Comparative analyses of immune marker levels in seronegative and seropositive Iraqi rheumatoid arthritis patients
Main Article Content
Keywords
rheumatoid arthritis, seronegative, seropositive, CCN4, VCAM-1, MMP-3
Abstract
Background: Rheumatoid arthritis (RA) comprises an inflammation-based condition with a clinical phenotype that is mainly reliant on the occurrence of rheumatoid factor and anti-citrullinated protein antibodies. Literature indicates that seronegativity might be accompanied by higher severity of clinical symptoms, while higher disease activity, based on the recent classification criteria should also be associated with seronegativity. Aim: This investigation targets the identification of more efficient immune markers of RA seropositivity as well as examining the possibility that the latter is associated with lower severity. Methods: Serum samples from 128 RA patients, 106 seropositive and 22 seronegative, were analyzed using ELISA to determine the levels of four biomarkers: Wnt-1-induced secreted protein-1 CCN4, vascular cell adhesion molecule-1 (VCAM-1), matrix melloprotenase-3 (MMP-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Additional clinical parameters were also investigated through a special questionnaire form that also covered demographic data. As a measure of RA activity, the parameter of joint disease activity score 28 (DAS28) was adopted. Results: Patients with seronegativity demonstrated higher RA activity, i.e., DAS28ESR score, in comparison with seropositive ones. Their sera also contained higher levels of the four tested immune markers in comparison with both seropositive patients and healthy controls. Das-28 ESR levels exhibited significant direct proportional correlations to CCN4, VCAM1, MMP3, GM-CSF, and Das-28CRP values. Conclusions: The tested four immune markers are considered biomarkers with high reliability and effectiveness to discriminate between seronegative and seropositive patients, as well as for the monitoring and prediction of RA activity and joint and bone damage in seronegative patients.
References
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3. Nordberg, L. B.; Lillegraven, S.; Lie, E.; Aga, A.; Olsen, I. C.; Hammer, H. B .etal,.Patients with Seronegative RA Have More in Fl Ammatory Activity Compared with Patients with Seropositive RA in an Inception Cohort of DMARD-Naïve Patients Classi Fi Ed According to the 2010 ACR/EULAR Criteria. Ann Rheum Dis, 2 0 1 7;76(2):341–345. https://doi./10.1136/annrheumdis-20 15-20 88 73.
4. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2006; 65(7):845-51. https: // doi: 10.1136/ard.2006.051391. Epub 2006 Apr 10. PMID: 16606649; PMCID: PMC1798205.
5. Farragher, T. M.; Lunt, M.; Plant, D.; Bunn, D. K.; Barton, A.; Symmons, D. P. M.etal Benefit of Early Treatment in Inflammatory Polyarthritis Patients With Anti – Cyclic Citrullinated Peptide Antibodies Versus Those Without Antibodies. Arthritis Care Res (Hoboken),2010, 62 (5): 664–675. https: //doi.Org /10.10 0/ acr .20207.
6. Smolen, J. S.; Landewé, R.; Breedveld, F. C.; Buch, M.; Burmester, G.; Dougados, M.etal,. EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Anti-rheumatic Drugs :2022 Update. Ann Rheum Dis.2023, 82(1):3-18. https://doi.org/10.1 136 /a n nrheumdis-2013-204573.
7. Deane, K. D.; Donnell, C. I. O.; Hueber, W.; Majka, D. S.; Lazar, A. A.; Derber, L. A.etal,. The Number of Elevated Cytokines and Chemokines in Preclinical Seropositive Rheumatoid Arthritis Predicts Time to Diagnosis in an Age-Dependent Manner. Arthritis Rheum.2010, 62 (11), 3161–3172. https: //doi .org /10 .10 02 /a rt.27638.
8. Fleischmann, R.; Connolly, S. E.; Maldonado, M. A.; Schiff, M. Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab. Arthritis Rheumatol. 2016, 68 (9):2083–2089. https://doi.org/10.1002/art.39714.
9. Macdonald, I. J.; Huang, C. C.; Liu, S. C.; Lin, Y. Y.; Tang, C. H. Targeting Ccn Proteins in Rheumatoid Arthritis and Osteoarthritis. Int. J. Mol. Sci. 2021, 22 (9). https:// doi .or g/ 10.3 390 /ijm s22 0 94340.
10. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ. WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev. 2000 ,1;14(5):585-95. PMID: 10716946; PMCID: PMC316421.
