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Li F, Xian D, Yang K. Mendelian randomization and mediation analysis reveal the role of immune cell subsets in the causal pathways between blood cell perturbation responses and rheumatoid arthritis. Clin Rheumatol 2025; 44:1537-1548. [PMID: 40072781 DOI: 10.1007/s10067-025-07387-y] [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: 09/11/2024] [Revised: 01/11/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune interactions. Elucidating the causal relationships between blood cell perturbations, immune cell subsets, and RA can provide valuable insights into its pathogenesis. METHODS This study employed bidirectional two-sample Mendelian Randomization (MR) to explore the causal effects of blood cell perturbations on RA risk, with a focus on immune cell mediation. Genetic data from large-scale Genome-Wide Association Studies (GWAS) were utilized to select instrumental variables (IVs) for exposure, mediator, and outcome. Inverse Variance Weighted (IVW) analysis was applied, supplemented by sensitivity tests. Mediation analysis was conducted to assess the indirect effects mediated by immune cells. RESULTS Significant causal associations were identified between perturbations in reticulocytes, monocytes, and lymphocytes and specific immune cell subsets, including CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + terminally differentiated CD8 + T cells (CD45RA + TD CD8 + cells). Erythropoiesis perturbation was associated with a reduced RA risk, while perturbations in monocytes and lymphocytes were found to facilitate RA progression through immune-mediated mechanisms. CONCLUSION This study underscores the pivotal role of immune cell subsets in mediating the effects of blood cell perturbations on RA development. These findings suggest that targeting immune cell-mediated pathways, particularly those involving Tregs and CD8 + T cells, can provide new therapeutic strategies for RA management. Key Points • Causal Relationships: Mendelian randomization (MR) analysis identified significant causal relationships between specific blood cell disturbances (e.g., reticulocytes, monocytes, and lymphocytes) and rheumatoid arthritis (RA). • Role of Immune Cells: CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + Terminally Differentiated CD8 + T cells (CD45RA + TD CD8 + cells) mediate the association between blood cell disturbances and RA. • Protective Role of Reticulocytes: Reticulocyte disturbances under potassium chloride (KCl) conditions are negatively associated with RA, potentially protecting joints from inflammatory damage by reducing oxidative stress. • Protective Role of Non-Classical Monocytes: Baseline disturbances in monocyte median side scatter are negatively associated with RA, suggesting non-classical monocytes may reduce RA-related inflammation. • Positive Association of Lymphocyte Disturbances with RA: Lymphocyte side scatter standard deviation under colchicine disturbances shows a significant positive association with RA, indicating abnormal T cell activation may exacerbate RA progression.AQ.
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Affiliation(s)
- Feng Li
- Spinal Orthopedics Department I, Neijiang Hospital of Traditional Chinese Medicine, Neijiang City, Sichuan Province, China
| | - Dehai Xian
- Laboratory of Human Anatomy, School of Basic Medicine Anatomy , Southwest Medical University, Xianglin Road, Longmatan District, Luzhou City, Sichuan Province, China.
| | - Kaiwen Yang
- Laboratory of Human Anatomy, School of Basic Medicine Anatomy , Southwest Medical University, Xianglin Road, Longmatan District, Luzhou City, Sichuan Province, China.
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Dwivedi SD, Yadav K, Bhoi A, Sahu KK, Sangwan N, Singh D, Singh MR. Targeting Pathways and Integrated Approaches to Treat Rheumatoid Arthritis. Crit Rev Ther Drug Carrier Syst 2024; 41:87-102. [PMID: 38305342 DOI: 10.1615/critrevtherdrugcarriersyst.2023044719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic symmetrical systemic disorder that not only affects joints but also other organs such as heart, lungs, kidney, and liver. Approximately there is 0.5%-1% of the total population affected by RA. RA pathogenesis still remains unclear due to which its appropriate treatment is a challenge. Further, multitudes of factors have been reported to affect its progression i.e. genetic factor, environmental factor, immune factor, and oxidative factor. Therapeutic approaches available for the treatment of RA include NSAIDs, DMARDs, enzymatic, hormonal, and gene therapies. But most of them provide the symptomatic relief without treating the core of the disease. This makes it obligatory to explore and reach the molecular targets for cure and long-term relief from RA. Herein, we attempt to provide extensive overlay of the new targets for RA treatment such as signaling pathways, proteins, and receptors affecting the progression of the disease and its severity. Precise modification in these targets such as suppressing the notch signaling pathway, SIRT 3 protein, Sphingosine-1-phosphate receptor and stimulating the neuronal signals particularly efferent vagus nerve and SIRT 1 protein may offer long term relief and potentially diminish the chronicity. To target or alter the novel molecules and signaling pathway a specific delivery system is required such as liposome, nanoparticles and micelles and many more. Present review paper discusses in detail about novel targets and delivery systems for treating RA.
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Affiliation(s)
- Shradha Devi Dwivedi
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492 010, India
| | - Krishna Yadav
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G), 492010, India
| | - Anita Bhoi
- School of Studies in Biotechnology, Pt. Ravishankar Shukla University, Raipur 492 010, India
| | - Keshav Kant Sahu
- School of studies in biotechnology, Pt. Ravishankar Shukla University, Raipur (C.G), 492010, India
| | - Neelam Sangwan
- Department of Biochemistry, School of Interdisciplinary and Applied Sciences, Central University of Haryana, Mahendergarh, 123031, India
| | - Deependra Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, 492010, India; National Centre for Natural Resources, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, 492010, India
| | - Manju Rawat Singh
- University Institute of pharmacy, Pt.Ravishankar Shukla University, Raipur.(C.G.) 2. National centre for natural resources, Pt. Ravishankar Shukla University, Raipur
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Elsawy NA, Ghazala RA, Elnemr R. Cartilage and bone loss in premenopausal women with rheumatoid arthritis: Radiological and laboratory assessments. Int J Rheum Dis 2023; 26:2195-2205. [PMID: 37731289 DOI: 10.1111/1756-185x.14915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/24/2023] [Accepted: 09/03/2023] [Indexed: 09/22/2023]
Abstract
INTRODUCTION To investigate the radiological and laboratory features of bone and cartilage losses in premenopausal women with rheumatoid arthritis (RA). METHODS This case-control study is the continuation of a study that was conducted on 48 women with RA and 48 matched healthy volunteers. All RA patients were previously subjected to clinical examination, disease activity assessment using the 28-joint Disease Activity Score (DAS28) and Clinical Disease Activity Index (CDAI), serological tests, dual-energy X-ray absorptiometry measuring bone mineral density (BMD), and plain X-ray of both hands. Added to these, matrix metalloproteinase 3 (MMP-3) and cartilage oligomeric matrix protein (COMP) were measured by enzyme-linked immunosorbent assay. RESULTS There were statistically significant differences between patients and controls regarding COMP and MMP-3, being higher in patients (p < .001). COMP and MMP-3 have significant positive correlation with serum levels of anti-cyclic citrullinated peptide (anti-CCP) and anti-carbamylated protein (anti-CarP). The original Sharp erosion score was positively correlated with the serum level of the studied antibodies and disease duration, but no significant correlation was found with either COMP, MMP-3, or DAS-28. Spine BMD and Z score were negatively correlated with disease activity and anti-CarP. There were significant positive relationhsips between indices of local cartilage and bone loss and the indices of systemic bone loss. MMP-3 had no correlation with indices of local cartilage and bone loss and disease activity scores. CONCLUSIONS The pathogenic mechanism of hand joint damage involved the three studied autoantibodies namely, rheumatoid factor, anti-CCP and anti-CarP antibodies. Anti-CarP antibody was involved in the reduction of BMD of the spine. The association between systemic osteoporosis and hand joint damage pointed to a common pathogenic mechanism.
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Affiliation(s)
- Noha A Elsawy
- Department of Physical Medicine Rheumatology and Rehabilitation, Faculty of Medicine Alexandria University, Alexandria, Egypt
| | - Rasha A Ghazala
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Rehab Elnemr
- Department of Physical Medicine Rheumatology and Rehabilitation, Faculty of Medicine Alexandria University, Alexandria, Egypt
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Calixto OJ, Meneses-Toro MA, Vera-Parra EC, Bello-Gualtero JM, Romero-Sanchez C, Perdomo SJ. Posttranslational modifications in psoriatic arthritis: A systematic literature review. Autoimmun Rev 2023; 22:103393. [PMID: 37487969 DOI: 10.1016/j.autrev.2023.103393] [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: 06/22/2023] [Accepted: 07/14/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND AND AIMS Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The aim of this systematic review was to collect all published evidence regarding posttranslational modifications in PsA, and the main outcome was to evaluate an association between disease outcomes and specific posttranslational modifications in PsA. METHODS A systematic electronic search was performed in Medline, PubMed, Cochrane, Virtual Health Library, and Embase databases. A total of 587 articles were identified; 59 were evaluated after removing duplicates and scanning, of which 47 were included. A descriptive analysis was conducted, with results grouped according to the type of posttranslational modification evaluated. The protocol was registered at the PROSPERO database. RESULTS Seven posttranslational modifications were identified: citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress. Anti-citrullinated peptide and anti-carbamylated protein have been evaluated in rheumatoid arthritis. There is now information suggesting that these antibodies may be helpful in improving the diagnosis of PsA and that they may demonstrate a correlation with worse disease progression (erosions, polyarticular involvement, and poor treatment response). Glycosylation was associated with increased inflammation and phosphorylation products related to the expression of SIRT2 and pSTAT3 or the presence of Th17 and cytokine interleukin-22, suggesting a possible therapeutic target. CONCLUSIONS Posttranslational modifications often play a key role in modulating protein function in PsA and correlate with disease outcomes. Citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress were identified as associated with diagnosis and prognosis.
