Introduction

​While ulcerative proctitis (UP) is considered to be a less severe form of ulcerative colitis (UC) it profoundly impairs quality of life. UP has been understudied with regard to potential treatments as it was historically excluded from UC phase 2 and 3 randomized controlled trials. There is currently limited evidence to support the use of tofacitinib in patients with UP.

Aims & Methods

We aimed to assess the effectiveness and safety of tofacitinib for the treatment of UP.
We conducted a retrospective multicenter study in seventeen GETAID centers. All consecutive patients with chronic anti-TNF refractory UP treated with tofacitinib were included. The primary outcome measure was steroid-free clinical remission at induction (assessed from week 8 to week 14), defined as a partial Mayo score of 2 or less with no individual subscore above 1. Secondary outcomes included clinical response (decrease of at least 30% of the partial Mayo score) at induction and steroid-free clinical remission and response at one year. Persistence rates of tofacitinib were assessed with Kaplan Meier survival analysis. Univariate and multivariate logistic regression with backward selection was performed to identify factors associated with steroid-free remission at induction.

Results

We enrolled 35 patients (median age of 45.9 year-old, interquartile range (IQR) [35-52.3]) who had previously received a median of 2 (IQR [2-3]) lines of biologics for UP, all of whom had been exposed to anti-TNF therapy, 74% to vedolizumab and 25% to ustekinumab. At the time of inclusion, the median partial Mayo score was 7 (IQR [5.5-7]), and all patients had an endoscopic subscore of 2 or 3 (endoscopic assessment available for 26 patients at baseline). After induction, 42.8% (15/35) of patients achieved clinical steroid-free remission, while 60% (21/35) achieved clinical response. At one year, the steroid-free clinical remission and response rates were 39.4% (13/33) and 45.5%, respectively (15/33).In multivariate analysis, the only factor independently inversely associated with steroid-free clinical remission at induction was the baseline partial Mayo (adjusted odds ratio of 0.56, 95%CI (0.33-0.95) for an increase of one unit) (Table 1).
Treatment persistence was estimated at 68% (95% Confidence Interval (CI) [54.1-85.6]) at 6 months, and 50.4% (95% CI [35.5-71.6]) at one year. Five (14.3%) adverse events were reported, with one case leading to treatment withdrawal (septic shock secondary to cholecystitis). In addition, one herpes zoster, one COVID, one bronchitis, and one bartholinitis occurred. No major acute cardiovascular event and no death occurred.

Conclusion

Here we present the largest real-world evidence of tofacitinib in patients with UP. These findings suggest that tofacitinib offers a therapeutic option for patients with anti-TNF refractory UP.

Introduction

Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking drug indicated for ulcerative colitis (UC), is administered intravenously at Weeks 0, 2, and 6, then every 8 weeks (Q8W). Dose escalation to every 4 weeks (Q4W) may recapture response to treatment in ~50% of patients with inadequate response. Real-world outcomes and factors associated with VDZ dose escalation from Q8W to Q4W remain underexplored.

Aims & Methods

Adults with moderate to severe UC initiating VDZ Q8W maintenance were prospectively followed in a Canadian patient support program (2015-2023). Two cohorts were included: 1) patients escalated to Q4W during maintenance after week 14 infusion (Q8W>Q4W maintenance) and 2) patients maintained on Q8W treatment for ≥2 years without escalating (Q8W maintenance). Rates of clinical remission (partial Mayo Score [PMS]<3) were described by prior biologic experience. Associations between baseline characteristics and clinical remission 3 months after Q4W dose escalation were assessed using Wilcoxon rank sum test and Fisher’s exact test. Treatment persistence at 12 and 24 months after initiation and dose escalation were evaluated in Q8W>Q4W maintenance using Kaplan-Meier survival analysis.

Results

373 patients (68% bio-naïve) and 300 patients (72% bio-naïve) were included in the Q8W>Q4W maintenance and Q8W maintenance cohorts, respectively. Median age at treatment initiation was 47 years in Q8W>Q4W maintenance and 48 years in Q8W maintenance. Both cohorts had a median baseline PMS score of 6. In Q8W>Q4W maintenance, median disease duration before treatment initiation was 4 years and median follow-up was 19 months. In Q8W maintenance, median disease and follow-up duration were 5 years and 35 months, respectively. 14 weeks post-treatment initiation, rates of remission in Q8W>Q4W maintenance were 49% (bio-naïve) and 42% (bio-experienced), and in Q8W maintenance were 72% (bio-naïve) and 70% (bio-experienced) (Table 1). Among patients in Q8W>Q4W maintenance not in remission when dose escalating, 40% achieved clinical remission 3 months after dose escalation. These patients were older at treatment initiation (49 vs. 41 years, p=0.043) and had longer disease duration (6 vs. 3 years, p=0.029) than those who did not achieve remission. In Q8W>Q4W maintenance, 12- and 24-month treatment persistence after initiation was 83% and 48% (bio-naïve) and 79% and 51% (bio-experienced), respectively. After dose escalation, 12- and 24-month treatment persistence was 48% and 39% (bio-naïve) and 53% and 45% (bio-experienced).

Conclusion

Patients with UC who underwent VDZ Q8W>Q4W dose escalation achieved lower rates of remission than those remaining on Q8W, regardless of prior bio-experience. Age at treatment initiation and disease duration were significantly associated with remission among those who escalated to Q4W.

