Introduction

Chronic inflammation in inflammatory bowel disease can lead to the development of intestinal fibrosis, exacerbating the disease. The activation of immune cells results in the release of pro-inflammatory cytokines suspected to drive the activation of fibroblasts and excessive formation of extracellular matrix proteins. While anti-inflammatory therapies exist, their direct effects on fibrogenesis are limited, and model systems for evaluating inflammation-dependent fibrosis are warranted.

Aims & Methods

We aimed to evaluate the profibrotic effects of activated macrophages in a gastrointestinal scar-in-a-jar model by quantifying type I, III, and type VI collagen and fibronectin formation biomarkers.
Macrophages (Mφ) were isolated from buffy coats from healthy donors and polarized to TNF-α producing M1-like macrophages (M1-Mφ) using 25 ng/mL IFN-γ and M-CSF over two rounds from days 0 to 6 and from days 7 to 12. The M1-conditioned media was collected on days 6 and 12 (experimental groups: days 0-6 and days 7-12). Colonic fibroblasts (CCD18-Co) were cultured in a crowded pseudo-3D environment using Ficoll (75 mg/mL Ficoll 400 and 112.5 mg/mL Ficoll 70) and supplemented with 50 µg/mL ascorbic acid to support collagen synthesis. Starting on day 0, exchanging the media every fourth day, the cells were stimulated with 0.3, 3, and 30% of M1 conditioned media, 50 pM TGF-β, or 25 ng/mL IFN-γ and M-CSF for 12 days, using 3% FBS as the control. The biomarkers PRO-C1, PRO-C3, PRO-C6, and FBN-C, quantifying type I, III, and VI collagen formation and fibronectin, were measured in the supernatants on days 0, 4, 8, and 12. The metabolic activity of the cells was assessed on days 0 and 12 using an Alamar Blue assay. The statistical differences in biomarker levels were calculated using the area under the curve (AUC) compared with the unstimulated FBS control applying Brown-Forsythe and Welch or one-way ANOVA tests.

Results

Quantified using the PRO-C1, PRO-C3, PRO-C6, and FBN-C biomarkers stimulation with 30% M1-Mφ media from days 0-6 and 7-12 resulted in a switch in collagen formation compared to the FBS control, reducing type I collagen and fibronectin and increasing type III and VI collagen formation (Table 1). A similar response was observed using 3% of 0.3% M1-Mφ media, though to a lesser degree (Table 1). The data suggest increased pathological fibroblast activity and fibrotic deposition of type III and VI collagen formation driven by Mφ-derived cytokines. TGF-β, a known profibrotic cytokine, induced a significant formation of type I, III, VI, and fibronectin compared to the FBS control (Table 1), demonstrating a different fibrotic biomarker profile than Mφ induced fibrosis. IFN-γ+M-CSF stimulation, used for Mφ activation, inhibited the formation of type III collagen (Table 1).

Conclusion

Stimulating colonic fibroblasts with conditioned media from activated macrophages induced a profibrotic response with increased type III and type VI collagen formation. The applied serological biomarkers enabled the objective quantification of collagen and fibronectin formation to assess fibrogenesis in the model and their potential use for investigating macrophage induced fibrosis.

Disclosure

Martin Pehrsson, Marta Alexdottir, Helene Hector, Morten Karsdal, and Joachim Mortensen are employed at Nordic Bioscience
Yi Luo and Eun Mi Hur are employed at Bristol-Meyers Squibb.
The remaining authors have no declaration of conflict.

Introduction

There is an ongoing paradigm shift toward serology-based diagnosis of celiac disease (CeD). It is essential to target potential endoscopies for those most likely to benefit. Anemia is a common symptom of CeD that may warrant further investigations, but the prevalence and clinical relevance of endoscopic findings in anemic CeD patients remain unclear.

Aims & Methods

The aim of this study was to compare the prevalence of upper and lower endoscopic findings between anemic patients and non-CeD controls, and to identify predictors of significant findings in CeD patients. Medical data, including upper and lower endoscopy findings, were collected from 162 CeD patients and 350 controls. Binary logistic regression analysis was used to identify predictors of findings.

