Biological Therapies In Ulcerative Colitis Research Articles

Efficacy of Second-Line Biological Therapies in Moderate to Severe Ulcerative Colitis Patients with Prior Failure of Anti-Tumor Necrosis Factor Therapy: A Multi-Center Study.

Few studies have compared the efficacy and safety of second-line biological therapies in ulcerative colitis (UC) patients with prior exposure to anti-tumor necrosis factor (TNF) therapy. We aim to compare the efficacy and safety between ustekinumab, vedolizumab, and tofacitinib, a current option as second-line biological therapy with different mechanisms in those patients. This retrospective multi-center study was conducted across five institutions from 2011 to 2022. We enrolled patients with moderate to severe UC who failed anti-TNF therapy and subsequently received ustekinumab, vedolizumab, or tofacitinib as second-line biological therapy. The outcomes were analyzed for clinical response/remission and endoscopic improvement/remission rates after induction therapy, drug persistency, and adverse events. A total of 70 UC patients were included and grouped into ustekinumab (11 patients), vedolizumab (40 patients), and tofacitinib (19 patients) treatments. The clinical response/remission rates after induction therapy were similar between ustekinumab (90.9/81.8%), vedolizumab (92.5/65.0%), and tofacitinib (94.7/73.7%). There were no significant differences in the endoscopic improvement/remission rates between the three groups: 90.9/18.2% for ustekinumab, 72.5/12.5% for vedolizumab, and 84.2/26.3% for tofacitinib. Drug persistence was similar across the three agents (p = 0.130). Three patients of the tofacitinib group experienced adverse events (herpes zoster and hypertriglyceridemia). Based on real-world data, second-line biological therapy with ustekinumab, vedolizumab, and tofacitinib showed comparable efficacy in patients with moderate to severe UC with prior exposure to anti-TNF therapy.

P691 Intestinal ultrasonography accuracy in the evaluation of patients with moderate to severe ulcerative colitis starting infliximab therapy

Abstract Background The diagnostic accuracy of detecting active ulcerative colitis (UC) by transabdominal intestinal ultrasonography (IUS) is well described. However, the value of repeated IUS measurements in tight monitoring during treatment remains to be established. The aim of the study is to evaluate the utility of IUS for monitoring biologic therapy in UC. Additionally, to establish the correlations between IUS findings and the endoscopic Mayo score (EMS), as well as clinical and biochemical severity indices. Methods In a prospective open-label study, individuals with moderate to severe ulcerative colitis who were initiating infliximab therapy were included, excluding those with proctitis. Patients were evaluated at baseline and after 3 months of biologics induction by means of clinical, biochemical, endoscopic mayo score, and IUS assessments. A Paired Wilcoxon analysis was conducted to compare data before and after therapy induction. The correlation between bowel wall thickness (BWT) and the endoscopic mayo score (EMS), C-reactive protein (CRP), calprotectin, and the Simple Clinical Colitis Activity Index (SCCAI) was analyzed across both visits. Results Thirty-two patients were enrolled and completed baseline evaluations and 21 completed follow-up assessments. The median age was 38 years (IQR 29-60), with 53% male, a median disease duration of 7 years (6-9), 41% having left-sided colitis, and 59% with pancolitis. All patients were treated with infliximab. No significant differences were observed at both time points in terms of BWT, EMS, CRP, and calprotectin (5.5 vs 4.4, p=0.2; 2 (2-3) vs 2 (1-3), p=0.4; 9.4 vs 9.6, p=0.4; 979 vs 394, p= 0.1, respectively). The only significant improvement was in terms of SCCAI (7 (4.8-8) vs 3 (1-5), p=0.009). BWT showed significant correlations with EMS (r= 0.43, p= 0.0015) (figure 1), CRP (r= 0.40, p= 0.007), and SCCAI (r= 0.28, p= 0.03), while no correlation was found with calprotectin (r= 0.19, p= 0.25). Conclusion Intestinal ultrasonography could serve as a substitute for lower endoscopy in evaluating disease activity.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

OP05 High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab therapy in ulcerative colitis

