Introduction

Precision medicine relies on accurate prediction of treatment response. Anti-integrin αvβ6 autoantibodies serve as a serum diagnostic biomarker for ulcerative colitis (UC) and associated with adverse UC-related outcomes.¹

Aims & Methods

We aimed to investigate the association between anti-αvβ6 autoantibody titers and treatment outcomes of advanced therapies. This study was conducted as a part of the prospective biobank in two centers in Japan and Israel. Patients with active UC who received advanced therapies between June 2017 and February 2023 were prospectively included and followed up for 1 year. The primary and secondary outcomes were treatment persistence rate for 1 year and clinical remission rate at week 6 in the anti-αvβ6 autoantibody low-titer versus high-titer groups, respectively. Treatment persistency was defined as continuation without switching to another advanced therapy or UC-related surgery, and clinical remission was defined as a two-item patient-reported outcome of ≤ 1 (rectal bleeding = 0 and stool frequency ≤ 1). The cumulative treatment persistence rate was analyzed using the log-rank test. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for treatment persistence. Week 6 remission rate was presented as numbers (%) and differences were analyzed using the Chi square test. Logistic regression models adjusted for confounders were used to estimate odds ratios (ORs) and 95% CIs for Week 6 remission.

Results

A total of 102 patients were enrolled in the cohort (median age, 41 years; male, 55.9%; median disease duration, 78.5 months; proctitis, 1%, left-sided colitis, 12.7%, extensive colitis, 86.3%; prior use of advanced therapies, 56.9%, median modified Mayo score, 7). The median observation period was 10 months (interquartile range [IQR]: 2-12 months), with treatment discontinuation occurring in 49 (48.0%) patients. The cumulative treatment persistence rate was significantly lower in the high-titer(>128 U/mL) compared to the low-titer (≤128 U/mL) group (p = 0.03). Multivariate Cox proportional hazards model analysis indicated that anti-αvβ6 autoantibodies were the sole independent predictor of treatment persistence (HR, 2.03 [95% CI, 1.04-3.95], p = 0.04) (Table). Clinical remission at Week 6 was achieved more frequently in the low-titer group than in the high-titer group (48.8% versus 18.2%, respectively, p = 0.04). Multivariate logistic regression analysis also showed that anti-αvβ6 autoantibody titer (OR, 3.52 [95% CI 1.08-11.47], p = 0.04) was a significant predictor associated with Week 6 remission, in addition to the modified Mayo score (OR, 0.35 [95% CI 0.14-0.90], p = 0.03).

Conclusion

Anti-αvβ6 autoantibodies are valuable for predicting the outcomes of advanced therapy in active UC.

References

1. Livanos AE, Dunn A, Mehandru S, et al. Anti-Integrin αvβ6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis. Gastroenterology. 2023;164(4):619-629

Disclosure

S. Sagami has served as a speaker for AbbVie, Eli Lilly, Janssen Pharmaceutical K.K., Gilead Sciences, Inc., JIMRO Co., Ltd., KISSEI Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, EA Pharma Co., Takeda Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Zeria Pharmaceutical Co., Ltd. He has also held endowed chairs sponsored by AbbVie, JIMRO Co., Ltd.; Zeria Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd., and has received research grants from Bristol-Myers Squibb and Ferring Pharmaceuticals.
M. Nakano has served as a speaker or a consultant in Covidien, Mochida Pharmaceutical, Takeda Pharmaceutical, Zeria Pharmaceutical, Kyorin Pharmaceutical, and Nippon Kayaku, received research funding from Mitsubishi Tanabe Pharma and Japanese foundation for research and promotion of endoscopy.
T. Hibi has received Lecture fees from, Abbvie GK , EA Pharma, Janssen, JIMRO, Mitsubishi-Tanabe Pharma, Mochida Pharmaceutical, Pfizer, Takeda Pharmaceutical, Zeria Pharmaceutical Co., Ltd., advisory/consultancy fees from Abbvie GK, Celltrion, EA Pharma, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe Pharma, Nichi-Iko Pharmaceutical, Takeda Pharmaceutical, Zeria Pharmaceutical and research grants from Abbvie GK, Activaid, Alfresa Pharma Corporation, JMDC Inc., Gilead Sciences, Inc., Eli Lilly Japan K.K., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Ferring Pharmaceuticals and Bristol-Myers Squibb; received scholarship contributions from EA Pharma, Mitsubishi Tanabe Pharma Corporation, Zeria Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd.; Pfizer Japan Inc. belonged to study group sponsorship by Alfresa Pharma Corporation, JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., and Mochida Pharmaceutical Co., Ltd. Miyarisan Pharmaceutical Co., Ltd.Zeria Pharmaceutical Co., Ltd.
N. Maharshak has received speaking and/ or consulting fees from Pfizer, Abbvie, Lilly, Takeda, Janssen, Ferring, BiomX, BMS, Nestle, Trobix Innovation, Teva and grant support from Takeda, Janssen, Abbott, Abbvie, Pfizer, BMS, and Nestle.
T. Kobayashi served as an advisory board member, consultant, or speaker for AbbVie, Activaid, Alfresa Pharma, Alimentiv, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical, and has received research funding from AbbVie, Alfresa Pharma, Bristol Myers Squibb, EA Pharma, Gilead Sciences, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda, and Zeria Pharmaceutical.

