Journal of Rheumatic Diseases Vol. 23, No. 2, April, 2016 http://dx.doi.org/10.4078/jrd.2016.23.2.96 Original Article 류마티스관절염활성도와호중구 - 림프구비, 혈소판 - 림프구비의상관관계 김성준 1 ㆍ이지현 1 ㆍ김성만 2 ㆍ박민기 1 ㆍ박수호 1 ㆍ김동규 1 ㆍ황지연 1 ㆍ최준설 1 ㆍ박석기 1 메리놀병원 1 류마티스내과, 2 순환기내과 Relationship between Neutrophil-lymphocyte, Platelet-lymphocyte Ratio and Rheumatoid Arthritis Activity Sung Jun Kim 1, Ji Hyun Lee 1, Seong Man Kim 2, Min Gi Park 1, Su Ho Park 1, Dong Kyu Kim 1, Ji Yeon Hwang 1, Joon Sul Choi 1, Suk Ki Park 1 Divisions of 1 Rheumatology and 2 Cardiology, Department of Internal Medicine, Maryknoll Medical Center, Busan, Korea Objective. Although previous trials suggested a relationship between neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic inflammatory response, clinical utility of NLR and PLR in rheumatoid arthritis (RA) is not well defined. This study was conducted to assess the efficiency of NLR and PLR as an inflammatory index in patients with RA. Methods. A total of 107 patients with newly diagnosed RA who had never used steroid and a control group of 50 age- and gender-matched healthy subjects whose high sensitive C-reactive protein (hscrp) was within normal range were included. Those with cerebrovascular diseases, diabetes, malignancies, or any cardiovascular diseases were excluded from both groups. The patients were divided into two groups according to the Disease Activity Score of 28 joints (DAS28). Group 1 included patients with a DAS28 score of 3.2 and lower (low disease activity) and group 2 included patients with a score higher than 3.2 (moderate to high disease activity). Results. NLR and PLR in the patient group were 2.99±2.04, 170.90±86.49, significantly higher than that of the control group. NLR and PLR in group 2 were 4.16±2.50, 225.23±93.21, significantly higher than those of group 1 patients (2.26±1.22, 137.15±61.92). NLR and PLR both showed correlation with rheumatoid factor, hscrp, serum albumin, Korean Heath Assesment Questionnaire, and DAS28. Conclusion. These data showed a positive correlation between NLR or PLR level and RA disease activity, suggesting that NLR or PLR can be used as an additional inflammatory marker in patients with RA. (J Rheum Dis 2016;23:96-100) Key Words. Neutrophil-to-lymphocyte ratio, Platelet-to-lymphocyte ratio, Rheumatoid arthritis, Inflammatory markers 서론 급성기반응은염증반응에동반되는주요한병태생리학적현상으로류마티스관절염의대표적인현상이다. 