Abstract Background The unpredictability of response to biological therapy in ulcerative colitis (UC) patients, including vedolizumab (VDZ), an anti-α4β7 integrin antibody, poses a serious challenge for medical care. This study aims to identify the relevant cellular and molecular signatures that mark response to VDZ by combining single-cell transcriptomics (scRNAseq) and high-dimensional flow cytometry (Cytek). Methods Gut biopsies and peripheral blood mononuclear cells (PBMCs) from patients with active UC were collected 2 weeks prior and 14 weeks after starting VDZ therapy. Response was evaluated at week 14 based on endoscopy and Physician Global Assessment. Transcriptome profiles of 159.188 and 95.057 high-quality single cells were generated from biopsies and PBMCs, respectively. Additional 797.670 CD45+ mucosal cells and 900.000 PBMCs were processed for validating scRNAseq results by Cytek. Results From a total of 25 UC patients (mean age 41±12.7 years, 52% female, 36% anti-TNFα naive), 15 patients (60%) reached response at week 14. Patients with no prior use of anti-TNFα were more likely to achieve remission with VDZ compared to anti-TNFα exposed patients (89% vs 44% response rate, respectively). Analysis of cell abundances revealed a partial recovery of the epithelial and stromal cell mucosal compartments in responders at week 14. Both scRNAseq and Cytek show that in responders VDZ prevented T cells (CD8+IL17+ and CD4+PD1+ subsets) and innate immune cells (NKs, DCs and inflammatory monocytes) from entering mucosa, resulting in their enrichment in PBMCs. In contrast, non-response to VDZ was marked by an expansion of inflammatory fibroblasts and activated endothelial cells, and depletion of most epithelial subsets. VDZ retained CD4 T cells in PBMCs in non-responders, but failed to halt active mucosal inflammation at week 14. Strikingly, involvement of the innate immune cells in UC inflammation prior to VDZ treatment was much more prominent in non-responders who showed higher baseline abundance of NKs, ILCs, γδ-T cells, DCs and inflammatory monocytes in their peripheral blood and mucosa compared to responders. While VDZ inhibited integrin β7 expression on circulating T cells in all patients, only in responders it coincided with the lower mucosal abundance of lymphocytes, suggesting that T cells in non-responders might employ alternative, β7-independent trafficking routes. Conclusion This is the largest prospective scRNAseq study addressing the response to biological therapy in UC. We showed that active, innate immune cell-mediated inflammation marks the primary non-response to VDZ that persists prior to and throughout the treatment, accompanied by β7-independent lymphocyte migration.

CO93 Rates of Disease-Related Hospitalization and Colectomy in Real-World Patients With Ulcerative Colitis on Anti-Tnf Agents: Evidence From a Systematic Review

Anti-TNF agents (ATAs) are generally the first-line biological therapy in ulcerative colitis (UC) patients who have failed treatment with corticosteroids and/or immunomodulators. Patients with non-response/loss of response with ATAs undergo treatment switch or colectomy/surgery. We assessed the rates of UC-related hospitalization and colectomy among patients on ATAs in real-world UC patients.

Potential molecular biomarkers used to predict the response to biological therapies in ulcerative colitis.

Potential molecular biomarkers used to predict the response to biological therapies in ulcerative colitis.

Positioning biologics and small molecules in the management of moderate to severe ulcerative colitis.

This review addresses the selection of biologic and small molecule therapy for patients with moderate to severe ulcerative colitis (UC). With several new treatment options approved within the past few years, an update in positioning is timely and relevant. Updates on the safety and comparative efficacy of approved therapeutic agents for UC are presented. Newly approved therapies including tofacitinib and ustekinumab, as well as where to position these treatments are discussed. Data on the first-ever head-to-head trial of biologic therapy in UC are examined. This review provides an evidence-based overview of the optimal management strategies of patients in both the inpatient and outpatient settings. As we move closer towards the goal of personalized therapy for our patients with UC, we hope to better select appropriate and effective treatment options. Newly approved therapies provide us with additional options for management. Future advancements in predictive serologic, mucosal, genetic, and fecal markers can enable us to tailor therapy to an individual patient.

Immune Cells and Transcriptional Signatures Revealed Novel Regulators and Predict Clinical Response to Biologic Therapy in Ulcerative Colitis

Inflammatory Bowel Disease (IBD), which includes Crohn’s Disease (CD) and Ulcerative Colitis (UC), has a heterogeneous pathogenesis underlined by genetic predisposition, intestinal barrier dysfunction, impaired immune response, and microbiota imbalance.

P826 A predictive molecular classification developed in UC patients with active disease is observed consistently in a heterogeneous group of IBD patients

