Minimally invasive retrieval and characterisation of tenosynovial tissue in rheumatoid arthritis: a novel approach to study at-risk, active, and remission stages

Objectives: Tenosynovial inflammation is a hallmark of rheumatoid arthritis (RA), even in the preclinical phase. However, tenosynovium retrieval and characterisation is beyond the current state-of-the-art. We aimed to (1) assess the rate of magnetic resonance imaging (MRI)-detected tenosynovitis in the wrists of patients with preclinical and clinical RA; (2) develop a technique for tenosynovium retrieval; and (3) characterise its cellular composition across disease phases, including the comparison to adjacent synovium. Methods: In total, 834 MRI wrist scans were analysed to assess extensor/flexor tendon tenosynovitis rate (168 autoantibody-positive clinical suspect arthralgia (CSA), 473 naïve to treatment RA, and 193 healthy controls). An ultrasound-guided minimally invasive technique was developed to collect tenosynovium from the wrist extensor tendons in an independent cohort: 16 autoantibody-positive CSA patients, 41 RA patients (14 of whom with adjacent synovium with comparable ultrasound-detected inflammation), and 8 osteoarthritis (OA) patients. Tissue representativity, lining hyperplasia, and inflammatory infiltrate degree were assessed by haematoxylin and eosin staining and immunohistochemistry (CD55, CD68, CD3, CD20, CD138, and CD21). Safety and tolerability were assessed. Results: Tenosynovitis of the wrist extensors/flexor tendons was observed in 34% of CSA and 68% of RA patient compared to 8% in healthy. Tenosynovium was successfully retrieved in 89.7% of cases without severe adverse events. Tenosynovial lining hyperplasia and inflammatory infiltrate were significantly higher in active RA than CSA patients without ultrasound-detected subclinical inflammation and RA remission, and comparable to inflamed adjacent synovium. CSA patients with subclinical inflammation showed early CD3pos and CD55pos cells enrichment compared to OA controls. Conclusions: Tenosynovium is frequently inflamed and readily accessible in CSA and RA. Future molecular studies of tenosynovial biopsies will advance understanding of the transition from pre-RA to RA.