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Affiliation(s)
- Omar-Javier Calixto
- Universidad Militar Nueva Granada, School of Medicine, Clinical Immunology Group, Bogotá, Colombia; Universidad El Bosque, Cellular and Molecular Immunology Group INMUBO, Bogotá, Colombia.
| | | | - Edward-Camilo Vera-Parra
- Universidad Militar Nueva Granada, School of Medicine, Clinical Immunology Group, Bogotá, Colombia
| | | | - Consuelo Romero-Sanchez
- Universidad Militar Nueva Granada, School of Medicine, Clinical Immunology Group, Bogotá, Colombia; Universidad El Bosque, Cellular and Molecular Immunology Group INMUBO, Bogotá, Colombia
| | - Sandra J Perdomo
- Universidad El Bosque, Cellular and Molecular Immunology Group INMUBO, Bogotá, Colombia
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Trier NH, Houen G. Anti-citrullinated protein antibodies as biomarkers in rheumatoid arthritis. Expert Rev Mol Diagn 2023; 23:895-911. [PMID: 37578277 DOI: 10.1080/14737159.2023.2247986] [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: 03/29/2023] [Revised: 07/15/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION The serological biomarker anti-citrullinated protein antibodies (ACPAs) may have several functions but is especially important for the diagnosis of rheumatoid arthritis (RA) along with clinical symptoms. AREAS COVERED This review provides an overview of ACPAs, which are useful in RA diagnostics and may improve our understanding of disease etiology. PubMed was searched with combinations of words related to antibodies recognizing epitopes containing the post-translationally modified amino acid citrulline in combination with rheumatoid arthritis; cyclic citrullinated peptide, CCP, anti-CCP, anti-citrullinated protein antibodies, ACPA, citrullination, peptide/protein arginine deiminase, PAD, filaggrin, vimentin, keratin, collagen, perinuclear factor, EBNA1, EBNA2, and others. From this search, we made a qualitative extract of publications relevant to the discovery, characterization, and clinical use of these antibodies in relation to RA. We highlight significant findings and identify areas for improvement. EXPERT OPINION ACPAs have high diagnostic sensitivity and specificity for RA and recognize citrullinated epitopes from several proteins. The best-performing single epitope originates from Epstein-Barr Virus nuclear antigen 2 and contains a central Cit-Gly motif, which is recognized by ACPAS when located in a flexible peptide structure. In addition, ACPAs may also have prognostic value, especially in relation to early treatment, although ACPAs' main function is to aid in the diagnosis of RA.
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Affiliation(s)
| | - Gunnar Houen
- Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
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Ali AA, Khalid KE, Mohammed SE, Akhtar MS, Saeed OK. Association of Human Leukocyte Antigen (HLA) class II ( DRB1 and DQB1) alleles and haplotypes with Rheumatoid Arthritis in Sudanese patients. Front Immunol 2023; 14:1178546. [PMID: 37426636 PMCID: PMC10324672 DOI: 10.3389/fimmu.2023.1178546] [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: 03/02/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
The aim of this study was to determine the Human Leukocyte Antigen (HLA) class II (DRB1 and DQB1) alleles and haplotype frequency in Rheumatoid Arthritis (RA) in the Sudanese population. The frequency of HLA-DRB1 and -DQB1 alleles and DRB1-DQB1 haplotypes were determined in 122 RA patients and 100 controls. HLA alleles were genotyped by the polymerase chain reaction-sequence specific primers (PCR-SSP) method. In RA patients, HLA-DRB1*04 and *10 alleles were high in frequency (9.6% vs 14.2%, P = 0.038 and P = 0.042, respectively), and dependently on anti-citrullinated protein antibodies (ACPAs) seropositivity (P = 0.044 and P = 0.027, respectively). In contrast, the frequency of the HLA-DRB1*07 allele was significantly low in patients than in controls (11.7% vs 5.0%, P = 0.010). Moreover, the HLA-DQB1*03 allele was strongly associated with RA risk (42.2%, P = 2.2x10-8), whereas, HLA-DQB1*02 and *06 showed protective effects against RA (23.1% and 42.2%, P = 0.024 and P = 2.2x10-6, respectively). Five different HLA haplotypes, DRB1*03-DQB1*03 (P = 0.00003), DRB1*04-DQB1*03 (P = 0.00014), DRB1*08-DQB1*03 (P = 0.027), DRB1*13-DQB1*02 (P = 0.004), and DRB1*13-DQB1*03 (P = 3.79x10-8) were significantly associated with RA risk, while 3 protective haplotypes, DRB1*03-DQB1*02 (Pc = 0.008), DRB1*07-DQB1*02 (Pc = 0.004), and DRB1*13-DQB1*06 (Pc = 0.02) were identified. This is the first study determining the association between HLA class II alleles and haplotypes and RA risk in our population.
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Affiliation(s)
- Adil Ahmed Ali
- Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
| | - Khalid Eltahir Khalid
- Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
- Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia
| | - Somaya Elhaj Mohammed
- Department of Pathology, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
| | - Mohammed Salman Akhtar
- Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia
| | - Osman Khalafalla Saeed
- Department of Internal Medicine, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
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Bashir M, Mateen W, Khurshid S, Mehmood Malik J, Agha Z, Khan F, Ajmal M, Ali SHB. A common missense variant rs874881 of PADI4 gene and rheumatoid arthritis: Genetic association study and in-silico analysis. Gene 2023; 854:147123. [PMID: 36535460 DOI: 10.1016/j.gene.2022.147123] [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: 09/07/2022] [Revised: 11/26/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
The peptidylarginine-deiminase 4 (PADI4) is involved in the post-translational catalytic conversion of arginine into citrulline. The autoantibodies including anti-citrullinated protein antibodies (ACPAs) produced in response to hypercitrullinated proteins are a hallmark of rheumatoid arthritis (RA) autoimmunity. Therefore, the role of a missense variant rs874881 (Gly112Ala) of PADI4 in RA susceptibility was analyzed, along with in-silico analysis of structural and functional impacts of this substitution. We did a case-control association study and in-silico analysis. For the case-control study, confirmed RA cases and healthy controls were recruited. Genotyping for rs874881 (n = 750) was performed through polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analysis was employed to determine association. The in-silico analysis was carried out through HOPE, VarMap, MutationAssessor, MutPred2, SIFT, PolyPhen, CADD, REVEL and MetaLR. In the case-control study, the rs874881 exhibited a strong association with increased RA susceptibility (G vs C odds ratio = 3.85, 95 % confidence interval = 2.81-5.27). Interaction analysis revealed significant interaction of genotype with smoking and gender (p < 0.05). Significant results (p < 0.05) were also obtained in stratified analysis by presence/absence of comorbidities and radiographic damage. According to in-silico pathogenicity prediction analysis, this Gly112Ala substitution does not exert a major effect on protein structure and function including its enzymatic activity. We report a significant association of PADI4 rs874881 with overall RA susceptibility. To our knowledge, this is the first study to do the interaction and stratified analyses on the PADI4 rs874881 in RA. Similar detailed studies should also be performed in other populations.
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Affiliation(s)
- Mutshaba Bashir
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Wajeeha Mateen
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Sadia Khurshid
- Pakistan Institute of Medical Sciences, Islamabad, Pakistan; Abbottabad International Medical College, Abbottabad, Pakistan
| | | | - Zehra Agha
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Fariha Khan
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Muhammad Ajmal
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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Delgado-Arévalo C, Calvet-Mirabent M, Triguero-Martínez A, Vázquez de Luis E, Benguría-Filippini A, Largo R, Calzada-Fraile D, Popova O, Sánchez-Cerrillo I, Tsukalov I, Moreno-Vellisca R, de la Fuente H, Herrero-Beaumont G, Ramiro A, Sánchez-Madrid F, Castañeda S, Dopazo A, González Álvaro I, Martin-Gayo E. NLRC4-mediated activation of CD1c+ DC contributes to perpetuation of synovitis in rheumatoid arthritis. JCI Insight 2022; 7:152886. [PMID: 36194479 DOI: 10.1172/jci.insight.152886] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/29/2022] [Indexed: 12/15/2022] Open
Abstract
The individual contribution of specific myeloid subsets such as CD1c+ conventional DC (cDC) to perpetuation of rheumatoid arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDC in patients with RA and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional, and functional characteristics of CD1c+ and CD141+ cDC and monocytes from the blood and synovial fluid of patients with RA. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC was associated with the presence of this DC subset in the synovial membrane in patients with RA. Moreover, synovial CD1c+ cDC are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFN-γ+IL-17+CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ receptors and NLRC4 as a potential molecular mechanism mediating pathogenic activation, CD64 upregulation, and functional specialization of CD1c+ cDC in response to dsDNA-IgG in patients with RA.
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Affiliation(s)
- Cristina Delgado-Arévalo
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Marta Calvet-Mirabent
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ana Triguero-Martínez
- Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | | | | | - Raquel Largo
- Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain
| | - Diego Calzada-Fraile
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | - Olga Popova
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ildefonso Sánchez-Cerrillo
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ilya Tsukalov
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | | | - Hortensia de la Fuente
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | | | - Almudena Ramiro
- Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain
| | - Francisco Sánchez-Madrid
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain.,Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain
| | - Santos Castañeda
- Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain
| | - Ana Dopazo
- Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | - Isidoro González Álvaro
- Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Enrique Martin-Gayo
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Infectious Diseases, Madrid, Spain
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Karami Fath M, Azami J, Jaafari N, Akbari Oryani M, Jafari N, Karim poor A, Azargoonjahromi A, Nabi-Afjadi M, Payandeh Z, Zalpoor H, Shanehbandi D. Exosome application in treatment and diagnosis of B-cell disorders: leukemias, multiple sclerosis, and arthritis rheumatoid. Cell Mol Biol Lett 2022; 27:74. [PMID: 36064322 PMCID: PMC9446857 DOI: 10.1186/s11658-022-00377-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/16/2022] [Indexed: 11/10/2022] Open
Abstract
Exosomes, known as a type of extracellular vesicles (EVs), are lipid particles comprising heterogeneous contents such as nucleic acids, proteins, and DNA. These bi-layered particles are naturally released into the extracellular periphery by a variety of cells such as neoplastic cells. Given that exosomes have unique properties, they can be used as vectors and carriers of biological and medicinal particles like drugs for delivering to the desired areas. The proteins and RNAs being encompassed by the circulating exosomes in B-cell malignancies are deemed as the promising sources for diagnostic and prognostic biomarkers, as well as therapeutic agents. Exosomes can also provide a "snapshot" view of the tumor and metastatic landscape at any particular time. Further, clinical research has shown that exosomes are produced by immune cells such as dendritic cells can stimulate the immune system, so these exosomes can be used in antitumor vaccines. Despite the great potential of exosomes in the fields of diagnostic and treatment, further studies are in need for these purposes to reach a convergence notion. This review highlights the applications of exosomes in multiple immune-related diseases, including chronic lymphocytic leukemia, multiple sclerosis, and arthritis rheumatoid, as well as explaining sundry aspects of exosome therapy and the function of exosomes in diagnosing diseases.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Jalil Azami
- Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Niloofar Jaafari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nafiseh Jafari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | | | | | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
- Immunology Research center, Tabriz University of Medical Science, Tabriz, Iran
| | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Dariush Shanehbandi
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
- Immunology Research center, Tabriz University of Medical Science, Tabriz, Iran
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Arunsi UO, Chioma OE, Etusim PE, Owumi SE. Indigenous Nigeria medicinal herbal remedies: A potential source for therapeutic against rheumatoid arthritis. Exp Biol Med (Maywood) 2022; 247:1148-1178. [PMID: 35708153 PMCID: PMC9335509 DOI: 10.1177/15353702221102901] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Rheumatoid arthritis (RA) is a debilitating disease associated with locomotion impairment, and conventional therapeutic drugs are not optimal for managing RA. There is an avalanche of medications used for the management of RA. Still, studies have shown that they are associated with severe side effects, including hepatotoxicity, retinopathy, and cardiotoxicity disorders of the central nervous system (CNS), skin, blood, and infections. Complementary and alternative medicine (CAM) is currently gaining attention as a novel panacea for managing debilitating diseases, such as RA. Nigerian folk herbal remedies are replete with a plethora of curative medicine, albeit unvalidated scientifically but with seemingly miraculous provenance. Studies of the identification of bioactive compounds present in these botanicals using advanced spectral analytical techniques have enhanced our understanding of the role of Nigerian herbal remedies in the treatment and management of RA. Interestingly, experimental studies abound that the bioactive compounds present in the extracts of plant botanicals protected animals from the development of RA in different experimental models and reduced the toxicity associated with conventional therapeutics. Validated mechanisms of RA amelioration in human and animal models include suppression of the expression of NF-κB, IL-1β, TNF-α, IL-6, IL-8, IL-17, IL-23, chemokines, TGF-β, RANKL, RANK, iNOS, arginase, COX-2, VEGFA, VEGFR, NFATC1, and TRAP in the synoviocytes. Decreased ROS, NO, MDA, carbonyl groups, and PGE2 in the synovial fluid increased the expression of PPARα/γ; antioxidant and anti-inflammatory molecules also improve RA etiology. In this mini-review, we discuss the global burden of RA, the novel role of plant-based botanicals as potential therapeutics against signaling pathways in RA. Also addressed is the possible repurposing/reprofiling of plant botanicals to increase their therapeutic index among RA patients that patronize traditional healers in Nigeria with a global projection.
