Rheumatoid arthritis

Background

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting predominantly the synovial joints. RA affects more women than men (3:1 female: male ratio), has a worldwide prevalence of just under 1% and a peak age of disease onset in the fifth decade of life. Despite the introduction in the last decade of novel therapies, RA continues to represent a significant health burden. Although the precise aetiology of RA remains unknown, twin and family studies have confirmed a role for both genetic and environmental factors in determining susceptibility to RA, the severity of symptoms and response to therapies. Environmental risk factors include smoking, obesity, diet and adverse pregnancy outcomes. Within the Arthritis Research UK Centre for Genetics and Genomics, our research has largely focussed on the identification and characterisation of genetic risk factors.

In the shorter term, the identification of genes that determine which patients will develop more severe disease; which will respond well to different medications and which patients are at greater risk of complications is likely to have a more immediate clinical benefit. It may allow better targeting of already available treatments or specific interventions in patients at high risk of a particular complication.

Research Programme

  1. To identify the genes associated with susceptibility to RA. By understanding the genes involved in causing RA, it may be possible to identify subgroups of disease, to identify the key pathways involved in inflammation and to identify novel targets to develop new drugs.
  2. To identify the genetic and genomic factors that predict outcome in RA. The aim of this programme is to develop an index, which may include genetic, serological (antibody) and clinical factors to define the risk to an individual when they first present with their inflammatory arthritis as to how severe the disease is likely to be and which complications they are at risk of developing. This would then allow individualised treatment plans to be instituted. Outcomes studied include:
    1. severe, erosive or disabling arthritis
    2. cardiovascular disease, the major cause of death in patients with inflammatory arthritis
    3. Treatment response

Cohorts available

RA Susceptibility: The National Repository is a multi-centre, national study that collects blood for DNA, RNA and serum from patients with RA. Within the Repository are samples from twins, families with more than one affected sibling, unaffected parents of patients with RA and large numbers of patients with sporadic RA as well as healthy control individuals.

Portfolio id: 7881

RA Prognosis: The Norfolk Arthritis Register (NOAR) is an inception cohort of patients with early inflammatory arthritis (2 or more swollen joints for 4 or more weeks) recruited from the region previously defined as the Norfolk Health Authority, and followed prospectively for up to 20 years. DNA and serum have been collected at several time points as well as a wide variety of clinical measures including XRays, HAQ scores and information on the cause of death.

Portfolio id: 2870


RA treatment response to Methotrexate: The RA Medication Study (RAMS) collects clinical data and blood samples from patients who are about to start therapy with methotrexate and then follows them prospectively to assess response to therapy over the first year of treatment. Data on >1,000 patients has been collected so far. Clinical information and biological samples (DNA, RNA, serum) are collected pre-treatment and at 4 weeks, 3, 6 and 12 months post-treatment initiation.

Portfolio id: 5118


RA treatment response to biologic drugs: The Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) collects clinical data and blood samples from patients who are about to start therapy with a biologic drug and then follows them prospectively to assess response to therapy over the first year of treatment. Data on >1,500 patients has been collected so far. Clinical information and biological samples (DNA, RNA, serum) are collected pre-treatment and at 3, 6 and 12 months post-treatment initiation.

Portfolio id: 5114

Collaborations

Name Institute
Peter Gregersen The Feinstein Institute for Medical Research, USA
Souyma Raychaudhuri Broad Institute of Harvard and Massachusetts Institute of Technology, USA
Lars Klareskog Karolinska Insitute, Sweden
Ele Zeggini Wellcome Trust Sanger Institute, Cambridge, UK
UKRAG consortium members:

Jane Worthington, Anne Barton, Wendy Thomson, Steve Eyre, Anne Hinks
Gerry Wilson, Deborah Bax
Ann Morgan, Paul Emery
Lynne Hocking, David M Reid
Sophia Steer
Paul Wordsworth



University of Manchester

University of Sheffield
Academic Unit of Musculoskeletal Disease, Leeds
University of Aberdeen
Kings College Hospital NHS Foundation Trust, London
University of Oxford

Research Summary

  • The most important genetic factor predisposing to RA is the HLA DRB1 gene and amino-acid positions 11, 71 and 74 within that gene. The HLA DP and HLA A genes also increase risk of disease.
  • The second most important gene is the PTPN22 gene
  • 99 other genes have now been identified that also increase disease risk.
  • Drugs have already been developed that target some of these genes, showing that associated genes can be good targets for drug development.
  • RA can be divided into two major subgroups: ACPA positive and ACPA negative RA and, although the two subtypes share some disease genes, there are also different genes that predispose to ACPA positive versus ACPA negative RA.
  • The biggest single predictor of developing joint damage is ACPA status.
  • The TRAF1/C5 gene and FOXO3 genes may also increase risk of joint damage.
  • Both HLA DRB1 and CCL21 genes predispose to cardiovascular disease in patients with RA
  • The HLA DRB1 gene also predicts response to anti-TNF drugs
  • Adherence (defined as self-reporting that the drug was taken as directed by a healthcare professional) influences treatment response with non-adherence predicting a poorer response to therapy.

 

Contacts/Principal investigators