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For Peer Review Only Journal: BMJ Open BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-009092 on 11 November 2015. Downloaded from HLA-B15 confers preferential susceptibility to peripheral spondyloarthritis while HLA-B27 preferentially relates to axial spondyloarthritis For peer review only Journal: BMJ Open Manuscript ID: bmjopen-2015-009092 Article Type: Research Date Submitted by the Author: 16-Jun-2015 Complete List of Authors: LONDONO, JOHN; Universidad de La Sabana, Rheumatology; Universidad de Navarra, Department of Internal Medicine Santos, Ana; Universidad de La Sabana, Immunology Peña, Paola; Hospital Militar Central, Rheumatology Calvo, Enrique; Universidad Nacional de Colombia, Radiology Espinosa, Luis; Louisiana State University, LSU Health Sciences Center Reveille, John; University of Texas Health Science Center, USA, Department of Internal Medicine, Division of Rheumatology and Clinical Immunogenetics Vargas-Alarcon, Gilberto; Inst Nacl Cardiol Ignacio, Jaramillo, Calos; Universidad de Los Andes, Department of Biological Sciences Valle-Oñate, Rafael; Hospital Militar Central, Rheumatology Avila, Mabel; Hospital Militar Central, Dirección de Educación e http://bmjopen.bmj.com/ Investigacion Romero, Consuelo; Hospital Militar Central, Rheumatology Medina, Juan; Universidad de Navarra, Internal Medicine <b>Primary Subject Rheumatology Heading</b>: Secondary Subject Heading: Immunology (including allergy) spondyloarthritis, axial spondyloarthritis, peripheral spondyloarthrtis, HLA- on September 29, 2021 by guest. Protected copyright. Keywords: B27, HLA-B15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 26 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-009092 on 11 November 2015. Downloaded from HLA-B15 and preferential susceptibility to pSpA 1 1 2 3 4 5 6 7 8 9 HLA-B15 confers preferential susceptibility to peripheral 10 11 12 spondyloarthritis while HLA-B27 preferentially relates to axial 13 14 15 spondyloarthritisFor peer review only 16 17 18 19 John Londono1, Ana Maria Santos1, Paola Peña1, Enrique Calvo2, Luis R. Espinoza3, 20 21 John D. Reveille4, Gilberto Vargas-Alarcon5, Carlos A. Jaramillo6, Rafael Valle-Oñate7, 22 23 Mabel Avila1,7, Consuelo Romero7 and Juan F. Medina8 24 25 26 27 28 1Department of Rheumatology, University of La Sabana, Chia, Cundinamarca, Colombia, 2Department of 29 Radiology, National University of Colombia, Bogota, Colombia, 3LSU Health Sciences Center, Louisiana 30 4 31 State University, New Orleans, USA, Division of Rheumatology and Clinical Immunogenetics, 32 Department of Internal Medicine, University of Texas Health Science Center, Houston, USA, 5 33 Interventional Genetic Study Group in Cardiovascular Diseases, Department of Molecular Biology, 6 34 National Institute of Cardiology Ignacio Chávez, Mexico DF, Department of Biological Sciences, http://bmjopen.bmj.com/ 35 University of Los Andes, Bogota, Colombia, 7Rheumatology and Immunology Unit, Department of Internal 36 Medicine, Hospital Militar Central, Bogota, Colombia, 8Department of Internal Medicine, School of 37 Medicine and Center for Applied Medical Research (CIMA), University of Navarra and Ciberehd, 38 Pamplona, Spain. 39 40 41 42 on September 29, 2021 by guest. Protected copyright. 43 44 Correspondence to: John Londono, MD, Department of Rheumatology, University of La Sabana and 45 Hospital Militar Central, Campus del Puente del Comun, Km. 7, Autopista Norte de Bogotá. CP 250001, 46 Chía, Cundinamarca, Colombia. Tel. (571)-8613503; FAX: (571)-8615618. E-mail: 47 48 [email protected] 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 26 BMJ Open: first published as 10.1136/bmjopen-2015-009092 on 11 November 2015. Downloaded from HLA-B15 and preferential susceptibility to pSpA 2 1 2 3 Abstract 4 5 Objective. HLA-B27 and B15 are associated with spondyloarthritis (SpA). Recent ASAS criteria 6 7 emphasize a distinction between SpA with axial and peripheral pattern. We analyzed whether HLA-A, -B 8 and -DRB1 alleles could associate with these patterns. 9 10 Methods. We studied 100 healthy individuals and 178 patients with SpA according to ESSG criteria. 11 12 Patients were then classified according to ASAS criteria, the axial pattern (axSpA) being defined by 13 ascertained sacroiliitis and the peripheral pattern (pSpA) by enthesitis and/or arthritis in extremities. A 14 15 mixed ax/p patternFor was also considered.peer review only 16 17 Results. Only HLA-B27 and -B15 alleles were associated with SpA. ASAS criteria for axSpA were met in 18 152 patients (12 with pure axSpA and 140 with a mixed ax/p pattern). When the ASAS peripheral criteria 19 20 were applied, 161 patients met these criteria (13 with pure pSpA and 148 with a mixed ax/p pattern). 