TNFRSF11A Exon 5 Variants in Early RA: Associations with Disease Activity and Biologic Treatment Response—A Prospective Cohort Study

TNFRSF11A Exon 5 Variants in Early RA: Associations with Disease Activity and Biologic Treatment Response—A Prospective Cohort 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 Article TNFRSF11A Exon 5 Variants in Early RA: Associations with Disease Activity and Biologic Treatment Response—A Prospective Cohort Study Gizem Nur Onay Celik¹, Ozgur Erkal², Ulku Ucar³, Oznur Kutluk³, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7963707/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: This study aimed to investigate the impact of polymorphisms in exon 5 of the TNFRSF11A gene on disease activity and treatment outcomes in newly diagnosed rheumatoid arthritis (RA). Methods In this prospective cohort, 57 newly diagnosed RA patients (2019 ACR/EULAR criteria) underwent genotyping for TNFRSF11A exon 5 polymorphisms by PCR and direct sequencing. Clinical and laboratory evaluations—including DAS28-CRP, CDAI, SDAI, ESR, and CRP—were performed at baseline and after six months of methotrexate (MTX). Treatment responses and initiation of biological agents were recorded. Results TNFRSF11A exon 5 polymorphisms were detected in 18% of patients. Both variant-positive and variant-negative groups showed significant improvements in disease activity indices after treatment (p < 0.05). Although not statistically significant, variant-positive patients tended to have lower baseline CRP levels, reduced post-treatment disease activity, fewer tender/swollen joints, and lower rates of biological agent initiation. A higher proportion of seronegative RA was observed in the variant-positive group. Conclusion No statistically significant associations were found between TNFRSF11A exon 5 polymorphisms and clinical outcomes. However, observed trends suggest that larger cohorts are warranted to clarify the potential prognostic value of these variants. Health sciences/Diseases Biological sciences/Genetics Biological sciences/Immunology Health sciences/Medical research Health sciences/Rheumatology Rheumatoid arthritis TNFRSF11A Genetic polymorphism Disease activity Treatment response Figures Figure 1 Figure 2 Introduction Rheumatoid arthritis (RA) is a chronic autoimmune condition in which persistent synovial inflammation gradually leads to progressive joint destruction, disability, and reduced quality of life [ 1 ]. The disease affects about 0.5–1% of the global population, with onset and course shaped by a complex interplay between inherited predisposition and environmental exposures [ 2 , 3 ]. Among the genetic contributors, HLA-DRB1 alleles remain the most important risk factors; nevertheless, a wide range of non-HLA genes also play critical roles in susceptibility and the heterogeneity of clinical expression [ 4 , 5 ]. The TNFRSF11A gene (chromosome 18q21) encodes receptor activator of nuclear factor kappa-B (RANK), a central regulator of osteoclast differentiation and bone metabolism [ 6 ]. The RANK/RANKL signalling pathway is essential in osteoclast-mediated bone resorption, a mechanism strongly implicated in RA-associated joint erosion [ 7 ]. Abnormal activity within this pathway accelerates bone damage and may also influence disease activity and treatment responsiveness [ 8 ]. Variants in TNFRSF11A have been linked to skeletal disorders such as Paget’s disease of bone and familial expansile osteolysis [ 9 ]. However, the influence of these polymorphisms on clinical manifestations and treatment outcomes in RA has not been sufficiently clarified. Evidence is accumulating that genetic variations in the RANK/RANKL system could alter disease progression and modulate therapeutic responses, including to methotrexate (MTX) and biologic agents [ 10 , 11 ]. Based on these considerations, this study explored the relationship between TNFRSF11A exon 5 polymorphisms and disease activity, prognosis, and treatment response in newly diagnosed RA patients receiving MTX. Insight into these genetic contributions could improve prediction of outcomes and support more individualised treatment strategies. Materials and Methods Study Design and Participants This prospective cohort enrolled 57 patients newly diagnosed with RA according to the 2019 ACR/EULAR classification criteria. Patients were recruited consecutively from the Rheumatology Outpatient Clinic between February 2023 and August 2023. Inclusion criteria were age ≥18 years, no prior RA‑specific treatment, absence of other rheumatologic or malignant diseases, and non‑pregnancy (Figure 1). The study protocol was approved by the Antalya Training and Research Hospital Clinical Research Ethics Committee (16/02/2023 approval number:3-5), and the study was conducted in accordance with the Helsinki Declaration. All participants provided written informed consent before enrollment. Clinical and Laboratory Assessments Baseline evaluation included clinical examination; disease activity by DAS28‑CRP, CDAI, and SDAI; and patient‑reported outcomes (VAS for global health, pain, fatigue; HAQ). Laboratory analyses encompassed ESR, CRP, rheumatoid factor (RF), anti‑cyclic citrullinated peptide (anti‑CCP) antibodies, and antinuclear antibodies (ANA). Genetic Analysis Peripheral blood samples were collected at baseline for DNA extraction. Polymerase chain reaction (PCR) followed by direct sequencing was used to analyse polymorphisms within exon 5 of TNFRSF11A . Patients