Default Normal Template Original Article Possible Role of Interleukin-6 in Rheumatoid Arthritis Batool A. Al-Haidary *Ph.D Summary: Background: Rheumatoid Arthritis (RA) is an autoimmune disease. Many etiological agents are proposed to play a role in its pathogenecity. One of these factors is cytokines such as Interleukin6. Material & Methods: ELISA method has been used for IL-6 estimation in 75 RA patients in comparison with 61 SLE as patient controls and 39 apparently healthy controls. J Fac Med Baghdad 2007; Vol. 49, No.2 Received July 2006 Accepted Jan. 2007 Results: This study showed that there was an elevation of IL-6 in the sera of RA patients with high significant differences between RA patients and controls (P< 0.001). Moreover a good correlation between IL-6 level & RF titer were observed. However, for most patients with high IL-6 were shown to be HLA-DR4. Conclusions: Interleukin-6 play a crucial role in the disease which may be participate in the severity of RA & subsequently its treatment. Key words: RA, IL-6, RF, HLA-DR4, ELISA, Microlymphocytotoxicity __________________________________________________________________________________________ Introduction:______________________________ The best knowledge of RA treatment depends on the studying the cellular & humoral factors that involved in the disease pathogenecity. On the tope of these factors are the cytokines, including IL-6 as an inflammatory factor. Recent study showed that there is a cross talk between IL-1 and IL-6 signaling pathways in RA synovial fibroblasts [1]. While a number of interleukins such as Interleukin-1 (IL-1) and (IL-10) seem to be pleiotrophic in their effects, (IL-6) may be considered the prototrophic cytokine. This is reflected in the variety of names originally assigned to 11-6 based on function, including Interferon (32, IL-1 inducible 26kD Protein, Hepatocyte Stimulating Factor, Cytotoxic Tcell Differentiation Factor, B cell Differentiation Factor (BCDF) and / or B cell Stimulating Factor 2 (BCSF2). All these activities associated with inflammatory process [2]. So IL-6 is considered as a pleiotrophic inflammatory cytokine produced by T cells, Monocytes, macrophages and synovial fibroblasts [3]. Originally identified as a factor that induces the final maturation of B cells into plasma cells. Recently an interesting studies involving the IL-1 and IL-6 in initiating the significant pathway in RA symptoms. Interleukin-6 was observed to be involved in diverse _________________________________________ * Clinical Immunology/ Ass. Prof./ College of Medical & Health Technology. biologic processes, such as the activation of T cells, induction of the acute-phase response, stimulation of the growth and differentiation of hematopoietic precursor cells, and proliferation of synovial fibroblasts results in synovial inflammation and ultimately joints damage [4].. The current study is a trail to estimate IL-6 concentration in the patients' sera in comparison with patient controls and apparent healthy controls. This , however, might open a gate for entrance into the treatment of this disease. Subjects & Methods: Seventy-five Rheumatoid Arthritis (RA) patients' sera samples have been studied for IL-6 in comparison with 61 SLE patients as patient controls besides 39 apparent healthy individuals. IL-6 has been estimated by using ELISA technique [Diaclone, France Lot. No. 1006-24]. All patients were diagnosed according to the modified criteria [revised criteria of the American Rheumatism Association [5].. In this study HLA- typing using micro-lymphocytotoxicity by were assessed [6]. Statistical Analysis: All the data have been analyzed statistically using Kriiskal- allis test and Mann-Whitney analysis for measuring the differences between the studying groups [7].. Results:: I. Interleukin-6 Level in the sera of RA patients and control groups: The results of IL-6 estimation in the sera of RA patients, patient controls and apparent healthy individuals are listed in the table-l. This table shows that there is high significant differences between IL-6 levels in the patients sera and controls (P < 0.001 for each comparison), with a median of 195, 50, and 8 pg / ml for RA patients, patient controls and healthy controls respectively. J Fac Med Baghdad Vol. 49 , No. 2 , 2007 249 Simpo PDF Merge and Split Unregistered Version - http://www.simpopdf.com Possible Role of Interleukin-6 in Rheumatoid Arthritis Batool A. Al-Haidary Table -1 IL-6 concentrations in the RA atients sera and control rou s Interleukin-6 (IL-6) concentration in pg / ml Sporadic RA (75) * Patient Control [PC] (61) Healthy Control [HC] (39) Range 21-576 pg. / ml 28-570 pg. / ml 1-157 pg. / ml Mean ± SD 216.2 ± 159.3 137.7 ± 166.58 16 ± 2 6.54 Median 195 50 8 P (Kruskal-Wallis) for the three groups differences = <0.001 P (Mann-Whitney) for the differences between two groups RA vs. PC = < 0.001, RA vs. HC = < 0.001 * = No. Between brackets represents the No. of patients. The above figure reveals the distribution of IL- 6 concentration in RA patient's sera according to its frequencies. This figure reveals that there was a normal distribution for the frequencies of IL-6 concentrations among RA patients sera, though the highest frequencies are observed between 25-125 pg / ml. II. The Correlation between IL-6 and RF: An interesting finding that elevation of IL-6 accompanied by high RF titer which is clearly shown in figure 3. This figure shows that the majority of patients [65 out of 75] with a high IL-6 level [extends to about 600 pg/ml] are sero-positive for RF [i.e. > 20 IU/ml] while the minority of patients [10 out of 75] with very low IL-6 concentration are sero-negative for RF . J Fac Med Baghdad 250 Vol. 49 , No. 2 , 2007 Simpo PDF Merge and Split Unregistered Version - http://www.simpopdf.com Possible Role of Interleukin-6 in Rheumatoid Arthritis Batool A. Al-Haidary III. Correlation between IL-6 and HLA- DR4: The current study shows that there is a prominent correlation between HLA-DR4 molecules and IL-6 concentration in the patient's sera as shown in the figure -4. This figure shows that the frequency of HLA-DR4 molecules are higher among patients with high IL-6 level [42] characterized by presence of HLA-DR4 molecules on the surfaces of their B cells while the others [33] whose sera apparent with low IL- 6 concentration posses other DR molecules rather than DR-4. J Fac Med Baghdad 251 Vol. 49 , No. 2 , 2007 Simpo PDF Merge and Split Unregistered Version - http://www.simpopdf.com Possible Role of Interleukin-6 in Rheumatoid Arthritis Batool A. Al-Haidary Discussion: Studies are denoted that IL-6 was elevated in rheumatoid arthritis patients' synovial fluids as well as their sera [8-9]. The results of the current study have revealed an increasing in IL-6 level in RA patients sera in comparison with the control groups which is reckoned as an inflammatory mediator particularly among those patients with disease flare up. This result was comparable to [9-11]. The observed median level is 195 pg./ml which is higher than that of abroad (106 'p g:/ml).'[12]. This variation may be related to the variation in the duration of the disease and its activity particularly most the patients included in this study are at the acute stage of the disease flare up time [13-14]. Treated RA patients had displayed significantly reduced serum IL-6 (mean, 9.9 pg/ml) [15]. Moreover this study showed that there was a good correlation between IL-6 and RF levels, in which the later usually enhances the disease severity and may act in synergetic fashion with IL-6. These findings were observed to be in consistent with that of [16], which revealed an association between IL-6 and other humoral inflammatory, disease activity parameters as CRP and ESR. Rheumatoid factor is considered as a prominent feature of RA and play a crucial role in RA pathogenecity [17]. The current study revealed a high correlation between RF and IL-6 which explains the role of RF in ICs formation, complement activation and finally cellular infiltration resulting in cytokine production [17]. It was denoted that the disease becomes worse in the presence of RF, HLA-DR4 molecules [signs of high disease activity], especially when they accompanied with elevation of IL-6 as shown by this study and other [18]. Sporadic patients are those with no familial history for RA , however, the frequency of HLA- DR4 was still higher than that for apparently healthy individuals [42 out of 75 RA patients]. This study demonstrated that (IL-6) is a protein overproduced in the sera of people with rheumatoid arthritis, where it's believed to be responsible for joint damage and swelling. Interleukin-6 may also be a cause of fever and excess blood platelets (thrombocytosis) in people with rheumatoid arthritis. Researchers hope that blocking IL6 can reduce the damage it does [19]. References: 1. Deon D, Ahmed S, Tai K, Scaletta N, Herrero C, Lee I-H, Krause A & Ivashkiv LB " Cross-Talk between IL-1 and IL-6 signaling pathways in Rheumatoid Arthritis ." The J. Immunol. , (2001) 167: 5395-5403 2. Arthritis Research Reagents : In Scope " INTERLEUKIN=6" ' http://\vww.,c / RnD systems.com October (2002). 