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

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

Inflammatory Bowel Disease (IBD) can be a chronic, disabling condition. Long-term symptoms, failed therapies, repeated hospital admissions and impairment of social functioning can result in significant emotional trauma (Taft et al., 2022). Such patients are at an increased risk of mood disorders and abnormal eating behaviours. Severely affected patients can be managed using a trauma informed approach (Bugwadia et al., 2024).
A 50-year-old woman with a BMI of 14.9 kg/m2, history of ileocolic resection for Crohn’s Disease (CD), anxiety, depression, anorexia nervosa and irritable bowel syndrome presented with symptoms of abdominal pain, diarrhoea and weight loss despite advanced medical therapy. A stricture at the site of her ileocolic anastomosis was identified, with chronic distention of the upstream ileum. Surgical resection with stoma formation was recommended by the multidisciplinary team.
Due to the number and complexity of her co-morbidities, a tailored, trauma-informed approach was used to facilitate her care. Pre-operatively, counselling was performed in a compassionate, staged manner in multidisciplinary consultations. Input from clinical psychology, nutrition and stoma care helped to de-escalate catastrophic thoughts, building trust. Encouragement to engage with peer-support groups improved her confidence. Post-operative care was responsive to her needs with further support from clinical psychology and nutrition. Early closure of the ileostomy allowed return to normal function as soon as was possible.
A trauma-informed care approach combining a team of IBD clinicians, dieticians, stoma nurses and clinical psychologists was crucial in managing a complex case of co-morbid anxiety, depression, anorexia and CD.

References

Bugwadia, A. K., Reed, S., Shapiro, M., Dave, S., Jayswal, N., Kohler, D. & Keefer, L. (2024) Medical trauma in young adults with inflammatory bowel disease: The role of trauma-informed care. Health Care Transitions. 2 100044. 10.1016/j.hctj.2024.100044.
Taft, T. H., Quinton, S., Jedel, S., Simons, M., Mutlu, E. A. & Hanauer, S. B. (2022) Posttraumatic Stress in Patients With Inflammatory Bowel Disease: Prevalence and Relationships to Patient-Reported Outcomes. Inflammatory Bowel Diseases. 28 (5), 710–719. 10.1093/ibd/izab152.

Introduction

Tulisokibart, a TL1A monoclonal antibody, has demonstrated significantly higher rates of clinical remission and endoscopic and histologic improvements vs. placebo in participants with moderately to severely active ulcerative colitis (UC) in the ARTEMIS-UC clinical trial ¹. Although histologic remission has been associated with improved long-term outcomes in UC, histology is inconsistently performed and heterogeneously evaluated in routine clinical care as an assessment of remission depth.

Aims & Methods

This analysis of ARTEMIS-UC explores the correlation between changes in clinical, biomarker, endoscopic, and histologic endpoints following tulisokibart treatment over 50 weeks, potentially providing additional accessible indicators of treatment efficacy. ARTEMIS-UC enrolled two cohorts based on a genetic diagnostic test (Dx) for anti-TL1A treatment response: Cohort 1 (participants regardless of Dx results) and Cohort 2 (only Dx positive participants). We examined 15 relationships between five clinical, endoscopic, and biomarker endpoints and three histologic endpoints at Week 12 after induction (Cohort 1) and Week 50 (Cohorts 1 and 2) among induction responders continuing maintenance tulisokibart. Histologic endpoints included histologic improvement, histologic-endoscopic mucosal improvement (HEMI), and mucosal healing (Table) assessed in the Histology Analysis Set (HAS), i.e., participants who received ≥1 dose of study medication and had Geboes scores at both Baseline and Week 12. Clinical/endoscopic/biomarker endpoints included Modified Mayo Score for clinical remission, clinical response, endoscopic improvement, normalization of fecal calprotectin, and hsCRP normalization. The Phi correlation coefficient assessed pairwise correlations between clinical/endoscopic/biomarker and histologic endpoints.

Results

There were 65 and 34 tulisokibart participants included in the HAS population for the Week 12 and Week 50 analyses, respectively. The strongest correlations were the following: endoscopic improvement:HEMI, endoscopic improvement:mucosal healing, clinical remission:HEMI, and clinical remission:mucosal healing, all >0.8 at Week 12 (post-induction in Cohort 1) and >0.9 at Week 50 (post-maintenance dosing in Cohorts 1 and 2). Normalization of fecal calprotectin also demonstrated a strong correlation with histologic endpoints (>0.7) at Week 50 (Table).

Table: Correlation between Clinical and Histologic Endpoints

Conclusion

Strong correlations exist between clinical, endoscopic, and histologic endpoints after 12 weeks of induction therapy with tulisokibart, followed by 38 weeks of maintenance therapy in induction responders. These findings underscore the potential for clinical remission to reflect both endoscopic and histologic healing in UC patients, which may enhance patient management strategies and enable a more comprehensive understanding of treatment efficacy. Moreover, these findings indicate the potential of tulisokibart in achieving deep remission² in patients with ulcerative colitis.

References

1) Sands BE et al. N Engl J Med. 2024 ;391:1119-1129; 2) Lobatón T et al. United European Gastroenterol J. 2018;6:765-772.

Disclosure

The submitting author of an abstract is requested to declare any potential conflict of interest for all authors during the abstract submission. Moreover, the authors’ names (full first names, family names), gender and affiliation (places of work/institution, city, country) must be provided.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), Roche, Sanofi, Takeda, Tillotts Pharma; speaker’s fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer
RWL discloses advisory board membership: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Takeda; research grant recipient: Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant, McKusker Charitable Foundation.
JL reports no financial competing interests
XH reports support from AbbVie, Abivax, Alphasigma, Arena, Cellgen, Gilead, Eli Lilly, Enterome, Janssen, InDex Pharmaceuticals, Pfizer, MSD, Roche, Salix, Sangamo, Takeda, and Theravance for clinical research; consulting fees from AbbVie, Abivax, Arena, Galapagos, Gilead, Janssen, Pfizer, Roche, Sangamo, Takeda, and Viatris; and lecture fees from AbbVie, Abivax, Amgen, Arena, Galapagos, Gilead, Fresenius-Kabi, Janssen, Pfizer, Roche, Sangamo, Takeda, and Mylan.
Brigid S. Boland: BSB has research grants from MSD, Mirador, Gilead as well as serves as a consultant for Abbvie, MSD, Celltrion.
JX, WZ, and MY are employees of MSD.