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Naovarat BS, Gensler L, Ward M, Hwang M, Tahanan A, Rahbar MH, Ishimori M, Lee M, Brown MA, Weisman MH, Reveille JD. Associations of sociodemographic, clinical factors and HLA-B alleles with enthesitis and peripheral arthritis in patients with ankylosing spondylitis. RMD Open 2025; 11:e004589. [PMID: 40081912 DOI: 10.1136/rmdopen-2024-004589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 11/20/2024] [Indexed: 03/16/2025] Open
Abstract
OBJECTIVES Factors associated with peripheral arthritis and enthesitis, especially Achilles tendonitis and plantar fasciitis, were examined in a longitudinal cohort of 1075 patients with ankylosing spondylitis (AS) (also known as radiographic axial spondyloarthritis). METHODS Patients were derived from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort. Disease activity and functional indices, as well as physical examination and medications used, were measured at every study visit. Univariable and multivariable analyses of the association of peripheral arthritis and enthesitis with clinical, sociodemographic factors were performed. Human leucocyte antigen (HLA)-B alleles were analysed by single-stranded conformational polymorphism analysis. RESULTS Those with peripheral arthritis on examination were more likely to have psoriasis (p=0.001, OR=1.68; CI, 1.11, 2.54), greater functional impairment (p<0.001 OR=1.72; CI, 1.31, 2.27), higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (p<0.001), greater tumour necrosis factor (TNF) inhibitor (p<0.001, OR=1.50; CI, 1.14, 1.97) and use methotrexate/sulfasalazine (p<0.001, OR=2.25, CI [1.57, 3.23]). Patients with enthesitis were less likely to be male (p<0.001, OR=0.57; CI, 0.43, 0.75) and have peripheral arthritis (p<0.001, OR=2.35; CI, 1.47, 3.75), greater functional impairment (p<0.001, OR=1.91; CI, 1.43, 2.55) and higher ESR/CRP levels (p<0.001). Patients with plantar fasciitis and/or Achilles' tendonitis on examination were less likely to male (p<0.001 OR=0.57; CI, 0.43, 0.75), to have significant functional impairment (p<0.001), to be using TNF inhibitors (p<0.001, OR=1.48; CI 1.13, 1.93) and to be using either sulfasalazine or methotrexate (p<0.001, OR=1.86, CI, 1.30, 2.67). HLA-B*15 (p=0.03, OR=1.84; CI, 1.05, 3.21) and HLA-B*37 (p=0.04, OR=3.00; CI, 1.03, 8.74) were marginally increased in frequency in those with peripheral arthritis on examination compared with those without. CONCLUSION There was a higher prevalence of peripheral musculoskeletal manifestations in women with AS, with significant impact on physical function and greater use of methotrexate or sulfasalazine and TNF inhibitors and enrichment for certain non-HLA-B27 HLA-B alleles.
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Affiliation(s)
- Benjamin Sornrung Naovarat
- Division of Rheumatology and Clinical Immunogenetics, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
| | - Lianne Gensler
- Division of Rheumatology, The University of California, San Francisco, California, USA
| | - Michael Ward
- Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
| | - Mark Hwang
- Division of Rheumatology and Clinical Immunogenetics, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
| | - Amirali Tahanan
- Division of Clinical and Translational Sciences, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
| | - Mohammad Hossein Rahbar
- Division of Clinical and Translational Sciences, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
| | - Mariko Ishimori
- Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - MinJae Lee
- Division of Biostatistics, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Matthew A Brown
- King's College London, London, UK
- Genomics England, London, UK
| | - Michael H Weisman
- Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - John D Reveille
- Division of Rheumatology and Clinical Immunogenetics, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
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Arnaiz-Villena A, Juarez I, Vaquero-Yuste C, Lledo T, Martin-Villa JM, Suarez-Trujillo F. Complex Interactions between the Human Major Histocompatibility Complex (MHC) and Microbiota: Their Roles in Disease Pathogenesis and Immune System Regulation. Biomedicines 2024; 12:1928. [PMID: 39200390 PMCID: PMC11352054 DOI: 10.3390/biomedicines12081928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/02/2024] Open
Abstract
The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota".
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Affiliation(s)
- Antonio Arnaiz-Villena
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Ignacio Juarez
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Christian Vaquero-Yuste
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Tomás Lledo
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - José Manuel Martin-Villa
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Fabio Suarez-Trujillo
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
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Frison E, Breban M, Costantino F. How to translate genetic findings into clinical applications in spondyloarthritis? Front Immunol 2024; 15:1301735. [PMID: 38327520 PMCID: PMC10847566 DOI: 10.3389/fimmu.2024.1301735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/08/2024] [Indexed: 02/09/2024] Open
Abstract
Spondyloarthritis (SpA) is characterized by a strong genetic predisposition evidenced by the identification of up to 50 susceptibility loci, in addition to HLA-B27, the major genetic factor associated with the disease. These loci have not only deepened our understanding of disease pathogenesis but also offer the potential to improve disease management. Diagnostic delay is a major issue in SpA. HLA-B27 testing is widely used as diagnostic biomarker in SpA but its predictive value is limited. Several attempts have been made to develop more sophisticated polygenic risk score (PRS). However, these scores currently offer very little improvement as compared to HLA-B27 and are still difficult to implement in clinical routine. Genetics might also help to predict disease outcome including treatment response. Several genetic variants have been reported to be associated with radiographic damage or with poor response to TNF blockers, unfortunately with lack of coherence across studies. Large-scale studies should be conducted to obtain more robust findings. Genetic and genomic evidence in complex diseases can be further used to support the identification of new drug targets and to repurpose existing drugs. Although not fully driven by genetics, development of IL-17 blockers has been facilitated by the discovery of the association between IL23R variants and SpA. Development of recent approaches combining GWAS findings with functional genomics will help to prioritize new drug targets in the future. Although very promising, translational genetics in SpA remains challenging and will require a multidisciplinary approach that integrates genetics, genomics, immunology, and clinical research.
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Affiliation(s)
- Eva Frison
- UMR1173, INSERM, UFR Simone Veil, Versailles-Saint-Quentin-Paris-Saclay University, Saint-Quentin-en-Yvelines, France
- Labex Inflamex, Paris Diderot Sorbonne Paris-Cité University, Paris, France
| | - Maxime Breban
- UMR1173, INSERM, UFR Simone Veil, Versailles-Saint-Quentin-Paris-Saclay University, Saint-Quentin-en-Yvelines, France
- Labex Inflamex, Paris Diderot Sorbonne Paris-Cité University, Paris, France
- Rheumatology Division, Ambroise Paré Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Boulogne-Billancourt, France
| | - Félicie Costantino
- UMR1173, INSERM, UFR Simone Veil, Versailles-Saint-Quentin-Paris-Saclay University, Saint-Quentin-en-Yvelines, France
- Labex Inflamex, Paris Diderot Sorbonne Paris-Cité University, Paris, France
- Rheumatology Division, Ambroise Paré Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Boulogne-Billancourt, France
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Orsini F, Crotti C, Cincinelli G, Di Taranto R, Amati A, Ferrito M, Varenna M, Caporali R. Bone Involvement in Rheumatoid Arthritis and Spondyloartritis: An Updated Review. BIOLOGY 2023; 12:1320. [PMID: 37887030 PMCID: PMC10604370 DOI: 10.3390/biology12101320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/02/2023] [Accepted: 10/06/2023] [Indexed: 10/28/2023]
Abstract
Several rheumatologic diseases are primarily distinguished by their involvement of bone tissue, which not only serves as a mere target of the condition but often plays a pivotal role in its pathogenesis. This scenario is particularly prominent in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Given the immunological and systemic nature of these diseases, in this review, we report an overview of the pathogenic mechanisms underlying specific bone involvement, focusing on the complex interactions that occur between bone tissue's own cells and the molecular and cellular actors of the immune system, a recent and fascinating field of interest defined as osteoimmunology. Specifically, we comprehensively elaborate on the distinct pathogenic mechanisms of bone erosion seen in both rheumatoid arthritis and spondyloarthritis, as well as the characteristic process of aberrant bone formation observed in spondyloarthritis. Lastly, chronic inflammatory arthritis leads to systemic bone involvement, resulting in systemic bone loss and consequent osteoporosis, along with increased skeletal fragility.
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Affiliation(s)
- Francesco Orsini
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy (A.A.)
- Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Chiara Crotti
- Bone Diseases Unit, Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Gilberto Cincinelli
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy (A.A.)
- Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Raffaele Di Taranto
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy (A.A.)
- Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Andrea Amati
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy (A.A.)
- Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Matteo Ferrito
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy (A.A.)
- Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Massimo Varenna
- Bone Diseases Unit, Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
| | - Roberto Caporali
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy (A.A.)
- Department of Rheumatology and Medical Sciences, ASST G.Pini-CTO, 20122 Milan, Italy
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Jo S, Lee SH, Jeon C, Jo HR, Ko E, Whangbo M, Kim TJ, Park YS, Kim TH. Elevated BMPR2 expression amplifies osteoblast differentiation in ankylosing spondylitis. JOURNAL OF RHEUMATIC DISEASES 2023; 30:243-250. [PMID: 37736586 PMCID: PMC10509643 DOI: 10.4078/jrd.2023.0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/31/2023] [Accepted: 06/21/2023] [Indexed: 09/23/2023]
Abstract
Objective Bone morphogenetic protein receptor type 2 (BMPR2) has been associated with radiographic changes in ankylosing spondylitis (AS), but further characterization of the cellular signaling pathway in osteoprogenitor (OP) is not clearly understood. The aim of this study was to investigate the expression of BMPR2 and bone morphogenetic protein 2 (BMP2)-mediated responsibility in AS. Methods We collected 10 healthy control (HC) and 14 AS-OPs derived from facet joints. Subsequently, we then conducted RNA sequencing with two samples per group and selected BMP-related genes. Facet joint tissues and derived primary OPs were evaluated by validation of selected RNA sequencing data, immunohistochemistry, and comparison of osteogenic differentiation potential. Results Based on RNA-sequencing analysis, we found that BMPR2 expression is higher in AS-OPs compared to in HC-OPs. We also validated the increased BMPR2 expression in facet joint tissues with AS and its derived OPs in messenger RNA and protein levels. Additionally, primary AS-OPs showed much greater response to osteogenic differentiation induced by BMP2 and a higher capacity for smad1/5/8-induced RUNX2 expression compared to HCs. Conclusion The expression of BMPR2 was found to be significantly increased in facet joint tissues of patients with AS. These findings suggest that BMPR2 may play a role in the BMP2-mediated progression of AS.
