Clinica Chimica Acta 438 (2015) 205–209
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The association of red blood cell distribution width with anemia and inflammation in patients with Takayasu arteritis Qing Liu, Ai-min Dang ⁎, Bing-wei Chen, Na-qiang Lv, Xu Wang, De-yu Zheng Department of Special Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
a r t i c l e
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Article history: Received 7 June 2014 Received in revised form 12 August 2014 Accepted 21 August 2014 Available online 27 August 2014 Keywords: Takayasu arteritis Red blood cell distribution width Anemia Inflammation Disease activity
a b s t r a c t Background: Red blood cell distribution width (RDW) has been shown to be related to both anemia and inflammation in various diseases. However, the role of RDW in patients with Takayasu arteritis (TA) is unknown. Therefore, we investigated the association of RDW with anemia, inflammation, and disease activity in TA. Methods: RDW was determined in 156 patients with TA and in 156 control subjects. Anemia status and disease activity were defined according to the World Health Organization and National Institutes of Health criteria, respectively. Results: RDW was significantly increased in patients with anemia (14.6 ± 2.2) compared with those without anemia (13.6 ± 1.3, p b 0.001) and control subjects (12.7 ± 0.6, p b 0.001). Regardless of the presence of anemia, RDW showed correlation with high-sensitivity C-reactive protein (hs-CRP) (both p b 0.05). RDW was higher in active TA than inactive TA in patients without anemia (14.1 ± 1.5 vs. 13.3 ± 1.1, p = 0.001). Moreover, multiple regression analysis showed that hs-CRP and mean corpuscular volume were independently associated with RDW. Conclusions: RDW is influenced by both anemia and inflammation, and RDW may be a useful marker to assess disease activity in patients without anemia. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Red blood cell distribution width (RDW) is a parameter routinely measured to quantify the heterogeneity of circulating erythrocytes. RDW has been traditionally used as a marker to discriminate between different types of anemia [1]. Recently, increased RDW has shown to be associated with mortality in the general population [2,3], heart failure [4,5], coronary artery disease [6,7], pulmonary hypertension [8,9], stroke [10,11], diabetes mellitus [12], and infectious diseases [13]. Although the exact mechanisms underlying these findings remain unclear, chronic inflammation has been proposed as a key point in the association of RDW with these adverse outcomes [5,7,14]. In this sense, it has been found that RDW increases in several inflammatory diseases, such as rheumatoid arthritis (RA) [15], systemic lupus erythematosus (SLE) [16,17], and inflammatory bowel disease (IBD) [18,19]. Moreover, RDW has been strongly associated with inflammatory markers and disease activity in patients with SLE [17] and IBD [18,19].
Takayasu arteritis (TA) is a chronic non-specific inflammatory disease, which primarily involves large vessels including the aorta and its main branches, and pulmonary and coronary arteries. Vessel wall inflammation may cause luminal stenosis, occlusion, dilation, or aneurysm formation [20]. As TA is often associated with anemia [21], it is possible that both anemia and inflammation may influence RDW values in these patients. The natural course of TA consists of active and quiescent phases, and accurate assessment of disease activity is essential for the management of TA. Erythrocyte sedimentation rate (ESR) and C-reactive protein are commonly used inflammatory markers to evaluate disease activity in TA, despite being shown to be neither sensitive nor specific enough [22,23]. As a novel indicator for inflammation, RDW may be also useful for disease activity assessment in TA. However, no studies evaluating the association of RDW with TA have been published. 2. Materials and methods 2.1. Patients and control subjects
⁎ Corresponding author at: Department of Special Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing 100037, China. Tel.: +86 10 88398040; fax: +86 10 88396323. E-mail address: [email protected] (A. Dang).
http://dx.doi.org/10.1016/j.cca.2014.08.025 0009-8981/© 2014 Elsevier B.V. All rights reserved.
A total of 156 consecutive Chinese patients with TA in Fuwai Hospital from 2011 to 2013 were included in this study. All patients fulfilled the American College of Rheumatology classification criteria for TA [24]. The control group included 156 age-, sex-, and body mass
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index (BMI)-matched healthy individuals who had routine checkup over the same period. The study protocol was approved by the Ethics Committee of the Fuwai Hospital, and informed consent was obtained from all participants.
were determined by Westergren method and immunonephelometry, respectively.
2.2. Classification criteria
All variables were tested for normality of distribution using the Kolmogorov–Smirnov test. Continuous variables were displayed as mean ± SD, and categorical variables were presented as total number (percentage). ESR, hs-CRP and RDW were log-transformed to improve normality for statistical testing. Differences between the groups were assessed using one-way ANOVA and post-hoc LSD tests, independent t test, or Mann–Whitney U test for continuous variables, and chisquare test or Fisher's exact test for categorical variables. The Spearman approach was used to analyze the correlation between RDW and other continuous variables. Multiple linear regression analysis was performed to determine the factors independently associated with RDW. p b 0.05 was accepted as statistically significant (SPSS 17.0).
