Y-ECCO Literature Review: Jonathan Digby-Bell
Expression levels of 4 genes in colon tissue might be used to predict which patients will enter endoscopic remission after vedolizumab therapy for Inflammatory Bowel Diseases
Verstockt B, Verstockt S, Veny M, et al.
Clinical Gastroenterology and Hepatology. 2020;18:1142–51.
© Jonathan Digby-Bell
In the past few years the armamentarium of drugs used to treat Inflammatory Bowel Disease (IBD) has accelerated, with the emergence of new therapies targeting differing immune pathways (ustekinumab and tofacitinib) and lymphocyte trafficking (vedolizumab). Furthermore, a number of promising new drugs are on the horizon (JAK-1 inhibitors, IL23p19 antibodies and S1P inhibitors) [1, 2]. However, as the choice of drugs expands, so the uncertainty over which drug should be selected by the clinician also increases. Drug selection may be determined by a number of factors such as cost, mechanism of delivery (e.g. oral, intravenous or subcutaneous), presence of co-morbidities (such as malignancy or multiple sclerosis) and presence of extraintestinal manifestations. However, no drug is effective in all patients, with between 10% and 40% of patients suffering from primary and secondary loss of response [3–5].
Precision medicine is the concept of tailoring treatment depending on patient-specific factors in order to maximise the likelihood of a specific treatment being effective in the individual patient. The aim is to reduce time to clinical remission, minimise corticosteroid use and reduce unnecessary exposure to ineffective drugs with a risk of side effects and added financial cost. However, precision medicine is dependent on the generation of biomarkers to aid decision making, which are currently essentially lacking for all IBD treatments. The few that do exist are usually single centre, with a small patient cohort, and mainly involve anti-TNFs [6, 7]. Transcriptomics, the study of gene expression, has become more widely used in the past decade to interrogate health and disease, mainly owing to falling costs of sequencing technologies, increased analytical expertise and novel computational tools that enable large-scale data analysis. RNA sequencing (RNAseq) uses high-throughput analysis of the entire transcriptome (all mRNA transcripts present in a particular sample ).
Verstockt et al. sought to establish a biomarker for vedolizumab treatment in Crohn’s Disease (CD) and Ulcerative Colitis (UC) by sampling colonic tissue from patients prior to commencing vedolizumab and performing RNAseq on the samples. Following RNA sequencing, they identified differentially expressed genes from patients who did and patients who did not achieve endoscopic healing.
Thirty-one patients (11 CD, 20 UC) were recruited, with 10/31 (32%) receiving vedolizumab as their first biologic. All were vedolizumab naïve. In the CD group, 6/11 (54.5%) achieved endoscopic remission (absence of ulcerations at 6 months), while in the UC group 13/20 (65%) achieved endoscopic remission (Mayo endoscopic subscore ≤1 at weeks 8–14).
Validation cohorts consisted of two internal cohorts (n=11 and n=16) and two external cohorts, including a GEMINI study cohort (n=13) and an independent Spanish cohort (n=37).
In total, 186 differentially expressed genes were identified between remitters and non-remitters with p<0.005. Pathway analysis of the differentially expressed genes revealed relevant significant enrichment of the Gene Ontology leucocyte migration gene set (p=0.006).
By using predictive modelling, the authors identified a four-gene panel (RGS13, DCHS2, MAATS1, PIWIL1) which could predict endoscopic remission in the discovery cohort (n=20) with an accuracy of 80.0%. The first internal validation cohort showed an accuracy of 100% (n=11) and the second had an accuracy of 81.3% (n=16). The external cohorts showed an accuracy of 76.9% (n=13) and 78.6% (n=37).
The ability of the individual genes from the four-gene signature to predict endoscopic remission was far worse (49%–70%).
The four-gene signature did not predict response to anti-TNF (n=20, accuracy 55%).
A key strength of this study is that the biomarker developed by Verstockt et al. has the potential to be utilised in virtually all IBD centres and not just those limited to academic institutions. RNAseq is expensive ($100s) and requires highly specialised bioinformaticians to scrutinise the data; moreover, analysis normally takes weeks, which is unrealistic in a patient group who require urgent treatment for their IBD. RT-qPCR is a commonly performed, relatively simple test which is already done in most hospital laboratories, e.g. hepatitis C RNA quantification. Therefore Verstockt et al.’s RT-qPCR-based biomarker has true applicability in the real world and has the potential to be inexpensive and locally performed, with a turnaround time of a few days.
Furthermore, the study endpoint was endoscopic, which is a robust objective measure of disease response. Utilisation of endoscopy to assess disease activity, whilst costly, invasive and accompanied by risk, provides unparalleled disease assessment, identifying aspects which may not be appreciated by clinical or biochemical scores. Endoscopic remission is becoming the gold standard approach to assess response in clinical trials and also in clinical practice .
However, even though this study was validated by two external cohorts, the total number of patients is relatively small (n=97) and more validation would be required before this biomarker could become part of clinical practice. Furthermore, the four genes identified (RGS13, DCHS2, MAATS1, PIWIL1) are little known in IBD, which invites more questions on their exact role in altering the efficacy of vedolizumab. Therefore, understanding the basic science behind the four genes would provide reassurance regarding the validity of the signature and further insights into the mechanism of action of vedolizumab.
Development of biomarkers to predict response to IBD therapies will remain a key research target for the IBD community in the coming years. Better utilisation of available treatments stratified by biomarkers will minimise time to remission, reduce corticosteroid exposure and avoid the unnecessary use of ineffective agents.
As the cost of RNAseq continues to fall and bioinformatics expertise becomes more widespread, the number of transcriptomic biomarker studies like that by Verstockt et al. will likely expand and these studies will in all likelihood provide new insights into the pathogenesis and treatments of IBD.
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Jonathan Digby-Bell – Short biography
Jonathan Digby-Bell is an IBD Fellow at Alfred Health in Melbourne, Australia and has an interest in precision medicine in IBD, transcriptomics and faecal microbiota transplantation.