李淅萌,聶英坤
摘要:結(jié)締組織病(CTD)泛指結(jié)締組織受累的自身免疫性疾病,目前病因尚不明確,一般認(rèn)為與遺傳、感染及免疫異常等因素相關(guān),其主要致病機(jī)制為非特異性炎癥反應(yīng)。疾病診斷主要依靠臨床表現(xiàn)及實(shí)驗(yàn)室檢查,隨著風(fēng)濕免疫學(xué)發(fā)展,多種新型炎癥因子逐漸應(yīng)用到自身免疫病的診斷與疾病活動(dòng)度評(píng)估中,這些新型炎癥因子包括中性粒/細(xì)胞淋巴細(xì)胞比值(NLR)、血小板/淋巴細(xì)胞比值(PLR)、紅細(xì)胞分布寬度(RDW)等,本文將對(duì)NLR、PLR及RDW在CTD中的相關(guān)研究展開綜述,以期為臨床醫(yī)務(wù)人員對(duì)CTD進(jìn)行診斷和活動(dòng)性評(píng)估提供參考依據(jù)。
關(guān)鍵詞:中性粒細(xì)胞/淋巴細(xì)胞比值;血小板/淋巴細(xì)胞比值;紅細(xì)胞分布寬度;結(jié)締組織病
中圖分類號(hào):R593.2 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? 文獻(xiàn)標(biāo)識(shí)碼:A ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? DOI:10.3969/j.issn.1006-1959.2019.22.09
文章編號(hào):1006-1959(2019)22-0024-04
Study on Novel Inflammatory Factors in Connective Tissue Diseases
LI Xi-meng,NIE Ying-kun
(Department of Rheumatology and Immunology,the Second Affiliated Hospital of Harbin Medical University,
Harbin 150000,Heilongjiang,China)
Abstract:Connective tissue disease(CTD) refers to the autoimmune diseases involved in connective tissue. The current cause is not clear. It is generally considered to be related to genetic, infection and immune abnormalities. The main pathogenic mechanism is non-specific inflammatory response. The diagnosis of diseases mainly depends on clinical manifestations and laboratory tests. With the development of rheumatic immunology, a variety of new inflammatory factors are gradually applied to the diagnosis of autoimmune diseases and the assessment of disease activity. These new inflammatory factors include neutrophil lymphocyte ratios(NLR), platelet lymphocyte ratio (PLR), red blood cell distribution width (RDW), etc. This article will review the related research of NLR, PLR and RDW in CTD, in order to diagnose and evaluate CTD for clinical medical staff to provide a reference basis.
Key words:Neutrophil/lymphocyte ratio;Platelet/lymphocyte ratio;Red blood cell distribution width;Connective tissue disease