were stratified as variant‑positive or variant‑negative. Treatment and Follow‑up This study was a prospective observational cohort conducted in routine clinical practice. All patients initiated methotrexate (MTX) in accordance with ACR/EULAR recommendations; dosing was titrated per clinical response and tolerability. Treatment decisions were made by the attending rheumatologists as part of standard care. Patients were followed for six months. Follow‑up assessments included repeat clinical and laboratory evaluations. Initiation of biological agents was recorded as an indicator of inadequate response to MTX. Statistical Analysis Data were analysed using SPSS v22.0 (IBM, Armonk, NY, USA). Continuous variables are presented as mean ± SD or median (IQR), and categorical variables as n (%). Between‑group comparisons used independent t‑tests or Mann–Whitney U tests for continuous variables and chi‑square or Fisher’s exact tests for categorical variables. Correlations were evaluated with Spearman’s rank test. Two‑tailed p < 0.05 was considered statistically significant. Results Demographic Characteristics Among 57 patients, 70.2% (n = 40) were female; mean BMI was 27.3 ± 5.0 kg/m²; and 29.8% were active smokers. Comorbidities included hypertension (14%), diabetes mellitus (10.5%), and hyperlipidaemia (5.3%). Family history of RA was reported in 24.6% of patients. There were no statistically significant differences between variant‑positive and variant‑negative patients in gender distribution (female predominance in both groups, p = 0.76) or mean age (56.4 ± 14.0 vs. 54.8 ± 12.1 years, p = 0.24). Smoking status (current or former), alcohol use, and working conditions did not differ significantly between groups. Polymorphisms in TNFRSF11A exon 5 were identified in 18% (n = 10). Specific variants included c.521+235T>C (9%), c.428‑106C>T (7%), and c.428‑338G>A (2%). No significant differences were observed in baseline demographics or initial clinical presentation between groups (Table 1). Regarding clinical features, initial symptom at disease onset tended to differ, with arthralgia more frequent in the variant‑positive group (70% vs. 46.8%), while arthritis was more common in the variant‑negative group (53.2% vs. 30%); this did not reach statistical significance (p = 0.16). The frequency of deformity (29.8% vs. 10%), joint restriction (68.1% vs. 60%), and family history of rheumatic disease (26.1% vs. 20%) showed no meaningful between‑group differences (Table 1). Clinical and Laboratory Parameters, Treatment Response, and Follow‑up Outcomes Clinical and laboratory parameters at baseline and follow‑up by variant status are summarised in Table 2. At baseline, there were no significant between‑group differences in DAS28‑CRP, CDAI, SDAI, ESR, or CRP (all p > 0.05). After six months of MTX therapy, both groups demonstrated substantial improvement in disease activity scores: mean DAS28‑CRP decreased to 2.9 ± 1.0 in variant‑negative and 2.6 ± 1.1 in variant‑positive patients (p = 0.28). CDAI and SDAI also declined in both groups without significant between‑group differences. Inflammatory markers (ESR, CRP) fell similarly (Figure 2). Overall, both variant‑positive and variant‑negative patients responded favourably to MTX. Variant‑positive patients consistently showed numerically lower disease activity scores at baseline and follow‑up—potentially reflecting a milder phenotype—although differences were not statistically significant, likely due to limited numbers (Figure 2). Variant‑positive patients also showed trends toward fewer tender/swollen joints, lower deformity frequency, reduced VAS fatigue, and lower post‑treatment DAS28‑CRP. Serologically, 50% of variant‑positive patients were anti‑CCP seronegative compared with 27.7% in variant‑negative patients (p > 0.05); RF positivity did not differ. Biologic agents were initiated in 32.6% (n = 15) overall. The initiation rate was lower in variant‑positive patients (13.3%) than in variant‑negative patients (86.7%), without statistical significance (p > 0.05) (Table 1). These trends may suggest that presence of the exon 5 variant could be associated with a more favourable clinical course and better response to treatment; however, the small number of variant‑positive cases limits statistical power. Discussion RA is a heterogeneous autoimmune condition arising from complex genetic–environmental interactions. Within this network, RANK (encoded by TNFRSF11A ) is a crucial mediator of osteoclast development and bone resorption—central processes in RA‑related joint damage [7,8]. While TNFRSF11A variants have been implicated in skeletal diseases such as Paget’s disease, their influence on RA outcomes remains unclear [10,11]. Earlier research suggested links between this pathway and RA characteristics. Wu et al. (2004) evaluated 237 early, seropositive RA patients and associated younger age at onset with combined HLA‑DRB1 and RANKL genotypes, underscoring the need for replication and further exploration of RANKL polymorphisms in RA pathogenesis [12]. Similarly, Álvaro‑Gracia et al. (2007) studied anti‑TNF‑treated RA and reported that serum RANKL/OPG ratios and RANKL levels may help predict responses and remission potential [13]. In this study, we examined TNFRSF11A exon 5 polymorphisms in newly diagnosed RA patients treated with MTX. We found no statistically significant associations between variant status and baseline disease activity or six‑month outcomes. Both groups improved