Serum RDW and MPV in Ankylosing Spondylitis: Can they show the disease activity?

Abstract

OBJECTIVE: To determine RDW and MPV levels in Ankylosing Spondylitis (AS) and to investigate their relations with disease activity.

MATERIALS AND METHODS: 133 patients with AS (male: 80, female: 53) and age-sex matched 133 controls (male: 79, female: 54) were enrolled. Demographic data, disease activity scores, Complete Blood Count (CBC), Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) levels were recorded.

RESULTS: The mean ages of patients and controls were 41.9±11.2 and 39.7±14.2 years respectively (p = 0.16). RDW (14.5±1.6% and 13.2±0.8%, p < 0.0001 respectively) and MPV (10.1±0.8fl and 9.9±0.7fl, p = 0.03, respectively) were significantly higher in patients with AS than in controls. There was a significant difference in RDW between patients with active AS (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >4) and those with inactive AS (BASDI <4) patients (14.84±1.79fl, 14.24±1.37fl, p = 0.035 respectively). RDW was positively correlated with BASDAI (r = 0.33, P < 0.0001), ESR (r = 0.45, P < 0.0001) and CRP (r = 0.42, P < 0.0001) and PLT levels (r = 0.24, P = 0.004). While MPV was not correlated with BASDAI, it was negatively correlated with ESR (r = –0.19, P = 0.03), CPR (r = –0.26, P = 0.004) and PLT levels (r = –0.39, P = <0.0001).

CONCLUSIONS: RDW and MPV were significantly higher in the patients with AS than in the controls. While RDW was correlated with BASDAI and APRs, MPV was only correlated with APRs.

Keywords

Ankylosing Spondylitis Red Cell Distrubution Width Mean Platelet Volume BASDAI

1 Introduction

Red Blood Cell Distribution Width (RDW) and Mean Platelet Volume (MPV) are two parameters of Complete Blood Count (CBC) analysis which are usually overlooked by clinicians [4, 21]. RDW is routinely used to describe the heterogeneity of red blood cells (i.e., anysocytosis) and to differentiate between thalassemia, megaloblastic anemia and iron deficiency anemia [7]. It has been reported in the literature that RDW is associated with the onset of cardiovascular diseases and their prognosis. This relation is independent of multiple confounding factors such as anemia, nutritional factors, hemoglobin A1c, and renal functions. It has been observed that CRP levels increase linearly with greater RDW quartiles [17, 30]. In fact, RDW has been shown to be strongly associated with CRP and ESR in a large cohort of unselected outpatients [15].

In addition, recent studies have shown that RDW is associated with the severity of Rheumatoid Arthritis (RA) [14], Inflammatory Bowel Disease (IBDs) [5, 22] and Behçet’s Disease (BD) [1]. Two new studies have also determined that RDW is increased in patients with Systemic Lupus Erythematosus (SLE) and related with SLE Disease Activity Index (SLEDAI), ESR and CRP [10, 26].

MPV is a machine-calculated measurement of the average size of platelets. It reflects the platelet size and the rate of platelet production in bone marrow, and it may be used as an indicator of platelet activation and severity of inflammation [3 , 24]. In recent years, it has been shown that increased platelet size, as a result of platelet activation, is associated with numerous inflammatory diseases such as RA and AS [13], Familial Mediterranean Fever (FMF) [20], juvenile SLE [28], systemic sclerosis (SS) [23] and IBDs [18].

As two novel indices for inflammation, RDW and MPV may be also useful to estimate the disease activity in AS. In one study, an association between MPV and disease activity has been demonstrated in patients with AS. However, the relation between RDW and disease activity indices and Acute Phase Reactans (APRs) in AS has not been investigated [13].

In this study, our aims were to analyze serum RDW and MPV in patients with AS patients and to evaluate their relationships with AFRs and disease activity index.

