Neutrophil to lymphocyte ratio in Behcet's disease as a marker of disease activity.
Behget's disease (BD) is a systemic autoimmune disease. Recurrent oral and genital mucosal ulcers, uveitis, and skin lesions are characteristic findings for BD (1). Histopathological features of BD lesions include perivascular lymphocytes, monocyte and neutrophil infiltration, and surrounding tissue necrosis (2). However the diagnosis of BD is made with clinical findings. The diagnostic criteria of the International Study Group for Behget's Disease include the presence of oral ulceration plus any two of the following: genital ulceration, typical defined eye lesions, typical defined skin lesions, or a positive pathergy test (3).
Recently, the neutrophil to lymphocyte ratio (NLR) has been widely used to determine the severity of inflammation in cardiovascular disease, malignancies, diabetes mellitus, hypertension, and autoinflammatory diseases (5-9). It is well known that neutrophil chemotaxis problems have been shown in BD (10). The NLR has not been previously studied in patients with BD. Therefore, the current study investigated the relation between the NLR and BD.
Sixty-five patients with BD and 100 healthy subjects that visited the outpatient dermatology clinic between May 2010 and June 2013 were enrolled in the study retrospectively. BD was diagnosed according to the criteria reported by the International Study Group for Behget's Disease (3). The patients' ages, duration of the disease, family history, presence of oral ulcers, genital ulcers, erythema nodosum, acneiform eruptions, epididymitis, arthralgia and arthritis, and vascular, pulmonary, gastrointestinal, neurological, and ophthalmic involvement were recorded. The patients included in the active group had two of the following clinical findings: oral ulcers, genital ulceration, pathergy test positivity, active uveitis, papulopustular or pseudofollicular cutaneous lesions, neurological involvement, and arthritis (10).
A complete blood count and CRP were obtained from the patients with BD and the controls. The complete blood count was measured with a laser-based flow cytometric impedance device (Mindray BC-6800, Nanshan, Shenzhen, China 2012), and the CRP was measured with a Beckman Coulter Immage nephelometry device. The white blood cell (WBC), neutrophil, and lymphocyte counts were also recorded, and the NLR was calculated from these parameters (4). The reference values for the CRP, WBCs, neutrophils, and lymphocytes in the hematology laboratory were 0-0.8 mg/ dl, 4.6-10.2 x 103/[micro]l, 2-6.9 x 103/[micro]l, and 0.6-3.4 x 103/[micro]l, respectively.
All statistical analyses were performed with SPSS version 19 software (IBM SPSS Statistics 19). Data were expressed as mean [+ or -] standard deviation. The Kolmogorov-Smirnov test was used to assess the normality of the groups. Comparisons between the groups with the nonparametric test were done using the Mann-Whitney U-test because the groups were not distributed normally. A chi square test was used for the categorical variable. A p value of 0.05 was considered significant.
Thirty-eight (58.5%) men and 27 (41.5%) women (n = 65) with BD and 56 (56%) men and 44 (44%) women without BD (n = 100) were included in the study (p > 0.05). The mean age of the patients with BD and the controls was 37.7 [+ or -] 12.3 and 38.8 [+ or -] 11.3 years, respectively (p = 0.57). Thirty-eight (58.5%) patients were active and 27 (41.5%) patients were inactive with regard to clinical finding of BD at the time of admission. The mean duration of BD was 7.4 [+ or -] 1 years. The clinical features of the patients are given in Table 1. Nine patients had a family history of BD. The NLR of the patients with BD and controls were 2.5 [+ or -] 1.5 and 1.7 [+ or -] 0.8, respectively (p < 0.001). Moreover, the CRP and WBC levels were higher in the BD group than controls (p < 0.001 and p = 0.026, respectively; Table 2) The NLR was higher in the active BD group than the inactive BD group (p = 0.033, Table 3). The NLR was also correlated with the levels of CRP and WBCs, both of which are major inflammation markers (p < 0.001 and p = 0.043, respectively).
The main finding of our study relates to identification of the NLR as a novel non-invasive marker of disease activity in patients with BD. Our results demonstrate that the NLR is higher in patients with active BD compared to controls and BD patients in remission. High NLR levels in the sera of active BD patients, compared to inactive BD and controls, support the view that neutrophils play a role in the inflammatory cascade of BD and disease pathophysiology.
BD is an inflammatory disease, characterized by the activation of innate and adaptive immunity (interaction of T lymphocytes and activated neutrophils) on the basis of genetic (HLA B 51) and infectious factors (Streptococcus sanguinis). This inflammation results in tissue damage in the organs affected (11). Innate immune system dysfunction such as neutrophil hyperactivity is the major pathogenetic factor in BD (12). The role of neutrophils in the pathogenesis of BD has been investigated in many studies (3, 13). Neutrophils are directly involved in specific lesions of BD. BD lesions show venous and arterial infiltrates of neutrophils in histopathological analysis (14). Due to these characteristics, BD is considered a neutrophilic inflammatory disease.
