Introduction

Cytomegalovirus (CMV) belongs to herpesvirus family. While common and mostly asymptomatic in general population, CMV infection can lead to serious condition in immunocompromised patients. Many definitions of CMV infection or intestinal disease are found in literature, which explains the different prevalence rates reported. (1)

Aims & Methods

To describe prevalence, and the clinical and prognosis outcomes of CMV infection in our IBD patients.
Methods : A retrospective study conducted from 01/2015 to 09/2022 including 505 patients with IBD diagnosis including ulcerative colitis and Crohn’s disease. Clinical, biological, endoscopic and histological data were collected from patient’s hospitalisations and follow-up reports. Parameters were analyzed using Microsoft Excel.

Results

505 patients were included. We considered CMV positive infection or intestinal disease in patients with the presence of inclusions on biopsies or a
positive CMV PCR. 5 patients had an intestinal CMV infection (0,9%), with a sex ratio M/F at 0,8. Mean age was 44,8 Y.O (26-69 YO). 4 patients were already followed-up for ulcerative colitis for an average of 3,3 years and were all under immunomodulators (thiopurines or methotrexate), while it was inaugural for the diagnosis in the other one. CMV intestinal disease was discovered during a severe acute colitis episode in 3 patients and moderate colitis in the remaining ones. Severe endoscopic lesions were found in 2 patients, while Mayo score was at 3 for all of them. Anatomopathology showed the presence of CMV inclusions in 40% (2 patients). Average CRP before treatment was 94 mg/l (22-169mg/l). Labtests showed positive CMV IgM antibodies in 4 patients. All patients were treated during 21 days using gemciclovir in consultation with infectious diseases physicians. For patients in acute severe colitis episode, mean Lichtiger at the end of the treatment was at 3, the other patients also had a good clinical outcome, such as the decrease of the number of stools and an improvement in the general state. Average CRP at the end of the treatment was at 20 mg/l(14-32).

Conclusion

Our study shows a low prevalence of CMV intestinal disease or infection, including the different definitions found in literature (1). Prevalence seems underestimated, and could be higher if diagnosis tools were more accessible. Even in our immunocompromised patients, CMV infection or intestinal disease had a good clinical and biological outcome in all of them after treatment.

References

(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716042/
(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339997/ https://www.ecco-ibd.eu/publications/congress-abstracts/item/p228-
cytomegalovirus-infection-is-it-a-cause-of-flare-up-in-inflammatory-bowel-diseases.ht&ml

Introduction

Being two immune-mediated diseases (IMIDs), the association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is plausible, but data in the literature are conflicting.

Aims & Methods

The aim of our study was to evaluate the possible association between IBD and MS in a cohort of patients with IBD.

Results

In a retrospective study, we examined the medical records of 5,739 patients with a confirmed diagnosis of IBD followed in our clinic between 1978 and 2022.
Among these patients, we identified 14 with MS, with a prevalence of 0.24%. The reported prevalence of MS in general population in northern Italy in 2021 was 0.18% (P = 0.24). For each of the patients with MS identified, more than ten patients without MS were analyzed. The 14 MS cases were then compared with 342 controls. From the 14 MS patients, 12 (85.7%) were female and 2 (14.3%) were male, while in the control group, 158 (46.2%) were female and 184 (53.8%) were male (P = 0.004). As for therapy, significant differences were found on mesalazine (5 (41.7%) cases vs. 317 (92.7%) controls, P < 0.0001) and anti-TNF treatment (0% cases vs 26.6% controls, P = 0.03, respectively) at the time of MS diagnosis. Moreover, Kaplan-Meier curve analysis showed that the 20-year survival probability was 98.4% for patients with IBD, while for patients diagnosed with MS and IBD it was 82.1% (P = 0.02).

Conclusion

In conclusion, patients with IBD have a similar risk of developing MS compared to the general population, but female sex appears to increase the risk. Indeed, life expectancy at 20 years for patients with IBD and MS is lower than for patients with IBD alone.

Introduction

The number of epidemiological population-based studies on unclassified inflammatory bowel disease (IBD-U) patients are very limited. The present study is a continuation of the Veszprem IBD population based cohort with a follow-up of the incidence and disease course of IBD-U since 1977.

Aims & Methods

Our aim was to evaluate incidence, prevalence, disease course, time to biological therapy and surgery rates in a prospective population-based database of incident IBD-U patients diagnosed between 1977 and 2018, with follow-up until 2020. Both in-hospital and outpatient records were collected. The source of age- and gender-specific demographic data was derived from the Hungarian Central Statistical Office. Medical therapy, time to first biological therapy, disease progression, and colectomy was registered.