급성반응단백은염증반응동안혈청에서적어도 25% 이상의변화가있는단백물질을말하며 C-반응단백 (C-reactive protein, CRP) 과혈청아밀로이드와같이혈중농도가증가하는물질과알부민, 트랜스페린 (transferrin) 과같이감소하는물질들이있다. 진단적특이성이부족하지만염증의정도를잘반영하므로임상에서유용하게사용되는데, 가장널리사용되는것은적혈구침강속도 (erythrocyte sedimentation rate, ESR) 와 CRP이다. 이들검사는류마티스 Received:July 14, 2015, Revised:(1st) August 18, 2015, (2nd) September 1, 2015, (3rd) September 15, 2015, Accepted:September 15, 2015 Corresponding to:ji Hyun Lee, Division of Rheumatology, Department of Internal Medicine, Maryknoll Medical Center, 121 Junggu-ro, Jung-gu, Busan 48972, Korea. E-mail:ete@lycos.co.kr pissn: 2093-940X, eissn: 2233-4718 Copyright c 2016 by The Korean College of Rheumatology. All rights reserved. This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited. 96
Neutrophil-lymphocyte, Platelet-lymphocyte Ratio in Rheumatoid Arthritis 관절염에서치료에대한반응을반영하며지속적상승은질병의지속적인진행으로인한방사선적진행과상관관계가있는것으로알려져있다 [1]. 염증반응의정도를반영하는또다른표지자로는백혈구수와그아형이있으며 [2], 이중호중구-림프구비 (neutrophil-lymphocyte ratio, NLR) 와염증반응과의상관성에대한연구결과가최근보고되고있다. 뇌졸중예후에대한연구에서호중구의증가는뇌경색재발과관계가있었으며림프구수가감소할수록뇌졸중재발률이높았다 [3]. 호중구증가와림프구감소의두가지측면을모두반영하는 NLR은여러가지백혈구지표중염증반응에대한표지자로의미를갖는다. NLR은관상동맥질환이나뇌경색등의질환에서혈관계통의초기염증반응의활성도를알려주며전체백혈구수에비해사망률에대한예측도가높은것으로보고되었다 [4,5]. 특히사망및심근경색의예측인자로서는기존연구에서보고한 CRP의예측도보다높았다 [6]. 혈소판-림프구비 (platelet-lymphocyte ratio, PLR) 역시동맥경화와관련이있으며말초혈관질환에서염증의정도및나쁜예후와관련이있는것으로보고되어있다 [7,8]. 이렇게 NLR, PLR과혈관질환의염증정도사이의상관성에대한보고가있어왔으나류마티스관절염에서 NLR, PLR이염증반응의정도를반영하는지에대해서는잘알려진바가없다. 특히류마티스관절염에서사용되는스테로이드의경우혈관벽및골수의호중구를혈관내로이동시켜호중구증가증을야기하고호산구와림프구는감소시키는경우가많아스테로이드를사용중인류마티스관절염환자에서 NLR, PLR이염증정도를잘반영하는지평가하기가쉽지않다. 이에저자들은연구대상을이전에스테로이드를사용한적이없는, 처음류마티스관절염으로진단받은환자로제한하고이환자군에서질병활성도와 NLR, PLR 사이에관련이있는지를알아보고자하였다. 대상및방법 대상 2013년 1월부터 2014년 12월까지본원류마티스내과에서미국류마티스학회분류기준 [9] 에따라류마티스관절염으로처음분류된환자 107명 (56.28±11.99세, 남자 33명, 여자 74명 ) 을대상으로하였다. 대조군의경우병원에건강검진을위해방문한 50명의건강한지원자 (58.60±9.02 세, 남자 16명, 여자 34명 ) 중 high sensitivity CRP (hscrp) 가정상범위내에있는자를선발하였다. 환자군과대조군모두에서설문을통해당뇨, 고혈압, 허혈성심질환, 심부전, 뇌졸중, 종양등과같은질환을가진자와 3개월이내에스테로이드사용력이있는자는제외하였다. 이연구는메리놀병원임상시험심사위원회의승인을받았다. 방법 1) 설문조사 검진당시구조화된설문지를통해발병시기및이환기간, 현재의약제복용력을확인하였고조사하였다. 또한류마티스관절염과관련된건강상태확인을위하여건강평가설문지 (Health Assessment Questionnaire, HAQ) [10] 와질병활성도점수 (Disease Activity Score with 28 joints, DAS28-CRP) [11] 를사용하였다. 2) 혈액검사 첫내원시채취한정맥혈을분석한결과를사용하였으며류마티스인자 (rheumatoid factor, RF) 는 turbid immunometry (Advia 1800; Siemens, Munich, Germany) 를사용하여 cut-off>15 IU/mL로정량화하였다. hscrp의혈장농도는 automated turbid immunometry (Advia 1800) 를사용하여측정하였다. 