meaningfully with MTX, consistent with expectations in early RA. Nevertheless, variant‑positive patients tended to exhibit lower post‑treatment disease activity, fewer tender/swollen joints, reduced fatigue, and decreased need for biologic escalation; a higher proportion was anti‑CCP seronegative. These patterns may indicate a milder phenotype among carriers, but limited sample size precluded firm conclusions. Limitations include modest sample size (n = 57) and low frequency of exon 5 variants, reducing power. The candidate‑gene focus overlooks the polygenic architecture of RA. Six‑month follow‑up precluded assessment of long‑term endpoints (e.g., radiographic progression). Functional experiments to elucidate variant effects on osteoclast or immune pathways were beyond scope. The background frequency of TNFRSF11A variants in the source population is unknown. Finally, absence of a healthy control group limits context. Accordingly, findings should be considered exploratory and hypothesis‑generating. Our results align with prior work implicating the RANK/RANKL pathway in variability of RA phenotypes and treatment responses [14,15]. Future investigations should integrate larger, multicentre cohorts with extended follow‑up and broader genomic profiling to clarify prognostic roles. Mechanistic studies could delineate how TNFRSF11A polymorphisms affect osteoclast biology and immune signalling. Declarations Ethical approval: Ethical approval for the study was obtained from the Clinical Research Ethics Board (16/02/2023 approval number:3-5), and the study was conducted in accordance with the Helsinki Declaration. Consent for publication: Not applicable. Availability of data and materials: All data generated and analyzed during this study are included within the article and are available from the corresponding author upon reasonable request. Conflict of interest: The authors declare that they have no conflict of interest. Funding : This research was funded by a grant from the University of Health Sciences, Antalya Training and Research Hospital medical specialty ethics committee. Declarations of interest: None Author Contributions: Conceptualization: GNOC, SB, OE; Methodology: SB, GNOC, OE, GS, UGU, OK; Data Curation: SB, GNOC, OE, GS, UGU, OK; Formal analysis and investigation: SB, GS, OE; Writing - original draft preparation: GNOC, SB, OE; Writing - review and editing: GNOC, SB; Supervision: SB. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements: Not applicable. References Littlejohn EA, Monrad SU. Early diagnosis and treatment of rheumatoid arthritis. Prim Care. 2018;45;237–255. Del Junco DJ, Luthra HS, Annegers JF, Worthington JW, Kurland LT. The familial aggregation of rheumatoid arthritis and its relationship to the HLA-DR4 association. Am J Epidemiol. 1984;119;813–829. Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M. Genetic implications in the pathogenesis of rheumatoid arthritis: an updated review. Gene. 2019;702;8–16. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum. 2010;62;1576–1582. Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information, and disease associations: 2004. Tissue Antigens. 2004;64;631–649. Orozco G, Rueda B, Martin J. Genetic basis of rheumatoid arthritis. Biomed Pharmacother. 2006;60;656–662. Begovich AB, Carlton VEH, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al. A missense single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75;330–337. Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K, et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998;253;395–400. Chung PYJ, Beyens G, Riches PL, Van Wesenbeeck L, de Freitas F, Jennes K, et al. Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget’s disease of bone. J Bone Miner Res. 2010;25;2316–2329. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43;30–37. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506;376–381. Wu J, Kumar S, McDonald H, et al. RANKL and HLA-DRB1 genotypes are associated with age of onset in rheumatoid arthritis. Arthritis Rheum. 2004;50;3438–3449. Álvaro-Gracia JM, Pascual-Salcedo D, Carreño L, et al. Serum levels of soluble RANK ligand and osteoprotegerin in rheumatoid arthritis patients treated with anti-TNFα therapy. Arthritis Rheum. 2007;57;607–613. Huizinga TWJ. Genetics in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2003;17;703–716. Mohamed RH, El-Shahawy EE. Relationship between RANK and RANKL gene polymorphisms with osteoporosis in rheumatoid arthritis patients. Genet Test Mol Biomarkers. 2016;20;249–254. Tables Table 1. Demographic and baseline clinical characteristics and biologic agent use by TNFRSF11A exon 5 variant status Variable Variant-negative (n=47) Variant-positive (n=10) p-value Gender, female 32 (68.1%) 8 (80.0%) 0.76 Gender, male 15 (31.9%) 2 (20.0%) Age, years (mean ± SD) 56.4 ± 14.0 54.8 ± 12.1 0.24 Smoker, current 14 (29.8%) 3 (30.0%) 0.31 Smoker, former 9 (19.1%) 4 (40.0%) Alcohol use 2 (4.3%) 0 0.67 Working condition (active) 27 (57.4%) 7 (70.0%) 0.35 Family history of RA 12 (26.1%) 2 (20.0%) 0.51 Initial symptom: arthralgia 22 (46.8%) 7 (70.0%) 0.16 Initial symptom: arthritis 25 (53.2%) 3 (30.0%) Presence of deformity 14 (29.8%) 1 (10.0%) 0.18 Joint restriction 32 (68.1%) 6 (60.0%) 0.44 Rheumatoid nodule 0 1 (10.0%) 0.17 Biologic agent use (yes) 13 (27.7%) 2 (20.0%) 0.91 Biologic agent use (no) 34 (72.3%) 8 (80.0%) Values are n (%), mean ± SD, or median [min–max]. Categorical variables were compared with chi-square or Fisher’s