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Affiliation(s)
- Uche O Arunsi
- Cancer Immunology and Biotechnology, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK,Department of Biochemistry, Faculty of Biological and Physical Sciences, Abia State University, Uturu, 440001, Nigeria
| | - Ogbuka E Chioma
- Department of Social and Environmental Forestry, Faculty of Renewable Natural Resources, University of Ibadan, Ibadan 200005, Nigeria
| | - Paschal E Etusim
- Department of Animal and Environmental Biology, Faculty of Biological and Physical Sciences, Abia State University, Uturu 200, Nigeria
| | - Solomon E Owumi
- Cancer Research and Molecular Biology Laboratories, Department of Biochemistry, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan 200005, Nigeria,Solomon Owumi.
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11
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Banda NK, Deane KD, Bemis EA, Strickland C, Seifert J, Jordan K, Goldman K, Morgan BP, Moreland LW, Lewis MJ, Pitzalis C, Holers VM. Analysis of Complement Gene Expression, Clinical Associations, and Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid Arthritis Patients Reveals Unique Pathophysiologic Features. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2482-2496. [PMID: 35500934 PMCID: PMC9133225 DOI: 10.4049/jimmunol.2101170] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/17/2022] [Indexed: 01/31/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression, both in the synovium and in blood. Our second objective was to determine the biodistribution using multiplex immunohistochemical staining of specific complement activation proteins and inhibitors from subjects in the Accelerating Medicines Partnership (AMP) RA/SLE study. In the PEAC study, there were significant positive correlations between specific complement gene mRNA expression levels in the synovium and DAS28-ESR for the following complement genes: C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1 Additionally, there were significant negative correlations between DAS28-ESR and Colec12, C5, C6, MASP-1, CFH, and MCP In the synovium there were also significant positive correlations between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A, and FcγR3A Notably, CFHR4 synovial expression was positively correlated following treatment with the DAS28-ESR at 6 mo, suggesting a role in worse therapeutic responses. The inverse correlation of C5 RNA expression in the synovium may underlie the failure of significant benefit from C5/C5aR inhibitors in clinical trials performed in patients with RA. Multiplex immunohistochemical analyses of early RA synovium reveal significant evidence of regional alterations of activation and inhibitory factors that likely promote local complement activation.
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Affiliation(s)
- Nirmal K Banda
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO;
| | - Kevin D Deane
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Elizabeth A Bemis
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Colin Strickland
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, CO
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Jennifer Seifert
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kimberly Jordan
- Human Immune Monitoring Shared Resource, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Katriona Goldman
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.; and
| | - B Paul Morgan
- Systems Immunity URI, Division of Infection and Immunity, and UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, U.K
| | - Larry W Moreland
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Myles J Lewis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.; and
| | - Costantino Pitzalis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.; and
| | - V Michael Holers
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
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12
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Akama-Garren EH, Carroll MC. T Cell Help in the Autoreactive Germinal Center. Scand J Immunol 2022; 95:e13192. [PMID: 35587582 DOI: 10.1111/sji.13192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 11/29/2022]
Abstract
The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.
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Affiliation(s)
- Elliot H Akama-Garren
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Michael C Carroll
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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13
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Ingegnoli F, Cavalli S, Giudice L, Caporali R. Caffeine and rheumatoid arthritis: A complicated relationship. Clin Exp Rheumatol 2022; 21:103117. [PMID: 35595049 DOI: 10.1016/j.autrev.2022.103117] [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: 05/01/2022] [Accepted: 05/15/2022] [Indexed: 11/02/2022]
Abstract
The current ideal goal of rheumatoid arthritis (RA) management is to resolve joint and systemic inflammation by using pharmacological interventions, assuming this will correspondingly lead to overall well-being. Nonetheless, it has emerged that a substantial number of RA patients do not reach optimal disease control. Thus suggesting the holistic management of subjective symptoms might be overlooked. This poses significant medical challenges; hence the proposal of incorporating lifestyle interventions as part of a multidimensional approach. Among these aspects, both patients and physicians perceive the important role of nutrition. This review shall examine how caffeine, one of the most studied bioactive components of the most widely consumed beverages, may potentially interfere with RA management. In particular, the mechanism by which caffeine affects RA pathogenesis, as a trigger for RA onset or flare, including its influence on rheumatic drug metabolism and the most common RA comorbidities and constitutional symptoms are outlined, highlighting important knowledge gaps and unmet research needs.
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Affiliation(s)
- Francesca Ingegnoli
- Clinical Rheumatology Unit, ASST Pini-CTO, Dept. of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy.
| | - Silvia Cavalli
- Clinical Rheumatology Unit, ASST Pini-CTO, Dept. of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy
| | - Laura Giudice
- Clinical Rheumatology Unit, ASST Pini-CTO, Dept. of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy
| | - Roberto Caporali
- Clinical Rheumatology Unit, ASST Pini-CTO, Dept. of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy
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14
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Reactivity of Rheumatoid Arthritis-Associated Citrulline-Dependent Antibodies to Epstein-Barr Virus Nuclear Antigen1-3. Antibodies (Basel) 2022; 11:antib11010020. [PMID: 35323194 PMCID: PMC8944695 DOI: 10.3390/antib11010020] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/17/2022] [Accepted: 03/08/2022] [Indexed: 12/22/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic disease which causes joint inflammation and, ultimately, erosion of the underlying bone. Diagnosis of RA is based on the presence of biomarkers, such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factors, along with clinical symptoms. Much evidence points to a link between the Epstein-Barr virus and RA. In this study, we analyzed ACPA reactivity to citrullinated peptides originating from Epstein-Barr nuclear antigens (EBNA1, EBNA2, and EBNA3) in order to elaborate the diagnostic potential of citrullinated EBNA peptides. Moreover, ACPA cross-reactivity to citrullinated peptides from myelin basic protein (MBP) was analyzed, as citrullinated MBP recently was described to be associated with multiple sclerosis, and some degree of sequence homology between MBP and citrullinated EBNA exists. A peptide from EBNA2, (EBNA2-A, GQGRGRWRG-Cit-GSKGRGRMH) reacted with approximately 70% of all RA sera, whereas only limited reactivity was detected to EBNA1 and EBNA3 peptides. Moreover, screening of ACPA reactivity to hybrid peptides of EBNA3-A (EPDSRDQQS-Cit-GQRRGDENRG) and EBNA2-A and peptides containing citrulline close to the N-terminal confirmed that ACPA sera contain different populations of ACPAs. No notable ACPA reactivity to MBP peptides was found, confirming that ACPAs are specific for RA, and that other factors than the presence of a central Cit-Gly motif are crucial for antibody binding. Collectively, these findings illustrate that citrullinated EBNA2 is an optimal candidate for ACPA detection, supporting current evidence that EBV is linked to RA onset.
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15
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Medhat BM, Abu-Zaid MH, Dorgham D, El-Ghobashy N, Afifi AY, El-Makawi S, Ayoub DR, Khalaf OO, Amer R, Koptan DMT, Maged LA. Prevalence of Anti-Nuclear Antibodies and Anti-Phospholipid Antibodies in an Egyptian Cohort with Schizophrenia: A Case-Control Study. Curr Rheumatol Rev 2021; 18:266-271. [PMID: 34751124 DOI: 10.2174/1573397117666211109115120] [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: 01/28/2021] [Revised: 05/19/2021] [Accepted: 09/01/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Psychiatric disorders, including schizophrenia could herald other manifestation(s) of systemic lupus erythematosus (SLE) potentially hindering timely and optimal management. Moreover, schizophrenia is among the described 'extra-criteria' manifestations of anti-phospholipid syndrome (APS). Hence, screening schizophrenia patients for SLE and APS may pose diagnostic and therapeutic implications. OBJECTIVES Examine schizophrenia patients with no overt connective tissue disease(s) manifestation(s) for clinical and/or serologic evidence of SLE and/or APS. METHODS The study included 92 schizophrenia patients [61 (66.3%) males] and 100 age- and gender-matched healthy controls. Both groups were tested for anti-nuclear antibodies (ANAs), anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies, complement 3 (C3) and C4, and criteria anti-phospholipid antibodies (aPL) [anticardiolipin Immunoglobulin (Ig) G and IgM, anti-beta-2-glycoprotein I IgG and IgM, and lupus anticoagulant (LAC)]. RESULTS The patients' mean age and disease duration were 28.8 ± 8.1 and 5.7 ± 2.2 years, respectively. The prevalence of ANA positivity, height of titre, and pattern was comparable between patients and controls (p = 0.9, p = 0.8 and p = 0.1, respectively). Anti-dsDNA antibodies and hypocomplementemia were absent in both groups. A significantly higher frequency of positive LAC was observed among patients compared with controls (7.6 % vs. 1 %, p = 0.02), whereas other aPL were comparable between both groups. None of the patients or controls demonstrated clinically meaningful (medium or high) aPL titres. CONCLUSION In our study, schizophrenia was solely associated with LAC. Thus, in the absence of findings suggestive of SLE or APS, routine screening for both diseases is questionable.
