The Genetics of Rheumatoid Arthritis

Risk and Protection in Different Stages of the Evolution of RA

Annie Yarwood; Tom W. J. Huizinga; Jane Worthington

Disclosures

Rheumatology. 2016;55(2):199-209. 

In This Article

Abstract and Introduction

Abstract

There is now a general consensus that RA has a spectrum of disease stages that can begin many years before the onset of clinical symptoms. It is widely thought that understanding the complex interplay between genetics and environment, and their role in pathogenesis, is essential in gaining further insight into the mechanisms that drive disease development and progression. More than 100 genetic susceptibility loci have now been identified for RA through studies that have focused on patients with established RA compared with healthy controls. Studying the early preclinical phases of disease will provide valuable insights into the biological events that precede disease and could potentially identify biomarkers to predict disease onset and future therapeutic targets. In this review we will cover recent advances in the knowledge of genetic and environmental risk factors and speculate on how these factors may influence the transition from one stage of disease to another.

Introduction

The heritability of RA has been shown from twin studies to be ~60%. Since 2007, rapid advances in technology underpinning the use of genome-wide association studies (GWASs) have allowed the identification of hundreds of genetic risk factors for many complex diseases. There are now >100 genetic loci that have been associated with RA (Table 1). The heritability of RA suggests that a large proportion of the disease could be the result of contributing environmental risk factors. It is widely thought that understanding the complex interplay between genetics and environment, and their roles in pathogenesis, is essential to gain further insight into the mechanisms that drive disease development and progression.

There is now a general consensus that RA has a spectrum of disease stages that can begin many years before the onset of clinical symptoms. Data showing the presence of autoantibodies and indicators of activation of the immune system years before disease onset indicate the presence of a long preclinical phase of disease potentially influenced by environmental factors.[20,21] This preclinical phase results in a continuum that eventually crosses a threshold leading to the manifestation of clinical symptoms and ultimately joint damage. It is hypothesized that genetic markers associated with disease, in combination with stochastic environmental risk factors, influence the transition from one disease stage to another.

This concept is relatively new, however, and as a result the majority of genetic and environmental studies to date have focused on patients with established RA, according to the 1987 ACR criteria for RA,[22] compared with healthy controls, and few studies have used cases in the early stages of disease or even in the preclinical phases of disease onset. In more recent years, research has focused on the earlier stages of disease.[20,21,23,24] This has been helped by the ACR/European League Against Rheumatism (EULAR) classification criteria published in 2010, which include earlier features of the disease, such as autoantibody status,[25] although it is only recently that researchers have begun establishing cohorts that will allow investigation of the earliest stages of disease. An initial challenge is definition of the disease phases; thus the EULAR Study Group for Risk Factors for RA recently published recommendations to classify individuals into different stages of disease for recruitment into prospective studies.[26]

Prior to the development of the EULAR recommendations, RA patients have typically been split into two groups based on autoantibody status.[26] Evidence from studies of ACPA-positive and negative disease subsets suggest that they are two distinct diseases with different underlying pathogenesis; this is discussed in more detail later. Studying patients who may be at risk of disease due to genetic and environmental risk factors gives researchers the chance to identify significant biological changes that may occur in the preclinical phase of RA, potentially providing invaluable opportunities for new treatment strategies.

ACPAs are of particular interest, as these autoantibodies are highly specific for RA and can be found in ~50% of early RA patients,[27] making ACPA an important early clinical biomarker. In addition, the presence of anti-CCP antibodies has been shown to predict disease severity and radiological damage,[28,29] meaning that ACPA could also be used as a biomarker for patients with a more severe disease phenotype and to select those patients eligible for more aggressive treatment.[30]

It is not clear how individuals progress from a pre-RA ACPA-positive state with no symptoms to clinical RA. Not all individuals with ACPA develop RA; therefore other triggers may be required to make the transition.

It has also been shown that the number of citrullinated antigens identified by ACPA increases exponentially leading up to disease onset. This is known as epitope spreading.[31,32] The expansion of the ACPA repertoire that occurs before the manifestation of clinical disease could potentially be used to predict the impending onset of disease. Although no specific single antigen or target has been identified, it may be that certain antigens contribute to an initial break in immune tolerance, resulting in epitope spreading and an immune response to other antigens. This could then result in the transition from preclinical to clinically apparent disease. In this review we will discuss the recent advances in knowledge of genetic susceptibility to RA and the study of environmental risk factors and will speculate on how these factors may influence the transition from one stage of disease to another. Reference made to EULAR disease phase refers to the EULAR disease classification defined in Gerlag et al..[26]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....