exact test; continuous variables with Student’s t-test or Mann–Whitney U test, as appropriate. Percentages are column-wise. The between-group comparison for “Biologic agent use (yes)” yielded p = 0.91 (2×2 chi-square with continuity correction). Significance threshold: p < 0.05. Table 2. Change from baseline to 6 months (Δ = follow-up − baseline) Parameter Variant-negative: Baseline Variant-negative: 6 months Δ (Variant-negative) Variant-positive: Baseline Variant-positive: 6 months Δ (Variant-positive) DAS28-CRP (mean) 4.35 2.90 −1.45 4.16 2.60 −1.56 CDAI (mean) 20.45 10.20 −10.25 19.20 10.86 −8.34 SDAI (mean) 23.20 11.10 −12.10 19.20 12.20 −7.00 ESR, mm/h (median) 13 8 −5 28 17 −11 CRP, mg/L (median) 12.0 5.15 −6.85 18.0 7.60 −10.40 Δ (change) = follow-up − baseline. “Variant-negative” denotes absence of any exon 5 TNFRSF11A polymorphism; “Variant-positive” denotes the presence of at least one polymorphism (c.521+235T>C, c.428−106C>T, or c.428−338G>A). Between-group comparison of Δ was not performed because patient-level change scores (or, at minimum, the SD of change and the baseline–follow-up correlation) were unavailable; therefore, Δ values are descriptive. Within-group change was assessed with paired tests and was significant across indices (p < 0.05). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7963707","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":549102912,"identity":"91b851ed-65c7-4ed1-a334-cc0176e1a706","order_by":0,"name":"Gizem Nur Onay Celik¹","email":"","orcid":"","institution":"Korkuteli Goverment Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gizem","middleName":"Nur Onay","lastName":"Celik¹","suffix":""},{"id":549102913,"identity":"1e09439c-7aeb-40f8-b5e7-eb31432afdc8","order_by":1,"name":"Ozgur Erkal²","email":"","orcid":"","institution":"Antalya Eğitim ve Araştırma 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1","display":"","copyAsset":false,"role":"figure","size":328207,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient enrollment.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7963707/v1/39446b28f7e6c17ca773a0f0.jpg"},{"id":96708807,"identity":"ef6c2bd2-9bcd-4d7a-a9a3-e69f9d8c9104","added_by":"auto","created_at":"2025-11-25 10:05:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43441,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline and 6‑month mean values of DAS28‑CRP, CDAI, SDAI, ESR, and CRP by TNFRSF11A exon 5 status (variant‑negative, left; variant‑positive, right). Error bars represent standard deviation.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eBaseline and 6-month mean values of disease activity indices and inflammatory markers by TNFRSF11A exon 5 status. Left panel: variant-negative; right panel: variant-positive. Bars show group means at baseline (black) and at 6 months (grey) for DAS28-CRP, CDAI, SDAI, ESR (mm/h), and CRP (mg/L); error bars denote standard deviations. Lower scores indicate lower disease activity/inflammation; thus, downward change reflects clinical improvement. Within-group decreases were significant (p\u0026lt;0.05).\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7963707/v1/d74173b7d6ab6625b179acc6.jpg"},{"id":98181314,"identity":"3ccbfe36-6444-42d7-9da2-41bb66679540","added_by":"auto","created_at":"2025-12-15 01:09:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1156142,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7963707/v1/b956b027-9356-4e4a-8f8c-e8b774b16100.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eTNFRSF11A Exon 5 Variants in Early RA: Associations with Disease Activity and Biologic Treatment Response—A Prospective Cohort Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic autoimmune condition in which persistent synovial inflammation gradually leads to progressive joint destruction, disability, and reduced quality of life [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease affects about 0.5\u0026ndash;1% of the global population, with onset and course shaped by a complex interplay between inherited predisposition and environmental exposures [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among the genetic contributors, \u003cem\u003eHLA-DRB1\u003c/em\u003e alleles remain the most important risk factors; nevertheless, a wide range of non-HLA genes also play critical roles in susceptibility and the heterogeneity of clinical expression [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe \u003cem\u003eTNFRSF11A\u003c/em\u003e gene (chromosome 18q21) encodes receptor activator of nuclear factor kappa-B (RANK), a central regulator of osteoclast differentiation and bone metabolism [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The RANK/RANKL signalling pathway is essential in osteoclast-mediated bone resorption, a mechanism strongly implicated in RA-associated joint erosion [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Abnormal activity within this pathway accelerates bone damage and may also influence disease activity and treatment responsiveness [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eVariants in \u003cem\u003eTNFRSF11A\u003c/em\u003e have been linked to skeletal disorders such as Paget\u0026rsquo;s disease of bone and familial expansile osteolysis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the influence of these polymorphisms on clinical manifestations and treatment outcomes in RA has not been sufficiently clarified. Evidence is accumulating that genetic variations in the RANK/RANKL system could alter disease progression and modulate therapeutic responses, including to methotrexate (MTX) and biologic agents [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBased on these considerations, this study explored the relationship between \u003cem\u003eTNFRSF11A\u003c/em\u003e exon 5 polymorphisms and disease activity, prognosis, and treatment response in newly diagnosed RA patients receiving MTX. Insight into these genetic contributions could improve prediction of outcomes and support more individualised treatment strategies.