High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease.
OBJECTIVE
The B cell chemoattractant chemokine ligand 13 (CXCL13) is emerging as a new biochemical marker in RA. This study was undertaken to dissect the relationship between CXCL13 expression levels in the synovium and clinico-pathological variables relevant to RA pathogenesis and outcome.


METHODS
Synovial tissues from 71 RA patients were evaluated by immunohistochemistry. Thirty paired samples were used for comparative gene expression analysis by quantitative real-time PCR. CXCL13 levels were analysed in relation to cellular, molecular and clinical features of inflammation, lymphocyte activation and joint damage.


RESULTS
In patients with early disease (<12 months duration), CXCL13 expression correlated significantly with synovial markers of local disease activity and systemic inflammation. Such correlation was less evident in established RA. Notably, the association with lymphocyte infiltration and with expression of B/T cell-related activation and proliferation genes, such as activation-induced cytidine deaminase, IFN-γ and IL-2, remained highly significant independent of disease duration and local disease activity. Patients featuring the highest levels of CXCL13 were more frequently ACPA positive and IgG ACPA titres were increased in the high CXCL13 expression group. Furthermore, the frequency of erosive disease on radiographs was significantly higher in the upper tertile of CXCL13 expression (P = 0.01 with adjustment for disease duration and ACPA). Accordingly, synovial CXCL13 and the local receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio significantly co-varied (ρ = 0.52, P < 0.01), independent of the level of local inflammation.


CONCLUSIONS
Synovial CXCL13 appears to be a marker of a more severe pattern of RA disease, characterized by increased lymphocyte activation and bone remodelling beyond the level of conventional markers of inflammation.
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Serena
S
Bugatti
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK. antonio.manzo@unipv.it.
Antonio
A
Manzo
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Barbara
B
Vitolo
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Francesca
F
Benaglio
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Elisa
E
Binda
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Martina
M
Scarabelli
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Frances
F
Humby
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Roberto
R
Caporali
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Costantino
C
Pitzalis
Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Italy and Centre for Experimental Medicine and Rheumatology, John Vane Science Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Carlomaurizio
C
Montecucco
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling; D054382:Chemokine CXCL13 / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; D054382:Chemokine CXCL13
B lymphocytes; CXCL13; biomarkers; rheumatoid arthritis; synovium