Results

Data of 119 incident IBD-U patients were analyzed (male/female: 55/64; median age at diagnosis: 34 years(y) (IQR: 24-47)). Adjusted mean incidence rate was 0.76 (CI95%: 0.63-0.9) /10⁵ person-years in the total study period, and 0.96 (CI95%: 0.79-1.16) /10⁵ person-years between 1990-2018. Disease extent at diagnosis was proctitis in 7.6%, one-sided colitis (left-sided colitis, or isolated right-sided colitis) in 36.1%, and extensive (pancolitis) in 56.3%. The probability of progression in colonic disease extent was 6.7% (SE:2.3) at 3 years, 10.3% (SE:2.8) at 5 years and 15.3% (SE:3.4) at 10 years. The probability of developing terminal ileitis, thus disease classification change – Crohn’s disease was 2.6% (SE:1.5) at 5 years and 3.5% (SE:1.7) at 10 years. Perianal disease developed in 5% (n=6) of all patients during the total follow-up. The probability of receiving biological therapy in patients diagnosed after the year 2000 (n=62), was 15.5% (SE:4.8) at 5 years, and 19.4% (SE:5.3) at 10 years. The overall resective surgery rate was 16.8% at the end of follow-up. Segment resection was performed in 5.0% of the patients, and 11.8% underwent subtotal- or total colectomy. The cumulative probability of resective surgery was 7.6% (SE:2.4) at 1 year, 9.3% (SE:2.7) at 5 years, 13.5% (SE:3.3) at 10 years, and 18.5% (SE:3.9) at 20 years. ​

Conclusion

Initial disease phenotype was severe in most cases of IBD-U and colonic progression is substantial over time. Disease classification change to Crohn’s disease with development of terminal ileitis or perianal disease was low. High rates of biological therapy and surgery are suggestive of a severe disease course of IBD-U.

Introduction

Gastric injury induces metaplasia is based on parietal cells loss and reprogramming chief cells into proliferative, mucin-rich spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Previously, we demonstrated that parietal cell-selective Slc26a9 deficiency in mice promotes the development of SPEM and progress to gastric intraepithelial neoplasia in mice (Liu et al., Cellular oncology; 2022; Deng et al., DDW2023). However, the exact role of Slc26a9 in injury-induced metaplasia is need further investigated.

Aims & Methods

We used immunostaining to characterize the expression pattern of Slc26a9 during murine gastric development, homeostasis, and injury in homeostasis, after conditionial genetic deletion of Slc26a9. Furthermore, to reveal the functional role of Slc26a9, Injury-induced metaplasia was established in Slc26a9^fl/fl mice and Slc26a9^fl/fl/Atp4b-Cre mice with high-dose tamoxifen.

Results

Mice with parietal cell selective Slc26a9 deficiency first developed spontaneous parietal cell damage, which subsequently led to SPEM. Parietal cell injury was associated with the release of typical pyroptosis factors, including NRLP3, Caspase-1, ASC, GasderminD, IL-1β and IL-18. At the same time, SLC26A9 colocalized with caspase1, NLRP3, GSDMD, and NLRP3 and GSDMD, and produced a large number of reactive oxygen species (ROS), markers of mitochondrial damage, thereby expanding membrane perforation of GSDMD-N fragments and amplifying inflammasome-mediated parietic cell pyrodeath. At the same time, electron microscopy showed that after the knockout of the Slc26a9 gene, the mitochondria of the murine wall cells were obviously swollen, the cell membrane structure was blurred and damaged, the matrix was more dissolved, the ridge was broken and disappeared, and there were many bubble protrusions. This suggests that parietal cell specific SLC26A9 gene deletion may lead to parietal cell scorch death through mitochondrial damage mediated by GSDMD. However, with a large number of parietal cell damage and loss, gastric hypergastrinemia stimulates Tuft cell proliferation and migration to the gastric mucosa for colonization, and secretes a series of alarm hormones such as IL-25, IL-33, HMGB1. Moreover, ILC2 cell secretory factors such as IL-17RA and IL-17RB, GATA3, CD90, CD25 were up-regulated. M2 macrophage polarization-related markers such as Arg1, Fizz1, Ym1, Klf4 and secreted chemokines such as CCL24 and CCL22 were significantly up-regulated. The immunofluorescence staining of F4/80+ and CD163+ was significantly increased. This suggests that the spontaneous injury of parietal cells caused by the deletion of SLC26A9 gene in gastric parietal cells may lead to gastric dysfunction (hypoacid and hypergastrinemia) and mucosal epithelial injury, which may promote the occurrence of SPEM through IL-25 mediating the activation of ILC2 cells to regulate the cellular immune mechanism of macrophage M2 polarization.

Conclusion

Slc26a9 target deletion in parietal cells leads to spontaneous damage and scorch death of parietal cells, which is the core target and cell origin of initiating SPEM. After parietal cell specific Slc26a9 gene deletion leads to spontaneous injury of parietal cells, gastric dysfunction and mucosal injury result in the release of alarm hormone IL-25, which promotes the development of SPEM by activating IL-25-ILC2-macrophage M2 polarization axis. Slc26a9 plays an important protective role in stabilizing gastric epithelial cell differentiation and gastric mucosal immune homeostasis.

Disclosure

No conflict of interest

Clinical Case Summary

Renal transplant recipients are at an increased risk of opportunistic infections, and a subset of this population may develop de novo inflammatory bowel disease (IBD). Differentiating the various forms of post-transplant colitis is challenging. Chronic active EBV enteritis is rarely reported and easily misdiagnosed as IBD, which results in death in severe cases.
A 61-year-old man with a history of kidney transplant presented with bloody diarrhea, fever and weight loss. Ileocolonoscopy showed ulcers in the ileum and the right colon. He was empirically started on ganciclovir and mycophenolate mofetil (MMF) was suspended. Colonic biopsies showed unspecific findings. Cytomegalovirus infection, Clostridioides difficile infection, intestinal tuberculosis and lymphoproliferative disease were excluded. The hypothesis of de novo IBD was postulated. Two months later the patient presented with non-bloody diarrhea and fever. Steroid therapy was increased and everolimus was added. A repeat ileocolonoscopy showed pancolitis and ileitis with oval transversal ulcers. Biopsies were positive for EBV by in-situ hybridization, suggesting an EBV-induced enteritis. Serum viral load was 1397 IU/mL. Immunosuppression was reduced and intravenous immunoglobulin therapy was administered. The patient did not respond and developed hemorrhagic shock with indication for salvage surgery (subtotal colectomy). Less than one month later the patient died due to hemorrhagic shock.
Chronic active EBV infective enteritis should be considered for patients who exhibit IBD-like symptoms and showing irregular ulcers in both colon and small intestine. Clinicians should recognize the presence of EBV infection to avoid misdiagnosis. However, chronic immunosuppression and opportunistic infections, such as EBV, are potential triggers of de novo IBD. Management is challenging and still controversial. Janus kinase inhibitors represent a promising treatment strategy as they target the EBV-driven pathway.

References

- Choi C, Yu Q, Deb PQ, Wang W. Rare case of EBV-induced colitis in an immunocompetent individual. BMJ Open Gastroenterol. 2020;7(1):e000360;
- Liu R, Wang M, Zhang L, et al. The clinicopathologic features of chronic active Epstein-Barr virus infective enteritis. Mod Pathol. 2019;32(3):387-395;
- Gioco R, Puzzo L, Patanè M, et al. Post-transplant colitis after kidney transplantation: clinical, endoscopic and histological features. Aging (Albany NY). 2020;12(24):24709-24720;
- Zhang H, Zhao S, Cao Z. Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease. Front Immunol. 2022;13:1001055;
- Lv K, Yin T, Yu M, Chen Z, Zhou Y, Li F. Treatment Advances in EBV Related Lymphoproliferative Diseases. Front Oncol. 2022;12:838817.

Introduction

Therapeutic goals and clinical guidelines in Crohn’s disease (CD) have evolved to include endoscopic outcomes being a key prognostic parameter in disease management. STRIDE-II guidelines comprise of clinical and patient-reported outcome remission, along with biomarker normalization and endoscopic healing. While available publications have correlated achievement of endoscopic response with long-term outcomes, few if any have adjusted for clinical remission status. Moreover, most of the data comes from patients treated with immunomodulators and/or TNFs. The objective of this analysis was to assess the impact of endoscopic response at the end of maintenance and long-term outcomes while adjusting for clinical remission status at maintenance.

