Iraqi J Pharm Sci, Vol.22(2) 2013 Neutrophil/ Lymphocyte ratio in rheumatoid arthritis 9 Neutrophil / Lymphocyte Ratio is not Correlated with Disease Activity in Rheumatoid Arthritis Patients Ehab M. Mikhael *,1 and TurathN.Ibrahim ** * Department of Clinical Pharmacy College of Pharmacy University of Baghdad, Baghdad ,Iraq. ** Department of Clinical Pharmacy College of Pharmacy Al-Mustansria University, Baghdad, Iraq. Abstract Rheumatoid arthritis is a chronic systemic inflammatory disease. Inflammation leads to joint damage and increases the risk of cardiovascular diseases. Neutrophil lymphocyte ratio (NLR) is a measure of inflammation in many diseases. Therefore, we aimed to evaluate the usefulness of NLR to detect inflammation in RA, and its correlation to RA disease activity indices and some hematological parameters. A cross-sectional study involving 24 patients with active rheumatoid arthritis (RA) who are using MTX participated in this study. All patients were clinically evaluated using disease activity score of 28 joints (DAS28) and simplified disease activity index (SDAI), whereas functional disability was assessed by health assessment questionnaire disability index (HAQDI); Moreover, blood specimen of each patient was used for measuring erythrocyte sedimentation rate (ESR), C – reactive protein (CRP), rheumatoid factor (RF), hemoglobin (Hb), white blood cells (WBC) count, platelets and red blood cells (RBCs) count, and NLR ratio.NLR was positively correlated with ESR and inversely correlated with Hb, but it didn’t show any correlation with other clinical and laboratory parameters. In conclusion NLR is less correlated with inflammation and not suitable to monitor disease activity in RA patients using MTX. Keywords: Rheumatoid arthritis, Inflammation, Neutrophil lymphocyte ratio. نسبة كريات الدم البيط العدلة إلى كريات الدم البيط اللوفاوية الترتبط هع فاعلية الورض عند الوصابين بالتهاب الوفاصل الروهاتىيدي ايهاب هضر هيخائيل ،*1 وتراث نبيل ابراهين ** * انؼشاق.تغذاد،فشع انصٛذنح انسشٚشٚح ،كهٛح انصٛذنح ،جايؼح تغذاد ، ** انؼشاق .تغذاد،، انجايؼح انًسرُصشٚحفشع انصٛذنح انسشٚشٚح ، كهٛح انصٛذنح ، الخالصة انرٓاب انًفاصم انشٔياذٕٚذ٘ يشض انرٓاتٙ يزيٍ ْٔزا االنرٓاب ٚؤد٘ إنٗ ذهف انًفصم ٔكًا ٚزٚذ يٍ خطٕسج األيشاض انمهثٛح نك انٕػائٛح. إٌ َسثح كشٚاخ انذو انثٛط انًؼرذنح إنٗ كشٚاخ انذو انثٛط انهًفأٚح ٚؼرثش لٛاسا نُسثح االنرٓاب فٙ كثٛش يٍ األيشاض. ٔنز فائذج ْزِ انُسثح نمٛاس يسرٕٖ االنرٓاب ػُذ يشظٗ انرٓاب انًفاصم انشٔياذٕٚذ٘ ٔػاللح ْزِ انُسثح تفاػهٛح يشض كاٌ ْذفُا ذمٛٛى يصاتا تانرٓاب انًفاصم انشٔياذٕٚذ٘ ٔانزٍٚ ٚسرؼًهٌٕ 42انرٓاب انًفاصم انشٔياذزيٙ ٔتؼط انًؼاٚٛش انذيٕٚح. شًهد انذساسح ٔيهحك فاػهٛح انًشض (DAS28)يفصم 42شٚشٚا تٕاسطح يؼٛاس فاػهٛح انًشض ل انًٛثٕذشكسٛد. ذى ذمٛٛى جًٛغ انًشظٗ س يهحك انؼجز. إظافح نزنك ػُٛاخ انذو سحثد نمٛاس –, أيا يمذاس اإلػالح فرى ذمًّٛٛ تٕاسطح اسرثٛاٌ ذمٛٛى انصحح (SDAI)انًثسط َسثح ذشسة كشٚاخ انذو انحًش, تشٔذٍٛ سٙ انفؼال, يمٛاس انشٔياذٕٚذ, انًٕٓٛغهٕتٍٛ, ػذد كشٚاخ انذو انحًش ٔانثٛط ٔانصفٛحاخ ط انؼذنح إنٗ كشٚاخ انذو انثٛط انذيٕٚح ٔ َسثح كشٚاخ انذو انثٛط انؼذنح إنٗ كشٚاخ انذو انثٛط انهًفأٚح. إٌ َسثح كشٚاخ انذو انثٛ انهًفأٚح كاٌ نٓا ػاللح اٚجاتٛح يغ َسثح ذشسٛة كشٚاخ انذو انحًش ٔػاللح ػكسٛح يغ انًٕٓٛغهٕتٍٛ ٔنكُٓا نى ذظٓش أ٘ ػاللح يغ تالٙ أٚح ذشذثط تؼاللح ظؼٛفح انًؼاٚٛش انسشٚشٚح ٔانًخرثشٚح. ٚسرُرج يٍ رنك إٌ َسثح كشٚاخ انذو انثٛط انؼذنح إنٗ كشٚاخ انذو انثٛط انهًف يغ االنرٓاب ٔغٛش يالئًح نًراتؼح فاػهٛح انرٓاب انًفاصم انشٔياذٕٚذ٘ نهًشظٗ انزٍٚ ٚسرؼًهٌٕ يٛثٕذشكسٛد. . كريات الدم البيط العدلة الى كريات الدم البيط اللوفاويةالكلوات الوفتاحية: التهاب الوفاصل الروهاتىيدي, التهاب, نسبة Introduction Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology that characterized by both articular and extra articular features (1) . Local inflammation of the joints is correlated to joint damage (2) whereas systemic inflammation increases the risk of atherogenesis and coronary heart disease in RA patients (3) . Several studies have explored the relationship between