Gene signatures and biomarkers predict onset of rheumatoid arthritis in at-risk individuals

June 13, 2018, European League Against Rheumatism (EULAR)

The results of two studies presented today at the Annual European Congress of Rheumatology (EULAR 2018) provide insight into molecular changes prior to the onset of arthritis which could inform future novel diagnostics and early therapeutic interventions.

Rheumatoid arthritis (RA) is characterised by joint inflammation leading to destruction of bone and cartilage. Since structural joint damage is irreversible, early recognition and treatment is a key focus in an effort to halt the progression of the disease. There is a phase before any evidence of RA where specific autoantibodies are present in the body. Individuals who have these antibodies are referred to as RA-risk, however only a subset of these will develop active disease in the short term.

"These studies may help us better understand and potentially identify which individuals classified as at-risk will go on to develop RA," said Professor Robert Landewé, Chairperson of the Scientific Programme Committee, EULAR. "This is important because it will contribute to the development of early preventative strategies including potential pharmacological treatment to prevent the onset of disease."

Study reveals synovial tissue gene signatures associated with development of disease in RA-risk individuals

Samples of synovial tissue were taken from the knee joint of 67 RA-risk individuals who were then followed to see if they went on to develop RA. An explorative genome-wide transcriptional profile study was carried out in 13 individuals to identify gene transcripts with a significant association with arthritis development. These 'gene signatures' were then validated using quantitative real-time PCR† to measure changes in specific genes.

"Our results clearly show molecular changes appearing in the synovial tissue before the onset of arthritis," said Dr. Lisa van Baarsen, Principal Investigator at the Amsterdam Rheumatology and Immunology Center | Academic Medical Center, the Netherlands. "The characterisation of these gene signatures will enable us to better understand the pathophysiology of the pre-clinical phase of the disease and potentially identify novel drug targets for preventive intervention."

An explorative genome-wide transcriptional profiling study in 13 individuals demonstrated that an increased expression of 3,151 transcripts was associated with a higher risk of arthritis development, and 2,437 transcripts with a lower risk. Further analysis revealed that individuals who developed RA had a higher expression of genes involved in several immune response-related pathways (e.g. T-cell and B-cell receptor pathways, cytokine and chemokine signalling and antigen processing and presentation) and lower expression of genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism.

Investigators chose 27 differentially expressed genes for validation in the whole study cohort using quantitative real-time PCR. This analysis classified the RA-risk individuals into two groups, where most individuals who developed RA were grouped together (p=0.03).

Immunohistochemistry analyses (n=54) of the samples taken at inclusion showed that most individuals already had an abundant expression of chemokine CXCL12 and its receptor CXCR4 which are known to accumulate in the synovium of rheumatoid arthritis patients. They also showed that RA-risk individuals that developed arthritis were more likely to show a positive gp38 staining and lower lipid staining.

BCR clones predict imminent onset of rheumatoid arthritis in at-risk patients

Another cohort study in 129 RA-risk individuals validated recent findings8 that dominant B-cell receptor (BCR) clones in peripheral blood, can accurately predict imminent onset of arthritis in RA-risk individuals.

"Our data support a new biomarker that demonstrates better predictive power compared with other available biomarkers evaluated so far," said Ms. Anne Musters, MD, Amsterdam Rheumatology and Immunology Center | Academic Medical Center, the Netherlands. "We think that peripheral BCR clones can be used to identify RA-risk individuals that will go on to develop arthritis, which will support the evaluation of early interventions to prevent the onset of disease."

Results of the study showed that the number of dominant BCR clones was significantly increased in RA-risk individuals who developed arthritis within three years (p<0.0001). The optimal cut-off for the test was calculated at five or more dominant BCR clones and applying this test to the study cohort resulted in 45 BCR positive and 84 BCR negative individuals. Over the complete 104 months follow up period, only 13% of BCR-clone negative individuals developed RA compared to 76% of the BCR-clone positive individuals. This resulted in a relative risk of 5.8 (95% CI 3.2-10.3, p<0.0001).

By subdividing the individuals further, it was demonstrated that the number of dominant BCR clones significantly correlated with the risk of developing arthritis. Having 10 or more dominant BCR clones corresponded with a positive predictive value of 94% within three years. Within this period none of the 84 BCR negative individuals developed arthritis, indicating that, based on such test results, these individuals may be reassured concerning imminent RA risk.

Explore further: Frequency of joint replacements halved in rheumatoid arthritis patients between 1997-2010

Related Stories

Frequency of joint replacements halved in rheumatoid arthritis patients between 1997-2010

June 13, 2018
The results of two studies presented today at the Annual European Congress of Rheumatology (EULAR 2018) investigate joint replacement procedures in rheumatoid arthritis (RA) patients. The first study demonstrates that joint ...

Gene expression study may help guide Arthritis care

February 22, 2018
Researchers who analyzed gene expression in synovial tissue samples from rheumatoid arthritis patients' joints identified different patterns that may be clinically meaningful. The findings, which are published in Arthritis ...

Rheumatoid arthritis linked to an increased risk of COPD

October 19, 2017
New research suggests that rheumatoid arthritis may increase the risk of developing chronic obstructive pulmonary disease (COPD). The findings, which appear in Arthritis Care & Research, indicate that greater vigilance may ...

Jawbone loss predates rheumatoid arthritis

December 1, 2017
Jawbone loss caused by periodontitis predates the onset of rheumatoid arthritis. This according to research from Umeå University in Sweden presented in the journal Arthritis & Rheumatology. The research also shows a causal ...

PET imaging agent could provide early diagnosis of rheumatoid arthritis

May 3, 2018
A novel PET tracer developed by Korean researchers can visualize joint inflammation and could provide early diagnosis of rheumatoid arthritis, a common autoimmune disease that causes chronic inflammation of joints and can ...

How environmental pollutants and genetics work together in rheumatoid arthritis

April 19, 2018
It has been known for more than three decades that individuals with a particular version of a gene—human leukocyte antigen (HLA)—have an increased risk for rheumatoid arthritis.

Recommended for you

Research shows diet has little influence on precursor to gout

October 11, 2018
Dietary factors have a far smaller influence on urate levels (a precursor to gout) than previously envisaged, new University of Otago research reveals.

More doctor visits lead to less suicide attempts for fibromyalgia patients

September 19, 2018
Fibromyalgia patients who regularly visit their physicians are much less likely to attempt suicide than those who do not, according to a new Vanderbilt University Medical Center study published in Arthritis Care & Research.

Antioxidant found to be effective in treating mice with osteoarthritis

September 14, 2018
A team of researchers in Belgium and the Netherlands has found that feeding a common antioxidant to test mice was effective in treating osteoarthritis. In their paper published in Science Translational Medicine, the group ...

Researchers find answers as to why some people are at risk of gout

September 12, 2018
University of Otago researchers have helped characterise a genetic variant that enables new understanding of why some people are at risk of gout, a painful and debilitating arthritic disease.

Emotions like anger and sadness may cause pain as well as being a result of it

September 10, 2018
While emotions such as anger or sadness are often thought of as being a result of stress or pain, findings recently published by Penn State researchers suggest that negative or mixed emotions could function as stressors themselves.

Dietary carbohydrates could lead to osteoarthritis, new study finds

August 9, 2018
Do your knees ache? According to new findings from the Oklahoma Medical Research Foundation, your diet could be a culprit.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.