Detection of antibodies to citrullinated tenascin-C in patients with early synovitis is associated with the development of rheumatoid arthritis

Correspondence to Dr Kim S Midwood; [email protected]. ac.uk Early treatment of rheumatoid arthritis (RA) results in more effective disease suppression and can be key to a successful patient response. However, not all people who exhibit early synovitis develop RA; for example, in some, synovial inflammation resolves spontaneously. The factors that drive RA development remain unclear and clinical tools to predict RA development are imperfect. Tenascin-C is a proinflammatory matrix molecule that is absent from healthy joints but highly expressed in the joints of patients with RA. 3 We identified an immunodominant peptide in citrullinated tenascin-C, cTNC5, antibodies against which are detected in around half of the patients with RA, and can be found years before disease onset in some individuals. Here, we sought to determine if anti-cTNC5 antibodies can discriminate among people with early synovial inflammation those who develop RA and those with other outcomes. Sera from 263 patients in the Birmingham early arthritis cohort were analysed. Patients were disease-modifying antirheumatic drug (DMARD) naïve with clinically apparent synovitis of ≥1 joint and with inflammatory joint symptoms of ≤3 months’ duration. Patients were followed for 18 months to ensure development of full disease phenotype and to allow any resolving arthritis time to resolve. At 18 months, patients were assigned to the following outcome categories: persistent RA according to the American College of Rheumatology (ACR) 2010 criteria (RA, n=101), persistent non-RA arthritis (PNRA, n=66) and resolving arthritis (no clinically apparent joint swelling, no DMARD/steroid use in the previous 3 months, n=96). Demographic and clinical parameters were recorded, and patients with RA divided into anti-cyclic citrullinated peptide (anti-CCP) antibody positive and negative subsets. 7 Antibodies recognising cTNC5 or the noncitrullinated control peptide (rTNC5) were analysed by ELISA as described. Anti-cTNC5 antibodies were found in 40.6% of people with early synovitis who went on to develop RA, but were detected in a low proportion of people who developed PNRA (6.1%), or whose disease resolved (3.1%). No significant antibody response to rTNC5 was detected (p=0.527) (table 1, see online supplementary figure S1). Anti-cTNC5 antibodies were significantly more prevalent in anti-CCP antibody positive compared with anti-CCP antibody negative patients with RA (81.3% vs 3.8%, p<0.0001) (table 1). Anti-cTNC5 antibody levels were higher in patients with anti-CCP antibodypositive RA (193.1±449.8 arbitrary units (AU)) compared with patients with anti-CCP antibody-negative RA (3.56±3.30 AU), PNRA (19.42±122.7 AU) and resolving arthritis (6.60±28.02 AU) (ANOVA p<0.0001). While anti-cTNC5 was not better at predicting the development of RA than anti-CCP antibody (specificity; sensitivity: 40.6%; 95.7% (cTNC5), 47.5%; 98.8% (CCP)), anti-cTNC5 did detect a subset of people who developed RA who were not anti-CCP antibody positive (3.8%). Patients with anti-cTNC5 antibodypositive RA were more frequently anti-CCP antibody and rheumatoid factor (RF) positive than anti-cTNC5 antibody-negative patients (table 2). Together these data reveal that detection of anti-cTNC5 antibodies in the sera of people with early synovitis is associated with the development of RA. While similar numbers of people who developed RA were