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Affiliation(s)
- Sungsin Jo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
| | - Seung Hoon Lee
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
| | - Chanhyeok Jeon
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Hye-Ryeong Jo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
| | - Eunae Ko
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Min Whangbo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Tae-Jong Kim
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Korea
| | - Ye-Soo Park
- Department of Orthopedic Surgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Tae-Hwan Kim
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
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Ward MM, Tan S. Syndesmophyte Growth in Ankylosing Spondylitis: from Laboratory to Bedside. Curr Rheumatol Rep 2023:10.1007/s11926-023-01104-x. [PMID: 37126093 DOI: 10.1007/s11926-023-01104-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2023] [Indexed: 05/02/2023]
Abstract
PURPOSE OF REVIEW This study aims to review recent studies on risk factors for syndesmophyte growth in ankylosing spondylitis (AS) and on treatment effects. RECENT FINDINGS New genetic studies, including a genome-wide association study, provided only limited evidence of specific genetic associations with radiographic severity. Measures of inflammation, including vertebral osteitis and C-reactive protein level, were strongly associated with radiographic progression, while studies of adipokines had mixed results. Mesenchymal stem cells from HLA-B27 positive AS patients were found to promote vertebral ossification via a pathway of B27 misfolding, retinoic acid receptor-β activation, and increased bone alkaline phosphatase. Low vertebral trabecular bone density is associated with syndesmophyte growth, with reciprocal effects when bridged. Several observational studies suggested radiographic severity was reduced by treatment with tumor necrosis factor inhibitors, particularly when longer than 2 years. Syndesmophyte development in AS is the result of a complex, incompletely understood, interplay of inflammatory and mechanical factors.
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Affiliation(s)
- Michael M Ward
- Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10CRC, Room 4-1339, 10 Center Drive, Bethesda, MD, 20892, USA.
| | - Sovira Tan
- Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10CRC, Room 4-1339, 10 Center Drive, Bethesda, MD, 20892, USA
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Nam B, Jo S, Bang SY, Park Y, Shin JH, Park YS, Lee S, Joo KB, Kim TH. Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis. Ann Rheum Dis 2023; 82:527-532. [PMID: 36543524 PMCID: PMC10086301 DOI: 10.1136/ard-2022-222796] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To identify clinical and genetic factors associated with severe radiographic damage in patients with ankylosing spondylitis (AS). METHODS We newly generated genome-wide single nucleotide polymorphism data (833K) for 444 patients with AS. The severity of radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). To identify clinical and genetic factors associated with severe radiographic damage, multiple linear regression analyses were performed. Human AS-osteoprogenitor and control-osteoprogenitor cells were used for functional validation. RESULTS The significant clinical factors of final mSASSS were baseline mSASSS (β=0.796, p=3.22×10-75), peripheral joint arthritis (β=-0.246, p=6.85×10-6), uveitis (β=0.157, p=1.95×10-3), and smoking (β=0.130, p=2.72×10-2) after adjusting for sex, age and disease duration. After adjusting significant clinical factors, the Ryanodine receptor 3 (RYR3) gene was associated with severe radiographic damage (p=1.00×10-6). For pathway analysis, the PI3K-Akt signalling pathway was associated with severe radiographic damage in AS (p=2.21×10-4, false discovery rate=0.040). Treatment with rhodamine B, a ligand of RYR3, dose-dependently induced matrix mineralisation of AS osteoprogenitors. However, the rhodamine B-induced accelerated matrix mineralisation was not definitive in control osteoprogenitors. Knockdown of RYR3 inhibited matrix mineralisation in SaOS2 cell lines. CONCLUSIONS This study identified clinical and genetic factors that contributed to better understanding of the pathogenesis and biology associated with radiographic damage in AS.
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Affiliation(s)
- Bora Nam
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, South Korea
| | - Sungsin Jo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, South Korea
| | - So-Young Bang
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, South Korea
| | - Youngho Park
- Department of Big Data Application College of Smart Convergence, Hannam University, Daejeon, South Korea
| | - Ji Hui Shin
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Ye-Soo Park
- Department of Orthopaedic Surgery, Hanyang University College of Medicine, Guri Hospital, Guri, South Korea
| | - Seunghun Lee
- Department of Radiology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Kyung Bin Joo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, South Korea
| | - Tae-Hwan Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul, South Korea
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Özdemirel AE, Güven SC, Doğancı A, Sarı Sürmeli Z, Özyuvalı A, Kurt M, Rüstemova D, Hassan S, Yalçın Sayın AP, Tutkak H, Ataman Ş. Anti-tumor necrosis factor alpha treatment does not influence serum levels of the markers associated with radiographic progression in ankylosing spondylitis. Arch Rheumatol 2023; 38:148-155. [PMID: 37235120 PMCID: PMC10208618 DOI: 10.46497/archrheumatol.2023.9974] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/21/2022] [Indexed: 10/15/2023] Open
Abstract
OBJECTIVES The study aimed to determine the levels of change of the markers related to radiographic progression, such as Dickkopf-1 (DKK-1), sclerostin (SOST), bone morphogenetic protein (BMP)-2 and -4, and interleukin (IL)-17 and -23, in ankylosing spondyloarthritis (AS) during anti-tumor necrosis factor alpha (TNF-α) treatment. PATIENTS AND METHODS Fifty-three anti-TNF-α naïve AS patients (34 males, 19 females; median: 38 years; range, 20 to 52 years) refractory to conventional treatments meeting the modified New York criteria or Assessment of SpondyloArthritis International Society classification criteria were enrolled to this cross-sectional, controlled study between October 2015 and January 2017. Fifty healthy volunteers (35 males, 15 females; median: 36 years; range, 18 to 55 years) with similar age and sex characteristics were recruited. Serum DKK-1, BMP-2, BMP-4, SOST, IL-17, and IL-23 levels were measured in both groups. The serum levels of the markers were measured again after about two years (mean follow-up duration of 21.7±6.4 months) in AS patients who started anti-TNF-α treatment. Demographic, clinical characteristics, and laboratory parameters were recorded. The disease activity at the time of inclusion was assessed through the Bath Ankylosing Spondylitis Disease Activity Index. RESULTS Serum DKK-1, SOST, IL-17, and IL-23 levels in the AS group before anti-TNF-a treatment were significantly higher compared to the control group (p<0.01 for DKK-1, p<0.001 for others). There was no difference regarding serum BMP-4 levels, whereas BMP-2 levels were significantly higher in the control group (p<0.01). Forty (75.47%) AS patients had serum marker levels measured after anti-TNF-α treatment. No significant change was observed in the serum levels of these 40 patients measured 21.7±6.4 months after the initiation of anti-TNF-α treatment (p>0.05 for all). CONCLUSION In AS patients, there was no change in DKK-1/SOST, BMP, and IL-17/23 cascade with anti-TNF-α treatment. This finding may suggest that these pathways act independently of each other, and their local effects are not influenced by systemic inflammation.
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Affiliation(s)
| | - Serdar Can Güven
- Department of Rheumatology, Ankara City Hospital, Ankara, Türkiye
| | - Alper Doğancı
- Department of Physical and Rehabilitation Medicine, Erzurum Regional Training and Research Hospital, Erzurum, Türkiye
| | | | - Ayla Özyuvalı
- Department of Physical and Rehabilitation Medicine, HFM Beyazpınar Physical Medicine And Rehabilitation Centre, Ankara, Türkiye
| | - Mehmet Kurt
- Department of Physical and Rehabilitation Medicine, Dr. Ergun Özdemir Görele State Hospital, Giresun, Türkiye
| | - Diana Rüstemova
- Department of Physical and Rehabilitation Medicine, Can Private Hospital, Manisa, Türkiye
| | - Selin Hassan
- Department of Physical and Rehabilitation Medicine, Başkent University Medical School, Ankara, Türkiye
| | | | - Hüseyin Tutkak
- Department of Immunology and Allergy, Ankara University Medical School, Ankara, Türkiye
| | - Şebnem Ataman
- Department of Rheumatology, Ankara University Medical School, Ankara, Türkiye
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Sun X, Zhou C, Chen L, Huang S, Ye Z, Yi M, Liao S, Li H, Jiang J, Chen J, Chen W, Chen T, Guo H, Zhang S, Zhu J, Liang T, Zhan X, Liu C. Epidemiological characteristics of ankylosing spondylitis in Guangxi Province of China from 2014 to 2021. Arch Med Sci 2023; 19:1049-1058. [PMID: 37560717 PMCID: PMC10408009 DOI: 10.5114/aoms/159343] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/16/2023] [Indexed: 08/11/2023] Open
Abstract
INTRODUCTION To explore the epidemiological characteristics of ankylosing spondylitis (AS) in Guangxi Province of China through a large sample survey of more than 50 million aboriginal aboriginal population. MATERIAL AND METHODS A systematic search was conducted using the International Classification of Diseases 10 (ICD-10) codes M45.x00(AS), M45.x03+(AS with iridocyclitis), and M40.101(AS with kyphosis) to search the database in the National Health Statistics Network Direct Reporting System (NHSNDRS). 14004 patients were eventually included in the study. The parameters analyzed included the number of patients, gender, marriage, blood type, occupation, age at diagnosis, and location of household registration data each year, and statistical analysis was performed. RESULTS AS incidence rates increased from 1.30 (95% CI: 1.20-1.40) per 100,000 person-years in 2014 to 5.71 (95% CI: 5.50-5.92) in 2020 in Guangxi Province, and decreased slightly in 2021. Males have a higher incidence than females; the ratio was 5.61 : 1. The mean age of diagnosis in male patients was 45.4 (95% CI: 45.1-45.7) years, in females 47.6 (95% CI: 46.8-48.4) years. The most frequent blood type was O, and the most frequent occupation was farmer. The AS incidence rate was disparate in different cities. Liuzhou city had the highest eight-year average AS incidence rates from 2014 to 2021, and Chongzuo city had the lowest (p < 0.05). There was no significant difference in the incidence between different ethnic groups (p > 0.05). CONCLUSIONS The AS person-years incidence rate was increasing in Guangxi province of China from 2014 to 2020, which had obvious gender and regional differences, showing the characteristics of local area aggregation.
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Affiliation(s)
- Xuhua Sun
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Chenxing Zhou
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Liyi Chen
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shengsheng Huang
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhen Ye
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ming Yi
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shian Liao
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Li
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jie Jiang
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jiarui Chen
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wuhua Chen
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Tianyou Chen
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Guo
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shiqing Zhang
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jichong Zhu
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Tuo Liang
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xinli Zhan
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Chong Liu
- Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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10
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Fatica M, D'Antonio A, Novelli L, Triggianese P, Conigliaro P, Greco E, Bergamini A, Perricone C, Chimenti MS. How Has Molecular Biology Enhanced Our Undertaking of axSpA and Its Management. Curr Rheumatol Rep 2023; 25:12-33. [PMID: 36308677 PMCID: PMC9825525 DOI: 10.1007/s11926-022-01092-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2022] [Indexed: 01/11/2023]
Abstract
PURPOSE This review aims at investigating pathophysiological mechanisms in spondyloarthritis (SpA). Analysis of genetic factors, immunological pathways, and abnormalities of bone metabolism lay the foundations for a better understanding of development of the axial clinical manifestations in patients, allowing physician to choose the most appropriate therapeutic strategy in a more targeted manner. RECENT FINDINGS In addition to the contribution of MHC system, findings emerged about the role of non-HLA genes (as ERAP1 and 2, whose inhibition could represent a new therapeutic approach) and of epigenetic mechanisms that regulate the expression of genes involved in SpA pathogenesis. Increasing evidence of bone metabolism abnormalities secondary to the activation of immunological pathways suggests the development of various bone anomalies that are present in axSpA patients. SpA are a group of inflammatory diseases with a multifactorial origin, whose pathogenesis is linked to the genetic predisposition, the action of environmental risk factors, and the activation of immune response. It is now well known how bone metabolism leads to long-term structural damage via increased bone turnover, bone loss and osteoporosis, osteitis, erosions, osteosclerosis, and osteoproliferation. These effects can exist in the same patient over time or even simultaneously. Evidence suggests a cross relationship among innate immunity, autoimmunity, and bone remodeling in SpA, making treatment approach a challenge for rheumatologists. Specifically, treatment targets are consistently increasing as new drugs are upcoming. Both biological and targeted synthetic drugs are promising in terms of their efficacy and safety profile in patients affected by SpA.
