Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort

Rhumatologie, Hôpitaux Universitaires de Strasbourg, Centre de Référence National des Maladies Auto-Immunes Systémique Rares, EA 3432 Physiopathologie des Arthrites, Strasbourg, France.
Arthritis research & therapy (Impact Factor: 3.75). 08/2009; 11(4):R114. DOI: 10.1186/ar2773
Source: PubMed


Little is known about systemic B-cell activation in early rheumatoid arthritis (RA). We therefore evaluated the serum levels of markers of B-cell activation in patients included in the ESPOIR early arthritis cohort.
In the ESPOIR early arthritis cohort (at least 2 swollen joints for more than 6 weeks but less than 6 months), 710 patients were assessed at 1 year and either met the 1987 American College of Rheumatology criteria for RA (n = 578) or had undifferentiated arthritis (n = 132). Baseline serum samples of patients naïve to corticosteroid and disease-modifying antirheumatic drug treatment were assessed for beta2-microglobulin, IgG, IgA, IgM, immunoglobulin free light chains of immunoglobulins, and B-cell activating factor of the tumor necrosis factor family (BAFF). The BAFF gene 871T>C polymorphism was genotyped in all patients.
All markers of B-cell activation except BAFF and IgM were significantly higher in patients with early RA than those with undifferentiated arthritis. Anti-cyclic citrullinated peptide (anti-CCP) and beta2-microglobulin were associated with a diagnosis of early RA in the multivariate analysis. Markers of B-cell activation, except BAFF, were associated with disease activity, rheumatoid factor and anti-CCP secretion. The BAFF gene polymorphism was not associated with early RA.
Markers of B-cell activation are elevated in patients with early RA, compared with undifferentiated arthritis, independently of any systemic increase in BAFF secretion, and correlate with disease activity. This study sheds new light on the early pathogenic role of B-lymphocytes in RA and suggests that targeting them might be a useful therapeutic strategy in early RA.