BD could lead to varying degrees of dysfunction, depending on the severity of the disease and the affected organ (1). Although many cytokines and biomarkers have been studied as indicators of activation in BD, there is no method available to predict the severity and activity of BD (15, 16). In a study by Aygunduz et al., serum amyloid A protein and serum beta 2 microglobulin levels were associated with disease activity (15). Sari et al. reported that E-selectin levels were higher in an active BD group compared to controls and inactive BD (16). In another study, the serum endocan levels were higher in patients with active BD (17). Although these biomarkers are effective indicators for disease activity, the biomarkers were not routinely measured due to cost-effectiveness. The use of the NLR in autoimmune diseases was recently reported in some studies. Ahsen et al. reported that NLR levels were higher in patients with familial Mediterranean fever than in controls (7). Celikbilek et al. found a higher NLR in patients with ulcerative colitis compared to controls (8). In addition, in another study, the NLR was found to be higher in patients with psoriasis than controls (18). In this study, we found a higher NLR in patients with BD compared to controls. To our knowledge, this is the first study indicating a higher NLR in BD.
On the other hand, in several chronic inflammatory diseases the NLR has been associated with disease activity. In a study by Torun et al., the NLR indicated the disease activity of ulcerative colitis. It was found that the NLR predicted disease activity in patients with ulcerative colitis with 81.8% sensitivity and 80.5% specificity (19). Celikbilek et al. showed that the NLR was significantly higher in active ulcerative colitis patients compared to inactive patient and controls (8). In this study, NLR elevation was found in active patients with BD compared to inactive patients and controls. We suggest that the NLR may be used as a routine test for BD activity because the NLR is an inexpensive and readily available test.
C-reactive protein (CRP), a major component of inflammatory reaction, is a plasma protein secreted by the liver. CRP can rapidly increase in inflammation, infection, and tissue injury as an acute-phase marker (20). CRP has been shown to increase during the active period of neutrophilic autoimmune diseases such as pyoderma gangrenosum and ulcerative colitis (21, 22). It was previously well demonstrated that CRP was higher during active disease in BD (23). In this study, elevated CRP levels were found in the active BD group compared to the inactive group and controls. In many studies, the NLR-which is an easily calculated and inexpensive routine laboratory test-shows inflammation and active disease to be correlated with CRP (7, 8). In particular, it has been shown that NLR levels are higher in the active BD group than inactive BD group and control in correlation with CRP.
In summary, our study demonstrates that the NLR is statistically higher in active BD. Unlike many other noninvasive markers of BD, the NLR is inexpensive and readily available.
Received: 13 August 2014 | Returned for modification: 28 September 2014 | Accepted: 2 October 2014
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Emine Nur Rifaioglu  [mail], Bilge Bulbul Sen , Ozlem Ekiz , Asena Cigdem Dogramaci 
 Department of Dermatology, Mustafa Kemal University School of Medicine, Hatay, Turkey. [mail] Corresponding author: email@example.com
Table 1 | Clinical findings of BD. Clinical findings of BD * Patients (n = 65) (%) Oral ulcer 65 100 Genital ulcer 58 89 Pathergy 14 22 Erythema nodosum 22 34 Acneiform lesion 22 34 Arthritis 9 14 Deep vein thrombosis 5 7.7 Thrombophlebitis 4 6.2 Ophthalmic involvement 11 17 Gastrointestinal involvement 4 0.6 Pulmonary involvement 1 0.2 Neurologic involvement 7 10.8 Epididymitis 1 0.2 * BD = Behfet's disease Table 2 | Demographic features of patients and controls and comparison of inflammation markers between control and BD groups (mean [+ or -] SD). Variables BD * (n = 65) Control (n = 100) p Age 37.7 [+ or -] 12.3 38.8 [+ or -] 11.3 0.57 Gender (M/F) 38/27 56/44 > 0.05 WBC ([dagger]) 8.68 [+ or -] 2.50 8.09 [+ or -] 6.34 0.026 (103/[micro]l) CRP ([double 1.25 [+ or -] 2.46 0.12 [+ or -] 0.84 < 0.001 dagger]) (mg/dl) NLR ([delta] 2.55 [+ or -] 1.57 1.79 [+ or -] 0.89 < 0.001 * BD = Behfet's disease ([dagger]) WBC = white blood cells ([double dagger]) CRP = C-reactive protein ([delta]) NLR = neutrophil to lymphocyte ratio Table 3 | Demographic features of patients and controls and comparison of inflammation markers between control and BD groups (mean [+ or -] SD). Variables Active BD (n = 38) Inactive BD * p (n = 27) WBC ([dagger]) 9.43 [+ or -] 2.78 7.62 [+ or -] 1.54 0.006 (103/[micro]l) CRP ([double 1.89 [+ or -] 3.07 0.36 [+ or -] 0.21 < 0.001 dagger]) (mg/dl) NLR ([delta]) 2.92 [+ or -] 1.83 2.02 [+ or -] 0.90 0.033 * BD = Behfet's disease ([dagger]) WBC = white blood cells ([double dagger]) CRP = C-reactive protein ([delta]) NLR = neutrophil to lymphocyte ratio
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|Author:||Rifaioglu, Emine Nur; Sen, Bilge Bulbul; Ekiz, Ozlem; Dogramaci, Asena Cigdem|
|Publication:||Acta Dermatovenerologica Alpina, Pannonica et Adriatica|
|Date:||Oct 1, 2014|
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