총백혈구수및백혈구백분율 (lymphocyte, monocyte, eosinophil, basophil, neutrophil) 의측정은 Coulter counter (Beckman coulter Inc., Brea, CA, USA) 로측정하였으며, NLR은전체혈구감별계산에서측정된호중구수를림프구수로나누어계산하였고 PLR은혈소판수를림프구수로나누어계산하였다. 3) 통계분석 통계분석은통계프로그램 IBM SPSS Statistics for Windows ver. 22.0 (IBM Co., Armonk, NY, USA) 을사용하여수행하였으며결과값은평균 ± 표준편차로표시하였다. 두그룹간의연속형자료의평균치비교는 independent t-test를시행하였다. 변수사이의연관성은 Pearson correlation tests을통한상관계수를계산하여확인하였다. 모든통계적유의성은 p-value가 0.05 미만일때로정의하였다. 결 임상적특징및혈액검사소견총환자 107명중남성은 33명, 여성은 74명, 평균유병기간은 14.6±19.1개월이었으며 RF는 85명 (79.4%) 에서양성이었다. 환자군이대조군에비해백혈구수, 호중구수, 혈소판수, NLR, PLR이현저히높았으며림프구수, 혈색소, 알부민수치는낮게나타났다 (Table 1). DAS28-CRP 에따른양상의비교전체환자를대상으로 DAS28-CRP의값을구했으며 DAS28-CRP가 3.2 미만인낮은질병활성도군 (group 1) 과 3.2 이상인중등도이상의질병활성도군 (group 2) 으로나누었다. Group 2는 group 1에비해 RF, hscrp, Korean HAQ (KHAQ), NLR, PLR 수치가통계적으로유의하게높았으며 과 www.jrd.or.kr 97
Sung Jun Kim et al. Table 1. Subjects characteristics Characteristic RA patients (n=107) Controls (n=50) p-value Age (yr) 56.28±11.99 58.60±9.02 0.181 Sex (male) 33 (30.8) 16 (32.0) 0.884 WBC count ( 10 3 /μl) 7,587.85±2,630.90 5,978.00±1,548.18 <0.001 PML (%) 63.34±10.99 52.78±9.46 <0.001 Lymphocyte (%) 26.58±9.60 37.25±9.39 <0.001 NLR 2.99±2.04 1.64±1.10 <0.001 Monocyte 7.42±2.28 6.91±2.03 0.178 Eosinophil 2.11±2.36 2.53±2.14 0.285 Hemoglobin (g/dl) 12.71±1.49 13.84±1.58 <0.001 Platelet count ( 10 3 /μl) 285.35±100.64 234.00±49.42 <0.001 PLR 170.90±86.49 117.01±43.40 <0.001 RF (IU/mL) 143.61±189.00 5.15±4.12 <0.001 hscrp (mmol/l) 15.94±28.00 0.29±0.23 <0.001 Albumin (g/dl) 4.19±0.38 4.49±0.25 <0.001 Values are presented as mean±standard deviation or number (%). hscrp: high sensitivity C-reactive protein, NLR: neutrophil-lymphocyte ratio, PLR: platelet-lymphocyte ratio, PML: polymorphonuclear leukocyte, RA: rheumatoid arthritis, RF: rheumatoid factor, WBC: white blood cell. Table 2. Subjects characteristics according to the DAS28 Characteristic Group 1 (DAS28<3.2) Group 2 (DAS28 3.2) p-value Age (yr) 57.94±10.57 53.61±13.70 0.088 Duration (mo) 18.20±22.98 8.80±7.82 0.003 Sex (male) 18 (27.3) 15 (36.6) 0.311 RF (IU/ ml) 112.57±165.41 193.58±214.57 0.030 hscrp (mmol/l) 2.99±4.50 36.78±36.37 <0.001 Albumin (g/dl) 4.29±0.28 4.03±0.45 0.001 Platelet ( 10 3 /μl) 242.16±91.84 354.90±69.26 <0.001 NLR 2.26±1.22 4.16±2.50 <0.001 PLR 137.15±61.92 225.23±93.21 <0.001 KHAQ 1.17±0.48 2.01±0.34 <0.001 Values are presented as mean±standard deviation or number (%). DAS28: Disease Activity Score with 28 joints, hscrp: high sensitivity C-reactive protein, KHAQ: Korean Health Assessment Questionnaire, NLR: neutrophil-lymphocyte ratio, PLR: platelet-lymphocyte ratio, RF: rheumatoid factor. 