TA is classified into 4 types according to Lupi-Herrera's criteria: type I, involvement of the aortic arch and its major branches; type II, involvement of the thoracic and abdominal aorta; type III, involvement of the whole aorta; and type IV, involvement of the pulmonary artery [25]. 2.3. Disease activity and anemia status assessment The disease activity in patients with TA was evaluated according to the National Institutes of Health criteria [22]. Active disease in TA was considered if a patient presented new onset or worsening of at least two of the following features: (1) systemic symptoms not attributable to other clinical conditions; (2) characteristics of vascular insufficiency, such as claudication, vascular pain, bruit, or asymmetry in pulses or blood pressure; (3) elevated ESR without infection or malignancy; and (4) typical angiographic characteristics. Anemic status in patients with TA was defined as a hemoglobin concentration lower than 130 g/l for males and 120 g/l for women according to World Health Organization criteria [26]. 2.4. Laboratory tests A 12-h fasting blood sample was collected for laboratory measurements that included hematological parameters, ESR, high-sensitivity C-reactive protein (hs-CRP), and other biochemical indexes. Hematological parameters, including hemoglobin, mean corpuscular volume (MCV), RDW, white blood cell (WBC), red blood cell (RBC), and platelets (PLT) counts, were analyzed by standard methods. ESR and hs-CRP
2.5. Statistical analysis
3. Results 3.1. Participant characteristics The clinical characteristics of 156 patients with TA and 156 healthy controls are shown in Table 1 and Table 2. The mean age of patients with TA was 40.0 ± 13.3 y and 86.5% were female. There were 69 patients (44.2%) in the active phase of the disease and anemia was observed in 55 patients (35.3%) at the outset of the study. Based on the classification criteria, 39.7% had type III TA, while 31.4%, 16.7%, and 10.3% had types I, II, and IV, respectively. One hundred and twelve patients (71.8%) received prednisone therapy, and the mean daily dosage was 20.0 ± 10.2 mg. 3.2. RDW and anemia status RDW values were significantly higher in patients with anemia (a-TA) (14.6 ± 2.2) and patients without anemia (na-TA) (13.6 ± 1.3)
Table 1 Demographic and clinical characteristics of 55 patients with anemia, 101 patients without anemia and 156 healthy controls.
Age, yrs Female, n (%) BMI, kg/m2 Disease duration, y Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) WBC counts, ×109/l RBC counts, ×1012/l Hemoglobin, g/l MCV, fl PLT, ×109/l RDW, % Creatine, umol/l ESR, mm/h Hs-CRP, mg/l Clinical classification, n (%) No vascular impairment Type I Type II Type III Type IV Prednisone, n (%) Daily prednisone dose, mg
All TA (N = 156)
a-TA (N = 55)
na-TA (N = 101)
Controls (N = 156)
P value
40.0 ± 13.3 135 (86.5%) 23.1 ± 3.3 10.3 ± 10.3 90 (57.7%) 9 (5.8%) 44 (28.2%) 7.9 ± 2.8 4.4 ± 0.6 129.0 ± 21.2 87.6 ± 7.2 232.7 ± 86.0 14.0 ± 1.7 66.2 ± 18.8 16.7 ± 18.0 5.0 ± 4.7
37.8 ± 13.1 51 (92.7%) 23.5 ± 3.2 8.5 ± 9.3 33 (60.0%) 2 (3.6%) 14 (25.5%) 7.6 ± 2.6 ⁎ 4.0 ± 0.4 ⁎,⁎⁎
41.2 ± 13.2 84 (83.2%) 23.0 ± 3.4 11.3 ± 10.7 57 (56.4%) 7 (6.9%) 30 (29.7%) 8.1 ± 3.0 ⁎
107.6 ± 11.2 ⁎,⁎⁎ 84.0 ± 8.7 ⁎,⁎⁎ 257.4 ± 97.5 ⁎,⁎⁎ 14.6 ± 2.2 ⁎,⁎⁎
4.7 ± 0.5 140.7 ± 15.4 89.6 ± 5.4 219.3 ± 76.2 13.6 ± 1.3 ⁎
65.6 ± 21.9 23.9 ± 21.3 ⁎⁎ 5.9 ± 5.4 ⁎
66.6 ± 16.9 12.7 ± 14.7 4.5 ± 4.2 ⁎
40.2 ± 7.2 135 (86.5%) 23.1 ± 1.7 – – – – 5.9 ± 1.5 4.6 ± 0.4 138.9 ± 11.6 90.1 ± 3.7 231.9 ± 44.8 12.7 ± 0.6 64.3 ± 10.6 – 1.1 ± 0.9
NS NS NS NS NS NS NS b0.001 b0.001 b0.001 b0.001 0.004 b0.001 NS b0.001 b0.001 NS
3 (1.9%) 49 (31.4%) 26 (16.7%) 62 (39.7%) 16 (10.3%) 112 (71.8%) 20.0 ± 10.2
1 (1.8%) 18 (32.7%) 10 (18.2%) 25 (45.5%) 1 (1.8%) 42 (76.4%) 20.8 ± 10.6
2 (2.0%) 31 (30.7%) 16 (15.8%) 37 (36.6%) 15 (14.9%) 70 (69.3%) 19.5 ± 10.0
– – – – – – –
NS NS
Data are presented as mean ± standard deviation or as number (percentage). TA: Takayasu arteritis; a-TA: TA with anemia; na-TA: TA without anemia; BMI: body mass index; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; PLT: platelets; RDW: red blood cell distribution width; ESR: erythrocyte sedimentation rate; Hs-CRP, high-sensitivity C-reactive protein. ⁎ p b 0.05 vs controls. ⁎⁎ p b 0.05 vs inactive TA.
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Table 2 Demographic and clinical characteristics of 69 patients with active disease, 87 patients in remission and 156 healthy controls.
