High rheumatoid factor does not diminish efficacy of TNF inhibitors in seropositive JIA

High rheumatoid factor does not diminish efficacy of TNF inhibitors in seropositive JIA | 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 High rheumatoid factor does not diminish efficacy of TNF inhibitors in seropositive JIA Boris Hugle, Johannes-Peter Haas This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3827176/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 Objectives: Rheumatoid factor (RF) binds to the immunoglobulin Fc portion, which might influence the efficacy of Fc-carrying TNF inhibitors (TNFi). This has been shown in studies of adults with RF-positive RA, but not yet in children. The aim of this study was to determine efficacy of TNFi in children with seropositive polyarthritis according to rheumatoid factor levels. Methods: A database was searched for patients with JIA/seropositive polyarthritis, admitted between January 2019 and March 2023. Data collected were demographic data, treatment with antirheumatic medications and JADAS and cJADAS prior to and after start of TNFi treatment. Changes in JADAS and cJADAS on TNFi were compared between patients with RF < 150 U/ml and RF ≥ 150 U/ml using repeated measures ANOVA. Results: 17 patients were included, 8 with RF < 150 U/ml at diagnosis, and 9 with RF ≥ 150 U/ml. 16 patients (94%) were treated with etanercept, and one with golimumab, 15 patients were additionally treated with methotrexate. Mean JADAS (cJADAS) at treatment start was 26.0 ± 16.9 (24.4±13.7), and 5.5 ± 6.0 (5.1±5.7) at assessment after starting TNFi. A repeated-measures ANOVA determined that mean JADAS and cJADAS scores did not differ significantly across the two time points. Conclusions: Unlike in adults, efficacy of TNFi was not diminished by elevated levels of RF in this cohort of pediatric patients with seropositive polyarthritis. Further studies are necessary to confirm these findings. Juvenile idiopathic arthritis rheumatoid factor TNF inhibitor Figures Figure 1 Figure 2 Introduction Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of chronic inflammatory joint disorders affecting children. Within this spectrum, seropositive polyarthritis stands out due to the presence of rheumatoid factor (RF), an autoantibody targeting the Fc portion of immunoglobulin G (IgG) [ 1 ]. This disease subset shares clinical and genetic features with adult rheumatoid arthritis (RA), making it the juvenile counterpart of the adult disease. It is treated in a similar fashion, including the use of tumor necrosis factor inhibitors (TNFi) [ 2 – 4 ]. TNFi, including drugs such as etanercept, adalimumab and golimumab, have revolutionized the management of various autoimmune diseases, suppressing inflammation, and improving functional outcomes in patients with seropositive polyarthritis and RA [ 3 , 5 ]. However, there is data demonstrating that RF binds to the Fc portion of TNFi carrying this moiety which leads to attenuation of their clinical efficacy [ 6 , 7 ]. The presence of high levels of RF in the blood has traditionally been associated with a worse prognosis in adult RA patients [ 8 ]. The influence of high titers of RF on the therapeutic response to TNFi in children with JIA has yet to be determined [ 9 ]. The aim of this study was therefore to determine efficacy of TNFi in children with seropositive polyarthritis according to their rheumatoid factor levels. Methods Patients The database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with JIA, category seropositive polyarthritis, admitted between January 2019 and March 2023. Patients were included if they started a TNFi during that time and had at least one assessment within 3 to 12 months after starting medication. Patients were excluded if they had any other disease or factor that would influence rheumatoid factor levels. The study was approved by the medical ethics committee of the Ludwig-Maximilians-University (Nr. 23–0456), and was performed according to good clinical practice regulations and the declaration of Helsinki. Data collection Data collected was age at time of diagnosis, RF at time of diagnosis, anti-CCP-antibodies at time of diagnosis, other drugs given at the time of start of TNFi, age at the start of TNFi treatment and JADAS27 and cJADAS27 prior to and after start of TNFi treatment Statistics Data was analyzed using descriptive statistics, and changes in JADAS and cJADAS on TNFi were compared between patients with RF < 150 U/ml and RF ≥ 150 U/ml using repeated measures ANOVA. Statistical analyses were performed with SPSS, version 26 (SPSS Inc., Chicago, USA). Results The demographic data of the patients is shown in Table 1 . 