Can molecular stratification improve the treatment of inflammatory bowel disease?

Abstract

Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease of the gastrointestinal (GI) tract. It affects more than 3.5 million people in the western world and places a huge financial burden on healthcare systems. IBD is highly heterogeneous; disease severity and outcomes in IBD are highly variable, and patients may experience episodes of relapse and remission. However, treatment often follows a step-up model whereby the patients start with anti-inflammatory agents (corticosteroids or immunosuppressants) and step-up to monoclonal anti-tumour necrosis factor-α (TNFα) antibodies and then other biologics if the initial drugs cannot control disease. Unfortunately, many patients do not respond to the costly biologics, and thus often still require gut-resective surgery, which decreases quality of life. In order to decrease rates of surgery and ineffective treatments, it is important to identify markers that accurately predict disease progression and treatment responses, to inform decisions about the best choice of therapeutics. Here we examine molecular approaches to patient stratification that aim to increase the effectiveness of treatments and potentially reduce healthcare costs. In the future, it may become possible to stratify patients based on their suitability for specific molecular-targeted therapeutic agents, and eventually use molecular stratification for personalised medicine in IBD.

Keywords: Anti-TNF; Biologics; CD; Crohn’s disease; Disease stratification; Faecal calprotectin; Genomics; Inflammatory bowel disease; Microbiomics; Molecular stratification; Precision medicine; Proteomics; Serological markers; Transcriptomics; Treatment response; UC; Ulcerative Colitis.

Graphical abstract

Fig. 1

The generation of T helper cell subsets in the intestine and their cytokine production profiles. Th1, Th2 and Th17 cells are involved in IBD immunopathogenesis through their production of the cytokines indicated and are polarized by activated APCs. Th17 cells can inhibit FoxP3+ Treg cells through IL-23, while FoxP3+ Treg cells can suppress Th17 cells using IL-10. The Th17/Treg balance is compromised in IBD patients.

Fig. 2

Current approaches to IBD treatment. Patients following step-up therapy are given frontline therapies, such as corticosteroids and aminosalicylates, followed by immunosuppressants, anti-TNF and non-TNF targeting biologics and JAK inhibitor tofacitinib (UC only) in a step-wise manner. Proceeding to the next therapy step depends on treatment responses, side effects and disease severity. An alternative treatment model, top-down therapy may be useful for patients with severe IBD. In this strategy, more specific biologics are administered sooner after diagnosis.

Fig. 3

Molecular stratification of patients with IBD. Patients following conventional therapy might be stratified based on predicted disease severity and outcome to determine if aggressive or milder therapeutics should initially be given. Subsequently, the patients may be further stratified based on their likelihood of responding to specific biologics.