Synovial fibroblast activation occurs before the onset of rheumatoid arthritis and influences the risk of developing disease

Objectives Activated synovial fibroblasts play a key role in rheumatoid arthritis (RA). Positron emission tomography-CT (PET-CT) using 68g allium-labelled fibroblast activation protein inhibitor (FAPI) allows the detection of FAP-expressing activated fibroblasts in humans in vivo. Herein, this study aimed to investigate whether fibroblast activation already occurs in the pre-clinical phase of RA and whether it is associated with the development of clinical disease. Methods 68 Ga-FAPI-46 PET-CT was performed in individuals positive for anti-citrullinated protein antibodies (ACPAs) with clinically suspect arthralgia without present or past signs of joint swelling or present or past anti-rheumatic therapy. All participants underwent structured clinical and laboratory evaluations and were followed for the development of RA. Synovial FAPI uptake was quantified and related to demographic characteristics, joint tenderness, ACPA levels and RA development. Findings Eighteen RA-at-risk individuals (male/female: 7/11; mean age, 47 (SD 14) years) underwent 68 Ga-FAPI-46 PET-CT and were followed for a median of 42 weeks. Five participants (28%) developed RA with a median of 12 weeks (IQR, 11–20), whereas 13 remained disease-free. Total lesion FAPI-uptake (TL-FAPI) was a significant predictor of RA development (HR 4.58, 95% CI 1.38 to 15.22, p=0.013). Increasing TL-FAPI at the joint level was also associated with tenderness (isk ratio 1.14, 95% CI 1.08 to 1.22, p=0.001). Conclusions The findings in this small RA-at-risk cohort suggest that synovial fibroblast activation occurs early in the disease process of RA and is associated with an increased risk for clinical RA onset. These results warrant further research on FAPI-PET-CT to improve risk assessment for clinical RA onset.