40 patients with seropositive polyarthritis were identified, of which 17 had documented assessments at start and between 3 and 12 months after start of treatment with TNF inhibitor: 8 with RF < 150 U/ml at diagnosis, and 9 with RF ≥ 150 U/ml. Median age at diagnosis was 14.6 years (range 7.3–15.7 years). Mean RF was 84.9 ± 40.7 U/ml for the low RF group, and 263.4 ± 64.1 U/ml for the high RF group; anti-CCP antibodies levels were 132.0 ± 137.3 U/ml and 239.1 ± 169.6 U/ml, respectively. 16 patients (94%) were treated with etanercept, and one with golimumab. 15 patients were additionally treated with methotrexate. Median time between assessments was 135 days (range 95–364 days). Table 1 Patient characteristics Variables Low RF (n = 8) High RF (n = 9) Female, no (%) 7/8 (88%) 8/9 (89%) Age at diagnosis (median, range) 14.1 years (11.2–16.7) 12.8 years (7.3–15.5) Disease duration at time of testing 14.7 years (11.3–17.7) 13.2 years (7.4–15.6) Rheumatoid factor (mean, standard deviation) 84.9 ± 40.7 U/l 263.4 ± 64.1 U/l Anti-CCP antibodies 132.0 ± 137.3 U/l 239.1 ± 169.6 U/l Medication Methotrexate Etanercept Golimumab 7/8 (88%) 8/8 (100%) - 8/9 (89%) 8/9 (89%) 1/9 (11%) Median age at start of TNFi treatment was 14.7 years (range 7.4–17.7 years). At that time, mean JADAS27 was 26.0 ± 16.9 (24.4 ± 13.7), and mean cJADAS27 5.5 ± 6.0 (5.1 ± 5.7) at time of assessment after starting TNFi. A repeated-measures ANOVA determined that mean JADAS27 and cJADAS27 scores did not differ significantly across the two time points for both groups (JADAS27: F(1, 16) = 1.901, p = .188, cJADAS27: F(1, 16) = 1.050, p = .327) (Fig. 1 , 2 ). Discussion The findings in this study deviate from observations in an adult RA cohort, where a diminished efficacy of TNFi with Fc fragment according to rheumatoid factor levels has been demonstrated, unlike TNFi without an Fc fragment [ 6 , 10 ]. Contrary to the expected negative impact of elevated RF levels on response to TNFi with Fc fragment, we found that TNFi efficacy in pediatric seropositive polyarthritis is not significantly compromised. These results not only highlight the uniqueness of JIA as a distinct disease entity but also underscore the intricate interplay between RF and TNFi in pediatric patients. A possible explanation for the differing response to TNFi between children and adults lies in the immunological differences between these two groups. The pathogenesis of seropositive polyarthritis involves complex interactions between genetic predisposition, environmental triggers, and dysregulated immune responses. In adults with RA, the presence of high levels of RF is associated with more aggressive disease and worse prognosis [ 6 , 8 , 10 ]. RF binds to the Fc portion of IgG, potentially impacting the efficacy of TNFi carrying an FC moiety. This binding could interfere with TNFi binding to their intended targets, leading to reduced clinical efficacy. Certolizumab is the only TNFi without Fc fragment commercially available and is not licensed in children and as a consequence rarely used, so unfortunately, we could not include this in our analysis. Another factor that may contribute to the observed differences is the heterogeneity of JIA itself. JIA encompasses several distinct disease subtypes with varied clinical and immunological features [ 11 ]. Within the seropositive polyarthritis category, there may be additional factors at play that modify the response to TNFi. It is possible that specific immunological profiles or genetic factors unique to children with seropositive polyarthritis modulate the impact of RF on TNFi efficacy. Exploring these potential modifiers may provide valuable insights into the distinct mechanisms underlying disease pathogenesis and treatment response in this subgroup of JIA patients. Moreover, differences in the overall disease burden and duration between pediatric and adult populations could contribute to the differential response to TNFi. Children often receive treatment earlier in the disease course compared to adults, potentially leading to better outcomes and higher treatment response rates [ 12 ]. In addition, the duration of disease prior to TNFi initiation may be shorter in pediatric patients, reducing the cumulative impact of disease-related factors and joint damage. The relatively shorter disease duration in the pediatric cohort may explain why the negative prognostic implications of high RF levels observed in adults with RA are less pronounced in children with seropositive polyarthritis. Concomitant medication use, such as methotrexate, a cornerstone of JIA treatment, could also modulate the RF-TNFi interplay. Methotrexate was used in the majority of patients in this cohort. This drug with its immunomodulatory effects may counteract any potential negative influence of RF on TNFi outcomes, thereby contributing to the observed disparities between pediatric and adult populations, although MTX use was generally similar in a previous study which did show attenuation of TNFi efficacy in RA patients [ 6 , 10 ]. The limitations of this study should be acknowledged. The relatively small sample size and retrospective