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Abstract：
BACKGROUND: The aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF).
METHODS: Active adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on.
RESULTS: Disease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups.
CONCLUSIONS: The high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.
METHODS: Active adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on.
RESULTS: Disease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups.
CONCLUSIONS: The high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.
摘要：
背景：这项前瞻性观察性队列研究的目的是揭示类风湿关节炎（RA）患者对托珠单抗（TCZ）治疗反应的预测因素，在临床特征和血清促炎细胞因子方面，特别是探索粒细胞巨噬细胞集落刺激因子(GM-CSF)的预测价值。
方法：本研究前瞻性招募了对MTX反应不足、打算接受TCZ治疗的活动性成年RA患者。共纳入174例严重RA患者，以确定治疗反应与以下特征之间的关联：药物,疾病活动,血清促炎细胞因子等。
结果：疾病持续时间（OR=0.996），招标接头数量（TJC）/68（OR=0.943），中性粒细胞比率（W4/基线）（OR=0.224），基线时GM-CSF水平>5ng/ml(OR=0.414)是RA患者TCZ治疗第24周(W24)时通过临床疾病活动指数(CDAI)评估的应答良好的独立不良预测因子.此外，DAS28-ESR（OR=2.951，P=0.002）和基线时GM-CSF水平>10ng/ml（OR=5.419，P=0.002）是反应不良的独立预测因子，但GM-CSF水平不>5ng/ml(OR=2.713,P=0.054)。高GM-CSF组患者DAS28-ESR和血清细胞因子(IL-17A,IL-1β,IL-6，TNF-α）在基线，以及明显更高的非良好反应率(62.8%vs.39.4%,P=0.010）和反应不佳（27.9%vs.9.1%，P=0.004）比W24时低GM-CSF组。此外,低反应者的GM-CSF水平明显高于中度和良好反应组，基线时血清IL-17A和IL-1β水平随之升高，而基线时血清IL-6和TNF-α水平在三个应答组中无显著差异。
结论：基线时GM-CSF的高水平（>5ng/ml和>10ng/ml）分别是W24时对TCZ反应不良和反应不良的独立预测因子。基线时高水平的GM-CSF是严重RA患者疾病活动性高的标志，也是TCZ反应差的预测因子。这可能有助于制定难治性RA的个体化治疗策略。
方法：本研究前瞻性招募了对MTX反应不足、打算接受TCZ治疗的活动性成年RA患者。共纳入174例严重RA患者，以确定治疗反应与以下特征之间的关联：药物,疾病活动,血清促炎细胞因子等。
结果：疾病持续时间（OR=0.996），招标接头数量（TJC）/68（OR=0.943），中性粒细胞比率（W4/基线）（OR=0.224），基线时GM-CSF水平>5ng/ml(OR=0.414)是RA患者TCZ治疗第24周(W24)时通过临床疾病活动指数(CDAI)评估的应答良好的独立不良预测因子.此外，DAS28-ESR（OR=2.951，P=0.002）和基线时GM-CSF水平>10ng/ml（OR=5.419，P=0.002）是反应不良的独立预测因子，但GM-CSF水平不>5ng/ml(OR=2.713,P=0.054)。高GM-CSF组患者DAS28-ESR和血清细胞因子(IL-17A,IL-1β,IL-6，TNF-α）在基线，以及明显更高的非良好反应率(62.8%vs.39.4%,P=0.010）和反应不佳（27.9%vs.9.1%，P=0.004）比W24时低GM-CSF组。此外,低反应者的GM-CSF水平明显高于中度和良好反应组，基线时血清IL-17A和IL-1β水平随之升高，而基线时血清IL-6和TNF-α水平在三个应答组中无显著差异。
结论：基线时GM-CSF的高水平（>5ng/ml和>10ng/ml）分别是W24时对TCZ反应不良和反应不良的独立预测因子。基线时高水平的GM-CSF是严重RA患者疾病活动性高的标志，也是TCZ反应差的预测因子。这可能有助于制定难治性RA的个体化治疗策略。
