Synovial tissue biomarkers predict patients at risk for RA

Lisa G. van Baarsen

AMSTERDAM — Infiltration of synovial T cells in the absence of overt synovitis may help identify patients at risk for developing rheumatoid arthritis, according to findings presented at the EULAR Annual Congress.

“In my research lab, we actually study rheumatoid arthritis as a model to investigate the earliest changes in autoimmunity, and we can do this because prior research has shown that before the onset of disease, you can find RA-associated antibodies in the blood,” Lisa G. van Baarsen, PhD, from the Amsterdam Rheumatology and Immunology Center at the Academic Medical Center/University of Amsterdam, said during a press conference.

“Having these antibodies already present before the onset of disease allows us to study these RA-risk individuals,” she noted. “What we wanted to know was whether the synovial tissue of these RA-risk individuals was already altered before the onset of disease.”

To examine the molecular variations occurring in the synovium prior to arthritis development in preclinical RA, van Baarsen and colleagues biopsied synovial tissue from the knee joints of a cohort of patients (n = 67) who were IgM rheumatoid factor and/or anti-citrullinated protein antibody (ACPA)-positive but had not yet exhibited any sign of arthritis.

The researchers then performed an explorative genome-wide transcriptional profile study in 13 individuals to identify gene transcripts with a significant association with developing arthritis. They then validated the expression level of differentially expressed genes using quantitative real-time PCR in the total cohort.

According to study results, six of the 13 individuals in the study subsequently developed RA after a median follow up of 20 months (IQR, 2–44), while the 7 individuals who did not develop RA had a median follow up time of 85 months (IQR, 69–86). The researchers noted, using a False Discovery Rate of less than 5%, that an increased expression of 3,151 transcripts were linked to a higher risk for arthritis development, whereas increased expression of 2,437 transcripts were linked to a lower risk.

Further, patients who developed RA exhibited a higher expression of genes involved in various immune response-related pathways, including T-cell and B-cell receptor pathways, cytokine and chemokine signaling and antigen processing and presentation, whereas lower expression of genes were involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism.

The researchers noted that immunohistochemistry analyses (n = 54) showed a profuse expression of CXCL12 and CXCR4 already in most RA-risk patients; synovial biopsies from the individuals who developed arthritis were also more likely to exhibit a positive gp38 staining and lower lipid staining.

“Before the onset of disease, we do find molecular changes in the synovial tissue reflected by a higher activity of immune response pathways and the lower of lipid metabolism,” van Baarsen said. “In future studies, I would like to study those resident stromal cells since we find an activation of these cells already before onset disease.”– by Bob Stott

Reference:
Van Baarsen LG, et al. Abstract #OP0266. EULAR Annual Congress; June 13-17, 2018; Amsterdam.

Disclosure: Van Baarsen reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.