Kuuliala Krista, Kuuliala Antti, Koivuniemi Riitta, Kautiainen Hannu, Repo Heikki, Leirisalo-Repo Marjatta
Bacteriology and immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Rheumatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
PLoS One. 2016 Dec 12;11(12):e0167975. doi: 10.1371/journal.pone.0167975. eCollection 2016.
To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA).
19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-γ, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test.
At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-γ -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042).
Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.
为了寻找改善病情抗风湿药（DMARDs）治疗反应的新预测指标，我们研究了类风湿关节炎（RA）患者循环白细胞中信号转导子和转录激活子（STAT）6和1的激活情况。
19例未经治疗的近期发病的RA患者、16例对合成DMARDs无反应的慢性RA患者和37名健康志愿者提供血样，用于全血流式细胞术分别测定细胞内STAT6和STAT1磷酸化水平，以相对荧光单位表示，分别对应白细胞介素-4（IL-4）和干扰素-γ（IFN-γ）刺激。在近期发病的RA患者中使用合成DMARDs治疗1年，在对合成DMARDs无反应的RA患者中使用生物DMARDs治疗1年后，重新研究磷酸化情况并确定治疗反应（根据欧洲抗风湿病联盟标准）。采用基于估计的精确逻辑回归分析来研究基线变量与治疗反应之间的关系。通过偏差校正自助法估计均值的95%置信区间，并通过置换检验计算基线值与随访值之间的显著性差异。
在基线时，未经治疗的RA患者中，对合成DMARDs治疗反应良好者的单核细胞中IL-4诱导的磷酸化STAT6（pSTAT6）水平高于反应不佳者（比值比2.74，95%置信区间1.05至9.47）；在慢性RA患者中，对生物药物治疗反应良好者的IFN-γ刺激的淋巴细胞pSTAT1水平高于反应不佳者（比值比3.91，95%置信区间1.12至20.68）。在随访期间，对合成DMARDs治疗反应良好的近期发病RA患者，淋巴细胞pSTAT6水平下降（p = 0.011），因此，淋巴细胞中pSTAT1/pSTAT6比值升高（p = 0.042）。
在这项初步研究中，细胞因子刺激的循环白细胞中STAT6和STAT1磷酸化与DMARDs的治疗反应相关。如果在更大规模的研究中得到证实，该结果可能有助于RA个性化医疗的发展。