結(jié)締組織疾病(connective tissue disease,CTD)是泛指結(jié)締組織受累的自身免疫性疾病,主要包括系統(tǒng)性紅斑狼瘡(SLE)、類風(fēng)濕關(guān)節(jié)炎(RA)、皮肌炎、干燥綜合征,又稱舍格倫綜合征(Sj?觟gren's syndrome,SS)等,該病呈進(jìn)行性進(jìn)展,可累及多臟器系統(tǒng)[1,2]。目前主要通過激素與免疫抑制劑的聯(lián)合應(yīng)用進(jìn)行治療,藥物劑量需根據(jù)疾病進(jìn)展的嚴(yán)重程度決定。因此,盡早診斷及綜合治療可顯著控制病情并改善預(yù)后。新型炎癥因子作為反映炎癥程度的指標(biāo)最早應(yīng)用于感染性疾病的診斷及預(yù)后評(píng)估當(dāng)中,近幾年相關(guān)研究發(fā)現(xiàn)部分新型炎癥因子可用于CTD活動(dòng)性的評(píng)估,且對(duì)其診斷有一定的輔助作用,這些新型炎癥因子主要包括中性粒細(xì)胞/淋巴細(xì)胞比值(NLR)、血小板/淋巴細(xì)胞比值(PLR)、紅細(xì)胞分布寬度(RDW)等,本文將從NLR、PLR及RDW在CTD中的相關(guān)研究進(jìn)行綜述,以期為臨床醫(yī)務(wù)人員對(duì)CTD進(jìn)行診斷和活動(dòng)性評(píng)估提供參考依據(jù)。
1新型炎癥因子
1.1中性粒細(xì)胞/淋巴細(xì)胞比值 ?中性粒細(xì)胞是白細(xì)胞的一種,具有趨化作用和吞噬功能,當(dāng)機(jī)體發(fā)生感染時(shí),中性粒細(xì)胞可快速到達(dá)感染部位,吞噬并清除入侵的病原體。淋巴細(xì)胞也是白細(xì)胞的一種,它由淋巴器官產(chǎn)生,在機(jī)體免疫應(yīng)答過程中發(fā)生重要作用。Bass DA等[3]提出NLR即中性粒細(xì)胞計(jì)數(shù)(Neutrophil,count,N)與淋巴細(xì)胞計(jì)數(shù)(Lym-phocyte count,L)的比值。Zahorec R等[4]認(rèn)為NRL作為一種炎癥標(biāo)志物可反應(yīng)疾病嚴(yán)重程度,病情越重,中性粒細(xì)胞增多越明顯,淋巴細(xì)胞減少越顯著,從而使NLR升高。近幾年NLR不僅僅只應(yīng)用在感染性疾病當(dāng)中,有研究顯示[5,6] ,NLR在心血管疾病、惡性腫瘤等疾病的診治及預(yù)后評(píng)估中同樣具有輔助價(jià)值。
1.2血小板/淋巴細(xì)胞比值 ?血小板是從骨髓成熟的巨核細(xì)胞胞漿解脫落下來的小塊胞質(zhì),在出血凝血過程中起重要作用。血小板不僅可以與各種細(xì)胞如T細(xì)胞、中性粒細(xì)胞、單核巨噬細(xì)胞等相互作用,還可以啟動(dòng)并加劇炎癥,活化的血小板也可以刺激白細(xì)胞遷移并粘附到血管壁觸發(fā)炎癥反應(yīng)[7],炎性反應(yīng)也會(huì)導(dǎo)致外周血中性粒細(xì)胞、血小板計(jì)數(shù)增高以及淋巴細(xì)胞計(jì)數(shù)降低,從而使血小板/淋巴細(xì)胞比值在炎癥反應(yīng)中具有一定意義[8,9]。此外,多項(xiàng)研究表明[10,11]PLR在心血管、腫瘤等疾病中的診斷及預(yù)后評(píng)估中也具有輔助作用。
1.3紅細(xì)胞分布寬度 ?RDW是反映紅細(xì)胞體積異質(zhì)性的參數(shù)[12],過去RDW多用在血液疾病的診斷及鑒別診斷中。研究表明[13],炎癥可以直接使血管內(nèi)皮細(xì)胞損傷,并同時(shí)激活補(bǔ)體系統(tǒng),使患者自身抗體或補(bǔ)體吸附于紅細(xì)胞表面,最終造成紅細(xì)胞破壞增加和體積異質(zhì)性增大,從而使RDW升高。此外炎癥因子也可抑制促紅細(xì)胞生成素對(duì)骨髓紅系干細(xì)胞的刺激,進(jìn)而在抗細(xì)胞凋亡和促紅細(xì)胞成熟方面發(fā)揮作用,最終使未成熟的紅細(xì)胞被提前釋放入外周血液循環(huán),使外周血紅細(xì)胞大小不一,最終導(dǎo)致RDW升高[14-16]。另有研究[17,18]證實(shí),RDW與超敏C反應(yīng)蛋白及血沉密切相關(guān),同時(shí)也與IL-1、TNF-α等有一定關(guān)聯(lián)[16]。因此,RDW不僅在血液相關(guān)性疾病中有一定應(yīng)用價(jià)值,在炎癥類疾病、腦卒中、肝臟疾病等中也有一定的輔助價(jià)值。