Abstract Background We have previously identified an unsupervised molecular classification of ulcerative colitis (UC) into two groups, UC1 and UC2, predictive of response to biologic therapy1. In that study, gene expression data in inflamed colonic biopsies from several published UC cohorts were used. UC1 is characterised by, for example, high expression of Cytochrome P450 26B1 (CYP26B1), calprotectin (S100A8) and interleukin 11 (IL11) and poor response to infliximab, which is also predicted by high expression of oncostatin M (OSM)2. In the current study the consistency of this classification was investigated in a heterogeneous group of inflammatory bowel disease (IBD) patients. Also, we sought to validate a quantitative polymerase chain reaction (qPCR) primer set as an alternative, more convenient methodology instead of microarray. Methods PCR primers for 7 differentially expressed genes that distinguished UC1 from UC2 in our microarray study were validated. OSM was also included. Separate gut biopsy samples (n = 44) from 15 patients, (8 Crohn’s disease, 7 UC), from different locations and at different time points, were analysed with qPCR. Results A heatmap of Pearson correlation coefficients (r) between gene expression levels and clinical factors for the pooled data was generated, Figure 1. Strong correlations, defined as 0.7 ≤ r ≤ 1.0, were found between OSM, CYP26B1, S100A8 and IL-11 (pairwise correlations were statistically significant, p < 0.00001). Similar inter-gene correlations were also observed within individual samples, (data not shown). Gene expression levels were not associated with inflammation, Figure 1. Conclusion These data demonstrate that the group genes we have previously identified as predictive of response to biologic therapy in UC, (CYP26B1, S100A8 and IL-11) plus OSM are also concordantly up-regulated in biopsy material from heterogeneous patients. Thus not only patients with active UC, but also other forms of IBD may be sub-grouped according to this gene expression pattern. The capacity of this gene expression profile to predict therapeutic response should therefore be tested in a broader range of IBD patients. The fact that the concordance of the up-regulation of these genes was independent of inflammation per se, supports the clinical significance of this molecular clustering. Establishment of qPCR-based characterisation into UC1 and UC2 presents a more convenient methodology for clinical stratification. References

DOP55 A real-world comparison of the effectiveness and safety of vedolizumab and anti-TNF therapies in early treatment initiation with first-line biologic therapy in ulcerative colitis: Results from EVOLVE

Abstract Background Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis. Methods This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts. Results This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes. Conclusion EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.

P409 Endoscopic and histological activity is associated with non-response to biologic therapy in ulcerative colitis

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterised by a relapsing and remitting course. Biologic therapy in UC has a 30% rate of primary non-response (PNR) and a further 5% loss of response per year. Prognostic indicators of non-response include younger age and longer disease duration. Emerging evidence suggests that endoscopic and histological activity is associated with adverse outcomes such as clinical relapse and colectomy. However, the role of endoscopic or histological disease activity in predicting non-response to biologic therapy is unclear. We aim to investigate the association of endoscopic and histological activity with non-response to biologic therapy in UC. Methods Patients with UC treated with biologic therapy between 2014 and 2019 were studied. Baseline endoscopic disease activity was assessed using the Mayo endoscopic subscore from endoscopy performed prior to commencing biologic therapy. Patients who underwent colonoscopy 3–9 months after commencing biologic therapy were selected for histopathological review. Sigmoid biopsies were evaluated by an expert gastrointestinal pathologist. Histological parameters were scored on a 4-point scale, with blinding to clinical and endoscopic outcomes. Results Sixty-six patients were followed for a median of 16 months (IQR 6–30), 12 (18%) of whom did not respond to biologic therapy initially and 3 (6%) of whom lost response secondarily. Baseline endoscopic activity was associated with non-response (OR 6.1, 95% confidence interval 1.3 – 29.4, for every 1-point increase in the 4-point Mayo endoscopic subscore). 23 patients were identified for histopathological review. Four (17%) patients exhibited PNR. Baseline crypt atrophy was associated with PNR (p = 0.014) and baseline bifid crypts and crypt atrophy were associated with 52-week clinical relapse (p = 0.482 and p = 0.0497). Conclusion For patients with UC, endoscopic disease activity assessed prior to commencing biologic therapy has the potential to predict non-response to biologic therapy. In addition, specific histological parameters relating to crypt inflammation and crypt architecture may also predict non-response. Further prospective studies should be conducted to investigate the clinical utility of assessing endoscopic and histological disease activity prior to commencing biologic therapy.

Short Disease Duration Is Associated With Increased Risk of Treatment Failure in Biologic-Treated Patients With Ulcerative Colitis.

Longer disease duration is associated with inferior response to biologic therapy in Crohn's disease. However, the effect of disease duration on response to biologic therapy in ulcerative colitis (UC) has not been well studied. In a single-center retrospective cohort study of outpatients with UC starting a biologic agent, we evaluated treatment response by disease duration. The primary outcome was treatment failure (composite outcome of inflammatory bowel disease [IBD]-related surgery/hospitalization or treatment modification including dose escalation, treatment discontinuation, or addition of corticosteroids); secondary outcomes were risk of IBD-related surgery/hospitalization and endoscopic remission. We conducted multivariate Cox proportional hazard analyses to evaluate the independent impact of disease duration on clinical outcomes. We included 160 biologic-treated UC patients (73% biologic-naïve) with a median age (interquartile range) of 36 (26-52) years and disease duration (range) of 4.5 (1-9) years. After adjusting for immunosuppressive medications, albumin, and body mass index, each 1-year increase in disease duration was associated with a 5% lower risk of treatment failure (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.91-0.99) and a 9% higher risk of achieving endoscopic remission (adjusted odds ratio, 1.09; 95% CI, 1.01-1.18). This association of short disease duration with treatment failure was observed only in biologic-naïve patients, but not biologic-experienced patients. No significant association was seen between disease duration and risk of surgery or hospitalization. Shorter disease duration is independently associated with increased risk of treatment failure in biologic-treated patients with UC. Requirement of biologic therapy early in the course of disease may be a negative prognostic marker in patients with UC.

P064 Intestinal expression of LAG-3 correlates with inflammatory activity and response to biological therapy in ulcerative colitis

P064 Intestinal expression of LAG-3 correlates with inflammatory activity and response to biological therapy in ulcerative colitis

P779 Clinical outcome with biological therapy in ulcerative colitis: Real-world clinical setting from a multi-centre observational study

P779 Clinical outcome with biological therapy in ulcerative colitis: Real-world clinical setting from a multi-centre observational study

Update on the Use of Biologic Therapy in Ulcerative Colitis.

Ulcerative colitis (UC) is a major form of inflammatory bowel disease and is characterized by chronic inflammation of the colon and rectum and by alternating periods of flares and remissions. Symptoms may include rectal bleeding, abdominal pain, and diarrhea. The pathogenesis of UC is complex and involves a combination of immune dysregulation, genetics, environmental factors, and microbiota. The goal of medical treatment is to induce and maintain remission. Traditionally, the treatment options for UC included 5-aminosalicylates, corticosteroids, and immunomodulators. However, over the past decade, with the approval of various biologic agents for treatment of UC, the management of UC has been revolutionized. Currently, the FDA-approved biologics for treatment of UC include infliximab, adalimumab, golimumab, and vedolizumab. There are a number of other agents which are under investigation and may become available soon as treatment options for UC. The purpose of this article is to provide a summary of various biologics in the treatment of UC.

Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis.

As biologic-based medication options for ulcerative colitis expand, our understanding of their optimal use in clinical practice is advancing as well. The appropriate use of combination therapy with immunomodulators can reduce the immunogenicity of biologic agents and raise serum drug levels of the biologic. A treat-to-target strategy with objective assessments of disease activity clearly defines the goals of biologic drug treatment. Mucosal healing is an evolving treatment goal and is associated with long-term remission and reduced incidence of colectomy. Furthermore, regular reassessments and therapeutic drug monitoring can allow clinicians to make evidence-based changes in therapy. Biologic drug de-escalation or re-initiation are less well developed topics, but are emerging areas of study. We review the evidence underlying these advances and a modern approach to the use of biologic therapy in ulcerative colitis.

Overview of biological therapy in ulcerative colitis: current and future directions.

The treatment of ulcerative colitis (UC) has changed over the last decade. It is extremely important to optimize the therapies which are available nowadays and commonly used in daily clinical practice, as well as to stimulate the search for more powerful drugs for the induction and maintenance of sustained and durable remission, thus preventing further complications. Therefore, it is mandatory to identify the patients' prognostic variables associated with an aggressive clinical course and to test the most potent therapies accordingly. To date, the conventional therapeutic approach based on corticosteroids, salicylates (sulfasalazine, 5-aminosalicylic acid) or immunosuppressive agents is commonly used as a first step to induce and to maintain remission. However, in recent years, knowledge of new pathogenetic mechanisms of ulcerative colitis have allowed us to find new therapeutic targets leading to the development of new treatments that directly target proinflammatory mediators, such as TNF-alpha, cytokines, membrane migration agents, cellular therapies. The aim of this review is to provide the most significant data regarding the therapeutic role of drugs in UC and to give an overview of biological and experimental drugs that will become available in the near future. In particular, we will analyse the role of these drugs in the treatment of acute flare and maintenance of UC, as well as its importance in mucosal healing and in treating patients at a high risk of relapse.

Su1120 Appropriateness and Long-Term Discontinuation Rate of Biological Therapies in Ulcerative Colitis

Su1120 Appropriateness and Long-Term Discontinuation Rate of Biological Therapies in Ulcerative Colitis

P556 Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis

P556 Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis

P321 The one-year efficacy of infliximab does not depend on the timing of biological therapy in ulcerative colitis

P321 The one-year efficacy of infliximab does not depend on the timing of biological therapy in ulcerative colitis