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). 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 CD4pos cell subpopulation assessment by flow cytometry, STAT3 and STAT5 expression by RT-PCR and IL-6, IL-12p70, TGFβ, and IL-10 serum levels by ELISA. The DAS and CDAI remission was assessed at 6 and 12 months. 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 CD4posCD25posFoxP3pos cells at 6 and 12 months, and of CD4posIL17pos cells after 12 months. PB CD4pos 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 naïve 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 CD4posCD25posFoxP3pos cells rate ≥ 6.0% significantly identifies naïve to b-DMARDs early RA patients more likely to achieve DAS remission at 6 months (83.3%) compared to RA patients with baseline CD4posCD25posFoxP3pos cells < 6.0% [16.7%, OR (95% Cis) 25.00 (1.00–336.81)]. Baseline IL-6 serum levels and peripheral blood-derived CD4pos subpopulations are putative novel prognostic biomarkers of CTLA4-Ig response in RA patients.

中文翻译：

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外周血 CD4posCD25posFoxP3pos 细胞和炎性细胞因子作为 CTLA4-Ig 治疗的类风湿关节炎患者反应的生物标志物

在类风湿关节炎 (RA) 的管理中，仍然缺乏对不同生物疾病改善抗风湿药物 (b-DMARDs) 治疗反应的预后生物标志物。34 名 b-DMARD 初治 RA 患者，按疾病持续时间分为早期（队列 1）和长期（队列 2），接受 CTLA4-Ig。在研究开始时，以及每 3 个月持续 1 年，每位患者通过流式细胞术进行外周血 (PB) 衍生的 CD4pos 细胞亚群评估，通过 RT-PCR 和 IL-6、IL-12p70、TGFβ 和 IL-6、IL-12p70、TGFβ 和ELISA检测的IL-10血清水平。在 6 个月和 12 个月评估 DAS 和 CDAI 缓解。16 名 (47.1%) 和 8 名 (23.5%) RA 患者分别在 12 个月内实现了 DAS 和 CDAI 定义的缓解。考虑到整个 RA 队列，CTLA4-Ig 诱导 IL-6 血清水平从基线显着降低至 6 和 12 个月，以及 PB CD4posCD25posFoxP3pos 细胞在 6 和 12 个月后显着降低，CD4posIL17pos 细胞在 12 个月后显着降低。RA 患者的 PB CD4pos 细胞的 STAT3 和 STAT5 表达高于健康对照组，在治疗 12 个月内保持不变。在研究开始时，达到 DAS 缓解的 RA 患者的 IL-6 血清水平显着低于未达到该结果的 RA 患者。特别是，基线 IL-6 血清水平 ≤ 8.4 pg/ml，与基线 IL 的 RA 患者相比，显着识别初治 b-DMARDs RA 患者在 CTLA4-Ig 下 6 个月时更有可能实现 DAS 缓解（66.7%） -6 血清水平 > 8.4 pg/ml [15.4%, OR (95% Cis) 11.00 (1.75–55.82)]。此外，具有 CD4posCD25posFoxP3pos 细胞率 ≥ 6。与基线 CD4posCD25posFoxP3pos 细胞<6.0% [16.7%, OR (95% Cis) 25.00 (1.00– 336.81)]。基线 IL-6 血清水平和外周血来源的 CD4pos 亚群是推定的 RA 患者 CTLA4-Ig 反应的新型预后生物标志物。