2新型炎癥因子在結(jié)締組織病中的相關(guān)研究
2.1 NLR、PLR、RDW在系統(tǒng)性紅斑狼瘡中的研究 ?系統(tǒng)性紅斑狼瘡是一種免疫系統(tǒng)對(duì)自身組織產(chǎn)生免疫應(yīng)答,最終導(dǎo)致多系統(tǒng)損害的慢性自身免疫性疾病[19],該病發(fā)病機(jī)制尚不明確。目前系統(tǒng)性紅斑狼瘡的活動(dòng)性指標(biāo)[20]主要包括dsDNA、補(bǔ)體、紅細(xì)胞沉降率(ESR),血清C反應(yīng)蛋白(CRP),高γ球蛋白血癥、類風(fēng)濕因子陽性、血小板計(jì)數(shù)等的增加,但這些反應(yīng)活動(dòng)性的指標(biāo)易受其他干擾因素影響,尋找新的活動(dòng)性指標(biāo)為臨床診斷疾病及判定系統(tǒng)性紅斑狼瘡活動(dòng)性有重大意義。
Oehadian A等[21]發(fā)現(xiàn)NLR在SLE患者中顯著升高,但其并未完全表明NLR與SLE臨床的相關(guān)性。后有學(xué)者在此基礎(chǔ)上進(jìn)行了NLR、PLR在SLE活動(dòng)度中的相關(guān)研究,結(jié)果表明,NLR與以往評(píng)估系統(tǒng)性紅斑狼瘡活動(dòng)性的指標(biāo)CRP、ESR以及系統(tǒng)性紅斑狼瘡活動(dòng)度評(píng)分(SLEDAI)呈正相關(guān),而PLR只與SLEDAI呈正相關(guān);在此研究中還發(fā)現(xiàn)NLR、PLR在狼瘡性腎炎患者中顯著升高,其中NLR可作為預(yù)測狼瘡性腎炎的指標(biāo),以上結(jié)論均支持NLR、PLR可以反映系統(tǒng)性紅斑狼瘡的活動(dòng)度。這與國內(nèi)對(duì)于NLR、PLR在系統(tǒng)性紅斑狼瘡活動(dòng)度相關(guān)性研究的結(jié)果一致[22]。Hu ZD等[23]研究了RDW與系統(tǒng)性紅斑狼瘡活動(dòng)度的相關(guān)性,該研究回顧性分析131例系統(tǒng)性紅斑狼瘡患者的RDW與CRP、ESR、dsDNA、免疫球蛋白及系統(tǒng)性紅斑狼瘡活動(dòng)評(píng)分等相關(guān)活動(dòng)性指標(biāo)的關(guān)聯(lián),最后發(fā)現(xiàn)SLE患者的RDW有所增加,其中RDW與SLE患者血清IgM、CRP、ESR及SLEDAI-2K呈正相關(guān),從而得出RDW在系統(tǒng)性紅斑狼瘡活動(dòng)度中可作為潛在評(píng)估指標(biāo)。另有學(xué)者[24]在研究RDW與SLE疾病活動(dòng)度的基礎(chǔ)上,觀察了SLE患者中RDW正?;颊呒吧呋颊咧委熀蟮膹?fù)發(fā)情況,研究得出RDW在SLE患者中與貧血無關(guān),而與CRP、SLEDAI-2K呈正相關(guān),在隨訪12個(gè)月后發(fā)現(xiàn)RDW正常患者的非進(jìn)展生存率高于RDW升高的患者。國內(nèi)有學(xué)者[25]發(fā)現(xiàn)RDW、NLR在與ANA、dsDNA等其他相關(guān)指標(biāo)聯(lián)合應(yīng)用時(shí)具有一定價(jià)值,但因不具有特異性,不能夠作為獨(dú)立診斷指標(biāo)。
2.2 NLR、PLR、RDW在類風(fēng)濕關(guān)節(jié)炎中的研究 ?RA是以炎性滑膜炎為主的系統(tǒng)性疾病,主要以侵蝕性、對(duì)稱性多關(guān)節(jié)炎為發(fā)病特點(diǎn),發(fā)病機(jī)制尚不完全明確,目前主要發(fā)病機(jī)制為在多種抗原刺激下,自身細(xì)胞因子 TNF-α、IL-6、IL-8等在關(guān)節(jié)滑膜處累積,從而使關(guān)節(jié)滑膜處于炎癥狀態(tài),晚期患者可出現(xiàn)關(guān)節(jié)畸形,嚴(yán)重影響患者的生活質(zhì)量。處于活動(dòng)期的RA患者體內(nèi)往往可以檢測到高水平的炎性生物指標(biāo),CRP和ESR已經(jīng)納入到RA疾病活動(dòng)度評(píng)估指標(biāo) DAS28中。雖然及時(shí)的診斷及治療已經(jīng)減少了患者關(guān)節(jié)畸形率的發(fā)生,但是隨著特異性指標(biāo)陰性的類風(fēng)濕關(guān)節(jié)炎逐漸增多,尋找新的診斷指標(biāo)及活動(dòng)度評(píng)定指標(biāo),對(duì)提高患者生活質(zhì)量有重要意義。
