Relationship between anti-Epstein-Barr virus early antigen diffuse type and restricted type immunoglobulin G antibodies and disease activity and autoantibodies in rheumatoid arthritis a retrospective observational study

Relationship between anti-Epstein-Barr virus early antigen diffuse type and restricted type immunoglobulin G antibodies and disease activity and autoantibodies in rheumatoid arthritis a retrospective observational study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Relationship between anti-Epstein-Barr virus early antigen diffuse type and restricted type immunoglobulin G antibodies and disease activity and autoantibodies in rheumatoid arthritis a retrospective observational study Noboru Kitamura, Yosuke Nagasawa, Kumiko Akiya, Hirotake Inomata, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5812683/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Oct, 2025 Read the published version in BMC Rheumatology → Version 1 posted 11 You are reading this latest preprint version Abstract Background This study aimed to examine the relationship of Epstein-Barr virus (EBV) in rheumatoid arthritis (RA) by evaluating disease activity and autoantibody levels in positive and negative cases using the anti-EBV early antigen diffuse type and restricted type (EA-DR) immunoglobulin G (IgG) antibody. Methods Patients undergoing RA treatment at our hospital with anti-EBV EA-DR IgG antibodies were selected. We confirmed their age, sex, RA duration, disease activity, laboratory findings, treatment details, and complications in patients with positive or negative anti-EBV EA-DR IgG antibodies and analyzed the relationship between RA activity, autoantibody production, and EBV. Results anti-EBV EA-DR IgG antibodies were measured in 70 RA cases (30 positive and 40 negative), with a positivity rate of 43.9%. Among the positive cases, 18 underwent EBV deoxyribonucleic acid polymerase chain reaction, with 14 testing positive. Univariate analysis revealed significantly higher levels of disease activity score in 28 joints with C-reactive protein, peripheral blood lymphocyte count, anti-cyclic citrullinated peptide antibody (ACPA), and rheumatoid factor in anti-EBV EA-DR IgG antibody-positive cases. Multivariate analysis identified peripheral blood lymphocyte count and ACPA levels as significant factors. Conclusions Patients with RA who tested positive for anti-EBV EA-Dr IgG antibodies had significantly higher ACPA than those who tested negative. anti-EBV EA-DR IgG ACPA rheumatoid arthritis Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes progressive joint destruction, limits daily activities, and reduces the quality of life (QOL). The etiology of RA remains incompletely understood, with researchers considering it a complex multifactorial disease influenced by genetic and environmental factors. Genetic factors such as human leukocyte antigen (HLA)-RD1 and DR4, belonging to HLA class II molecules, and peptidylarginine deiminase type 4 (PADI4), a non-major histocompatibility complex (MHC) gene associated with RA susceptibility, have been identified [1]. However, several environmental factors are also implicated in RA pathogenesis. Smoking [4] and periodontal disease [5] are known environmental factors, and viral infections, especially Epstein-Barr virus (EBV) infections, play a major role in the pathogenesis of RA [6]. Various studies have investigated the association between EBV and RA. Takei et al. first reported the presence of EBV in the synovium of RA in 1997 [5], a finding subsequently corroborated by numerous independent studies [6–8]. Furthermore, an autoantibody specific for RA, the anti-cyclic citrullinated peptide antibody (ACPA), recognizes EBV-nuclear antigen (EBNA)-1, a nuclear antigen of EBV [9], indicating that EBV infection may cause ACPA production. However, no studies have demonstrated the relationship of EBV infection in RA disease activity or autoantibody production in clinical practice. In clinical practice, antibodies against EBV are known to include anti-EBV viral capsid antigen (VCA) immunoglobulin M (IgM) antibodies, anti-EBV VCA IgG antibodies, anti-EBV early antigen diffuse type and restricted type (EA-DR) IgG and anti-EBV EBNA IgG antibodies are known, while anti-EBV EA-DR IgG antibodies are antibodies with the property of rising during acute infection, disappearing, and then rising again during reactivation [10]. In this study, we retrospectively examined the relationship of EBV in RA by evaluating disease activity and autoantibody levels in positive and negative cases using the anti-EBV EA-DR immunoglobulin G (IgG) antibody, an indicator of EBV reactivation. Methods Patients This is a retrospective observational study. Patients were diagnosed with RA by the American College of Rheumatology (ACR) from 2012 to 2021 at Nihon University Itabashi Hospital using the 2010 classification criteria [11] and were ACPA and Rheumatoid Factor (RF)-positive. Seventy patients (52 women and 18 men) with anti-EBV EA-DR IgG and anti-EBV VCA IgG antibodies were included in the study. Anti-EBV EA-DR IgG antibodies and anti-EBV VCA IgG antibodies were measured at the same time as ACPA and RF measurements at our first visit. Thirty patients (22 women and eight men) were in the positive group for anti-EBV EA-DR IgG antibodies, and 40 (30 women and 10 men) were in the negative group. All patients were positive for anti-EBV VCA IgG antibodies. For the anti-EBV EA-DR IgG antibody measurements case, the disease duration was 12.5 ± 9.9 years in the positive group and 12.0 ± 6.8 years in the negative group. Methotrexate (MTX) use was 73% in the positive group at a mean dose of 8.5 ± 2.4 mg/week and 64% in the negative group at a mean dose of 8.0 mg ± 1.9 mg/week. Biological disease modifying anti rheumatic drugs (bDMARDs) were used by 23.3% of the patients in the positive group and 28.0% in the negative group, targeting systemic disease modifying anti rheumatic drugs (tsDMARDs) were used by 10.4% of the patients in the positive group and 10.9% of the negative group. No difference was observed in the use of DMARDs between the two groups (Table 1 ). Table 1 Patient characteristics. Anti-EBV EA-DR IgG positive group Anti-EBV EA-DR IgG negative group n = 30 n = 40 Age (year; mean ± SD) 62.6 ± 15.7 64.6 ± 13.5 Sex (male/female) 8/22 10/30 Duration (year; mean ± SD) 1.2 ± 9.9 12.0 ± 6.8 MTX (usage rate/mg/week; mean ± SD) 73%/8.5 ± 2.4 64%/ 8.0 ± 1.9 PSL (usage rate (%)/mg; mean ± SD) 33/ 4.1 ± 2.2 28/ 5.3 ± 3.0 bDMARDs usage rate (%) 23.3 28.0 tsDMARDs usage rate (%) 10.4 10.9 EBV; Epstein-Barr virus, EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, MTX; methotrexate, PSL; prednisolone, bDMARDs; biological disease-modifying anti-rheumatoid drugs, tsDMARDs; targeted synthetic DMARDs. Measurement of anti-EBVEA-DR IgG, anti-EBV VCA IgG antibodies and EBV real-time polymerase chain reaction (PCR) Anti-EBV EA-DR IgG, and anti-EBV VCA IgG antibodies were measured using a BioPlex EBV IgG kit from Bio-Rad (Tokyo, Japan) [12]. Readings greater than 1.1 index were considered positive. The kit was not cross-reactive with rheumatoid factor (RF) or antinuclear antibodies. Peripheral blood serum EBV deoxyribonucleic acid (DNA) was measured by real-time polymerase chain reaction (PCR) using a TaqMan system (Applied Biosystems, USA) [13]. Ethics This study was approved by the Ethics Committee of Nihon University School of Medicine (approval number: RK-220712-5) and conducted in accordance with the principles of the Declaration of Helsinki. Statistical analysis Univariate analysis comparing each item between the anti-EBV EA-DR IgG antibody-positive and negative groups was conducted using the Mann-Whitney U test, a nonparametric statistical method, for continuous data with confirmed normality, and the independent t-test for those with confirmed and rejected normality. Multivariate logistic regression analysis was then conducted to determine if anti-EBV EA-DR IgG antibodies independently predicted RA activity and autoantibody production. Factors showing significant