11. Sakkas, L. I.; Platsoucas, C. D. The Role of T Cells in the Pathogenesis of Osteoarthritis. Arthritis Rheum. 2007 , 56 (2), 40 9 –424. https://doi.org/10.1002/art.22369.
12. Lee, K. M. C.; Achuthan, A. A.; Hamilton, J. A. GM-CSF : A Promising Target in Inflammation and Autoimmunity. Immunotargets Ther. 2020; 29(9):225-240. doi: 10.21 47/IT T.S26 2566 . eCollection 2020.S262566. PMID: 33150139; PMCID: PMC 760 5919
13. Peter S. Burrage 1, K. S. M. 2 and C. E. B. Matrix Metalloproteinases: Role In Arthritis. Front. Biosci. 2006, 1(11): 529–543. https://doi.org/10.2741/1817.
14. Aletaha, D.; Neogi, T.; Silman, A. J.; Funovits, J.; Felson, D. T.; Iii, C. O. B.etal,.2010 Rheumatoid Arthritis Classifi Cation Criteria : An American College of Rheumatology / European League Against Rheumatism Collaborative Initiative. Arthritis Rheum.2010 ;62 (9):2569-81. doi: 10.1002/art.27584. PMID: 20699241.2010, 1580–1588.
15. Sokolove, J.; Bromberg, R.; Deane, K. D.; Lahey, L. J.; Derber, L. A.; Chandra, P. E.; etal,. Autoantibody Epitope Spreading in the Preclinical Phase Predicts Progression to Rheumatoid Arthritis. PLoS One. 2012;7(5):e35296. doi: 10.13 71/jo urnal .po ne. 00 35 296.
16. Masi, A. T.; Rehman, A. A.; Elmore, K. B.; Aldag, J. C. Innate Immunity Serum Acute Phase Protein and Inflammatory Cytokine Network Correlations : Comparison of a Pre-Rheumatoid Arthritis and Non-Rheumatoid Arthritis Community Cohort. J Innate Immun. 2013; 5(2):100-113. https://doi.org/10.1159/000345700.
17. Karlson, E. W.; Schaardenburg, D. Van; Mil, A. H. V. D. H. RA .From Risk Factors and Pathogenesis to Prevention Strategies to Predict Rheumatoid Arthritis Development in at-Risk Populations. Rheumatology (Oxford), 2016; 55(1):6-15 ttps: //do i.or g/10 .109 3/rh eu matology/keu287.
18. Carbonell-bobadilla, N.; Soto-fajardo, C.; Amezcua-guerra, L. M.; Batres-marroquín, A. B.; Vargas, T.; Hernández-diazcouder, A.; Jiménez-rojas, V.; Medina-garcía, A. C.; Pineda, C.; Silveira, L. H. Patients with Seronegative Rheumatoid Arthritis Have a Di Erent Phenotype than Seropositive Patients : A Clinical and Ultrasound Study. Front Med (Lausanne). 2022, 16(9):978351. doi: 1 0. 3 38 9/fmed.2022.978351. PMID: 36052337; PMCID: PM C94 24641
19. Nair, B.; Taylor-gjevre, R.; Wu, L.; Jin, S.; Quail, J. M. Incidence and Prevalence of Rheumatoid Arthritis in Saskatchewan, Canada : BMC Rheumatol. 2019, 18(3):28. doi: 10.1186/s41927-019-0077-4. PMID: 31360913; PMCID: PMC6637565.
20. Ali, E. T.; Jabbar, A. S.; Mohammed, A. N. A Comparative Study of Interleukin 6, Inflammatory Markers, Ferritin, and Hematological Profile in Rheumatoid Arthritis Patients with Anemia of Chronic Disease and Iron Deficiency Anemia. Anemia.2019, 1:2019:3457347. doi: 10.1155/2019/3457347.
21. Teixeira, S.; Almeida, M.; Vicente, J.; Almeida, M.; Bertolo, M. B. Características Demográficas e Clínicas de Pacientes Com Artrite Reumatoide No Piauí , Brasil – Avaliac ¸ Ão de 98 Pacientes ଝ. Rev Bras Reumatol. 2014 ,54(5):360-5. Portuguese. https:// doi.org / 10.1 016/j.rbr.2014.02.005. PMID: 25627299.
22. Mathkhor, A. J.; Khoudhairy, A. H. A. & A. S. Demographic, Clinical, and Serological Features of Iraqi Patients with Rheumatoid Arthritis: Evaluation of 470 Patients. Int. J. Clin. Rheumtol. 2021, 16 (3), 099-103.