design may limit the generalizability of the findings. Additionally, the study focused on a specific cohort of pediatric patients from a single center, potentially introducing selection bias. Future studies should aim to include larger and more diverse patient populations to validate these findings and minimize potential confounders. Conclusion In conclusion, this study demonstrates that elevated RF levels do not diminish the efficacy of TNFi therapy in children with seropositive polyarthritis, in contrast to findings in adult patients with RA. Possible explanations for this discrepancy include immunological differences, disease heterogeneity, shorter disease duration, and the influence of concomitant medications. Further studies, including e.g. the investigation of additional immunological markers, such as anti-cyclic citrullinated peptide (anti-CCP) antibodies, could provide further insights into the disease processes specific to pediatric patients [ 13 ]. Abbreviations JIA Juvenile Idiopathic Arthritis RA Rheumatoid Arthritis RF Rheumatoid Factor TNFi Tumor Necrosis Factor Inhibitor Declarations Ethics approval The study was approved by the Ethics Committee of the Medical Faculty, Ludwig-Maximilians University Munich, Germany (Nr. 23-0456). Consent for publication Not applicable Availability of data and material The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors’ contributions JPH participated in the analysis, BH designed the study, performed the data collection and the analysis. All authors read and approved the final manuscript. References Syed RH, Gilliam BE, Moore TL. Rheumatoid factors and anticyclic citrullinated peptide antibodies in pediatric rheumatology. Curr Rheumatol Rep. 2008;10(2):156–63. Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging. Arthritis Rheumatol. 2022;74(4):570–85. Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, Ilowite NT, Wallace CA, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000;342(11):763–9. Hinks A, Bowes J, Cobb J, Ainsworth HC, Marion MC, Comeau ME, Sudman M, Han B, Juvenile Arthritis Consortium for I, Becker ML et al. Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 2017, 76(4):765–772. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810–20. Nakayama Y, Watanabe R, Murakami K, Murata K, Tanaka M, Ito H, Yamamoto W, Ebina K, Hata K, Hiramatsu Y, et al. Differential efficacy of TNF inhibitors with or without the immunoglobulin fragment crystallizable (Fc) portion in rheumatoid arthritis: the ANSWER cohort study. Rheumatol Int. 2022;42(7):1227–34. Salgado E, Maneiro JR, Carmona L, Gomez-Reino J. Rheumatoid factor and response to TNF antagonists in rheumatoid arthritis: systematic review and meta-analysis of observational studies. Joint Bone Spine. 2014;81(1):41–50. Vittecoq O, Pouplin S, Krzanowska K, Jouen-Beades F, Menard JF, Gayet A, Daragon A, Tron F, Le Loet X. Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a three-year prospective study in community-recruited patients. Rheumatology (Oxford). 2003;42(8):939–46. Bobbio-Pallavicini F, Caporali R, Alpini C, Avalle S, Epis OM, Klersy C, Montecucco C. High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis. Ann Rheum Dis. 2007;66(3):302–7. Takeuchi T, Miyasaka N, Inui T, Yano T, Yoshinari T, Abe T, Koike T. High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study. Arthritis Res Ther. 2017;19(1):194. Martini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R, Ilowite NT, Khubchandani R, Laxer RM, Lovell DJ, et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, Pediatric Rheumatology International Trials Organization International Consensus. J Rheumatol. 2019;46(2):190–7. Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA: the journal of the American Medical Association. 2005;294(13):1671–84. Dewint P, Hoffman IE, Rogge S, Joos R, Union A, Dehoorne J, Delanghe J, Veys EM, De Keyser F, Elewaut D. Effect of age on prevalence of anticitrullinated protein/peptide antibodies in polyarticular juvenile idiopathic arthritis. Rheumatology (Oxford). 2006;45(2):204–8. 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-3827176","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":268115949,"identity":"c47e6ac8-2a7f-42ea-9251-ced860c46f8a","order_by":0,"name":"Boris Hugle","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-1145-6719","institution":"Deutsches Zentrum für Kinder- und Jugendrheumatologie: Kinderklinik Garmisch-Partenkirchen gGmbH","correspondingAuthor":true,"prefix":"","firstName":"Boris","middleName":"","lastName":"Hugle","suffix":""},{"id":268115950,"identity":"cf240d48-5231-4dc8-8e92-c89ed878deaf","order_by":1,"name":"Johannes-Peter Haas","email":"","orcid":"","institution":"Deutsches Zentrum für Kinder- und Jugendrheumatologie: Kinderklinik Garmisch-Partenkirchen gGmbH","correspondingAuthor":false,"prefix":"","firstName":"Johannes-Peter","middleName":"","lastName":"Haas","suffix":""}],"badges":[],"createdAt":"2024-01-01 