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Affiliation(s)
- Mauro Fatica
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Arianna D'Antonio
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lucia Novelli
- UniCamillus, Saint Camillus International University of Health Sciences, Rome, Italy
| | - Paola Triggianese
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Paola Conigliaro
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Elisabetta Greco
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Alberto Bergamini
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maria Sole Chimenti
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
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11
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Reveille JD, Ridley LK. Spondyloarthritis. Clin Immunol 2023. [DOI: 10.1016/b978-0-7020-8165-1.00058-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
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12
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Wu F, Han X, Liu J, Zhang Z, Yan K, Wang B, Yang L, Zou H, Yang C, Huang W, Jin L, Wang J, Qian F, Niu Z. An ankylosing spondylitis risk variant alters osteoclast differentiation. Rheumatology (Oxford) 2022; 62:1980-1987. [PMID: 36124946 DOI: 10.1093/rheumatology/keac542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/08/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To explore whether the variants in non-MHC proteasome gene is associated with ankylosing spondylitis and explain the role of the variant in the disease. METHODS Case-control analysis to identify ankylosing spondylitis predisposition genes; dual-luciferase reporter assay, immunoblot analysis and osteoclastogenesis assays to detect the function of the positive variant. Affected individuals was diagnosed according to the modified New York Criteria by at least two experienced rheumatologists, and rechecked by another rheumatologist. RESULTS The study included 1037 AS patients and 1014 no rheumatic and arthritis disease controls. The main age of AS onset is between 16 and 35 years old. HLA-B27-positive subjects comprised 90.0% of patients. A nonsynonymous SNP rs12717 in proteasome gene PSMB1 significantly associated with ankylosing spondylitis. Individuals with CC genotype had a higher onset risk compared with those with GG/GC genotypes (OR = 1.89, p= 0.0047). We also discovered that PSMB1 regulates the receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) signalling pathway and the disease-associated variant PSMB1-Pro11 significantly inhibits RANKL-induced NF-κB pathway in osteoclast differentiation via the degradation of IKK-β compared with PSMB1-Ala11. RANKL induced osteoclast differentiation was significantly lower in primary monocyte osteoclast precursor from individuals with genotype PSMB131C/31C compared with individuals with genotype PSMB131G/31G. CONCLUSIONS These results reveal a novel understanding of the bone formation and reabsorbing imbalance in AS. The new bone formation phenotype can be attributed to the inhibition of osteoclast differentiation by a more functional PSMB1 gene.
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Affiliation(s)
- Fangyi Wu
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China
| | - Xuling Han
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China
| | - Jing Liu
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China
| | - Zhenghua Zhang
- Division of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Kexiang Yan
- Division of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Beilan Wang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Institute for Biomedical and Pharmaceutical Technologies; Shanghai, China
| | - Lin Yang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Institute for Biomedical and Pharmaceutical Technologies; Shanghai, China
| | - Hejian Zou
- Division of Rheumatology, Huashan Hospital, Fudan University; Shanghai, China
| | - Chengde Yang
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine; Shanghai, China
| | - Wei Huang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Institute for Biomedical and Pharmaceutical Technologies; Shanghai, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China
| | - Feng Qian
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China.,Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Zhenmin Niu
- State Key Laboratory of Genetic Engineering, Shanghai Public Health Clinical Center, Human Phenome Institute, Zhangjiang Fudan International Innovation Center and School of Life Sciences, Fudan University; Shanghai, China.,Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Institute for Biomedical and Pharmaceutical Technologies; Shanghai, China
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13
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van der Linden SM, Khan MA, Li Z, Baumberger H, Zandwijk HV, Khan MK, Villiger PM, Brown MA. Recurrence of axial spondyloarthritis among first-degree relatives in a prospective 35-year-follow-up family study. RMD Open 2022; 8:rmdopen-2022-002208. [PMID: 35868737 PMCID: PMC9315900 DOI: 10.1136/rmdopen-2022-002208] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 04/11/2022] [Indexed: 11/30/2022] Open
Abstract
Objective The lifetime recurrence rate (RR) of axial spondyloarthritis (axSpA) among first-degree relatives (FDR) and the effect of proband’s gender, HLA-B27 and radiographic status is unclear. Our 35-year-follow-up family study has enabled these issues to be addressed. Methods In 1985, 363 ankylosing spondylitis (AS) probands (members of the Swiss AS Patient Society) and 806 FDR recruited into the study, completed questionnaires regarding axSpA manifestations, underwent a physical examination and most also underwent pelvic radiography and HLA-B27 typing. At follow-up in 2018–2019, of the former participants whose current addresses could be retrieved, 162 had died and 485 (125 patients with AS plus 360 FDR) completed a postal questionnaire. Results At follow-up, 48 of 177 HLA-B27(+) FDR had developed axSpA, an RR of 27.1% (95% CI 20.6% to 33.7%). 27/148 (18.2%) children of AS probands (modified New York (mNY) criteria) were affected versus 2/50 (4.0%) children of non-radiographic axSpA probands (p=0.0138, OR=5.36; 95% CI 1.23 to 23.40). Children of female probands were more often affected (12/22; 54.5%) than of male probands (15/78; 19.2%) (p=0.0003; OR=4.89; 95% CI 1.96 to 12.23). This increased risk applies equally to sons and daughters. Conclusion The lifetime RR of axSpA for HLA-B27(+) FDR is substantial (27.1%), and disease severity (as defined by radiographic sacroiliitis by the mNY criteria) is an additional risk factor. Affected mothers pass on the disease significantly more often to their offspring than do affected fathers. These findings may lead to better assessment of lifetime risk for axSpA in the offspring. Moreover, investigation of this gender effect may uncover additional putative disease susceptibility factors.
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Affiliation(s)
- Sjef M van der Linden
- University of Bern, Bern, Switzerland .,Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Muhammad Asim Khan
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Zhixiu Li
- Centre for Genomics and Personalised Health, Brisbane, Queensland, Australia.,Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Heinz Baumberger
- Former President of the Swiss Ankylosing Spondylitis Patient Society, Flims, Switzerland
| | | | | | - Peter M Villiger
- University of Bern, Bern, Switzerland.,Department of Rheumatology and Clinical Immunology, Medical Center Monbijou, Bern, Switzerland
| | - Matthew A Brown
- Department of Medical and Molecular Genetics, King's College London Faculty of Life Sciences and Medicine, London, UK .,Genomics England, London, UK
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14
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Daoussis D, Kanellou A, Panagiotopoulos E, Papachristou D. DKK-1 Is Underexpressed in Mesenchymal Stem Cells from Patients with Ankylosing Spondylitis and Further Downregulated by IL-17. Int J Mol Sci 2022; 23:ijms23126660. [PMID: 35743102 PMCID: PMC9224314 DOI: 10.3390/ijms23126660] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 02/01/2023] Open
Abstract
Dickkopf-1 (Dkk-1) is a key regulator of bone remodeling in spondyloarthropathies. Nevertheless, data regarding its expression in cells of pathophysiologic relevance, such as mesenchymal stem cells (MSCs), are lacking. Herein, we aimed to address DKK1 gene expression and Wnt pathway activation in MSCs from patients with ankylosing spondylitis (AS) and explore the effect of IL-17 on MSCs with respect to DKK-1 expression and Wnt pathway activation. Primary MSCs were isolated from the bone marrow of the femoral head of two patients with AS and two healthy controls undergoing orthopedic surgery. MSCs were cultured for 7 days in expansion medium and for 21 days in osteogenic medium in the presence or absence of IL-17A. Gene expression of DKK-1 and osteoblastic markers was determined by RT-PCR. Alkaline phosphatase activity, alizarin red and Van Kossa staining were used to assess osteoblastic function and mineralization capacity. DKK-1 was significantly downregulated in MSCs and osteoblasts from patients with AS compared to controls. Moreover, MSCs and osteoblasts from AS patients displayed increased Wnt pathway activation and enhanced osteoblastic activity, as indicated by increased expression of osteoblast marker genes and alkaline phosphatase activity. IL-17 downregulated DKK-1 expression and increased osteoblastic activity and mineralization capacity. DKK-1 is underexpressed in MSCs from AS patients compared to controls, whereas IL-17 has an inhibitory effect on DKK-1 expression and stimulates osteoblastic function. These data may have pathogenetic and clinical implications in AS.
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Affiliation(s)
- Dimitrios Daoussis
- Department of Rheumatology, University of Patras Medical School, Patras University Hospital, 26504 Patras, Greece
- Correspondence: (D.D.); (A.K.); Tel.: +30-2613-603-693 (D.D.); Fax: +30-2610-993-982 (D.D.)
| | - Anastasia Kanellou
- Laboratory of Bone and Soft Tissue Studies, Department of Anatomy-Histology-Embryology, University of Patras Medical School, 26504 Patras, Greece;
- Correspondence: (D.D.); (A.K.); Tel.: +30-2613-603-693 (D.D.); Fax: +30-2610-993-982 (D.D.)
| | - Elias Panagiotopoulos
- Department of Orthopedics, University of Patras Medical School, Patras University Hospital, 26504 Patras, Greece;
| | - Dionysios Papachristou
- Laboratory of Bone and Soft Tissue Studies, Department of Anatomy-Histology-Embryology, University of Patras Medical School, 26504 Patras, Greece;
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15
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Li Z, van der Linden SM, Khan MA, Baumberger H, Zandwijk HV, Khan MK, Villiger PM, Brown MA. Heterogeneity of axial spondyloarthritis: genetics, sex and structural damage matter. RMD Open 2022; 8:rmdopen-2022-002302. [PMID: 35523521 PMCID: PMC9083385 DOI: 10.1136/rmdopen-2022-002302] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/06/2022] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVE Axial spondyloarthritis (axSpA) comprises both radiographic and non-radiographic disease. However, the paucity of specific objective measures for the disease and current classification criteria showing suboptimal specificity contribute to disease heterogeneity observed in clinical practice and research. We used a historical cohort of patients with axSpA to assess sources of heterogeneity. METHODS The study involved 363 axSpA probands recruited from membership of the Swiss Ankylosing Spondylitis Patient Society. Participants underwent examination by a rheumatologist, completed questionnaires and provided blood samples for HLA typing. Patients underwent radiography of sacroiliac joints and were categorised according to the New York (NY) criteria (ankylosing spondylitis (AS) or non-radiographic axSpA (nr-axSpA)) and HLA-B27 status. Genetic characterisation by single nucleotide polymorphism microarray was performed and AS polygenic risk scores (PRS) were calculated. RESULTS Considerable heterogeneity was observed. The male to female ratio for AS (NY+) was 3:1, but 1:1 for nr-axSpA. For HLA-27(+) AS, the ratio was 2.5:1, but nearly 1:1 for HLA-B27(-) disease. Women with nr-axSpA had strikingly lower mean PRS and lower HLA-B27 prevalence than men with nr-axSpA or NY(+) male and female patients with AS. PRS was able to distinguish male but not female patients with nr-axSpA from related healthy first-degree relatives. Radiographic sacroiliitis was strongly associated with HLA-B27, especially in men. CONCLUSION Women clinically diagnosed with axSpA but without radiographic sacroiliitis as a group have a disease that is distinct from AS by the modified New York criteria overall and from nr-axSpA in men. Given the high degree of heterogeneity, stratified or adjusted analysis of effectiveness studies is indicated, taking genetics, sex and radiographic damage (sacroiliitis) into account.