2 Methods

This study has a retrospective and case-control design. Data about 150 patients with AS and 150 controls obtained from the electronic database of Mersin University Hospital were retrospectively reviewed. The population of this study included the patients admitted to Physical Medicine and Rehabilitation outpatient clinic of Mersin University Hospital between January 2010 and January 2013. One hundred and thirty three patients with AS (male to female ratio: 80/53, mean age: 41.9±11.2) and sex and age matched 133 controls (male to female ratio: 79/54, mean age: 39.7±14.2), treated for mechanical pain (low back pain, neck pain, etc), were included into the study sample. All AS patients fulfilled the 1987 Modified New York criteria for AS [25]. Patients treated with only non steroidal anti inflammatory drugs were included. Patients and controls with one of the following combined diseases/situations were excluded: 1) other autoimmune diseases such as Sjogren Syndrome (SS), SLE, RA, IBDs and psoriasis; 2) acute or chronic infection; 3) malignant diseases; 4) end stage renal disease; 5) liver disease such as hepatitis and liver cirrhosis, 6) hematological disorders or received blood transfusion during the past 4 months, 7) acute myocardial infarction, hypertension, diabetes mellitus, cerebrovascular disease, 8) pregnancy or postpartum 6 months, 9) body mass index >30, 10) active smoker. All patients were received only non-steroid anti inflammatory drugs.

Laboratory test results of both groups and examination findings of patients with AS were gathered from medical records of the patients. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to evaluate disease activity [8].

CBC, ESR and CRP levels were measured with XT2000-i sysmex, Japan, Test-1 TH Alifax, Italy and Cobas integra 800 Roche, Germany, respectively.

The study protocol was approved by the Local Research Ethics Committee of Mersin University. The study was conducted according to the Declaration of Helsinki.

2.1 Statistical methods

Propensity scores were used to match groups by age and sex. Student-t and ANOVA tests were used to compare the means of the groups. Pearson correlation coefficient and Spearman correlation coefficient were used to evaluate the linear relationship between predictive variables. Sensitivity, specificity and cut-off values were determined by using Receiver Operating Characteristic (ROC) curves and diagrams. Chi-square tests were used to compare categorical data. MedCalc 13.0 was used to perform statistical tests and to create graphs.

3 Results

Mean ages of 133 patients (male: 80; female: 53) and 133 controls (male: 79; female: 54) were 41.9±11.2 years and 39.7±14.2 years respectively (p = 0.16). Clinical characteristics of patients with AS were summarized in Table 1. RDW and MPV were significantly higher in the patients with AS (14.5±1.6%, 10.1±0.8 fl, respectively) than in the controls groups (13.2±0.8%, p < 0.0001 and 9.9±0.7 fl, p = 0.03, respectively). On the contrary, hemoglobin levels were significantly lower in the patients than in the controls (p < 0.0001, Table 2).

The cut-off value of RDW was 14.8% (sensitivity 43.6%, specificity 97.7%, AUC: 0.76, 95% CI: 0.708 to 0.814, P < 0.0001, Figs. 1–2) and the cut-off value of MPV was 10.4 fl (sensitivity 35.9%, specificity 85%, AUC: 0.58, 95% CI: 0.521 to 0.647, P = 0.01, Figs. 3–4).

BASDAI (4.6±2.1, 3.1±2.1, P < 0.0001, respectively), ESR (25.8±18.0 mm/h, 10.7±8.8 mm/h, P < 0.0001, respectively), CRP (19.2±15.7 mg/L, 6.9±10.6 mg/L, P < 0.0001, respectively) and PLT levels (308.5±74.3×10.e3/u, 275.8±55.6×10.e3/u, P = 0.006 respectively) were significantly higher in the AS patients with RDW >14.8% than in those with RDV <14.8% (Table 3). There was a significant difference in RDW between the patients with inactive AS and those with active AS (14.24±1.37%, 14.84±1.79%, p = 0.035 respectively, Table 4). However, RDW was positively correlated with BASDAI (r = 0.33, P < 0.0001), ESR (r = 0.45, P < 0.0001), CRP (r = 0.42 and P < 0.0001) and PLT levels (r = 0,24 and P = 0,004).