알부민수치는통계적으로유의하게낮았다 (Table 2). 고 찰 NLR, PLR 과다른임상적인자와의관계전체환자를대상으로보았을때 NLR는 RF, hscrp, KHAQ, DAS28, PLR과유의한양의상관관계를보였으며, 알부민수치와는유의한음의상관관계를나타내었다. PLR 역시유병기간과는관련이없었으나 RF, hscrp, KHAQ, DAS28, NLR과유의한양의상관관계를보였으며, 알부민수치와는유의한음의상관관계를나타내었다 (Table 3). 이연구에서저자들은이전에스테로이드나항류마티스약제를사용한적이없는, 처음류마티스관절염으로진단받은환자에서질병활성도및 CRP의증가와 NLR 사이에관련이있는지를알아보고자하였다. 현재까지류마티스관절염에서염증의지표로널리사용되고있는급성반응단백은 ESR과 CRP이다. CRP의경우 ESR에비해염증외다른요소에의한영향을덜받고반감기가 18시간으로짧아염증을평가하는데유용하게사용되고, 류마티스관절염의질병활성도와연관성이있어침범관절의개수와함께질병활성도평가를위한지표의일부분으로사용된다. 최근연구들에따르면 NLR의증가가염증반응과관련이 98 J Rheum Dis Vol. 23, No. 2, April, 2016
Neutrophil-lymphocyte, Platelet-lymphocyte Ratio in Rheumatoid Arthritis Table 3. Correlation coefficients between clinical parameters and NLR, PLR Characteristic NLR r p r p PLR Age 0.023 0.815 0.001 0.992 Duration 0.116 0.235 0.185 0.057 RF 0.375 <0.001 0.380 <0.001 hscrp 0.419 <0.001 0.371 <0.001 Albumin 0.370 <0.001 0.359 <0.001 NLR Uncalculable Uncalculable 0.751 <0.001 PLR 0.751 <0.001 Uncalculable Uncalculable KHAQ 0.520 <0.001 0.480 <0.001 DAS28 0.533 <0.001 0.486 <0.001 DAS28: Disease Activity Score with 28 joints, hscrp: high sensitivity C-reactive protein, KHAQ: Korean Health Assessment Questionnaire, NLR: neutrophil-lymphocyte ratio, PLR: platelet-lymphocyte ratio, RF: rheumatoid factor. 있으며여러질병에서재발및예후와관련이있는인자로보고했다. Tamhane 등 [4] 은경피관상동맥중재술을받은환자와급성관상동맥증후군환자에서 NLR이예후와관련있다고보고하였으며감염성심내막염 [12] 이나급성충수돌기염 [13] 과같은염증질환에서도예후와관련이있다고알려져있다. 또한전이성신장암에서호중구가불량한예후와관계가있음이보고된이후 [14], 간암, 담도암, 직장암, 신장암, 유방암, 위암, 췌장암, 폐암, 갑상선암등여러암에서술전 NLR이재발및예후에연관이있다는보고들도있다 [15]. PLR 역시말초혈관질환에서염증의정도및나쁜예후와관련이있는것으로보고되어있다 [7,8]. 말초혈액내백혈구수는급성염증, 조직손상및다양한염증상태의객관적지표로서일반적으로전신적염증반응의발생시호중구수는증가하고림프구수는감소하는경향이있다 [16]. 호중구증가증은일반적으로백혈구의재분배나증가된골수의배출에기인하며, 드물게혈액내순환기간이연장되어나타날수있다. 혈액내호중구수는연령, 성별, 인종등에따라참고범위가다르고임신, 운동, 약물등의여러가지요인에의해서도증가될수있다. 가임기여자는남자보다호중구수가다소높으며월경주기에따라변화된다. 임신기간에는호중구수가더욱증가되며분만이나출산후까지증가가계속된다. 심한통증도호중구증가증을일으킬수있으며스테로이드는경구투여하루후나정맥주사수시간후호중구수를증가시킬수있다. 백혈구수의분획에대한유용성은여러연구에서평가되었으나백혈구의어느분획이더중요한지는다소차이가있었다. Prentice 등 [17] 은호중구, 호산구와단핵구수가심혈관계질환의발생과연관이있다고보고하였으며, Paris prospective study II에서는 [18] 관상동맥질환의다른위험인자들을교정한후에도단핵구의수가 100개 /μl 증가할때마다심혈관계질환의위험도가 1.15배증가한다고 보고하였다. Sweetnam 등 [19] 의연구에서는관상동맥질환의상대위험도가호중구, 호산구, 림프구, 단핵구, 호염기구수가높은군에서 2배이상증가되었다고하였고제2 형당뇨병에서대사증후군과백혈구수와의관계를본국내의한연구 [20] 에서는대사증후군의항목을만족시키는개수가증가할수록호중구, 림프구, 단핵구, 호산구의수가증가하지만통계적유의성은없다고보고하였다. 