ASSOCIATION OF HLA-B AND HLA-DRB1 LOCI AND INFLAMMATORY CYTOKINES WITH THE CLINICAL PRESENTATION OF PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS
Keywords:
Juvenile idiopathic arthritis, HLA-B, HLA-DRB1, inflammatory cytokines, IL-1, IL-6, TNF-alpha, biological therapyAbstract
Juvenile idiopathic arthritis (JIA) is the most common rheumatic chronic disease in childhood presented with various clinical symptoms of arthritis in children younger than 16 years.The aim of this study was to evaluate the correlation between HLA-B, HLA-DRB1 and inflammatory cytokines with the clinical presentation of juvenile idiopathic arthritis.
In this study, we analyzed 35 patients with juvenile idiopathic arthritis diagnosed at the University Clinic for Pediatric Diseases in Skopje, North Macedonia in the period from 2018 - 2024. All patients fulfilled the inclusion criteria for entering the study, that is, the ILAR reevaluated criteria from 2001 for diagnosis of juvenile idiopathic arthritis. Patients were genotyped for HLA-B and HLA-DRB1 loci. Concentrations of IL-1, IL-6 and TNF-alpha were determined in patients’ serum at two time points, before starting the treatment and 6 months after therapy. These analyses were performed at the Institute of Immunobiology and Human Genetics, Faculty of Medicine in Skopje, North Macedonia.
The most frequent HLA-B allelic groups in our patients were HLA-B*27, B*35 and B*18, whilst in HLA-DRB1 locus the most frequent were DRB1*11, *01, *04 and *16. Increased risk for development of JIA was detected for HLA-B27 (p=0.001959, OR=3.39), B*15 (p=0.000058, OR=7.29) and DRB1*08 (p=0.02758, OR=4.54). Cytokine levels in patients decreased after therapy.
Conclusion: HLA typing is important in JIA patients for detection of different subtypes and detection of the concentration of proinflammatory cytokines helps in the therapy management of these patients.
References
Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007; 369(9563): 767-778. doi: 10.1016/S0140-6736(07)60363-8.
Zaripova LN, Midgley A, Christmas SE, Beresford MW, Baildam EM, Oldershaw RA. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Pediatr Rheumatol Online J 2021; 19(1): 135. doi: 10.1186/s12969-021-00629-8.
Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31(2): 390-392. PMID: 14760812.
Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011; 377(9783): 2138-2149. doi: 10.1016/S0140-6736(11)60244-4.
Stoll ML, Punaro M. Psoriatic juvenile idiopathic arthritis: a tale of two subgroups. Curr Opin Rheumatol 2011; 23(5): 437-443. doi: 10.1097/BOR.0b013e328348b278.
Martini A. Systemic juvenile idiopathic arthritis. Autoimmun Rev 2012; 12(1): 56-59. doi: 10.1016/j.autrev.2012.07.022.
Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol 2016; 68(3): 566-576. doi: 10.1002/art.39332.
Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Caifeng Li, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol 2014; 66(11): 3160-3169. doi: 10.1002/art.38802.
Rigante D, Bosco A, Esposito S. The Etiology of Juvenile Idiopathic Arthritis. Clin Rev Allergy Immunol 2015; 49(2): 253-261. doi: 10.1007/s12016-014-8460-9.
Twilt M, Pradsgaard D, Spannow AH, Horlyck A, Heuck C, Herlin T. Joint cartilage thickness and automated determination of bone age and bone health in juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2017; 15(1): 63. doi: 10.1186/s12969-017-0194-9.
De Silvestri A, Capittini C, Poddighe D, Marseglia GL, Mascaretti L, Bevilacqua E, et al. HLA-DRB1 alleles and juvenile idiopathic arthritis: Diagnostic clues emerging from a meta-analysis. Autoimmun Rev 2017; 16(12): 1230-1236. doi: 10.1016/j.autrev. 2017.10.007.
