Introduction

Vedolizumab has demonstrated efficacy in moderate-severe Ulcerative Colitis (UC). To date, few tools are available to predict medium- and long-term response to the drug. The aim of the study is to characterise the profile of circulating cytokines associated with the pathophysiology of inflammatory bowel disease (IBD) to identify markers of immune response to vedolizumab in UC patients. As a secondary objective, we analysed the possible involvement of baseline characteristics such as smoking and disease duration until drug initiation, previous exposure to other biologics, and baseline faecal calprotectin (FCP) and C-reactive protein (CRP) values in the response to the drug.

Aims & Methods

Retrospective single-centre cohort study including 28 patients diagnosed with UC with inflammatory activity objectified by clinical and biochemical data who started treatment with vedolizumab in the period from 2015 to 2022. Participants consented and authorised the collection of biological samples. Plasma samples were collected prior to drug initiation and response to treatment was assessed at the end of follow-up. Response to treatment was based on clinical remission (pMAYO < 3 with no subscore >1) together with a biochemical response (reduction in FCP and/or CRP > 50%) at the end of follow-up. In patients where colonoscopy was available, endoscopic response was defined as an endoscopic Mayo of 0 or 1. Cytokines were determined by Magpix® Luminex using a Milliplex® Human High Sensitivity T Cell Magnetic Bead Panel containing 12 proteins. The cytokines studied were (interferon-gamma, interleukin 10, interleukin 12, interleukin 13, interleukin 17A, interleukin 10, interleukin 2, interleukin 21, interleukin 23, interleukin 7, interleukin 8, TNF-alpha).

Results

Twenty-eight patients with UC (100% pancolitis or left colitis) and S2+S3 94.7% were included in the study. 85.2% were bioexposed (infliximab in 75%). 50% of patients received concomitant corticosteroid therapy at the start of vedolizumab.
Vedolizumab response was seen in 13 patients (46.4%) after a median overall treatment duration in both cohorts of 2.79 years (IQR 7.55). The responder group was on vedolizumab treatment for a median of 5.58 (IQR 6.9) years vs 1.17 (IQR 5.13) years in the non-responder group, p=0.005. There were no baseline differences between responders in pMayo or in FCP and CRP values. Active smoking, disease duration until vedolizumab initiation and previous exposure to other biologics were not associated with response/non-response to vedolizumab treatment.
Vedolizumab responders had significantly lower median interleukin 8 (IL8) levels at baseline than vedolizumab non-responders (median IL8 1.67 pg/mL versus 3.03 pg/mL, p=0.016). No statistically significant differences in baseline concentrations were found in any of the other interleukins analysed.

Conclusion

In our series of UC patients treated with vedolizumab, patients with long-term response to the drug show lower plasma IL8 levels than non-responders at baseline. Therefore, IL8 could serve as a predictive marker of long-term response to vedolizumab in UC patients. These results should be confirmed in prospective studies with larger sample sizes.

Introduction

Vedolizumab is one of the current treatments for patients with inflammatory bowel disease (IBD). The efficacy and safety, along with its gut specificity, make this drug an appealing therapeutic option for IBD patients with moderate to severe disease. However, as observed for other biologic treatments, a significant proportion of patients do not have an initial response to vedolizumab treatment. Currently, there is a lack of reliable predictive tools for vedolizumab treatment response, although this would help to alleviate the socioeconomic costs derived from this disease.

Aims & Methods

The primary aim of this study is to show putative transcriptional signatures associated with vedolizumab treatment response.
Methods: For the realization of this study, we used RNA-seq datasets from the Gene Expression Omnibus (GEO) database: GSE191328. This dataset includes samples from peripheral blood cells from responder and non-responder ulcerative colitis (UC) patients treated with vedolizumab and infliximab at baseline. Gene Set Enrichment Analysis (GSEA) was performed to compare the differential expression and the enrichment analysis was calculated using ssGSEA of the different groups under study.

Results

The analysis of the transcriptome of peripheral blood cells from responder (R) and non-responder (NR) vedolizumab-treated patients at baseline revealed interesting enrichment results. We found 20 gene sets positively enriched in NR versus R and only 9 gene sets negatively enriched in the same phenotypes. In order to find vedolizumab specific transcriptional signatures, we performed a similar analysis in samples from infliximab-treated patients. After that second round of analysis, we observed that around 50% of the enriched gene sets were similar for both biological treatments. Nevertheless, several interesting biological functions such as peroxisome function, reactive oxygen function or beta-catenin signalling are specifically enriched in NR patients to vedolizumab treatment.

