CXCL13: a novel biomarker of B-cell return following rituximab treatment and synovitis in patients with rheumatoid arthritis.

OBJECTIVES The B-cell chemokine, CXCL13, is a proposed serum biomarker of synovitis in RA. Its behaviour in the context of B-cell depletion therapy and reconstitution was studied during treatment of RA with rituximab. METHODS Serum samples from 20 RA patients were analysed for CXCL13, RF-IgM and anti-CCP by ELISA before and 2 and 6 months following rituximab treatment. B cells were monitored by flow cytometry. Gene expression in blood and synovial biopsies was determined by qPCR. RESULTS Patients with detectable B cells at 6 months had significantly higher levels of CXCL13 and RF-IgM and slightly higher levels of anti-CCP throughout the study, including at baseline, compared with patients with undetectable B cells at 6 months. Conversely, 10 of 12 patients with high baseline CXCL13 had detectable circulating B cells at 6 months, whereas no B cells could be detected at 6 months in patients with low baseline CXCL13. Synovial CXCL13 expression at baseline correlated significantly with serum CXCL13 levels, and the synovium of patients with high serum CXCL13 expressed elevated levels of IL-1β, IL-8, MMP1 and MMP3. In addition, synovial CXCL13 expression correlated significantly with several synovial inflammatory markers. CONCLUSIONS Serum CXCL13 is predictive of the rate of B-cell repopulation following a course of rituximab in RA. Serum CXCL13 correlates with synovial CXCL13 measured at a single joint, suggesting synovitis as an important source of circulating CXCL13. Within the synovium, CXCL13 expression is highly correlated with markers of synovitis. TRIAL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00147966.

[1]  M. Haubitz,et al.  B-cell-attracting chemokine CXCL13 as a marker of disease activity and renal involvement in systemic lupus erythematosus (SLE). , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  J. Skurnick,et al.  Serum levels of CXCL13 are elevated in active multiple sclerosis , 2009, Multiple sclerosis.

[3]  S. Rai,et al.  Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion. , 2009, Cancer letters.

[4]  H. Papadaki,et al.  Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response , 2009, Arthritis research & therapy.

[5]  J. Harrison,et al.  Data Sources for Improving Estimates of the Global Burden of Injuries: Call for Contributors , 2009, PLoS medicine.

[6]  Stephen Kelly,et al.  Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium , 2009, PLoS medicine.

[7]  F. Dell’Accio,et al.  Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. , 2008, Arthritis and rheumatism.

[8]  Dennis McGonagle,et al.  Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. , 2008, Arthritis and rheumatism.

[9]  C. Bokemeyer,et al.  Chemokine CXCL13 is overexpressed in the tumour tissue and in the peripheral blood of breast cancer patients , 2008, British Journal of Cancer.

[10]  Felicia A Tucci,et al.  Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis. , 2008, Blood.

[11]  K. Kalunian,et al.  Elevated autoantibody content in rheumatoid arthritis synovia with lymphoid aggregates and the effect of rituximab , 2008, Arthritis research & therapy.

[12]  I. Rioja,et al.  Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor alpha, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. , 2008, Arthritis and rheumatism.

[13]  B. Zheng,et al.  Gene expression profiles at different stages of collagen-induced arthritis , 2008, Autoimmunity.

[14]  T. Huizinga,et al.  Immunohistochemical analysis as a means to predict responsiveness to rituximab treatment. , 2007, Arthritis and rheumatism.

[15]  M. Keating,et al.  Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. , 2007, Blood.

[16]  A. Zwinderman,et al.  Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response , 2007, Annals of the rheumatic diseases.

[17]  P. Petrow,et al.  CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. , 2007, Arthritis and rheumatism.

[18]  F. Breedveld,et al.  Rituximab Pharmacokinetics in Patients With Rheumatoid Arthritis: B‐Cell Levels Do Not Correlate With Clinical Response , 2007, Journal of clinical pharmacology.

[19]  K. Kalunian,et al.  Assessment of rituximab’s immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results , 2007, Annals of the rheumatic diseases.

[20]  T. Dorner,et al.  Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[21]  S. Berrih-Aknin,et al.  The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. , 2006, Blood.

[22]  F. Aloisi,et al.  Lymphoid neogenesis in chronic inflammatory diseases , 2006, Nature Reviews Immunology.

[23]  M. Leandro,et al.  Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[24]  R. Detels,et al.  Serum levels of the homeostatic B cell chemokine, CXCL13, are elevated during HIV infection. , 2005, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[25]  B. Bresnihan,et al.  Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis , 2005, European journal of immunology.

[26]  B. Zheng,et al.  CXCL13 neutralization reduces the severity of collagen-induced arthritis. , 2005, Arthritis and rheumatism.

[27]  E. S. Baekkevold,et al.  Monocyte-like and mature macrophages produce CXCL13 (B cell-attracting chemokine 1) in inflammatory lesions with lymphoid neogenesis. , 2004, Blood.

[28]  P. Emery,et al.  Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. , 2004, The New England journal of medicine.

[29]  W. Bugbee,et al.  Quantitative biomarker analysis of synovial gene expression by real-time PCR , 2003, Arthritis research & therapy.

[30]  M. Leandro,et al.  Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. , 2003, Arthritis and rheumatism.

[31]  G. Firestein.  Evolving concepts of rheumatoid arthritis , 2003, Nature.

[32]  W. O'Fallon,et al.  Lymphoid Neogenesis in Rheumatoid Synovitis1 , 2001, The Journal of Immunology.

[33]  E. Butcher,et al.  Subspecialization of Cxcr5+ T Cells , 2001, The Journal of experimental medicine.

[34]  P. Lipsky,et al.  Lymphoid Chemokine B Cell-Attracting Chemokine-1 (CXCL13) Is Expressed in Germinal Center of Ectopic Lymphoid Follicles Within the Synovium of Chronic Arthritis Patients1 , 2001, The Journal of Immunology.

[35]  R. Beckenbaugh,et al.  Tissue cytokine patterns distinguish variants of rheumatoid synovitis. , 1997, The American journal of pathology.

[36]  I. Randen,et al.  The Identification of Germinal Centres and Follicular Dendritic Cell Networks in Rheumatoid Synovial Tissue , 1995, Scandinavian journal of immunology.

[37]  P. Gregersen,et al.  The human Ig-beta cDNA sequence, a homologue of murine B29, is identical in B cell and plasma cell lines producing all the human Ig isotypes. , 1993, Journal of immunology.

[38]  G. Heller,et al.  B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny. , 1990, Blood.

[39]  C. Lam,et al.  Elevated Production of B Cell Chemokine CXCL13 is Correlated with Systemic Lupus Erythematosus Disease Activity , 2009, Journal of Clinical Immunology.