3. Van Snick J "Interleukin-6: An overview." Ann.Rev. Immunol. (1990) 8: 253-78. 4. Choy , E.H.S. & Panayi , G.S. : Cytokine pathways & joint inflammation in rheumatoid arthritis . Educational series ; Medical Sciences, Update (2001) 2(7) - July. 5. Arnett FC, Edworthy SM, Bloch DA, et. al., "The American Association 1987 revised criteria for the classification of rheumatoid arthritis." Arthritis Rheum. (1988) 31: 315-24 . 6. Terasaki P and McClelland J, "Micro-droplet assay of human serum cytotoxins" Nature (1964), 204: 998- 1000. 7. Sorlie DE "Medical biostatistics and Epidemiology: Examination and Broad Review." 1St Ed; (1995) Norwalk Connecticut Appleton and Lange Com: 74-88. 8. Bertazzolo N, Punzil L, Stefani MP , et al., "Interrelationships between interleukin(IL)-1, IL-6 and IL-8 in synovial fluid of various arthropathies." Agents actions (1994) Mar; 41(1-2): 90-2. 9. Lacki JK, Samborski W & Mackiewicz SH "Interleukin-l0 and interleukin-6 in lupus erthymatosus and rheumatoid arthritis, correlations with acute phase proteins." Clin. Rheumatol. (1997) May; 16(3): 275-8. 10. Robak T, Gladalska A, Stepien H, &.Robak K. " Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. "Mediators-Inflamm. (1998) 7(5): 347-53 11. Oelzner P, Franke S, Muller A, Hein G & Stein G "Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis." Rheumatology- Oxford (1999) Sep; 38(9): 841-7 12. Al-Awadhi A, Olusi S, Al-Zaid N, & Prabha K. " Serum concentration of interleukin-6, osteocalcin, intact parathyroid hormone, and marker of bone resorption in patients with rheumatoid arthritis." J. Immunol. (1999) Jun; 26(6): 1250-6 13. Roony M, David J, Symons J, Di-Giovine F, Varsani H & Woo P " Inflammatory cytokine responses in juvenile chronic arthritis," Br. J. Rheurnatol. (1995) May ; 34(5): 454-60. 14. Lacki JK, Klama K, Mackewicz SH, Mackiewicz H & Muller W. "Circulating interleukin-10 and interleukin-6 serum levels in rheumatoid arthritis patients treated with methotrexate, gold salts: Preliminary report." Inflamm.Res. (1995 ) Jan 44(1): 24-6. 15. Wellby ML; Kennedy JA; Pile K; True BS; Barreau P. "Serum interleukin-6 and thyroid hormones in rheumatoid arthritis." Metabolism (2001) 50(4):4637 (ISSN: 0026-0495) 16. Boss B & Neek G, " Correlation pf IL-6 with the classical humoral disease activity parameters ESR and CRP and with cortisol, reflecting the activity of the_ HPA axis in active rheumatoid arthritis. " Z- Rheumatol. (2000) 59 Suppl. 211:624 17. Al-Haidary BA, Mousawy KM, & Al-Khafaji JT,. "HLA-typing for Rheumatoid Arthritis Patients (Familial Profile) " A thesis submittecF''to- tlie.. College of Medicine and Committee of Graduated studies of University of Baghdad in partial fulfillment of requirement for the degree of Doctorate Philosophy in Medical Microbiology/ Clinical Immunology, (2004). 18. Kloppenburg M, Dijkmans BA, Verwej CL, & Breedveld FC." Infalammatory and immunological parameters of disease activity in rheumatoid arthritis patients treated with minocycline" Immunopharmacology ,1996 Mar 31(2-3): 163-9 19. van-Zeben and Breedveld, "Prognostic factors in rheumatoid arthritis" J. Rheumatol. Suppl. (1996) Mar; 44: 31-3 J Fac Med Baghdad 252 Vol. 49 , No. 2 , 2007 Simpo PDF Merge and Split Unregistered Version - http://www.simpopdf.com http://systems.com/ 1.DOC 2.doc References List all authors when six or less; when seven or more, list only first three and add et al. Tables Submission of manuscripts Mail the required number of manuscript copies in a heavy-paper envelope, enclosing the manuscript copies and figures in cardboard. Manuscripts should be accompanied by a covering letter from the author who will be responsible for correspondence regarding the manuscript. The covering letter should contain a statement that the manuscript has been seen and approved by all authors. 