Introduction

Currently three JAK inhibitors (JAKi) are licensed for use in UC. Establishing real-world data, via large multicentre cohorts is key in gaining a better understanding of their effectiveness and safety in day to day practice.

Aims & Methods

Our aims were to evaluate the real-world effectiveness and safety of the JAKi; upadacitinib, tofacitinib and filgotinib for the treatment of UC across Scotland, UK. We conducted a retrospective, multicentre, cohort study including data from 14 hospitals in Scotland, UK. Adult patients (>18 years) with a diagnosis of UC or IBDU favouring UC and minimum of 8-weeks follow up post initiation of JAKi for active disease were included. Patients receiving JAKi for indication of acute severe UC were excluded. The primary outcome was treatment persistence of each JAK-i (tofacitinib, upadacitinib, filgotinib) at week 24. Secondary endpoints included un-adjusted comparison of persistence (Kaplan-Meier survival analysis, log-rank test for comparison), predictors of JAKi persistence (multi-variable Cox regression analysis), corticosteroid-free clinical remission, biochemical remission (C-reactive protein ≤5 mg/L) and faecal calprotectin remission (<250 µg/g) at week 8 and 24. Patients who stopped therapy due to lack of efficacy prior to these time points were considered failures. Serious adverse events (SAE) (defined as events leading to to hospitalisation, cessation of drug, disability or death), adverse events (AE) of infection and AE of interest were also documented.

Results

A total of 480 patients (upadacitinib, n=71; tofacitinib, n=208; filgotinib, n=201) had received a JAKi between 2019 (2nd Quarter) and 2023 (4th Quarter) and also fulfilled our inclusion criteria. The median follow-up of the total cohort was 1.4 years (IQR 0.6-2.6 years). The median age and disease duration was 39.0 years (IQR 29.0-52.0 years) and 5.9 years (IQR 2.2-11.1 years), respectively. Cumulative treatment persistence was 83.3%, 76.5% and 80.8% at week 24 in the upadacitinib, tofacitinib and filgotinib cohorts, respectively. There was no significant difference in un-adjusted persistence at week 24 between the three types of JAKi (log-rank, p=0.69). Multi-variable Cox regression revealed that patients with mild (HR 0.5, 95% CI 0.3-0.9, p=0.02) and moderate (HR 0.6, 95% CI 0.4-1.0, p=0.046) clinical disease activity at baseline had a lower risk of treatment cessation, whilst female patients (HR 1.5, 95% CI 1.0-2.2, p=0.03) and current smokers (HR 3.2, 95% CI 1.1-7.4, p=0.02) had a greater risk of treatment cessation. Effectiveness outcomes were similar across the three JAKi cohorts (Table 1). SAEs and AE of infection were lowest in the filgotinib cohort, with a signal towards higher rates of Herpes Zoster with tofacitinib (Table 1).

Table 1. Effectiveness and safety outcomes of ScotJAK cohort.
(PGA, physician's global assessment; pMayo, partial Mayo score; SCCAI, simple clinical colitis acitivity index; MACE, major adverse cardiovascular events; VTE, venous thromboembolism).

Conclusion

We have shown in a large, multi-centre study, encompassing a broad range of hospital practices that all three JAK-i are effective at treating patients with UC in the real-world.

Introduction

Epithelial injury is a hallmark of chronic mucosal damage in Crohn’s disease (CD), which can lead to fibrostenotic strictures. Type VII collagen, a critical component of the epithelial basement membrane, forms U-shaped anchoring fibrils that link the basement membrane to the interstitial matrix by binding fibrillar collagen. Genetic mutations in the COL7A1 gene, which encodes type VII collagen, are known to impair fibril formation and reduce tissue tensile strength, resulting in epithelial dysfunction, as seen in disorders such as dystrophic epidermolysis bullosa. This highlights the essential structural role of type VII collagen in maintaining matrix stability. In CD, the importance of this protein is underscored by the presence of autoantibodies targeting type VII collagen in up to 50% of patients with CD. Loss of tissue integrity, because of loss of the interaction between the basement and interstitial matrix, leads to tissue dysfunction and fibrosis.