Disclosure

JFL: AbbVie, BMS, Janssen, Frenesius-Kabi, Pfizer, Sandoz, Takeda.
EJB: 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.
AHS: Advisory Board Membership/Consultant: Abbvie, Amgen, BioJAMP, BMS, Celltrion, 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.
PW: Personal fees from AbbVie, Ferring, Biogen, and Janssen
MJA, AW, RW: were employees of Takeda Canada Inc. at the time of the study.
RM, JW, CP: were employees of Pentavere Research Group Inc. at the time of the study.
LPB: Consulting from AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HACPharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio; grants from Takeda, Fresenius Kabi, and Celltrion; and lecture fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, and Medac.
BB: 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.

Introduction

Biologic therapies such as anti-TNF-alpha agents (infliximab, adalimumab), interleukin modulators, and gut-selective integrin antagonists like vedolizumab have significantly improved outcomes in inflammatory bowel disease (IBD), leading to enduring remission, better quality of life, and reduced surgical intervention and hospitalizations. However, many patients may eventually lose response, often due to factors like the formation of anti-drug antibodies, altered drug metabolism, or individual patient characteristics. Dose escalation—by increasing dosage or reducing intervals—is commonly used to counteract this loss, especially for anti-TNF therapies guided by therapeutic drug monitoring. Vedolizumab poses a greater challenge in this regard due to the lack of standardized monitoring protocols. We aimed to investigate the effectiveness of dose-escalated infliximab, adalimumab, and vedolizumab in IBD patients who worsened after initial response, evaluating outcomes such as treatment persistence and clinical remission, to guide more personalized, cost-effective treatment strategies.

Aims & Methods

We conducted a retrospective analysis of IBD patients who underwent Infliximab (IFX), vedolizumab, or adalimumab (ADA) therapy dose escalation between 2020-2024 at a tertiary IBD centre. Primary outcomes included clinical remission using disease activity scores (Simple Clinical Colitis Activity/SCCAI Index for UC, Harvey-Bradshaw Index/HBI for CD), biochemical markers (CRP, faecal calprotectin) and treatment persistence, evaluated at 3-12 months, 12 months, and annually up to 36 months post-escalation.

Results

A total of 155 patients (median age 31 years, 46% female) were included, of which 89 patients (57%) were prescribed dose-escalated IFX, 48 patients (31%) were prescribed dose-escalated ADA and 18 patients (12%) were prescribed dose-escalated Vedolizumab. Of those included, 118 patients (76%) had Crohn’s disease, 36 patients (23%) had ulcerative colitis (UC) and 1 patient (1%) had indeterminate disease. Indications for dose escalation included secondary loss of response (SLOR) (105/155; 68%) and/or low drug levels (65/155; 42%). Dose-escalated IFX led to significant improvements in disease activity scores at 3 months (HBI: p=0.002; SCCAI: p=0.0003). Improvement in SCCAI was maintained at 12 months (p=0.00007), 2 years (p=0.0008) and 3 years (p=0.025). Improvement in HBI was maintained at 2 years (p=0.01) and 3 years (p=0.049). Significant improvement in CRP following dose-escalated IFX was reported at 3 months (p=0.011), 12 months (p=0.004), 2 years (p=0.006) and 3 years (p=0.03). Dose-escalated ADA led to a significant improvement in HBI at 3 months (p=0.023). This improvement was maintained at 12 months (p=0.005) and 2 years (p=0.008). Early improvement in faecal calprotectin was reported at 3 months (p=0.046). Significant initial improvement in SCCAI following dose-escalated Vedolizumab was reported at 3 months (p=0.043). This improvement was not maintained at any further follow-up points (p>0.05). Minor adverse events were reported in 3 patients receiving dose escalated ADA and in 6 patients receiving dose escalated IFX.

Conclusion

Our study demonstrates that biologic dose escalation is an effective and safe mechanism to recapture clinical remission, with high rates of treatment persistence.

Introduction

Granulocyte-monocyte apheresis (GMA) with Adacolumn® is a non-pharmacological treatment approved for the management of ulcerative colitis (UC), especially in steroid-dependent cases. The precise mechanism of action and immunological changes associated with GMA are still not fully understood. Gene expression analysis at the single-cell level (through scRNA-Seq) has emerged as a key tool to characterize drug responses at the molecular level.

Aims & Methods

Results

Conclusion

Introduction

Pancreatic cancer is a highly lethal disease, commonly characterized by aggressiveness and a unique tumor microenvironment, where mutant KRAS signaling stands as a hallmark event in its pathophysiology.

Aims & Methods

To deepen our understanding of KRAS-dependent signaling, stem cell-derived pancreatic ductal-like organoids (PDLOs) were induced by oncogenic KRAS expression, followed by time-resolved single-cell RNA- and bulk ATAC-sequencing. This unique precancerous state model facilitated a comprehensive characterization of early oncogenic events at cellular resolution.

Results

Specifically, mutated KRAS triggers two distinct gene signature programs: extracellular matrix remodeling and inflammation-related signaling. Correlation with published datasets underscored relevance of these distinct gene signatures in advanced cancer states within human patients. Various co-culture systems showed that KRAS^G12D-expressing PDLOs could induce cancer-associated fibroblast (CAF) activation while simultaneously shielding KRAS-activated, yet non-cancerous, organoids from T cell infiltration in vitro. Furthermore, in silico approaches were employed to reconstruct a virtual pancreatic cancer space, demonstrating that our PDLOs transcriptomically bridge healthy and malignant duct, while also unveiling the KRAS driven pathways mediating CAF reprogramming and T cell shielding preceding cancer onset.

Conclusion

In summary, our human PDLO model enables us to explore the transition from normal to cancerous states, overcoming gaps in our understanding of tumor development and tumor niche preparation.