Background Synovial inflammation is known to play a central role in the development of bony erosions and articular cartilage degradation in RA. We aimed to determine if circulating metalloproteinase-3(MMP-3), hyaluronic acid (HA), serum amyloid A(SAA), interleukin 6(IL-6) and calprotectin (S100A8/A9) would outperform CRP as surrogate biomarkers for synovitis detection.
Methods Patients were recruited to a randomised controlled trial;1 baseline samples and clinical data were included in this analysis. Patients fulfilled 1987 ACR RA classification criteria, had 3–12 month symptom duration, active disease (DAS44 > 2.4) and were DMARD naïve. In a subset, grey scale (GS) and power Doppler (PD) ultrasound (US) semi-quantitative scores (0–3) were assigned to wrists, MCPs and PIPs 2 and 3 and MTPs 1–5 bilaterally. Both counts (joints scoring GS > 1, PD > 0, simultaneously GS > 1 and PD > 0) and score totals were created. To reflect synovitis burden, joint measures were weighted by multiplying each joint’s score by a relative area weight,2 before summating. Samples were tested for MMP-3, HA, SAA, IL-6, S100A8/A9 using research-use-only multiplex platform IMPACT (Immunological Multi-Parameter Chip Technology) (Roche Professional Diagnostics, Germany),3 CRP was measured in the routine lab. We calculated bootstrapped confidence intervals (CI) for the differences between CRP and the other markers in the strength of Kendall’s tau-a rank correlation with the joint assessments using Stata 13.1.
Results Fifty-nine patients were included: mean (SD) age 52.7 (13.8) years, 71% female, median (IQR) disease duration 1.0 (0.7, 1.6) months. Marker values [median (IQR)] were CRP 16.4 (8.2, 52.0); MMP3 58.9 (42.1, 119.3); HA 36.5 (20.5, 70.2); SAA 36.5 (6.3, 249.0); IL-6 46.3 (21.4, 69.1); S100 A8/A9 12.1 (8.6, 15.2).
Associations were stronger when joint weights were used, particularly for CRP and MMP3 (data not shown), but remained weak-to-moderate; the strongest were between weighted clinical joint counts and CRP. The association with SJC28 was substantively stronger for CRP (tau = 0.46) than for any of the other markers and was significantly stronger than for HA (tau = 0.24; difference 0.04–0.44). Similar values were obtained using 28- or 44-joint clinical counts. CRP, MMP3 and IL-6 were associated with US to a comparable degree (tau circa 0.30); associations with US for SAA and S100A8/A9 were slightly weaker than CRP, although differences were not significant.
Conclusion Weighting for joint area improved correlation with circulating inflammatory markers. None of the markers outperformed CRP as a surrogate biomarker of synovitis across the full range of observed values. We intend to investigate their utility in patients with low/normal CRP.
Funding: Roche Professional Diagnostics provided free of charge access to the IMPACT platform and IMPACT reagents. This work was also supported by grants from Arthritis Research UK and the NIHR.
Nam JL, Villeneuve E, Hensor EMA, et al . Ann Rheum Dis 2014; 73 :75.
Lansbury J, Haut DD. Am J Med Sci 1956; 232 :150.
Claudon A, Vergnaud P, Valverde C, et al . Clin Chem 2008; 54 :1554.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.