Introduction

Chronic inflammatory bowel disease (IBD) is an early onset disease most often between the 2nd and 3rd decade, a second peak of incidence between 50 and 70 years old has been recognized.

Aims & Methods

The aim of our study was to describe the prevalence of elderly patients in IBD as well as the epidemiological, evolutionary and therapeutic profiles of these patients. Then, we compared the evolution of their IBD to younger patients.
We conducted a retrospective, descriptive, comparative study including patients hospitalized for IBD over a 9-year period [January 2011-January 2020]. Patients with less than 2 years of follow-up were excluded. We defined the elderly patients group, or group 1, as patients in whom IBD was diagnosed at an age ≥ 60 years. Group 2 represented younger patients.

Results

Of the 452 patients included, 6.8% (n=31) were elderly patients.
We first described this group of patients. The mean age was 64 years with extremes ranging from 60 to 80 years. The sex ratio M/F=1.6. Fourteen were smokers and 9 were occasional drinkers. For the history, 6 patients were diabetic, 7 had hypertension, and 2 were dyslipidemic. Only one patient had an associated autoimmune disease such as ALS-like syndrome. Fourteen patients had a BMI > 25kg/m². Sixteen patients had Crohn's disease (CD) and 15 had ulcerative colitis (UC). UC was of pancolic location in 7 patients, left in 3 and distal in 5 of them. For CD, it was mainly a colonic localization (n=6) and an inflammatory phenotype (n=9). A phenotypic progression was noted in only one patient, from stenosing phenotype to fistulizing phenotype. Twelve patients had extra-intestinal manifestations, exclusively rheumatological. Severe acute colitis was noted in 10 patients. Corticosteroids were used in 61% of the patients with a good response in 87% of them. Immunosuppressive therapy was used in 9 patients. Thiopurines were used in 100% of cases. Treatment with an anti-TNF α was indicated in 3 patients. Eight patients underwent surgery. These were mainly ileo-caecal resections (n=6).
After comparison, we found that patients in group 1 were significantly more overweight and obese compared to group 2 (45.2 vs 23%, p=0.006). The proportion of UC was significantly higher in group 1 (p=0.001). For patients with CD, there were significantly more ano-perineal manifestations in group 2 (p=0.015), however, the proportion of upper GI tract involvement was equivalent in both groups (p=1). The rate of surgical intervention was comparable in both groups (p=0,9). Nevertheless, the rate of use of immunosuppressive therapy was higher in group 2 (30% vs. 60%, p=0.045). Similarly for the rate of use of anti-TNF α therapy which was 9.6% and 33% in group 1 and 2 respectively (p=0.009).

Conclusion

In our study, we showed that elderly IBD has a mild disease course compared to younger patients. We found significantly lower rate of initiation of IBD medications in elderly patients.

Introduction

As the therapeutic armamentarium for inflammatory bowel diseases (IBD) is rapidly expanding, it is of increasing importance to optimize treatment sequencing. However, head-to-head trials comparing efficacy of vedolizumab (VDZ) in bio-naïve versus bio-experienced patients are scarce.

Aims & Methods

Aim: To compare the effectiveness of VDZ in bio-naïve versus bio-experienced patients with IBD in a real world setting.
Methods: A retrospective monocentric study was performed in IBD patients treated with VDZ at a Belgian University Hospital, from January 2018 to June 2021 with follow-up until December 2021. Primary endpoints considering efficacy after induction and after 1 year of therapy were: clinical response (CRp) and remission (CRm), biochemical response (BRp) and remission (BRm) and endoscopic response (ERp) and remission (ERm). Secondary endpoint was treatment survival during follow-up. For assessment of risk factors influencing efficacy and treatment survival, a multivariate logistic regression and Cox regression model (CRM) were applied.