systemic inflammation and cardiovascular mortality (4, 5) .Systemic inflammation can be measured by using a variety of biochemical and hematological markers (6) CRP is a strong predictor of future 1 Corresponding author E-mail:ehab_pharma84@yahoo.com Received:3/11/2012 Accepted:19/5/2013 Iraqi J Pharm Sci, Vol.22(2) 2013 Neutrophil/ Lymphocyte ratio in rheumatoid arthritis 10 cardiovascular events in individuals both with and without overt cardiovascular disease (CVD) (7) . Additionally, CRP correlates directly with the presence of atherosclerosis in patients with RA (8) whereas; ESR is significantly associated with the risk of CVD in RA (9). Neutrophil lymphocyte ratio (NLR) is an important measure of systemic inflammation as it is readily available and could be calculated easily (10) . Many studies found that NLR is a useful measure to detect inflammation and predict long term outcomes in patients with renal failure, cancer and heart diseases (11 -13) . Aim of the Study To evaluate the usefulness of NLR to detect inflammation in RA, and its correlation to various RA disease activity indices and some hematological parameters. Patients and Methods A cross-sectional study was conducted in Baghdad Teaching Hospital, Rheumatology Unit from December 2011 to May 2012. A total of 24 patients (7 males and 17 females) with active RA were involved in this study. Patients were diagnosed to have RA by the rheumatologist according to American College of Rheumatology (ACR) classification criteria for RA (14) . All patients included in the study signed an informed consent form according to the declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Baghdad University, College of Medicine, Department of Medicine. Patients with diseases other than rheumatoid arthritis were excluded from the study. Demographic data of patients were reported regarding their age, duration of the disease, and medication history (Table 1). Laboratory Investigations Blood specimens were taken from all patients. Hematological investigations that include complete blood count (WBC, RBC and Platelet), differential WBC count and Hb were measured using hematology auto analyzer (Ruby – CELL – DYN 08H56 – 02) from Abbott Company USA. ESR was measured by Westergren method (15) . CRP was measured semi quantitatively according to method of Singer et al using serial dilutions of serum; each dilution was mixed with a latex reagent and observed for the presence of Agglutination (16) using a ready made kit (Agapee, Switzerland) whereas RF was measured qualitatively (16) by a ready made kit (Spectrum, Egypt). Clinical Evaluation The 28 joints included bilateral knees, shoulders, elbows,wrists, metacarpophalangeal and proximal interphalangeal joints, were palpated to count the number of tender and swelling joints. The patients were asked to mark on the VAS of 0 – 100mm according to their global assessment of their general health and pain. The physician marked on the VAS of 0-10 cm according to the physician global assessment of the disease activity. Disease activity was measured by both DAS28 and SDAI. DAS28 was calculated from the TJC, SJC and ESR according to the following formula [17]: DAS28 = {(0.56 • √[TJC28]) + (0.28 • √[SJC28]) + (0.70 • In[ESR])} • 1.08 Whereas SDAI was calculated by the following formula [18]: SDAI = CRP + TJC + SJC + VAS (0-10) + EGA (0-10)Functional status of the patients was measured using Health assessment questionnaire disability index [19]. Additionally morning stiffness of each patient was calculated according to patient approximate. Statistical Analysis SPSS version 12 was used for data input and analysis. Shapiro wilk test (web version) used to check if data is normally or abnormally distributed. Spearman correlation coefficient was used to assess the correlation between abnormally distributed continuous variables. All p values used were asymptotic and two sided. Values