Elsevier

The Lancet

Volume 372, Issue 9632, 5–11 July 2008, Pages 67-81
The Lancet

New Drug Class
Crohn's disease: beyond antagonists of tumour necrosis factor

https://doi.org/10.1016/S0140-6736(08)60995-2Get rights and content

Summary

In the past few years, antagonists of tumour necrosis factor have resulted in unforetold therapeutic benefits in Crohn's disease, but the magnitude and duration of responses are variable. New agents are therefore needed. Their development has benefited from advances in the understanding of the pathophysiology of this disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. With increasing evidence of an implication of the innate immune system and the intestinal epithelium, the therapeutic paradigm is also shifting from mere immunosuppression to the reinforcement of the intestinal barrier. We review mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials. We discuss future directions, including new strategies with optimum endpoints.

Introduction

Crohn's disease results from a dysregulated response of the mucosal immmune system to intraluminal antigens of bacterial origin in people who are genetically predisposed to this disease.1, 2 The traditional view of the pathogenesis of Crohn's disease is that intestinal inflammation is mediated by cells of the acquired immune system, with overly aggressive activity of effector lymphocytes and proinflammatory cytokines.1, 2 Emerging evidence suggests that disease development implicates a dysregulated dialogue between the intestinal microbiota and components of both the innate and adaptive immune systems.3, 4 The host response to the intestinal microbiota can be categorised into three basic components: the intestinal epithelium, innate immune cells of the myeloid lineages (eg, monocytes, dendritic cells, and granulocytes), and adaptive immune cells (B and T cells) (figure 1). Models with defects in each of these components have been associated with pathogenesis of inflammatory bowel disease in mice.3, 4

Investigators have long sought to identify a micro-organism that causes inflammatory bowel disease. The present theory suggests a breakdown in the balance between putative species of protective versus harmful bacteria—a notion that has been termed dysbiosis.5 Recent studies emphasised the potential importance of adherent invasive Escherichia coli in the initiation and maintenance of inflammation in Crohn's disease.6, 7 However, our understanding of the microbial flora is still incomplete. Metagenomic and computational analyses of the so-called microbiome might provide a foundation to achieve a more accurate understanding of the relevant, functional diversity of the flora in the context of inflammatory bowel disease.4, 8

The intestinal epithelium, which is considered to be part of the innate immune system, has an active role in maintenance of mucosal homoeostasis. Epithelial cells form a tight, highly selective barrier between the body and the intraluminal environment. Failure of this barrier can result in intestinal inflammation, most likely through exposure to fecal antigens leading to inapppropriate activation of the mucosal immune system.1 In human beings, the importance of the epithelial barrier in disease predisposition is supported by the finding of abnormal intestinal permeability in first-degree relatives of patients with Crohn's disease.4, 9

The innate immune system is the body's non-specific defence against pathogens. It is regarded as the first line of defence that reacts to the chemical properties of the antigen.1 Evidence of the role of the innate immune system comes from the identification of nucleotide-binding oligomerisation domain containing 2 (NOD2) as a susceptibility gene for Crohn's disease.10, 11 Individuals who are either homozygotes or compound heterozygotes for any one of the three germline variations of NOD2 that are commonly identified have as much as a 40-fold increased likelihood of developing ileal Crohn's disease. The NOD2 protein is an intracellular receptor for a component of the bacterial cell wall, and is expressed in macrophages, dendritic cells, intestinal epithelial cells, and Paneth cells, providing specific support for the long-held hypothesis that Crohn's disease results from a genetically dysregulated host immune response to luminal bacteria.4 Furthermore, natural antimicrobial peptides, such as defensins, are expressed in an NOD2-dependent manner, and patients with this disease can have reduced defensin production in their intestine,12 contributing to inadequate microbial clearance.

Adaptive immunity is the most proximate driver of tissue damage that arises in patients with inflammatory bowel disease, although innate immune responses seem to be a prerequisite for the excessive activation of adaptive immunity.4 Adaptive responses toward a specific antigen are affected by a combination of resident and recruited cell populations. These populations consist of mucosal B cells producing immunoglobulins and a mixture of T cells that are dominated by a T-helper (Th) 1, Th2, or Th17 phenotype, and the coincident presence of regulatory T or B cells.4 Th1 development is triggered by microbes that stimulate production of interleukin-12p40 and interferon γ, which then activate macrophages and the release of interleukin 1, interleukin 6, and tumor necrosis factor α (TNFα) (figure 1 and webfigure 1). Classic Crohn's disease has a Th1-type cytokine profile. Another CD4 T-cell lineage (Th17) that is distinct from Th1 and Th2 has now been linked to the pathogenesis of Crohn's disease. In a genome-wide association study involving a North American case-control cohort with this disease, typing more than 300 000 single nucleotide polymorphims, an interleukin 23R coding variant was associated with reduced risk of inflammatory bowel disease.13 Th17-cell development is driven by transforming growth factor β (TGFβ) and interleukin 6, whereas interleukin 23 seems to expand and maintain Th17-cell populations. The interleukin-23 receptor consists of the interleukin-23R subunit and interleukin 12RB1, whereas the interleukin-23 cytokine consists of p19 and p40 subunits.3 In addition to helper-cell activation, evidence in human beings and murine models also suggest a role for regulatory T cells producing interleukin 10 or TGFβ, or both, in maintenance of intestinal homoeostasis4 (webfigure 1).