There was not a significant difference in terms of BASDAI between patients with MPV higher than 10.4 fl and those with MPV lower than 10.4 fl. In AS patients with MPV >10.4 fl compared to those with MPV <10.4 fl, CRP (7.3±6.7 mg/L, 13.6±15.6 mg/L, P = 0.003, respectively), and PLT levels (271.3±54.8×10.e3/u, 300.1±67.3×10.e3/u, P = 0.01, respectively) were significantly lower (Table 5). MPV was negatively correlated with ESR (r = –0.19, P = 0.03), CPR (r = –0.26, P = 0.004), and PLT (r = –0.39, P = <0.0001), but it was not correlated with BASDAI.

4 Discussion

In this study, serum RDW and MPV in the AS patients and their correlations with disease activity index (BASDAI) and APRs (CRP, ESR) were investigated. RDW was significantly higher in both the patients with active AS and those with inactive AS than in the controls. The cut-off value of RDW was 14.8% (sensitivity 43.6%, specificity 97.7%, [AUC]: 0.76, p < 0.0001) and RDW was higher than 14.8% in the patients with active AS. Moreover, RDW was positively correlated with BASDAI, ESR, CRP and PLT.

Lippi et al. [15] conducted a large-scale cohort study on 3,845 subjects and investigated the correlation of RDW with ESR and CRP. They concluded that RDW increased during inflammation as well as other inflammatory parameters like ESR and CRP.

This association between RDW and inflammatory markers has been shown in other studies on inflammatory diseases. Lee and Kim [14] investigated the potential correlation of RDW with ESR and CRP in RA and they found a correlation between RDW and CRP in both anemic patients and nonanemic ones. RDW was significantly higher in the patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC) than in the controls. RDW was the most sensitive and specific marker for active CD, but not for for UC. They concluded that increased RDW could be used as an early indicator of active disease in IBDs [5, 22].

Consistent with the results of the present study, Akgül et al. [1] showed that RDW was significantly higher in patients with active BD and those with inactive BD than in the controls and was positively correlated with ESR (r = 0.368, P < 0.0001), CRP (r = 0.330, P < 0.0001) and disease duration (r = 0.320, P = 0.001). Also, RDW significantly increased in SLE patients as compared to healthy individuals and was positively correlated with CRP, ESR, and SLE Disease Activity Index (SLEDAI-2-K). The authors suggested that RDW could be useful to evaluate the disease activity of SLE patients with accompanying infection based on the evidence from the literature that the lifespan of red blood cell is approximately 130 days and that RDW may not be affected by recently infectious events[10, 26].

In the light of all these results, chronic inflammation can adversely influence erythropoiesis by a variety of mechanisms, including direct myelosuppression of erythroid precursors, reducing renal erythropoietin production and the bioavailability of iron, increasing erythropoietin resistance in erythroid precursor cell lines, and by promoting cell apoptosis Thus, inflammation can lead to anisocytosis from secretion of immature red blood cells into the peripheral circulation [17]. Exposure to oxidative stress might be another potential contributing pathobiologic mechanism. High oxidative stress can also cause anisocytosis by reducing red blood cell survival; thereby, premature red blood cells are released into the peripheral circulation [30]. In the present study, higher RDW might be predictive of a high level of oxidative stress and/or a potential cardiovascular event in addition to chronic inflammation in the AS patients. However, the relationship between RDW and cardiovascular disease risk in patients with AS was not investigated in the current study. Therefore, new prospective studies are needed to investigate this issue.

Wang F et al. showed that platelet count as well as ESR and CRP were higher in AS patients than in normal controls. They concluded that high expression of PLT in AS patients does not only indicate platelet activation but also can be a symbol of inflammation [27]. Similarly, the present study showed that PLT levels in addition to ESH and CRP were significantly higher in the patients with AS than in the controls groups.

