Rheumatoid Arthritis May Target Certain Joints Due to Differences Set Before Birth

Some finger joints may be predisposed to rheumatoid arthritis by differences established before a person is even born, according to researchers at the Kennedy Institute at the University of Oxford. Their study, published in Nature Immunology, examined whether differences built into joint tissue during development help explain why the disease repeatedly affects certain joints while sparing others.

Rheumatoid arthritis is an autoimmune disease in which the immune system attacks the synovium, the tissue lining a joint, causing pain, swelling and stiffness that can eventually damage cartilage and bone. The researchers compared two types of finger joints with very different susceptibility to the disease: proximal interphalangeal (PIP) joints, which are commonly affected, and distal interphalangeal (DIP) joints near the fingertips, which are usually spared.

The PIP joints had a larger volume of synovial tissue and higher levels of PI16-positive fibroblasts, a specialized type of connective tissue cell. Because these differences were already present before birth, the findings suggest that the structure of individual joints may help determine their later susceptibility to disease. "The cellular and structural characteristics established during development may help determine where inflammation takes hold later in life," said Christopher Buckley, Kennedy Professor of Translational Rheumatology at Oxford.

To reach these findings, the researchers mapped developing human finger joints using single-cell sequencing, image analysis and high-resolution 3D X-ray scanning at the Diamond Light Source facility at Harwell. The PI16-positive fibroblasts in PIP joints were concentrated around blood vessels and where tendons and ligaments connect with surrounding tissue, and reacted differently to inflammatory signals than other fibroblast populations.

"We found that joints commonly affected by rheumatoid arthritis already contain distinct cellular populations before birth," said Dr. Sarah Davidson, a postdoctoral researcher at the Kennedy Institute and one of the study's first authors. "PI16+ fibroblasts were enriched in vulnerable joints and responded differently to inflammatory signals. Their location and behavior suggest they could help shape where disease develops."