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Affiliation(s)
- Basma M Medhat
- Rheumatology and Rehabilitation Department, Al Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Mohammed H Abu-Zaid
- Rheumatology and Rehabilitation Department, Faculty of Medicine, Tanta University, Tanta. Egypt
| | - Dalia Dorgham
- Rheumatology and Rehabilitation Department, Al Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Nehal El-Ghobashy
- Rheumatology and Rehabilitation Department, Al Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Angie Yousri Afifi
- Rheumatology and Rehabilitation Department, Al Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Shirin El-Makawi
- Psychiatry Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Doaa R Ayoub
- Psychiatry Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Ola O Khalaf
- Psychiatry Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Reham Amer
- Neuropsychiatry Department, Faculty of Medicine, Tanta University, Tanta. Egypt
| | - Dina M T Koptan
- Clinical and Chemical Pathology Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
| | - Lobna A Maged
- Rheumatology and Rehabilitation Department, Al Kasr Alainy Faculty of Medicine, Cairo University, Cairo. Egypt
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16
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Elsawy NA, Mohamed RA, Ghazala RA, Abdelshafy MA, Elnemr R. Anti-carbamylated protein antibodies in premenopausal rheumatoid arthritis women: relation to disease activity and bone loss. Rheumatology (Oxford) 2021; 60:1419-1428. [PMID: 32995835 DOI: 10.1093/rheumatology/keaa549] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/28/2020] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES Anti-carbamylated protein antibodies (anti-CarP Abs) are present in patients with RA, however, their association with bone loss is not confirmed. The purpose of this study was to determine the relation between the serum level of anti-CarP Abs in premenopausal RA women and disease activity and bone loss. METHODS This case-control study was conducted on 48 premenopausal women with RA and 48 matched healthy premenopausal women. All RA women were subjected to clinical examination, disease activity assessment using the 28-joint DAS (DAS28) and Clinical Disease Activity Index (CDAI), functional assessment using the HAQ, physical activity assessment using the International Physical Activity Questionnaire (IPAQ), fatigue assessment using the Modified Fatigue Impact Scale (MFIS), serological tests as well as anti-CarP Abs using ELISA. Moreover, the BMD was measured by DXA and plain X-ray of both hands was done to assess juxta-articular osteopenia and erosions. RESULTS The anti-CarP Abs level was significantly higher in RA patients than in healthy controls. The serum level of anti-CarP Abs had a significant positive correlation with the RA DAS28, CDAI, HAQ, MFIS and original Sharp score, while a significant negative correlation was present with the IPAQ. Anti-CarP Abs were negatively correlated with either spine BMD or Z-score and positively correlated with the original Sharp score. CONCLUSION Anti-CarP Abs were higher in premenopausal RA women compared with older and BMI matched healthy women. Anti-CarP Abs are associated with higher RA disease activity, increased disability and fatigability and decreased physical activity. Moreover, anti-CarP Abs are associated with systemic trabecular bone loss as well as local bone loss.
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Affiliation(s)
- Noha A Elsawy
- Department of Physical Medicine Rheumatology and Rehabilitation, Alexandria, Egypt
| | - Rim A Mohamed
- Department of Radiodiagnosis and Intervention, Alexandria, Egypt
| | - Rasha A Ghazala
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | - Rehab Elnemr
- Department of Physical Medicine Rheumatology and Rehabilitation, Alexandria, Egypt
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17
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Végh E, Gaál J, Géher P, Gömöri E, Kovács A, Kovács L, Nagy K, Posta EF, Tamási L, Tóth E, Varga E, Domján A, Szekanecz Z, Szűcs G. Assessing the risk of rapid radiographic progression in Hungarian rheumatoid arthritis patients. BMC Musculoskelet Disord 2021; 22:325. [PMID: 33794855 PMCID: PMC8017697 DOI: 10.1186/s12891-021-04192-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
Background The outcome of rheumatoid arthritis (RA) should be determined early. Rapid radiological progression (RRP) is > or = 5 units increase according to the van der Heijde-Sharp score within a year. The risk of RRP can be estimated by a matrix model using non-radiographic indicators, such as C-reactive protein (CRP), rheumatoid factor (RF) and swollen joint count (SJC). Patients and methods A non-interventional, cross-sectional, retrospective study was conducted in eleven Hungarian arthritis centres. We assessed RRP risk in biologic-naïve RA patients with the prevalence of high RRP risk as primary endpoint. RRP was calculated according to this matrix model. As a secondary endpoint, we compared RRP in methotrexate (MTX) responders vs non-responders. Results We analyzed data from 1356 patients. Mean CRP was 17.7 mg/l, RF was 139.3 IU/ml, mean 28-joint disease activity score (DAS28) was 5.00 and mean SJC was 6.56. Altogether 18.2% of patients had high risk (≥40%) of RRP. RA patients with high RRP risk of RRP (n = 247) had significantly lower age compared to those with RRP < 40% (n = 1109). MTX non-response (OR: 16.84), male gender (OR: 1.67), erosions at baseline (OR: 1.50) and ACPA seropositivity (OR: 2.18) were independent predictors of high-risk RRP. Male gender (OR: 5.20), ACPA seropositivity (OR: 4.67) and erosions (OR: 7.98) were independent predictors of high RRP risk in MTX responders. Conclusions In this Hungarian study, high RRP risk occurred in 18% of RA patients. These patients differ from others in various parameters. RRP was associated with non-response to MTX.
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Affiliation(s)
- Edit Végh
- Department of Rheumatology, University of Debrecen, Faculty of Medicine, Nagyerdei str 98, Debrecen, 4032, Hungary
| | - János Gaál
- Department of Rheumatology, University of Debrecen Kenézy Teaching Hospital, Debrecen, Hungary
| | - Pál Géher
- Department of Rheumatology and Immunology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Edina Gömöri
- Department of Rheumatology, Pándy Hospital, Gyula, Hungary.,Department of Rheumatology, Aladár Petz Hospital, Győr, Hungary
| | - Attila Kovács
- Department of Rheumatology, Hospital of State Railways, Szolnok, Hungary.,Semmelweis Hospital, Kiskunhalas, Hungary
| | - László Kovács
- Department of Rheumatology and Immunology, University of Szeged, Faculty of Medicine, Szeged, Hungary
| | - Katalin Nagy
- Department of Rheumatology, Ferenc Markhot Hospital, Eger, Hungary
| | - Edit Feketéné Posta
- Department of Rheumatology, University of Debrecen, Faculty of Medicine, Nagyerdei str 98, Debrecen, 4032, Hungary.,Department of Rheumatology, András Jósa Hospital, Nyiregyháza, Hungary
| | - László Tamási
- Department of Rheumatology, Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, Miskolc, Hungary
| | - Edit Tóth
- Department of Rheumatology, Ferenc Flór Hospital, Kistarcsa, Hungary
| | - Eszter Varga
- Department of Rheumatology, Markusovszky Hospital, Szombathely, Hungary
| | - Andrea Domján
- Department of Rheumatology, University of Debrecen, Faculty of Medicine, Nagyerdei str 98, Debrecen, 4032, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, University of Debrecen, Faculty of Medicine, Nagyerdei str 98, Debrecen, 4032, Hungary.
| | - Gabriella Szűcs
- Department of Rheumatology, University of Debrecen, Faculty of Medicine, Nagyerdei str 98, Debrecen, 4032, Hungary
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18
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Cioffi G, Viapiana O, Orsolini G, Ognibeni Sonographer F, Dalbeni A, Gatti D, Adami G, Fassio A, Rossini M, Giollo A. Left ventricular hypertrophy predicts poorer cardiovascular outcome in normotensive normoglycemic patients with rheumatoid arthritis. Int J Rheum Dis 2021; 24:510-518. [PMID: 33719195 DOI: 10.1111/1756-185x.14082] [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: 10/11/2020] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Patients with rheumatoid arthritis (RA) develop early changes in left ventricular (LV) geometry and experience cardiovascular events in excess than in the general population. This study was designed to assess prevalence, predictors and prognostic role of LV hypertrophy (LVH) in a selected group of RA patients with normal blood pressure and glycemia who should be at low risk for LVH. METHODS We prospectively analyzed 241 normotensive normoglycemic RA patients (mean age 53 ± 12 years, 61% women) involved in a primary prevention program for cardiovascular diseases who were followed-up for 40 (24-56) months. LVH was detected by echocardiography and defined as LV mass ≥49.2 g/m2.7 for men and ≥46.7 g/m2.7 for women. Primary outcome was a composite of cardiovascular death/hospitalization. RESULTS LVH was detected in 39 patients (16%). Older age (>53 years), greater body mass index (BMI > 25 kg/m2 ), longer duration of RA disease, anti-cyclic citrullinated peptide antibody (ACPA) positivity and concentric LV geometry were the variables associated with LVH. During the follow-up, a cardiovascular event occurred in 12 of 39 (31%) patients with LVH and in 22 of 202 (11%; P < .001) patients without LVH. LVH independently predicted cardiovascular events (hazards ratio 3.28 [95% CI 1.03-9.20], P = .03) at Cox regression analysis together with C-reactive protein and ACPA positivity. CONCLUSIONS Nearly one-sixth of normotensive normoglycemic RA patients analyzed in a primary prevention program for cardiovascular diseases has LVH which is associated with obesity and older age, and strongly predicts cardiovascular event in these subjects.
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Affiliation(s)
- Giovanni Cioffi
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy.,Division of Cardiac Rehabilitation, S. Pancrazio Hospital, Trento, Italy
| | - Ombretta Viapiana
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Giovanni Orsolini
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | | | - Andrea Dalbeni
- Department of Medicine, General Medicine and Hypertension and Liver Unit, University of Verona & Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Davide Gatti
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Giovanni Adami
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Angelo Fassio
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Maurizio Rossini
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Alessandro Giollo
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
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19
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Lamacchia C, Courvoisier DS, Jarlborg M, Bas S, Roux-Lombard P, Möller B, Ciurea A, Finckh A, Bentow C, Martinez-Prat L, Mahler M, Gabay C, Nissen MJ. Predictive value of anti-CarP and anti-PAD3 antibodies alone or in combination with RF and ACPA for the severity of rheumatoid arthritis. Rheumatology (Oxford) 2021; 60:4598-4608. [PMID: 33502443 DOI: 10.1093/rheumatology/keab050] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 12/14/2020] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES The objective of this study was to analyse the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies, alone or in combination with RF and ACPA, to identify patients at high risk of developing severe RA outcomes. METHODS Patients within the Swiss Clinical Quality Management registry with a biobank sample were tested for RF, ACPA, anti-CarP, and anti-PAD3 antibodies. We examined the association of each autoantibody with DAS28, HAQ and radiographic damage (Ratingen) at baseline and longitudinally. RESULTS Analyses included 851 established RA patients and 516 disease controls [axial spondyloarthritis (axSpA = 320) and PsA (196)]. Anti-CarP and anti-PAD3 antibodies were, respectively, present in 22.4% and 10.7% of the whole RA population, and in 13.2% and 3.8% of the RF and ACPA double seronegative patients. At baseline, RA patients with anti-PAD3 had higher DAS28 (4.2 vs 3.7; P= 0.005) and significantly more radiographic damage (14.9 vs 8.8; P= 0.02) than anti-PAD3-negative patients. In the ACPA-negative subgroup, baseline Ratingen scores were significantly higher in anti-PAD3-positive patients (P= 0.01). The combination of anti-PAD3, RF IgM, and ACPA was associated with significantly higher baseline radiographic scores than the double seropositive group (P= 0.04). The presence of any two of the previous autoantibodies was associated with significantly greater radiographic progression over 10 years than if all were absent (P= 0.02). There were no differences in RA outcome measures with regards to anti-CarP. CONCLUSIONS Anti-PAD3 antibodies are associated with higher disease activity and joint damage scores in RA patients.