differences in the univariate analysis were included as explanatory variables, whereas the spontaneous regression and progression groups were set as objective variables. Statistical significance was set at P < 0.05. All statistical analyses were performed using the SPSS Statistics version 26 (IBM Corporation, Armonk, NY, USA). Results Anti-EBV EA-DR IgG antibody positive vs. negative group; disease activity Disease activity was examined in anti-EBV EA-DR IgG antibody positive and negative groups. Data were collected on tender joints, swollen joints, patient global assessment of disease activity (PtGA), provider global assessment of disease activity (PrGA), disease activity score in 28 joints with C-reactive protein (DAS28-CRP), DAS28 with erythrocyte sedimentation rate (DAS28-ESR), simplified disease activity index (SDAI), and clinical disease activity index (CDAI). Only the DAS28 CRP was significantly higher in the positive group than in the negative group (Table 2 ). Table 2 Comparison of disease activity between anti-EBV EA-DR IgG antibody positive and negative groups. Anti-EBV EA-DR IgG positive group n = 30 Anti-EBV EA-DR IgG negative group n = 40 P value TjC 2.4 ± 2.5 2.7 ± 3.5 0.4432 SjC 1.6 ± 1.2 0.6 ± 0.9 0.0512 PtGA 14.9 ± 13.4 19.6 ± 16.1 0.7523 PrGA 13.3 ± 12.8 13.2 ± 15.1 0.7094 DAS 28-CRP 2.9 ± 0.9 2.3 ± 0.9 0.0450* DAS 28-ESR 3.2 ± 0.5 2.8 ± 0.9 0.0523 SDAI 9.5 ± 6.2 5.3 ± 3.7 0.0920 CDAI 9.0 ± 5.9 5.0 ± 3.7 0.0858 EBV; Epstein-Barr Virus, EA-DR; EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, TjC, tender joint count; SjC, swollen joint count; PtGA, patient global assessment of disease activity; PrGA, provider global assessment of disease activity; DAS, disease activity score; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SDAI, simplified disease activity index; CDAI, clinical disease activity index. *; p < 0.05 Anti-EBV EA-DR IgG antibody positive vs. negative group; laboratory findings Laboratory findings were examined in the anti-EBV EA-DR IgG antibody positive and negative groups, including CRP, ESR, matrix metalloproteinase 3 (MMP-3), white blood cell count (WBC), lymphocyte cell count, hemoglobin (Hb), platelet count, IgG, rheumatoid RF, ACPA, and anti-Sjögren's-syndrome-related antigen A/Ro (SS-A/Ro) antibody. MMP-3, RF, and ACPA were significantly higher in the positive group than in the negative group, and lymphocyte cell count was significantly lower in the positive group than in the negative group (Table 3 ). Table 3 Comparison of laboratory findings between anti-EBV EA-DR IgG antibody positive and negative groups. Anti-EBV EA-DR IgG positive group n = 30 Anti-EBV EA-DR IgG negative group n = 40 P value CRP (mg/dL) 0.8 ± 1.3 0.36 ± 0.61 0.4770 ESR (mm/h) 23.5 ± 22.1 23.3 ± 18.7 0.7360 MMP-3 (ng/mL) 182.0 ± 162.9 85.2 ± 59.3 0.0358* WBC (/µL) 5233.3 ± 986.8 6085.0 ± 1208.7 0.0521 Ly (/µL) 1221.4 ± 201.4 1486.2 ± 256.6 0.0370* Hb (g/dL) 12.2 ± 2.3 12.9 ± 1.3 0.3970 Plt (×10 4 /µL) 22.5 ± 6.7 23.9 ± 5.1 0.9025 IgG (mg/dL) 1134.8 ± 144.0 1317.8 ± 286.5 0.0810 RF (IU/mL) 126.4 ± 78.2 74.1 ± 84.4 0.0491* ACPA (U/mL) 257.9 ± 448.7 51.4 ± 40.6 0.0028* Anti SS-A Ab (usage rate; %) 13.3 15.0 0.5627 EBV, Epstein-Barr virus; EA-DR;early antigen diffuse type and restricted type, IgG༛ immunoglobulin G, CRP; C-reactive protein; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; WBC, blood cell count; Ly, lymphocyte; Hg, hemoglobin; Plt, platelet; RF, rheumatoid factor; ACPA, anti-citrullinated peptide antibody; SS-A, Sjögren syndrome-A. *; p < 0.05 Anti-EBV EA-RD IgG antibody positive vs. negative group; organ complications Laboratory findings were examined in anti-EBV EA-DR IgG antibody-positive and negative groups. Significant differences between the positive and negative groups were examined for respiratory diseases (excluding interstitial lung disease, airway involvement, pleurisy, rheumatoid nodules, and respiratory infections), cardiovascular diseases (cardiovascular events, pericarditis, and myocarditis), Sjögren's syndrome, and lymphoproliferative disorder (LPD). LPD showed a trend toward a higher complication rate in the positive group compared to the negative group; however, this difference was not statistically significant (Table 4 ). Table 4 Comparison of organ complications between anti-EBV EA-DR IgG antibody positive and negative groups. Anti-EBV EA-DR IgG positive group n = 30 Anti-EBV EA-DR IgG negative group n = 40 P value Respiratory disease 8/22; 36.4% 16/24; 66.7% 0.4990 CVD 2/28; 0.07% 2/38; 0.05% 0.7968 SS 2/28; 0.07% 2/38; 0.05% 0.7758 LPD 6/24; 25.0% 0/40; 0.0% 0.0710 EBV; Epstein-Barr virus; EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, CVD; cardiovascular disease, SS; Sjögren’s syndrome, LPD; lymphoproliferative disorder. Comparison of anti-EBV EA-DR IgG antibody positive and negative groups by multivariate analysis Logistic regression analysis was performed using anti-EBV EA-DR IgG antibody positivity and negativity as objective variables and five factors–DSS28 CRP, MMP-3, lymphocyte cell count, RF, and ACPA–which were significant in the univariate analysis, as explanatory variables. The ACPA and lymphocyte cell count were identified as significant factors (Table 5 ). Table 5 Comparison of anti-EBV EA-DR IgG antibody positive and negative groups by multivariate analysis. B SD Wald Degree of freedom P value OR 95% CI ACPA 0.031 0.015* 4.282 1 0.039* 1.032 1.002-1,063 RF 1.113 0.663 2.823 1 0.093 3.044 0.831–11.156 MMP-3 0.007 0.006 1.300 1 0.254 1.007 0.995–1.019 DAS28 CRP 0.000 0.001 0.187 1 0.665 1.000 0.999–1.002 Ly -0.010 0.005 4.095 1 0.043* 0.990 0.980-1.000 constant 7.564 6.202 1.488 1 0.223 1928.306 OR; odds ratio, CI; confidence interval, SD; standard deviation, ACPA; anti-citrullinated peptide antibody, RF; rheumatoid factor, MMP-3; matrix metalloproteinase-3, DAS; disease activity score, CRP; C-reactive protein, Ly; lymphocytes. *; p < 0.05 Positivity of EBV PCR in peripheral blood of patients positive for anti-EBV EA-DR IgG antibodies Among the 30 patients with anti-EBV EA-DR IgG antibody positivity, serum EBV PCR was measured in 18 cases, of which 14 (77.8%) were positive (Table 6 ). Table 6 Positivity of EBV PCR in peripheral blood of patients positive for anti-EBV EA-DR IgG antibodies. EBV PCR (+) EBV PCR (-) Anti EBV EA-DR IgG (+) (n = 18) 14 4 EBV; Epstein–Barr virus, EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, PCR; polymerase chain reaction, RA; rheumatoid arthritis. Discussion RA results from a combination of genetic and environmental factors [4]. The relationship between EBV and RA has been investigated extensively. Alspaugh et al. [14] identified RA nuclear antigen antibody (RANA), an antibody against the nuclear component of EBV-infected cells, in the peripheral blood of patients with RA. The major epitope recognized by RANA is the glycine-alanine repeat structure of EBNA-1 [15]. Similar protein molecules have been identified in RA synovial lesions [16], suggesting that the molecular homology between RA lesions and EBV may play an important role in RA pathogenesis. Subsequently, Takei et al. [5] demonstrated the presence of EBV in RA synovial lesions using PCR and in situ hybridization. Furthermore, EBV-DNA and EBV-encoded small ribonucleic acid RNA (EBER)-1 were detected at high rates in synovial lesions of patients with RA with HLA-DRB1 * 0401, 0404, 0405, or 0408 alleles. These HLA class II molecules have shown a strong association with RA, and the EBV-positive frequency is indelibly higher than in normal controls [17]. Mahraein et al. [18] demonstrated the expression of EBER and latent membrane protein (LMP)-1, an EBV membrane-associated protein found during latent EBV infection, in synovial surface cells. LMP-1 plays an important role in transforming EBV-infected B cells [19], suggesting that it may be involved in the proliferation of RA synovial cells. These reports also suggest that EBV is present in the synovial tissue of patients with RA and is involved in joint lesions. In this study, the positivity rate of anti-EBV EA-DR IgG was 