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective cohort enrolled 57 patients newly diagnosed with RA according to the 2019 ACR/EULAR classification criteria. Patients were recruited consecutively from the Rheumatology Outpatient Clinic between February 2023 and August 2023. Inclusion criteria were age \u0026ge;18 years, no prior RA‑specific treatment, absence of other rheumatologic or malignant diseases, and non‑pregnancy (Figure\u0026nbsp;1). The study protocol was approved by the Antalya Training and Research Hospital Clinical Research Ethics Committee (16/02/2023 approval number:3-5), and the study was conducted in accordance with the Helsinki Declaration. All participants provided written informed consent before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical and Laboratory Assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline evaluation included clinical examination; disease activity by DAS28‑CRP, CDAI, and SDAI; and patient‑reported outcomes (VAS for global health, pain, fatigue; HAQ). Laboratory analyses encompassed ESR, CRP, rheumatoid factor (RF), anti‑cyclic citrullinated peptide (anti‑CCP) antibodies, and antinuclear antibodies (ANA).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePeripheral blood samples were collected at baseline for DNA extraction. Polymerase chain reaction (PCR) followed by direct sequencing was used to analyse polymorphisms within exon 5 of \u003cem\u003eTNFRSF11A\u003c/em\u003e. Patients were stratified as variant‑positive or variant‑negative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment and Follow‑up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was a prospective observational cohort conducted in routine clinical practice. All patients initiated methotrexate (MTX) in accordance with ACR/EULAR recommendations; dosing was titrated per clinical response and tolerability. Treatment decisions were made by the attending rheumatologists as part of standard care. Patients were followed for six months. Follow‑up assessments included repeat clinical and laboratory evaluations. Initiation of biological agents was recorded as an indicator of inadequate response to MTX.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were analysed using SPSS v22.0 (IBM, Armonk, NY, USA). Continuous variables are presented as mean \u0026plusmn; SD or median (IQR), and categorical variables as n (%). Between‑group comparisons used independent t‑tests or Mann\u0026ndash;Whitney U tests for continuous variables and chi‑square or Fisher\u0026rsquo;s exact tests for categorical variables. Correlations were evaluated with Spearman\u0026rsquo;s rank test. Two‑tailed p \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 57 patients, 70.2% (n\u0026nbsp;=\u0026nbsp;40) were female; mean BMI was 27.3\u0026nbsp;\u0026plusmn;\u0026nbsp;5.0\u0026nbsp;kg/m\u0026sup2;; and 29.8% were active smokers. Comorbidities included hypertension (14%), diabetes mellitus (10.5%), and hyperlipidaemia (5.3%). Family history of RA was reported in 24.6% of patients. There were no statistically significant differences between variant‑positive and variant‑negative patients in gender distribution (female predominance in both groups, p\u0026nbsp;=\u0026nbsp;0.76) or mean age (56.4\u0026nbsp;\u0026plusmn;\u0026nbsp;14.0 vs. 54.8\u0026nbsp;\u0026plusmn;\u0026nbsp;12.1\u0026nbsp;years, p\u0026nbsp;=\u0026nbsp;0.24). Smoking status (current or former), alcohol use, and working conditions did not differ significantly between groups.\u003c/p\u003e\n\u003cp\u003ePolymorphisms in \u003cem\u003eTNFRSF11A\u003c/em\u003e exon 5 were identified in 18% (n = 10). Specific variants included c.521+235T\u0026gt;C (9%), c.428‑106C\u0026gt;T (7%), and c.428‑338G\u0026gt;A (2%). No significant differences were observed in baseline demographics or initial clinical presentation between groups (Table 1).\u003c/p\u003e\n\u003cp\u003eRegarding clinical features, initial symptom at disease onset tended to differ, with arthralgia more frequent in the variant‑positive group (70% vs. 46.8%), while arthritis was more common in the variant‑negative group (53.2% vs. 30%); this did not reach statistical significance (p\u0026nbsp;=\u0026nbsp;0.16). The frequency of deformity (29.8% vs. 10%), joint restriction (68.1% vs. 60%), and family history of rheumatic disease (26.1% vs. 20%) showed no meaningful between‑group differences (Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical and Laboratory Parameters, Treatment Response, and Follow‑up Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical and laboratory parameters at baseline and follow‑up by variant status are summarised in Table\u0026nbsp;2. At baseline, there were no significant between‑group differences in DAS28‑CRP, CDAI, SDAI, ESR, or CRP (all p \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003eAfter six months of MTX therapy, both groups demonstrated substantial improvement in disease activity scores: mean DAS28‑CRP decreased to 2.9\u0026nbsp;\u0026plusmn;\u0026nbsp;1.0 in variant‑negative and 2.6\u0026nbsp;\u0026plusmn;\u0026nbsp;1.1 in variant‑positive patients (p\u0026nbsp;=\u0026nbsp;0.28). CDAI and SDAI also declined in both groups without significant between‑group differences. Inflammatory markers (ESR, CRP) fell similarly (Figure\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eOverall, both variant‑positive and variant‑negative patients responded favourably to MTX. Variant‑positive patients consistently showed numerically lower disease activity scores at baseline and follow‑up\u0026mdash;potentially reflecting a milder phenotype\u0026mdash;although differences were not statistically significant, likely due to limited numbers (Figure\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eVariant‑positive patients also showed trends toward fewer tender/swollen joints, lower deformity frequency, reduced VAS fatigue, and lower post‑treatment DAS28‑CRP. Serologically, 50% of variant‑positive patients were anti‑CCP seronegative compared with 27.7% in variant‑negative patients (p\u0026nbsp;\u0026gt;\u0026nbsp;0.05); RF positivity did not differ.\u003c/p\u003e\n\u003cp\u003eBiologic agents were initiated in 32.6% (n\u0026nbsp;=\u0026nbsp;15) overall. The initiation rate was lower in variant‑positive patients (13.3%) than in variant‑negative patients (86.7%), without statistical significance (p\u0026nbsp;\u0026gt;\u0026nbsp;0.05) (Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003eThese trends may suggest that presence of the exon 5 variant could be associated with a more favourable clinical course and better response to treatment; however, the small number of variant‑positive cases limits statistical power.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRA is a heterogeneous autoimmune condition arising from complex genetic\u0026ndash;environmental interactions. Within this network, RANK (encoded by \u003cem\u003eTNFRSF11A\u003c/em\u003e) is a crucial mediator of osteoclast development and bone resorption\u0026mdash;central processes in RA‑related joint damage [7,8]. While \u003cem\u003eTNFRSF11A\u003c/em\u003e variants have been implicated in skeletal diseases such as Paget\u0026rsquo;s disease, their influence on RA outcomes remains unclear [10,11].\u003c/p\u003e\n\u003cp\u003eEarlier research suggested links between this pathway and RA characteristics. Wu et al. (2004) evaluated 237 early, seropositive RA patients and associated younger age at onset with combined \u003cem\u003eHLA‑DRB1\u003c/em\u003e and \u003cem\u003eRANKL\u003c/em\u003e genotypes, underscoring the need for replication and further exploration of \u003cem\u003eRANKL\u003c/em\u003e polymorphisms in RA pathogenesis [12]. Similarly, \u0026Aacute;lvaro‑Gracia et al. (2007) studied anti‑TNF‑treated RA and reported that serum RANKL/OPG ratios and RANKL levels may help predict responses and remission potential [13].\u003c/p\u003e\n\u003cp\u003eIn this study, we examined \u003cem\u003eTNFRSF11A\u003c/em\u003e exon 5 polymorphisms in newly diagnosed RA patients treated with MTX. We found no statistically significant associations between variant status and baseline disease activity or six‑month outcomes. Both groups improved meaningfully with MTX, consistent with expectations in early RA. Nevertheless, variant‑positive patients tended to exhibit lower post‑treatment disease activity, fewer tender/swollen joints, reduced fatigue, and decreased need for biologic escalation; a higher proportion was anti‑CCP seronegative. These patterns may indicate a milder phenotype among carriers, but limited sample size precluded firm conclusions.\u003c/p\u003e\n\u003cp\u003eLimitations include modest sample size (n = 57) and low frequency of exon 5 variants, reducing power. The candidate‑gene focus overlooks the polygenic architecture of RA. Six‑month follow‑up precluded assessment of long‑term endpoints (e.g., radiographic progression). Functional experiments to elucidate variant effects on osteoclast or immune pathways were beyond scope. The background frequency of \u003cem\u003eTNFRSF11A\u003c/em\u003e variants in the source population is unknown. Finally, absence of a healthy control group limits context. Accordingly, findings should be considered exploratory and hypothesis‑generating.\u003c/p\u003e\n\u003cp\u003eOur results align with prior work implicating the RANK/RANKL pathway in variability of RA phenotypes and treatment responses [14,15]. Future investigations should integrate larger, multicentre cohorts with extended follow‑up and broader genomic profiling to clarify prognostic roles. Mechanistic studies could delineate how \u003cem\u003eTNFRSF11A\u003c/em\u003e polymorphisms affect osteoclast biology and immune signalling.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e Ethical approval for the study was obtained from the Clinical Research Ethics Board (16/02/2023 approval number:3-5), and the study was conducted in accordance with the Helsinki Declaration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: All data generated and analyzed during this study are included within the article and are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research was funded by a grant from the University of Health Sciences, Antalya Training and Research Hospital medical specialty ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations of interest:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: GNOC, SB, OE; Methodology: SB, GNOC, OE, GS, UGU, OK; Data Curation: SB, GNOC, OE, GS, UGU, OK; Formal analysis and investigation: SB, GS, OE; Writing - original draft preparation: GNOC, SB, OE; Writing - review and editing: GNOC, SB; Supervision: SB. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLittlejohn EA, Monrad SU. Early diagnosis and treatment of rheumatoid arthritis. Prim Care. 2018;45;237\u0026ndash;255.\u003c/li\u003e\n\u003cli\u003eDel Junco DJ, Luthra HS, Annegers JF, Worthington JW, Kurland LT. The familial aggregation of rheumatoid arthritis and its relationship to the HLA-DR4 association. Am J Epidemiol. 1984;119;813\u0026ndash;829.\u003c/li\u003e\n\u003cli\u003eKarami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M. Genetic implications in the pathogenesis of rheumatoid arthritis: an updated review. Gene. 2019;702;8\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003eMyasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955\u0026ndash;2007. Arthritis Rheum. 2010;62;1576\u0026ndash;1582.\u003c/li\u003e\n\u003cli\u003eShiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information, and disease associations: 2004. Tissue Antigens. 2004;64;631\u0026ndash;649.\u003c/li\u003e\n\u003cli\u003eOrozco G, Rueda B, Martin J. Genetic basis of rheumatoid arthritis. Biomed Pharmacother. 2006;60;656\u0026ndash;662.\u003c/li\u003e\n\u003cli\u003eBegovich AB, Carlton VEH, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al. A missense single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75;330\u0026ndash;337.\u003c/li\u003e\n\u003cli\u003eNakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K, et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998;253;395\u0026ndash;400.\u003c/li\u003e\n\u003cli\u003eChung PYJ, Beyens G, Riches PL, Van Wesenbeeck L, de Freitas F, Jennes K, et al. Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget\u0026rsquo;s disease of bone. J Bone Miner Res. 2010;25;2316\u0026ndash;2329.\u003c/li\u003e\n\u003cli\u003eMacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43;30\u0026ndash;37.\u003c/li\u003e\n\u003cli\u003eOkada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506;376\u0026ndash;381.\u003c/li\u003e\n\u003cli\u003eWu J, Kumar S, McDonald H, et al. RANKL and HLA-DRB1 genotypes are associated with age of onset in rheumatoid arthritis. Arthritis Rheum. 2004;50;3438\u0026ndash;3449.\u003c/li\u003e\n\u003cli\u003e\u0026Aacute;lvaro-Gracia JM, Pascual-Salcedo D, Carre\u0026ntilde;o L, et al. Serum levels of soluble RANK ligand and osteoprotegerin in rheumatoid arthritis patients treated with anti-TNF\u0026alpha; therapy. Arthritis Rheum. 2007;57;607\u0026ndash;613.\u003c/li\u003e\n\u003cli\u003eHuizinga TWJ. Genetics in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2003;17;703\u0026ndash;716.\u003c/li\u003e\n\u003cli\u003eMohamed RH, El-Shahawy EE. Relationship between RANK and RANKL gene polymorphisms with osteoporosis in rheumatoid arthritis patients. Genet Test Mol Biomarkers. 2016;20;249\u0026ndash;254.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Demographic and baseline clinical characteristics \u003cstrong\u003eand biologic agent use\u003c/strong\u003e by TNFRSF11A exon 5 variant status\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariant-negative (n=47)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariant-positive (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGender, female\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 (68.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGender, male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (31.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAge, years (mean \u0026plusmn; SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e56.4 \u0026plusmn; 14.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e54.8 \u0026plusmn; 12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSmoker, current\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (29.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSmoker, former\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (19.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAlcohol use\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eWorking condition (active)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27 (57.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (70.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFamily history of RA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (26.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eInitial symptom: arthralgia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22 (46.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (70.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eInitial symptom: arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25 (53.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePresence of deformity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (29.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eJoint restriction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 (68.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRheumatoid nodule\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBiologic agent use (yes)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (27.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBiologic agent use (no)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34 (72.