TY - JOUR
T1 - Peripheral blood CD4posCD25posFoxP3pos cells and inflammatory cytokines as biomarkers of response in rheumatoid arthritis patients treated with CTLA4-Ig
AU - Gremese, Elisa
AU - Tolusso, Barbara
AU - Petricca, Luca
AU - Di Mario, Clara
AU - Gigante, Maria Rita
AU - Ferraccioli, Gianfranco
AU - Alivernini, Stefano
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Abatacept
KW - Antirheumatic Agents
KW - Arthritis, Rheumatoid
KW - Biomarkers
KW - CTLA-4 Antigen
KW - CTLA4-Ig
KW - Cytokines
KW - Forkhead Transcription Factors
KW - Humans
KW - Interleukin-6
KW - Rheumatoid arthritis
KW - STAT5 Transcription Factor
KW - T-Lymphocytes, Regulatory
KW - Abatacept
KW - Antirheumatic Agents
KW - Arthritis, Rheumatoid
KW - Biomarkers
KW - CTLA-4 Antigen
KW - CTLA4-Ig
KW - Cytokines
KW - Forkhead Transcription Factors
KW - Humans
KW - Interleukin-6
KW - Rheumatoid arthritis
KW - STAT5 Transcription Factor
KW - T-Lymphocytes, Regulatory
UR - http://hdl.handle.net/10807/220068
U2 - 10.1186/s13075-022-02827-5
DO - 10.1186/s13075-022-02827-5
M3 - Article
SN - 1478-6354
VL - 24
SP - 143-N/A
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
ER -