THU0090 Survivin but not FMS-like Tyrosine Kinase Ligand (FLT3L) is Up-Regulated Before Onset of Rheumatoid Arthritis
Authors: M. Bokarewa, M. Brink, M. Erlandsson, S. Rantapää Dahlqvist
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Presence of antibodies against citrullinated peptides (anti-CCP2) and increased levels of cytokines and chemokines precedes the development of rheumatoid arthritis (RA) by several years [1, 2]. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been associated with RA and RA associated joint damage [3, 4]. <h3>Objectives</h3> To investigate the potential of survivin and Flt3L as predictors of RA and their relationships to cytokines and anti-CCP antibodies in blood samples from individuals before onset of symptoms of RA. <h3>Methods</h3> This study includes 47 individuals sampled before onset of symptoms of RA (median 2.5 years (IQR 1.1-5.6) and 155 population controls matched for sex and age, all donors to the Medical Biobank of Northern Sweden. 36 of the pre-symptomatic individuals were also sampled at the time of RA diagnose (ACR criteria 1987). Levels of survivin and Flt3L were measured using sandwich ELISAs (both, R&amp;D Systems, Minneapolis, MN). Anti-CCP antibodies was analyzed using ELISA (Euro-Diagnostica AB, Malmö, Sweden) and 29 cytokines, and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, eotaxin, IL-1Ra, bFGF, G-CSF, GM-CSF, IFNγ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGFBB, TNFα, VEGF, Mig, MIF and IL-2Rα by multiplex detection (Bio-Rad, Hercules, CA). The cut-off levels were for survivin 450 pg/mL, and for Flt3L 130 pg/mL. <h3>Results</h3> The levels of survivin were increased in the pre-symptomatic individuals compared with the controls (p=0.003) whilst the levels of Flt3-ligand (p=0.21) were similar. The frequency of survivin in the pre-symptomatic individuals was increased compared with controls (36.2 vs. 14.2% p=0.001). The odds ratio (OR) for predicting disease development in individuals with survivin levels above cut-off was 3.4 (95%CI 1.6-7.2). The frequencies of survivin and Flt3L were increased in RA patients compared with controls (both, p&lt;0.0001. OR12.1 [95%CI, 5.3-27.6] and OR11.0 [3.9-30.9], respectively). Anti-CCP positive pre-diseased individuals and RA-patients had significantly higher concentrations of survivin compared with those being negative. After correction for the number of comparisons, IL-1β, GM-CSF in pre-symptomatic individuals was correlated with survivin and IL-1α, IL-10, eotaxin and TNF-α was correlated with Flt3L, while IL-2, IL-9 and IL12 was correlated with both survivin and Flt3L in the pre-symptomatic individuals. <h3>Conclusions</h3> The proto-oncogene survivin was increased in individuals before onset of symptoms of RA and it was related to cytokines suggesting its role in the events preceding development of the disease. <h3>References</h3> Rantapää-Dahlqvist S et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003; 48:2741-9. Kokkonen H, et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 2010; 62:383-91. Svensson B et al. Increased expression of proto-oncogene survivin predicts joint destruction in early rheumatoid arthritis. Ann Med 2010,42: 45-54. Andersson SE, et al. Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis. PloS one. 2012; 7:e47668. <h3>Disclosure of Interest</h3> None Declared