Aims & Methods

We investigated C7M, a biomarker of type VII collagen degradation, to assess its specificity for intestinal mucosal damage. We analyzed serum samples from CD patients enrolled in a prospective cohort study. The cohort included 62 CD patients undergoing surgical resection for fibrostenotic strictures and 49 patients with luminal disease receiving treatment adjustments without surgery. Serum was collected at baseline, post-operative day 1 (POD1), and one-month post-resection. C7M levels were quantified using a competitive ELISA.

Results

At baseline, C7M levels were significantly elevated in fibrostenotic CD patients (median: 9.79ng/mL) compared to those with luminal CD patients (median: 6.03ng/mL) (p<0.01, AUC: 0.69). In the resected group, C7M levels rose sharply on POD1 (p<0.0001, AUC: 0.81), suggesting acute release in response to surgical injury. By one-month post-surgery, C7M levels had returned to baseline, closely resembling those observed in luminal CD patients (p<0.0001, AUC: 0.80). C7M also demonstrated mild-moderate correlations to biochemical markers of inflammation, including CRP (rho=0.62, p<0.0001), hemoglobin (rho=-0.28, p=0.0024), thrombocytes (rho=0.24, p=0.0105), albumin (rho=-0.52, p<0.0001), and fecal calprotectin (rho=0.25, p=0.019).

Conclusion

C7M was elevated in fibrostenotic CD patients relative to luminal CD, indicating its potential as a biomarker of more severe or complex mucosal pathology. The pronounced but transient increase following surgery, with normalization within one month, further supports C7M as a dynamic marker of intestinal epithelial damage. These findings suggest C7M may serve as a novel, disease-specific biomarker for assessing mucosal integrity and inflammatory burden in CD.

Disclosure

Full time employee at Nordic Bioscience

Introduction

Janus kinase inhibitors (JAKi) exhibit distinct performance characteristics versus monoclonal antibody (mABs) biological agents in the management of ulcerative colitis (UC). There is a lack of direct comparative effectiveness data of JAKi small molecules versus mABs in the real world.

Aims & Methods

In the absence of direct head-to-head comparisons, we determined the persistence of tofacitinib (TOF) versus vedolizumab and tumour necrosis factor inhibitor (TNFi) mABs in advanced therapy (AT)-naïve and AT-exposed real-world UC subjects from a population-based prospective registry.

The Persistence Australian National IBD Cohort (PANIC5) registry collected AT prescribing data for the entire Australian population up until Dec 2021. In Australia, all advanced therapies for IBD are prescribed without a hierarchical order in subjects with moderate-severe UC refractory to conventional therapies, irrespective of occupation and insurance status. Treatment is provided indefinitely in those that enter into clinical remission. Non-persistence was defined as failure to continue AT prescriptions for >6-months. Propensity score matching (PSM) statistically controlled for baseline selection biases. Kaplan-Meier survival curves were generated for AT persistence and compared using the log-rank test. Cox proportional hazards regression models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI). P<0.05 was deemed statistically significant (SPSS, USA).

Results

A total of 9,671 consecutive UC patients were recruited (53% male, 23,348 patient-years of follow up). The cohort comprised 14,772 treatment lines: 6,044 infliximab (IFX), 1,981 adalimumab (ADA), 5,467 vedolizumab (VED), 750 golimumab (GOL) and 530 tofacitinib (TOF). TOF exhibited superior persistence versus IFX (HR: 1.88, 95%CI: 1.34-2.63, P<0.001), ADA (HR: 2.10, 95%CI: 1.49-2.94, P<0.001) and GOL (HR: 2.20, 95%CI: 1.55-3.11, P<0.001) but not versus VED (HR: 1.28, 95%CI: 0.92-1.80, P=0.14). Following PSM, TOF was not significantly higher in persistence compared to mABs among AT-naïve subjects (all P>0.05). However, TOF showed superior persistence compared to all mABs among AT-exposed (all P<0.001). The persistence of TOF (P=0.77) did not significantly decline moving from AT-naive- to AT-exposed treatment status, unlike for TNFi (-8 months) and VED (-19 months, both P<0.001). PSM-multivariate Cox regression showed predictors of higher persistence to be use of TOF, AT-naïve status, use of immunomodulator. Rankings of persistence of ATs are presented for AT-naïve- and AT-exposed UC subjects (Table).

