Background Increased expression of type I interferon (IFN) response genes, “the type I IFN signature”, has been described in several autoimmune inflammatory disorders including rheumatoid arthritis (RA). The IFN-gamma-inducible protein 16 (IFI16) is highly expressed in sera from patients with systemic lupus erythematosus, primary Sjogren's syndrome, systemic sclerosis and RA compared to healthy subjects (1-2). Such overexpression leads to the loss of tolerance towards this self-protein and the development of autoantibodies (autoAbs).
Objectives Aim of the present study was to investigate the possible clinical significance of IFI16 protein and anti-IFI16 autoAbs in RA.
Methods Serum samples were obtained from 154 patients with RA and 182 healthy donors (HD). Synovial fluid (SF) samples were obtained from 23 RA patients and 25 patients with osteoarthritis (OA). IFI16 protein concentration and anti-IFI16 titer were assessed in serum and SF with ELISA. At the time of enrollment clinical and serological parameters were recorded and possible association with IFI16 protein and anti-IFI16 autoAbs was assessed with Chi-Square test and binary logistic regression.
Results The mean serum levels of both IFI16 and anti-IFI16 Abs were higher in RA than in HD and a direct correlation between IFI16 concentration and anti-IFI16 Abs titer was observed in the patients. Almost all (94.6%) RA patients with significant IFI16 protein levels in the serum were positive for RF/ACPA, being only 3/56 IFI16+ patients negative for both. Also anti-IFI16 Abs were essentially present in RF/ACPA+ RA subjects (84.4%). Of great interest was the finding on the prevalence of RA-associated pulmonary disease among the different patient subgroups, since this extra-articular manifestation was closely associated with the presence of IFI16, but not anti-IFI16 Abs, in the serum. The odds ratio (OR) for pulmonary disease in presence of IFI16 was 4 (95% confidence interval-CI=1.6-10.4; p=0.003) and this association was independent of the concurrent presence of anti-IFI16 Abs, gender and smoking habit. When the same analysis was performed taking into account the concentration, rather than the presence/absence, of IFI16, it appeared that increasing amounts of the protein did not further increase the OR for pulmonary involvement. The mean concentrations of IFI16 protein and anti-IFI16 Abs in SF were both higher in RA patients than in control OA subjects. In both patient groups, no association between SF total/differential cell count and levels of IFI16 or anti-IFI16 Abs was found.
Conclusions Our data demonstrated that the high serum levels of IFI16 in RA are essentially present in subjects with RF/ACPA positivity and are closely associated with pulmonary involvement. These findings, intriguing from a pathogenic point of view, may also provide the rational to employ IFI16 as soluble biomarker for this manifestation in clinical practice.
Costa S et al. Rheumatology 2011;50:674-681
Caneparo V et al. Lupus. 2013;22:607-13
Disclosure of Interest None declared
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