류마티스관절염에서는백혈구수는대부분정상이지만약간증가되는경우도있다. 일반적으로질병활성도와비례하는것은빈혈정도와혈소판증가정도이다. 일반적으로혈소판은급성염증반응으로증가되는데이로인해혈전증은잘생기지않는것으로알려져있다. 최근류마티스관절염환자에서 NLR과질병활성도의상관관계를본연구들이보고되었는데, Uslu 등 [21] 과 Fu 등 [22] 은 NLR과 DAS28 간에상관관계가관찰된다고보고하였다. 이번연구는 NLR에대한스테로이드의영향을배제하기위해이전에스테로이드를사용한적이없는, 처음류마티스관절염으로진단받은환자들을대상으로하였으며 NLR, PLR 모두 RF, hscrp, KHAQ, DAS28과유의한양의상관관계를보였고알부민수치와는유의한음의상관관계를보였다. 이와같은결과는 NLR이나 PLR을뇌혈관질환이나심혈관질환, 여러종양에서뿐만아니라류마티스관절염에서도염증반응의정도를반영하는또다른표지자로사용할수있음을시사한다. 향후 NLR이나 PLR 의지속적상승이질병의지속적인진행으로인한방사선적진행과상관관계가있는지에대한추가연구는필요할것이다. 이번연구에는몇가지제한점이있다. 첫째, 적은환자수로인하여결과를일반화하기어렵고단일기관연구로대상자선별에있어선택치우침의가능성이있다. 둘째, 단면연구로진행되었기때문에시간에따른인과관계를알수없다. 염증수치인 hscrp 및 NLR, PLR은첫내원당시에측정된결과만을사용하였고시간이지남에따라이 www.jrd.or.kr 99
Sung Jun Kim et al. 수치의변화에대한평가를하지않았다. 따라서향후추적관찰시의변화나질병활성도와의연관성에대한추가적인관찰이필요할것으로생각되며예후인자와의연관성등에대한연구도시행되어야할것이다. 결 론 이번연구에서는 NLR, PLR이류마티스관절염의질병활성도를나타내는 hscrp, KHAQ, DAS28과유의한양의상관관계를보였으며알부민수치와는유의한음의상관관계를보였다. 상기기술한제한점을고려하여향후더많은대상을포함한비교연구가필요하다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Amos RS, Constable TJ, Crockson RA, Crockson AP, McConkey B. Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation rates to radiographic changes. Br Med J 1977;1:195-7. 2. Margolis KL, Manson JE, Greenland P, Rodabough RJ, Bray PF, Safford M, et al; Women's Health Initiative Research Group. Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women's Health Initiative Observational Study. Arch Intern Med 2005;165:500-8. 3. Grau AJ, Boddy AW, Dukovic DA, Buggle F, Lichy C, Brandt T, et al; CAPRIE Investigators. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke 2004;35:1147-52. 4. Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol 2008;102:653-7. 5. Park JK, Oh HG, Park TH. Neutrophil to lymphocyte ratio at admission: prognostic factor in patients with acute ischemic stroke. J Korean Neurol Assoc 2010;28:172-8. 6. Horne BD, Anderson JL, John JM, Weaver A, Bair TL, Jensen KR, et al; Intermountain Heart Collaborative Study Group. Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardiol 2005;45:1638-43. 7. Gary T, Pichler M, Belaj K, Hafner F, Gerger A, Froehlich H, et al. Platelet-to-lymphocyte ratio: a novel marker for critical limb ischemia in peripheral arterial occlusive disease patients. PLoS One 2013;8:e67688. 