{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T04:22:00Z","timestamp":1793766120161,"version":"4.6.1"},"reference-count":199,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T00:00:00Z","timestamp":1633824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["17K09973"],"award-info":[{"award-number":["17K09973"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines tumor necrosis factor (TNF)-\u03b1 and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1\u03b2, IL-18, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.<\/jats:p>","DOI":"10.3390\/ijms222010922","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T21:23:25Z","timestamp":1633901005000},"page":"10922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":550,"title":["Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8985-3055","authenticated-orcid":false,"given":"Naoki","family":"Kondo","sequence":"first","affiliation":[{"name":"Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Health Administration Center, Niigata University, 2-8050 Ikarashi, Nishi-ku, Niigata City 950-2181, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0384-8678","authenticated-orcid":false,"given":"Daisuke","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City 951-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.3899\/jrheum.111453","article-title":"Treatment with biologic agents improves the prognosis of patients with rheumatoid arthritis and amyloidosis","volume":"39","author":"Kuroda","year":"2012","journal-title":"J. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.smim.2011.01.014","article-title":"Smoking, citrullination and genetic varia-bility in the immunopathogenesis of rheumatoid arthritis","volume":"23","author":"Klareskog","year":"2011","journal-title":"Semin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3","article-title":"The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide","volume":"43","author":"Schellekens","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1002\/art.27594","article-title":"HLA\u2013DR1001 presents \u201caltered-self\u201d peptides derived from joint-associated proteins by accepting citrulline in three of its binding pockets","volume":"62","author":"James","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/art.23284","article-title":"Induction of macrophage secretion of tumor necrosis factor through Fc receptor IIa engagement by rheumatoid arthritis\u2013specific autoantibodies to citrullinated proteins complexed with fibrinogen","volume":"58","author":"Clavel","year":"2018","journal-title":"Arthritis Rheum."},{"key":"ref_8","first-page":"498","article-title":"JAK\/STAT pathway in pathology of rheumatoid arthritis","volume":"20","author":"Ciobanu","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.biopha.2017.05.055","article-title":"Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy","volume":"92","author":"Alam","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nrrheum.2015.171","article-title":"Cytokines in rheumatoid arthritis\u2014Shaping the immunological landscape","volume":"12","author":"McInnes","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.4049\/jimmunol.165.3.1557","article-title":"Heterogeneous effects of IL-2 on collagen-induced arthritis","volume":"165","author":"Thornton","year":"2000","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.4049\/jimmunol.1701502","article-title":"IL-2-Anti-IL-2 Mono-clonal antibody immune complexes inhibit collagen induced arthritis by augmenting regulatory T cell functions","volume":"201","author":"Yokoyama","year":"2018","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrrheum.2015.169","article-title":"TNF biology, pathogenic mechanisms and emerging therapeutic strategies","volume":"12","author":"Kalliolias","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.3389\/fimmu.2019.01146","article-title":"Ontogeny of synovial macrophages and the roles of synovial macrophages from different origins in arthritis","volume":"10","author":"Tu","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41590-019-0378-1","article-title":"Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry","volume":"20","author":"Zhang","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: Nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1016\/S0140-6736(17)31472-1","article-title":"Pathogenetic insights from the treatment of rheumatoid arthritis","volume":"389","author":"McInnes","year":"2017","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/BOR.0000000000000356","article-title":"Anticitrullinated protein antibodies: Origin and role in the pathogenesis of rheumatoid arthritis","volume":"29","author":"England","year":"2017","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1002\/art.40587","article-title":"Affinity maturation drives epitope spreading and generation of proinflammatory anti-citrullinated protein antibodies in rheumatoid arthritis","volume":"70","author":"Elliott","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1084\/jem.20132413","article-title":"Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF","volume":"30","author":"Finsterbusch","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1084\/jem.20070906","article-title":"Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases","volume":"205","author":"Armaka","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"a031245","DOI":"10.1101\/cshperspect.a031245","article-title":"Osteoimmunology","volume":"9","author":"Okamoto","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1084\/jem.20072707","article-title":"Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells","volume":"205","author":"Notley","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1136\/annrheumdis-2019-216068","article-title":"Contrasting