Results

CeD patients were younger (median 49 vs 66 years, p<0.001) and had fewer risk factors such as smoking (14% vs 25%, p<0.001), alcohol abuse (4% vs 14%, p<0.001), chronic comorbidities (55% vs 83%, p<0.001), and previous malignancies (1% vs 8%, p=0.002).
In comparison of upper endoscopy findings, CeD patients had fewer significant findings (21% vs 53%, p<0.001), H. Pylori positive gastritis (6% vs 19%, p<0.001), gastric ulcers (0% vs 5%, p=0.006), and atrophic gastritis (3% vs 9%, p=0.005) compared to the controls.
Twenty-four patients and 208 controls had undergone lower endoscopy with celiac patients more frequently demonstrating significant findings (54% vs 28%, p=0.008), non-specific inflammation (21% vs 1%, p<0.001) and colorectal cancer (25% vs 9%, p=0.018).
Predictors of significant upper endoscopy findings in CeD patients were older age (OR 1.03, 95% CI 1.01-1.05), age >50 (2.44, 1.18-5.06), co-existing chronic conditions (3.45, 1.53-7.78), gastrointestinal symptoms (2.31, 1.07-4.98), and use of acetylsalicylic acid (2.38, 1.01-5.06), and of colonoscopy findings older age (1.01, 0.99-1.04), co-existing conditions (3.48, 1.12-10.8), and gastrointestinal symptoms (4.73, 1.34-16.7).

Conclusion

CeD patients had fewer findings on upper endoscopy but, despite being younger and having fewer risk factors, showed more findings on lower endoscopy compared to controls. In older CeD patients presenting with anemia, lower endoscopy should be strongly considered.

Introduction

Vedolizumab (VDZ) is a gut-selective anti-lymphocyte trafficking drug indicated for the treatment of CD and UC [1] administered by intravenous (IV) infusion at Weeks 0, 2, and 6 followed by IV infusions every 8 weeks (Q8W) or subcutaneous injections every 2 weeks [2,3]. For IV treated patients who experience a suboptimal or loss of response (LOR), dose escalation to every four-week infusions (Q4W) may recapture response to treatment [4] but there is a lack of large-scale real-world data describing outcomes of dose-escalated patients [5].

Aims & Methods

Patients with moderately to severely active UC or CD were prospectively followed in a patient support program in Canada from 2015 to 2023. Harvey-Bradshaw Index (HBI, CD) and Partial Mayo Scores (PMS, UC) were assessed 2, 6, and 14 weeks after treatment initiation to understand VDZ induction effectiveness. HBI or PMS were assessed 12 weeks post dose Q4W escalation to understand the effectiveness of dose escalation in the presence of suboptimal or LOR. Results are presented for patients who dose escalated to Q4W from Q8W maintenance (Q8W > Q4W), initiated Q4W at week 14 (w14>Q4W), or at week 10 (w10>Q4W). Remission was defined as HBI <5, or PMS <3. Response was defined as achieving remission or an HBI decrease of ≥3 points from baseline, or a PMS decrease of ≥2 points and ≥25% from baseline.

Results

1056 CD (45% bio-naïve) patients and 1959 UC patients (71% bio-naïve) were eligible for this study. The median follow up was 18 months (range 3-61). The median age was 48 years (range: 18-92), and 44 years (range:18-89) for CD and UC patients respectively. 60% of CD patients and 51% of UC patients were female. For CD patients the median baseline HBI score was 10 (range 8-40), and for UC patients the median baseline PMS score was 6 (range 5-20). Disease duration prior to VDZ was longer in bio-experienced patients compared to bio-naïve; CD (Medians: 14 vs 4 years) and UC (Medians: 6 vs 4 years). To further characterise the patient cohort induction effectiveness is reported. For CD patients, remission and response were 25% and 56% at 2 weeks, 34% and 66% at 6 weeks and 40% and 68% at 14 weeks. For UC patients, remission and response were 32% and 64% at 2 weeks, 48% and 78% at 6 weeks and 55% and 81% at 14 weeks. In CD, 39% (183 of 473) of bio-naïve patients and 52% (302 of 583) of bio-experienced patients dose-escalated to Q4W within the first two years. In UC, 37% (520 of 1399) of bio-naïve patients and 49% (275 of 560) of bio-experienced patients dose-escalated to Q4W within the first two years. At Q4W dose escalation, 319 CD patients (110 bio-naïve, 209 bio-experienced) and 514 UC patients (334 bio-naïve, 180 bio-experienced) were not in HBI or PMS remission. For these patients, remission and response 12-weeks post dose escalation to Q4W are presented in table 1.

Table 1: 12-week remission and response rates for pts dose escalated to Q4W from maintenance (Q8W>Q4W), at week 14 (W14>Q4W) or at week 10 (W10>Q4W)

Conclusion

Conclusion: IBD patients experienced clinically meaningful remission and response rates following induction with IV VDZ. For those that have a suboptimal or LOR this study demonstrates the real-world effectiveness of dose escalating VDZ to Q4W in Canadian patients with IBD to complement previous clinical trials, and real-world studies.

References

1. Argollo, M., et al., Novel therapeutic targets for inflammatory bowel disease. J Autoimmun, 2017. 85: p. 103-116.
2. Sandborn, W.J., et al., Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med, 2013. 369(8): p. 711-21.
3. Feagan, B.G., et al., Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med, 2013. 369(8): p. 699-710.
4. Varghese, D., et al., P632 Vedolizumab dose escalation in patients with inflammatory bowel disease experiencing loss of response: A systematic review and meta-analysis of real-world evidence. Journal of Crohn's and Colitis, 2020. 14(Supplement_1): p. S524-S525.
5. Peyrin-Biroulet, L., et al., Loss of Response to Vedolizumab and Ability of Dose Intensification to Restore Response in Patients With Crohn's Disease or Ulcerative Colitis: A Systematic Review and Meta-analysis.

Disclosure

Jessica Weiss - Employee of Pentavere Research Group Inc.
Dr. Christopher Pettengell - Employee of Pentavere Research Group Inc.
Dr. Jean-Frédéric LeBlanc - AbbVie, BMS, Janssen, Frenesius-Kabi, Pfizer, Sandoz, Takeda.
Dr. Edmond-Jean Bernard - Fees of SICLEO for my presentations, Participation in advisory boards or speaker services: Abbvie, Janssen, Takeda, Pfizer, Merck, Amgen, Pendopharm, Jamp, Fresenius, Kabi, Bausch Health, Celltrion, Eli Lilly, BMS, Grant/Research:Janssen, Abbvie, Any other investment or relationship that could be judged by a reasonable and knowledgeable participant to have the potential to influence the content of the training activity: Abbvie, Janssen, Takeda, Pfizer, Merck, Amgen, Pendopharm, Jamp, Fresenius, Kabi, Bausch Health, Celltrion, BMS
Dr. Brian Bressler: Advisor/Speaker: Ferring, Janssen, Abbvie, Takeda, Pfizer, BMS, Merck, Sandoz, Organon, Lifelabs, Celltrion. Advisor: Alimentiv, Gilead, Iterative Health, AMT, Celgene, Merck, Amgen, Pendopharm, Eli Lilly, BMS, Fresenius Kabi, Mylan, Viatris, Bausch Health, Celltrion Healthcare, BioJamp Pharma, Eupraxia. Research support: Janssen, Abbvie, GSK, BMS, Amgen, Genentech, Merck. Stock Options: Qu Biologic
Dr. A. Hillary Steinhart: Advisory Board Membership/Consultant: Abbvie, Amgen, BioJAMP, BMS, Fresenius Kabi, Janssen, McKesson, Mylan Pharmaceuticals, Organon, Pendopharm, Roche, Pfizer, Sandoz, Takeda, Viatris,Speakers’ Bureau: Abbvie, Amgen, Ferring, Fresenius Kabi, Janssen, Organon, Pfizer, Sandoz, Takeda,Research Grants: Abbvie, Arena, Celgene/BMS, Genentech, Janssen, Roche, Takeda
Dr. Ryan Ward - Employee of Takeda
Abhinav Wadhwa - Employee of Takeda