Disease Stratification by ACPA in RA According to Biological Features of Synovium
Orr C, McGarry T, Ng CT, Creevey K, McCormick J, Young F, Fearon U, Veale DJ.
Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, University College Dublin, Ireland.
The first order of RA stratification is now understood to be ACPA positive (+) and ACPA negative (-) disease, and it is known that each have distinct characteristics. Despite a worse prognosis overall, patients positive for ACPA have been shown to have better responses to therapy, in particular to rituximab, supporting the hypothesis that B-cells play a more significant role in the ACPA positive disease. Despite these well reported differences in clinical disease expression, little has been reported on the differences at the principal target of aberrant inflammation, the synovium, between these two important disease phenotypes at a macroscopic, cellular, and cytokine level.
To study the synovium of patients with the two RA phenotypes, examining:
1. Macroscopic scores of synovitis and vascularity at knee arthroscopy
2. Histology inflammatory scores and immunohistochemistry of synovial tissue
3. Synovial fluid cytokine analysis
4. Response of explant biopsies to adalimumab
Patients with active RA were recruited to undergo knee arthroscopy, where the operator recorded separately a macroscopic score of synovitis and vascularity, graded at 5 unit intervals between 0-100. Biopsies were taken and stained for various markers. Where synovial fluid was retrieved at arthroscopy, levels of various cytokines were measured. The Mann-Whitney test was employed to determine differences in each parameter between those positive and negative for ACPA.
Patients positive for ACPA had lower macroscopic vascularity scores and lower synovitis scores (p≤0.02) but higher serum CRP levels at the time of arthroscopy. ACPA+ patients had higher histological scores of inflammation (p≤0.01) as well as more CD3 (p≤0.01) and CD8 (p≤0.03) expression in the sublining layer, with no significant differences in other markers. The synovial fluid of ACPA+ patients demonstrated higher levels of the cytokines INFγ (p≤0.01) and IL1β (p≤0.04) when compared to that of ACPA- patients. Finally, IL6 and IL8 levels in the supernatants of explant biopsies of ACPA+ patients were significantly suppressed by TNFi after 72hours incubation (p≤0.0002 and p≤0.0001 respectively), but this was not seen in biopsies from ACPA- patients.
ACPA differentiates between two clear RA phenotypes. Analysis of immunophenotype and molecular biomarkers is now underway.