The changes in serum interleukin - 6 in patients with rheumatoid arthritis

Nội dung text: The changes in serum interleukin - 6 in patients with rheumatoid arthritis

1. Journal of military phrmaco-medicine n O7-2017 THE CHANGES IN SERUM INTERLEUKIN-6 IN PATIENTS WITH RHEUMATOID ARTHRITIS Nguyen Huy Thong*; Doan Van De*; Nguyen Dang Dung** SUMMARY Objectives: To evaluate serum levels of interleukin (IL)-6 in rheumatoid arthritis (RA) patients and to assess the correlations of this cytokine with clinical and laboratory parameters . Subjects and methods: 86 patients with RA and 30 healthy volunteers were enrolled in the study. Disease activity was determined by disease activity score (DAS28) in patients with RA. Patients with RA were categorized as low and moderate (DAS28 ≤ 5.1) and high (5.1 > DAS28) according to DAS28. The serum levels of IL-6 cytokine was measured by Fluorescence Covalent Microbead Immunosorbent Assay (FCMIA). Results: Serum IL-6 levels was significantly elevated in RA patients comparing with controls (p = 0.042). Serum IL-6 showed no significant correlations with mesurements of disease activity. Conclusions: This study showed that patients with RA had a significantly increased cytokine level for IL-6, but high level of serum IL-6 cytokine was not associated with disease activity measurements. However, further follow-up studies involving large samples are required to clarify precise role of this cytokine in development and progress disease. * Keywords: Rheumatoid arthritis; IL-6; Disease activity. INTRODUCTION its effect on osteoclasts [3], thus it may Rheumatoid arthritis is a chronic influence on levels of disease activity in inflammatory disease characterized by RA patients. joint swelling, joint tenderness, and Several disease activity indices based destruction of synovial joints, leading to on different clinical, laboratory, and physical severe disability and premature mortality [1]. measures have been introduced. Most of Cytokine networks, including IL-6, are these, including the Disease Activity Score critical for the initiation and perpetuation (DAS), the modified DAS in 28 joints of both systemic and local inflammatory (DAS28), the Simplified Disease Activity responses seen in chronic inflammatory Index (SDAI), the Clinical Disease Activity arthritis [2]. IL-6 may also be mediating Index (CDAI), rely on either quantitative many of the systematic manifestations of joint counts, patient-reported outcomes or RA including inducing the acute-phase both, and erythrocyte sedimentation rate reaction [including C-reactive protein (CRP)], (ESR) and serum CRP, those have some anaemia through hecipidin production, limitations and can be influenced by aging, fatigue via the hypothalmic - pituitary - sex and conditions other than RA (eg., adrenal (HPA) axis and osteoporosis from osteoarthritis, fibromyalgia, anemia) [4, 5]. ** 103 Hospital ** Vietnam Military Medical University Corresponding author: Nguyen Huy Thong (bsthong103@gmail.com) Date received: 10/07/2017 Date accepted: 08/08/2017 151
2. Journal of military parmaco-medicine n 07-2017 The aim of this study was: To evaluate activity were evaluated using a 10 cm serum levels of IL-6 in RA patients and its horizontal visual analog scale (VAS). role in assessing of disease activity. We also calculated SDAI (Simplified Disease Activity Index) and CDAI (Clinical SUBJECTS AND METHODS Disease Activity Index). Erythrocyte 1. Subjects. sedimentation rate (ESR) and C-reactive This study was conducted at Department protein (CRP) were recorded. of Rheumatology and Endocrinology of 103 * Laboratory analysis: Military Hospital between May, 2012 and Blood samples of patients and controls June, 2015. were collected and put in a sterile plain Eighty six patients, 75 women and tube and stored frozen at -80 oC until 11 men, with the diagnosis of RA fulfilled analysis. We used commercially available the ACR/EULAR 2010 RA classification human fluorescence covalent microbead criteria [1]. Before entering study, 43 and immunosorbent assay (FCMIA) kits for IL-6, 4 patients were taking glucocorticoids and IL-17 and TNF-α (R&D systems MN, USA). conventional synthetic disease-modifying The procedure for the FCMIA method was antirheumatic drugs (DMARDs), respectively. performed according to the instructions Patients with other concomitant rheumatic provided by the manufacturer. The levels disease, severe infection, chronic autoimmune of cytokines were recorded as a pg/mL. disease, and/or taking bio-DMARDs, which * Statistical analysis: may affect laboratory and cytokine profile were excluded from the study. All statistical analyses were performed using the statistical package for the social - Healthy subject population: thirty sciences (SPSS), version 18.0, for Windows sex-matched healthy controls (age mean (SPSS, Chicago, IL, USA). Continuos 41.60 ± 4.57; range 35 - 50 years, 26 women variables are presented as the mean ± and 4 men) were included in the study. standard deviation or median. The normality 2. Methods. of the distribution for all variables was * Clinical assessment: assessed by the Kolmogorov-Smirnov test. Disease activity was assessed by the Intergroup comparisons were made using 28-joint disease activity score C-reactive the student’s t-test for normally distributed protein (DAS28 CRP) [6] in RA patients. variables and Mann - Whitney U test for Based on the DAS28 CRP, the patients non-parametric variables. To assess the were subdivided into 2 subgroups: low and correlations between variables, Sperman’s moderate group (DAS28 ≤ 5.1), and high rank or Pearson’s correlation analysis group (DAS28 > 5.1). Patient global were used according to data distribution. assessment of disease activity and Values of p < 0.05 were considered provider global assessment of disease statistically significant. 152
3. Journal of military phrmaco-medicine n O7-2017 RESULTS 1. Patients and demographic, clinical characteristics. Table 1: Demographic and clinical characteristics of RA patients and control. RA group (n = 86) Control group (n = 30) Mean age ± SD, min - max (years) 53.44 ± 7.30; 35 - 66 41.60 ± 4.57; 35 - 50 Sex, n (female/male) 75/11 26/4 Mean disease duration ± SD (years) 4.29 ± 5.34 Mean tender joint count ± SD (range 0 - 28) 14.13 ± 9.08; 13.00 Mean swollen joint count ± SD (range 0 - 28) 10.52 ± 7.38; 9.0 Mean morning stiffness ± SD (minutes) 37.25 ± 33.82; 30.00 Mean patient global assessment of disease 7.16 ± 2.25 activity ± SD (cm) Mean provider global assessment of disease 5.65 ± 1.92 activity ± SD (cm) Mean ESR ± SD (mm/h) 79.68 ± 44.37; 85.50 7.66 ± 3.86 Mean plasma CRP ± SD (mg/L) 68.37 ± 47.24, 65.10 0.52 ± 0.36 Mean, DAS28 CRP 6.19 ± 1.36; 2.81 - 8.50 DAS28 CRP Low and moderate (n; %) 17; 20.5 High (n, %) 66 (79.5) Pre-study treatment Glucorticoids (n, %) 43 (50.6) DMARDs (n, %) 4 (4.7) (DAS28 (CRP) is missing in three patients Abbreviations: anti-CCP: anti-cyclic citrulinated peptide; CRP: C-reative protein; DAS28: Disease Activity Score; ESR: Erythrocyte Sedimentation Rate) Patients and controls did not significantly differ in sex. The mean age of controls was lower than that of RA patients. The mean disease duration in RA patients was 4.29 ± 5.34 years. The mean DAS28 CRP was 6.19 ± 1.36 (range 2.81 - 8.50). Seventeen (20.5%) and sixty six (79.5%) patients had low-moderate and high DAS28 CRP, respectively. 153
4. Journal of military parmaco-medicine n 07-2017 2. Comparison of laboratory parameters among patients and healthy subjects. Figure 1: The comparision of serum interleukin Figure 2: The correlation of serum interleukin (IL)-6 levels between RA patients and controls (IL)-6 levels and serum tumor necrosis factor (p, test Mann - Whitney) (TNF)-α levels in rheumatoid arthritis patients (numbers are Spearman correlation coefficients) The mean and median of serum IL-6 of RA patients and controls was 19.06 ± 22.94; 10.49 and 9.19 ± 8.43; 7.18 (pg/mL), respectively. Median of serum IL-6 concentrations in RA patients was significantly higher than that in controls group (p = 0.042). Serum IL-6 had a positive correlation with serum TNF-α in RA patients (r = 0.233, p = 0.035). 3. Correlation between serum IL-6 and clinical, laboratory variables in RA patients group. Table 2: The comparison of serum IL-6 based on measurements of disease activity. Plasma IL-6 levels (pg/ml) p Mean ± SD Median Joint tender count 28 1 - 4 (n = 13) 26.20 ± 36.12 11.16 0.974 ≥ 5 (n = 68) 17.57 ± 19.72 10.18 Joint swollen count 28 1 - 4 (n = 20) 22.07 ± 33.49 5.74 0.332 ≥ 5 (n = 61) 17.93 ± 18.70 12.14 DAS28 CRP Low and moderate 22.07 ± 34.46 7.23 (n = 14) 0.581 High (n = 65) 16.27 ± 16.53 10.60 (Abbreviations: DAS28 CRP: Disease Activity Score C-Reactive Protein). 154