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Affiliation(s)
- Zhixiu Li
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
| | - Sjef M van der Linden
- University of Bern, Bern, Switzerland.,Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands
| | - Muhammad Asim Khan
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | | | | | | | - Peter M Villiger
- Medical Center Monbijou, Meikirch, Switzerland.,Rheumatology and Clinical Immunology, Medical Center Monbijou, Meikirch, Switzerland
| | - Matthew A Brown
- Department of Medical and Molecular Genetics, King's College London, London, UK .,Genomics England, London, UK
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16
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Lems W, Miceli-Richard C, Haschka J, Giusti A, Chistensen GL, Kocijan R, Rosine N, Jørgensen NR, Bianchi G, Roux C. Bone Involvement in Patients with Spondyloarthropathies. Calcif Tissue Int 2022; 110:393-420. [PMID: 35066596 DOI: 10.1007/s00223-021-00933-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/24/2021] [Indexed: 11/02/2022]
Abstract
Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.
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Affiliation(s)
- Willem Lems
- Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands.
| | - Corinne Miceli-Richard
- INSERM U 1153, Université de Paris-APHP.Centre, Service de Rhumatologie, Hopital Cochin, Paris, France
- Immunoregulation Unit, Department of Immunology, Institut Pasteur, Paris, France
| | - Judith Haschka
- I Medical Department, Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of OEGK & Hanusch Hospital Vienna, Heinrich-Collin-Straße 30, 1140, Vienna, Austria
- Karl Landsteiner Institute for Rheumatology and Gastroenterology, Rheuma-Zentrum Wien-Oberlaa, 1100, Vienna, Austria
| | - Andrea Giusti
- Rheumatology Unit, Department of Medical Specialties, Local Health Trust 3, Via Missolungi 14, 16147, Genoa, Italy
| | | | - Roland Kocijan
- Medical Faculty of Bone Diseases, Sigmund Freud University Vienna, Freudplatz 1, 1020, Vienna, Austria
| | - Nicolas Rosine
- INSERM U 1153, Université de Paris-APHP.Centre, Service de Rhumatologie, Hopital Cochin, Paris, France
- Sorbonne Université, Service de Rhumatologie Hôpital Pitié Salpêtrière, APHP, Paris, France
| | | | - Gerolamo Bianchi
- Rheumatology Unit, Department of Medical Specialties, Local Health Trust 3, Via Missolungi 14, 16147, Genoa, Italy
| | - Christian Roux
- INSERM U 1153, Université de Paris-APHP.Centre, Service de Rhumatologie, Hopital Cochin, Paris, France
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Wang JX, Jing FY, Xu YC, Zong HX, Chu YR, Wang C, Chen KM, Tong WQ, Wang XL, Xu SQ. The Potential Regulatory Mechanism of lncRNA 122K13.12 and lncRNA 326C3.7 in Ankylosing Spondylitis. Front Mol Biosci 2021; 8:745441. [PMID: 34746233 PMCID: PMC8566704 DOI: 10.3389/fmolb.2021.745441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/22/2021] [Indexed: 01/31/2023] Open
Abstract
This work aims to analyze and construct a novel competing endogenous RNA (ceRNA) network in ankylosing spondylitis (AS) with bone bridge formation, lncRNA. Using RNA sequencing and bioinformatics, we analyzed expression profiles of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in whole blood cells from 5 AS patients and 3 healthy individuals. Next, we verified the expression levels of candidate lncRNAs in 97 samples using the ΔΔCt value of real-time quantitative polymerase chain reaction (qRT-PCR). We used multivariate logistic regression analysis to screen lncRNAs and clinical indicators for use in the prediction model. Both SPSS 24.0 and R software were used for data analysis and prediction model construction. The results showed that compared with the normal controls, 205 long noncoding RNAs (lncRNAs), 961 microRNAs (miRNAs), and 200 mRNAs (DEmRNAs) were differentially expressed in the AS patients. We identified lncRNA 122K13.12 and lncRNA 326C3.7 among 205 lncRNAs differentially expressed between AS patients and healthy humans. Then, we noted that 30 miRNAs and five mRNAs formed a ceRNA network together with these two lncRNAs. These ceRNA networks might regulate the tumor necrosis factor (TNF) signaling pathway in AS development. In addition, the expression level of lncRNA 122K13.12 and lncRNA 326C3.7 correlated with various structural damage indicators in AS. Specifically, the lncRNA 326C3.7 expression level was an independent risk factor in bone bridge formation [area under the ROC curve (AUC) = 0.739 (0.609–0.870) and p = 0.003], and the best Youden Index was 0.405 (sensitivity = 0.800 and specificity = 0.605). Moreover, we constructed a lncRNA-based nomogram that could effectively predict bone bridge formation [AUC = 0.870 (0.780–0.959) and p < 0.001, and the best Youden Index was 0.637 (sensitivity = 0.900 and specificity = 0.737)]. In conclusion, we uncovered a unique ceRNA signaling network in AS with bone bridge formation and identified novel biomarkers and prediction models with the potential for clinical applications.
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Affiliation(s)
- Jian-Xiong Wang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Feng-Yang Jing
- Department of Dental Implant Center, Key Laboratory of Oral Diseases Research of Anhui Province, Stomatologic Hospital and College, Anhui Medical University, Hefei, China
| | - Yue-Chen Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - He-Xiang Zong
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yi-Ran Chu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Cong Wang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ke-Ming Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wan-Qiu Tong
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xi-le Wang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Sheng-Qian Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Ni F, Zhang Y, Peng Y, Peng X, Li J. Serum RANKL levels in Chinese patients with ankylosing spondylitis: a meta-analysis. J Orthop Surg Res 2021; 16:615. [PMID: 34663371 PMCID: PMC8522048 DOI: 10.1186/s13018-021-02721-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/13/2021] [Indexed: 11/22/2022] Open
Abstract
Objective We aimed to determine the association between serum receptor activator of nuclear factor-kappa B ligand (sRANKL) levels and ankylosing spondylitis (AS) in Chinese patients. Methods The PubMed, Cochrane Library, Embase, Chinese Biomedical Database, Web of Science, China National Knowledge Infrastructure, VIP, and Wan Fang databases were searched for studies conducted before October 1, 2020, without language restrictions. STATA version 12.0 and Revman version 5.3 were used to analyze the data. The standard mean differences (SMDs) and corresponding 95% confidence intervals (95% CIs) were calculated. Results Twelve clinical case–control studies, including 585 patients with AS and 423 healthy controls, were included. The combined SMD for sRANKL suggested that the sRANKL level was significantly higher in Chinese patients with AS than in healthy controls (SMD: 3.27, 95% CI 2.11–4.43, P < 0.00001). Serum RANKL-related factor osteoprotegerin (OPG) levels (SMD: 0.86, 95% CI 0.09–1.64, P < 0.03) were lower in the Chinese patients with AS than in healthy controls, and the RANKL/OPG ratio (SMD = 1.05, 95% CI 0.64–1.46, P < 0.00001) in Chinese patients with AS was approximately the same as that of healthy controls. Subgroup analysis indicated that patients from North and South China had higher sRANKL levels than controls; the sRANKL levels of patients from South China were higher in the subgroup with a Bath Ankylosing Spondylitis Functional Index (BASFI) of > 4 than those of patients in other subgroups. In terms of duration, patients with AS for > 8 years had higher sRANKL levels than health controls. Other subgroup analyses were conducted by region, language, source of control, age, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). In these subgroups, the sRANKL levels were significantly higher in the patients with AS than in healthy controls. The BASFI and BASDAI were sources of heterogeneity. Conclusions The sRANKL levels are higher in Chinese patients with AS, especially among those from South China. sRANKL levels may be positively correlated with the pathogenesis of AS among Chinese patients.
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Affiliation(s)
- Feifei Ni
- Department of Orthopaedics, Shengjing Hospital of China Medical University, Sanhao Street No. 36, Heping District, Shenyang, Liaoning, 110004, People's Republic of China
| | - Yanchao Zhang
- Department of Orthopedics, Tianjin Baodi Hospital/Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People's Republic of China
| | - Yi Peng
- Department of Urological, Nantong University Danyang Teaching Hospital, Zhenjiang, 212300, People's Republic of China
| | - Xiaoxiao Peng
- Daxing Teaching Hospital of Capital Medical University, Beijing, 102600, People's Republic of China
| | - Jianjun Li
- Department of Orthopaedics, Shengjing Hospital of China Medical University, Sanhao Street No. 36, Heping District, Shenyang, Liaoning, 110004, People's Republic of China.
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19
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Kusuda M, Haroon N, Nakamura A. Complexity of enthesitis and new bone formation in ankylosing spondylitis: current understanding of the immunopathology and therapeutic approaches. Mod Rheumatol 2021; 32:484-492. [PMID: 34918137 DOI: 10.1093/mr/roab057] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 01/20/2023]
Abstract
Despite increasing availability of treatments for spondyloarthritis (SpA) including tumour necrosis factor (TNF) and interleukin-17 (IL-17) inhibitors, there is no established treatment that abates new bone formation (NBF) in ankylosing spondylitis (AS), a subset of SpA. Recent research on TNF has revealed the increased level of transmembrane TNF in the joint tissue of SpA patients compared to that of rheumatoid arthritis patients, which appears to facilitate TNF-driven osteo-proliferative changes in AS. In addition, there is considerable interest in the central role of IL-23/IL-17 axis in type 3 immunity and the therapeutic potential of blocking this axis to ameliorate enthesitis and NBF in AS. AS immunopathology involves a variety of immune cells, including both innate and adoptive immune cells, to orchestrate the immune response driving type 3 immunity. In response to external stimuli of inflammatory cytokines, local osteo-chondral progenitor cells activate intra-cellular anabolic molecules and signals involving hedgehog, bone morphogenetic proteins, receptor activator of nuclear factor kappa-B ligand, and Wnt pathways to promote NBF in AS. Here, we provide an overview of the current immunopathology and future directions for the treatment of enthesitis and NBF associated with AS.
