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The aim of this paper was to look for predictors of abatacept (ABA) therapy discontinuation in patients with rheumatoid arthritis (RA). Seventy-one RA patients treated with ABA were followed up. Demographical, clinical, and laboratory parameters of the patients, including peripheral blood T and B cell populations, different rheumatoid factor and anti-cyclic citrullinated peptide autoantibodies isotypes, and serum free light chains were evaluated. Comparing patients who discontinued ABA with those still in therapy we observed: a higher proportion of smokers (51.9 vs 25.6 %; p = 0.03); a non significant lower proportion of anti-cyclic citrullinated peptide positivity (76 vs 89.5 %; p = 0.13); a lower proportion of terminally differentiated effector memory cells (TDEM) among total CD8+ T lymphocytes at baseline (22.0 % (7.8-39.2) vs 38.7 % (20.7-55.9); p = 0.002). Logistic multivariate analysis showed that only the proportion of CD8+TDEM T cells was an independent predictive factor of therapy discontinuation (OR (95 % IC) = 6.2 (1.2 to 30.8); p = 0.026). Receiver-operating characteristic analysis showed a significant performance of this biomarker for prediction of therapy discontinuation (using a cut-off of 30.6 %: AUC: 0.760 ± 0.07; p = 0.002). Patients with a low proportion of CD8+TDEM at baseline had a higher probability of discontinuing the treatment during time (log-rank test: p < 0.01). T cell characterization for identification of TDEM CD8+ T cells might be a useful test to predict discontinuation of ABA therapy.

Objectives: A possible role of granzyme B (GZMB) in the pathogenesis of joint erosions in rheumatoid arthritis (RA) has been suggested. Since CD28neg T-cells may be an important source of GZMB, and we have previously shown that co-stimulation blockade by abatacept can prevent the generation of the CD28neg T-cell populations, we evaluated the effect of abatacept therapy on GZMB serum levels in patients with RA., Methods: The serum levels of GZMB were evaluated by an indirect solid-phase enzyme immunoassay before the start of treatment with abatacept (T0) in 53 patients with RA and after 6 months of therapy (T6) in 25 patients., Results: At T0, GZMB serum levels were correlated with disease activity measured by DAS28-CRP (p=0.0022) and percentages of circulating CD4+CD28neg and CD8+CD28neg T-cells (p=0.007; p=0.031). The levels of GZMB in 18 patients with a moderate or good EULAR clinical response to ABA significantly decreased from T0 to T6 (p=0.023), whereas no variation was observed in 7 non responders. The variation of GZMB levels was directly correlated with that of DAS28-PCR (p=0.040), but not with those of circulating CD28-neg T-cell subsets., Conclusions: Costimulation blockade by ABA can decrease the serum levels of GZMB in RA patients responding to the treatment, suggesting that this might be one of the mechanism by which abatacept can prevent radiographic erosions. However, the lack of correlation of such decrease with the numbers of circulating CD28-neg T cells suggests that these cells probably are not the main source of serum GZMB.

Background: CD28(neg) T cells, which display functional characteristic of oligoclonally expanded cytotoxic memory T lymphocytes, are believed to be pathologically relevant in rheumatoid arthritis manifestation. The CD28 co-stimulation blockade by abatacept can prevent the generation of CD28(neg) T-cell populations in these patients., Methods: Samples were obtained before and after 12 months of abatacept therapy. T-cell phenotype and T-cell receptor diversity were evaluated by flow cytometry and complementarity-determining region-3 spectratyping, respectively, while telomerase reverse-transcriptase gene level was measured by real-time PCR., Results: Abatacept induces a decrease of the percentage and number of CD4(+)CD28(neg) T cells and a reduction of T-cell repertoire restrictions; these features are directly correlated. Thymic output and telomerase activity are not modified by the therapy., Conclusions: Abatacept-induced decrease of peripheral T-cell repertoire restrictions can due to a reduced generation of senescent, chronically stimulated CD4(+)CD28(neg) T cells.

Objective: Abatacept (ABA) is a chimeric molecule, able to block the CD28-mediated costimulatory pathway. To evaluate the hypothesis that, through this mechanism of action, ABA may down-modulate the immune responses of B lymphocytes in rheumatoid arthritis (RA), we investigated the serum levels of immunoglobulins (Ig), free light chains (FLC), anticitrullinated protein antibodies (ACPA), and rheumatoid factor (RF), as well as the number of B lymphocytes differentiated into post-switch memory cells in patients treated with ABA., Methods: The serum levels of Ig, FLC, different ACPA, RF isotypes, and the B cell phenotype were longitudinally evaluated in 30 patients with RA treated with ABA., Results: At baseline, the proportion of total and post-switch memory B cells was lower in RA than in healthy individuals. After 6 months of ABA treatment we observed significant reductions of serum levels of IgG, IgA, and IgM, as well as FLC, with a normalization in many patients who had initially abnormal values. A significant reduction of the titers of IgG- and IgA-ACPA, as well as of IgM-, IgA-, and IgG-RF was also observed. A decrease of autoantibodies below the upper limits of normal values was found in 2 of 26 patients (8%) initially seropositive for IgG-ACPA, 1 of 14 (7%) for IgA-ACPA, 5 of 22 (23%) for IgM-RF, 7 of 22 (30%) for IgA-RF, and 5 of 16 (31%) for IgG-RF. After treatment, the proportion of circulating post-switch memory B cells was also further significantly decreased., Conclusion: ABA treatment in patients with RA can reduce signs of polyclonal B cell activation, inducing a trend toward normalization of serum levels of different classes of Ig and of FLC, decreasing titers of ACPA and RF, and percentages of post-switch memory B cells.