Conclusion

Our data suggest that vedolizumab NR patients specifically show a transcriptional enrichment profile, which differs from vedolizumab R patients. Also, the comparative analysis with infliximab-treated patients reveals that those specific transcripts are modulated in response to this α4β7 integrin antibodies in peripheral blood cells. Therefore, we found a solid system to search for vedolizumab therapy predictive response markers using low invasive techniques.

Introduction

Disease clearance (DC), defined as combined clinical, endoscopic and histologic remission, has been proposed as the ultimate therapeutic target in ulcerative colitis (UC). However, the addition of faecal calprotectin (FC) remission to DC, now proposed as ‘complete disease clearance (CDC)’, in predicting for relapse is unknown. We aimed to explore the use of composite therapeutic endpoints, including DC and CDC, in predicting long-term outcomes for UC patients on vedolizumab (VED).

Aims & Methods

The phase IV Vedolizumab Immunomodulator Enforced Withdrawal Study (VIEWS) prospectively recruited UC patients in steroid-free clinical remission on VED 300mg IV q8w. Baseline evaluation (week 0) included FC, endoscopy, histology, and serum VED trough levels. Remission definitions were FC<150µg/g, centrally-read Mayo endoscopic score (MES)=0 and centrally read Nancy index (NI)=0 by a gastrointestinal pathologist. FC value differentiated DC and CDC. DC was defined as FC≥150µg/g, MES=0 and NI=0. CDC was defined as FC<150µg/g, MES=0 and NI=0. Clinical relapse, defined as partial Mayo score ≥3 and FC≥150µg/g or MES increase of ≥1, was evaluated for 2 years. Cox regression, Kaplan-Meier curves and log rank statistics were performed to assess the time to clinical relapse. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for dichotomous categorial variables. Multivariate logistic regression models were performed to identify predictive factors of relapse. P<0.05 was deemed statistically significant (IBM SPSS Statistics, version 30).

Results

62 consecutively recruited UC patients were followed over 24 months. Of 54 patients with endoscopic assessments at baseline, 80% were in endoscopic remission, 76% histologic remission, 68% had DC, and 63% had CDC. Baseline CDC was associated with significantly lower rates of clinical relapse compared with DC and clinical/endoscopic remission alone (log rank P<0.001; HR: 0.17 [95%CI:0.04-0.64], P=0.009) (Figure 1). Baseline CDC had an OR of 0.16 (95%CI:0.04-0.75, P=0.01) in predicting relapse, versus DC (OR: 0.20 [95%CI:0.05-0.89], P=0.03), endoscopic remission (OR:0.91 (95%CI:0.16-5.15), P=0.92), histologic remission (OR: 0.10 [95%CI:0.02-0.50], P=0.002), and neither endoscopic nor histologic remission (OR:4.44 [95%CI:0.55-35.90], P=0.13). Univariate predictors of CDC at baseline were female sex (P=0.03), UC disease duration < 5 years (P=0.01), smoking status (P=0.004) and serum VED concentrations (P=0.03). On multivariate analysis, only female sex (OR: 7.0 [95%CI: 1.17-42.33], P=0.03) predicted for CDC.

Conclusion

CDC, a novel composite endpoint, predicted for significantly lower rates of relapse compared with DC in UC patients on VED. Female sex was associated with baseline CDC. FC should be incorporated into composite endpoints with endoscopy and histology.

Disclosure

Aviv Pudipeddi has received speaking and consulting fees from AbbVie and Takeda.
Sudarshan Paramsothy has received speaking and consulting fees from AbbVie, Janssen and Takeda.
Craig Haifer has received speaking and consulting fees from Takeda.
Jakob Begun has received speaking and consulting fees from Takeda.
Crispin Corte has received speaking and consulting fees from AbbVie, Takeda, Janssen, Pfizer, Ferring and Celltrion.
Mark Ward has received speaking and consulting fees from AbbVie, Takeda, Janssen and Pfizer.
Peter De Cruz has received speaking and consulting fees from AbbVie, Janssen and Celltrion.
Rupert Leong has received unrestricted funding from Takeda.