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Affiliation(s)
| | | | | | | | | | - Burkhard Möller
- Department of Rheumatology, Immunology and Allergy, Bern University Hospital, Bern
| | - Adrian Ciurea
- Department of Rheumatology, Zurich University Hospital, Zurich, Switzerland
| | | | - Chelsea Bentow
- Research and Development, Inova Diagnostics, San Diego, CA, USA
| | | | - Michael Mahler
- Research and Development, Inova Diagnostics, San Diego, CA, USA
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Traditional and modern management strategies for rheumatoid arthritis. Clin Chim Acta 2020; 512:142-155. [PMID: 33186593 DOI: 10.1016/j.cca.2020.11.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/03/2020] [Accepted: 11/03/2020] [Indexed: 12/20/2022]
Abstract
Rheumatoid arthritis (RA) is a serious disorder of the joints affecting 1 or 2% of the population aged between 20 and 50 years worldwide. RA is the foremost cause of disability in developing and Western populations. It is an autoimmune disease-causing inflammation and pain involving synovial joints. Pro-inflammatory markers, including cytokines, such as interleukin -1 (IL-1), IL-6, IL-7, IL-8, and tumor necrosis factor-α (TNF-α) are involved in RA. RA treatment involves TNF-α blockade, B cell therapy, IL-1 and IL-6 blockade, and angiogenesis inhibition. Synthetic drugs available for the treatment of RA include disease-modifying anti-rheumatic drugs (DMARD), such as cyclophosphamide, sulfasalazine, methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), and intramuscular gold. These agents induce adverse hepatorenal effects, hypertension, and gastric ulcers. We found that patients diagnosed with chronic pain, as in RA, and those refractory to contemporary management are most likely to seek traditional medicine. Approximately 60-90% of patients with arthritis use traditional medicines. Therefore, the efficacy and safety of these traditional medicines need to be established. The treatment for RA entails a comprehensive multidisciplinary strategy to reduce pain and inflammation and to restore the activity of joints. The potential medicinal plants exhibiting anti-arthritic and anti-rheumatic pharmacological activity are reviewed here.
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Matsumoto H, Fujita Y, Asano T, Matsuoka N, Temmoku J, Sato S, Yashiro-Furuya M, Watanabe H, Migita K. T cell immunoglobulin and mucin domain-3 is associated with disease activity and progressive joint damage in rheumatoid arthritis patients. Medicine (Baltimore) 2020; 99:e22892. [PMID: 33126340 PMCID: PMC7598883 DOI: 10.1097/md.0000000000022892] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
T cell immunoglobulin and mucin domain-3 (TIM-3) is a surface molecule expressed on immune cells which play a role in immune regulation. The aims of the present study were to determine whether circulating soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) are elevated in rheumatoid arthritis (RA) patients, and investigate the relationships between sTIM-3 and clinical features of RA.The study included 116 patients with established RA and 27 healthy control subjects. Serum levels of sTIM-3 were measured via the enzyme-linked immunosorbent assays (ELISA). Correlations between serum sTIM-3 and a range of parameters including anti-citrullinated peptide antibody (ACPA) titer, erythrocyte sedimentation rate (ESR), and matrix metalloproteinase-3 (MMP-3) were assessed.Serum sTIM-3 was significantly elevated in RA patients compared with those in healthy subjects, and it was positively correlated with ACPA titer (r = 0.27 P = .005), ESR (r = 0.27, P = .004) and MMP-3 (r = 0.35, P < .001). In RA patients with high ACPA titers (≥200 U/mL), sTIM-3 was not correlated with ESR or MMP-3. Whereas, sTIM-3 was significantly correlated with ESR and MMP-3 in RA patients with low ACPA titers (<200 U/mL).Serum sTIM-3 was increased in RA patients, and it was associated with proinflammatory markers and disease activity in RA patients under a particular ACPA status. Our data suggest that circulating sTIM-3 may be a useful biomarker for the determination of disease activity in RA patients.
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Aiman AQ, Nesrin M, Amal A, Nassar AD. A new tool for early diagnosis of rheumatoid arthritis using combined biomarkers; synovial MAGE-1 mRNA and serum anti-CCP and RF. Pan Afr Med J 2020; 36:270. [PMID: 33088399 PMCID: PMC7545977 DOI: 10.11604/pamj.2020.36.270.21827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/27/2020] [Indexed: 11/15/2022] Open
Abstract
Introduction rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Biomarkers have the potential to aid in the clinical diagnosis of the disease, or to provide means of detecting early signs of the disease. Evaluating Melanoma associated antigen genes (MAGE-1) mRNA expression rate in synovial fluid cells and serum levels of anti-cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) for RA early diagnosis. Methods a total of 213 subjects were enrolled in the study, 135 RA patients and 78 normal subjects with traumatic knee joints (control group). Serum RF and anti-CCP were estimated quantitatively using ELISA. MAGE-1 mRNA expression rate was analyzed by RT-PCR. Results a significant increase in serum levels of RF IgM and anti-CCP in RA patients compared to the controls. A positively significant correlation was found between serum anti-CCP and RF IgM. The expression rate of MAGE-1 mRNA was 100% in RA patients versus the controls (0%). The specificity and the sensitivity of the three biomarkers was 100%. Conclusion the high expression rate of MAGE-1 in synovial fluid cells of RA patients is encouraging its utilization as a diagnostic biomarker for RA. The combined use of MAGE-1 transcript in synovial fluid cells, serum RF and anti-CCP is recommended for improving early diagnostic ability of RA.
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Affiliation(s)
- Al-Qtaitat Aiman
- Department of Anatomy and Histology, Faculty of Medicine, Mutah University, Mutah, Jordan
| | - Mwafi Nesrin
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Mutah, Jordan
| | - Albtoosh Amal
- Department of Anatomy and Histology, Faculty of Medicine, Mutah University, Mutah, Jordan
| | - Al-Dalaien Nassar
- Department of Orthopedic Surgery, Jordan University Hospital, The University of Jordan, Mutah, Jordan
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Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population. DISEASE MARKERS 2020; 2020:1910215. [PMID: 32831971 PMCID: PMC7422001 DOI: 10.1155/2020/1910215] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/17/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022]
Abstract
Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.
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Kang J, Jeong SH, Lee K, Park N, Jung H, Lee K, Ju JH. Exacerbation of symptomatic arthritis by cigarette smoke in experimental arthritis. PLoS One 2020; 15:e0230719. [PMID: 32218599 PMCID: PMC7100974 DOI: 10.1371/journal.pone.0230719] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 03/06/2020] [Indexed: 12/29/2022] Open
Abstract
Introduction Epidemiologically, cigarette smoking is a well-known risk factor for the pathogenesis of rheumatoid arthritis (RA). However, there has been few plausible explanations why cigarette smoking aggravated RA. We investigated the causal effect of smoking in experimental model of arthritis development. Methods During induction of experimental arthritis with collagen challenge, mice were exposed to a smoking environment with 3R4F cigarettes. Generated smoke was delivered to mice through a nose-only exposure chamber (ISO standard 3308). Human cartilage pellet was challenged by cigarette smoke extract to identify citrullinating potential in vitro. Results Cigarette smoke exacerbated arthritis in a collagen-induced arthritis (CIA) model. Exposure to smoke accelerated the onset of arthritis by 2 weeks compared to the conventional model without smoke. Citrullination of lung tissue as well as tarsal joints were revealed in smoke-aggravated CIA mice. Interestingly, tracheal cartilage was a core organ regarding intensity and area size of citrullination. The trachea might be an interesting organ in viewpoint of sharing cartilage with joint and direct smoke exposure. Anti-CCP antibodies were barely detected in the serum of CIA mice, they were significantly elevated in cigarette smoke group. Citrullinated antigens were increased in the serum of smoke-exposed mice. Lastly, a cigarette smoke extract enhanced human cartilage citrullination in vitro. Conclusions Missing link of arthritic mechanism between smoke and RA could be partially explained by tracheal citrullination. To control tracheal cartilage citrullination may be beneficial for preventing arthritis development or aggravation if cigarette smoke is becoming a risk factor to pre-arthritic individual.
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Affiliation(s)
- Jaewoo Kang
- CiSTEM laboratory, Catholic Induced Pluripotent Stem Cell (iPSC) Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Hoon Jeong
- CiSTEM laboratory, Catholic Induced Pluripotent Stem Cell (iPSC) Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kijun Lee
- CiSTEM laboratory, Catholic Induced Pluripotent Stem Cell (iPSC) Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Narae Park
- CiSTEM laboratory, Catholic Induced Pluripotent Stem Cell (iPSC) Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyerin Jung
- CiSTEM laboratory, Catholic Induced Pluripotent Stem Cell (iPSC) Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyuhong Lee
- Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Jeollabuk-do, Republic of Korea
| | - Ji Hyeon Ju
- CiSTEM laboratory, Catholic Induced Pluripotent Stem Cell (iPSC) Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
- * E-mail:
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Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 2020; 16:145-154. [PMID: 32066940 DOI: 10.1038/s41584-020-0373-9] [Citation(s) in RCA: 365] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2020] [Indexed: 11/08/2022]
Abstract
Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.
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Elsayed SA, Esmail MA, Ali RM, Mohafez OM. Diagnostic and prognostic value of anti-CarP antibodies in a sample of Egyptian rheumatoid arthritis patients. Clin Rheumatol 2019; 38:2683-2689. [DOI: 10.1007/s10067-019-04616-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/25/2019] [Accepted: 05/16/2019] [Indexed: 12/31/2022]
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Stuhlmüller B, Schneider U, González-González JB, Feist E. Disease Specific Autoantibodies in Idiopathic Inflammatory Myopathies. Front Neurol 2019; 10:438. [PMID: 31139133 PMCID: PMC6519140 DOI: 10.3389/fneur.2019.00438] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 04/10/2019] [Indexed: 01/21/2023] Open
Abstract
Idiopathic inflammatory myopathies represent still a diagnostic and therapeutic challenge in different disciplines including neurology, rheumatology, and dermatology. In recent years, the spectrum of idiopathic inflammatory myopathies has been significantly extended and the different manifestations were described in more detail leading to new classification criteria. A major breakthrough has also occurred with respect to new biomarkers especially with the characterization of new autoantibody-antigen systems, which can be separated in myositis specific antibodies and myositis associated antibodies. These markers are detectable in approximately 80% of patients and facilitate not only the diagnostic procedures, but provide also important information on stratification of patients with respect to organ involvement, risk of cancer and overall prognosis of disease. Therefore, it is not only of importance to know the significance of these markers and to be familiar with the optimal diagnostic tests, but also with potential limitations in detection. This article focuses mainly on antibodies which are specific for myositis providing an overview on the targeted antigens, the available detection procedures and clinical association. As major tasks for the near future, the need of an international standardization is discussed for detection methods of autoantibodies in idiopathic inflammatory myopathies. Furthermore, additional investigations are required to improve stratification of patients with idiopathic inflammatory myopathies according to their antibody profile with respect to response to different treatment options.
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Affiliation(s)
- Bruno Stuhlmüller
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany
| | - Udo Schneider
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany
| | - José-B González-González
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany.,Labor Berlin-Charité Vivantes GmbH, Berlin, Germany
| | - Eugen Feist
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany
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Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M. Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review. Gene 2019; 702:8-16. [PMID: 30904715 DOI: 10.1016/j.gene.2019.03.033] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 03/09/2019] [Accepted: 03/17/2019] [Indexed: 01/11/2023]
Abstract
Three important factors, including genetics, environment factors and autoimmunity play a role in the pathogenesis of rheumatoid arthritis (RA). The heritability of RA has been accounted to be 50-60%, while the HLA involvement in heritability of the disease has been accounted to be 10-40%. It has been documented that shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, some HLA alleles like HLA-DRB1*13 and DRB1*15 are connected to RA susceptibility. An advanced classification of SE categorizes SE alleles into four main groups namely, S1, S2, S3D, and S3P. The S2 and S3P groups have been linked to susceptibility of seropositive RA. Various genome-wide association studies (GWAS) have discovered many susceptibility loci implicated in pathogenesis of RA. Some of the important single nucleotide polymorphisms (SNPs) linked to RA are TRAF1, STAT4, CTLA4, IRF5, CCR6, PTPN22, IL23R, and PADI4. HLA and non-HLA genes may discriminate anti-cyclic citrullinated peptide (anti-CCP) antibody-positive and anti-CCP-negative RA groups. Furthermore, risk of the disease has also been linked to environmental agents, mainly cigarette smoking. Pharmacogenomics has also confirmed SNPs or genetic patterns that might be linked to drugs responses. Different aspects of genetic involvement in the pathogenesis, etiology, and RA complications are reviewed in this article.
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Affiliation(s)
- Jafar Karami
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Garshasbi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Bird P, Hall S, Nash P, Connell CA, Kwok K, Witcombe D, Thirunavukkarasu K. Treatment outcomes in patients with seropositive versus seronegative rheumatoid arthritis in Phase III randomised clinical trials of tofacitinib. RMD Open 2019; 5:e000742. [PMID: 30886732 PMCID: PMC6397430 DOI: 10.1136/rmdopen-2018-000742] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 11/13/2018] [Accepted: 12/03/2018] [Indexed: 12/20/2022] Open
Abstract
Objectives Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA. Methods Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). ‘Serotype’ subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared. Results Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups. Conclusion Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients.
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Affiliation(s)
- Paul Bird
- University of New South Wales, Sydney, New South Wales, Australia
| | - Stephen Hall
- Cabrini Health and Monash University, Melbourne, Victoria, Australia
| | - Peter Nash
- University of Queensland, Brisbane, Queensland, Australia
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de Brito Rocha S, Baldo DC, Andrade LEC. Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis. Adv Rheumatol 2019; 59:2. [PMID: 30657101 DOI: 10.1186/s42358-018-0042-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 11/29/2018] [Indexed: 12/20/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune/inflammatory disease affecting 0.5 to 1% of adults worldwide and frequently leads to joint destruction and disability. Early diagnosis and early and effective therapy may prevent joint damage and lead to better long-term results. Therefore, reliable biomarkers and outcome measures are needed. Refinement of the understanding of molecular pathways involved in disease pathogenesis have been achieved by combining knowledge on RA-associated genes, environmental factors and the presence of serological elements. The presence of autoantibodies is a distinctive feature of RA. Rheumatoid Factor and Anti-Citrullinated Protein Antibodies are the two most remarkable autoantibodies in RA and provide different clinical and pathophysiological information. They precede the onset of disease symptoms and predict a more severe disease course, indicating a pathogenetic role in RA. Therefore, they promote a more accurate prognosis and contribute for a better disease management. Several RA-associated autoantibody systems have been identified: Anti-Carbamylated Antibodies, Anti-BRAF, Anti-Acetylated, Anti-PAD4 antibodies and others. Hopefully, the characterization of a comprehensive array of novel autoantibody systems in RA will provide unique pathogenic insights of relevance for the development of diagnostic and prognostic approaches compatible with an effective personalized medicine.
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Affiliation(s)
- Sara de Brito Rocha
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, Disciplina de Reumatologia, Rua Botucatu 740, 3o andar, São Paulo, SP, ZIP:04023-062, Brazil.
| | - Danielle Cristiane Baldo
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, Disciplina de Reumatologia, Rua Botucatu 740, 3o andar, São Paulo, SP, ZIP:04023-062, Brazil
| | - Luis Eduardo Coelho Andrade
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, Disciplina de Reumatologia, Rua Botucatu 740, 3o andar, São Paulo, SP, ZIP:04023-062, Brazil
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Ather JL, Dienz O, Boyson JE, Anathy V, Amiel E, Poynter ME. Serum Amyloid A3 is required for normal lung development and survival following influenza infection. Sci Rep 2018; 8:16571. [PMID: 30410021 PMCID: PMC6224415 DOI: 10.1038/s41598-018-34901-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023] Open
Abstract
Serum amyloid A (SAA) proteins are a family of acute phase apolipoproteins implicated to directly modulate innate and adaptive immune responses. However, new studies comparing endogenous SAAs and recombinant forms of these proteins have questioned the function of SAA in inflammation and immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to lung development and immune-mediated lung disease. While SAA3 deficiency does not affect the generation of house dust mite-induced allergic asthma, mice lacking SAA3 develop adult-onset obesity, intrinsic airway hyperresponsiveness, increased inflammatory and fibrotic gene expression in the lung, and elevated levels of lung citrullinated proteins. Polyclonally stimulated CD4+ T cells from SAA3-/- mice exhibit impaired glycolytic activity, decreased TH2 and TH1 cytokine secretion, and elevated IL-17A production compared to wild type cells. Polyclonally stimulated CD8+ T cells from SAA3-/- mice also exhibit impaired glycolytic activity as well as a diminished capacity to produce IL-2 and IFNγ. Finally, SAA3-/- mice demonstrate increased mortality in response to H1N1 influenza infection, along with higher copy number of viral RNAs in the lung, a lack of CD8+ T cell IFNγ secretion, and decreased flu-specific antibodies. Our findings indicate that endogenous SAA3 regulates lung development and homeostasis, and is required for protection against H1N1 influenza infection.
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Affiliation(s)
- Jennifer L Ather
- Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT, 05405, USA
| | - Oliver Dienz
- Department of Surgery, University of Vermont, Burlington, VT, 05405, USA
| | - Jonathan E Boyson
- Department of Surgery, University of Vermont, Burlington, VT, 05405, USA
| | - Vikas Anathy
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, 05405, USA
| | - Eyal Amiel
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05405, USA
| | - Matthew E Poynter
- Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT, 05405, USA.
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Arana P, Salazar D, Amaya S, Medina M, Moreno-Correa S, Moreno F, González H, Contreras A. Microorganismos periodontales en el líquido sinovial de pacientes con artritis reumatoide. Revisión sistemática de la literatura 2017. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/j.rcreu.2018.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Dong X, Zheng Z, Zhai Y, Zheng Y, Ding J, Jiang J, Zhu P. ACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis. Autoimmun Rev 2018; 17:845-853. [DOI: 10.1016/j.autrev.2018.02.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 02/20/2018] [Indexed: 01/17/2023]
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Dudics S, Venkatesha SH, Moudgil KD. The Micro-RNA Expression Profiles of Autoimmune Arthritis Reveal Novel Biomarkers of the Disease and Therapeutic Response. Int J Mol Sci 2018; 19:ijms19082293. [PMID: 30081592 PMCID: PMC6121685 DOI: 10.3390/ijms19082293] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/01/2018] [Accepted: 08/03/2018] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints affecting about 0.3–1% of the population in different countries. About 50–60 percent of RA patients respond to presently used drugs. Moreover, the current biomarkers for RA have inherent limitations. Consequently, there is a need for additional, new biomarkers for monitoring disease activity and responsiveness to therapy of RA patients. We examined the micro-RNA (miRNA) profile of immune (lymphoid) cells of arthritic Lewis rats and arthritic rats treated with celastrol, a natural triterpenoid. Experimental and bioinformatics analyses revealed 8 miRNAs (miR-22, miR-27a, miR-96, miR-142, miR-223, miR-296, miR-298, and miR-451) and their target genes in functional pathways important for RA pathogenesis. Interestingly, 6 of them (miR-22, miR-27a, miR-96, miR-142, miR-223, and miR-296) were further modulated by celastrol treatment. Interestingly, serum levels of miR-142, miR-155, and miR-223 were higher in arthritic versus control rats, whereas miR-212 showed increased expression in celastrol-treated rats compared with arthritic rats or control rats. This is the first study on comprehensive miRNA expression profiling in the adjuvant-induced arthritis (AA) model and it also has revealed new miRNA targets for celastrol in arthritis. We suggest that subsets of the above miRNAs may serve as novel biomarkers of disease activity and therapeutic response in arthritis.