with p < 0.05 were considered significant. Results Table (1) showed general demographic data for the patients that participated in this study. Table (2) showed the values (mean ± SD) for the different studied variables, When these valuescorrelated, with neutrophil/lymphocyte ratio there was a significant positive correlation with ESR (r = 0.495, P = 0.014) and a significant negative correlation with Hb (r = -0.426 , P = 0.034), CRP has a weak positive correlation that didn’t achieve statistical significance , whereas other parameters didn’t show a significant correlation with NLR (Table 3). Iraqi J Pharm Sci, Vol.22(2) 2013 Neutrophil/ Lymphocyte ratio in rheumatoid arthritis 11 Table (1): General demographic data of the patients Parameter Patients with Moderate Disease activity Patients with High disease activity All participated patients Age, years Mean  SD 5112.11 45.2411.08 46.9211.44 Female percent 14.85 88.24 66.67% Disease duration, years Mean  SD 6.714.57 5.885.16 6.134.91 Drug used (MTX/HCQ) (5/2) 17/0 (22/2) RF positive n (%) 5 (71.4) 9 (52.94) 14 (58.33) Smoking percent 42.86 0 12.5% MTX = Methotrexate; HCQ = Hydroxychloroquine; SD = Standard deviation; RF = rheumatoid factor. Table (2): Clinical and laboratory parameters in RA patients participated in Table (3): Correlation of different parameters with NLR the study JC = Tender joint count; SJC = Swelling joint count; VAS = Visual analogue scale; EGA = Evaluator global assessment; DAS28 = Disease activity score 28 joints; SDAI = Simplified disease activity score; CRP = C – reactive protein; ESR = Erythrocyte sedimentation rate; RF = Rheumatoid factor; Hb = Hemoglobin; WBC =White blood cells; RBC = Red blood cell HAQDI = Health assessment questionnaire disability index. JC = Tender joint count; SJC = Swelling joint count; VAS = Visual analogue scale; EGA = Evaluator global assessment; DAS28 = Disease activity score 28 joints; SDAI = Simplified disease activity score; CRP = C – reactive protein; ESR = Erythrocyte sedimentation rate; RF = Rheumatoid factor; Hb = Hemoglobin; WBC =White blood cells; RBC = Red blood cell HAQDI = Health assessment questionnaire disability index. Parameter Correlation Coefficient P Value TJC -0.001 0.997 SJC 0.051 0.813 VAS 0.179 0.404 EGA 0.232 0.276 Morning stiffness -0.139 0.516 DAS28 0.351 0.093 SDAI 0.150 0.484 CRP (mg/dl) 0.368 0.077 ESR (mm/hr) 0.495 0.014 Hb ( gm/dl) -0.435 0.034 WBC (cell/ nano liter) 0.306 0.146 RBC (cell/ nano liter) -0.084 0.698 Platelet (cell/ nano liter) 0.339 0.105 HAQDI 0.146 0.496 Parameter Value (Mean  SD) TJC 10.544.53 SJC 5.133.03 VAS 54.1725.70 EGA 5.132.35 Morning stiffness 26.238.1 DAS28 5.431.46 SDAI 27.9213.62 CRP ( mg/dl) 1.652.34 ESR ( mm/hr) 3822.14 RF 0.580.50 Hb ( g/dl) 12.281.62 WBC (cell/ nano liter) 9.753.27 RBC (cell / nano liter) 4.670.76 Platelet (cell/ nano liter) 28887.82 HAQDI 1.360.74 Iraqi J Pharm Sci, Vol.22(2) 2013 Neutrophil/ Lymphocyte ratio in rheumatoid arthritis 12 Additionally Table (4) showed that NLR not differ significantly between highly active and moderately active RA (P = 0.07), while ESR, CRP and DAS28 values varied significantly (P<0.05) between moderately and highly active RA patients. Table (5) showed a highly positive correlation between VAS and EGA. Table (4): Comparison of some parameters between patients with highly active RA and those with moderately active RA Parameter Patients with moderate RA disease activity (7) Patients with high RA activity ( 17) P Value NLR 2.110.46 3.171.68 0.070 DAS28 3.851.49 6.080.85 0.000 CRP 0.430.90 2.152.57 0.047 ESR 18.8614.96 45.8819.86 0.004 NLR= Neutrophil lymphocyte ratio; DAS28 = Disease activity score of 28 joints; CRP = C – reactive protein; ESR = Erythrocyte sedimentation rate Table (5): Correlation between Visual Analogue Sale (VAS) and Evaluator Global Assessment (EGA) Disease activity Number of cases VAS EGA Spearman Correlation