42.9% (30/70), and Miljanovic et al. [20] showed that active/recent EBV infection was more common in patients with RA (42%) than in controls (16%), which is similar to our results. A significantly higher rate of EBV infection was observed in patients with RA than in controls. The signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) gene may be involved in RA and EBV infections. The SAP gene enhances the cytotoxic activity of T and NK cells, facilitating the elimination of EBV-infected B cells [21]. X-linked lymphoproliferative syndrome (XLP), a congenital immunodeficiency disorder, is characterized by fatal infectious mononucleosis, dysgammaglobulinemia, and malignant lymphoma. This syndrome is primarily caused by persistent EBV infection due to a selective deficiency of the SAP gene, with a mortality rate exceeding 90% [22]. The SAP gene that activates these EBV-specific cytotoxic T cells (CTL) has already been cloned [23]; however, the expression of SAP mRNA in T cells in the peripheral blood is low in patients with RA [24]. Therefore, RA might impair EBV-specific CTLs in EBV-infected cells, resulting in EBV reactivation. In this study, we used anti-EBV EA-DR IgG antibody as an indicator of EBV reactivation. Although EBV PCR was measured in a few cases, 18 underwent testing, revealing a notably high positivity rate of 77.8%. Moreover, anti-EBV EA-DR IgG antibodies rise when EBV is reactivated [25], suggesting that positive anti-EBV EA-DR IgG antibodies are related with EBV reactivation. In addition, all presents cases were positive for anti-EBV VCA IgG antibodies. Although anti-EBV VCA IgM was not measured, we believe that the cases positive for anti-EBV EA DR IgG antibodies in this study were not first-time EBV infections but reactivations. In this study, we conducted a comparison between the anti-EBV EA-DR IgG-positive and negative groups, revealing ACPA as a significant factor in the multivariate analysis. Several reports exist on the association between EBV and ACPA. Trier et al. [26] examined the reactivity of ACPA to citrullinated EBNA-1 and found antibodies to citrullinated EBNA-1 peptides in 67% of patients with RA, indicating that these peptides may be substrates for ACPA detection and that EBV may be related in ACPA induction. Furthermore, Sakkas et al. [27] suggested that antibodies to citrullinated peptides derived from EBNA appear several years before the onset of RA and cross-react with human citrullinated fibrin, suggesting that citrullinated proteins may be the cause of ACPA production and autoantigens for arthritis development in RA. Although the present study is the result of a limited retrospective observational study, this study suggests that EBV may be involved in ACPA production. The present study cannot strictly conclude whether EBV is involved in the pathogenesis of RA or whether the immune abnormalities underlying RA induce EBV activation. However, we have also demonstrated that humanized mice infected with EBV develop an erosive arthritis similar to rheumatoid arthritis [29,29]. If these results are confirmed in humans, citrullinated proteins cross-reactivated upon EBV reactivation may be partially responsible for ACPA production and the development of RA erosive arthritis. Limitation Because this is a retrospective, observational study, we did not measure serum EBV PCR in all anti-EBV EA-DR IgG antibody-positive cases. Also, because X-rays were not taken in a part of patients, the degree of progression of bone destruction on X-rays could not assessed. In addition, since it is not possible to measure antibody titers of the four types of EBV in Japanese medical insurance, 2 types of antibodies, such as anti-EBV VCA IgG and anti-EBV EA-DR IgG antibodies has been measured as indicators of reactivation. Conclusion In this study, we showed that patients with RA positive for anti-EBV EA-DR IgG antibodies had significantly higher ACPA compared to those negative for anti-EA-DR IgG antibodies. Given that ACPA serves as a specific antibody and a risk factor for RA, the involvement of EBV in its production is suggested. Further studies on EBV regarding RA pathogenesis and disease activity are warranted. Abbreviations RA Rheumatoid arthritis QOL The quality of life HLA Human leukocyte antigen PADI4 Peptidylarginine deiminase type 4 MHC Major histocompatibility complex EBV Epstein-Barr virus ACPA Anti-cyclic citrullinated peptide antibody EBNA Epstein-Barr virus-nuclear antigen VCA Viral capsid antigen EA-DR Early antigen diffuse type and restricted type IgG Immunoglobulin G ACR American College of Rheumatology RF Rheumatoid Factor MTX Methotrexate bDMARDs Biological disease modifying anti rheumatic drugs tsDMARDs Targeting syatemic disease modifying anti rheumatic drugs DNA Deoxyribonucleic acid PtGA Patient global assessment of disease activity PrGA Provider global assessment of disease activity DAS28 Disease activity score in 28 joints CRP C-reactive protein ESR Erythrocyte sedimentation rate SDAI Simplified disease activity index CDAI Clinical disease activity index WBC White blood cell count Hb Hemoglobin MMP-3 Matrix metalloproteinase 3 SS-A/Ro Sjögren's-syndrome-related antigen A/Ro LPD Lymphoproliferative disorder RANA Rheumatoid arthritis nuclear antigen antibody EBER Epstein-Barr virus -encoded small ribonucleic acid RNA LMP Latent membrane protein SLAM Signaling lymphocytic activation molecule SAP Signaling lymphocytic activation molecule-associated protein XLP X-linked lymphoproliferative syndrome CTL Cytotoxic T cells Declarations Acknowledgments We would like to thank Editage (www.editage.com) for English language editing. Author contributions NK: Data collection, writing and editing of the tables and manuscript, YN: Data collection, writing and editing manuscript, YA: data collection, HI: worked on statistics, data analysis and editing the manuscript, HN: Data collection, review, writing and editing of the manuscript. Funding There is no direct funding for this study. Data availability The patient data in this study were extracted from electronic medical records of patients at Nihon University School of Medicine, Itabashi Hospital from 2012 to 2021. The data were compiled into a spreadsheet as anonymized patient information and shared as supplementary charts/additional files for review. Ethics approval and consent to participate This study was approved by the Ethics Committee of Nihon University School of Medicine (approval number: RK-220712-5) and conducted in accordance with the principles of the Declaration of Helsinki. 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Cite Share Download PDF Status: Published Journal Publication published 21 Oct, 2025 Read the published version in BMC Rheumatology → Version 1 posted Editorial decision: Revision requested 25 Feb, 2025 Reviews received at journal 22 Feb, 2025 Reviewers agreed at journal 23 Jan, 2025 Reviews received at journal 21 Jan, 2025 Reviewers agreed at journal 21 Jan, 2025 Reviewers agreed at journal 16 Jan, 2025 Reviewers agreed at journal 16 Jan, 2025 Reviewers invited by journal 15 Jan, 2025 Editor assigned by journal 14 Jan, 2025 Submission checks completed at journal 13 Jan, 2025 First submitted to journal 12 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5812683","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":401830097,"identity":"ab0318a5-7e00-4b20-a5eb-c0f44eea9543","order_by":0,"name":"Noboru Kitamura","email":"data:image/png;base64,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","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Noboru","middleName":"","lastName":"Kitamura","suffix":""},{"id":401830098,"identity":"c5b596fd-6f0a-46ba-880d-0d33f5e322ce","order_by":1,"name":"Yosuke Nagasawa","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Nagasawa","suffix":""},{"id":401830099,"identity":"9cfecdfb-7ef3-4c61-91b8-b002b836010c","order_by":2,"name":"Kumiko Akiya","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kumiko","middleName":"","lastName":"Akiya","suffix":""},{"id":401830100,"identity":"fa4719ca-c335-4d33-86dc-f8ef0dd3af4b","order_by":3,"name":"Hirotake