A5.14 Serum CXCL13 is a non-invasive synovitis marker holding non-redundant information compared with acute phase reactants and autoantibodies in patients with rheumatoid arthritis

Abstract

Background and objectivesNewly identified B-cell related markers beyond autoantibodies may help better stratifying and predicting the heterogeneous outcome of rheumatoid arthritis (RA). The aim of this study was to investigate whether serum levels of the B-cell chemoattractant CXCL13 can implement information provided by traditional laboratory markers in patient with early RA.Materials and methodsThe pathological correlates of CXCL13, acute phase reactants and autoantibodies were determined in 60 RA patients with paired serum and synovial tissue samples. Baseline associations, responsiveness to change and predictive validity for response to therapy were assessed in a prospective cohort of 213 early RA patients undergoing treatment with methotrexate aiming at low disease activity (LDA).ResultsIn paired serum and synovial samples, CXCL13 covaried with tissue levels of the chemokine (rho 0.56, p = 0.01) and was the only laboratory marker able to discriminate high degrees of B-cell infiltration (AUROC [95% CI] 0.74 [0.61 to 0.85]). Serum CXCL13 showed lower correlation with disease activity and lower responsiveness to change after 2 months of therapy compared with acute phase reactants. Levels were increased in anti-citrullinated protein antibody-positive (ACPA) subjects, approximatively half of whom had high CXCL13 (3rd tertile, >106 pg/ml), and correlated with rheumatoid factor (RF) titres. High CXCL13 alone independently predicted failure to achieve LDA after 12 months of therapy with an adjusted OR (95% CI) of 2.87 (1.42 to 5.82) (p = 0.003), a high negative predictive value (NPV) (79.9%, 95% CI 72.1% to 86.3%) but a quite low positive predictive value (PPV) (50.7%, 95% CI 38.4% to 63%). Combining high CXCL13 with autoantibody positivity (ACPA and/or RF) significantly increased the PPV (61%, 95% CI 44.5% to 75.8%) without affecting the NPV (77.2%, 95% CI 69.9% to 83.4%).ConclusionsIn early RA patients treated with conventional synthetic disease-modifying anti-rheumatic drugs, serum CXCL13 appears a novel lymphoid-linked biomarker holding non-redundant information with respect to acute phase reactants and autoantibodies, and able to stratify patients into different prognostic subgroups.

A systematic review of CXCL13 as a biomarker of disease and treatment response in rheumatoid arthritis

“…EstRA bDMARD Serum by ELISA EstRA > HC Not published Correlation: DAS28-CRP ( r = 0.52) Loza et al* (2016) [ 18 ] N = 916. ERA Anti-IL6 Serum by ELISA/MSD /Luminex EstRA > HC Not published Bugatti et al* (2016) [ 19 ] N = 213. EstRA csDMARD Both, method not published Not published Lower correlation with disease activity compared to CRP (data not presented).…”

“…The remaining studies used Luminex -based assays [ 35 ], electrochemiluminescent (ECLA) [ 40 ], or a combination of ELISA, Luminex or Meso Scale Discovery (MSD) [ 18 , 41 ]. Six studies did not mention the immunoassay method used [ 19 , 30 , 33 , 34 , 37 , 42 ]. The method of measurement is of importance as data generated with Luminex technology is sensitive to heterophilic antibodies in the serum, such as rheumatoid factor and may result in false positive cytokine levels.…”

“…Not seen with IFX Loza et al* (2016) [ 18 ] N = 916. ERA Anti-IL6 Cohort Serum by ELISA, MSD, Luminex No change with sirukumab Bugatti et al* (2016) [ 19 ] N = 213. EstRA csDMARD Cohort Both, method not published B/L high levels predict failure of remission Greisen et al (2014) [ 23 ] N = 114.…”

“…Four studies evaluated the association between CXCL13 level and seropositivity (RF and CCP). CXCL13 levels were found to be higher in RF and ACPA positive patients [ 16 , 19 , 32 ], with a positive correlation between synovial CXCL13 expression and ACPA titres [ 22 ]. Two studies assessed the association with CXCL13 and radiological evidence of erosive disease, demonstrating a strong association with progression of joint destruction in patients with high baseline CXCL13 levels [ 32 ].…”

“…In csDMARD treated patients, high baseline levels of CXCL13 were associated with a reduced likelihood of achieving low disease activity. Bugatti reported a high negative predictive value of 80% for remission after 12 months of methotrexate therapy [ 19 ]. With anti-TNF therapy, the findings were not consistent across studies.…”