Peripheral blood CD4posCD25posFoxP3pos cells and inflammatory cytokines as biomarkers of response in rheumatoid arthritis patients treated with CTLA4-Ig

Background Prognostic biomarkers of treatment response to distinct biologic disease-modifying anti-rheumatic drugs (b-DMARDs) are still lacking within the management of rheumatoid arthritis (RA). Methods Thirty-four b-DMARDs naive RA patients, divided by disease duration into early (cohort 1) and long standing (cohort 2), received CTLA4-Ig. At study entry, and every 3 months for 1 year, each patient underwent peripheral blood (PB)-derived CD4(pos) cell subpopulation assessment by flow cytometry, STAT3 and STAT5 expression by RT-PCR and IL-6, IL-12p70, TGF beta, and IL-10 serum levels by ELISA. The DAS and CDAI remission was assessed at 6 and 12 months. Results DAS- and CDAI-defined remission within 12 months was achieved by 16 (47.1%) and 8 (23.5%) RA patients, respectively. Considering the whole RA cohort, CTLA4-Ig induced a significant decrease of IL-6 serum levels from baseline to 6 and 12 months, as well as of PB CD4(pos)CD25(pos)FoxP3(pos) cells at 6 and 12 months, and of CD4(pos)IL17(pos) cells after 12 months. PB CD4(pos) cells of RA patients showed higher STAT3 and STAT5 expression than healthy controls, which remained unchanged within 12 months of treatment. At study entry, RA patients achieving DAS remission had significantly lower IL-6 serum levels than RA patients not achieving this outcome. In particular, having baseline IL-6 serum levels <= 8.4 pg/ml, significantly identified naive to b-DMARDs RA patients more likely to achieve DAS-remission under CTLA4-Ig at 6 months (66.7%) compared to RA patients with baseline IL-6 serum levels > 8.4 pg/ml [15.4%, OR (95%Cis) 11.00 (1.75-55.82)]. Moreover, having CD4(pos)CD25(pos)FoxP3(pos) cells rate >= 6.0% significantly identifies naive to b-DMARDs early RA patients more likely to achieve DAS remission at 6 months (83.3%) compared to RA patients with baseline CD4(pos)CD25(pos)FoxP3(pos) cells < 6.0% [16.7%, OR (95% Cis) 25.00 (1.00-336.81)]. Conclusions Baseline IL-6 serum levels and peripheral blood-derived CD4(pos) subpopulations are putative novel prognostic biomarkers of CTLA4-Ig response in RA patients.