有外國學(xué)者研究了NLR、PLR與RA患者DAS28活動(dòng)評(píng)分的相關(guān)性,結(jié)果顯示NLR和PLR與DAS-28明顯相關(guān),NLR和PLR是兩個(gè)新的炎癥標(biāo)志物,可以用于評(píng)估RA患者的疾病活動(dòng)性[26]。Calabria M等[27]收集了66名RA受試者,通過評(píng)估受試者血清中hs-CRP、ESR、紅細(xì)胞壓積(HCT)、RDW等相關(guān)指標(biāo)來判斷RDW與類風(fēng)濕關(guān)節(jié)炎活動(dòng)度評(píng)分DAS-28的相關(guān)性,結(jié)果得出RDW與類風(fēng)濕關(guān)節(jié)炎DAS-28評(píng)分呈正相關(guān),雖然這種關(guān)聯(lián)的基礎(chǔ)機(jī)制尚不明確,可能與疾病潛在的炎癥狀態(tài)、氧化應(yīng)激的增加及紅細(xì)胞受損有關(guān),但最終結(jié)果表明RDW可以更好地描述類風(fēng)濕關(guān)節(jié)炎的活動(dòng)性,幫助臨床醫(yī)生確定更合適的治療方法及診斷策略,該研究與錢成榮[28]、彭婉嬋[29]等學(xué)者的研究一致。
2.3 NLR、PLR、RDW在干燥綜合征中的研究 ?SS是一種累及唾液腺、淚腺等外分泌腺體及全身多系統(tǒng)的慢性炎癥性自身免疫性疾病[30],其發(fā)病機(jī)制尚不完全明確。SS是三大常見的自身免疫性疾病之一,在世界不同國家和地區(qū)的患病率為0.5%~2%[31],有內(nèi)臟損害者經(jīng)恰當(dāng)治療后大多可控制病情,如治療不及時(shí),病情可惡化甚至危及生命,所以提高該病重視度極其重要。Hu ZD等[32]研究了RDW、NLR與干燥綜合征的相關(guān)性,該研究回顧性收集52例PSS患者和58名健康對(duì)照者,采用Spearman相關(guān)分析和多元線性回歸模型分析RDW、NLR與患者臨床特征的相關(guān)性,結(jié)果表明RDW和NLR在PSS患者增中普遍高,并與舍格倫綜合征活動(dòng)指數(shù)(SSDAI)呈正相關(guān),RDW和NLR可能是評(píng)估PSS疾病活動(dòng)的有用指標(biāo),但該實(shí)驗(yàn)的局限性是樣本量較小,尚缺少大樣本數(shù)據(jù)分析,因此該項(xiàng)研究有待進(jìn)一步考察。目前PLR與SS相關(guān)性的報(bào)道較少見。
3總結(jié)
結(jié)締組織病是累及多系統(tǒng)的自身免疫性疾病,盡早的診斷及確定治療方案可以改善患者生活質(zhì)量,每種結(jié)締組織病均有相關(guān)的診斷標(biāo)準(zhǔn),在疾病的活動(dòng)性評(píng)定中也有一定的評(píng)判指標(biāo),尋找新的診斷指標(biāo)及活動(dòng)性指標(biāo),可以盡早確定治療方案。新型炎癥指標(biāo)NLR、PLR、RDW已不僅僅應(yīng)用在感染性疾病及腫瘤疾病的預(yù)后判斷,在心血管、肝臟、神經(jīng)內(nèi)科等相關(guān)疾病中也逐漸有應(yīng)用。近幾年,多項(xiàng)研究表明新型炎癥因子與結(jié)締組織病有一定相關(guān)性,具體相關(guān)機(jī)制尚不完全明確,這可能與自身免疫性疾病導(dǎo)致自身炎癥反應(yīng)相關(guān),除上述已被證實(shí)的與RA、SLE及SS相關(guān)的炎癥因子外,另有C反應(yīng)蛋白與纖維蛋白比值、C反應(yīng)蛋白與白蛋白比值等其他新型炎癥因子逐漸應(yīng)用到結(jié)締組織病的研究中。盡管這些炎癥因子在診斷及判斷結(jié)締組織病上缺乏特異性,但在協(xié)助疾病診治及活動(dòng)性判斷中有一定作用,為結(jié)締組織病診斷指標(biāo)的研究提供新的思路。
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收稿日期:2019-8-5;修回日期:2019-9-12
編輯/肖婷婷