09:27:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3827176/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3827176/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50115972,"identity":"347bc3a6-0e69-4531-919a-ad6f5d17cc87","added_by":"auto","created_at":"2024-01-24 18:47:22","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":185472,"visible":true,"origin":"","legend":"\u003cp\u003eJADAS 27 for both groups prior to and after start of TNFi treatment\u003c/p\u003e\n\u003cp\u003eAlso shown is the p value of the repeated measures ANOVA analysis\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3827176/v1/c8524c6e4742508fe0aa9795.jpeg"},{"id":50117178,"identity":"94b336c9-ce8a-4edc-9c3b-72b4f62f0a61","added_by":"auto","created_at":"2024-01-24 18:55:21","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130246,"visible":true,"origin":"","legend":"\u003cp\u003ecJADAS 27 for both groups prior to and after start of TNFi treatment\u003c/p\u003e\n\u003cp\u003eAlso shown is the p value of the repeated measures ANOVA analysis\u003c/p\u003e","description":"","filename":"floatimage312.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3827176/v1/7ebc20cfc490934ba660c74d.jpeg"},{"id":57245644,"identity":"62f960b5-7e82-4709-8404-65ae80c2708e","added_by":"auto","created_at":"2024-05-28 05:37:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":569977,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3827176/v1/bef4ceb2-d5e7-40aa-9f0c-eda191ba758f.pdf"}],"financialInterests":"","formattedTitle":"High rheumatoid factor does not diminish efficacy of TNF inhibitors in seropositive JIA","fulltext":[{"header":"Introduction","content":"\u003cp\u003eJuvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of chronic inflammatory joint disorders affecting children. Within this spectrum, seropositive polyarthritis stands out due to the presence of rheumatoid factor (RF), an autoantibody targeting the Fc portion of immunoglobulin G (IgG) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This disease subset shares clinical and genetic features with adult rheumatoid arthritis (RA), making it the juvenile counterpart of the adult disease. It is treated in a similar fashion, including the use of tumor necrosis factor inhibitors (TNFi) [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTNFi, including drugs such as etanercept, adalimumab and golimumab, have revolutionized the management of various autoimmune diseases, suppressing inflammation, and improving functional outcomes in patients with seropositive polyarthritis and RA [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, there is data demonstrating that RF binds to the Fc portion of TNFi carrying this moiety which leads to attenuation of their clinical efficacy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The presence of high levels of RF in the blood has traditionally been associated with a worse prognosis in adult RA patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe influence of high titers of RF on the therapeutic response to TNFi in children with JIA has yet to be determined [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The aim of this study was therefore to determine efficacy of TNFi in children with seropositive polyarthritis according to their rheumatoid factor levels.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cstrong\u003ePatients\u003c/strong\u003e \u003cp\u003eThe database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with JIA, category seropositive polyarthritis, admitted between January 2019 and March 2023. Patients were included if they started a TNFi during that time and had at least one assessment within 3 to 12 months after starting medication. Patients were excluded if they had any other disease or factor that would influence rheumatoid factor levels. The study was approved by the medical ethics committee of the Ludwig-Maximilians-University (Nr. 23\u0026ndash;0456), and was performed according to good clinical practice regulations and the declaration of Helsinki.\u003c/p\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eData collected was age at time of diagnosis, RF at time of diagnosis, anti-CCP-antibodies at time of diagnosis, other drugs given at the time of start of TNFi, age at the start of TNFi treatment and JADAS27 and cJADAS27 prior to and after start of TNFi treatment\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eData was analyzed using descriptive statistics, and changes in JADAS and cJADAS on TNFi were compared between patients with RF\u0026thinsp;\u0026lt;\u0026thinsp;150 U/ml and RF\u0026thinsp;\u0026ge;\u0026thinsp;150 U/ml using repeated measures ANOVA. Statistical analyses were performed with SPSS, version 26 (SPSS Inc., Chicago, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe demographic data of the patients is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 40 patients with seropositive polyarthritis were identified, of which 17 had documented assessments at start and between 3 and 12 months after start of treatment with TNF inhibitor: 8 with RF\u0026thinsp;\u0026lt;\u0026thinsp;150 U/ml at diagnosis, and 9 with RF\u0026thinsp;\u0026ge;\u0026thinsp;150 U/ml. Median age at diagnosis was 14.6 years (range 7.3\u0026ndash;15.7 years). Mean RF was 84.9\u0026thinsp;\u0026plusmn;\u0026thinsp;40.7 U/ml for the low RF group, and 263.4\u0026thinsp;\u0026plusmn;\u0026thinsp;64.1 U/ml for the high RF group; anti-CCP antibodies levels were 132.0\u0026thinsp;\u0026plusmn;\u0026thinsp;137.3 U/ml and 239.1\u0026thinsp;\u0026plusmn;\u0026thinsp;169.6 U/ml, respectively. 