8. Kwon HC, Kim SH, Oh SY, Lee S, Lee JH, Choi HJ, et al. Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers 2012;17:216-22. 9. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81. 10. Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical applications. Health Qual Life Outcomes 2003;1:20. 11. Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44-8. 12. Turak O, Özcan F, Işleyen A, Başar FN, Gül M, Yilmaz S, et al. Usefulness of neutrophil-to-lymphocyte ratio to predict in-hospital outcomes in infective endocarditis. Can J Cardiol 2013;29:1672-8. 13. Choi WJ. A review of WBC count and neutrophil/lymphocyte ratio in patients with acute appendicitis. J Korean Soc Coloproctol 2000;16:456-61. 14. Lopez Hänninen E, Kirchner H, Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol 1996;155:19-25. 15. Han SW, Kang SY, Kim SK, Youn HJ, Jung SH. Clinical significance of blood neutrophil-to-lymphocyte ratio in patients with papillary thyroid carcinoma. Korean J Endocr Surg 2014;14:184-9. 16. Jilma B, Blann A, Pernerstorfer T, Stohlawetz P, Eichler HG, Vondrovec B, et al. Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. Am J Respir Crit Care Med 1999;159:857-63. 17. Prentice RL, Szatrowski TP, Fujikura T, Kato H, Mason MW, Hamilton HH. Leukocyte counts and coronary heart disease in a Japanese cohort. Am J Epidemiol 1982;116:496-509. 18. Olivares R, Ducimetière P, Claude JR. Monocyte count: a risk factor for coronary heart disease? Am J Epidemiol 1993;137:49-53. 19. Sweetnam PM, Thomas HF, Yarnell JW, Baker IA, Elwood PC. Total and differential leukocyte counts as predictors of ischemic heart disease: the Caerphilly and Speedwell studies. Am J Epidemiol 1997;145:416-21. 20. Shim WS, Kim HJ, Kang ES, Ahn CW, Lim SK, Lee HC, et al. The association of total and differential white blood cell count with metabolic syndrome in type 2 diabetic patients. Diabetes Res Clin Pract 2006;73:284-91. 21. Uslu AU, Küçük A, Şahin A, Ugan Y, Yılmaz R, Güngör T, et al. Two new inflammatory markers associated with Disease Activity Score-28 in patients with rheumatoid arthritis: neutrophil-lymphocyte ratio and platelet-lymphocyte ratio. Int J Rheum Dis 2015;18:731-5. 22. Fu H, Qin B, Hu Z, Ma N, Yang M, Wei T, et al. Neutrophiland platelet-to-lymphocyte ratios are correlated with disease activity in rheumatoid arthritis. Clin Lab 2015;61: 269-73. 100 J Rheum Dis Vol. 23, No. 2, April, 2016