Objectives: Abatacept (ABA), a molecule used in the treatment of rheumatoid arthritis (RA), competes with the engagement of CD28, a T-cell receptor for co-stimulatory signals. CD28-mediated signalling regulates several T-cell functions, including inflammatory cytokine production and regulatory T cells (Treg) differentiation. Therefore, our objective was to evaluate the effects of ABA on peripheral blood T-lymphocyte cytokine production and on the number of circulating Treg., Methods: In 24 RA patients treated with ABA for at least 6 months the proportions and absolute numbers of peripheral blood T cells producing interferon-gamma (IFN-γ) and interleukin-17 (IL-17) after in vitro stimulation, as well as those of Treg were longitudinally evaluated by flow cytometry., Results: At baseline, compared with 16 healthy controls, RA patients had a higher percentage of CD4+ and CD8+ T cells producing IL-17 (p=0.021, and p=0.006, respectively), as well as of circulating Treg (p=0.041). After 6 months of therapy with ABA, there was a decrease of the percentage of IFN-γ- and IL-17-producing CD8+ T cells (p=0.033 and p=0.035, respectively), and of Treg (p=0.008), while that of IL-17-producing CD4+ T cells decreased after 12 months of treatment (p=0.005). The number of IL-17-producing T cells and of Treg, higher than in controls at baseline, normalised after ABA therapy. All these variations were statistically significant only in RA patients with EULAR good clinical response (n=17)., Conclusions: The blockade of CD28 signal caused by ABA induces the decrease in peripheral blood of IL-17- and IFN-γ-producing T cells.

Objective: To evaluate the number of circulating CD28-negative (CD28-) T cells as a predictor of clinical response to abatacept in patients with rheumatoid arthritis (RA)., Methods: Peripheral blood CD28- T cell subsets were evaluated by flow cytometry at baseline in 32 patients with RA treated with abatacept. Receiver-operator curves were applied to examine the predictive value of T cell populations and to choose the cutoff for the best performance of the test. Remission was defined using the Disease Activity Score 28 based on C-reactive protein., Results: The overall predictive values of the CD8+CD28- and CD4+CD28- cells for remission after 6 months of abatacept therapy were 0.802 (SE 0.078) and 0.743 (SE 0.089), respectively. Cutoff values of < 87 CD8+CD28- cells/μl and < 28 CD4+CD28- cells/μl had 80.0% sensitivity and 81.8% specificity (Fisher test: p = 0.001), and 60.0% sensitivity and 77.3% specificity (p = 0.043), respectively, for prediction of remission at 6 months. Patients having low baseline numbers of CD8+CD28- T cells had a more than 4-fold higher probability of achieving remission within 6 months than patients with higher levels of these cells., Conclusion: A simple laboratory measure, the baseline number of circulating CD28- T cells, predicted remission after 6 months of abatacept treatment in patients with RA.

Objective: To verify the hypothesis that blockade of CD28 costimulation by treatment with abatacept in patients with rheumatoid arthritis (RA) might induce a reduction in the number of CD28- T cells, as well as other effector T cell populations. We evaluated whether these variations correlate with clinical response., Methods: Peripheral blood T cell subsets were longitudinally evaluated by flow cytometry through the analysis of CD28, CD45RA, and CCR7 expression in 16 patients with RA who were treated with abatacept., Results: After 48 weeks of treatment, the proportion and the absolute number of circulating CD8+CD28- T cells decreased (p = 0.008, p = 0.055, respectively, compared with baseline), as well as the proportion of the CD8+CD45RA+CCR7- cells, thought to represent terminally differentiated effector T cells (p = 0.03). Reductions of percentages of circulating CD4+CD28- and CD8+CD28- T cells, and (CCR7-) CD8+ total effector T cells were directly correlated with the reduction of Disease Activity Score 28 C-reactive protein (r = 0.58, p = 0.014; r = 0.47, p = 0.059; r = 0.59, p = 0.012, respectively)., Conclusion: After therapy with abatacept, circulating CD28- T cells and other effector populations decrease in patients with RA. This decrease is correlated with clinical response.