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Affiliation(s)
- Masaki Kusuda
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Nigil Haroon
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Spondylitis Program, Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.,Division of Rheumatology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Akihiro Nakamura
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Spondylitis Program, Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.,Division of Rheumatology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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20
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Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol 2021; 17:387-404. [PMID: 34113018 DOI: 10.1038/s41584-021-00625-y] [Citation(s) in RCA: 169] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/20/2022]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.
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21
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Wordsworth BP, Cohen CJ, Davidson C, Vecellio M. Perspectives on the Genetic Associations of Ankylosing Spondylitis. Front Immunol 2021; 12:603726. [PMID: 33746951 PMCID: PMC7977288 DOI: 10.3389/fimmu.2021.603726] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.
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Affiliation(s)
- B Paul Wordsworth
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Institute of Musculoskeletal Sciences, Oxford, United Kingdom.,Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom
| | - Carla J Cohen
- Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom
| | - Connor Davidson
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Matteo Vecellio
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Institute of Musculoskeletal Sciences, Oxford, United Kingdom.,Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom.,Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
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22
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Brown MA, Xu H, Li Z. Genetics and the axial spondyloarthritis spectrum. Rheumatology (Oxford) 2021; 59:iv58-iv66. [PMID: 33053195 PMCID: PMC7566537 DOI: 10.1093/rheumatology/keaa464] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.
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Affiliation(s)
- Matthew A Brown
- Guy's & St Thomas' NHS Foundation Trust and King's College London NIHR Biomedical Research Centre, London, UK
| | - Huji Xu
- Department of Rheumatology and Immunology, Changzheng Hospital, Second Military Medical University, Shanghai, China.,Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China.,Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Zhixiu Li
- Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, QLD, Australia
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23
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Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis. Nat Rev Rheumatol 2020; 16:415-433. [PMID: 32661321 DOI: 10.1038/s41584-020-0454-9] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2020] [Indexed: 02/07/2023]
Abstract
Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.
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24
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Reveille JD, Lee M, Gensler LS, Ward MM, Hwang MC, Learch TJ, Tahanan A, Diekman L, Rahbar MH, Ishimori ML, Weisman MH. The changing profile of ankylosing spondylitis in the biologic era. Clin Rheumatol 2020; 39:2641-2651. [PMID: 32648102 DOI: 10.1007/s10067-020-05260-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To compare disease characteristics, comorbidities, and medication utilization of 1141 patients with ankylosing spondylitis (AS) with short (< 20 years) and long (≥ 20 years) disease duration enrolled in the Prospective Study of Outcomes in AS (PSOAS) study over three different periods of time and followed longitudinally. METHODS Study visits were carried out every 6 months examining disease activity (Bath AS Disease Activity Index (BASDAI), C-reactive protein, erythrocyte sedimentation rate), functional impairment, depression, and medication utilization as well as radiographic severity. Groups were compared with regression models using generalized estimating equation, linear, and Poisson regressions after adjusting for sites and for patients withdrawing from the study at less than 2 years follow-up. RESULTS Overall, AS patients with long disease duration were more likely to be married, white, receiving disability, and to be with higher functional impairment and radiographic severity, more uveitis, diabetes, hypertension, cardiovascular disease, and osteoporosis, and with less nonsteroidal anti-inflammatory drug (NSAID) and more opioid use than those with short disease duration. Current smoking decreased between 2002 and 2019 regardless of disease duration. Lower baseline NSAID and methotrexate/sulfasalazine use and higher TNF inhibitor usage were seen only in those with shorter disease duration, though NSAID use and functional impairment decreased over time in both groups. Disease activity, depression scores, and NSAID use decreased and anti-TNF use increased in those followed > 8 years. CONCLUSIONS Patients with AS enrolling in this multicenter longitudinal cohort have different disease profiles and medication utilization over time, perhaps reflecting innovations in treatment and increasing disease awareness. Key Points • The use of NSAIDs, nonbiologic DMARDs, and prednisone has decreased over the past 16 years in patients with AS. • The use of anti-TNF agents has dramatically increased. • In treated patients, disease activity, depression scores, and functional impairment have decreased over time.
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Affiliation(s)
- John D Reveille
- Department of Internal Medicine, Division of Rheumatology, McGovern Medical School at The University of Texas Health Science Center Houston, 6431 Fannin St., Houston, TX, 77030, USA.
| | - MinJae Lee
- Division of Biostatistics, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lianne S Gensler
- Department of Medicine, Division of Rheumatology, University of California San Francisco, San Francisco, CA, USA
| | - Michael M Ward
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mark C Hwang
- Department of Internal Medicine, Division of Rheumatology, McGovern Medical School at The University of Texas Health Science Center Houston, 6431 Fannin St., Houston, TX, 77030, USA
| | - Thomas J Learch
- Department of Radiology, Cedars-Sinai Medical Center Los Angeles, Los Angeles, CA, USA
| | - Amirali Tahanan
- Department of Internal Medicine, Division of Clinical and Translational Sciences, McGovern Medical School at The University of Texas Health Science Center Houston, Houston, TX, USA
| | - Laura Diekman
- Department of Internal Medicine, Division of Rheumatology, McGovern Medical School at The University of Texas Health Science Center Houston, 6431 Fannin St., Houston, TX, 77030, USA
| | - Mohammad H Rahbar
- Department of Internal Medicine, Division of Clinical and Translational Sciences, McGovern Medical School at The University of Texas Health Science Center Houston, Houston, TX, USA
| | - Mariko L Ishimori
- Division of Rheumatology, Cedars Sinai Medical Center Los Angeles, Los Angeles, CA, USA
| | - Michael H Weisman
- Division of Rheumatology, Cedars Sinai Medical Center Los Angeles, Los Angeles, CA, USA
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25
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Abstract
The term axial spondyloarthritis (axSpA) encompasses a heterogeneous group of diseases that have variable presentations, extra-articular manifestations and clinical outcomes, and that will respond differently to treatments. The prototypical type of axSpA, ankylosing spondylitis, is thought to be caused by interaction between the genetically primed host immune system and gut microbiota. Currently used biomarkers such as HLA-B27 status, C-reactive protein and erythrocyte sedimentation rate have, at best, moderate diagnostic and predictive value. Improved biomarkers are needed for axSpA to assist with early diagnosis and to better predict treatment responses and long-term outcomes. Advances in a range of 'omics' technologies and statistical approaches, including genomics approaches (such as polygenic risk scores), microbiome profiling and, potentially, transcriptomic, proteomic and metabolomic profiling, are making it possible for more informative biomarker sets to be developed for use in such clinical applications. Future developments in this field will probably involve combinations of biomarkers that require novel statistical approaches to analyse and to produce easy to interpret metrics for clinical application. Large publicly available datasets from well-characterized case-cohort studies that use extensive biological sampling, particularly focusing on early disease and responses to medications, are required to establish successful biomarker discovery and validation programmes.
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26
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Hile G, Kahlenberg JM, Gudjonsson JE. Recent genetic advances in innate immunity of psoriatic arthritis. Clin Immunol 2020; 214:108405. [PMID: 32247832 DOI: 10.1016/j.clim.2020.108405] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/28/2020] [Accepted: 03/28/2020] [Indexed: 12/19/2022]
Abstract
Psoriatic arthritis (PsA) is a heterogeneous disease that affects multiple organ systems including the peripheral and axial joints, entheses and nails. PsA is associated with significant comorbidities including cardiovascular, metabolic, and psychiatric diseases. The pathogenesis of PsA is complex and involves genetic, immunologic and environmental factors. Recent evidence suggests the heritability for PsA to be stronger and distinct from that of PsC. Prominent genes identified via GWAS for PsA include HLA-B/C, HLAB, IL12B, IL23R, TNP1, TRAF3IP3, and REL. We review the genetics of psoriatic arthritis and discuss the role of the innate immune system as important in the pathogenesis of PsA by focusing on key signaling pathways and cellular makeup. Understanding the candidate genes identified in PsA highlights pathways of critical importance to the pathogenesis of psoriatic disease including the key role of the innate immune response, mediated through IL-23/IL-17 axis, RANK and NFκB signaling pathways.
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Affiliation(s)
- Grace Hile
- Department of Dermatology, University of Michigan, Ann Arbor 48109, MI, USA.
| | - J Michelle Kahlenberg
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Johann E Gudjonsson
- Department of Dermatology, University of Michigan, Ann Arbor 48109, MI, USA.
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27
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Wang R, Bathon JM, Ward MM. Nonsteroidal Antiinflammatory Drugs as Potential Disease-Modifying Medications in Axial Spondyloarthritis. Arthritis Rheumatol 2020; 72:518-528. [PMID: 31705611 PMCID: PMC7113090 DOI: 10.1002/art.41164] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 11/07/2019] [Indexed: 12/17/2022]
Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) are the first-line pharmacotherapy for patients with axial spondyloarthritis (SpA). In recent years, treatment options have expanded with the availability of biologic agents, including tumor necrosis factor inhibitors and interleukin-17 inhibitors. However, a treatment strategy that clearly prevents syndesmophyte formation has not been established. Observational studies of patients with ankylosing spondylitis indicated potential disease-modifying effects of NSAIDs, but two randomized trials came to different conclusions. More broadly, whether any of the currently available medications for axial SpA have an effect on spine radiographic progression, beyond symptom control, remains inconclusive. In this article, we will review clinical studies of the disease modification effects of NSAIDs and biologics in axial SpA; examine genetic, animal, and clinical evidence of the effects of NSAIDs on bone formation; and discuss how future studies may investigate the question of disease modification in axial SpA.
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Affiliation(s)
- Runsheng Wang
- Columbia University College of Physicians and Surgeons, New York, New York
| | - Joan M Bathon
- Columbia University College of Physicians and Surgeons, New York, New York
| | - Michael M Ward
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
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28
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Asquith M, Sternes PR, Costello ME, Karstens L, Diamond S, Martin TM, Li Z, Marshall MS, Spector TD, le Cao KA, Rosenbaum JT, Brown MA. HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome. Arthritis Rheumatol 2019; 71:1642-1650. [PMID: 31038287 DOI: 10.1002/art.40917] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 04/25/2019] [Indexed: 12/28/2022]
Abstract
OBJECTIVE HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype-disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA-B27 and HLA-DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. METHODS Five hundred sixty-eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. RESULTS Associations were observed between the overall microbial composition and both the HLA-B27 genotype and the HLA-DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). CONCLUSION This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA-B27 and HLA-DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.
