed a redness of ~10x6 cm in the lower third of the left upper arm and a necrotic area of 3 cm in the middle of the upper arm which was very painful to palpate. The patient was hospitalized for suspected extraintestinal signs of ulcerative colitis, but colonoscopy revealed no changes. The wound was treated with incision, lavage, necrectomy and a/b therapy according to the culture results. During the course of treatment, the patient developed a new skin lesion on the right hip and an unexpected decrease in prothrombin from 70% to 6%, which normalized after vitamin K injections. A wound biopsy revealed necrotic-inflammatory lesions, differentiating between autoimmune vasculitis and possible chemical damage. Suspecting a factitious disorder (Munchausen syndrome) the patient's rucksack was searched and syringes together with a small vial of liquid (subsequently identified as formalin) were found. Furthermore, it was revealed that patient's son was treated for 10 months in the other hospital due to deep necrotic wounds that are difficult to heal, immunodeficiency of unknown origin, repeated disruptions in the coagulation system (prothrombin 3%) and dead at age 11 month from secondary sepsis 2 years ago.
The hospital appealed to the prosecutor's office, a forensic psychiatric expert found the patient guilty, and the court sentenced her to 16 years' imprisonment for killing her son.