Results

A total of 84 patients were treated with VDZ, 42 bio-naïve and 42 bio-experienced. At baseline, significantly more bio-experienced patients had prior intestinal resection (IR) (40.5% (17/42) vs. 16.7% (7/42), P=0.016), used an immunomodulator (IMM) (35.7% (15/42) vs. 16.7% (7/42), P=0.047) and had a longer disease duration (12.5 vs. 3.5 years, P<0.001). Bio-naïve patients had more moderate to severe comorbidities (21.4% (9/42) vs. 2.4% (1/42), P=0.007). After VDZ induction, CRp rate was higher in bio-naïve patients (60.9% (39/42) vs 39.1% (25/42), P<0.001). Multiple logistic regression analyses revealed that bio-naïve patients had a higher chance reaching CRp (aOR 14.69, 95%CI [3.12-69.14], P<0.001)(table). CRm was reached in 35.7% bio-naïve and 19% bio-experienced patients (P=0.087). No significant difference in BRp (P=0.932) or BRm (P=0.730) rate was found . A significantly higher ERp rate was seen in bio-naïve patients (90.3% (28/31) vs. 66.7% (18/27), P=0.027). Multiple logistic regression analyses showed a trend towards higher ERp rate in bio-naïve patients (aOR 4.65, [0.99-21.84], P= 0.051)(table). No significant difference was seen for ERm (32.3 % (10/31) vs. 11.1% (3/27), P=0.054). After 1 year of VDZ, CRp was significantly higher in bio-naïve patients (82.9% (34/41) vs. 62.5% (25/40), P=0.039). Multiple logistic regression analyses showed no significant difference between both groups. Univariate analyses showed significantly higher CRm rate in bio-naïve patients (70.7% (29/41) vs. 37.5% (15/40), P=0.003). After adjustment for age, disease duration, IMM use and prior IR, this difference was no longer significant. Patients without prior IR had significantly higher odds of reaching CRm (aOR 4.33,[1.13-16.59], P=0.032). No significant difference was seen for BRp (P=0.443) and BRm (P=0.313), nor for ERp (P=0.184) or ERm (P=0.061) in univariate analyses. Cox regression analysis showed significantly longer treatment survival in bio-naïve patients (aHR 2.32, [1.03-5.23], P=0.043).

Conclusion

In this tertiary real-world cohort of patients treated with VDZ, overall, a better efficacy was seen in bio-naïve compared to bio-experienced patients.

Disclosure

No conflict of interest

Introduction

Interleukin 33 (IL-33) is a pro-inflammatory cytokine that has been implicated in the pathophysiology of inflammatory bowel disease (IBD), ulcerative colitis (UC) in particular. IL-33 as a cytokine and an alarmin might evoke systemic inflammation, which could have ramifications for the functioning of the central nervous system, contributing to mood and sleep disorders. Disruptions in IL-33 concentration are well known to occur in the course of numerous psychiatric disorders as well as obstructive sleep apnea, a condition characterized by chronic low-grade inflammation and sleep fragmentation. To date, however, this protein has not been studied in relation to insomnia or poor sleep quality, frequently comorbid to chronic inflammatory and psychiatric diseases.

Aims & Methods

The study aimed to compare serum IL-33 concentrations of IBD patients and healthy controls as well as evaluate the association between the expression level of this interleukin, depression, sleep quality, and insomnia. IBD patients (n=81) and healthy controls (HC=44) were recruited. Harvey-Bradshaw index or partial Mayo were applied in the assessment of clinical disease activity for Crohn’s disease (CD) or UC respectively. Venous blood samples as well as questionnaires: Beck Depression Inventory (BDI), Epworth sleepiness scale (ESS), Athens Insomnia Scale (AIS), and Pittsburgh Sleep Quality Index (PSQI) were collected. Human IL-33 High Sensitivity Magnetic Luminex Performance Assay was used for the analysis of serum IL-33 protein concentration according to the manufacturer’s protocol. Fluorescence measurements were taken with MAGPIX, Luminex. The study has been funded by National Science Centre, Poland (2018/31/N/NZ5/03715).

Results

No differences were noted regarding IL-33 concentrations, sleep, or psychological variables between IBD patients and HC, except for sleep efficiency, which was higher in HC (p=0.004). Only in the IBD group, a positive correlation between IL-33 concentration and BDI, PSQI, and AIS (R=0.521, p=0.003; R=0.458, p=0.01; R=0.40, p=0.03), as well as negative one with sleep efficiency (R=-0.475, p=0.008) was noted. IBD individuals with high scores on ESS or PSQI (ESS>10, PSQI>5) had elevated IL-33 serum level compared to IBD patients without sleep problems (IL-33 concentration [pg/ml]: 53.385 (30.070-313.020) vs 18.795 (11.790-26.175), P=0.01 for PSQI; 270.900 (156.225-438.680) vs 21.840 (11.870-47.720), P=0.006 for ESS). IL-33 concentrations and questionnaire scores were comparable in patients with different disease activity. As for IBD types, in the CD, but not the UC group, IL-33 was positively correlated with the severity of depression symptoms and poor sleep quality (R=0.581, p=0.02; R=0.531, p=0.03) and negatively with sleep efficiency (R=-0.667, p=0.005).

Conclusion

IL-33 might be associated with mood and sleep disorders in IBD. It could exert its effect by promoting systemic and neuroinflammation, thus negatively affecting the well-being of IBD patients. Further research on the subject of changes in mental health of IBD patients in the context of anti-inflammatory or immunosuppressive treatment would be valuable.

