Background B cells play a central role in the pathophysiology of Rheumatoid Arthritis (RA). In particular, they can produce rheumatoid factor (RF) and other autoantibodies, including anti-cyclic citrullinated peptide (anti-CCP), whose presence is associated to a more severe disease. The capability of producing different classes of immunoglobulines (Ig), including autoantibodies is acquired, after antigen presentation in lymphoid tissue with the “help” of T lymphocytes, by a portion of B cells that can be identified phenotypically as post-switch memory cells (CD19+CD27+IgD-). Moreover, B cells can act as antigen-presenting cells, and activate T cells providing costimulation signals via CD80/CD86 to the CD28 receptor.
Abatacept (ABA) is a fusion protein useful in the treatment of RA, which through its CTLA4 portion can bind to CD80 and CD86 on B cells, thereby inhibiting CD28 costimulation. Since CD28-mediated costimulation plays a crucial role in the acquisition of the T cell “helper” function, through the up-regulation of CD154 on T cell surface and the consequent engagement of CD40 (constitutively present on B cell membrane), it can be hypothesized that ABA may down-modulate the immune responses of B lymphocytes.
Objectives To demonstrate whether the blockade of costimulation performed by ABA treatment may reduce the capability of B lymphocytes to differentiate into post-switch memory B cells and to produce anti-CCP and RF.
Methods 30 RA patients (sex: 4 male, 26 female; age: 54 years (10th-90th percentile: 45-62)) treated for at least 6 consecutive months with ABA were enrolled in the study. B cell immune-phenotype was assessed by flow-cytometry. RF and anti-CCP Ab were measured by ELISA assays. The range of sensitivity for RF assay was 0.1-100.0 UI/mL. The clinical disease activity and the response to the treatment were evaluated respectively with the DAS28 (based on CRP) and the EULAR Criteria of Response to the treatment.
Results At baseline 87% and 47% of patients resulted positive for anti-CCP IgG and IgA Ab respectively; 60%, 7%, 33% showed the presence of RF IgM, IgG and IgA.
After 6 months of ABA treatment, 74% and 61% of patients achieved the EULAR good clinical response and the clinical remission, respectively. At this time, we observed a significant reduction of the titer of anti-CCP IgG: (from 273 (13-2354) to 184 (12-3044) IU/ml, p: 0.05), anti-CCP IgA (from 16 (2-549) to 13 (2-496) IU/ml, p:0.03), RF IgG (from 7.1 (0.8-33.0) to 2.8 (0-59.0) IU/ml, p:0.05), RF IgA (from 19.7 (1.4->100.0) to 12.4 (1.1->100.0) IU/ml, p:0.02), RF IgM (from >100.0 UI/mL (2.4->100.0) to 31.0 (0.5->100.0) IU/ml, p:0.01), as well as of the proportion of post-switch memory B cells (from 9.1 (3.8-16.6) to 6.6 (3.5-9.1)% of B cells; p:0.03). No correlations was observed between the variation of these parameters and the modification of disease activity.
Conclusions The costimulation blockade performed by ABA reduces serum levels of different classes of anti-CCP and RF, and limits the differentiation of B lymphocytes to the effector population of post-switch memory cells.
Acknowledgements We acknowledge Bristol-Myers-Squibb for the support to our study
Disclosure of Interest None Declared
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