Conclusion

This is the first real-world study comparing treatment effectiveness using a national universal insurance persistence dataset. It found that tofacitinib had significantly greater persistence than biological agents in patients with ulcerative colitis who had previously received advanced therapy. Unlike monoclonal antibodies, tofacitinib did not show a decline in persistence after exposure to advanced therapy. Given these findings, JAK inhibitors like tofacitinib should be strongly considered for patients switching advanced therapies in ulcerative colitis.

Disclosure

RL advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, MRFF

Introduction

In corticosteroid-resistant acute severe ulcerative colitis (ASUC), second-line treatment involves infliximab or cyclosporine (CYCLO). With increasing antiTNFα exposed patients, CYCLO is often chosen to prevent emergency colectomy but is limited to the induction phase due to tolerability, serving as a bridge until effective maintenance therapy. In this setting, limited data on vedolizumab (VDZ) and ustekinumab (UST) as maintenance make the choice of an optimal bridge strategy challenging. This study aimed to compare the efficacy of VDZ and UST after CYCLO induction in corticosteroid-resistant ASUC.

Aims & Methods

This single-center retrospective cohort included all patients hospitalized for ASUC, responding to CYCLO induction, and starting VDZ or UST maintenance. ASUC was defined by modified Truelove and Witts criteria, with response to CYCLO defined by a Lichtiger score reduction to <10 points for 2 consecutive days, with a minimum 3-point decrease by day 7. The primary outcome was colectomy-free survival; secondary outcomes were treatment persistence and safety.

Results

From 2014-2024, 62 ASUC patients received CYCLO. Eighteen were excluded (non-response, tofacitinib [n=7], infliximab [n=3], and/or emergency colectomy [n=14]), leaving 44 CYCLO-responsive ASUC patients (median age 39, IQR 30-58, 60% female), with 35 on VDZ (79%) and 9 on UST (21%). ASUC was related to ulcerative colitis in 84% (73% pancolitis) and undetermined or Crohn's colitis in 16%. Disease duration was 7 years (IQR 2-15), with 91% prior biologic exposure, primarily antiTNF. Presentation included Lichtiger score 10 (IQR 10-12), CRP 46 mg/L (22-79), albumin 29 g/L (27-30), fecal calprotectin 778 µg/g (450-1650), UCEIS 7 (5-8), and Mayo endoscopic score 3 (3-3). Colectomy-free survival at 2 years was 79% with VDZ and 47% with UST (p=0.03). Treatment persistence at 2 years was 43% with VDZ, and 47% with UST (p=0.47). After adjusting for maintenance therapy, disease type, and severity, colectomy risk factors included hypoalbuminemia (HR=1.2; 95%CI:1.02-1.4, p=0.018) and prior tofacitinib exposure (HR=9.1; 95%CI:1.5-55.6, p=0.017). Over a median 37-month follow-up (95%CI:35-40), 34% of patients experienced adverse events, with 19% severe (mainly CYCLO-related), including 2 deep vein thromboses in the VDZ group and 1 infection in the UST group. No deaths occurred.

Conclusion

Our study suggests that VDZ may provide higher colectomy-free survival at 2 years than UST in CYCLO-responsive ASUC, with comparable treatment persistence. Hypoalbuminemia and prior tofacitinib exposure were identified as independent risk factors for colectomy, emphasizing the role of patient profiling in treatment selection. Further prospective studies are needed to refine bridge strategies in ASUC.