Inomata","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hirotake","middleName":"","lastName":"Inomata","suffix":""},{"id":401830101,"identity":"eb8aeeee-b140-4713-ad8b-211b93cb77c0","order_by":4,"name":"Hiddeki Nakamura","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiddeki","middleName":"","lastName":"Nakamura","suffix":""}],"badges":[],"createdAt":"2025-01-12 08:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5812683/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5812683/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41927-025-00576-x","type":"published","date":"2025-10-21T16:17:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":94490460,"identity":"736d32a5-5e84-4738-8ada-8ec11f8a321e","added_by":"auto","created_at":"2025-10-27 17:10:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":944691,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5812683/v1/1d221a38-00c1-48f3-a350-3a53ea02759a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Relationship between anti-Epstein-Barr virus early antigen diffuse type and restricted type immunoglobulin G antibodies and disease activity and autoantibodies in rheumatoid arthritis a retrospective observational study","fulltext":[{"header":"Background","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes progressive joint destruction, limits daily activities, and reduces the quality of life (QOL). The etiology of RA remains incompletely understood, with researchers considering it a complex multifactorial disease influenced by genetic and environmental factors. Genetic factors such as human leukocyte antigen (HLA)-RD1 and DR4, belonging to HLA class II molecules, and peptidylarginine deiminase type 4 (PADI4), a non-major histocompatibility complex (MHC) gene associated with RA susceptibility, have been identified [1]. However, several environmental factors are also implicated in RA pathogenesis. Smoking [4] and periodontal disease [5] are known environmental factors, and viral infections, especially Epstein-Barr virus (EBV) infections, play a major role in the pathogenesis of RA [6].\u003c/p\u003e \u003cp\u003eVarious studies have investigated the association between EBV and RA. Takei et al. first reported the presence of EBV in the synovium of RA in 1997 [5], a finding subsequently corroborated by numerous independent studies [6\u0026ndash;8]. Furthermore, an autoantibody specific for RA, the anti-cyclic citrullinated peptide antibody (ACPA), recognizes EBV-nuclear antigen (EBNA)-1, a nuclear antigen of EBV [9], indicating that EBV infection may cause ACPA production.\u003c/p\u003e \u003cp\u003eHowever, no studies have demonstrated the relationship of EBV infection in RA disease activity or autoantibody production in clinical practice.\u003c/p\u003e \u003cp\u003eIn clinical practice, antibodies against EBV are known to include anti-EBV viral capsid antigen (VCA) immunoglobulin M (IgM) antibodies, anti-EBV VCA IgG antibodies, anti-EBV early antigen diffuse type and restricted type (EA-DR) IgG and anti-EBV EBNA IgG antibodies are known, while anti-EBV EA-DR IgG antibodies are antibodies with the property of rising during acute infection, disappearing, and then rising again during reactivation [10].\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively examined the relationship of EBV in RA by evaluating disease activity and autoantibody levels in positive and negative cases using the anti-EBV EA-DR immunoglobulin G (IgG) antibody, an indicator of EBV reactivation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis is a retrospective observational study. Patients were diagnosed with RA by the American College of Rheumatology (ACR) from 2012 to 2021 at Nihon University Itabashi Hospital using the 2010 classification criteria [11] and were ACPA and Rheumatoid Factor (RF)-positive. Seventy patients (52 women and 18 men) with anti-EBV EA-DR IgG and anti-EBV VCA IgG antibodies were included in the study. Anti-EBV EA-DR IgG antibodies and anti-EBV VCA IgG antibodies were measured at the same time as ACPA and RF measurements at our first visit.\u003c/p\u003e \u003cp\u003eThirty patients (22 women and eight men) were in the positive group for anti-EBV EA-DR IgG antibodies, and 40 (30 women and 10 men) were in the negative group. All patients were positive for anti-EBV VCA IgG antibodies. For the anti-EBV EA-DR IgG antibody measurements case, the disease duration was 12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9 years in the positive group and 12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 years in the negative group. Methotrexate (MTX) use was 73% in the positive group at a mean dose of 8.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4 mg/week and 64% in the negative group at a mean dose of 8.0 mg\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 mg/week. Biological disease modifying anti rheumatic drugs (bDMARDs) were used by 23.3% of the patients in the positive group and 28.0% in the negative group, targeting systemic disease modifying anti rheumatic drugs (tsDMARDs) were used by 10.4% of the patients in the positive group and 10.9% of the negative group. No difference was observed in the use of DMARDs between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG positive group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG negative group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.6\u0026thinsp;\u0026plusmn;\u0026thinsp;15.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10/30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (year; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMTX (usage rate/mg/week; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73%/8.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64%/ 8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSL (usage rate (%)/mg; mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33/ 4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28/ 5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ebDMARDs usage rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etsDMARDs usage rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eEBV; Epstein-Barr virus, EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, MTX; methotrexate, PSL; prednisolone, bDMARDs; biological disease-modifying anti-rheumatoid drugs, tsDMARDs; targeted synthetic DMARDs.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasurement of anti-EBVEA-DR IgG, anti-EBV VCA IgG antibodies and EBV real-time polymerase chain reaction (PCR)\u003c/h3\u003e\n\u003cp\u003eAnti-EBV EA-DR IgG, and anti-EBV VCA IgG antibodies were measured using a BioPlex EBV IgG kit from Bio-Rad (Tokyo, Japan) [12]. Readings greater than 1.1 index were considered positive. The kit was not cross-reactive with rheumatoid factor (RF) or antinuclear antibodies. Peripheral blood serum EBV deoxyribonucleic acid (DNA) was measured by real-time polymerase chain reaction (PCR) using a TaqMan system (Applied Biosystems, USA) [13].\u003c/p\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e This study was approved by the Ethics Committee of Nihon University School of Medicine (approval number: RK-220712-5) and conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eUnivariate analysis comparing each item between the anti-EBV EA-DR IgG antibody-positive and negative groups was conducted using the Mann-Whitney U test, a nonparametric statistical method, for continuous data with confirmed normality, and the independent t-test for those with confirmed and rejected normality. Multivariate logistic regression analysis was then conducted to determine if anti-EBV EA-DR IgG antibodies independently predicted RA activity and autoantibody production. Factors showing significant differences in the univariate analysis were included as explanatory variables, whereas the spontaneous regression and progression groups were set as objective variables. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using the SPSS Statistics version 26 (IBM Corporation, Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAnti-EBV EA-DR IgG antibody positive vs. negative group; disease activity\u003c/h2\u003e \u003cp\u003eDisease activity was examined in anti-EBV EA-DR IgG antibody positive and negative groups. Data were collected on tender joints, swollen joints, patient global assessment of disease activity (PtGA), provider global assessment of disease activity (PrGA), disease activity score in 28 joints with C-reactive protein (DAS28-CRP), DAS28 with erythrocyte sedimentation rate (DAS28-ESR), simplified disease activity index (SDAI), and clinical disease activity index (CDAI). Only the DAS28 CRP was significantly higher in the positive group than in the negative group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of disease activity between anti-EBV EA-DR IgG antibody positive and negative groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG positive group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG negative group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTjC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.4432\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSjC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0512\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePtGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDAS 28-CRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0450*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDAS 28-ESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSDAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0920\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCDAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eEBV; Epstein-Barr Virus, EA-DR; EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, TjC, tender joint count; SjC, swollen joint count; PtGA, patient global assessment of disease activity; PrGA, provider global assessment of disease activity; DAS, disease activity score; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SDAI, simplified disease activity index; CDAI, clinical disease activity index. *; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAnti-EBV EA-DR IgG antibody positive vs. negative group; laboratory findings\u003c/h3\u003e\n\u003cp\u003eLaboratory findings were examined in the anti-EBV EA-DR IgG antibody positive and negative groups, including CRP, ESR, matrix metalloproteinase 3 (MMP-3), white blood cell count (WBC), lymphocyte cell count, hemoglobin (Hb), platelet count, IgG, rheumatoid RF, ACPA, and anti-Sj\u0026ouml;gren's-syndrome-related antigen A/Ro (SS-A/Ro) antibody. MMP-3, RF, and ACPA were significantly higher in the positive group than in the negative group, and lymphocyte cell count was significantly lower in the positive group than in the negative group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of laboratory findings between anti-EBV EA-DR IgG antibody positive and negative groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG positive group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG negative group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.4770\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR (mm/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7360\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMP-3 (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182.0\u0026thinsp;\u0026plusmn;\u0026thinsp;162.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.2\u0026thinsp;\u0026plusmn;\u0026thinsp;59.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0358*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5233.3\u0026thinsp;\u0026plusmn;\u0026thinsp;986.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6085.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1208.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0521\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLy (/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1221.4\u0026thinsp;\u0026plusmn;\u0026thinsp;201.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1486.2\u0026thinsp;\u0026plusmn;\u0026thinsp;256.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0370*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.3970\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlt (\u0026times;10\u003csup\u003e4\u003c/sup\u003e/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1134.8\u0026thinsp;\u0026plusmn;\u0026thinsp;144.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1317.8\u0026thinsp;\u0026plusmn;\u0026thinsp;286.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0810\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRF (IU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126.4\u0026thinsp;\u0026plusmn;\u0026thinsp;78.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.1\u0026thinsp;\u0026plusmn;\u0026thinsp;84.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0491*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACPA (U/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e257.9\u0026thinsp;\u0026plusmn;\u0026thinsp;448.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.4\u0026thinsp;\u0026plusmn;\u0026thinsp;40.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0028*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti SS-A Ab (usage rate; %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.5627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eEBV, Epstein-Barr virus; EA-DR;early antigen diffuse type and restricted type, IgG༛ immunoglobulin G, CRP; C-reactive protein; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; WBC, blood cell count; Ly, lymphocyte; Hg, hemoglobin; Plt, platelet; RF, rheumatoid factor; ACPA, anti-citrullinated peptide antibody; SS-A, Sj\u0026ouml;gren syndrome-A. *; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eAnti-EBV EA-RD IgG antibody positive vs. negative group; organ complications\u003c/h3\u003e\n\u003cp\u003eLaboratory findings were examined in anti-EBV EA-DR IgG antibody-positive and negative groups. Significant differences between the positive and negative groups were examined for respiratory diseases (excluding interstitial lung disease, airway involvement, pleurisy, rheumatoid nodules, and respiratory infections), cardiovascular diseases (cardiovascular events, pericarditis, and myocarditis), Sj\u0026ouml;gren's syndrome, and lymphoproliferative disorder (LPD). LPD showed a trend toward a higher complication rate in the positive group compared to the negative group; however, this difference was not statistically significant (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of organ complications between anti-EBV EA-DR IgG antibody positive and negative groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG positive group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnti-EBV EA-DR IgG negative group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8/22; 36.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16/24; 66.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.4990\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/28; 0.07%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2/38; 0.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7968\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/28; 0.07%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2/38; 0.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6/24; 25.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0/40; 0.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eEBV; Epstein-Barr virus; EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, CVD; cardiovascular disease, SS; Sj\u0026ouml;gren\u0026rsquo;s syndrome, LPD; lymphoproliferative disorder.