contributions of TNF from distinct cellular sources in arthritis","volume":"79","author":"Kruglov","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/art.40413","article-title":"Selective activation of tumor necrosis factor receptor II induces antiinflammatory responses and alleviates experimental arthritis","volume":"70","author":"Fischer","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/cmi.2017.138","article-title":"Stimulation of TNF receptor type 2 expands regulatory T cells and ameliorates established collagen-induced arthritis in mice","volume":"16","author":"Lamontain","year":"2019","journal-title":"Cell. Mol. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.4049\/jimmunol.157.7.3178","article-title":"Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice","volume":"157","author":"Mori","year":"1996","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21666","DOI":"10.1073\/pnas.1909687116","article-title":"TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells","volume":"116","author":"Tseng","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/intimm\/dxt060","article-title":"Foxp3\u207a T(reg) cells in humoral immunity","volume":"26","author":"Wing","year":"2014","journal-title":"Int. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.3389\/fimmu.2019.02040","article-title":"Targeting regulatory T cells by addressing tumor necrosis factor and its receptors in allogeneic hematopoietic cell transplantation and cancer","volume":"10","author":"Wajant","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/art.41134","article-title":"Involvement of tumor necrosis factor receptor type II in FoxP3 stability and as a marker of Treg cells Specifically expanded by anti-tumor necrosis factor treatments in rheumatoid arthritis","volume":"72","author":"Santinon","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nm.3085","article-title":"Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-\u03b1 in rheumatoid arthritis","volume":"19","author":"Nie","year":"2013","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1002\/eji.201948393","article-title":"Tumor necrosis factor receptor family costimulation in-creases regulatory T-cell activation and function via NF-\u03baB","volume":"50","author":"Ronin","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1016\/j.celrep.2017.08.068","article-title":"The TNF Receptor Superfamily-NF-kappaB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues","volume":"20","author":"Vasanthakumar","year":"2017","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1126\/science.1199214","article-title":"The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice","volume":"332","author":"Tang","year":"2011","journal-title":"Science"},{"key":"ref_36","first-page":"131.e144016","article-title":"TNFR2\/14-3-3\u03b5 signaling complex instructs macrophage plasticity in inflammation and autoimmunity","volume":"16","author":"Fu","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7370","DOI":"10.1038\/s41598-018-24240-2","article-title":"Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis","volume":"8","author":"Karouzakis","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1136\/annrheumdis-2012-201526","article-title":"DNA methylome signature in rheumatoid arthritis","volume":"72","author":"Nakano","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.4049\/jimmunol.1202572","article-title":"Regulation of DNA methylation in rheumatoid arthritis synoviocytes","volume":"190","author":"Nakano","year":"2013","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1136\/annrheumdis-2014-205635","article-title":"Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression","volume":"75","author":"Angiolilli","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1136\/annrheumdis-2018-214783","article-title":"TNF-induced inflammatory genes escape repres-sion in fibroblast-like synoviocytes: Transcriptomic and epigenomic analysis","volume":"78","author":"Loh","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","first-page":"191","article-title":"Possible anti-inflammatory effects of mesenchymal stem cells transplantation via changes in CXCL8 levels in patients with refractory rheumatoid arthritis","volume":"8","author":"Ghoryani","year":"2019","journal-title":"Int. J. Mol. Cell. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s13075-017-1353-6","article-title":"Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: Relevance for arthritis","volume":"19","author":"Lee","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13075-017-1224-1","article-title":"Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker","volume":"19","author":"Pandya","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Tsuchiya, H., Ota, M., Sumitomo, S., Ishigaki, K., Suzuki, A., Sakata, T., Tsuchida, Y., Inui, H., Hirose, J., and Kochi, Y. (2020). Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis. Ann. Rheum. Dis.","DOI":"10.1101\/861781"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1080\/14397595.2017.1380250","article-title":"Efficacy and safety of infliximab: A comparison with other biological disease-modifying anti-rheumatic drugs","volume":"28","author":"Kobayashi","year":"2018","journal-title":"Mod. Rheumatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.semarthrit.2017.02.007","article-title":"Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis","volume":"47","author":"Maneiro","year":"2017","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_48","first-page":"CD012183","article-title":"Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: A systematic re-view and network meta-analysis","volume":"5","author":"Singh","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_49","first-page":"CD012437","article-title":"Biologic or to-facitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying an-ti-rheumatic drug (DMARD) failure: A Cochrane Systematic Review and network meta-analysis (NMA)","volume":"11","author":"Singh","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_50","first-page":"CD012591","article-title":"Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: A systematic review and network meta-analysis","volume":"3","author":"Singh","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_51","first-page":"CD012657","article-title":"Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: A systematic review and network meta-analysis","volume":"5","author":"Singh","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"m2288","DOI":"10.1136\/bmj.m2288","article-title":"Comparative effectiveness of biological medicines in rheumatoid arthritis: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data","volume":"370","author":"Janke","year":"2020","journal-title":"BMJ"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fphar.2019.00282","article-title":"Paradoxical skin reactions to biologics in patients with rheumatologic disorders","volume":"10","author":"Garcovich","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1002\/art.38755","article-title":"Selective tumor necrosis factor receptor I blockade is antiinflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis","volume":"66","author":"McCann","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/intimm\/dxaa078","article-title":"IL-6 in inflammation, autoimmunity and cancer","volume":"33","author":"Hirano","year":"2021","journal-title":"Int. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1002\/art.37853","article-title":"Tumor necrosis fac-tor alpha induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts","volume":"65","author":"Lee","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.immuni.2008.07.018","article-title":"Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction","volume":"29","author":"Ogura","year":"2008","journal-title":"Immunity"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.1073\/pnas.1912702117","article-title":"CUX1 and IkappaBzeta (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts","volume":"117","author":"Slowikowski","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1146\/annurev-biophys-083012-130338","article-title":"Molecular basis of NF-kappaB signaling","volume":"42","author":"Napetschnig","year":"2013","journal-title":"Annu. Rev. Biophys."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.imlet.2016.01.006","article-title":"Atypical IkappaB proteins in immune cell differentiation and function","volume":"171","author":"Annemann","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/ni.3632","article-title":"Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T(H)17 cells","volume":"18","author":"Heink","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1093\/intimm\/dxm045","article-title":"IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state","volume":"19","author":"Nishihara","year":"2007","journal-title":"Int. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.celrep.2017.05.013","article-title":"Genome-wide analysis of STAT3-mediated transcription during early human Th17 cell differentiation","volume":"19","author":"Tripathi","year":"2017","journal-title":"Cell Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.immuni.2008.05.007","article-title":"Molecular antagonism and plasticity of regulatory and inflammatory T cell programs","volume":"29","author":"Yang","year":"2008","journal-title":"Immunity"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nm.3432","article-title":"Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis","volume":"20","author":"Komatsu","year":"2014","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.immuni.2019.04.011","article-title":"T follicular helper cell biology: A decade of discovery and diseases","volume":"50","author":"Crotty","year":"2019","journal-title":"Immunity"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.4049\/jimmunol.1203032","article-title":"Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation","volume":"190","author":"Choi","year":"2013","journal-title":"J. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1038\/ni.2947","article-title":"The cytokine TGF-beta co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells","volume":"15","author":"Schmitt","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41413-018-0016-9","article-title":"Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies","volume":"6","author":"Guo","year":"2018","journal-title":"Bone Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s10456-015-9477-2","article-title":"The pathogenic role of angiogenesis in rheumatoid arthritis","volume":"18","author":"Elshabrawy","year":"2015","journal-title":"Angiogenesis"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/art.11143","article-title":"Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis","volume":"48","author":"Nakahara","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000505379","article-title":"Late-stage failures of monoclonal antibody drugs: A retrospective case study analysis","volume":"105","author":"Sun","year":"2020","journal-title":"Pharmacology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/1529-0131(200003)43:3<522::AID-ANR7>3.0.CO;2-Y","article-title":"Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: Results from 394 patients in the Oslo County Rheumatoid Arthritis register","volume":"43","author":"Haugeberg","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3899\/jrheum.180668","article-title":"Comorbidities in patients with rheumatoid arthritis and their association with patient-reported outcomes: Results of claims data linked to questionnaire survey","volume":"46","author":"Redeker","year":"2019","journal-title":"J. Rheumatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1136\/ard.2008.091611","article-title":"Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: Arrest of bone loss","volume":"68","author":"Wijbrandts","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hoff, M., Kvien, T.K., K\u00e4lvesten, J., Elden, A., Kavanaugh, A., and Haugeberg, G. (2011). Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: Subanalysis of the PREMIER study. BMC Musculoskelet. Disord., 12.","DOI":"10.1186\/1471-2474-12-54"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Haugeberg, G., Helgetveit, K.B., F\u00f8rre, \u00d8., Garen, T., Sommerseth, H., and Pr\u00f8ven, A. (2014). Generalized bone loss in early rheumatoid arthritis patients followed for ten years in the biologic treatment era. BMC Musculoskelet. Disord., 15.","DOI":"10.1186\/1471-2474-15-289"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00198-016-3769-2","article-title":"Biologic therapies and bone loss in rheumatoid arthritis","volume":"28","author":"Zerbini","year":"2017","journal-title":"Osteoporos. Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1093\/rheumatology\/ket468","article-title":"The effect of tocilizumab on bone mineral density in patients with methotrexate-resistant active rheumatoid arthritis","volume":"53","author":"Kume","year":"2014","journal-title":"Rheumatology"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Chen, Y.M., Chen, H.H., Huang, W.N., Liao, T.L., Chen, J.P., Chao, W.C., Lin, C.T., Hung, W.T., Hsieh, C.W., and Hsieh, T.Y. (2017). Tocilizumab potentially prevents bone loss in patients with anticitrullinated protein antibody-positive rheumatoid arthritis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188454"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s13075-020-02163-6","article-title":"Sarilumab and adalimumab differential effects on bone remodeling and cardiovascular risk biomarkers, and predictions of treatment outcomes","volume":"22","author":"Gabay","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e001470","DOI":"10.1136\/rmdopen-2020-001470","article-title":"Inflammaging as a link between autoimmunity and cardiovascular disease: The case of rheumatoid arthritis","volume":"7","author":"Pizano","year":"2021","journal-title":"RMD Open"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s10067-017-3657-y","article-title":"The effect of TNF-a antagonists on aortic stiffness and wave reflections: A meta-analysis","volume":"37","author":"Vlachopoulos","year":"2018","journal-title":"Clin. Rheumatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1002\/acr.23875","article-title":"Comparative risk of cardiovascular events with biologic and synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: A Systematic Review and Meta-Analysis","volume":"72","author":"Singh","year":"2020","journal-title":"Arthritis Care Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"637829","DOI":"10.3389\/fimmu.2021.637829","article-title":"Role of IL-23\/IL-17 pathway in rheumatic diseases: An overview","volume":"12","author":"Schinocca","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1365-2567.2011.03522.x","article-title":"Interleukin-23: As a drug target for autoimmune inflammatory diseases","volume":"135","author":"Tang","year":"2012","journal-title":"Immunology"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Bunte, K., and Beikler, T. (2019). Th17 cells and the IL-23\/IL-17 axis in the pathogenesis of periodontitis and immune-mediated inflammatory diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143394"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nm.3895","article-title":"IL-12 and IL-23 cytokines: From discovery to targeted therapies for immune-mediated inflammatory diseases","volume":"21","author":"Teng","year":"2015","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/nri3707","article-title":"The IL-23-IL-17 immune axis: From mechanisms to therapeutic testing","volume":"14","author":"Gaffen","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3389\/fimmu.2019.00353","article-title":"Effector functions of CD4+ T cells at the site of local autoimmune inflammation-lessons from rheumatoid