Background 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].
Objectives 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.
Methods 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&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.
Results 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<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.
Conclusions 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.
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.
Disclosure of Interest None Declared