5. Journal of military phrmaco-medicine n O7-2017 Table 3: The correlation of serum IL-6 levels in RA patients with measurements of disease activity. TJC28 SJC28 MS PtGA PGA CRP ESR IL-6 r 0.035 0.033 -0.050 0.120 0.026 -0.028 -0.001 p 0.758 0.769 0.663 0.289 0.818 0.802 0.991 (Abbreviations: TJC: Tender joint count; SJC: Swollen joint count; MS: Morning stiffness; PtGA: Patient global assessment of disease activity’ PGA: Provider global assessement of disease activity; r: Spearman’s correlation coefficient) There were no differences according to joint tender count 28, joint swollen count 28 and DAS28 CRP. Table 4: The correlation of serum IL-6 levels with composite indices in RA patients. DAS28 CRP DAS28 ESR SDAI CDAI IL-6 r 0.101 0.107 0.063 0.055 p 0.374 0.392 0.581 0.627 (Abbreviations: DAS28 CRP: Disease Activity Score C-reactive protein; DAS28 ESR: Disease Activity Score erythrocyte sedimentation rate; SDA:, Simplified disease activity index; CDAI: Clinical disease activity index; r: Spearman’s correlation coefficient) There were no associations between the serum IL-6 levels of RA patients with measurements of disease activity. DISCUSSION In accordance with other authors [10, In the present study, we evaluated 11, 12], we found that serum IL-6 was serum levels of IL-6 cytokine in patients significantly increased in RA patients with RA, and its associations with clinical compared to healthy subjects ( figure 1 ). and laboratory parameters. In the current study, serum IL-6 had a IL-6 is a pleiotropic cytokine with diverse significantly positive correlation with activities. IL-6 plays an important role serum TNF-α ( figure 2 ). In consistent of in inflammation, bone metabolic, our observation, Manicourt D.H et al haematopoiesis, immune regulation [7]. (1993) also reported that serum IL-6 had These activities contribute to both systemic a positive correlation with serum TNF-α and local symptoms associated with RA (r = 0.487, p = 0.007). These studies [2]. IL-6 is involved in pathology of chronic supports the concept that TNF-α played inflammation of synovium, joint damage a key role in pathogenesis of RA by as well as systemic symptoms such as stimulating pro-inflammation cytokines anemia [8], fatigue [9], osteoporosis [9]. including IL-6. 155
6. Journal of military parmaco-medicine n 07-2017 IL-6 is a pleiotropic cytokine and Our study has some limitations. The contributes to both systemic and local sample size of patients was relatively symptoms associated with RA [2], so it small, and the patients were on drug may influence the disease activity of RA treatment including glucorticoids DMARDs. patients. We assessed the change of In fact, our study had a cross-sectional serum IL-6 according to measurements of design, and cytokines profile had wide disease activity to value serum IL-6 in range. assessing levels of disease activities in RA patients. In the present study, serum CONCLUSION IL-6 median of low and moderate disease Our study demonstrated a significant group lower than high group but it was not higher increase of serum IL-6 in RA significant (p = 0.581) ( table 2 ). Ibrahim patients compared with healthy controls. Tekeog˘lu et al (2016) found a significant However, we did not find any associations difference in serum IL-6 mean between between serum IL-6 levels and measurements high disease activity group and low group of disease activity in RA patients. (p = 0.046), however there was no difference between patients had a moderate and low REFERENCES disease activity. In the present study we also did not 1. Võ Tam, Phan Th ị Thu Tâm. Nghiên observe the correlation between serum cứu n ồng độ IL-6 huy ết thanh trên b ệnh nhân IL-6 with measurements of disease activity viêm kh ớp d ạng th ấp. Ch ươ ng trình báo cáo Hội ngh ị Khoa h ọc Công ngh ệ Tu ổi tr ẻ such as joint tender count 28, joint swollen Tr ường Đại h ọc Hu ế l ần th ứ XVI. 2016, count 28, morning stiffness, PtGA, PGA, tr.754-758. ESR, plasma CRP levels as well as 2. Aletaha D, T. Neogi, A.J. Silman et al. composite index DAS28 CRP, DAS28 2010 Rheumatoid arthritis classification criteria: ESR, SDAI and CDAI. In consistent of our an American College of Rheumatology/European observation, Soo-Jin Chung et al (2011) League Against Rheumatism collaborative found that serum IL-6 was not associated initiative . Arthritis Rheum. 2010, 62 (9), with DAS28 ESR [11]. However, contrary to pp.2569-2581. our results, other studies found serum IL-6 3. Cronstein B.N. IL-6: a key mediator of had a positive association with DAS28 systemic and local symptoms in rheumatoid CRP and DAS28 ESR. do Prado et al arthritis . Bull NYU Hosp Jt Dis. 2007, 65, found a positive correlation between IL-6 Suppl 1: pp.S11-5. levels and TJC28 (r = 0.39; p < 0.01) [12]. 4. Srirangan S, E.H. Choy. The role of IL-6 Thus, there are many controversial studies in the pathophysiology of rheumatoid arthritis . regarding the relationship between serum Ther Adv Musculoskelet Dis. 2010, 2 (5), IL-6 as an assessing role of disease pp.247-256. activity and measurements of disease 5. Gabay C.I. Kushner . Acute-phase activity in RA patients, so we need more proteins and other systemic responses to studies with larger sample size to inflammation . N Engl J Med. 1999, 340 (6), discover this interesting correlation. pp. 448-454. 156
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