Introduction

Ustekinumab has been recently approved for the treatment of moderately to severe ulcerative colitis (UC). Data from the UNIFI clinical trial are encouraging; nevertheless, real-world assessment is needed.

Aims & Methods

We assess the effectiveness, safety and pharmacokinetics of ustekinumab in a cohort of refractory UC patients.
Multicentre and observational study of UC patients who received ustekinumab for active disease. Values for Partial Mayo Score (PMS), endoscopic activity, C reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8, 24 and 52 weeks and at 18 and 24 months when was possible. Demographic and clinical data, previous treatments, adverse events (AEs), surgeries and hospitalizations were documented. Possible predictors of response were examined.

Results

Two patients only received the first IV dose. During follow-up, 58 patients (54%) required interval reduction (every 4 weeks (76%) and every 6 weeks (24%)) after a median of 22.3 weeks [11.6, 41.2]. Intravenous reinduction doses were administered to 20 (18.5%) after 27.7 weeks [6.64, 56.3]. Three patients required a maintenance therapy with IV administration. The clinical remission (PMS≤ 2) rates were 39.6%, 41%, 51% at 8, 24 and 52 weeks, respectively, and 61%, and 57.7% at 18 and 24 months, respectively. FC levels returned to normal (<250 μg/g) in the 39.6%, 41%, 51%, 61%, 58% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively. CRP returned to normal (<3 mg/L) in the 79%, 75%, 76.5%, 71% and 70% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively.
Fewer previous anti‐TNF agents and the loss of response to anti-TNF were associated with clinical response and with normalization of FC respectively. No variables at baseline (body mass index, serum albumin, and lymphocytes count) were associated with ustekinumab through levels. Of the 17 patients with endoscopy before and after treatment, 6 were in remission and 3 with mild activity. The AEs were recorded in 5 (4.6%) patients, 12 (11%) were hospitalized and 9 (8.3%) had surgery. A total of 23 patients (21%) discontinued ustekinumab over time, the persistence rates were 98%, 91%, 83% and 81% at 8, 24, 48 and 96 weeks respectively.

Conclusion

This is the first study to show the real‐world long-term effectiveness, persistence, endoscopic improvement and safety of ustekinumab in a cohort of highly refractory UC patients. The clinical remission preceded the FC normalization. Ustekinumab through levels and their pharmacokinetic require further investigations.

Introduction

Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4β7) integrin, suppresses immune cell migration by blocking the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule 1, and is used to treat patients with UC with moderate-to-severe activity. Reports about histological features that predict vedolizumab efficacy are scarce.

Aims & Methods

We evaluated the infiltration of inflammatory cells in the colonic mucosa prior to the induction of vedolizumab and examined the association between histological features and vedolizumab efficacy.
This was a multicenter, retrospective study. Patients with UC who were treated with vedolizumab between November 2018 and April 2021 were enrolled in this study. All eligible patients had moderate-to-severe disease activity at the time of the initial treatment with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 per unit area of the lamina propria were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified.

Results

A total of 42 patients were included in this study. 17 (40.5%) patients achieved clinical remission at week 22. Significantly more CD4+ cells were found in the colonic mucosal tissues of patients with remission than in those without remission (odds ratio [OR]=1.44, P=0.014). In contrast, the CD68-positive area and the CD45-positive were not significantly different between the two groups. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR=0.11, P=0.008 and OR=0.50, P=0.009, respectively).

Conclusion

A high CD4+ infiltration in the colonic mucosa was associated with remission after vedolizumab treatment. Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

Introduction

Inflammatory bowel disease (IBD) describes two chronic inflammatory intestinal diseases: Ulcerative Colitis (UC) and Crohn’s Disease (CD). Treatment of these conditions is often through immunosuppression to induce remission then maintenance. Cytomegalovirus (CMV) is a virus commonly found latent in all humans with seroprevalence rates existing between 40-100% depending on geographical location (1). Pathological reactivation of CMV is triggered by inflammation and immunosuppression; both present in the pathogenesis and treatment of IBD respectively (2). Consequentially, CMV reactivation occurs in IBD flare-ups around a rate of 25% (2) and greater than 30% in steroid-refractory patients (1, 3). Whether CMV reactivation is associated with escalating medical therapy, further hospital admissions, and worse clinical outcomes such as toxic megacolon or colectomy when compared to non-CMV associated flare-ups remains controversial. As such, the aims of this study were to follow up patients with IBD following an index episode of CMV colitis and analyse disease progression, relapse of CMV colitis, and clinical outcomes.