Age, yrs Female, n (%) BMI, kg/m2 Disease duration, y Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) WBC counts, ×109/l RBC counts, ×1012/l Hemoglobin, g/l MCV, fl PLT, ×109/l RDW, % Creatine, umol/l ESR, mm/h Hs-CRP, mg/l Clinical classification, n (%) No vascular impairment Type I Type II Type III Type IV Prednisone, n (%) Daily prednisone dose, mg
All TA (N = 156)
Active TA (N = 69)
Inactive TA (N = 87)
Controls (N = 156)
P value
40.0 ± 13.3 135 (86.5%) 23.1 ± 3.3 10.3 ± 10.3 90 (57.7%) 9 (5.8%) 44 (28.2%) 7.9 ± 2.8 4.4 ± 0.6 129.0 ± 21.2 87.6 ± 7.2 232.7 ± 86.0 14.0 ± 1.7 66.2 ± 18.8 16.7 ± 18.0 5.0 ± 4.7
40.2 ± 13.7 61 (88.4%) 23.1 ± 3.5 9.0 ± 9.4 42 (60.9%) 4 (5.8%) 25 (36.2%) ⁎⁎ 8.5 ± 3.0 ⁎,⁎⁎ 4.5 ± 0.7 ⁎
39.8 ± 13.0 74 (85.1%) 23.2 ± 3.2 11.3 ± 10.9 48 (55.2%) 5 (5.7%) 19 (21.8%) 7.5 ± 2.6 ⁎ 4.4 ± 0.5 ⁎
63.6 ± 13.9 7.7 ± 4.3 2.1 ± 2.0 ⁎
40.2 ± 7.2 135 (86.5%) 23.1 ± 1.7 – – – – 5.9 ± 1.5 4.6 ± 0.4 138.9 ± 11.6 90.1 ± 3.7 231.9 ± 44.8 12.7 ± 0.6 64.3 ± 10.6 – 1.1 ± 0.9
NS NS NS NS NS NS 0.047 b0.001 0.002 b0.001 b0.001 NS b0.001 NS b0.001 b0.001 NS
3 (1.9%) 49 (31.4%) 26 (16.7%) 62 (39.7%) 16 (10.3%) 112 (71.8%) 20.0 ± 10.2
1 (1.4%) 22 (31.9%) 12 (17.4%) 26 (37.7%) 8 (11.6%) 56 (81.2%) ⁎⁎ 27.0 ± 8.9 ⁎⁎
2 (2.3%) 27 (31.0%) 14 (16.1%) 36 (41.4%) 8 (9.2%) 56 (64.4%) 13.1 ± 5.9
– – – – – – –
126.9 ± 24.5 ⁎ 86.4 ± 8.0 ⁎,⁎⁎ 239.7 ± 100.3 14.5 ± 1.8 ⁎,⁎⁎ 69.5 ± 23.2 28.0 ± 22.0 ⁎⁎ 8.6 ± 4.6 ⁎,⁎⁎
130.6 ± 18.0 ⁎ 88.6 ± 6.5 227.2 ± 72.9 13.6 ± 1.6 ⁎
0.021 b0.001
Data are presented as mean ± standard deviation or as number (percentage). TA: Takayasu arteritis; BMI: body mass index; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; PLT: platelets; RDW: red blood cell distribution width; ESR: erythrocyte sedimentation rate; Hs-CRP, high-sensitivity C-reactive protein. ⁎ p b 0.05 vs controls. ⁎⁎ p b 0.05 vs inactive TA.
than those in the control subjects (12.8 ± 0.6, both p b 0.001; Fig. 1). There was also significant difference in RDW values between a-TA and na-TA (p b 0.001, Fig. 1). Inflammatory marker ESR was significantly higher in a-TA than those in na-TA (23.9 ± 21.3 vs. 12.7 ± 14.7 mm/h, p b 0.001), but not hs-CRP (5.9 ± 5.4 vs. 4.5 ± 4.2 mg/l, p = 0.439; Table 1). Hematological parameters, such as hemoglobin, MCV and RBC counts were significantly lower, while PLT counts were significantly higher in a-TA than those in na-TA and controls (Table 1). WBC counts were increased in both TA groups compared with controls (Table 1). RDW was significantly negative correlated with hemoglobin and MCV in a-TA (hemoglobin, ρ = − 0.593, p b 0.001; MCV, ρ = − 0.559, p b 0.001), but not in na-TA (hemoglobin, ρ = 0.169, p = 0.092; MCV, ρ = −0.096, p = 0.338).
p b 0.001), and the values in both of the TA groups were higher than those in the control subjects (12.8 ± 0.6, both p b 0.001; Fig. 2). Inflammation parameters, including ESR and hs-CRP, were significantly higher in patients with active TA than those in remission (Table 2). Hematological parameters hemoglobin and RBC counts were significantly lower, while WBC counts were significantly higher in both TA groups than controls (Table 2). MCV was found to be lower in active TA than those in inactive TA and controls (Table 2). However, when patients were divided into two groups by anemia status, RDW values were significantly higher in patients with active disease than those in inactive patients in na-TA (14.1 ± 1.5 vs. 13.3 ± 1.1, p = 0.001), but not in a-TA (14.9 ± 2.1 vs. 14.3 ± 2.2, p = 0.362). 3.4. RDW and TA classification
3.3. RDW and TA activity RDW values were significantly increased in patients with active TA (14.5 ± 1.8) compared with those in inactive patients (13.6 ± 1.6,
Fig. 1. RDW values were significantly higher in patients with anemia (a-TA) compared with those without anemia (na-TA) and healthy controls. There was also significant difference between na-TA and controls. *p b 0.001 vs na-TA and controls. #p b 0.001 vs controls.
Considering the extent of arterial involvement, no significant differences regarding RDW values were found in TA patients with Type I (14.1 ± 1.9), Type II (13.8 ± 1.3), Type III (13.8 ± 1.5), and type IV (14.2 ± 1.8, p = 0.584; Fig. 3).