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eValues are n (%), mean \u0026plusmn; SD, or median [min\u0026ndash;max]. Categorical variables were compared with chi-square or Fisher\u0026rsquo;s exact test; continuous variables with Student\u0026rsquo;s t-test or Mann\u0026ndash;Whitney U test, as appropriate. Percentages are column-wise. The between-group comparison for \u0026ldquo;Biologic agent use (yes)\u0026rdquo; yielded p = 0.91 (2\u0026times;2 chi-square with continuity correction). Significance threshold: p \u0026lt; 0.05.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Change from baseline to 6 months (\u0026Delta; = follow-up \u0026minus; baseline)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariant-negative: Baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariant-negative: 6 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta; (Variant-negative)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariant-positive: Baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariant-positive: 6 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta; (Variant-positive)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDAS28-CRP (mean)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;1.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;1.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCDAI (mean)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;10.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;8.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSDAI (mean)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;12.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;7.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eESR, mm/h (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRP, mg/L (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;6.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;10.40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003e\u0026Delta; (change) = follow-up \u0026minus; baseline. \u0026ldquo;Variant-negative\u0026rdquo; denotes absence of any exon 5 TNFRSF11A polymorphism; \u0026ldquo;Variant-positive\u0026rdquo; denotes the presence of at least one polymorphism (c.521+235T\u0026gt;C, c.428\u0026minus;106C\u0026gt;T, or c.428\u0026minus;338G\u0026gt;A). Between-group comparison of \u0026Delta; was not performed because patient-level change scores (or, at minimum, the SD of change and the baseline\u0026ndash;follow-up correlation) were unavailable; therefore, \u0026Delta; values are descriptive. Within-group change was assessed with paired tests and was significant across indices (p \u0026lt; 0.05).\u003c/em\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rheumatoid arthritis, TNFRSF11A, Genetic polymorphism, Disease activity, Treatment response","lastPublishedDoi":"10.21203/rs.3.rs-7963707/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7963707/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e\u003cp\u003eThis study aimed to investigate the impact of polymorphisms in exon 5 of the \u003cem\u003eTNFRSF11A\u003c/em\u003e gene on disease activity and treatment outcomes in newly diagnosed rheumatoid arthritis (RA).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eIn this prospective cohort, 57 newly diagnosed RA patients (2019 ACR/EULAR criteria) underwent genotyping for \u003cem\u003eTNFRSF11A\u003c/em\u003e exon 5 polymorphisms by PCR and direct sequencing. Clinical and laboratory evaluations\u0026mdash;including DAS28-CRP, CDAI, SDAI, ESR, and CRP\u0026mdash;were performed at baseline and after six months of methotrexate (MTX). Treatment responses and initiation of biological agents were recorded.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e\u003cem\u003eTNFRSF11A\u003c/em\u003e exon 5 polymorphisms were detected in 18% of patients. Both variant-positive and variant-negative groups showed significant improvements in disease activity indices after treatment (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Although not statistically significant, variant-positive patients tended to have lower baseline CRP levels, reduced post-treatment disease activity, fewer tender/swollen joints, and lower rates of biological agent initiation. A higher proportion of seronegative RA was observed in the variant-positive group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eNo statistically significant associations were found between \u003cem\u003eTNFRSF11A\u003c/em\u003e exon 5 polymorphisms and clinical outcomes. However, observed trends suggest that larger cohorts are warranted to clarify the potential prognostic value of these variants.\u003c/p\u003e","manuscriptTitle":"TNFRSF11A Exon 5 Variants in Early RA: Associations with Disease Activity and Biologic Treatment Response—A Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 10:32:51","doi":"10.21203/rs.3.rs-7963707/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6ad0bb15-9328-4abf-9441-11b80cebff98","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58496117,"name":"Health sciences/Diseases"},{"id":58496118,"name":"Biological sciences/Genetics"},{"id":58496119,"name":"Biological sciences/Immunology"},{"id":58496120,"name":"Health sciences/Medical research"},{"id":58496121,"name":"Health sciences/Rheumatology"}],"tags":[],"updatedAt":"2025-12-15T01:09:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 10:32:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7963707","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7963707","identity":"rs-7963707","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}