21 HLA-B27 was found in 83% of patients with axSpA and 43% of ax/pSpA patients according to axASAS. 22 23 HLA-B27 occurred in 7% controls but not in any patient with pure pSpA. HLA-B15 was encountered in 24 31% of patients with pure pSpA and 20% of ax/pSpA patients according to pASAS criteria. Moreover, 2 25 26 healthy controls, but none of our patients with pure axSpA were positive for HLA-B15. 27 28 Conclusion. Our data suggest that the presence of HLA-B15 favors the development of pure/mixed 29 peripheral rather than pure axSpA, while HLA-B27 promotes a pure/mixed axial disease and exclude a 30 31 peripheral pattern. HLA-B15 should be considered in addition to HLA-B27 when diagnosing SpA patients 32 according to ASAS criteria. 33 34 http://bmjopen.bmj.com/ 35 36 37 Key words: spondyloarthritis; axial spondyloarthritis; peripheral spondyloarthrtis, HLA-B27; HLA-B15. 38 39 Strengths and limitations of this study 40 41 • The HLA-B15 has been associated with SpA and oligoarthritis in different populations. This study 42 on September 29, 2021 by guest. Protected copyright. 43 clearly establishes this association, through a detailed analysis of the clinical and radiological aspects 44 in a group of patients not Anglo-Saxon origin. 45 46 • In this study, conducted on a group of Latin American patients with SpA, the presence of HLA-B15 47 and HLA-B27 clearly influence the pattern of presentation of the disease. The HLA-B15 favors a 48 preferably peripheral pattern while the HLA-B27 promotes a pure/mixed axial disease and exclude a 49 50 pure peripheral pattern. 51 • HLA-B15 should be considered in addition to HLA-B27 when diagnosing SpA Colombian patients 52 53 according to ASAS criteria. 54 55 • This study use the ASAS criteria in an alternating manner to discriminate the association of the 56 disease with the HLA-B27 and HLA-B15. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 26 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-009092 on 11 November 2015. Downloaded from HLA-B15 and preferential susceptibility to pSpA 3 1 2 3 • The results of this study need to be verified in a research involving a larger number of patients with 4 5 SpA. 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 29, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 26 BMJ Open: first published as 10.1136/bmjopen-2015-009092 on 11 November 2015. Downloaded from HLA-B15 and preferential susceptibility to pSpA 4 1 2 3 Introduction 4 5 Spondyloarthritis (SpA) comprises a group of inflammatory chronic diseases that share similar clinical 6 7 presentations, radiological findings, HLA-B27 association, and positive family history.[1] According to the 8 9 European Spondyloarthropathy Study Group (ESSG) criteria,[2] SpA has been traditionally classified as 10 11 follows: ankylosing spondylitis (AS), reactive arthritis (ReA), undifferentiated spondyloarthritis (uSpA), 12 13 psoriatic arthritis (PsA), and arthritis associated with inflammatory bowel disease (IBD).[3] Its prevalence 14 15 varies from 0.1 toFor 1.4% of thepeer general population review depending on onlythe geographical region studied.[4] 16 17 Predominantly, SpA begins in individuals younger than 45 years of age and clinically compromises the 18 19 axial spine, peripheral joints, tendons and ligament insertions (entheses), having also extra- 20 21 musculoskeletal manifestations in the skin, mucosa, gut and the eyes.[5] 22 23 HLA-B27 is the biggest risk factor for the development of SpA, and while it does have a central role 24 25 in its etiopathogenesis, the association is not the same across all ethnic groups.[6] It has been estimated 26 27 that this allele is responsible for up to 28% of the etiology of SpA.[7] But there are other factors that 28 29 impact on the onset of the disease, such as environmental factors, and other genetic factors, including 30 31 those within the Major Histocompatibility Complex (MHC) Class I − HLA-B60/B40,[8] -B39,[9] -B14,[10] 32 33 and -B15[11] − and Class II − DRB1[12] − alleles. 34 http://bmjopen.bmj.com/ 35 Current new technologies are allowing more specific examination of disease susceptibility, such as 36 37 those that look at Single Nucleotide Polymorphisms (SNPs), Genome-Wide Association Studies (GWAS) 38 39 and genomic resequencing which underscore the polygenic nature of SpA.[13 14] There are more than 40 41 40 genes implicated in the pathogenesis of SpA which may also affect the clinical manifestations, 42 on September 29, 2021 by guest. Protected copyright. 43 including the age of onset and the duration and severity of the disease.[15] 44 45 The diagnosis of SpA is made principally based on clinical, radiologic, and laboratory findings.
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