Fig. 2. RDW values were significantly higher in active TA compared with those in inactive TA and healthy controls. There was also significant difference between inactive TA and controls. *p b 0.001 vs inactive TA and controls. #p b 0.001 vs controls.
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Fig. 3. There was no significant difference regarding RDW values among patients with Type I, Type II, Type III, and type IV TA.
3.5. RDW and inflammatory markers of TA Regardless of the presence of anemia, RDW showed correlation with hs-CRP (ρ = 0.325, p = 0.015 in a-TA; ρ = 0.317, p = 0.001 in na-TA), but no correlation with ESR was found either in a-TA (ρ = 0.199, p = 0.145) or in na-TA (ρ = 0.036, p = 0.719). The results of multiple linear regression analysis showed that hs-CRP (standardized beta coefficient = 0.175, p = 0.04) and MCV (standardized beta coefficient = −0.377, p b 0.001) were independently associated with RDW in patients with TA after adjusting for age, sex, BMI, disease duration, hemoglobin, serum creatinine, ESR and the usage of prednisone (Table 3). 4. Discussion Patients with active disease showed significantly higher RDW values than those in remission in na-TA. Moreover, inflammatory marker hs-CRP, but not ESR, was independently associated with RDW in TA. Anemia is a common condition in chronic disease, which is known to be of great importance in RDW values [21]. As described in patients with SLE [16], our results found that RDW values were increased in a-TA compared with those in na-TA and control subjects. RDW was also negatively correlated with hemoglobin and MCV in patients with TA. These results indicated that RDW was associated with anemia in TA. However, our results also showed that RDW values were higher in na-TA than those in control subjects, which was consistent with previous findings in other systemic inflammatory diseases [16–19]. These results indicated that apart from anemia, RDW may also be associated with inflammation. As expected, hs-CRP levels were increased in
Table 3 Independent predictors of red cell distribution width by multivariate linear regression analysis.
Age Sex BMI Disease duration Hemoglobin MCV Creatinine Log (ESR) Log (hs-CRP) Prednisone
Standardized β
95% Confidence Interval
P value
0.019 0.109 −0.095 −0.065 −0.099 −0.377 0.035 −0.039 0.175 0.064
−0.175–0.213 −0.063–0.280 −0.243–0.054 −0.247–0.116 −0.298–0.100 −(0.555–0.200) −0.123–0.194 −0.227–0.149 0.008–0.342 −0.088–0.215
NS NS NS NS NS b0.001 NS NS 0.040 NS
BMI: body mass index; MCV: mean corpuscular volume; ESR: erythrocyte sedimentation rate; hs-CRP, high-sensitivity C-reactive protein.
both TA groups when compared with those in controls. Hs-CRP was also positively correlated with RDW in patients with TA. The exact mechanisms of the relationship between RDW and inflammation remain unclear. As a chronic inflammatory disease, TA manifests as an imbalance between pro- and anti-inflammatory cytokines [27–30]. It is estimated that these pro-inflammatory cytokines may induce changes in iron metabolism, the production of erythropoietin, the proliferation of erythroid progenitor cells, and the life span of erythrocytes, which may contribute to increased RDW values [21]. By these pathways, inflammation may lead to anisocytosis from release of juvenile red blood cells into the peripheral circulation [5,6,21]. Considering the impact of anemia on RDW, TA cases were divided into anemic and non-anemic groups. We found that regardless of the presence of anemia, RDW showed significant correlation with hs-CRP, but not ESR, which was in agreement with the findings in patients with RA [15]. The results of multivariate analysis also showed that hs-CRP, but not ESR, was independently associated with RDW in patients with TA. However, RDW was found to be associated with both hs-CRP and ESR in a large cohort of unselected outpatients [14] as well as in patients with SLE [17] and IBD [19]. This discrepancy may be explained by the effect of anemia on ESR, different patient cohorts and treatment measures in various studies. The association between RDW and ESR may be mediated by anemia in patients with TA. As described in SLE [17] and IBD [18,19], we also investigated whether RDW could be a potential index to evaluate disease activity in patients with TA. We found that among all patients with TA, RDW values were higher in patients with active disease than those in remission. This phenomenon was also present in non-anemic group, but absent in anemic group. Moreover, RDW was strongly associated with hemoglobin and MCV in a-TA, but not in na-TA. These results suggested that the influence of anemia on RDW was stronger in a-TA, and RDW may be a useful marker to assess disease activity only in na-TA. Several limitations should be considered in this study. First, since our study is cross-sectional, it is difficult to establish a causal relationship between RDW and TA. Further prospective studies are needed to investigate whether RDW can provide prognostic information of TA. Second, the sample size is relatively small for the comparison of active to inactive TA among anemic patients, and the insignificance between the two groups may be a lack of statistical power. However, this reflects the rarity of TA, especially for anemia cases. Third, data on the levels of serum iron, folic acid or vitamin B 12 which may affect RDW values were not available. These parameters were measured only in patients with clinical indication in our study. In conclusion, the present study has demonstrated that RDW is influenced by both anemia and inflammation in patients with TA. RDW is a newly recognized and useful marker for disease activity assessment in patients without anemia. The exact biological mechanisms underlying this association merit investigation. As RDW is routinely measured by automated blood cell analyzers with no additional cost, future prospective studies with larger samples are needed to validate the clinical value of RDW in patients with TA. Abbreviations IBD Inflammatory bowel disease TA Takayasu arteritis a-TA Takayasu arteritis patients with anemia na-TA Takayasu arteritis patients without anemia
Acknowledgments This work was supported by the National Natural Science Foundation of China (grant no. 81170285) and the Research Fund for the Doctoral Program of Higher Education of China (grant no. 20101106110012).