Download full-text


Available from: Xavier Mariette, Dec 23, 2013
  • Source
    • "The interpretation of their possible prognostic value thus requires caution and should take into account confounding factors. Yet, in the ESPOIR cohort, some B-cell markers, such as total IgA and kappa FLCs, turned out to be independently associated with radiographic erosions at disease onset [92], and IL-6 and IL-21 serum levels were also predictive of rapid radiographic progression at 1 year irrespective of clinical inflammation [93]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The therapeutic benefit of depleting B cells in rheumatoid arthritis (RA) has refocused attention on B cells with increasing awareness on their role in autoimmunity and their function beyond autoantibody production. The rapid increase in our comprehension of B-cell pathobiology is progressively opening novel perspectives in the area of B cell-targeted therapies with the expectation to define more specific approaches able to preserve the homeostasis of the humoral response while disrupting the pathogenic components. In parallel, B-cell activity in RA is starting to be explored in its clinical value, in search of novel biomarkers embedded in the pathogenic process that could help classifying the disease and predicting its heterogeneous outcome beyond inflammation dynamics. In this review, we summarize current knowledge on the multiple roles that B cells play in several aspects of RA. We also analyze their distribution and potential function in different anatomic compartments with specific reference to the main sites in which the disease may be sustained and exert its detrimental effects: the systemic circulation, synovium, bone marrow, and draining lymph nodes. We also highlight novel data encouraging further research in the field of biomarkers related to B cells and their regulatory factors.
    Full-text · Article · Apr 2014
  • Source
    • "Analytes measured included soluble CD23 (sCD23-the low affinity FcεR), which is enzymatically cleaved and released from naïve B-cells following activation through Toll-Like Receptors (TLR) [19],  k and l  (SFLC) as measures of plasmablast activity. Overproduction of SFLC has been described in patients with RA [20] and suggested to be useful for monitoring disease activity [21] [22]. In an extension of our earlier reports [7] [23] we have also measured the levels of isotypes of the main autoantibody specificities found in RA, levels of protective antibodies, and of the key B-cell cytokine B-cell activating factor (BAFF-TNFSF13b or BLyS). "
    [Show abstract] [Hide abstract]
    ABSTRACT: B-cell depletion therapy (BCDT) based on rituximab (RTX) induces clinical remission in a majority of seropositive patients with Rheumatoid arthritis (RA). However, all patients eventually relapse. The aim of this study was to determine whether dynamic changes in combinations of serological measures of B-cell activation were associated over up to three cycles of BCDT. We included only RA patients who gave an adequate clinical response, as measured by DAS28. Twenty three patients were studied over 1 cycle, 21 over 2, and 15 over 3 cycles of BCDT. Serum analytes including isotypes of Rheumatoid factors (RhF) and anti-citrullinated protein/peptide antibodies (ACPA), B-cell activating factor (BAFF), serum free light chains (SFLC), soluble CD23 (sCD23), antibodies to tetanus toxoid (TT) and to pneumococcal capsular polysaccharide (PCP) were measured by ELISA at 4 key points in each cycle, namely: Baseline (pre-RTX in each cycle); when B-cell depleted (CD19+B-cells < 5/μl); at B-cell return (CD19+B-cells ≥ 5/μl); and at clinical relapse (ΔDAS28 > 1.2). SFLC were used as a measure of plasmablast activity. As sCD23 is cleaved from naïve B-cells coincident with attaining CD27 expression, levels were used as a novel measure of maturation of B-cells to CD27+. The most consistent changes between baseline and B-cell depletion within all 3 cycles were in SFLC, sCD23 and IgM-RhF which fell and in BAFF levels which rose. After 3 complete cycles of BCDT, both IgM autoantibodies and IgG-CCP had decreased, BAFF levels were higher (all p < 0.05); other analytes remained unchanged compared with baseline. Dynamic changes in λSFLC, sCD23, IgM-RhF and BAFF were also consistently associated with relapse in patients with longer clinical responses after B-cell return. Incremental rises in sCD23 levels in cycles 2 and 3 were correlated with time to relapse. Repopulation of the periphery after BCDT is initiated by naïve B-cells and precedes relapse. Our study showed that differentiation into plasmablasts, attended by sCD23 and SFLC production and IgM-RhF specificity may be required to precipitate relapse in patients experiencing longer responses after RTX. These studies also provide novel information related to the resumption of autoimmune responses and their association with B-cell kinetics following BCDT.
    Full-text · Article · Dec 2013 · Journal of Autoimmunity
  • Source
    • "Serum samples were collected at enrolment and immediately stored at -80°C in a single biologic resource centre. A central laboratory was used for determining anti-citrullinated cyclic peptide (anti-CCP) antibodies (anti-CCP2; Dia-Sorin, Saluggia (Vercelli), Italy; positive >50 U/ml) and rheumatoid factor (RF) (Menarini France, Rungis Cedex, France; positive >9 IU/ml) with enzyme-linked immunosorbent assay (ELISA), as previously described [23]. ELISA kits were used for assay of serum levels of total adiponectin (Bühlman, Basel, Switzerland), leptin (Quantikine; R&D Systems, Oxford, UK), and visfatin/NAMPT (Bühlman, Basel, Switzerland). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adipokines as adiponectin, leptin and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA. A total of 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifferenciees Recentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). ELISA was used to assess baseline serum levels of adiponectin, leptin and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and 1) baseline radiographic damage and 2) radiographic disease progression defined as a change > 0 or >= 5 in total Sharp-van der Heijde Score ([increment]SHS) between inclusion and 1 year ([increment]SHS >=1 or rapid radiographic progression: [increment]SHS >= 5) adjusting for confounders (age, sex, body-mass-index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, auto-antibody status, steroid use and radiographic evidence of RA damage at inclusion). Adiponectin level was independently associated with baseline total SHS (adjusted beta = 0.12; p = 0.006). It was also associated with [increment]SHS >=1 (adjusted odds ratio [aOR] = 1.84 [1.25-2.72]) involving erosive as well as narrowing disease progression (aOR = 1.73 [1.17-2.55] and 1.93 [1.04-3.57], respectively). Serum adiponectin level predicted [increment]SHS >= 5 (aOR = 2.0 [1.14-3.52]). Serum leptin level was independently associated only with [increment]SHS > 0 (aOR = 1.59 [1.05-2.42]). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-off were 4.14 mug/mL for [increment]SHS >= 1 and 6.04 mug/mL for [increment]SHS >= 5 with a good specificity (58% and 75% for [increment]SHS >= 1 and [increment]SHS >= 5, respectively) and high negative predictive values (75% and 92% for [increment]SHS >= 1 or [increment]SHS >= 5, respectively). Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA independent of RA-confounding factors and metabolic status.
    Full-text · Article · Dec 2013 · Arthritis research & therapy
Show more