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Affiliation(s)
| | - Peter R Sternes
- Queensland University of Technology, Brisbane, Queensland, Australia
| | | | | | | | | | - Zhixiu Li
- Queensland University of Technology, Brisbane, Queensland, Australia
| | - Mhairi S Marshall
- Queensland University of Technology, Brisbane, Queensland, Australia
| | | | | | - James T Rosenbaum
- Oregon Health & Science University and Legacy Devers Eye Institute, Portland
| | - Matthew A Brown
- Queensland University of Technology, Brisbane, Queensland, Australia
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29
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Yang J, Xu S, Chen M, Yuan Y, Zhang X, Ma Y, Wu M, Han R, Hu X, Liu R, Deng J, Guan S, Gao X, Pan M, Xu S, Shuai Z, Jiang S, Guan S, Chen L, Pan F. Serum Sclerostin and Bone Morphogenetic Protein-2 Levels in Patients with Ankylosing Spondylitis: A Meta-Analysis. Calcif Tissue Int 2019; 105:37-50. [PMID: 30911810 DOI: 10.1007/s00223-019-00542-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 03/16/2019] [Indexed: 12/17/2022]
Abstract
Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI - 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI) < 4 had statistically significant lower serum sclerostin concentrations compared to controls. Chinese and Korean AS patients as well as patients with lower CRP had higher serum BMP-2 levels than controls, and country may be a source of heterogeneity across the studies. No publication bias existed and sensitivity analysis confirmed the stability of results. Serum BMP-2, but not sclerostin levels may be closely related to the development of AS.
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Affiliation(s)
- Jiajia Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Shanshan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Mengya Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Yaping Yuan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Xu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Meng Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Renfang Han
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Xingxing Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Rui Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Jixiang Deng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Shiyang Guan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Xing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Meijuan Pan
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Zongwen Shuai
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China
| | - Shanqun Jiang
- School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, 230601, People's Republic of China
| | - Shihe Guan
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, NO. 678#, Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Liwen Chen
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, NO. 678#, Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China.
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China.
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Klasen C, Meyer A, Wittekind PS, Waqué I, Nabhani S, Kofler DM. Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis. Arthritis Res Ther 2019; 21:159. [PMID: 31253169 PMCID: PMC6599260 DOI: 10.1186/s13075-019-1948-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/18/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). However, the mechanism underlying enhanced Th17 cell accumulation in AS remains unknown. The prostaglandin E2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Interestingly, recent genome-wide association studies (GWAS) have identified five risk alleles for AS in PTGER4, the gene encoding for EP4. The aim of this study was to reveal a possible link between EP4 and disease activity in patients with AS. METHODS Th17 cells from patients with AS were analyzed for the transcriptional expression of prostaglandin receptor genes by quantitative RT-PCR. Th17 cells from patients with rheumatoid arthritis (RA) and from healthy individuals served as controls. EP4 receptor expression in Th17 cells was assessed ex vivo by flow cytometry and by western blot. Functional analysis using EP4-specific agonists was performed to reveal how EP4 regulates Th17 cells. RESULTS EP4 is significantly overexpressed in Th17 cells from patients with AS compared to Th17 cells from healthy individuals or patients with RA or psoriatic arthritis (PsA). EP4 upregulation is unique to Th17 cells and is not found in other CD4+ T cell subsets. Specific activation of EP4 drives Th17 cell development and promotes EP4 expression in a positive feedback loop in AS but not in RA or PsA. Mechanistically, EP4 acts via upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORγt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. Increased EP4 expression levels in Th17 cells from AS patients correlate with high disease activity as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 (r = 0.7591, p = 0.0016). CONCLUSIONS EP4 is a potential marker of disease activity in patients with AS. Aberrant EP4 expression might contribute to pathogenic Th17 cell accumulation and represent a new target for the treatment of AS.
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Affiliation(s)
- Charlotte Klasen
- Division of Clinical Immunology and Rheumatology, Department I of Internal Medicine, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
| | - Anja Meyer
- Division of Clinical Immunology and Rheumatology, Department I of Internal Medicine, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
| | - Paula S Wittekind
- Division of Clinical Immunology and Rheumatology, Department I of Internal Medicine, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
| | - Iris Waqué
- Division of Clinical Immunology and Rheumatology, Department I of Internal Medicine, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
| | - Schafiq Nabhani
- Division of Clinical Immunology and Rheumatology, Department I of Internal Medicine, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
| | - David M Kofler
- Division of Clinical Immunology and Rheumatology, Department I of Internal Medicine, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany.
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Reyer H, Oster M, Wittenburg D, Murani E, Ponsuksili S, Wimmers K. Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs. Front Genet 2019; 10:590. [PMID: 31316547 PMCID: PMC6610066 DOI: 10.3389/fgene.2019.00590] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 06/04/2019] [Indexed: 12/18/2022] Open
Abstract
Blood values of calcium (Ca), inorganic phosphorus (IP), and alkaline phosphatase activity (ALP) are valuable indicators for mineral status and bone mineralization. The mineral homeostasis is maintained by absorption, retention, and excretion processes employing a number of known and unknown sensing and regulating factors with implications on immunity. Due to the high inter-individual variation of Ca and P levels in the blood of pigs and to clarify molecular contributions to this variation, the genetics of hematological traits related to the Ca and P balance were investigated in a German Landrace population, integrating both single-locus and multi-locus genome-wide association study (GWAS) approaches. Genomic heritability estimates suggest a moderate genetic contribution to the variation of hematological Ca (N = 456), IP (N = 1049), ALP (N = 439), and the Ca/P ratio (N = 455), with values ranging from 0.27 to 0.54. The genome-wide analysis of markers adds a number of genomic regions to the list of quantitative trait loci, some of which overlap with previous results. Despite the gaps in knowledge of genes involved in Ca and P metabolism, genes like THBS2, SHH, PTPRT, PTGS1, and FRAS1 with reported connections to bone metabolism were derived from the significantly associated genomic regions. Additionally, genomic regions included TRAFD1 and genes coding for phosphate transporters (SLC17A1-SLC17A4), which are linked to Ca and P homeostasis. The study calls for improved functional annotation of the proposed candidate genes to derive features involved in maintaining Ca and P balance. This gene information can be exploited to diagnose and predict characteristics of micronutrient utilization, bone development, and a well-functioning musculoskeletal system in pig husbandry and breeding.
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Affiliation(s)
- Henry Reyer
- Genomics Unit, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Michael Oster
- Genomics Unit, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Dörte Wittenburg
- Biomathematics and Bioinformatics Unit, Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Eduard Murani
- Genomics Unit, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Siriluck Ponsuksili
- Functional Genome Analysis Unit, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Klaus Wimmers
- Genomics Unit, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany.,Department of Animal Breeding and Genetics, Faculty of Agricultural and Environmental Sciences, University of Rostock, Rostock, Germany
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Evaluation of serum fibroblast growth factor-23 in patients with axial spondyloarthritis and its association with sclerostin, inflammation, and spinal damage. Rheumatol Int 2019; 39:835-840. [PMID: 30968207 DOI: 10.1007/s00296-019-04298-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/01/2019] [Indexed: 12/17/2022]
Abstract
The mechanisms underlying new bone formation in individuals with axial spondyloarthritis (axSpA) remain unclear; however, low levels of sclerostin (SOST) may be associated with development of syndesmophytes in those with ankylosing spondylitis (AS). Expression of fibroblast growth factor-23 (FGF-23), another osteocyte factor, is high in those with osteoporosis and chronic renal failure, but levels in those with axSpA are unknown. To evaluate serum FGF-23 and SOST levels in axSpA patients, and to assess their relationship with inflammation and structural damage. In total, 109 axSpA patients (55 with AS and 54 with non-radiographic axSpA) and 57 healthy control (HC) subjects were included in the analysis. Serum concentrations of FGF-23 and SOST were measured and correlation analysis was performed. The presence of syndesmophytes and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were used to assess structural damage. Levels of serum FGF-23 in axSpA patients were significantly higher than those in HCs [median (interquartile range-IQR) FGF-23 level, pg/ml; AxSpA = 144 (82.3-253.2), HC = 107 (63.3-192.8), p = 0.010]; however, there was no difference in SOST levels. FGF-23 levels correlated with the erythrocyte sedimentation rate (ESR) (r = 0.265, p = 0.006) and serum C-reactive protein (CRP) level (r = 0.229, p = 0.010). In the axSpA, SOST levels correlated negatively with mSASSS (r = - 0.283, p = 0.007), whereas those in the AS group correlated negatively with CRP (r = - 0.426, p = 0.001). Serum FGF-23 levels were high in axSpA patients. Increased FGF-23 was associated with inflammation, but not with SOST levels or disease activity. SOST correlated negatively with both inflammation and structural damage.
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Abstract
During the past decade, the well-known disease called ankylosing spondylitis has come to be considered as a subset of the broader entity referred as axial spondyloarthritis (axSpA), which also includes non-radiographic axSpA. The need of this new classification was aimed to improve the sensitivity for an early diagnosis, to reduce diagnostic delay, and to allow an early treatment. Although there is improvement in the recognition, the management of patients, and the treatment strategies of axSpA, unmet needs persist. There is still a substantial gap of 5-8 years between the onset of symptoms and the diagnosis of axSpA and, even in patients diagnosed early, 20-40% of them do not respond or have a loss of response to anti-TNF treatment. Moreover, the pathogenesis of the disease and, in particular, the mechanisms of new bone formation are far to be completely understood. Nevertheless, the discovery of IL-23/IL-17 axis with the development of biologic inhibitors, the identification of new subsets of effector cells, together with the interest in the detection of potential biomarkers of bone formation brought the approach to axSpA into a new era. This review is intended to enhance awareness and understanding of axSpA and to identify and discuss the current unmet needs in axSpA, including diagnosis, classification, biomarkers, pathogenesis, management, and treatment strategies.
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Affiliation(s)
- Ennio Lubrano
- Dipartimento di Medicina e Scienze della Salute "Vincenzo Tiberio", Università degli Studi del Molise, Via Giovanni Paolo II, C/da Tappino, 86100, Campobasso, Italy.
| | - Antonia De Socio
- Dipartimento di Medicina e Scienze della Salute "Vincenzo Tiberio", Università degli Studi del Molise, Via Giovanni Paolo II, C/da Tappino, 86100, Campobasso, Italy
| | - Fabio Massimo Perrotta
- Dipartimento di Medicina e Scienze della Salute "Vincenzo Tiberio", Università degli Studi del Molise, Via Giovanni Paolo II, C/da Tappino, 86100, Campobasso, Italy
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Lories RJ. Advances in understanding the pathophysiology of spondyloarthritis. Best Pract Res Clin Rheumatol 2019; 32:331-341. [PMID: 31171306 DOI: 10.1016/j.berh.2018.12.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 11/10/2018] [Indexed: 01/02/2023]
Abstract
Progressive understanding of the underlying pathophysiology of axial spondyloarthritis has successfully translated into innovative therapeutic strategies and successful management of patients in the clinic. This review summarizes the key roles of the pro-inflammatory cytokines tumor necrosis factor and interleukin-17 in the onset and progression of disease and how these cytokines are instrumental in shaping the concept that enthesitis is a key feature of axial spondyloarthritis. Advances in immunological technologies have led to the important insight that different cell populations, part of both the innate and adaptive immune system, play a key role in axial spondyloarthritis. In addition to inflammation, structural damage to the axial skeleton, in particular progressive ankylosis of the sacroiliac joints and the spine, is key to the outcome of patients. Novel data integrate the role of pro-inflammatory cytokines and enthesitis in this context.