16 patients (94%) were treated with etanercept, and one with golimumab. 15 patients were additionally treated with methotrexate. Median time between assessments was 135 days (range 95\u0026ndash;364 days).\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 \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow RF (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh RF (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, no (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/8 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/9 (89%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis (median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.1 years (11.2\u0026ndash;16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.8 years (7.3\u0026ndash;15.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration at time of testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.7 years (11.3\u0026ndash;17.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.2 years (7.4\u0026ndash;15.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid factor (mean, standard deviation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.9\u0026thinsp;\u0026plusmn;\u0026thinsp;40.7 U/l\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e263.4\u0026thinsp;\u0026plusmn;\u0026thinsp;64.1 U/l\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-CCP antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e132.0\u0026thinsp;\u0026plusmn;\u0026thinsp;137.3 U/l\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e239.1\u0026thinsp;\u0026plusmn;\u0026thinsp;169.6 U/l\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedication\u003c/p\u003e \u003cp\u003eMethotrexate\u003c/p\u003e \u003cp\u003eEtanercept\u003c/p\u003e \u003cp\u003eGolimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/8 (88%)\u003c/p\u003e \u003cp\u003e8/8 (100%)\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/9 (89%)\u003c/p\u003e \u003cp\u003e8/9 (89%)\u003c/p\u003e \u003cp\u003e1/9 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMedian age at start of TNFi treatment was 14.7 years (range 7.4\u0026ndash;17.7 years). At that time, mean JADAS27 was 26.0\u0026thinsp;\u0026plusmn;\u0026thinsp;16.9 (24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7), and mean cJADAS27 5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 (5.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7) at time of assessment after starting TNFi. A repeated-measures ANOVA determined that mean JADAS27 and cJADAS27 scores did not differ significantly across the two time points for both groups (JADAS27: F(1, 16)\u0026thinsp;=\u0026thinsp;1.901, p\u0026thinsp;=\u0026thinsp;.188, cJADAS27: F(1, 16)\u0026thinsp;=\u0026thinsp;1.050, p\u0026thinsp;=\u0026thinsp;.327) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings in this study deviate from observations in an adult RA cohort, where a diminished efficacy of TNFi with Fc fragment according to rheumatoid factor levels has been demonstrated, unlike TNFi without an Fc fragment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Contrary to the expected negative impact of elevated RF levels on response to TNFi with Fc fragment, we found that TNFi efficacy in pediatric seropositive polyarthritis is not significantly compromised. These results not only highlight the uniqueness of JIA as a distinct disease entity but also underscore the intricate interplay between RF and TNFi in pediatric patients.\u003c/p\u003e \u003cp\u003eA possible explanation for the differing response to TNFi between children and adults lies in the immunological differences between these two groups. The pathogenesis of seropositive polyarthritis involves complex interactions between genetic predisposition, environmental triggers, and dysregulated immune responses. In adults with RA, the presence of high levels of RF is associated with more aggressive disease and worse prognosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. RF binds to the Fc portion of IgG, potentially impacting the efficacy of TNFi carrying an FC moiety. This binding could interfere with TNFi binding to their intended targets, leading to reduced clinical efficacy. Certolizumab is the only TNFi without Fc fragment commercially available and is not licensed in children and as a consequence rarely used, so unfortunately, we could not include this in our analysis.