Researchers at the Kennedy Institute of Rheumatology have discovered that certain joints may be predisposed to inflammatory arthritis before birth, potentially explaining why rheumatoid arthritis (RA) selectively targets specific joints. The study, “The embryonic origins of site-specific arthritis,” published in Nature Immunology, indicates that biological differences established during joint development, in addition to immune system factors, may influence a joint’s susceptibility to RA. The researchers compared proximal interphalangeal (PIP) joints, which are frequently affected by RA, with distal interphalangeal (DIP) joints, which are typically spared, and found that PIP joints had a larger volume of synovial tissue and contained more PI16-positive (PI16+) fibroblasts, differences present before birth [https://www.sciencedaily.com/releases/2026/09/260901070538.htm].
Further analysis revealed that PI16+ fibroblasts were more abundant in PIP joints and were concentrated around blood vessels and at locations where tendons and ligaments connect with nearby tissue. These cells responded differently to inflammatory signals compared to PI16- fibroblasts, exhibiting distinct changes in biological pathways involved in immune regulation and tissue organization. Additionally, high-resolution 3D imaging showed that PIP joints had more synovial tissue organized differently from joints typically spared by RA. These findings suggest that the local tissue environment of a joint, shaped during development, may influence the likelihood of inflammation taking hold later in life, providing a developmental perspective on the site-specific nature of rheumatoid arthritis.