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The association of red blood cell distribution width with anemia and inflammation in patients with Takayasu arteritis Qing Liu, Ai-min Dang ⁎, Bing-wei Chen, Na-qiang Lv, Xu Wang, De-yu Zheng Department of Special Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
a r t i c l e
i n f o
Article history: Received 7 June 2014 Received in revised form 12 August 2014 Accepted 21 August 2014 Available online 27 August 2014 Keywords: Takayasu arteritis Red blood cell distribution width Anemia Inflammation Disease activity
a b s t r a c t Background: Red blood cell distribution width (RDW) has been shown to be related to both anemia and inflammation in various diseases. However, the role of RDW in patients with Takayasu arteritis (TA) is unknown. Therefore, we investigated the association of RDW with anemia, inflammation, and disease activity in TA. Methods: RDW was determined in 156 patients with TA and in 156 control subjects. Anemia status and disease activity were defined according to the World Health Organization and National Institutes of Health criteria, respectively. Results: RDW was significantly increased in patients with anemia (14.6 ± 2.2) compared with those without anemia (13.6 ± 1.3, p b 0.001) and control subjects (12.7 ± 0.6, p b 0.001). Regardless of the presence of anemia, RDW showed correlation with high-sensitivity C-reactive protein (hs-CRP) (both p b 0.05). RDW was higher in active TA than inactive TA in patients without anemia (14.1 ± 1.5 vs. 13.3 ± 1.1, p = 0.001). Moreover, multiple regression analysis showed that hs-CRP and mean corpuscular volume were independently associated with RDW. Conclusions: RDW is influenced by both anemia and inflammation, and RDW may be a useful marker to assess disease activity in patients without anemia. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Red blood cell distribution width (RDW) is a parameter routinely measured to quantify the heterogeneity of circulating erythrocytes. RDW has been traditionally used as a marker to discriminate between different types of anemia [1]. Recently, increased RDW has shown to be associated with mortality in the general population [2,3], heart failure [4,5], coronary artery disease [6,7], pulmonary hypertension [8,9], stroke [10,11], diabetes mellitus [12], and infectious diseases [13]. Although the exact mechanisms underlying these findings remain unclear, chronic inflammation has been proposed as a key point in the association of RDW with these adverse outcomes [5,7,14]. In this sense, it has been found that RDW increases in several inflammatory diseases, such as rheumatoid arthritis (RA) [15], systemic lupus erythematosus (SLE) [16,17], and inflammatory bowel disease (IBD) [18,19]. Moreover, RDW has been strongly associated with inflammatory markers and disease activity in patients with SLE [17] and IBD [18,19].
Takayasu arteritis (TA) is a chronic non-specific inflammatory disease, which primarily involves large vessels including the aorta and its main branches, and pulmonary and coronary arteries. Vessel wall inflammation may cause luminal stenosis, occlusion, dilation, or aneurysm formation [20]. As TA is often associated with anemia [21], it is possible that both anemia and inflammation may influence RDW values in these patients. The natural course of TA consists of active and quiescent phases, and accurate assessment of disease activity is essential for the management of TA. Erythrocyte sedimentation rate (ESR) and C-reactive protein are commonly used inflammatory markers to evaluate disease activity in TA, despite being shown to be neither sensitive nor specific enough [22,23]. As a novel indicator for inflammation, RDW may be also useful for disease activity assessment in TA. However, no studies evaluating the association of RDW with TA have been published. 2. Materials and methods 2.1. Patients and control subjects
⁎ Corresponding author at: Department of Special Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing 100037, China. Tel.: +86 10 88398040; fax: +86 10 88396323. E-mail address: [email protected] (A. Dang).
http://dx.doi.org/10.1016/j.cca.2014.08.025 0009-8981/© 2014 Elsevier B.V. All rights reserved.
A total of 156 consecutive Chinese patients with TA in Fuwai Hospital from 2011 to 2013 were included in this study. All patients fulfilled the American College of Rheumatology classification criteria for TA [24]. The control group included 156 age-, sex-, and body mass
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index (BMI)-matched healthy individuals who had routine checkup over the same period. The study protocol was approved by the Ethics Committee of the Fuwai Hospital, and informed consent was obtained from all participants.
were determined by Westergren method and immunonephelometry, respectively.
2.2. Classification criteria
All variables were tested for normality of distribution using the Kolmogorov–Smirnov test. Continuous variables were displayed as mean ± SD, and categorical variables were presented as total number (percentage). ESR, hs-CRP and RDW were log-transformed to improve normality for statistical testing. Differences between the groups were assessed using one-way ANOVA and post-hoc LSD tests, independent t test, or Mann–Whitney U test for continuous variables, and chisquare test or Fisher's exact test for categorical variables. The Spearman approach was used to analyze the correlation between RDW and other continuous variables. Multiple linear regression analysis was performed to determine the factors independently associated with RDW. p b 0.05 was accepted as statistically significant (SPSS 17.0).