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Affiliation(s)
- Rik J Lories
- KU Leuven, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, Leuven, Belgium; University Hospitals Leuven, Division of Rheumatology, Leuven, Belgium.
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Costantino F, Breban M, Garchon HJ. Genetics and Functional Genomics of Spondyloarthritis. Front Immunol 2018; 9:2933. [PMID: 30619293 PMCID: PMC6305624 DOI: 10.3389/fimmu.2018.02933] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 11/29/2018] [Indexed: 12/12/2022] Open
Abstract
Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. It encompasses several entities that share common clinical features. Most of the genetic studies in SpA have been restricted to ankylosing spondylitis (AS), the prototypical form of SpA. However, there is growing evidence of shared genetic background between all the SpA subtypes and also with some other immune-mediated diseases. The most important part of SpA heritability comes from the HLA-B27 allele in the major histocompatibility complex (MHC) that explains around 25% of the attributable heredity. Several other loci outside of the MHC have been shown to be involved in the disease. However, all these non-MHC loci explain only a small additional fraction of disease predisposition. Thus, a substantial fraction of SpA genetic basis remains poorly understood. Gene expression profiling is a complementary approach to elucidate the underlying mechanisms and pathways that drive the disease. Several expression profiling studies have been undertaken in SpA. However, results have been quite disappointing with little overlap between the studies largely due to the small sample sizes, resulting in limited power to discover small effects. In this review, we summarize current knowledge on genetic findings concerning SpA and we describe strategic approaches for identification of additional variants, with a focus on rare variants in familial forms. We also provide an overview of gene expression studies in SpA and discuss the possibilities offered by high-throughput RNA sequencing technologies, in particular in sorted cells. Finally, issues in establishing molecular mechanisms underlying genetic association hits and potential translational applications will be addressed.
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Affiliation(s)
- Félicie Costantino
- UMR 1173 INSERM/Versailles Saint-Quentin-en-Yvelines University, Montigny le Bretonneux, France.,Rheumatology Division Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France
| | - Maxime Breban
- UMR 1173 INSERM/Versailles Saint-Quentin-en-Yvelines University, Montigny le Bretonneux, France.,Rheumatology Division Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France
| | - Henri-Jean Garchon
- UMR 1173 INSERM/Versailles Saint-Quentin-en-Yvelines University, Montigny le Bretonneux, France.,Genetics Division Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France
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Dendritic cells in the pathogenesis of ankylosing spondylitis and axial spondyloarthritis. Clin Rheumatol 2018; 38:1231-1235. [DOI: 10.1007/s10067-018-4388-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 11/28/2018] [Indexed: 01/01/2023]
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Arévalo M, Gratacós Masmitjà J, Moreno M, Calvet J, Orellana C, Ruiz D, Castro C, Carreto P, Larrosa M, Collantes E, Font P. Influence of HLA-B27 on the Ankylosing Spondylitis phenotype: results from the REGISPONSER database. Arthritis Res Ther 2018; 20:221. [PMID: 30285828 PMCID: PMC6235234 DOI: 10.1186/s13075-018-1724-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE To assess HLA-B27 influence on the clinical phenotype of Ankylosing Spondylitis (AS) patients. METHOD An observational, cross-sectional and descriptive study of AS patients from the Spanish REGISPONSER database was performed. Demographic, clinical, disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)), and radiographic data (Bath Ankylosing Spondylitis Radiology Index (BASRI) score) were compared regarding HLA-B27 status. A univariate and multivariate analysis was performed to identify variables independently related to the presence of HLA-B27. RESULTS Data from 1235 patients (74.8% male) were analyzed; 1029 were HLA-B27 positive (83%). HLA-B27-positive patients showed higher family aggregation and an earlier onset of disease compared with those who were HLA-B27 negative. HLA-B27-negative patients presented statistically higher BASDAI and BASFI scores and higher prevalence of arthritis, dactylitis, and extra-articular manifestations (psoriasis and inflammatory bowel disease (IBD)) but not anytime uveitis compared with those who were HLA-B27 positive. In the multivariate analysis, family history (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.27-3.49), younger age at diagnosis (OR 0.97, 95% CI 0.96-0.98), presence of peripheral arthritis (OR 0.53, 95% CI 0.32-0.89), dactylitis (OR 0.16, 95% CI 0.05-0.56), psoriasis (OR 0.45, 95% CI 0.26-0.78), and IBD (OR 0.22, 95% CI 0.12-0.40) were the main variables independently related to the presence or not of HLA-B27. CONCLUSION In Caucasian AS patients, the presence of HLA-B27 is related to an earlier disease onset and higher family aggregation. Absence of HLA-B27 is related to a higher frequency of peripheral arthritis, dactylitis, and extra-articular manifestations. Being HLAB27 positive is not related to a higher burden of disease or anytime uveitis.
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Affiliation(s)
- Marta Arévalo
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
| | - Jordi Gratacós Masmitjà
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
| | - Mireia Moreno
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
| | - Joan Calvet
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
| | - Cristobal Orellana
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
| | - Desirée Ruiz
- Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain
| | - Carmen Castro
- Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain
| | - Pilar Carreto
- Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain
| | - Marta Larrosa
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
| | - Eduardo Collantes
- Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain
| | - Pilar Font
- Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain
| | - REGISPONSER group
- Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona Spain
- Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain
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Rahbar MH, Lee M, Hessabi M, Tahanan A, Brown MA, Learch TJ, Diekman LA, Weisman MH, Reveille JD. Harmonization, data management, and statistical issues related to prospective multicenter studies in Ankylosing spondylitis (AS): Experience from the Prospective Study Of Ankylosing Spondylitis (PSOAS) cohort. Contemp Clin Trials Commun 2018; 11:127-135. [PMID: 30094388 PMCID: PMC6071581 DOI: 10.1016/j.conctc.2018.07.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 07/10/2018] [Accepted: 07/24/2018] [Indexed: 01/13/2023] Open
Abstract
Ankylosing spondylitis (AS) is characterized by inflammation of the spine and sacroiliac joints causing pain and stiffness and, in some patients, ultimately new bone formation, and progressive joint ankyloses. The classical definition of AS is based on the modified New York (mNY) criteria. Limited data have been reported regarding data quality assurance procedure for multicenter or multisite prospective cohort of patients with AS. Since 2002, 1272 qualified AS patients have been enrolled from five sites (4 US sites and 1 Australian site) in the Prospective Study Of Ankylosing Spondylitis (PSOAS). In 2012, a Data Management and Statistical Core (DMSC) was added to the PSOAS team to assist in study design, establish a systematic approach to data management and data quality, and develop and apply appropriate statistical analysis of data. With assistance from the PSOAS investigators, DMSC modified Case Report Forms and developed database in Research Electronic Data Capture (REDCap). DMSC also developed additional data quality assurance procedure to assure data quality. The error rate for various forms in PSOAS databases ranged from 0.07% for medications data to 1.1% for arthritis activity questionnaire-Global pain. Furthermore, based on data from a sub study of 48 patients with AS, we showed a strong level (90.0%) of agreement between the two readers of X-rays with respect to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). This paper not only could serve as reference for future publications from PSOAS cohort but also could serve as a basic guide to ensuring data quality for multicenter clinical studies.
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Affiliation(s)
- Mohammad H. Rahbar
- Department of Epidemiology, Human Genetics, and Environmental Sciences (EHGES), University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Division of Clinical and Translational Sciences, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - MinJae Lee
- Division of Clinical and Translational Sciences, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Manouchehr Hessabi
- Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Amirali Tahanan
- Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Matthew A. Brown
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Thomas J. Learch
- Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Laura A. Diekman
- Division of Rheumatology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Michael H. Weisman
- Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - John D. Reveille
- Division of Rheumatology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Quantifying the genetic risk for the development of axial spondyloarthropathy: could this become a diagnostic tool? Curr Opin Rheumatol 2018; 30:319-323. [PMID: 29702496 DOI: 10.1097/bor.0000000000000517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To assess the utility of recent genetic findings in ankylosing spondylitis (AS) and axial spondyloarthropathy (SpA) in relation to diagnostic testing, prognosis and responses to biologic treatment and the development of new therapies. RECENT FINDINGS AS and other forms of SpA are polygenic with more than 100 genes contributing to disease susceptibility. The role of genes in determining the outcome of the disease and response to treatment is less clear. Here, we review some of the progress that has been made over the past decade in understanding the genetic contribution to these diseases and how this may be used to inform the development of new treatments. In those with a high pretest probability of SpA human leukocyte antigen (HLA)-B27 testing can increase the posttest predictive value to almost 100% in some cases. There are currently no reliable genetic predictors of disease severity or response to treatment. SUMMARY The utility of HLA-B27 as a diagnostic tool when coupled with careful clinical assessment is well established but other genetic markers probably have relatively little to add. In contrast, novel drug targets are likely to be identified from genetic association studies.
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Smoking quantity determines disease activity and function in Chinese patients with ankylosing spondylitis. Clin Rheumatol 2018; 37:1605-1616. [PMID: 29589132 DOI: 10.1007/s10067-018-4016-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 12/21/2017] [Accepted: 01/29/2018] [Indexed: 12/17/2022]
Abstract
The objective of this study was to systemically and comprehensively evaluate the associations between smoking and disease outcomes in patients with ankylosing spondylitis (AS). Information on smoking, clinical features, and sociodemographic characteristics was collected by a questionnaire administered directly to the patient. Group differences were analyzed by t test or chi-square test. Logistic regression analysis was conducted with the Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), C-reactive protein, and erythrocyte sedimentation rate as the dependent variables and different stratification of smoking duration, smoking intensity, and cumulative smoking as independent variables. In order to compare our results with previous studies, meta-analysis was performed to calculate standardized mean difference (SMD) for relationship between outcomes and smoking status. A total of 1178 AS patients were analyzed. Compared with non-smokers, the risk of having active disease (BASDAI ≥ 4) was higher in patients who smoked at least 15 years, or 15 cigarettes per day, or 15 pack-years (OR = 1.70 [1.06, 2.73], 1.75 [1.08, 2.82], and 1.97 [1.06, 3.67], respectively); and smokers had increasing risk of BASDAI ≥ 4 with increasing years of smoking, or cigarettes per day, or pack-years (p-trend = 0.010, 0.008 and 0.006, respectively). The risk of having active disease was higher in patients who smoked at least 15 cigarettes per day or 15 pack-years (OR = 1.74 [1.06, 2.84] and 2.89 [1.56, 5.35], respectively), with increasing number of cigarettes per day and pack-years. Smokers had an increased risk of BASFI ≥ 4 (p-trend = 0.040 and 0.007, respectively). By meta-analysis, current, former and ever smokers had significantly higher BASDAI (SMD = 0.34 [0.18, 0.48], 0.10 [0.01, 0.19], and 0.27 [0.20, 0.34], respectively) and BASFI (SMD = 0.35 [0.16, 0.55], 0.30 [0.22, 0.39], and 0.35 [0.21, 0.50], respectively) compared to non-smokers. Smoking is a risk factor for greater disease activity and worse functioning in AS patients.
