Rheumatoid Arthritis Risk May Begin Before Birth, Researchers Discover New Vulnerability - Video

Researchers have found that some joints may be predisposed to rheumatoid arthritis (RA) before birth, offering a possible explanation for why the disease affects certain joints more often than others. The study, published in Nature Immunology, was led by researchers at the Kennedy Institute.

RA is an autoimmune disease in which the immune system attacks the synovium, causing pain, swelling and stiffness and potentially damaging cartilage and bone. Researchers compared proximal interphalangeal (PIP) finger joints, which are commonly affected by RA, with distal interphalangeal (DIP) joints, which are usually spared.

Using single-cell sequencing, advanced imaging and high-resolution 3D X-ray scanning, the team found that the two joint types already had distinct cellular and structural features during development. PIP joints had a larger volume of synovial tissue and higher levels of PI16-positive (PI16+) fibroblasts, specialized connective tissue cells.

These fibroblasts were concentrated around blood vessels and areas where tendons and ligaments attach to surrounding tissues. They also responded differently to inflammatory signals compared with other fibroblasts, showing changes in pathways involved in tissue organization and immune regulation.

The researchers found that the synovial lining can develop from both cartilage cells and surrounding fibroblasts. Local conditions, including low oxygen levels, appeared to influence this process, potentially shaping how joint tissues develop and function.

The findings suggest that RA susceptibility may depend not only on immune activity but also on the cellular environment and architecture of individual joints established during development. PI16+ fibroblasts may play an important role in determining where inflammation takes hold later in life.

Researchers say these findings could eventually help identify why certain joints are vulnerable to RA and reveal new treatment targets aimed at modifying the tissue environment. However, further research is needed to determine whether these developmental differences directly cause increased disease susceptibility in humans.

REFERENCE: Sarah Davidson, et al.; The embryonic origins of site-specific arthritis; 8 June 2026, Nature Immunology; DOI: 10.1038/s41590-026-02542-2