Introduction

Failure of anti-TNF therapy contributes to the socio-economic burden of inflammatory bowel disease (IBD). This is particularly relevant when new drugs targeting α4β7 integrin, IL-12/IL-23, Janus kinases or sphingosine-1 are added to the IBD therapeutic armamentarium. Anti-TNFs are the usual first-line biologic agents and, therefore, pre-treatment discrimination of patients who will be refractory to these therapies is important to prevent IBD patients from being exposed to multiple therapeutic failures. Many studies have reported predictive biomarkers for response to anti-TNF therapy. However, the implementation of easily readable biomarkers in daily clinical practice is an unmet need. Due to the active role of the metalloproteinase (MMP) family in the development of intestinal inflammation, we wanted to isolate robust and reproducible transcriptional markers capable of specifically predicting response to anti-TNF therapy by comprehensive analysis of these proteases.

Aims & Methods

We analysed the expression of twelve MMPs in publicly available microarray and RNAseq datasets from the Gene Expression Omnibus and the European Bioinformatics Institute: GSE12251, GSE16879, GSE73661 and E-MTAB-7845 for colon biopsies from ulcerative colitis (UC) patients before anti-TNF or vedolizumab therapy. The R package was used for differential expression analysis and receiver operating characteristic (ROC) calculation. Cytoscape software and Morpheus (broadinstitute.org) were used for network data integration and visualisation. In addition, we evaluated the expression of these twelve MMPS by RT-qPCR in peripheral blood mononuclear cells and polymorphonuclear cells from a local cohort of UC patients (n=21).

Results

We isolated a colonic transcriptional signature consisting of twelve MMPs that is highly associated with disease activity. Most of the transcripts of this signature were significantly up-regulated in colon biopsies of non-responders to anti-TNFs before treatment in three different microarray datasets, but not in vedolizumab-treated patients. ROC curves of the twelve MMPs showed variability in correlation with anti-TNF response in all datasets analysed. However, the combination of MMP2, MMP3, MME and PHEX efficiently discriminated patients who failed anti-TNF therapy (ROC AUC = 84%). Interestingly, this four-gene signature was not able to predict the response to vedolizumab (ROC AUC = 63%). For completeness, we observed that of the twelve MMPs analysed, only MME showed increased expression in peripheral mononuclear cells from patients refractory to anti-TNF therapy, confirming that this MMP could be a feasible biomarker in both colonic tissue and peripheral blood.

Conclusion

Overall, our study reveals a novel and robust colonic transcriptional signature consisting of four MMPs associated with anti-TNF, but not vedolizumab, therapy response. Furthermore, MME levels in peripheral blood cells emerge as a novel, easily readable predictive biomarker of anti-TNF response. Nevertheless, our results should be confirmed in independent cohorts of UC patients to test their efficacy and sensitivity in the clinical setting.

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.