Aims & Methods

As such, the aims of this study were to follow up patients with IBD following an index episode of CMV colitis and analyse disease progression, relapse of CMV colitis, and clinical outcomes.
A retrospective study of patients treated at Royal Melbourne Hospital, Parkville, Australia treated between 2018-2023 was completed. Patients were included if they had a diagnosis of IBD, had positive immunohistochemistry for CMV on biopsy, and were treated with Ganciclovir or Valganciclovir for CMV colitis. Data collected included
demographic details and laboratory investigations at time of first episode of CMV colitis. Data regarding treatment for IBD and CMV colitis at time of CMV colitis was also collected. Outcome results were collected at 6-month and 12-month time points after first episode of CMV colitis. Fourteen patients were included in this study; 13 with UC and 1 with CD.

Results

Recurrence of CMV colitis occurred in 21% of cases at 6 months and 29% at 12 months. Additional courses of corticosteroids remained constant at 21% of cases at 6 and 12 months. Forty-three percent of patients had changed their biologic at 6 months and this stayed constant at 12 months. Similarly, 29% of patients had escalated their biologic dose at 6 months which was the same at 12 months. At 6 months, 43% of patients had been re-hospitalised due to IBD or CMV including 2 colectomies. At 12 months, these figures increased to 36% and 3 respectively. Disease remission was only achieved by 7% of patients at 6 months, increasing to 29% at 12 months.

Conclusion

While a descriptive study, our results when compared with previous studies (4) suggest that CMV colitis is a negative prognostic marker in patients with IBD, resulting in higher rates of hospitalisation, failed medical therapy requiring medication change or dose escalation, and colectomy. These risks may be greater at <6 months from index episode of CMV colitis. Further research regarding effective management of CMV colitis is needed to minimise poor outcomes in these patients.

References

1. Maher MM, Nassar MI. Acute cytomegalovirus infection is a risk factor in refractory and complicated inflammatory bowel disease. Digestive diseases and sciences. 2009;54:2456-62.
2. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Official journal of the American College of Gastroenterology| ACG. 2006;101(12):2857-65.
3. Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. The American journal of gastroenterology. 2001;96(3):773-5.
4. Zhang M, Bai X, Zhang H, You Y, Lv H, Li Y, et al. The role of cytomegalovirus colitis on short- and long-term outcomes for patients with ulcerative colitis. Scandinavian Journal of Gastroenterology. 2022;57(3):282-9.

Introduction

Limited evidence is available about predictors of response to specific medications for ulcerative colitis (UC). OCTN1, an organic cation transporter, with its variants, could modulate the inflammatory response and potentially predict individual response to immune-modulatory therapy (anti-TNFα and vedolizumab).

Aims & Methods

We first confirmed the ability of OCTN1 to differentially modulate IL1β secretion under different stimuli in a human leukemia monocytic cell line (THP-1) and in human peripheral blood mononuclear cells. We therefore prospectively enrolled a cohort of UC patients starting either anti-TNFα or vedolizumab, determined their OCTN1 genotype and evaluated their clinical features at baseline and clinical response to therapy after six months, as well as two years therapy persistance.

Results

OCTN1-deficient THP1 cells showed reduced IL-1β secretion in response to peptidoglycan (PGN) and Fusobacterium nucleatum (Fn), whilst primary monocytes bearing OCTN1 503F variant displayed an increased production of IL-1β in response to PGN and live bacteria. We therefore enrolled 90 patients, of which 50 starting anti-TNFα and 40 vedolizumab. At the multivariate analysis, an overall better response to therapy was observed with the mutated 503F variant (OR=16.72, p=0.011) in comparison to wild type (503L) and heterozygous variants; nevertheless, a significant reduction of clinical response after six months was observed in patients with 503F variant treated with vedolizumab (OR=0.02, p=0.04). Furthermore, the same trends were observed the two years steroid free therapy persistence wa taken inot consideration.

Conclusion

Mutated OCNT1 genotype (503F) could favor an increased IL1β secretion from human leukocytes, thus suggesting a worse disease course and lower response to vedolizumab as compared to homozygous 503L and heterozygous.