23. Pluchino, N.; Canny, G.; Gabay, C.; Finckh, A. Review The Role of Female Hormonal Factors in the Development of Rheumatoid Arthritis. Rheumatology, 2017; 56 (8): 1254–1263. https:/ /d oi. org/10.1093/rheumatology/kew318.
24. Namas, R.; Joshi, A.; Ali, Z.; Saleh, J. Al; Abuzakouk, M. Demographic and Clinical Patterns of Rheumatoid Arthritis in an Emirati Cohort from United Arab Emirates. Int J Rheumatol. 2019 Int J Rheumatol. 2019 Sep 25; 2019:3057578. doi: 10.1155/2 019 /357578. PMID: 31662761; PMCID: PMC6778867.
25. George MD, Baker JF. The Obesity Epidemic and Consequences for Rheumatoid Arthritis Care. Curr Rheumatol Rep. 2016 Jan;18(1):6. doi: 10.1007/s11926-015-0550-z. PMID: 26739963; PMCID: PMC4809046.
26. Baker, J. F.; Østergaard, M.; George, M.; Shults, J.; Emery, P.; Baker, D. G.; Conaghan, P. G. Greater Body Mass Independently Predicts Less Radiographic Progression on X-Ray and MRI over 1 – 2 Years. Ann Rheum Dis. 2014;73(11):1923-8.2014, 1923–1928. https://doi.org/10.1136/annrheumdis-2014-205544.
27. George, M. D.; Østergaard, M.; Conaghan, P. G.; Emery, P.; Baker, D. G.; Baker, J. F. Obesity and Rates of Clinical Remission and Low MRI Inflammation in Rheumatoid Arthritis. Ann Rheum Dis.2017 ;76(10):1743-1746. doi: 10.1136/annrheumdis-2017-21156 9. 2017, 1–4. https://doi.org/10.1136/annrheumdis-2017-211569.
28. Kong, D. H.; Kim, Y. K.; Kim, M. R.; Jang, J. H.; Lee, S. Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. Int. J. Mol. Sci. 2018, 19 (4), 13–17. https://doi.org/10.3390/ijms19041057.
29. Saner, C.; Sonawale, A.; Mulkalwar, A.; Sonawale, K.; Keswani, R. A Comparative Study of Patients with Seropositive and Seronegative Rheumatoid Arthritis. Rheumatol Immunol Res. 2024 r 31; 5(1):57-65. doi: 10.1515/rir-2024-0007. PMID: 3857 1932; PMCID: PMC10985701.
30. Barra L, Pope JE, Orav JE, Boire G, Haraoui B, Hitchon C, Keystone EC, Thorne JC, Tin D, Bykerk VP; CATCH Investigators. Prognosis of seronegative patients in a large prospective cohort of patients with early inflammatory arthritis. J Rheumatol. 2014;41(12):2361-9. doi: 10.3899/jrheum.140082. 2014. PMID: 252 74 8 84.
31. Report, E. Anti-CCP Antibody Test Predicts the Disease Course during 3 Years in Early Rheumatoid Arthritis (the Swedish TIRA Project). Ann Rheum Dis, 2004, 63(9):1085–10 9 0 . https:/ /doi. Org /10.1136/ard.2003.016808.
32. Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B; BARFOT Study Group. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004 Sep; 63(9):1090-5. doi: 10.1136/ard.2003.014233. PMID: 15308 8; PMCID: PMC1755129.
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Jul 15, 2024
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Comparative analyses of immune marker levels in seronegative and seropositive Iraqi rheumatoid arthritis patients. Iraqi Natl J Med [Internet]. 2024 Jul. 15 [cited 2024 Oct. 10];6(2):91-8. Available from: https://www.iqnjm.com/index.php/homepage/article/view/200
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Author Biographies
Ahmed Aledany, a:1:{s:2:"en";s:3:"MOH";}
master student ,Department of Clinical Laboratory Sciences,
College of Pharmacy,
University of Basrah
Eman T. Ali, Department of Clinical Laboratory Sciences, College of Pharmacy, University of Basrah, Basrah, Iraq
Assistant Professor in Immunology
Ali Nazar Mohammed, Rheumatologist, Rheumatology Department, Alsayab Teaching Hospital, Basrah, Iraq
Consultant Rheumatologist, Rheumatology Department
Falah Hassan Shari, College of Pharmacy, University of Almaaqal, Basrah, Iraq
professor in clinical biochemistry
College of Pharmacy, University of Almaaqal, Basrah, Iraq