Introduction

IL-33/ST2 axis and gut microbiota are important factors in the pathogenesis of IBD with a potential reciprocal influence. IL-33/ST2 axis controls the mucosal healing process during intestinal inflammation. Restorative proctocolectomy with ileal pouch-anal anastomosis is a surgical procedure in patients with ulcerative colitis (UC) refractory to medical therapies. Pouchitis, the most common complication, is the inflammation of the pouch with a controversial etiology.

Aims & Methods

We aimed to explore the potential role of IL-33/ST2 and gut microbiota axis in the inflammatory process of pouchitis.
30 UC patients with ileal pouch-anal anastomosis were enrolled. After clinical, endoscopic and histological assessment 18 showed pouchitis and 12 a normal pouch. Mucosal samples were collected from the afferent ileal loop and from the pouch and processed for cytokines assessment, histological evaluation and gut microbiota analyses. Multiplex analysis for inflammatory and regulatory cytokines was performed. ELISA and western blot were run to assess IL-33/ST2 protein levels and to evaluate protein isoforms, respectively. IHC was done to evaluate mucosal IL-33/ST2 expression and localization. Microbiota was analyzed by 16S ribosomal RNA gene amplicon pyrosequencing. Pouchitis Disease Activity Index and Pouchitis Histological Score were calculated, and CRP and fecal calprotectin were obtained for each patient. Multivariate analyses were run to generate transcriptional interaction networks and identify biomarkers for patients with inflamed pouches.

Results

IL-1Ra, IL-6, IL-8, IL-17, IP-10, MCP-1, MIP-1a, MIP-1b resulted increased in inflamed pouch vs. normal pouch. No differences were registered between samples obtained from the afferent ileal loop. In pouchitis, IL-7 resulted reduced in the inflamed pouch vs. the afferent ileal loop. In pouchitis, IL-33 and ST2 protein levels were reduced in the pouch vs. the afferent ileal loop and resulted overall decreased vs. patients with normal pouch indicating a potential IL-33/ST2-mediated defective healing process. Full-length, bioactive IL33, ST2L and sST2 were expressed in all experimental groups; the cleaved, less active form of IL33 was increased in only patients with pouchitis. IHC confirmed these observations. IL-33 and ST2 staining was less intense within the inflamed and ulcerated mucosa of pouchitis patients compared to normal pouch, and in close proximity to areas of re-epithelialization. An overall decreased biodiversity in patients with pouchitis vs. patients with normal pouch (both at pouch and afferent ileal loop level) was shown. Lower levels of Verrucomicrobia and increased abundance of Actinobacteria were recorded in inflamed pouch vs normal pouch. In pouchitis, the afferent ileal loop and the pouch showed significantly decreased levels of Akkermansia muciniphila and augmented abundance of Collinsella vs. samples obtained from patients with normal pouch. In pouchitis, multivariate analyses evidenced a significant inverse correlation between Collinsella e Collinsella aereofaciens abundance and ST2 levels.

Conclusion

In patients with pouchitis vs patients with normal pouch divergent inflammatory molecular pathways and microbial populations distinctly characterize the pouch and the afferent ileal loop. Overall, our results suggest a potential role for IL-33/ST2 and gut microbiota axis in driving the gut mucosal wound healing in patients with ileal pouch-anal anastomosis. Further studies are underway to determine mechanisms of action that support these findings.

Introduction

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory bowel disease, whose cause involves the interaction between genetic and environmental factors. At present, the pathogenesis of IBD has not been fully understood. Although there is a recognized link between immune response and IBD, the causal relationship between circulating immune cell counts and IBD remains controversial.

Aims & Methods

This study aimed to elucidate the causal relationship between genetically predicted circulating immune cell counts and IBD. We conducted a bidirectional two-sample Mendelian randomization (MR) study using aggregated statistics from genome-wide association studies. The causal relationship between five circulating leukocytes cells (monocytes, lymphocytes, eosinophils, basophils and neutrophils) counts and IBD, including Ulcerative colitis (UC) and Crohn's disease (CD) was analyzed. Inverse variance weighting (IVW) was used as the primary MR analysis method, and horizontal pleiotropy test and heterogeneity test were used to ensure the stability of the results.

Results

Our findings indicated that monocytes, lymphocytes, eosinophils, and basophils count were not significantly associated with IBD, however, elevated circulating neutrophils count was significantly associated with higher risk of IBD [odds ratio (OR): 1.002; 95% confidence interval (CI): 1.001–1.003; p = 0.009] and UC [OR: 2.465; 95%CI: 1.236–4.916; p = 0.01]. In addition, we also found that IBD [ OR: 12.07; 95% CI: 1.909-76.316; P = 0.008] and UC [OR: 2.465; 95% CI: 1.236 - 4.916; P = 0.01] were significantly associated with higher circulating neutrophils count in reverse MR.

Conclusion

This MR study provides genetic evidence for the causal relationship between the genetically predicted increase in circulating neutrophils count and the risk of IBD (UC and CD). This finding stresses the need for further exploring physiological functions of neutrophils in order to develop effective strategies against IBD.

Disclosure

The authors state that the study was conducted in the absence of any business or financial relationships that could be interpreted as potential conflicts of interest.

Introduction

Insulin-like growth factor binding protein 3 (IGFBP3) signals through the death receptor TMEM219 to modulate survival of target cells; inhibition of this signaling has been associated with a rescue of intestinal stem cell death.

Aims & Methods

Here we report the screening, generation, and characterization of fully human IgG monoclonal antibodies (mAbs) through phage display or by hybridoma technology, that block IGFBP3 or TMEM219. We used in vitro large crypts organoids (mini-guts) generated by crypts obtained from healthy subjects and from patients with inflammatory bowel disease to test the effect of the mAbs on the regenerative potentials. Expression of intestinal stem cell markers and apoptotic markers by RT-PCR was also analyzed.

Results

Both anti-IGFBP3 and anti-TMEM219 mAbs showed high affinity binding with the target antigens and potent effects in protecting self-renewal ability of intestinal stem cells in in vitro relevant assays. Among all the mAbs tested, anti-TMEM219 mAbs generated by phage display, particularly Ent001, showed the highest score in displacing the IGFBP3/TMEM219 binding and in rescuing ISC expression and function in IGFBP3-cultured human mini-guts obtained from healthy donors. In human in vitro proof-of-concept studies, in which we generated mini-guts from patients with immune-mediated intestinal disease such as Crohn’s disease, Ent001 successfully restored mini-guts growth and ISC markers’ expression, while expression of the proapoptotic IGFBP3-related factor Caspase 8 was downregulated.

Conclusion

Ent001 may represent a novel IGFBP3/TMEM219 inhibitor to be further tested and developed in in vivo models and in clinical studies as a novel therapeutic in human diseases.

Disclosure

P.F. and F.D. hold a patent on IGFBP3/TMEM219 axis. V.M., M.N., F.C. are employees of Enthera S.r.l.

Introduction

Nowadays, Non-Alcoholic Fatty Liver Disease (NAFLD) is a leading cause of liver disease and liver transplantation. Although obesity is a well-recognized risk factor for NAFLD, there are data to support that not all patients with NAFLD are necessarily obese. However, the evidence on the prevalence and risk factors for NAFLD in lean individuals with Inflammatory Bowel Disease (IBD) is scarce.

Aims & Methods

The aim of the study was to assess the prevalence and risk factors for NAFLD in lean population with IBD. This is a cross-sectional, case control study including lean individuals with IBD (cases) and lean individuals without IBD (controls), matched for age and sex. Patients with risky alcohol consumption, previous diagnosis of chronic liver disease (immune, viral, genetic) and secondary causes of NAFLD were excluded. All included patients were performed a liver ultrasound, transient elastography and laboratory tests. Lean individuals were defined as Body Mass Index < 25 kg/m², and NAFLD as ultrasound steatosis and/or Controlled Attenuation Paremeter >248 dB/m. A descriptive analysis was carried out, and the relationship between variables was assessed using Chi square test/Fisher´s test (categorical variables) or T-student/Mann-Whitney U test (quantitative variables), as appropiate. In addition, a multivariate analysis was performed, presented as adjusted Odds Ratio (OR) and 95% Confidence Interval (95%CI).

Results

A total of 443 participants, 363 lean cases and 80 lean controls, were included in the study. No differences were observed in terms of age, sex and metabolic risk factors between both groups (Table 1). The prevalence of NAFLD in lean individuals with IBD was significantly higher compared to lean individuals without NAFLD (22% vs. 10%, p=0.015). Multivariate analysis confirmed that IBD was an independent risk factor for NAFLD in lean population (OR 2.75 95%CI (1.18-6.41)). In addition, male sex (OR 1.78 95%CI (1.04-3.05)) and older age (OR 1.03 95%CI (1.01-1.05)) were identified as risk factors for NAFLD in lean individuals.

Table 1. Baseline characteristics of cases and controls.

Conclusion

The prevalence of NAFLD is significantly higher in lean population with IBD, suggesting that IBD could play a role in the development of NAFLD in lean individuals.

Disclosure

This project has received funding from “Diputación General de Aragón” (code: DGACOVID-02).