TA is classified into 4 types according to Lupi-Herrera's criteria: type I, involvement of the aortic arch and its major branches; type II, involvement of the thoracic and abdominal aorta; type III, involvement of the whole aorta; and type IV, involvement of the pulmonary artery [25]. 2.3. Disease activity and anemia status assessment The disease activity in patients with TA was evaluated according to the National Institutes of Health criteria [22]. Active disease in TA was considered if a patient presented new onset or worsening of at least two of the following features: (1) systemic symptoms not attributable to other clinical conditions; (2) characteristics of vascular insufficiency, such as claudication, vascular pain, bruit, or asymmetry in pulses or blood pressure; (3) elevated ESR without infection or malignancy; and (4) typical angiographic characteristics. Anemic status in patients with TA was defined as a hemoglobin concentration lower than 130 g/l for males and 120 g/l for women according to World Health Organization criteria [26]. 2.4. Laboratory tests A 12-h fasting blood sample was collected for laboratory measurements that included hematological parameters, ESR, high-sensitivity C-reactive protein (hs-CRP), and other biochemical indexes. Hematological parameters, including hemoglobin, mean corpuscular volume (MCV), RDW, white blood cell (WBC), red blood cell (RBC), and platelets (PLT) counts, were analyzed by standard methods. ESR and hs-CRP
2.5. Statistical analysis
3. Results 3.1. Participant characteristics The clinical characteristics of 156 patients with TA and 156 healthy controls are shown in Table 1 and Table 2. The mean age of patients with TA was 40.0 ± 13.3 y and 86.5% were female. There were 69 patients (44.2%) in the active phase of the disease and anemia was observed in 55 patients (35.3%) at the outset of the study. Based on the classification criteria, 39.7% had type III TA, while 31.4%, 16.7%, and 10.3% had types I, II, and IV, respectively. One hundred and twelve patients (71.8%) received prednisone therapy, and the mean daily dosage was 20.0 ± 10.2 mg. 3.2. RDW and anemia status RDW values were significantly higher in patients with anemia (a-TA) (14.6 ± 2.2) and patients without anemia (na-TA) (13.6 ± 1.3)
Table 1 Demographic and clinical characteristics of 55 patients with anemia, 101 patients without anemia and 156 healthy controls.
Age, yrs Female, n (%) BMI, kg/m2 Disease duration, y Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) WBC counts, ×109/l RBC counts, ×1012/l Hemoglobin, g/l MCV, fl PLT, ×109/l RDW, % Creatine, umol/l ESR, mm/h Hs-CRP, mg/l Clinical classification, n (%) No vascular impairment Type I Type II Type III Type IV Prednisone, n (%) Daily prednisone dose, mg
All TA (N = 156)
a-TA (N = 55)
na-TA (N = 101)
Controls (N = 156)
P value
40.0 ± 13.3 135 (86.5%) 23.1 ± 3.3 10.3 ± 10.3 90 (57.7%) 9 (5.8%) 44 (28.2%) 7.9 ± 2.8 4.4 ± 0.6 129.0 ± 21.2 87.6 ± 7.2 232.7 ± 86.0 14.0 ± 1.7 66.2 ± 18.8 16.7 ± 18.0 5.0 ± 4.7
37.8 ± 13.1 51 (92.7%) 23.5 ± 3.2 8.5 ± 9.3 33 (60.0%) 2 (3.6%) 14 (25.5%) 7.6 ± 2.6 ⁎ 4.0 ± 0.4 ⁎,⁎⁎
41.2 ± 13.2 84 (83.2%) 23.0 ± 3.4 11.3 ± 10.7 57 (56.4%) 7 (6.9%) 30 (29.7%) 8.1 ± 3.0 ⁎
107.6 ± 11.2 ⁎,⁎⁎ 84.0 ± 8.7 ⁎,⁎⁎ 257.4 ± 97.5 ⁎,⁎⁎ 14.6 ± 2.2 ⁎,⁎⁎
4.7 ± 0.5 140.7 ± 15.4 89.6 ± 5.4 219.3 ± 76.2 13.6 ± 1.3 ⁎
65.6 ± 21.9 23.9 ± 21.3 ⁎⁎ 5.9 ± 5.4 ⁎
66.6 ± 16.9 12.7 ± 14.7 4.5 ± 4.2 ⁎
40.2 ± 7.2 135 (86.5%) 23.1 ± 1.7 – – – – 5.9 ± 1.5 4.6 ± 0.4 138.9 ± 11.6 90.1 ± 3.7 231.9 ± 44.8 12.7 ± 0.6 64.3 ± 10.6 – 1.1 ± 0.9
NS NS NS NS NS NS NS b0.001 b0.001 b0.001 b0.001 0.004 b0.001 NS b0.001 b0.001 NS
3 (1.9%) 49 (31.4%) 26 (16.7%) 62 (39.7%) 16 (10.3%) 112 (71.8%) 20.0 ± 10.2
1 (1.8%) 18 (32.7%) 10 (18.2%) 25 (45.5%) 1 (1.8%) 42 (76.4%) 20.8 ± 10.6
2 (2.0%) 31 (30.7%) 16 (15.8%) 37 (36.6%) 15 (14.9%) 70 (69.3%) 19.5 ± 10.0
– – – – – – –
NS NS
Data are presented as mean ± standard deviation or as number (percentage). TA: Takayasu arteritis; a-TA: TA with anemia; na-TA: TA without anemia; BMI: body mass index; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; PLT: platelets; RDW: red blood cell distribution width; ESR: erythrocyte sedimentation rate; Hs-CRP, high-sensitivity C-reactive protein. ⁎ p b 0.05 vs controls. ⁎⁎ p b 0.05 vs inactive TA.
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Table 2 Demographic and clinical characteristics of 69 patients with active disease, 87 patients in remission and 156 healthy controls.