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Wu M, Chen M, Ma Y, Yang J, Han R, Yuan Y, Hu X, Wang M, Zhang X, Xu S, Liu R, Jiang G, Xu J, Shuai Z, Zou Y, Pan G, Pan F. Dickkopf-1 in ankylosing spondylitis: Review and meta-analysis. Clin Chim Acta 2018; 481:177-183. [PMID: 29544750 DOI: 10.1016/j.cca.2018.03.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/11/2018] [Accepted: 03/11/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Current findings regarding serum Dickkopf-1 (DKK-1) concentration in ankylosing spondylitis (AS) have proven inconsistent. This meta-analysis was performed to provide a better understanding of serum DKK-1 and AS. METHODS Online electronic databases were used to retrieve all relevant articles published before November 2017. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. RESULTS 23 studies, containing 1348 AS patients and 909 healthy controls, were included in this meta-analysis. No significant difference in serum DKK-1 concentration was found between AS patients and healthy controls (pooled SMD = 0.488, 95%CI = -0.176 to 1.152, p = 0.150). Subgroup analyses suggested that serum DKK-1 in patients with increased C-reactive protein (CRP) (CRP > 10 mg/L) and high modified Stroke AS Spine Score (mSASSS) (mSASSS > 30) were significantly lower than healthy controls. Serum DKK-1 was, however, increased in patients with normal CRP (CRP ≤ 10 mg/L). CONCLUSION Although serum DKK-1 concentration was not significantly different in AS vs. healthy controls, it may be used as a biomarker of inflammation and radiographic damage in AS.
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Affiliation(s)
- Meng Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Mengya Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Jiajia Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Renfang Han
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yaping Yuan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xingxing Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Mengmeng Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Xu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Rui Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Guangming Jiang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Jianhua Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Zongwen Shuai
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Yanfeng Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Guixia Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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The severity of ankylosing spondylitis and responses to anti-tumour necrosis factor biologics are not influenced by the tumour necrosis factor receptor polymorphism incriminated in multiple sclerosis. Genes Immun 2018. [DOI: 10.1038/s41435-018-0017-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Nossent JC, Sagen-Johnsen S, Bakland G. IL23R gene variants in relation to IL17A levels and clinical phenotype in patients with ankylosing spondylitis. Rheumatol Adv Pract 2018; 2:rky006. [PMID: 31431955 PMCID: PMC6649922 DOI: 10.1093/rap/rky006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 01/30/2018] [Indexed: 12/18/2022] Open
Abstract
Background IL23 receptor (IL23R) binding by IL23 is required for the maturation of CD4+ cells into Th17 cells and subsequent generation of IL17A and TNF. As IL23R variations contribute to AS susceptibility, we investigated the effect of IL23R variants on cytokine levels and disease measures in an AS cohort. Methods This was a cross-sectional study of AS patients (n = 334, 90% B27+, age 45 years). IL23R genotyping for three non-synonymous single-nucleotide polymorphisms (rs11209026, protective allele A; rs10489629, protective allele A; and rs11209032, risk allele A) was done by Taqman RT-PCR. IL23, IL17A, TNF and IL6 concentrations were determined by sandwich ELISA. Genotypic associations were analysed with non-parametric methods. Results Twenty-two AS patients (6.6%) carried the protective rs11209026 A allele, whereas 206 (61.7%) carried the rs11209032A risk allele (P = 0.03). Two patients homozygous for rs11209026A had late onset, no co-morbidity and undetectable cytokine levels. IL23R genotypes and five common haplotypes were unrelated with age at onset, BASFI or co-morbidity (all P >0.2). There was no overall difference in the concentration of IL17A (184 vs 233 pg/ml, P > 0.2) or IL23 (276 vs 262 pg/ml, P > 0.4) between AS patients and controls, but a global haplotype association (P = 0.01) was observed for IL23 concentrations. Conclusion Homozygosity for rs11209026A is rare in AS patients, but may ameliorate the clinical presentation. IL17A and IL23 levels are similar in controls and AS patients. IL23R variants influence IL23 levels but not IL17A levels in AS patients, suggesting that IL23R impacts more on cell types other than Th17 cells.
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Affiliation(s)
- Johannes C Nossent
- Department Rheumatology, School of Medicine, University of Western Australia.,Sir Charles Gairdner Hospital, Perth, WA, Australia
| | | | - Gunnstein Bakland
- Department Rheumatology, University Hospital North Norway, Tromsø, Norway
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Lories RJ, Haroon N. Evolving concepts of new bone formation in axial spondyloarthritis: Insights from animal models and human studies. Best Pract Res Clin Rheumatol 2017; 31:877-886. [DOI: 10.1016/j.berh.2018.07.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 06/29/2018] [Accepted: 07/06/2018] [Indexed: 12/17/2022]
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Xu Z, Wang X, Zheng Y. Screening for key genes and transcription factors in ankylosing spondylitis by RNA-Seq. Exp Ther Med 2017; 15:1394-1402. [PMID: 29434723 PMCID: PMC5774495 DOI: 10.3892/etm.2017.5556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 07/07/2017] [Indexed: 12/14/2022] Open
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory arthritis and autoimmune disease, the etiology and pathogenesis of which remain largely unknown. In the present study, blood samples were harvested from patients with AS and from healthy volunteers as a normal control (NC) for RNA-sequencing. Differentially expressed genes (DEGs) in the AS group compared with the NC group were identified, and gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently performed. Protein-protein interaction (PPI) network and AS-specific transcriptional regulatory network construction was performed for the DEGs. A total of 503 DEGs, including 338 upregulated and 165 downregulated DEGs, were identified in patients with AS compared with the NC group. Three upregulated DEGs identified, interferon-induced protein with tetratricopeptide repeats (IFIT)1, IFIT3 and radical S-adenosyl methionine domain containing (RSAD)2, are interferon (IFN)-stimulated genes that serve a role in the IFN signaling pathway. The most significantly enriched GO term was response to other organisms. Osteoclast differentiation was a significantly enriched pathway for eight DEGs [High affinity immunoglobulin gamma Fc receptor (FCGR)1A, FCGR2B, four and a half LIM domains 2, integrin β3, signal transducer and activator of transcription 2 (STAT2), suppressor of cytokine signaling 3 (SOCS3), leukocyte immunoglobulin like receptor (LILR)A4 and LILRA6]. The six hub genes in the PPI network constructed were interferon-stimulated gene 15, heat shock protein β1, microtubule-associated proteins 1A/1B light chain 3A, IFIT1, IFIT3 and SOCS3. POU domain class 2 transcription factor 1 (1-Oct) and ecotropic virus integration site-1 (Evi-1) were identified as two important transcription factors (TFs) in AS according to the AS-specific transcriptional regulatory network constructed. In addition, IFIT1 and IFIT3 were identified as targets of 1-Oct. The results of the present study indicate that osteoclast differentiation, the IFN signaling pathway and genes associated with these two signaling pathways, particularly FCGR2B, STAT2, SOCS3, IFIT1 and IFIT3, may serve a role in AS. In addition, Evi-1 and 1-Oct may be two important TFs associated with AS. These results may provide a basis for elucidating the underlying mechanisms of and developing novel treatments for AS.
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Affiliation(s)
- Zhongyang Xu
- Department of Orthopedics, Shandong University Qilu Hospital, Jinan, Shandong 250012, P.R. China.,Department of Orthopedics, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Xiuyu Wang
- Department of Anesthesia, Shandong University Qilu Hospital, Jinan, Shandong 250012, P.R. China
| | - Yanping Zheng
- Department of Orthopedics, Shandong University Qilu Hospital, Jinan, Shandong 250012, P.R. China
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Abstract
PURPOSE OF REVIEW We review our current knowledge about the clinical features of patients with ankylosing spondylitis (AS) who possess HLA-B*27 versus those who lack this gene. RECENT FINDINGS ERAP1 association is present only in HLA-B*27+ patients, but other genetic associations are similar between the two groups. A genetic study supports the existence of an HLA-B27-independent common link between gut inflammation and AS. It is unusual to observe familial occurrence of primary AS among families of northern European extraction that show no segregation of HLA-B*27, psoriasis, or IBD. Although there are many similarities among AS patients possessing HLA-B*27 versus those lacking this gene, the former group has a younger age of onset, a shorter delay in diagnosis, a better clinical response to tumor necrosis factor inhibitors, a greater familial occurrence, a greater risk for occurrence of acute anterior uveitis, and a lower risk for occurrence of psoriasis and IBD. ERAP1 association is present only in HLA-B*27+ patients, but other genetic associations are similar between the two groups. It is unusual to observe occurrence of primary AS among families of northern European extraction that show no segregation of HLA-B*27, IBD, or psoriasis. A recent genetic study supports the existence of an HLA-B*27-independent common link between gut inflammation and AS.
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Maksymowych WP. An update on biomarker discovery and use in axial spondyloarthritis. Expert Rev Mol Diagn 2017; 17:965-974. [DOI: 10.1080/14737159.2017.1381562] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Serum Sclerostin Levels in Patients with Ankylosing Spondylitis and Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9295313. [PMID: 28553652 PMCID: PMC5434265 DOI: 10.1155/2017/9295313] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 03/23/2017] [Accepted: 04/11/2017] [Indexed: 12/17/2022]
Abstract
Objective. Current studies of serum sclerostin levels in AS and RA patients are inconsistent. This meta-analysis was performed to identify the association of serum sclerostin level with AS and RA patients. Methods. Embase, PubMed, MEDLINE, and Cochrane Library databases (up to 25 January 2017) were used to collect all relevant published articles. Studies were pooled and standard mean difference (SMD) with 95% confidence interval (CI) was calculated. All data analyses were performed using RevMan 5.3. Results. Totally eight studies of AS including 420 AS patients and 317 healthy controls (HC) and three studies of RA including 145 RA patients and 127 HC were finally included in this meta-analysis. The results revealed that the serum sclerostin levels in both AS patients (SMD = −0.14; 95% CI = [−0.39,0.11]; P = 0.28) and RA patients (SMD = −0.10; 95% CI = [−0.34,0.15]; P = 0.43) were not significantly different from those in HC. Conclusion. The difference of serum sclerostin levels in AS and RA patients was not significantly different from HC, indicating that the sclerostin may not associate with the development of AS and RA.
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Neerinckx B, Lories RJ. Structural Disease Progression in Axial Spondyloarthritis: Still a Cause for Concern? Curr Rheumatol Rep 2017; 19:14. [DOI: 10.1007/s11926-017-0639-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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