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison of anti-EBV EA-DR IgG antibody positive and negative groups by multivariate analysis\u003c/h2\u003e \u003cp\u003eLogistic regression analysis was performed using anti-EBV EA-DR IgG antibody positivity and negativity as objective variables and five factors\u0026ndash;DSS28 CRP, MMP-3, lymphocyte cell count, RF, and ACPA\u0026ndash;which were significant in the univariate analysis, as explanatory variables. The ACPA and lymphocyte cell count were identified as significant factors (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of anti-EBV EA-DR IgG antibody positive and negative groups by multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWald\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDegree of freedom\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.015*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.039*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.002-1,063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.663\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.831\u0026ndash;11.156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMP-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.995\u0026ndash;1.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDAS28 CRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u0026ndash;1.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.043*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.980-1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003econstant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1928.306\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eOR; odds ratio, CI; confidence interval, SD; standard deviation, ACPA; anti-citrullinated peptide antibody, RF; rheumatoid factor, MMP-3; matrix metalloproteinase-3, DAS; disease activity score, CRP; C-reactive protein, Ly; lymphocytes. *; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePositivity of EBV PCR in peripheral blood of patients positive for anti-EBV EA-DR IgG antibodies\u003c/h2\u003e \u003cp\u003eAmong the 30 patients with anti-EBV EA-DR IgG antibody positivity, serum EBV PCR was measured in 18 cases, of which 14 (77.8%) were positive (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePositivity of EBV PCR in peripheral blood of patients positive for anti-EBV EA-DR IgG antibodies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEBV PCR (+)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEBV PCR (-)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti EBV EA-DR IgG (+) (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eEBV; Epstein\u0026ndash;Barr virus, EA-DR; early antigen diffuse type and restricted type, IgG; immunoglobulin G, PCR; polymerase chain reaction, RA; rheumatoid arthritis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRA results from a combination of genetic and environmental factors [4]. The relationship between EBV and RA has been investigated extensively. Alspaugh et al. [14] identified RA nuclear antigen antibody (RANA), an antibody against the nuclear component of EBV-infected cells, in the peripheral blood of patients with RA. The major epitope recognized by RANA is the glycine-alanine repeat structure of EBNA-1 [15]. Similar protein molecules have been identified in RA synovial lesions [16], suggesting that the molecular homology between RA lesions and EBV may play an important role in RA pathogenesis. Subsequently, Takei et al. [5] demonstrated the presence of EBV in RA synovial lesions using PCR and in situ hybridization. Furthermore, EBV-DNA and EBV-encoded small ribonucleic acid RNA (EBER)-1 were detected at high rates in synovial lesions of patients with RA with HLA-DRB1 * 0401, 0404, 0405, or 0408 alleles. These HLA class II molecules have shown a strong association with RA, and the EBV-positive frequency is indelibly higher than in normal controls [17]. Mahraein et al. [18] demonstrated the expression of EBER and latent membrane protein (LMP)-1, an EBV membrane-associated protein found during latent EBV infection, in synovial surface cells. LMP-1 plays an important role in transforming EBV-infected B cells [19], suggesting that it may be involved in the proliferation of RA synovial cells. These reports also suggest that EBV is present in the synovial tissue of patients with RA and is involved in joint lesions.\u003c/p\u003e \u003cp\u003eIn this study, the positivity rate of anti-EBV EA-DR IgG was 42.9% (30/70), and Miljanovic et al. [20] showed that active/recent EBV infection was more common in patients with RA (42%) than in controls (16%), which is similar to our results. A significantly higher rate of EBV infection was observed in patients with RA than in controls. The signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) gene may be involved in RA and EBV infections. The SAP gene enhances the cytotoxic activity of T and NK cells, facilitating the elimination of EBV-infected B cells [21]. X-linked lymphoproliferative syndrome (XLP), a congenital immunodeficiency disorder, is characterized by fatal infectious mononucleosis, dysgammaglobulinemia, and malignant lymphoma. This syndrome is primarily caused by persistent EBV infection due to a selective deficiency of the SAP gene, with a mortality rate exceeding 90% [22]. The SAP gene that activates these EBV-specific cytotoxic T cells (CTL) has already been cloned [23]; however, the expression of SAP mRNA in T cells in the peripheral blood is low in patients with RA [24]. Therefore, RA might impair EBV-specific CTLs in EBV-infected cells, resulting in EBV reactivation. In this study, we used anti-EBV EA-DR IgG antibody as an indicator of EBV reactivation. Although EBV PCR was measured in a few cases, 18 underwent testing, revealing a notably high positivity rate of 77.8%. Moreover, anti-EBV EA-DR IgG antibodies rise when EBV is reactivated [25], suggesting that positive anti-EBV EA-DR IgG antibodies are related with EBV reactivation. In addition, all presents cases were positive for anti-EBV VCA IgG antibodies. Although anti-EBV VCA IgM was not measured, we believe that the cases positive for anti-EBV EA DR IgG antibodies in this study were not first-time EBV infections but reactivations.\u003c/p\u003e \u003cp\u003eIn this study, we conducted a comparison between the anti-EBV EA-DR IgG-positive and negative groups, revealing ACPA as a significant factor in the multivariate analysis. Several reports exist on the association between EBV and ACPA. Trier et al. [26] examined the reactivity of ACPA to citrullinated EBNA-1 and found antibodies to citrullinated EBNA-1 peptides in 67% of patients with RA, indicating that these peptides may be substrates for ACPA detection and that EBV may be related in ACPA induction. Furthermore, Sakkas et al. [27] suggested that antibodies to citrullinated peptides derived from EBNA appear several years before the onset of RA and cross-react with human citrullinated fibrin, suggesting that citrullinated proteins may be the cause of ACPA production and autoantigens for arthritis development in RA. Although the present study is the result of a limited retrospective observational study, this study suggests that EBV may be involved in ACPA production. The present study cannot strictly conclude whether EBV is involved in the pathogenesis of RA or whether the immune abnormalities underlying RA induce EBV activation. However, we have also demonstrated that humanized mice infected with EBV develop an erosive arthritis similar to rheumatoid arthritis [29,29]. If these results are confirmed in humans, citrullinated proteins cross-reactivated upon EBV reactivation may be partially responsible for ACPA production and the development of RA erosive arthritis.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitation\u003c/h2\u003e \u003cp\u003eBecause this is a retrospective, observational study, we did not measure serum EBV PCR in all anti-EBV EA-DR IgG antibody-positive cases. Also, because X-rays were not taken in a part of patients, the degree of progression of bone destruction on X-rays could not assessed. In addition, since it is not possible to measure antibody titers of the four types of EBV in Japanese medical insurance, 2 types of antibodies, such as anti-EBV VCA IgG and anti-EBV EA-DR IgG antibodies has been measured as indicators of reactivation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we showed that patients with RA positive for anti-EBV EA-DR IgG antibodies had significantly higher ACPA compared to those negative for anti-EA-DR IgG antibodies. Given that ACPA serves as a specific antibody and a risk factor for RA, the involvement of EBV in its production is suggested. Further studies on EBV regarding RA pathogenesis and disease activity are warranted.