[BSR文摘] 如何解释CRP正常而多普勒超声显示关节炎活动的RA亚型

如何解释CRP正常而多普勒超声显示关节炎活动的RA亚型

Braford CM, et al.Rheumatology 2016. Present ID: 72.

                       

背景：临床门诊越来越多地利用肌肉骨骼超声(US)来评估类风湿关节炎(RA)患者的关节侵蚀和病情活动度。随着数据积累,已发现一个不典型的RA亚型,它的活动性病情由明显的多普勒超声信号所证实但C反应蛋白(CRP)水平是正常的。我们提出疑问,这种亚型是否与诊断延误、治疗相对不充分有关,这组患者出现更糟糕预后或残疾的风险是否增加。进而,我们提出假设,了解这组非典型患者的免疫病理可能会直接影响治疗关注对象,这些患者的治疗需求尚未得到满足。

方法：本研究招募了27例有活动性滑膜炎的RA患者,活动性滑膜炎的定义是,≥1个关节存在多普勒超声信号。其中, 17例患者CRP水平正常(≤5mg/L), 10例CRP水平升高(> 5mg/L)。在超声检查的同时,采集患者外周血单个核细胞(PBMC)、血清、以及详细的临床和疾病活动度评分。选择18例性别和年龄匹配的志愿者并采集血样。为明确CRP有差异的两组患者是否与独特的免疫细胞谱有关联,本研究采用多色流式细胞术对PBMC进行免疫分型,并用流式微球技术对血清细胞因子进行检测。

结果：两组患者在自身抗体水平、ESR、病情活动度评分方面没有显著差异。然而, CRP正常组的侵蚀演变速率相较于CRP升高组是增加的,提示CRP正常组患者已经存在更多与疾病相关的关节损伤。血清细胞因子分析显示,两组患者炎性细胞因子水平均升高,包括IL-1β(p = 0.0364; p = 0.0233)和IL-6(p = 0.0007; p = 0.0009),这两者均是已知能激发CRP表达的细胞因子。这提示CRP正常组患者可能存在IL-6下游信号传导缺陷,或者有另一种可能性, CRP正常组患者的发病机制可能不依赖于IL-6。由于已知IL-6参与T细胞和T滤泡辅助细胞(Tfh)的活化和分化,我们比较了两组患者的外周血T细胞表型。

正如所料,检测数据表明CRP升高组患者外周血炎性细胞谱正是典型的活动性RA,尤其是CD4 + T细胞被活化(p = 0.0054),中枢记忆细胞(T-CM)(p = 0.0380)和Th17细胞的阳性率较健康对照组增高。CRP正常组与此相反,尽管在超声发现滑膜炎以及较高的侵蚀演进速率,这组患者外周血T细胞炎性表型较弱,其特征为有较高水平的调节性T细胞(p = 0.0036)以及血清IL-10水平上调,这些发现提示CRP正常组患者的免疫调控已经部分增强。

结论：总体来说,以上发现表明, CRP正常而滑膜炎活动的RA患者的免疫调控机制相较于CRP增高组患者而言发生了改变,这些发现可能会对临床治疗有所裨益。

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原文链接或参见以下信息。

LACK OF C-REACTIVE PROTEIN RESPONSE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS- WHAT ARE THE IMMUNOLOGICAL CAUSES?

             

Authors

Claire M. Bradford¹, Lindsey Kidd¹, Victoria Howard¹, Coziana Ciurtin¹, Elizabeth C. Jury¹, Manson J. Jessica², ¹Rheumatology, University College London, London, UNITED KINGDOM, ²Rheumatology, University College London Hospital, London, UNITED KINGDOM.

 April 26, 2016, 10:30 AM - 11:30 AM

  

Abstract

Background: Musculoskeletal ultrasound (US) clinics are used increasingly to assess joint erosions and disease activity in patients with rheumatoid arthritis (RA). Using this technology an atypical patient subgroup has been identified with active disease demonstrated by significant Power Doppler, but normal C-reactive protein (CRP) levels. We questioned whether this presentation was associated with delayed diagnosis or relative under treatment, risking worse disease outcome and/or disability. Furthermore, we hypothesized that understanding the underlying immune pathology in this atypical subset of patients could directly influence therapeutic targeting in patients whose needs are not currently met.

Methods: Twenty seven RA patients with active synovitis were recruited, defined by at least one joint with Power Doppler signal detected by musculoskeletal US, 17 had normal (n)CRP (≤5 mg/L) and 10 had high (h)CRP (>5 mg/L) levels. Peripheral blood mononuclear cells (PBMCs) and serum as well as detailed clinical and disease activity scores were collected at the time of the scan. Blood was also collected from 18 age and sex matched healthy donors. To identify whether the disparity in CRP levels in the two patient groups was associated with a distinct immune profile we used multicolour flow cytometry to perform in depth PBMC immunophenotyping and serum cytokines were assessed using a 14 panel Cytometric Bead Array.

Results: No significant differences were detected between the patient groups in terms of autoantibody levels, ESR, disease activity scores; however, the erosion accrual rate was elevated in patients with nCRP compared to hCRP suggesting that this group of patients acquired more disease-associated joint damage. Analysis of serum revealed increased levels of inflammatory cytokines in both nCRP and hCRP patients including IL-1β (p=0.0364; 0.0233) and IL6 (p=0.0009; 0.0007) which is known to trigger CRP production. This suggested that nCRP patients could have defects in downstream IL6 signaling, or alternatively, the disease mechanism may not be IL6-dependent in the nCRP group. Since IL6 is known to support T-cell and T-follicular helper-cell (Tfh) activation and differentiation we compared the T-cell phenotype in the two patient groups.

As predicted, the data suggest that the hCRP patients have an inflammatory profile that is typical of active RA, in particular CD4+ T-cells were activated (p=0.0054) and increased frequencies of central memory (p=0.0380, T-CM) and Th17 populations were seen compared to healthy controls. In contrast, T cells in the nCRP group had a less inflammatory phenotype as characterized by higher levels of regulatory T cells (p=0.0036) and increased serum Il-10, despite synovitis on scan and high erosion accrual, suggesting increased immune modulation in these patients.

Conclusion: Overall, this supports altered immunological mechanisms in nCRP compared to hCRP patients which could have therapeutic implications.