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Synovial Tissue Sublining CD68 Expression Is A Biomarker Of Therapeutic Response In Rheumatoid Arthritis Clinical Trials: Consistency Across Centers

BARRY BRESNIHAN, ELIZA PONTIFEX, ROGIER M. THURLINGS, MARJOLEIN VINKENOOG, HANI EL-GABALAWY, URSULA FEARON, OLIVER FITZGERALD, DANIELLE M. GERLAG, TERENCE ROONEY, MARLEEN G. van de SANDE, DOUGLAS VEALE, KOEN VOS, PAUL-PETER TAK

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Objective.To determine whether the correlation between the mean change in disease activity and the mean change in synovial sublining (sl) CD68 expression could be demonstrated across different academic centers.Methods.Synovial biopsies obtained at arthroscopy from patients with rheumatoid arthritis before and 160 days after rituximab therapy were selected and coded. Paired sections were processed independently at Amsterdam Medical Center (AMC) and at St. Vincent’s University Hospital (SVUH), Dublin. Digital image analysis (DIA) was employed at both centers to quantify sublining CD68 expression.Results.After analysis of CD68sl expression at centers in 2 different countries, high levels of intracenter and intercenter agreement were observed. For the pooled sections stained at AMC, the correlation between 2 investigators was R = 0.942, p = 0.000, and for sections stained at SVUH, R = 0.899, p = 0.001. Similarly, the intracenter correlations for ΔCD68sl expression after treatment were R = 0.998, p = 0.000, for sections stained at AMC and R = 0.880, p = 0.000, for sections stained at SVUH. The intercenter correlation for the pooled scores of sections stained at AMC was R = 0.85, p = 0.000, and for the sections stained at SVUH, R = 0.62, p = 0.001. The consistent correlation between ΔDAS (Disease Activity Score) and ΔCD68sl expression across different studies (Pearson correlation = 0.895, p < 0.001) was confirmed. The standardized response mean values for ΔCD68sl, calculated from analyses at both AMC and SVUH, were consistently 0.5 or greater, indicating a moderate to high potential to detect change.Conclusion.The correlation between mean ΔDAS and mean ΔCD68sl expression was confirmed across 2 centers. Examination of serial biopsy samples can be used reliably to screen for interesting biological effects at the site of inflammation at an early stage of drug development.