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Affiliation(s)
- Steven Dudics
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
| | - Shivaprasad H Venkatesha
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
| | - Kamal D Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
- Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Systemic Inflammatory Response and Atherosclerosis: The Paradigm of Chronic Inflammatory Rheumatic Diseases. Int J Mol Sci 2018; 19:ijms19071890. [PMID: 29954107 PMCID: PMC6073407 DOI: 10.3390/ijms19071890] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 06/17/2018] [Accepted: 06/20/2018] [Indexed: 12/17/2022] Open
Abstract
Patients with Chronic Inflammatory Rheumatic diseases (CIRD) are at increased risk of cardiovascular disease (CVD), ascribed not only to classical risk factors, but also to the presence of chronic systemic inflammatory response. Αtherosclerosis, the cornerstone of CVD, is known to be accelerated in CIRD; rheumatoid arthritis promotes atheromatosis and associates with preclinical atherosclerosis equivalent to Diabetes Mellitus, which also seems to apply for systemic lupus erythematosus. Data on ankylosing spondylitis and psoriatic arthritis, albeit more limited, also support an increased CV risk in these patients. The association between inflammation and atherosclerosis, has been thoroughly investigated in the last three decades and the role of inflammation in the pathogenesis and progression of atherogenesis has been well established. Endothelial dysfunction, oxidative stress in vascular endothelial cells and macrophage accumulation, toll-like receptor signaling, NLPR-3 formation and subsequent pro-inflammatory cytokine production, such as TNFa, IL-1β, IL-6, and TNF-like cytokine 1A, are few of the mechanisms implicated in the atherogenic process. Moreover, there is evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL1β agents, can decelerate the atherogenic process, thus setting new therapeutic targets for early and effective disease control and suppression of inflammation, in addition to aggressive management of classical CV risk factors.
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Zhong Q, Gong FY, Gong Z, Hua SH, Zeng KQ, Gao XM. IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcriptomic and Epigenetic Reprogramming in Rheumatoid Arthritis. THE JOURNAL OF IMMUNOLOGY 2018; 200:3913-3925. [PMID: 29712771 DOI: 10.4049/jimmunol.1701756] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/04/2018] [Indexed: 12/31/2022]
Abstract
Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long-lasting inflammatory functional state, characterized by a strong TNF-α response to cellular proteins representing damage-associated molecular patterns and microbe-derived pathogen-associated molecular patterns. Importantly, plate-coated human IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG-induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the development of RA.
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Affiliation(s)
- Qiao Zhong
- Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.,Department of Laboratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China.,Suzhou Municipal Hospital, Suzhou 215002, China
| | - Fang-Yuan Gong
- Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Zheng Gong
- Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Sheng-Hao Hua
- Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Ke-Qin Zeng
- Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.,Department of Rheumatology, The First Affiliated Hospital of Soochow University, Suzhou 215001, China
| | - Xiao-Ming Gao
- Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China; .,Jiangsu Key Laboratory of Infection and Immunity, Suzhou 215123, China; and.,Key Laboratory of Systemic Biomedical Study, Suzhou 215123, China
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Effects of non-surgical periodontal therapy on periodontal laboratory and clinical data as well as on disease activity in patients with rheumatoid arthritis. Clin Oral Investig 2018; 23:141-151. [DOI: 10.1007/s00784-018-2420-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 03/13/2018] [Indexed: 12/31/2022]
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Huang Z, Niu Q, Yang B, Zhang J, Yang M, Xu H, Cai B, Hu J, Wu Y, Wang L. Genetic polymorphism of rs9277535 in HLA-DP associated with rheumatoid arthritis and anti-CCP production in a Chinese population. Clin Rheumatol 2018; 37:1799-1805. [PMID: 29476350 DOI: 10.1007/s10067-018-4030-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 01/15/2018] [Accepted: 02/07/2018] [Indexed: 02/05/2023]
Abstract
HLA-II molecules are critical in triggering human immune response, especially in activating CD4+ T cells. HLA-DP, belonging to HLA-II molecules, draws increasing attention for its role in presentation of viral antigen and autoantigen to T cells. Researches reported single nucleotide polymorphism (SNP) of HLA-DP associated with HBV infection and autoimmune diseases such as SLE. However, little is known about the relationship between HLA-DP and rheumatoid arthritis (RA). Rs9277535 is located in 3' UTR region of HLA-DPB1, a subunit of HLA-DP, and was reported to affect HLA-DP mRNA expression. In the present study, we explored the relationship between gene polymorphism of rs9277535 in HLA-DPB1 and RA susceptibility and progression. Samples from 254 patients with RA and 391 age- and sex-matched healthy controls were collected and genotyped by a polymerase chain reaction-high-resolution melting (PCR-HRM) assay. Serological tests (anti-CCP, rheumatoid factor, C-reactive protein, anti-keratin antibody) were detected by laboratory assays. Strong association was observed between SNP rs9277535 in HLA-DP and RA susceptibility (allele frequency distribution: OR = 1.409, 95%CI = 1.121-1.773, P = 0.004). Further validation was provided by disease model analysis (recessive model: OR = 1.889, 95%CI = 1.194-2.990, P = 0.008; dominant model: OR = 1.464, 95%CI = 1.050-2.041, P = 0.025; additive model: OR = 2.208, 95%CI = 1.335-3.652, P = 0.003). Allele A was correlated to increased risk of RA. Serological test results demonstrated patients carrying allele A of rs9277535 had elevated serum anti-CCP antibody level. The present study provided evidence that HLA-DP gene polymorphism associated with RA susceptibility. Allele A of rs9277535 in HLA-DP correlated to increased risk of RA and elevated serum anti-CCP level.
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Affiliation(s)
- Zhuochun Huang
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Qian Niu
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Bin Yang
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Junlong Zhang
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Min Yang
- Department of rheumatology and immunology, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, China
| | - Huan Xu
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Bei Cai
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Jing Hu
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Yongkang Wu
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China
| | - Lanlan Wang
- Department of lab medicine, West China Hospital, Sichuan University, Sichuan Province, Chengdu, China.
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Gaafar AGA, Messiha BAS, Abdelkafy AML. Nicorandil and theophylline can protect experimental rats against complete Freund's adjuvant-induced rheumatoid arthritis through modulation of JAK/STAT/RANKL signaling pathway. Eur J Pharmacol 2018; 822:177-185. [PMID: 29337196 DOI: 10.1016/j.ejphar.2018.01.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 12/20/2017] [Accepted: 01/10/2018] [Indexed: 12/23/2022]
Abstract
Signaling pathways are interesting fields of study of pathogenesis and treatment trials. We elucidated the possible protective effects of nicorandil (15mg/kg/day) and theophylline (20mg/kg/day) on experimentally-induced RA, focusing on the role of JAK (Janus Kinase) / STAT (Signal Transducer and Activator of Transcription) / RANKL (Receptor Activator of Nuclear factor-Kappa B Ligand) / cytokine signaling pathway. Four sets of experiments were performed. First, effect of test agents on normal animals was evaluated. Second, effect of test agents was evaluated on Complete Freund's Adjuvant (CFA; 0.3ml, s.c.)-induced RA to investigate anti-arthritic effect. Third, effect of test agents was evaluated on growth hormone (GH; 2mg/kg/day, s.c.)-induced stimulation of JAK/STAT/RANKL/cytokine signaling pathway to investigate the role of this signaling pathway in their anti-arthritic effect. Fourth, the effect of test agents was performed on CFA/GH-induced RA. To fulfill this purpose, serum anti-citrullinated peptide antibody (ACPA), interleukin-6 (IL-6), and cartilage oligomeric matrix protein (COMP), together with tissue JAK2, STAT3, RANKL, inducible and endothelial nitric oxide synthases (iNOS and eNOS) as well as macrophage inflammatory protein (MIP1α) were estimated using ELISA, Western blotting and PCR techniques, confirmed by a histopathological study. Test agents significantly corrected JAK2, STAT3, RANKL and IL-6 values in animals receiving GH. Additionally, test agents could correct ACPA, IL-6, COMP, JAK2, STAT3, RANKL, iNOS, eNOS and MIP1α levels compared with the respective CFA or CFA/GH controls. These results conclude that nicorandil and theophylline have good anti-arthritic effects related to modulation of JAK/STAT/RANKL signaling pathway. Further clinical trials are claimed.
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Jung H, Jung SM, Rim YA, Park N, Nam Y, Lee J, Park SH, Ju JH. Arthritic role of Porphyromonas gingivalis in collagen-induced arthritis mice. PLoS One 2017; 12:e0188698. [PMID: 29190705 PMCID: PMC5708830 DOI: 10.1371/journal.pone.0188698] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 11/10/2017] [Indexed: 12/29/2022] Open
Abstract
Epidemiological studies show an association between rheumatoid arthritis (RA) and periodontal disease. Porphyromonas gingivalis (P.gingivalis) is a well-known pathogen in periodontitis. This study investigated the pathogenic effects of P.gingivalis on autoimmune arthritis in vivo. Collagen-induced arthritis (CIA) mice were intraperitoneally injected with W83 and 2561 strains of P.gingivalis. Infection with P.gingivalis exacerbated arthritis score in CIA mice. Synovial inflammation and bone destruction in CIA mice infected with P.gingivalis were more severe than in uninfected CIA mice. Both W83 and 2561 strains were more pro-arthritic after arthritis symptom was fully activated. Interestingly, only W83 strain was arthritogenic before autoimmune reaction initiated. Citrullination was detected in synovial tissue of CIA mice and CIA mice inoculated with P.gingivalis, but not in normal control mice. The citrullinated area was greater in P.gingivalis-infected CIA mice than in non-infected CIA mice. This study showed that P.gingivalis exacerbated disease in a mouse model of autoimmune arthritis and increased the expression of citrullinated antigens in the synovium. The arthritogenic effects of P.gingivalis were at least in part, dependent upon the bacterial strain with or without fimbriae expression, route and time of infection. P.gingivalis-mediated citrullination may explain the possible link between periodontal disease and RA.
