[BSR文摘] 如何解釋CRP正常而多普勒超聲顯示關節炎活動的RA亞型

如何解釋CRP正常而多普勒超聲顯示關節炎活動的RA亞型

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

                       

背景：臨牀門診愈來愈多地利用肌肉骨骼超聲(US)來評估類風溼關節炎(RA)患者的關節侵蝕和病情活動度。隨着數據積累,已發現一個不典型的RA亞型,它的活動性病情由明顯的多普勒超聲信號所證明但C反應蛋白(CRP)水平是正常的。咱們提出疑問,這種亞型是否與診斷延誤、治療相對不充分有關,這組患者出現更糟糕預後或殘疾的風險是否增長。進而,咱們提出假設,瞭解這組非典型患者的免疫病理可能會直接影響治療關注對象,這些患者的治療需求還沒有獲得知足。

方法：本研究招募了27例有活動性滑膜炎的RA患者,活動性滑膜炎的定義是,≥1個關節存在多普勒超聲信號。其中, 17例患者CRP水平正常(≤5mg/L), 10例CRP水平升高(> 5mg/L)。在超聲檢查的同時,採集患者外周血單個核細胞(PBMC)、血清、以及詳細的臨牀和疾病活動度評分。選擇18例性別和年齡匹配的志願者並採集血樣。爲明確CRP有差別的兩組患者是否與獨特的免疫細胞譜有關聯,本研究採用多色流式細胞術對PBMC進行免疫分型,並用流式微球技術對血清細胞因子進行檢測。

結果：兩組患者在自身抗體水平、ESR、病情活動度評分方面沒有顯著差別。然而, CRP正常組的侵蝕演變速率相較於CRP升高組是增長的,提示CRP正常組患者已經存在更多與疾病相關的關節損傷。血清細胞因子分析顯示,兩組患者炎性細胞因子水平均升高,包括IL-1β(p = 0.0364; p = 0.0233)和IL-6(p = 0.0007; p = 0.0009),這二者均是已知能激發CRP表達的細胞因子。這提示CRP正常組患者可能存在IL-6下游信號傳導缺陷,或者有另外一種可能性, CRP正常組患者的發病機制可能不依賴於IL-6。因爲已知IL-6參與T細胞和T濾泡輔助細胞(Tfh)的活化和分化,咱們比較了兩組患者的外周血T細胞表型。

正如所料,檢測數據代表CRP升高組患者外周血炎性細胞譜正是典型的活動性RA,尤爲是CD4 + T細胞被活化(p = 0.0054),中樞記憶細胞(T-CM)(p = 0.0380)和Th17細胞的陽性率較健康對照組增高。CRP正常組與此相反,儘管在超聲發現滑膜炎以及較高的侵蝕演進速率,這組患者外周血T細胞炎性表型較弱,其特徵爲有較高水平的調節性T細胞(p = 0.0036)以及血清IL-10水平上調,這些發現提示CRP正常組患者的免疫調控已經部分加強。

結論：整體來講,以上發現代表, CRP正常而滑膜炎活動的RA患者的免疫調控機制相較於CRP增高組患者而言發生了改變,這些發現可能會對臨牀治療有所裨益。

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原文連接或參見如下信息。

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.