Gene Signatures and Biomarkers Predict RA Onset

Rheumatoid arthritis is characterized 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 rheumatoid arthritis (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.

Scientists from the Amsterdam Rheumatology and Immunology Center (Amsterdam, the Netherlands) and others took 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. The individuals were defined as those with painful joints (arthralgia) but without arthritis, but who tested positive for IgM rheumatoid factor (IgM-RF) and/or anti-citrullinated protein antibody (ACPA) 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 polymerase chain reaction (PCR) to measure changes in specific genes.

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 signaling and antigen processing and presentation) and lower expression of genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism.

Immunohistochemistry analyses of 54 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. B-cell receptor (BCR) clones predict imminent onset of rheumatoid arthritis in at-risk patients. Another cohort study in 129 RA-risk individuals validated recent findings that dominant BCR clones in peripheral blood, can accurately predict imminent onset of arthritis in RA-risk individuals. 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.

Anne Musters, MD, a senior author of the study said, “Our data support a new biomarker that demonstrates better predictive power compared with other available biomarkers evaluated so far. 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.” The studies were presented at the Annual European Congress of Rheumatology, held June 13-16, 2018, in Amsterdam, the Netherlands.

Related Links:
Amsterdam Rheumatology and Immunology Center