Hollenbach JA, Thompson SD, Bugawan TL, Ryan M, Sudman M, Marion M, et al. Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects. Arthritis Rheum 2010; 62(6): 1781-1791. doi: 10.1002/art.27424.
Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: A comprehensive review. J Autoimmun 2015; 64: 113-124. doi: 10.1016/j.jaut.2015. 08.002.
Cobb JE, Hinks A, Thomson W. The genetics of juvenile idiopathic arthritis: current understanding and future prospects. Rheumatology (Oxford) 2014; 53(4): 592-599. doi: 10.1093/rheumatology/ket314.
Prahalad S, Glass DN. A comprehensive review of the genetics of juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2008; 6: 11. doi: 10.1186/1546-0096-6-11.
Arve-Butler S, Schmidt T, Mossberg A, Berthold E, Gullstrand B, Bengtsson AA, et al. Synovial fluid neutrophils in oligoarticular juvenile idiopathic arthritis have an altered phenotype and impaired effector functions. Arthritis Res Ther 2021; 23(1): 109. doi: 10.1186/s13075-021-02483-1.
Schmidt T, Berthold E, Arve-Butler S, Gullstrand B, Mossberg A, Kahn F, et al. Children with oligoarticular juvenile idiopathic arthritis have skewed synovial monocyte polarization pattern with functional impairment-a distinct inflammatory pattern for oligoarticular juvenile arthritis. Arthritis Res Ther 2020; 22(1): 186. doi: 10.1186/s13075-020-02279-9.
Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum 2013; 65(10): 2499-2512. doi: 10.1002/art.38092.
Balevic SJ, Rabinovich CE. Profile of adalimumab and its potential in the treatment of uveitis. Drug Des Devel Ther 2016; 10: 2997-3003. doi: 10.2147/DDDT.S94188.
Ferrara G, Mastrangelo G, Barone P, La Torre F, Martino S, Pappagallo G, et al. Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting. Pediatr Rheumatol Online J 2018; 16(1): 46. doi: 10.1186/s12969-018-0255-8.
Papadopoulou C, Kostik M, Böhm M, Nieto-Gonzalez JC, Gonzalez-Fernandez MI, Pistorio A, et al. Methotrexate therapy may prevent the onset of uveitis in juvenile idiopathic arthritis. J Pediatr 2013; 163(3): 879-884. doi: 10.1016/j.jpeds.2013.03.047.
Ayaz NA, Karadağ ŞG, Çakmak F, Çakan M, Tanatar A, Sönmez HE. Leflunomide treatment in juvenile idiopathic arthritis. Rheumatol Int 2019; 39(9): 1615-1619. doi: 10.1007/s00296-019-04385-7.
Scott C, Meiorin S, Filocamo G, Lanni S, Valle M, Martinoli C, et al. A reappraisal of intra-articular corticosteroid therapy in juvenile idiopathic arthritis. Clin Exp Rheumatol 2010; 28(5): 774-781. PMID: 20863449.
Sasaki K, Ueno T. [CHARISMA study]. Nihon Rinsho. 2016; 74(Suppl 4) 1: 715-719. Japanese. PMID: 27534256.
Kirijas M, GenadievaStavrik S, Senev A, Efinska Mladenovska O, Petlichkovski A. HLA-A, -B, -C and -DRB1 allele and haplotype frequencies in the Macedonian population based on a family study. Hum Immunol 2018; 79(3): 145-153. doi: 10.1016/j.humimm.2017.12.003.
Spîrchez M, Samaşca G, Iancu M, Bolba C, Miu N. Relation of interleukin-6, TNF-alpha and interleukin-1alpha with disease activity and severity in juvenile idiopathic arthritis patients. Clin Lab 2012; 58(3-4): 253-260. PMID: 22582498. 26.
Rooney M, David J, Symons J, Di Giovine F, Varsani H, Woo P. Inflammatory cytokine responses in juvenile chronic arthritis. Br J Rheumatol 1995; 34(5): 454-460. doi: 10.1093/rheumatology/34.5.454.