coefficient P value Moderate 7 31.4320.35 27.1418.90 0.924 0.003 High 17 63.8921.18 60.5616.97 0.795 0.000 Moderate and high 24 54.825.35 51.222.97 0.867 0.000 Discussion This study showed that NLR as a measure of inflammation in RA patients was positively correlated with ESR, similar finding was observed when NLR was evaluated as a measure of inflammation in ulcerative colitis patients (20) . Moreover, NLR was inversely correlated with Hb, however, there is no any study in this respect and it is the 1 st time to get such result. This finding is acceptable since Hb in RA patients is inversely correlated with inflammation and RA disease activity (21) . Regarding CRP, there is a modest but a non significant correlation with NLR, there is an agreement of this finding in a trial that followed up patients with cancer (22) . According to the above, and since NLR is well correlated with ESR and not well correlated with CRP, so NLR may be not sufficient laboratory test to predict CVD risk in RA patients and further studies areneeded to evaluate the association of NLR with the severity and extent ofcoronary atherosclerosis. Results from the current study also showed that NLR didn’t correlate with RA clinical parameters like tender joint count, swelling joint count and HAQDI, this result may be rationale since it has been found that many of clinical parameters that were used to diagnose RA like TJC, SJC, morning stiffness and HAQDI were less correlated with inflammation (23-25). This study showed a direct positive correlation between VAS and EGA and also showed that there is no correlation between VAS and EGA with NLR. This finding can be explained according to the finding of Naredoetal (24) at which VAS was not correlated with inflammation ( especially with ESR) and since this study showed that NLR was directly correlated with ESR, so it can be concluded that there is no correlation between VAS or EGA with NLR . Additionally hematological parameters like WBC, RBC and platelets count were not correlated with NLR. There was very complex hematological parameters in active RA patients that use MTX who participated in this study, since active RA disease is associated with anemia, leucocytosis and thrombocytosis (26,27) , whereas MTX may causes neutropenia and thrombocytopenia (28) . Consequently absence of correlation between NLR and hematological parameters may result from the unsuitable patient sample selection and further studies are needed to correlate between NLR and hematological parameters in RA patients using DMARDs other than MTX. Iraqi J Pharm Sci, Vol.22(2) 2013 Neutrophil/ Lymphocyte ratio in rheumatoid arthritis 13 Finally, results from the current study showed that NLR is not correlated with RA disease activity as measured by either DAS28 or SDAI; similarly FauziaImtiazet al also found that there was a non significant relationship between NLR and rheumatoid arthritis (29). This finding was strengthened by absence of statistical difference in NLR between patients with moderately and those with highly active RA, and only CRP and ESR showed a significant difference between the 2 groups of patients similar to that of DAS28; Consequently ESR and CRP is better than NLR to detect RA disease activity. Conclusion NLR is less correlated with inflammation and not suitable to monitor disease activity in RA patients using MTX. Reference 1. Manole Cojocaru, Inimioara Mihaela Cojocaru, Isabela Silosi , et al. Extra- articular Manifestations in Rheumatoid Arthritis. Maedica (Buchar) 2010; 5(4): 286–91. 2. Conaghan PG, O'Connor P, McGonagle D, et al. Elucidation of the relationship between synovitis and bone damage: a randomized magnetic resonance imaging study of individual joints in patients with early rheumatoid arthritis. Arthritis Rheum. 2003;48(1):64-71. 3. NaveedSattar, David W. McCarey, Hilary Capell, et al. 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