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.

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 modify drug response to immune-modulatory therapy (anti-TNFα and Vedolizumab), perhaps predicting individual response.

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 or disease remission (according to clinical Mayo score) after six weeks (T1) and six months (T2). We finally enrolled a cohort of UC patients in clinical and endoscopic remission (according to full Mayo score) under immune-modulatory therapy (anti-TNFα or Vedolizumab) for at least two years.

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, 50 starting anti-TNFα and 40 Vedolizumab. Patients with 503F genotype showed higher rates of pancolitis as compared to 503L genotype. Among patients with 503L phenotype, Vedolizumab results highly associated with long-term response (OR 8.92, 95%CI 0.50-11.0; p=0.019), whilst conversely co-presence of 503F genotype and Vedolizumab therapy disclosed an opposite role on the long-term response rate (OR 0.02, 95%CI 0.00-0.81; p=0.038).
The population of UC patients in clinical and endoscopic remission was composed by 92 patients, 63 under anti-TNFα and 29 under Vedolizumab. Of note, similar trends of disease extension were observed across genotypes: higher rates of pancolitis were observed in the 503F population as compared to 503L (62.5% vs 44%). Furthermore, among patients in remission with 503F genotype, the percentage of subjects receiving Vedolizumab was sensibly lower than among patients with 503L genotype (87.5% anti-TNFα vs 12.5% Vedolizumab among 503F genotype; 56% anti-TNFα vs 44% Vedolizumab among 503L genotype).

Conclusion

Mutated OCTN1 genotype (503F) favors an increased IL1β secretion from human stimulated leukocytes, thus suggesting a worse disease course with higher rate of pancolitis and lower response to Vedolizumab as compared to 503L.

Introduction

Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial aetiology, which is still not completely understood. OCTN1, an organic cation transporter could have a role in modulating the inflammatory response, whose genetic polymorphisms were associated to increased risk of inflammatory bowel diseases. Up to now, limited information exists on its role in predicting/modulating response to therapies.

Aims & Methods

The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and immune composition to Infliximab therapy in murine colitis. Dextran sodium sulphate model of colitis on C57BL/6 mice and ocnt1 gene knockout mice was used to assess clinical efficacy of infliximab administered intravenously. Stool, colon and mesenteric lymph node samples were collected to assess differences in gut microbiota composition, histology for Rachmilewitz score and T cell populations respectively.

Results

Octn1^-/-influences microbiota profile and is associated with a worse dysbiosis in colitis mice. Infliximab treatment attenuates colitis-associated dysbiosis with increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1^-/- mice have a higher baseline percentage of Treg, Tmemory, Th2 and Th17.

Conclusion

Our data support murine model to study OCTN1 genetic asset in inflammatory bowel diseases. This could be the first step to consider this membrane transporter as a biomarker in inflammatory conditions and as a predictor of response to therapies.

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

The effectiveness of fecal microbiota transplantation (FMT) in Ulcerative colitis (UC) remains unclear, with significant differences in protocols and procedures among clinical trials (1).

Aims & Methods

This study aimed to investigate the feasibility and effectiveness of a FMT protocol with close infusions in patients with active UC, also exploring the microbial modulation underlying its therapeutic efficacy.

In this prospective cohort study, subjects with mild-to-moderately active UC received three consecutive fecal infusions by colonoscopy, at baseline, T1 (2 weeks) and T2 (6 weeks) respectively. Faeces were collected by the donor on the day of the infusion and processed within 6 hours. A control population with the same baseline features undergoing Infliximab treatment was enrolled. Primary outcomes were the number of adverse events and the compliance rate. Secondary outcomes were: clinical remission; clinical response; endoscopic remission; microbial differences.

Results

Nineteen patients with mild-to-moderately active UC were enrolled.
During the protocol, 2 patients dropped out because of disease worsening and 1 patients dropped out because of hospitalization due to nephrolithiasis.
Clinical response was obtained in 6 of 16 patients at week-2 (PP=37%; ITT=31%), in 8 of 16 at week-6 (PP=50%; ITT=42%), and in 9 at week-12 (PP=56%; ITT=47%). Clinical response was maintained in 8 patients at week 24 (PP=50%; ITT=42%). Clinical remission was achieved in 4 subjects at week-2, in 5 at week-6 (PP=31%; ITT=26%), and in 5 at week-12 (PP=31%; ITT=26%). Endoscopic remission at week 12 was reached in 6 patients (PP=37%; ITT=31%). In the control population, 13 of 19 patients achieved clinical response at week 6 and 10 of 19 patients maintained clinical response after 6 months.
During the time course, the microbiota richness was higher in responders compared with the non-responders. Peptostreptococcus, Lactobacillus and Veillonella were higher in non-responders while Parabacteroides, Bacteroides, Faecalibacterium and Akkermansia were higher in responders in all time points.

Conclusion

Serial FMT infusions appear to be feasible, safe, and able to provide a considerable clinical and microbial response in UC patients. In particular, the comparison with patients under biologic therapy suggests a potential role in maintaining clinical response or enhancing maintenance. Gut microbiota profiling highlighted the role of specific intestinal bacteria in predicting both negative and positive response to FMT.

References

1. Tan XY, Xie YJ, Liu XL, Li XY, Jia B. A Systematic Review and Meta-Analysis of Randomized Controlled Trials of Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease. Evid Based Complement Alternat Med. 2022;2022:8266793. Published 2022 Jun 26. doi:10.1155/2022/8266793

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

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.