Evidence of fibrinogen as a target of citrullination in IgM rheumatoid factor-positive polyarticular juvenile idiopathic arthritis

Abstract

BackgroundSeveral studies have noted the significance of measuring anti-cyclic citrullinated peptide (CCP) antibodies in juvenile idiopathic arthritis (JIA) as an important indicator for destructive disease, as is the case in rheumatoid arthritis (RA). While the role of anti-CCP antibodies in RA and JIA has become better understood, the identity of the target proteins of this modification has remained elusive. In this study, we evaluated serum from patients with various subtypes of JIA to investigate the presence of anti-deiminated (citrullinated) fibrinogen and anti-citrullinated α-enolase antibodies, and their association with RF and anti-CCP antibody isotypes.MethodsSera were obtained from 96 JIA patients, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. All sera were measured for antibodies against citrullinated and native fibrinogen and α-enolase by an enzyme linked immunosorbent assay (ELISA). In addition, all sera were assayed for anti-CCP antibody isotypes and rheumatoid factor (RF) isotypes by ELISA. The relationship between anti-citrullinated fibrinogen and anti-α-enolase antibodies and disease activity and joint damage were also investigated. All results were correlated with clinical and laboratory parameters using Spearman's rho correlation coefficient. Multiple logistic regression analysis was utilized to identify which variables were associated with joint erosions and diagnosis of JIA.ResultsThirty-one JIA patients (32%) demonstrated reactivity to citrullinated fibrinogen and 9 (9%) to citrullinated α-enolase. Reactivity to citrullinated fibrinogen and α-enolase was predominantly found in IgM RF-positive polyarthritis patients. Fourteen JIA patients reacted with native α-enolase and a higher percentage of SLE patients reacted with citrullinated α-enolase when compared to JIA patients. Anti-citrullinated fibrinogen antibodies correlated with the presence of IgG anti-CCP antibodies and IgA and IgM RF. The presence of anti-citrullinated α-enolase antibodies correlated with IgA anti-CCP antibodies. IgG anti-CCP antibodies were significantly associated with joint damage and anti-citrullinated fibrinogen antibodies were strongly associated with JIA when compared to control groups. Anti-citrullinated fibrinogen antibodies demonstrated high sensitivity (81%) for IgM RF-positive polyarticular JIA. IgG anti-CCP antibodies had the highest specificity (95%) for JIA, with anti-citrullinated fibrinogen antibodies, IgA anti-CCP antibodies and IgA RF all following at 84%.ConclusionsJIA patient sera exhibited strong reactivity to anti-citrullinated fibrinogen antibodies and demonstrated high sensitivity and specificity for JIA, primarily in IgM RF-positive polyarthritis patients. Fibrinogen is one of several protein targets for citrullination in JIA.

Diagnostic performance of anti-citrullinated protein/peptide antibodies in juvenile idiopathic arthritis

“…Our findings showed that the prevalence rates of all ACPAs in the whole population of JIA patients were less than 30% and much lower than those of adult RA patients, which agrees with the results reported in previous studies on anti-CCP (Avcin et al, 2002;Bongi et al, 2004;Kasapçopur et al, 2004;Kwok et al, 2005;Gilliam et al, 2011;Tebo et al, 2012). Therefore, we confirmed that ACPAs cannot serve as screening biomarkers for the general JIA population due to their low sensitivity.…”

Levels of interleukin-1 beta can predict response to tocilizumab therapy in rheumatoid arthritis: the PETITE (predictors of effectiveness of tocilizumab therapy) study

“…Fibrinogen plays roles in blood clotting, fibrinolysis, cellular and matrix interactions, the inflammatory response, wound healing and neoplasia [33]. Recent findings have shown that fibrin plays key roles in both inflammatory response and the development of RA [34], and fibrinogen levels correlate closely with ESR in RA patients [35]. Indeed, ESR might be influenced by several factors other than inflammatory response, such as anemia and aging.…”

Association of Fibrinogen, Erythrocyte Sedimentation Rate and C-Reactive Protein Levels with Rheumatoid Arthritis

“…The fibrinogen molecule is a soluble, large plasma glycoprotein that is converted by thrombin into fibrin during blood clot formation [3]. Fibrinogen is synthesized in the liver by the hepatocytes [9]. Research from 2011 has shown that fibrin plays a key role in the inflammatory response and development of rheumatoid arthritis [10].…”