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Rheumatoid arthritis\u003c/p\u003e\n\u003cp\u003eQOL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The quality of life\u003c/p\u003e\n\u003cp\u003eHLA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Human leukocyte antigen\u003c/p\u003e\n\u003cp\u003ePADI4\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Peptidylarginine deiminase type 4\u003c/p\u003e\n\u003cp\u003eMHC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Major histocompatibility complex\u003c/p\u003e\n\u003cp\u003eEBV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Epstein-Barr virus\u003c/p\u003e\n\u003cp\u003eACPA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Anti-cyclic citrullinated peptide antibody\u003c/p\u003e\n\u003cp\u003eEBNA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Epstein-Barr virus-nuclear antigen\u003c/p\u003e\n\u003cp\u003eVCA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Viral capsid antigen\u003c/p\u003e\n\u003cp\u003eEA-DR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Early antigen diffuse type and restricted type\u003c/p\u003e\n\u003cp\u003eIgG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Immunoglobulin G\u003c/p\u003e\n\u003cp\u003eACR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;American College of Rheumatology\u003c/p\u003e\n\u003cp\u003eRF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Rheumatoid Factor\u003c/p\u003e\n\u003cp\u003eMTX\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Methotrexate\u003c/p\u003e\n\u003cp\u003ebDMARDs\u0026nbsp; \u0026nbsp; \u0026nbsp;Biological disease modifying anti rheumatic drugs\u003c/p\u003e\n\u003cp\u003etsDMARDs\u0026nbsp; \u0026nbsp; \u0026nbsp;Targeting syatemic disease modifying anti rheumatic drugs\u003c/p\u003e\n\u003cp\u003eDNA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Deoxyribonucleic acid\u003c/p\u003e\n\u003cp\u003ePtGA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Patient global assessment of disease activity\u003c/p\u003e\n\u003cp\u003ePrGA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Provider global assessment of disease activity\u003c/p\u003e\n\u003cp\u003eDAS28\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Disease activity score in 28 joints\u003c/p\u003e\n\u003cp\u003eCRP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;C-reactive protein\u003c/p\u003e\n\u003cp\u003eESR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Erythrocyte sedimentation rate\u003c/p\u003e\n\u003cp\u003eSDAI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Simplified disease activity index\u003c/p\u003e\n\u003cp\u003eCDAI Clinical disease activity index\u003c/p\u003e\n\u003cp\u003eWBC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;White blood cell count\u003c/p\u003e\n\u003cp\u003eHb\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hemoglobin\u003c/p\u003e\n\u003cp\u003eMMP-3\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Matrix metalloproteinase 3\u003c/p\u003e\n\u003cp\u003eSS-A/Ro\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Sj\u0026ouml;gren\u0026apos;s-syndrome-related antigen A/Ro\u003c/p\u003e\n\u003cp\u003eLPD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Lymphoproliferative disorder\u003c/p\u003e\n\u003cp\u003eRANA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Rheumatoid arthritis nuclear antigen antibody\u003c/p\u003e\n\u003cp\u003eEBER\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Epstein-Barr virus -encoded small ribonucleic acid RNA\u003c/p\u003e\n\u003cp\u003eLMP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Latent membrane protein\u003c/p\u003e\n\u003cp\u003eSLAM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Signaling lymphocytic activation molecule\u003c/p\u003e\n\u003cp\u003eSAP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Signaling lymphocytic activation molecule-associated protein\u003c/p\u003e\n\u003cp\u003eXLP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;X-linked lymphoproliferative syndrome\u003c/p\u003e\n\u003cp\u003eCTL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cytotoxic T cells\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNK: Data collection, writing and editing of the tables and manuscript, YN: Data collection, writing and editing manuscript, YA: data collection, HI: worked on statistics, data analysis and editing the manuscript, HN: Data collection, review, writing and editing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no direct funding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient data in this study were extracted from electronic medical records of patients at Nihon University School of Medicine, Itabashi Hospital from 2012 to 2021. The data were compiled into a spreadsheet as anonymized patient information and shared as supplementary charts/additional files for review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Nihon University School of Medicine (approval number: RK-220712-5) and conducted in accordance with the principles of the Declaration of Helsinki. In addition, this study was a retrospective observational study based on medical record review, and because our hospital obtains comprehensive consent at the time of the first consultation, we did not obtain individual consent to participate this time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enone \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eDedmon LE. The genetics of rheumatoid arthritis. Rheumatology (Oxford). 2020;59: 2661–70.\u003c/li\u003e\n \u003cli\u003eSugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010;69:70–81.\u003c/li\u003e\n \u003cli\u003eWegner N, Wait R, Sroka A, Eick S, Nguyen KA, Lundberg K, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010;62:2662–72.\u003c/li\u003e\n \u003cli\u003eBalandraud N, Roudier J. Epstein-Barr virus and rheumatoid arthritis. Joint Bone Spine. 2018;85:165–70.\u003c/li\u003e\n \u003cli\u003eTakei M, Mitamura K, Fujiwara S, Horie T, Ryu J, Osaka S, et al. Detection of Epstein-Barr virus-encoded small RNA 1 and latent membrane protein 1 in synovial lining cells from rheumatoid arthritis patients. Int Immunol. 1997;9:739–43.\u003c/li\u003e\n \u003cli\u003eEdinger JW, Bonneville M, Scotet E, Houssaint E, Schumacher HR, Posnett DN. EBV gene expression not altered in rheumatoid synovia despite the presence of EBV antigen-specific T cell clones. J Immunol. 1999;162:3694–701.\u003c/li\u003e\n \u003cli\u003eTakeda T, Mizugaki Y, Matsubara L, Imai S, Koike T, Takada K. Lytic Epstein-Barr virus infection in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 2000;43:1218–25.\u003c/li\u003e\n \u003cli\u003eMehraein Y, Lennerz C, Ehlhardt S, Remberger K, Ojak A, Zang KD. Latent Epstein-Barr virus (EBV) infection and cytomegalovirus (CMV) infection in synovial tissue of autoimmune chronic arthritis determined by RNA- and DNA-in situ hybridization. Mod Pathol. 2004;17:781–9.\u003c/li\u003e\n \u003cli\u003ePratesi F, Tommasi C, Anzilotti C, Chimenti D, Migliorini P. Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheum. 2006;54:733–41.\u003c/li\u003e\n \u003cli\u003eDe Paschale M, Clerici P. Serological diagnosis of Epstein-Barr virus infection: Problems and solutions. World J Virol. 2012;12:31-43.\u003c/li\u003e\n \u003cli\u003eNeogi T, Aletaha D, Silman AJ, Naden RL, Felson DT, Aggarwal R, et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum. 2010;62:2582–91.\u003c/li\u003e\n \u003cli\u003eKlutts JS, Liao RA, Dunne Jr WM, Gronowski M. Evaluation of a multiplexed bead assay for assessment of Epstein-Barr virus immunologic status. J Clin Microbiol. 2004; 42:4996–5000.\u003c/li\u003e\n \u003cli\u003eKimura H, Morita M, Yabuta Y, Kuzushima K, Kato K, Kojima S, et al. Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol. 1999;37:132–6.