Age, yrs Female, n (%) BMI, kg/m2 Disease duration, y Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) WBC counts, ×109/l RBC counts, ×1012/l Hemoglobin, g/l MCV, fl PLT, ×109/l RDW, % Creatine, umol/l ESR, mm/h Hs-CRP, mg/l Clinical classification, n (%) No vascular impairment Type I Type II Type III Type IV Prednisone, n (%) Daily prednisone dose, mg
All TA (N = 156)
Active TA (N = 69)
Inactive TA (N = 87)
Controls (N = 156)
P value
40.0 ± 13.3 135 (86.5%) 23.1 ± 3.3 10.3 ± 10.3 90 (57.7%) 9 (5.8%) 44 (28.2%) 7.9 ± 2.8 4.4 ± 0.6 129.0 ± 21.2 87.6 ± 7.2 232.7 ± 86.0 14.0 ± 1.7 66.2 ± 18.8 16.7 ± 18.0 5.0 ± 4.7
40.2 ± 13.7 61 (88.4%) 23.1 ± 3.5 9.0 ± 9.4 42 (60.9%) 4 (5.8%) 25 (36.2%) ⁎⁎ 8.5 ± 3.0 ⁎,⁎⁎ 4.5 ± 0.7 ⁎
39.8 ± 13.0 74 (85.1%) 23.2 ± 3.2 11.3 ± 10.9 48 (55.2%) 5 (5.7%) 19 (21.8%) 7.5 ± 2.6 ⁎ 4.4 ± 0.5 ⁎
63.6 ± 13.9 7.7 ± 4.3 2.1 ± 2.0 ⁎
40.2 ± 7.2 135 (86.5%) 23.1 ± 1.7 – – – – 5.9 ± 1.5 4.6 ± 0.4 138.9 ± 11.6 90.1 ± 3.7 231.9 ± 44.8 12.7 ± 0.6 64.3 ± 10.6 – 1.1 ± 0.9
NS NS NS NS NS NS 0.047 b0.001 0.002 b0.001 b0.001 NS b0.001 NS b0.001 b0.001 NS
3 (1.9%) 49 (31.4%) 26 (16.7%) 62 (39.7%) 16 (10.3%) 112 (71.8%) 20.0 ± 10.2
1 (1.4%) 22 (31.9%) 12 (17.4%) 26 (37.7%) 8 (11.6%) 56 (81.2%) ⁎⁎ 27.0 ± 8.9 ⁎⁎
2 (2.3%) 27 (31.0%) 14 (16.1%) 36 (41.4%) 8 (9.2%) 56 (64.4%) 13.1 ± 5.9
– – – – – – –
126.9 ± 24.5 ⁎ 86.4 ± 8.0 ⁎,⁎⁎ 239.7 ± 100.3 14.5 ± 1.8 ⁎,⁎⁎ 69.5 ± 23.2 28.0 ± 22.0 ⁎⁎ 8.6 ± 4.6 ⁎,⁎⁎
130.6 ± 18.0 ⁎ 88.6 ± 6.5 227.2 ± 72.9 13.6 ± 1.6 ⁎
0.021 b0.001
Data are presented as mean ± standard deviation or as number (percentage). TA: Takayasu arteritis; BMI: body mass index; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; PLT: platelets; RDW: red blood cell distribution width; ESR: erythrocyte sedimentation rate; Hs-CRP, high-sensitivity C-reactive protein. ⁎ p b 0.05 vs controls. ⁎⁎ p b 0.05 vs inactive TA.
than those in the control subjects (12.8 ± 0.6, both p b 0.001; Fig. 1). There was also significant difference in RDW values between a-TA and na-TA (p b 0.001, Fig. 1). Inflammatory marker ESR was significantly higher in a-TA than those in na-TA (23.9 ± 21.3 vs. 12.7 ± 14.7 mm/h, p b 0.001), but not hs-CRP (5.9 ± 5.4 vs. 4.5 ± 4.2 mg/l, p = 0.439; Table 1). Hematological parameters, such as hemoglobin, MCV and RBC counts were significantly lower, while PLT counts were significantly higher in a-TA than those in na-TA and controls (Table 1). WBC counts were increased in both TA groups compared with controls (Table 1). RDW was significantly negative correlated with hemoglobin and MCV in a-TA (hemoglobin, ρ = − 0.593, p b 0.001; MCV, ρ = − 0.559, p b 0.001), but not in na-TA (hemoglobin, ρ = 0.169, p = 0.092; MCV, ρ = −0.096, p = 0.338).
p b 0.001), and the values in both of the TA groups were higher than those in the control subjects (12.8 ± 0.6, both p b 0.001; Fig. 2). Inflammation parameters, including ESR and hs-CRP, were significantly higher in patients with active TA than those in remission (Table 2). Hematological parameters hemoglobin and RBC counts were significantly lower, while WBC counts were significantly higher in both TA groups than controls (Table 2). MCV was found to be lower in active TA than those in inactive TA and controls (Table 2). However, when patients were divided into two groups by anemia status, RDW values were significantly higher in patients with active disease than those in inactive patients in na-TA (14.1 ± 1.5 vs. 13.3 ± 1.1, p = 0.001), but not in a-TA (14.9 ± 2.1 vs. 14.3 ± 2.2, p = 0.362). 3.4. RDW and TA classification
3.3. RDW and TA activity RDW values were significantly increased in patients with active TA (14.5 ± 1.8) compared with those in inactive patients (13.6 ± 1.6,
Fig. 1. RDW values were significantly higher in patients with anemia (a-TA) compared with those without anemia (na-TA) and healthy controls. There was also significant difference between na-TA and controls. *p b 0.001 vs na-TA and controls. #p b 0.001 vs controls.
Considering the extent of arterial involvement, no significant differences regarding RDW values were found in TA patients with Type I (14.1 ± 1.9), Type II (13.8 ± 1.3), Type III (13.8 ± 1.5), and type IV (14.2 ± 1.8, p = 0.584; Fig. 3).