\u003c/p\u003e \u003cp\u003eAnother factor that may contribute to the observed differences is the heterogeneity of JIA itself. JIA encompasses several distinct disease subtypes with varied clinical and immunological features [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Within the seropositive polyarthritis category, there may be additional factors at play that modify the response to TNFi. It is possible that specific immunological profiles or genetic factors unique to children with seropositive polyarthritis modulate the impact of RF on TNFi efficacy. Exploring these potential modifiers may provide valuable insights into the distinct mechanisms underlying disease pathogenesis and treatment response in this subgroup of JIA patients.\u003c/p\u003e \u003cp\u003eMoreover, differences in the overall disease burden and duration between pediatric and adult populations could contribute to the differential response to TNFi. Children often receive treatment earlier in the disease course compared to adults, potentially leading to better outcomes and higher treatment response rates [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In addition, the duration of disease prior to TNFi initiation may be shorter in pediatric patients, reducing the cumulative impact of disease-related factors and joint damage. The relatively shorter disease duration in the pediatric cohort may explain why the negative prognostic implications of high RF levels observed in adults with RA are less pronounced in children with seropositive polyarthritis.\u003c/p\u003e \u003cp\u003eConcomitant medication use, such as methotrexate, a cornerstone of JIA treatment, could also modulate the RF-TNFi interplay. Methotrexate was used in the majority of patients in this cohort. This drug with its immunomodulatory effects may counteract any potential negative influence of RF on TNFi outcomes, thereby contributing to the observed disparities between pediatric and adult populations, although MTX use was generally similar in a previous study which did show attenuation of TNFi efficacy in RA patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe limitations of this study should be acknowledged. The relatively small sample size and retrospective design may limit the generalizability of the findings. Additionally, the study focused on a specific cohort of pediatric patients from a single center, potentially introducing selection bias. Future studies should aim to include larger and more diverse patient populations to validate these findings and minimize potential confounders.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study demonstrates that elevated RF levels do not diminish the efficacy of TNFi therapy in children with seropositive polyarthritis, in contrast to findings in adult patients with RA. Possible explanations for this discrepancy include immunological differences, disease heterogeneity, shorter disease duration, and the influence of concomitant medications. Further studies, including e.g. the investigation of additional immunological markers, such as anti-cyclic citrullinated peptide (anti-CCP) antibodies, could provide further insights into the disease processes specific to pediatric patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eJIA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJuvenile Idiopathic Arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRheumatoid Arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRheumatoid Factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNFi\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumor Necrosis Factor Inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of the Medical Faculty, Ludwig-Maximilians University Munich, Germany (Nr. 23-0456).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJPH participated in the analysis, BH designed the study, performed the data collection and the analysis. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSyed RH, Gilliam BE, Moore TL. Rheumatoid factors and anticyclic citrullinated peptide antibodies in pediatric rheumatology. Curr Rheumatol Rep. 2008;10(2):156\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOnel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for Nonpharmacologic Therapies, Medication Monitoring, Immunizations, and Imaging. Arthritis Rheumatol. 2022;74(4):570\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, Ilowite NT, Wallace CA, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000;342(11):763\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHinks A, Bowes J, Cobb J, Ainsworth HC, Marion MC, Comeau ME, Sudman M, Han B, Juvenile Arthritis Consortium for I, Becker ML et al. Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. \u003cem\u003eAnn Rheum Dis\u003c/em\u003e 2017, 76(4):765\u0026ndash;772.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359(8):810\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakayama Y, Watanabe R, Murakami K, Murata K, Tanaka M, Ito H, Yamamoto W, Ebina K, Hata K, Hiramatsu Y, et al. Differential efficacy of TNF inhibitors with or without the immunoglobulin fragment crystallizable (Fc) portion in rheumatoid arthritis: the ANSWER cohort study. Rheumatol Int. 2022;42(7):1227\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalgado E, Maneiro JR, Carmona L, Gomez-Reino J. Rheumatoid factor and response to TNF antagonists in rheumatoid arthritis: systematic review and meta-analysis of observational studies. Joint Bone Spine. 2014;81(1):41\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVittecoq O, Pouplin S, Krzanowska K, Jouen-Beades F, Menard JF, Gayet A, Daragon A, Tron F, Le Loet X. Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a three-year prospective study in community-recruited patients. Rheumatology (Oxford). 2003;42(8):939\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBobbio-Pallavicini F, Caporali R, Alpini C, Avalle S, Epis OM, Klersy C, Montecucco C. High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis. Ann Rheum Dis. 2007;66(3):302\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeuchi T, Miyasaka N, Inui T, Yano T, Yoshinari T, Abe T, Koike T. High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study. Arthritis Res Ther. 2017;19(1):194.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R, Ilowite NT, Khubchandani R, Laxer RM, Lovell DJ, et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, Pediatric Rheumatology International Trials Organization International Consensus. J Rheumatol. 2019;46(2):190\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA: the journal of the American Medical Association. 2005;294(13):1671\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDewint P, Hoffman IE, Rogge S, Joos R, Union A, Dehoorne J, Delanghe J, Veys EM, De Keyser F, Elewaut D. Effect of age on prevalence of anticitrullinated protein/peptide antibodies in polyarticular juvenile idiopathic arthritis. Rheumatology (Oxford). 2006;45(2):204\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"Juvenile idiopathic arthritis, rheumatoid factor, TNF inhibitor ","lastPublishedDoi":"10.21203/rs.3.rs-3827176/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3827176/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eObjectives:\u003c/em\u003e \u0026nbsp;Rheumatoid factor (RF) binds to the immunoglobulin Fc portion, which might influence the efficacy of Fc-carrying TNF inhibitors (TNFi). This has been shown in studies of adults with RF-positive RA, but not yet in children.\u003c/p\u003e\n\u003cp\u003eThe aim of this study was to determine efficacy of TNFi in children with seropositive polyarthritis according to rheumatoid factor levels.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods:\u003c/em\u003e A database was searched for patients with JIA/seropositive polyarthritis, admitted between January 2019 and March 2023. Data collected were demographic data, treatment with antirheumatic medications and JADAS and cJADAS prior to and after start of TNFi treatment. Changes in JADAS and cJADAS on TNFi were compared between patients with RF \u0026lt; 150 U/ml and RF ≥ 150 U/ml using repeated measures ANOVA.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResults: \u003c/em\u003e17 patients were included, 8 with RF \u0026lt; 150 U/ml at diagnosis, and 9 with RF ≥ 150 U/ml. 16 patients (94%) were treated with etanercept, and one with golimumab, 15 patients were additionally treated with methotrexate. Mean JADAS (cJADAS) at treatment start was 26.0 ± 16.9 (24.4±13.7), and 5.5 ± 6.0 (5.1±5.7) at assessment after starting TNFi. A repeated-measures ANOVA determined that mean JADAS and cJADAS scores did not differ significantly across the two time points.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusions:\u003c/em\u003e Unlike in adults, efficacy of TNFi was not diminished by elevated levels of RF in this cohort of pediatric patients with seropositive polyarthritis. Further studies are necessary to confirm these findings.\u003c/p\u003e","manuscriptTitle":"High rheumatoid factor does not diminish efficacy of TNF inhibitors in seropositive JIA","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-24 18:47:17","doi":"10.21203/rs.3.rs-3827176/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":"2ef20dd0-0afd-406e-be7b-e209ac200a7a","owner":[],"postedDate":"January 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-11T00:38:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-24 18:47:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3827176","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3827176","identity":"rs-3827176","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}