arthritis","volume":"10","author":"Chemin","year":"2019","journal-title":"Front. Immnol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.cyto.2015.02.002","article-title":"The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis","volume":"74","author":"Paulissen","year":"2015","journal-title":"Cytokine"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13075-017-1305-1","article-title":"Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis","volume":"19","author":"Penatti","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrrheum.2015.53","article-title":"The IL-23-IL-17 axis in inflammatory arthritis","volume":"11","author":"Lubberts","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.cyto.2013.07.022","article-title":"IL-17 family: Cytokines, receptors and signaling","volume":"64","author":"Gu","year":"2013","journal-title":"Cytokine"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00774-020-01162-6","article-title":"Osteoclast differentiation by RANKL and OPG signaling pathways","volume":"39","author":"Udagawa","year":"2021","journal-title":"J. Bone Miner. Metab."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/art.23290","article-title":"The abundant synovial expression of the RANK\/RANKL\/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation","volume":"58","author":"Vandooren","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Aureal, M., Machuca-Gayet, I., and Coury, F. (2020). Rheumatoid arthritis in the view of osteoimmunology. Biomolecules, 11.","DOI":"10.3390\/biom11010048"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/1529-0131(200002)43:2<259::AID-ANR4>3.0.CO;2-W","article-title":"Involvement of receptor activator of nuclear factor kappaB ligand\/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis","volume":"43","author":"Takayanagi","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1093\/rheumatology\/ken363","article-title":"IL-6 trans-signaling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17","volume":"47","author":"Hashizume","year":"2008","journal-title":"Rheumatology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.molimm.2017.09.003","article-title":"Interleukin 17 regulates SHP-2 and IL-17RA\/STAT-3 dependent Cyr61, IL-23 and GM-CSF expression and RANKL mediated osteoclastogenesis by fibroblast-like synoviocytes in rheumatoid arthritis","volume":"91","author":"Ganesan","year":"2017","journal-title":"Mol. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.bbrc.2018.02.164","article-title":"IL-17A regulates the autophagy activity of osteoclast precursors through RANKL-JNK1signaling during osteoclastogenesis in vitro","volume":"497","author":"Ke","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1002\/art.39837","article-title":"RANK-independent osteoclast formation and bone erosion in inflammatory arthritis","volume":"68","author":"Fissel","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.3389\/fimmu.2018.02263","article-title":"Bone remodeling and the role of TRAF3 in osteoclastic bone resorption","volume":"9","author":"Boyce","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/art.38218","article-title":"Combination of tumor necrosis factor alpha and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo","volume":"66","author":"Yokota","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/art.41666","article-title":"Characterization and function of tumor necrosis factor and interleukin-6-induced osteoclasts in rheumatoid arthritis","volume":"73","author":"Yokota","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s12016-018-8702-3","article-title":"The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis","volume":"55","author":"Blauvelt","year":"2018","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/art.27334","article-title":"LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study","volume":"62","author":"Genovese","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1136\/annrheumdis-2012-201601","article-title":"Efficacy and safety of secukinumab in patients with rheumatoid arthritis: A phase II, dose-finding, double-blind, randomised, placebo controlled study","volume":"72","author":"Genovese","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"414421","DOI":"10.3899\/jrheum.130637","article-title":"One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: Phase II, dose-finding, doubleblind, randomized, placebo-controlled study","volume":"41","author":"Genovese","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"R164","DOI":"10.1186\/ar4347","article-title":"A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis","volume":"15","author":"Martin","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1002\/art.38617","article-title":"A Phase II randomized study of subcutaneous ixekizumab, an anti\u2013interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis fac-tor inhibitors","volume":"66","author":"Genovese","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1007\/s00296-016-3480-9","article-title":"Anti-IL-17 therapy in treatment of rheumatoid arthritis: A systematic literature review and meta-analysis of randomized controlled trials","volume":"36","author":"Kunwar","year":"2016","journal-title":"Rheumatol. Int."