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Affiliation(s)
- Hyerin Jung
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Min Jung
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Yeri Alice Rim
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Narae Park
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoojun Nam
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jennifer Lee
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Hyeon Ju
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- * E-mail:
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IRAK2 is associated with susceptibility to rheumatoid arthritis. Clin Rheumatol 2017; 37:927-933. [DOI: 10.1007/s10067-017-3906-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/31/2017] [Accepted: 11/02/2017] [Indexed: 01/30/2023]
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Nakken B, Papp G, Bosnes V, Zeher M, Nagy G, Szodoray P. Biomarkers for rheumatoid arthritis: From molecular processes to diagnostic applications-current concepts and future perspectives. Immunol Lett 2017; 189:13-18. [DOI: 10.1016/j.imlet.2017.05.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 05/10/2017] [Accepted: 05/15/2017] [Indexed: 12/31/2022]
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Shafrin J, Tebeka MG, Price K, Patel C, Michaud K. The Economic Burden of ACPA-Positive Status Among Patients with Rheumatoid Arthritis. J Manag Care Spec Pharm 2017; 24:4-11. [PMID: 29290168 PMCID: PMC10398189 DOI: 10.18553/jmcp.2017.17129] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Anticitrullinated protein antibodies (ACPAs) are serological biomarkers associated with early, rapidly progressing rheumatoid arthritis (RA), including more severe disease and joint damage. ACPA testing has become a routine tool for RA diagnosis and prognosis. Furthermore, treatment efficacy has been shown to vary by ACPA-positive status. However, it is not clear if the economic burden of patients with RA varies by ACPA status. OBJECTIVE To determine if the economic burden of RA varies by patient ACPA status. METHODS IMS PharMetrics Plus health insurance claims and electronic medical record (EMR) data from 2010-2015 were used to identify patients with incident RA. Patients were aged ≥ 18 years, had ≥ 1 inpatient or ≥ 2 outpatient claims reporting an RA diagnosis code (ICD-9-CM code 714.0), and had an anticyclic citrullinated peptide (anti-CCP; a surrogate of ACPA) antibody test within 6 months of diagnosis. Incident patients were defined as those who had no claims with an RA diagnosis code in the 6 months before the first observed RA diagnosis. The primary outcome of interest was RA-related medical expenditures, defined as the sum of payer- and patient-paid amounts for all claims with an RA diagnosis code. Secondary outcomes included health care utilization metrics such as treatment with a disease-modifying antirheumatic drug (DMARD) and physician visits. Generalized linear regression models were used for each outcome, controlling for ACPA-positive status (defined as anti-CCP ≥ 20 AU/mL), age, sex, and Charlson Comorbidity Index score as explanatory variables. RESULTS Of 647,171 patients diagnosed with RA, 89,296 were incident cases, and 47% (n = 42,285) had an anti-CCP test. After restricting this sample to patients with a linked EMR and reported anti-CCP test result, 859 remained, with 24.7% (n = 212) being ACPA-positive. Compared with ACPA-negative patients, adjusted results showed that ACPA-positive patients were more likely to use either conventional (71.2% vs. 49.6%; P < 0.001) or biologic (20.3% vs. 11.8%; P < 0.001) DMARDs during the first year after diagnosis and had more physician visits (5.58 vs. 3.91 times per year; P < 0.001). Annual RA-associated total expenditures were $7,941 for ACPA-positive and $5,243 for ACPA-negative patients (Δ = $2,698; P = 0.002). RA-associated medical expenditures were $4,380 for ACPA-positive and $3,427 for ACPA-negative patients (Δ = $954; P = 0.168), whereas DMARD expenditures were $3,560 and $1,817, respectively (Δ = $1,743; P = 0.001). CONCLUSIONS RA-related economic burden is higher for patients who are ACPA-positive compared with those who are ACPA-negative. Providers may wish to inform patients diagnosed with ACPA-positive RA about the likely future disease and economic burden in hopes that both stakeholders can be more proactive in addressing them. DISCLOSURES Funding for this research was contributed by Bristol-Myers Squibb. Patel and Price are employees and stockholders of Bristol-Myers Squibb. Shafrin and Tebeka are employees of Precision Health Economics, a health care consulting firm that received funding from Bristol-Myers Squibb to conduct this study. Michaud has received a grant from Pfizer and is employed by the National Data Bank for Rheumatic Diseases, which has received funds from Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, and Regeneron. Study concept and design were contributed by Shafrin, Price, Patel, and Michaud. Shafrin, Price, and Patel collected the data, and all authors contributed equally to data analysis. The manuscript was written by Shafrin and Tebeka and revised by Shafrin, Price, Patel, and Michaud.
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Affiliation(s)
- Jason Shafrin
- 1 Precision Health Economics, Los Angeles, California
| | | | - Kwanza Price
- 2 Bristol-Myers Squibb, Princeton Pike, New Jersey
| | - Chad Patel
- 2 Bristol-Myers Squibb, Princeton Pike, New Jersey
| | - Kaleb Michaud
- 3 University of Nebraska Medical Center, Omaha, and National Data Bank for Rheumatic Diseases, Wichita, Kansas
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Soleimani A, Mobedi Z, Al-E-Rasul M, Sharifi A, Vardanjani AK. Effect of Anti-Cyclic Citrullinated Peptide and HLA-DRB1 Subtypes on Clinical Disease Activity Index in Rheumatoid Arthritis Patients. J Clin Diagn Res 2017; 11:OC09-OC12. [PMID: 28511426 DOI: 10.7860/jcdr/2017/8567.9436] [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: 01/20/2014] [Accepted: 08/26/2015] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a crippling disease with a global prevalence of approximately 0.5%-1% in adults. Genetic, environmental and immunologic factors contribute importantly to pathogenesis of RA. American College of Rheumatology (ACR) assists in early diagnosis of the disease. AIM The aim of this study was to investigate the effects of HLA-DRB1 gene and anti-Cyclic Citrullinated Peptide (CCP) antibody on Clinical Disease Activity Index (CDAI) and to determine the frequency of HLA-DRB1 alleles in the patients with RA. MATERIALS AND METHODS In this descriptive-analytical study, 64 patients with RA referring rheumatology clinic of Hajar Hospital, Shahr-e-Kord, Iran were enrolled based on ACR criteria (1987) by convenience sampling. All patients were examined to assess primary CDAI and referred to laboratory for serologic tests [Rheumatoid Factor (RF) and anti-CCP]. After the patients' DNA was extracted, HLA-DRB1 was determined per single specific primer-polymerase chain reaction by inno-train kits. The patients were re-examined six months later. RESULTS The most prevalent type of HLA-DRB1 in the studied patients was 04. In patients with HLA-DRB1 (04), HLA-DRB1 (01), and HLA-DRB1 (15), CDAI decreased pronouncedly after six months, but in other patients it did not (p<0.05). Of the patients, 81.3% had high titers of anti-CCP, but no association between anti-CCP and CDAI was found. CONCLUSION RA could be a multifactorial disease. The patients with HLA-DRB1 (04), HLA-DRB1 (01) and HLA-DRB1 (15) showed a good response to routine treatments. The patients with HLA-DRB1 (04) are likely to have no decrease in secondary CDAI. High titers of anti-CCP in patients may indicate the severity of RA in the studied region and perhaps environmental, genetic and unknown or idiopathic factors are aetiologically crucial.
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Affiliation(s)
- Akbar Soleimani
- Faculty, Department of Internal Medicine, Shahr-e-Kord University of Medical Sciences, Shahr-e-Kord, Iran
| | - Zahra Mobedi
- Faculty, Department of Rheumatology, Shahr-e-Kord University of Medical Sciences, Shahr-e-Kord, Iran
| | - Maryam Al-E-Rasul
- Faculty, Department of Gynaecology and Obstetrics, Shahr-e-Kord University of Medical Sciences, Shahr-e-Kord, Iran
| | - Abolghasem Sharifi
- Deputy of Research and Technology, Shahr-e-Kord University of Medical Sciences, Shahr-e-Kord, Iran
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Sadeghi A, Pezeshgi A, Karimimoghaddam A, Moghimi M, Kamali K, Naseri M, Esmaeilzadeh A. Evaluation of anti-mutated citrullinated vimentin antibodies, anti-cyclic citrullinated peptide antibodies in patients with rheumatoid arthritis in comparison with other rheumatic diseases; a nephrology point of view. J Nephropharmacol 2017. [DOI: 10.15171/npj.2017.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Song X, Lin Q. Genomics, transcriptomics and proteomics to elucidate the pathogenesis of rheumatoid arthritis. Rheumatol Int 2017; 37:1257-1265. [DOI: 10.1007/s00296-017-3732-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/29/2017] [Indexed: 01/23/2023]
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Genetic markers as therapeutic target in rheumatoid arthritis: A game changer in clinical therapy? Rheumatol Int 2016; 36:1601-1607. [PMID: 27638722 DOI: 10.1007/s00296-016-3563-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 09/01/2016] [Indexed: 12/19/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic, inflammatory, multi-systemic autoimmune disease unremitted by genetic and environmental factors. The factors are crucial but inadequate in the development of disease; however, these factors can be representative of potential therapeutic targets and response to clinical therapy. Insights into the contribution of genetic risk factors are currently in progress with studies querying the genetic variation, their role in gene expression of coding and non-coding genes and other mechanisms of disease. In this review, we describe the significance of genetic markers architecture of RA through genome-wide association studies and meta-analysis studies. Further, it also reveals the mechanism of disease pathogenesis investigated through the mutual findings of functional and genetic studies of individual RA-associated genes, which includes HLA-DRB1, HLA-DQB1, HLA-DPB1, PADI4, PTPN22, TRAF1-C5, STAT4 and C5orf30. However, the genetic background of RA remains to be clearly depicted. Prospective efforts of the post-genomic and functional genomic period can travel toward real possible assessment of the genetic effect on RA. The discovery of novel genes associated with the disease can be appropriate in identifying potential biomarkers, which could assist in early diagnosis and aggressive treatment.
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Morita T, Shima Y, Kakigano A, Ogata A, Kumanogoh A. Serum anti-citrullinated protein antibodies of a mother with rheumatoid arthritis pass through the placenta but do not cause arthritis in her neonate. Scand J Rheumatol 2016; 46:85-86. [PMID: 27574903 DOI: 10.1080/03009742.2016.1195871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- T Morita
- a Department of Respiratory Medicine, Allergy and Rheumatic Diseases , Osaka University Graduate School of Medicine , Osaka , Japan
| | - Y Shima
- a Department of Respiratory Medicine, Allergy and Rheumatic Diseases , Osaka University Graduate School of Medicine , Osaka , Japan
| | - A Kakigano
- b Department of Obstetrics and Gynaecology , Osaka University Graduate School of Medicine , Osaka , Japan
| | - A Ogata
- a Department of Respiratory Medicine, Allergy and Rheumatic Diseases , Osaka University Graduate School of Medicine , Osaka , Japan.,c Division of Allergy, Rheumatology and Connective Tissue Disease , NTT WEST Japan Osaka Hospital , Osaka , Japan
| | - A Kumanogoh
- a Department of Respiratory Medicine, Allergy and Rheumatic Diseases , Osaka University Graduate School of Medicine , Osaka , Japan
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Markovics A, Ocskó T, Katz RS, Buzás EI, Glant TT, Mikecz K. Immune Recognition of Citrullinated Proteoglycan Aggrecan Epitopes in Mice with Proteoglycan-Induced Arthritis and in Patients with Rheumatoid Arthritis. PLoS One 2016; 11:e0160284. [PMID: 27466816 PMCID: PMC4965111 DOI: 10.1371/journal.pone.0160284] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 07/15/2016] [Indexed: 01/11/2023] Open
Abstract
Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. Methods We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)-containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. Results Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. Conclusions We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitope-induced T-cell activation or antibody deposition may occur in the joints of RA patients.
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Affiliation(s)
- Adrienn Markovics
- Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Tímea Ocskó
- Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Robert S Katz
- Rheumatology Associates, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Edit I Buzás
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Tibor T Glant
- Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Katalin Mikecz
- Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America
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Autoimmune atherosclerosis in 3D: How it develops, how to diagnose and what to do. Autoimmun Rev 2016; 15:756-69. [PMID: 26979271 DOI: 10.1016/j.autrev.2016.03.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 03/07/2016] [Indexed: 12/11/2022]
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