MPV is a parameter generated by routine complete blood count test, which is usually overlooked by clinicians. It is another platelet function index and reflects the platelet production rate and stimulation [4, 21]. Increased MPV shows larger platelet volume. It is known that large platelets are more active in releasing a variety of pro-inflammatory and thrombotic agents than smaller size platelets. They increase during acute inflammation [19].

In the present study, MPV was higher in the AS patients than in the controls. The cut-off value of MPV was 10.4 fL (sensitivity 35.9%, specificity 85%, [AUC] 0.58, P = 0.016) for AS activation. However, MPV was inversely related to ESR, CRP and PLT levels. Therefore, as APRs increased, MPV decreased. However, MPV was not correlated with BASDAI. Compatible with the present study, Gasparyan et al. [9] retrospectively evaluated the laboratory parameters, including MPV and PLT in 400 RA patients and in 360 healthy controls. They reported that PLT levels and MPV were higher in the RA patients than in the controls. Coban et al. [6] identified significantly high MPV in patients with FMF and suggested a link between inflammation, platelet activation and prothrombotic state. Yavuz et al. [28] detected significantly higher MPV in juvenile SLE. It was positively correlated with SLEDAI, ESR and CRP and negatively correlated with albumin and Hb. They showed that MPV was 8.4 fL as predictive cut-off value of SLE activation. It was lower than the one found in the present study. In fact, the cut-off value of MPV was found to be 10.4 fL for AS activation in this study.

Karabudak et al. [12] found that MPV was significantly higher in psoriatic patients than in controls and positively correlated with PASI scores. Also, a recent study showed that MPV was significantly elevated in Systemic Sclerosis (SSc) and related to cardiac involvement and digital ulcers. Moreover, a significantly negative correlation was detected between MPV and Valentini score and Disease Severity Index [23]. It may be related to vascular pathology in SSc, and MPV as a negative acute phase reactant would be a predictive marker in the early diagnosis of macrovascular (cardiovascular) and microvascular (digital ulcers) involvement of SSc.

In contrast to results of the abovementioned studies, some studies showed that MPV was lower in active IBDs, RA and AS [11 , 29]. This decrease in MPV may result from the selective consumption of larger platelets as a result of increased hemostatic demand. Balta et al. reported that low-grade inflammatory conditions were associated with high MPV and high-grade inflammatory diseases were associated with low MPV. Overproduction of pro-inflammatory cytokines and acute-phase reactants can suppress the size of platelets by interfering megakaryopoiesis and subsequently small size platelets release from the bone marrow [2].

Kapsoritakis et al. [11] showed that MPV significantly decreased in IBDs, which was well correlated with the extent of the disease. Kisacik et al. [13] found that MPV was significantly lower in both AS patients and RA patients with active disease as compared to controls. After treatment, MPV values significantly increased in AS and RA. There was a negative correlation between MPV values and BASDAI scores of AS patients after two months of treatment modification. Unlike the above study, the present study did not reveal a correlation between MPV and BASDAI score. However, MPV was negatively associated with AFRs. This can be attributed to the fact that BASDAI is a more subjective measurement method and that APRs are a more objective measurement method.

There are some limitations of the present study: Firstly, it has a retrospective design. The data were obtained from only a single center through the electronic database of the hospital; therefore, patient selection bias was not completely avoided. Secondly, no information regarding the nutritional status or serum folic acid, iron or vitamin B12 levels could be accessed. Deficiency of these vitamins and/or minerals may result in anemia, which may affect RDW.

5 Conclusion

Based on the results of the current study, it can be suggested that assessment of RDW and MPV in AS may provide additional information about inflammation and RDW and that MPV might be a potential index to evaluate disease activity of AS. These parameters can be considered as appropriate, confirmatory tests for CRP and ESR. Hemogram is a routine test for diagnosis and follow up of rheumatic disease. MPV and RDW are part of hemogram and they do not cause additional costs. However, new prospective studies including larger study groups are required to verify the findings of the present study.

Conflict of interest

The authors declare that they have no conflict of interest.

Compliance with ethical standards

We have not received any support or payment for this research from a company.

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