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1007\/s10067-019-04608-z","article-title":"Meta-analysis of IL-17 inhibitors in two populations of rheumatoid arthritis patients: Biologic-na\u00efve or tumor necrosis factor inhibitors inadequate responders","volume":"38","author":"Wu","year":"2019","journal-title":"Clin. Rheumatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1007\/s10067-019-04595-1","article-title":"Efficacy and safety of secukinumab in active rheumaqtoid arthritis with an inadequate response to tumor necrosis factor inhibitors: A meta-analysis of Phase III randomized controlled trials","volume":"38","author":"Huang","year":"2019","journal-title":"Clin. Rheumatol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1136\/annrheumdis-2018-214943","article-title":"Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: A proof-of-concept study","volume":"78","author":"Glatt","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Yago, T., Nanke, Y., Kawamoto, M., Kobashigawa, T., Yamanaka, H., and Kotake, S. (2017). IL-23 and Th17 disease in inflamma-tory arthritis. J. Clin. Med., 6.","DOI":"10.3390\/jcm6090081"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1136\/annrheumdis-2016-209831","article-title":"A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate","volume":"76","author":"Smolen","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.2174\/138161212800165979","article-title":"Interleukin-7: A key mediator in T-cell driven autoimmunity, inflammation, and tissue destruction","volume":"18","author":"Bikker","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_119","first-page":"115","article-title":"Serum IL-7 as diagnostic biomarker for rheumatoid arthritis, validation with EULAR 2010 classification criteria","volume":"36","author":"Burska","year":"2018","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/cmi.2010.22","article-title":"The cytokine milieu in the interplay of pathogenic Th1\/Th17 cells and regulatory T cells in autoimmune disease","volume":"7","author":"Leung","year":"2010","journal-title":"Cell. Mol. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaut.2019.01.013","article-title":"Clinical significance and immunobiology of IL-21 in autoimmunity","volume":"99","author":"Long","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.1002\/jcp.26158","article-title":"Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future perspectives","volume":"233","author":"Dinesh","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/jcph.158","article-title":"Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: A phase I, first-in-human study","volume":"54","author":"Hua","year":"2014","journal-title":"J. Clin. Pharmacol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"243","DOI":"10.5414\/CP202474","article-title":"Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal an-tibody in a first-in-human trial","volume":"54","author":"Ignatenko","year":"2016","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/bcp.13748","article-title":"Anti-IL-7 receptor \u03b1 monoclonal antibody (GSK2618960) in healthy subjects\u2014A randomized, double-blind, placebo-controlled study","volume":"85","author":"Ellis","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/art.21528","article-title":"Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis","volume":"54","author":"Catrina","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1136\/ard.2005.044198","article-title":"Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis","volume":"65","author":"Vis","year":"2006","journal-title":"Ann. Rheum. Dis"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3109\/s10165-004-0373-7","article-title":"Infliximab acts directly on human osteoclast precursors and enhances osteoclast formation induced by receptor activator of nuclear factor kappaB ligand in vitro","volume":"15","author":"Takita","year":"2005","journal-title":"Mod. Rheumatol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/164_2019_346","article-title":"Cytokines and bone: Osteoimmunology","volume":"262","author":"Lorenzo","year":"2020","journal-title":"Bone Regul. Osteoporos. Ther."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.4049\/jimmunol.169.6.3353","article-title":"IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulates the expression of receptor activator of NF-kB ligand, osteoprotegerin, and receptor activator of NF-kB in mouse calvariae","volume":"169","author":"Palmqvist","year":"2002","journal-title":"J. Immunol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1136\/annrheumdis-2018-214894","article-title":"Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis","volume":"78","author":"Finzel","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.yexmp.2008.03.003","article-title":"Early effects of tocilizumab on bone and bone marrow lesions in a collagen-induced arthritis monkey model","volume":"84","author":"Kato","year":"2008","journal-title":"Exp. Mol. Pathol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13075-018-1527-x","article-title":"Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner","volume":"20","author":"Bozec","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"234","DOI":"10.3899\/jrheum.091066","article-title":"Abatacept for rheumatoid arthritis: A Cochrane systematic review","volume":"37","author":"Maxwell","year":"2010","journal-title":"J. Rheumatol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1136\/ard.2007.080713","article-title":"CTLA-4 directly inhibits osteoclast formation","volume":"67","author":"Axmann","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"235ra60","DOI":"10.1126\/scitranslmed.3007764","article-title":"T cell costimulation molecules CD80\/86 inhibit osteoclast differentiation by inducing