Aims & Methods

Data from two randomized clinical trials (GALAXI-1, NCT03466411 and IM-UNITI, NCT01369355) were pooled to assess the impact of endoscopic response at 1 year on long-term patient relevant outcomes including clinical response, clinical remission, quality of life as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), and risk for hospitalizations/surgeries. This post-hoc analysis assessed endoscopic response at the end of maintenance (~48 weeks) and patient relevant outcomes in the long-term extension (LTE) duration (~96 weeks). Patients without LTE outcome data and placebo treated patients were excluded. Multivariate analyses with trial as a random effect were conducted and adjusted for treatment arm during maintenance, clinical remission status at end of maintenance (EOM), and endoscopic response at EOM.

Results

A total of 461 patients had available endoscopy and clinical remission status at EOM (IM-UNITI, N=177; GALAXI-1, N=284). The number of patients with available LTE outcomes ranged from 290 (IBDQ remission) to 383 (clinical remission/clinical response). Endoscopic response at EOM was significantly associated with higher odds of LTE clinical remission and IBDQ remission with ORs of 1.91 and 1.99 respectively, with corresponding p values below 0.05. Endoscopic response at EOM was also associated with lower odds of LTE C-reactive Protein abnormality (OR=0.46, p<0.005), a marker of inflammation and disease activity. Lastly, a greater percentage of patients without endoscopic response at EOM experienced hospitalizations/surgeries though the difference was not significant due to low event counts (16% versus 9%, p=0.1237).

Conclusion

This analysis uses clinical data from robust trials and adjusted for patients’ clinical remission status at the end of maintenance to isolate the benefit of endoscopic response in predicting long-term outcomes. Endoscopic response is significantly associated with more patients reaching clinical remission and better quality of life. Further investigation in large datasets with longer follow-up is needed to better understand whether measures of endoscopic improvement are also good surrogates for reductions in hospitalizations and surgeries.

Disclosure

Janssen Global Services provided funding for this research and I am an employee of Janssen

Introduction

The incidence of elderly-onset ulcerative colitis (EO-UC) and Crohn’s disease (EO-CD) is increasing globally. However, whether the initial disease presentation of EO-UC and EO-CD differs from that in adult-onset (AO) is currently poorly investigated.

Aims & Methods

The aims of this study were to explore the initial presentation, severity, and disease course of newly diagnosed EO-UC and EO-CD (age ≥60 years) in comparison to AO-UC and AO-CD (18–59 years). The study was conducted as an ongoing prospective population-based inception cohort, IBD Prognosis Study, with enrollment between May 2021 and April 15^th, 2023, within a catchment population of 1.050.000 citizens (~20% of the Danish population). We defined severe disease course as requiring surgery or initiation of biological therapies within six months of diagnosis.

Results

The cohort comprised 501 patients, including 398 (79.4%) with AO disease (AO-UC: 223 (56.0%), AO-CD: 145 (36.4%), AO-IBDU: 30 (7.5%)), and 99 (19.8%) with EO disease (EO-UC: 64 (64.6%), EO-CD: 35 (35.4%), EO-IBDU: 5 (5.1%)). A comparison of the clinical presentation, severity, and initial disease course is presented in Table 1. As shown, EO-UC and EO-CD did not differ significantly from AO-UC and AO-CD in terms of demographic factors, disease phenotype, severity, and initial therapy. However, a significantly higher proportion of patients with EO-UC had left-sided UC, and tended to be treated less frequently with biological therapies and immunomodulators.
In a Cox multivariable regression model with Bonferroni correction adjusting for disease type and gender, patients with EO-UC (adjusted hazard ratio (aHR)=1.9 (95% confidence interval (CI) 0.5-7.3)) and EO-CD (aHR =4.1 (95% CI 0.3-12.3)) were not at different risk of requiring surgery or initiation of biological therapies within six months of diagnosis than patients with adult-onset IBD.
Table 1: Pairwise comparison of newly diagnosed elderly-onset and adult-onset inflammatory bowel diseases

Conclusion

In this population-based study, we found no difference between EO-IBD and AO-IBD in terms of initial disease presentation, severity, and course. However, patients with EO-IBD tended to be treated with less biological therapies and immunomodulators.

Disclosure

Mohamed Attauabi: None
Gorm Roager Madsen: None
Flemming Bendtsen: Tillotts, Ferring
Klaus Theede: Ferring, Janssen, Takeda, Pfizer, and Tillotts
Jakob Benedict Seidelin: has received research grants from Takeda, Janssen and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. None of these pertain to the research submitted here.
Johan Burisch: reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos, outside the submitted work.