\u003c/li\u003e\n \u003cli\u003eAlspaugh MA, Jensen FC, Rabin H, Tan EM. Lymphocytes transformed by Epstein-Barr virus. Induction of nuclear antigen reactive with antibody in rheumatoid arthritis. J Exp Med. 1978;147:1018–27.\u003c/li\u003e\n \u003cli\u003eBillings PB, Hoch SO, White PJ, Carson DA, Vaughan JH. Antibodies to the Epstein-Barr virus nuclear antigen and to rheumatoid arthritis nuclear antigen identify the same polypeptide. Proc Natl Acad Sci U S A. 1983;80:7104–8.\u003c/li\u003e\n \u003cli\u003eRoudier J, Rhodes G, Petersen J, Vaughan JH, Carson DA. The Epstein-Barr virus glycoprotein gp110, a molecular link between HLA DR4, HLA DR1, and rheumatoid arthritis. Scand J Immunol. 1988;27:367–71.\u003c/li\u003e\n \u003cli\u003eSaal JG, Krimmel M, Steidle M, Gerneth F, Wagner S, Fritz P, et al. Synovial Epstein-Barr virus infection increases the risk of rheumatoid arthritis in individuals with the shared HLA-DR4 epitope. Arthritis Rheum. 1999;42:1485–96.\u003c/li\u003e\n \u003cli\u003eMehraein Y, Lennerz C, Ehlhardt S, Remberger K, Ojak A, Zang KD. Latent Epstein-Barr virus (EBV) infection and cytomegalovirus (CMV) infection in synovial tissue of autoimmune chronic arthritis determined by RNA- and DNA-in situ hybridization. Mod Pathol. 2004;17:781–9.\u003c/li\u003e\n \u003cli\u003eFåhraeus R, Rymo L, Rhim JS, Klein G. Morphological transformation of human keratinocytes expressing the LMP gene of Epstein- Barr virus. Nature. 1990;345:447–9.\u003c/li\u003e\n \u003cli\u003eMiljanovic D, Cirkovic A, Jermic I, Basaric M, Lazarevic I, Grk M, et al. Markers of Epstein-Barr virus infection in association with the onset and poor control of rheumatoid arthritis: a prospective cohort study. Microorganisms. 2023;11:1958.\u003c/li\u003e\n \u003cli\u003eSawada S, Takei M. Possible involvement of Epstein-Barr virus and its regulatory gene in rheumatoid synovitis. Autoimmun Rev. 2004;3 Suppl 1:S69–71.\u003c/li\u003e\n \u003cli\u003eHislop AD, Palendira U, Leese AM, Arkwright PD, Rohrlich PS, Tangye SG, et al. Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets. Blood. 2010;116:3249–57.\u003c/li\u003e\n \u003cli\u003eSawada S, Takei M, Ishiwata T. SAP discovery: the sword edges--beneficial and harmful. Autoimmun Rev. 2007;6:444–9.\u003c/li\u003e\n \u003cli\u003eShinkura R, Yamamoto N, Koriyama C, Shinmura Y, Eizuru Y, Tokunaga M. Epstein-Barr virus-specific antibodies in Epstein-Barr virus-positive and -negative gastric carcinoma cases in Japan\u003cstrong\u003e. \u003c/strong\u003eJ Med Virol. 2000;60:411–6.\u003c/li\u003e\n \u003cli\u003eTakei M, Ishiwata T, Mitamura K, Fujiwara S, Sasaki K, Nishi T, et al. Decreased expression of signaling lymphocytic-activation molecule-associated protein (SAP) transcripts in T cells from patients with rheumatoid arthritis. Int Immunol. 2001;13:559–65.\u003c/li\u003e\n \u003cli\u003eTrier NH, Holm BE, Slot O, Locht H, Lindegaard H, Svendsen A, et al. Application of synthetic peptides for detection of anti-citrullinated peptide antibodies. Peptides. 2016;76:87–95.\u003c/li\u003e\n \u003cli\u003eSakkas LI, Daoussis D, Liossis SN, Bogdanos DP. The infectious basis of ACPA-positive rheumatoid arthritis. Front Microbiol. 2017;8:1853.\u003c/li\u003e\n \u003cli\u003eKuwana Y, Takei M, Yajima M, Imadome K, Inomata H, Shiozaki M, et al. Epstein-Barr virus induces erosive arthritis in humanized mice\u003cstrong\u003e.\u003c/strong\u003e PLoS One. 2011;6(10) [Epub]: e26630. DOI: 10.1371/journal.pone.0026630.\u003c/li\u003e\n \u003cli\u003eNagasawa Y, Takei M, Iwata M, Nagatsuka Y, Tsuzuki H, Imai K, et al. Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγnull mice. PLoS One. 2021;16(4) [Epub]: e0249340. DOI: 10.1371/journal.pone.0249340.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brhm","sideBox":"Learn more about [BMC Rheumatology](http://bmcrheumatol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/brhm/default.aspx","title":"BMC Rheumatology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"anti-EBV EA-DR IgG, ACPA, rheumatoid arthritis","lastPublishedDoi":"10.21203/rs.3.rs-5812683/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5812683/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis study aimed to examine the relationship of Epstein-Barr virus (EBV) in rheumatoid arthritis (RA) by evaluating disease activity and autoantibody levels in positive and negative cases using the anti-EBV early antigen diffuse type and restricted type (EA-DR) immunoglobulin G (IgG) antibody.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients undergoing RA treatment at our hospital with anti-EBV EA-DR IgG antibodies were selected. We confirmed their age, sex, RA duration, disease activity, laboratory findings, treatment details, and complications in patients with positive or negative anti-EBV EA-DR IgG antibodies and analyzed the relationship between RA activity, autoantibody production, and EBV.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eanti-EBV EA-DR IgG antibodies were measured in 70 RA cases (30 positive and 40 negative), with a positivity rate of 43.9%. Among the positive cases, 18 underwent EBV deoxyribonucleic acid polymerase chain reaction, with 14 testing positive. Univariate analysis revealed significantly higher levels of disease activity score in 28 joints with C-reactive protein, peripheral blood lymphocyte count, anti-cyclic citrullinated peptide antibody (ACPA), and rheumatoid factor in anti-EBV EA-DR IgG antibody-positive cases. Multivariate analysis identified peripheral blood lymphocyte count and ACPA levels as significant factors.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePatients with RA who tested positive for anti-EBV EA-Dr IgG antibodies had significantly higher ACPA than those who tested negative.\u003c/p\u003e","manuscriptTitle":"Relationship between anti-Epstein-Barr virus early antigen diffuse type and restricted type immunoglobulin G antibodies and disease activity and autoantibodies in rheumatoid arthritis a retrospective observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-15 09:44:58","doi":"10.21203/rs.3.rs-5812683/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-25T20:15:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-22T18:44:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31593780824588356267715261515062150196","date":"2025-01-23T17:10:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-21T21:35:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10783309297506936786688828480690501333","date":"2025-01-21T21:14:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51275200978332269413808662729101225858","date":"2025-01-16T13:26:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85639014894645415806508238513205523783","date":"2025-01-16T10:43:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-01-15T16:01:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-14T05:44:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-13T12:46:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Rheumatology","date":"2025-01-12T08:31:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brhm","sideBox":"Learn more about [BMC Rheumatology](http://bmcrheumatol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/brhm/default.aspx","title":"BMC Rheumatology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a17efd87-cf4d-45eb-b20a-fef51f4ff8ad","owner":[],"postedDate":"January 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T16:28:52+00:00","versionOfRecord":{"articleIdentity":"rs-5812683","link":"https://doi.org/10.1186/s41927-025-00576-x","journal":{"identity":"bmc-rheumatology","isVorOnly":false,"title":"BMC Rheumatology"},"publishedOn":"2025-10-21 16:17:25","publishedOnDateReadable":"October 21st, 2025"},"versionCreatedAt":"2025-01-15 09:44:58","video":"","vorDoi":"10.1186/s41927-025-00576-x","vorDoiUrl":"https://doi.org/10.1186/s41927-025-00576-x","workflowStages":[]},"version":"v1","identity":"rs-5812683","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5812683","identity":"rs-5812683","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}