Fig. 2. RDW values were significantly higher in active TA compared with those in inactive TA and healthy controls. There was also significant difference between inactive TA and controls. *p b 0.001 vs inactive TA and controls. #p b 0.001 vs controls.
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Fig. 3. There was no significant difference regarding RDW values among patients with Type I, Type II, Type III, and type IV TA.
3.5. RDW and inflammatory markers of TA Regardless of the presence of anemia, RDW showed correlation with hs-CRP (ρ = 0.325, p = 0.015 in a-TA; ρ = 0.317, p = 0.001 in na-TA), but no correlation with ESR was found either in a-TA (ρ = 0.199, p = 0.145) or in na-TA (ρ = 0.036, p = 0.719). The results of multiple linear regression analysis showed that hs-CRP (standardized beta coefficient = 0.175, p = 0.04) and MCV (standardized beta coefficient = −0.377, p b 0.001) were independently associated with RDW in patients with TA after adjusting for age, sex, BMI, disease duration, hemoglobin, serum creatinine, ESR and the usage of prednisone (Table 3). 4. Discussion Patients with active disease showed significantly higher RDW values than those in remission in na-TA. Moreover, inflammatory marker hs-CRP, but not ESR, was independently associated with RDW in TA. Anemia is a common condition in chronic disease, which is known to be of great importance in RDW values [21]. As described in patients with SLE [16], our results found that RDW values were increased in a-TA compared with those in na-TA and control subjects. RDW was also negatively correlated with hemoglobin and MCV in patients with TA. These results indicated that RDW was associated with anemia in TA. However, our results also showed that RDW values were higher in na-TA than those in control subjects, which was consistent with previous findings in other systemic inflammatory diseases [16–19]. These results indicated that apart from anemia, RDW may also be associated with inflammation. As expected, hs-CRP levels were increased in
Table 3 Independent predictors of red cell distribution width by multivariate linear regression analysis.
Age Sex BMI Disease duration Hemoglobin MCV Creatinine Log (ESR) Log (hs-CRP) Prednisone
Standardized β
95% Confidence Interval
P value
0.019 0.109 −0.095 −0.065 −0.099 −0.377 0.035 −0.039 0.175 0.064
−0.175–0.213 −0.063–0.280 −0.243–0.054 −0.247–0.116 −0.298–0.100 −(0.555–0.200) −0.123–0.194 −0.227–0.149 0.008–0.342 −0.088–0.215
NS NS NS NS NS b0.001 NS NS 0.040 NS
BMI: body mass index; MCV: mean corpuscular volume; ESR: erythrocyte sedimentation rate; hs-CRP, high-sensitivity C-reactive protein.
both TA groups when compared with those in controls. Hs-CRP was also positively correlated with RDW in patients with TA. The exact mechanisms of the relationship between RDW and inflammation remain unclear. As a chronic inflammatory disease, TA manifests as an imbalance between pro- and anti-inflammatory cytokines [27–30]. It is estimated that these pro-inflammatory cytokines may induce changes in iron metabolism, the production of erythropoietin, the proliferation of erythroid progenitor cells, and the life span of erythrocytes, which may contribute to increased RDW values [21]. By these pathways, inflammation may lead to anisocytosis from release of juvenile red blood cells into the peripheral circulation [5,6,21]. Considering the impact of anemia on RDW, TA cases were divided into anemic and non-anemic groups. We found that regardless of the presence of anemia, RDW showed significant correlation with hs-CRP, but not ESR, which was in agreement with the findings in patients with RA [15]. The results of multivariate analysis also showed that hs-CRP, but not ESR, was independently associated with RDW in patients with TA. However, RDW was found to be associated with both hs-CRP and ESR in a large cohort of unselected outpatients [14] as well as in patients with SLE [17] and IBD [19]. This discrepancy may be explained by the effect of anemia on ESR, different patient cohorts and treatment measures in various studies. The association between RDW and ESR may be mediated by anemia in patients with TA. As described in SLE [17] and IBD [18,19], we also investigated whether RDW could be a potential index to evaluate disease activity in patients with TA. We found that among all patients with TA, RDW values were higher in patients with active disease than those in remission. This phenomenon was also present in non-anemic group, but absent in anemic group. Moreover, RDW was strongly associated with hemoglobin and MCV in a-TA, but not in na-TA. These results suggested that the influence of anemia on RDW was stronger in a-TA, and RDW may be a useful marker to assess disease activity only in na-TA. Several limitations should be considered in this study. First, since our study is cross-sectional, it is difficult to establish a causal relationship between RDW and TA. Further prospective studies are needed to investigate whether RDW can provide prognostic information of TA. Second, the sample size is relatively small for the comparison of active to inactive TA among anemic patients, and the insignificance between the two groups may be a lack of statistical power. However, this reflects the rarity of TA, especially for anemia cases. Third, data on the levels of serum iron, folic acid or vitamin B 12 which may affect RDW values were not available. These parameters were measured only in patients with clinical indication in our study. In conclusion, the present study has demonstrated that RDW is influenced by both anemia and inflammation in patients with TA. RDW is a newly recognized and useful marker for disease activity assessment in patients without anemia. The exact biological mechanisms underlying this association merit investigation. As RDW is routinely measured by automated blood cell analyzers with no additional cost, future prospective studies with larger samples are needed to validate the clinical value of RDW in patients with TA. Abbreviations IBD Inflammatory bowel disease TA Takayasu arteritis a-TA Takayasu arteritis patients with anemia na-TA Takayasu arteritis patients without anemia
Acknowledgments This work was supported by the National Natural Science Foundation of China (grant no. 81170285) and the Research Fund for the Doctoral Program of Higher Education of China (grant no. 20101106110012).
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