the IDO\/tryptophan pathway","volume":"6","author":"Bozec","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1002\/jbmr.3754","article-title":"CTLA4-Ig directly inhibits osteoclastogenesis by interfering with intracellular calcium oscillations in bone marrow macrophages","volume":"34","author":"Okada","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/s12276-020-0445-6","article-title":"The JAK1\/STAT3\/SOCS3 axis in bone development, physiology, and pathology","volume":"52","author":"Sims","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1002\/pro.3519","article-title":"The molecular details of cytokine signaling via the JAK\/STAT pathway","volume":"27","author":"Morris","year":"2018","journal-title":"Protein Sci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1038\/leu.2012.17","article-title":"Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanism of action on bone marrow HSC niches and bone formation","volume":"26","author":"Winkler","year":"2012","journal-title":"Leukemia"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1002\/art.34649","article-title":"JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production","volume":"64","author":"LeBranche","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1093\/rheumatology\/kex258","article-title":"Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model","volume":"57","author":"Vidal","year":"2018","journal-title":"Rheumatology"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.intimp.2018.03.021","article-title":"Stattic inhibits RANKL-mediated osteoclastogenesis by suppressing activation of STAT3 and NF-\u03baB pathways","volume":"58","author":"Li","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Murakami, K., Kobayashi, Y., Uehara, S., Suzuki, T., Koide, M., Yamashita, T., Nakamura, M., Takahashi, N., Kato, H., and Udagawa, N. (2017). A Jak1\/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181126"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"584116","DOI":"10.3389\/fimmu.2020.584116","article-title":"Rheumatoid arthritis synovial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species, and neutrophil extracellular traps","volume":"11","author":"Wright","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1182\/blood-2004-09-3662","article-title":"A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation","volume":"106","author":"Lee","year":"2005","journal-title":"Blood"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s00774-015-0656-4","article-title":"Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases","volume":"33","author":"Callaway","year":"2015","journal-title":"J. Bone Miner. Metab."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3904\/kjim.2016.329","article-title":"N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL in rheumatoid arthritis","volume":"34","author":"Kim","year":"2019","journal-title":"Korean J. Intern. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13018-020-01595-9","article-title":"The JNK pathway represents a novel target in the treatment of rheumatoid arthritis through the suppression of MMP-3","volume":"15","author":"Kanai","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.1002\/eji.1830211039","article-title":"Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: Regulation by tumor necrosis factor-alpha","volume":"21","author":"Haworth","year":"1991","journal-title":"Eur. J. Immunol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1084\/jem.170.3.865","article-title":"Cytokines in chronic inflammatory arthritis. IV. Granulocyte\/macrophage colony-stimulating factor-mediated induction of class II MHC antigen on human monocytes: A possible role in rheumatoid arthritis","volume":"170","author":"Zvaifler","year":"1989","journal-title":"J. Exp. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s100670200006","article-title":"Interleukin-2 levels are elevated in the bone marrow serum of patients with mutilans-type rheumatoid arthritis","volume":"21","author":"Kuroda","year":"2002","journal-title":"Clin. Rheumatol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/ni.3489","article-title":"Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis","volume":"17","author":"Klose","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.immuni.2018.04.009","article-title":"Autoimmune Th17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis","volume":"48","author":"Tanaka","year":"2018","journal-title":"Immunity"},{"key":"ref_155","first-page":"39","article-title":"Targeting GM-CSF in rheumatoid arthritis","volume":"34","author":"Avci","year":"2016","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/art.1780390116","article-title":"Synovial tissue macrophage populations and articular damage in rheumatoid arthritis","volume":"39","author":"Mulherin","year":"1996","journal-title":"Arthritis Rheum."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1182\/blood-2008-12-164004","article-title":"The granulocyte-macrophage colony-stimulating factor receptor: Linking its structure to cell signaling and its role in disease","volume":"114","author":"Hercus","year":"2009","journal-title":"Blood"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"4181","DOI":"10.1002\/j.1460-2075.1993.tb06102.x","article-title":"Signal transduction by the high-affinity GM-CSF receptor: Two distinct cytoplasmic regions of the common beta subunit responsible for different signaling","volume":"12","author":"Sato","year":"1993","journal-title":"EMBO J."