Over the past decade, the advent of antiTNFα agent infliximab has changed the way that refractory Crohn's disease is treated. Infliximab rapidly induces and maintains response and remission,14, 15 spares steroids,15, 16 and induces and maintains fistula closure.17, 18 Nevertheless, about a third of patients do not respond at all to this drug, and an additional third has only some response. This finding can be explained by the presence of different effector pathways in responders and non-responders.1 Newer antiTNF drugs such as certolizumab pegol and adalimumab have similar efficacy to infliximab.19, 20, 21 Patients who have been previously given infliximab who have lost response or become intolerant can respond to alternative biological drugs targeting TNF.22 However, an overall decrease is noted in the absolute proportion of responses to the second agent, suggesting that some patients who previously responded might not have benefits of targeting TNF.22 This finding emphasises the need for developing novel biological drugs for the treatment of Crohn's disease.

These advances in our understanding of the pathophysiology of inflammatory bowel disease have led to new therapeutic opportunities (figures 1 and webfigure 1).2, 23 The many therapies being investigated include cytokine and anticytokine therapies, T-cell blocking agents, antiadhesion molecules, and new immunomodulatory strategies (Table 1, Table 2). In this review, we will discuss mechanisms of action of new biological drugs, their efficacy, and safety profiles, and will review previous innovative therapies and future directions for treatment of Crohn's disease (table 3).

Section snippets

T-cell blockade

The T cell is pivotal in orchestration and promotion of the immune response in inflammatory bowel disease. Most therapies for inflammatory bowel disease aim to inhibit T-cell function, block the generation of T-cell pro-inflammatory cytokines, or induce apoptosis of T cells or a particular subset of these cells.23 CD4+ T lymphocytes recognise antigens that have been processed and are presented in association with a self class II MHC molecule to initiate the immune response.23, 74 After the

T-cell blockade

Table 1 shows the efficacy of new biological drugs in clinical trials. First attempts to block CD4+ T-cell function with cM-T412 have failed in two open-labelled pilot studies enrolling 24 patients.24, 45 Visilizumab has been assessed in both luminal and fistulising Crohn's disease in two phase I trials26, 27 and in ulcerative colitis.95 Eight patients with luminal Crohn's disease refractory to infliximab therapy received 10 μg/kg intravenous visilizumab once every day for 2 days and were

Adverse effects of novel biological drugs

Table 2 shows the adverse effects of biological drugs that are in clinical trials. Most adverse events were mild or moderate in severity with T-cell blocking agents. No lymphoproliferative or life-threatening adverse events were reported in patients given visilizumab, but two serious adverse events were noted, although no details were given.26 The long-term safety profile of visilizumab remains to be established in a large cohort of patients. A cytokine release syndrome (fatigue, nausea,

Short-term perspective

None of the T-cell blocking agents developed so far have reached phase III studies in Crohn's disease, despite a well established Th1-type cytokine profile. In molecules that are capable of blocking T-cell differentiation or activation, a lot is expected from abatacept, since infusion every month of abatacept significantly reduced disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate.101 Abatacept has been approved by the US Food and Drug

Future directions

Table 3 shows the compounds that are being developed for inflammatory bowel disease.

In the near future, present technologies, such as humanised or chimeric monoclonal antibodies, will still be used to target new pathways. For example, an antivacular adhesion protein-1 (VAP-1) monoclonal antibody is being investigated. VAP-1 is a cell-associated, inflammation-inducible, endothelial cell-adhesion molecule that mediates the interaction between leucocytes and activated endothelial cells in inflamed

Search strategy and selection criteria

We did a computerised search of English and non-English language publications listed in the electronic databases of Medline (source PubMed, from 1966 to March, 2008), the Cochrane Library, and Embase (from 1980 to March, 2008). We searched for the terms: “Crohn's disease”, “inflammatory bowel disease”, “treatment”, “biological therapy”, “cytokine”, “T-cell”, “adhesion”, “growth factors”. We also hand-searched abstracts from the yearly meetings of Digestive Disease Week between 2003 and

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