3.doc Modified Sugiura Operation for Portal Hypertension and Bleeding Esophageal Varices 172 Omar S. Khattab,Samie B. Safar Post-Surgical Loco Regional Recurrence Of Breast Carcinoma In Iraq 193 Ali M. Al-saiegh 4.doc 5.doc Modified Sugiura Operation for Portal Hypertension and Bleeding Esophageal Varices Omar S. Khattab*, M.B.Ch.B , H.D.S , H.D.L.M , F.I.C.M.S, C.A.B.S Samie B. Safar, M.B.Ch.B , F.R.C.P, F.R.C.S, F.A.C.S 6.doc Introduction:______________________________ Types of Incisional hernias: - _________________________________________ Clinical types of Incisional hernias: - Patients And Methods: Discussion Conclusions References 7.doc 8.doc 9.doc Post-Surgical Loco Regional Recurrence Of Breast Carcinoma In Iraq Ali M. Al-saiegh * M.B.CH.B. D.S F.I.C.M.S. Summary Conclusion: Carcinoma of the breast affecting Iraqi females at younger ages in a high & increasing rate than other studies with a higher Loco-regional recurrence rate. Significant association were found regarding latency period, staging, histopathology & grading of primary tumour . Aims Of Study: 1. To assess the incidence of post operative loco regional recurrence of breast carcinoma in Iraqi female patients. 2. To determine the significance of certain variables that may affect the loco regional recurrence rate . Introduction:______________________________ * Head of Department of surgery- medical college Kufa university Results: Discussion: Conclusion References 10.doc 11.doc 12.doc 13.doc 14.doc 15.doc 16.doc Back ground: Oxidative damage has been suggested to play a key role in accelerating inflammation and to be involved in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). Many studies had shown that those patients have low antioxidants level and are at risk of increased oxidative stress. Objective: This study was designed to examine the levels of serum Total Antioxidant Status (TAS). Malondialdehyde (MDA) as index of lipid peroxidation and C–Reactive Protein (CRP) as a marker of oxidative stress in patients with RA and OA and compared them with healthy control. __________________________________________________________________________________________ Introduction:_______________________________ **Lecturer, College of Dentistry – University of Mosul Patients and Method: Results: 17.doc 18.doc 19.doc HLA -A HLA-B Total Increased frequency Study groups Blood groups 20.doc Subject and Methods: - 21.doc 22.doc 23.doc 24.doc 25.doc 26.doc Rabab .N. AL-Saadi.* FICMS Back ground: Psoriasis is a chronic relapsing disorder with no life long cure, many systemic and topical modalities are available, one of these topical modalities is the vitamin D analogue (calcipotriene) which is widely used recently to treat psoriasis and many other skin problems. 27.doc 28.doc 29.doc 30.doc 31.DOC 16.pdf Back ground: Oxidative damage has been suggested to play a key role in accelerating inflammation and to be involved in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). Many studies had shown that those patients have low antioxidants level and are at risk of increased oxidative stress. Objective: This study was designed to examine the levels of serum Total Antioxidant Status (TAS). Malondialdehyde (MDA) as index of lipid peroxidation and C–Reactive Protein (CRP) as a marker of oxidative stress in patients with RA and OA and compared them with healthy control. __________________________________________________________________________________________ Introduction:_______________________________ **Lecturer, College of Dentistry – University of Mosul Patients and Method: Results: 166.pdf Back ground: Oxidative damage has been suggested to play a key role in accelerating inflammation and to be involved in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). Many studies had shown that those patients have low antioxidants level and are at risk of increased oxidative stress. Objective: This study was designed to examine the levels of serum Total Antioxidant Status (TAS). Malondialdehyde (MDA) as index of lipid peroxidation and C–Reactive Protein (CRP) as a marker of oxidative stress in patients with RA and OA and compared them with healthy control. __________________________________________________________________________________________ Introduction:_______________________________ **Lecturer, College of Dentistry – University of Mosul Patients and Method: Results: