FRI0101 The value of gene signatures in the diagnosis of pre-clinical ra
Authors: J. Lubbers, L. van de Stadt, S. Vosslamber, J. G. Wesseling, D. van Schaardenburg, C. Verweij
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Diagnosis of the preclinical phase of rheumatoid arthritis (RA) allows timely start of treatment with the potential to prevent disease progression. It is known that antibodies against citrullinated proteins (ACPA) and rheumatoid factor (RF) have diagnostic value to identify pre-clinical RA. However, since only 20-40% of ACPA<sup>+</sup>/RF<sup>+</sup> arthralgia patients develop arthritis within 5 years, better prognostic markers are needed. Recently, we demonstrated involvement of Interferon (IFN) response and B-cell gene signatures in pre-clinical RA. <h3>Objectives</h3> The objective of this study is to demonstrate the diagnostic value of the IFN and B-cell gene signatures in the diagnosis of pre-clinical RA. <h3>Methods</h3> Peripheral blood (Paxgene) was collected from 115 ACPA<sup>+</sup>/RF<sup>+</sup> arthralgia patients from the Jan van Breemen Research Institute | Reade Amsterdam. Patients where clinically followed for arthritis development, one or more swollen joints, with a mean follow-up time of 23 months (IQR 12-30). IFN response and B-cell related gene expression was measured by multiplex qPCRs. An IFN score was calculated based on 7 highly correlating Type I IFN response genes. A B-cell score was calculated based on three highly correlating B-cell related genes. Cut-off levels for the IFN and B-cell high or low definition were determined by the 85% specificity of the individual IFN and B-cell Receiver Operating Characteristics (ROC)-curves. Cox regression analysis and ROC-curve analysis were used to demonstrate prognostic and diagnostic significance. <h3>Results</h3> Out of 115 arthralgia patients 44 developed arthritis after a median time of 8 months (IQR 5-13). Stratification of these individuals based on the IFN score revealed that 60% of the IFN<sup>high</sup> patients converted to arthritis compared to 32% in IFN<sup>low</sup> patients (P=0.011). For the B-cell signature, 58% in B-cell<sup>low</sup> patients developed arthritis, compared to 33% of B-cell<sup>high</sup> patients (P=0.020). Combined analysis revealed a significant high risk for arthritis development in IFN<sup>high</sup>/B-cell<sup>low</sup> patients (80%, hazard ratio (HR)(6.22, P=0.003) and a low risk for IFN<sup>low</sup>/B-cell<sup>high</sup> patients (26%, HR 0.16, P=0.003). To demonstrate clinical utility a ROC-curve was constructed of ACPA<sup>+</sup>/RF<sup>+</sup> alone and in combination with both signatures. The area under the curve reached 0.619 (P=0.032, C.I. 0.514-0.724) for ACPA<sup>+</sup>/RF<sup>+</sup> and increased to 0.803 (P=0.0001, C.I. 0.718-0.888) with IFN and B-cell signatures included. The sensitivity to diagnose pre-clinical RA increased from 16% to 52% when both signatures are included, with a cut-off of 94% specificity. <h3>Conclusions</h3> These findings demonstrate the clinical value of IFN and B-cell gene signatures as biomarkers for the diagnosis of pre-clinical RA. <h3>Acknowledgements</h3> This research was supported by the Center for Translational Molecular Medicine (CTMM) consortium “TRACER”. <h3>Disclosure of Interest</h3> J. Lubbers Grant/research support from: CTMM TRACER, L. van de Stadt Grant/research support from: Dutch Arthritis Foundation, S. Vosslamber: None Declared, J. G. Wesseling Grant/research support from: CTMM TRACER, D. van Schaardenburg Grant/research support from: Dutch Arthritis Foundation, C. Verweij Grant/research support from: CTMM TRACER