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1136\/ard.2010.146225","article-title":"Mavrilimumab, a human monoclonal anti-body targeting GM-CSF receptor-\u03b1, in subjects with rheumatoid arthritis: A randomised, double-blind, placebo-controlled, phase I, first-in-human study","volume":"70","author":"Burmester","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1136\/annrheumdis-2012-202450","article-title":"Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis","volume":"72","author":"Burmester","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1136\/annrheumdis-2019-215164","article-title":"Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan","volume":"78","author":"Takuchi","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1136\/annrheumdis-2014-206478","article-title":"Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate","volume":"74","author":"Keystone","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/s41584-019-0277-8","article-title":"The IL-1 family of cytokines and receptors in rheumatic diseases","volume":"15","author":"Dinarello","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.it.2011.01.003","article-title":"Inflammasome activation and IL-1v and IL-18 processing during infection","volume":"32","author":"Veerdonk","year":"2011","journal-title":"Trends Immunol"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.cytogfr.2011.10.001","article-title":"Understanding the mechanism of IL-1\u03b2 secretion","volume":"22","author":"Brough","year":"2011","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"7727","DOI":"10.1074\/jbc.272.12.7727","article-title":"The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP Kinases)","volume":"272","author":"Wesche","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.4049\/jimmunol.154.3.1432","article-title":"Balance of IL-1 receptor antagonist\/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10","volume":"154","author":"Chomarat","year":"1995","journal-title":"J. Immunol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"iii2","DOI":"10.1093\/rheumatology\/keh201","article-title":"The role of interleukin-1 in the pathogenesis of rheumatoid arthritis","volume":"43","author":"Kay","year":"2004","journal-title":"Rheumatology"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1056\/NEJMoa2027892","article-title":"A phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis","volume":"384","author":"Klein","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1136\/annrheumdis-2020-217419","article-title":"Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: Results from the randomised phase III CLUSTER trial","volume":"79","author":"Ozen","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/art.10870","article-title":"Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multi-center, placebo-controlled trial","volume":"48","author":"Fleischmann","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1002\/art.20115","article-title":"Lack of response to anakinra in rheumatoid ar-thritis following failure of tumor necrosis factor blockade","volume":"50","author":"Buch","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"25737","DOI":"10.1074\/jbc.272.41.25737","article-title":"Purification and characterization of the human in-terleukin-18 receptor","volume":"72","author":"Torigoe","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/art.10814","article-title":"Association of interleukin-18 expression with enhanced levels of both interleukin-1beta and tumor necrosis factor alpha in knee synovial tissue of patients with rheumatoid arthritis","volume":"48","author":"Joosten","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1136\/ard.2003.018481","article-title":"Interleukin (IL) 18 stimulates osteoclast formation through synovial T cells in rheumatoid arthritis: Comparison with IL1\u03b2 and tumour necrosis factor \u03b1","volume":"63","author":"Dai","year":"2004","journal-title":"Ann. Rheum. Dis."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/s41598-017-00532-x","article-title":"Identification of small molecule inhibitors of Interleukin-18","volume":"7","author":"Krumm","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/BF03191127","article-title":"Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis","volume":"31","author":"Tak","year":"2006","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1158\/1078-0432.CCR-06-0121","article-title":"Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer","volume":"12","author":"Robertson","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s12079-019-00544-4","article-title":"A comprehensive pathway map of IL-18-mediated signaling","volume":"14","author":"Rex","year":"2020","journal-title":"J. Cell Commun. Signal."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Nozaki, Y., Ri, J., Sakai, K., Niki, K., and Kinoshita, K. (2019). Inhibition of the IL-18 receptor signaling pathway ameliorates disease in a murine model of rheumatoid arthritis. Cells, 9.","DOI":"10.3390\/cells9010011"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.immuni.2008.03.002","article-title":"Cytokine signaling modules in inflammatory responses","volume":"28","author":"Murray","year":"2008","journal-title":"Immunity"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"5668","DOI":"10.1073\/pnas.96.10.5668","article-title":"Defining therapeutic targets by using adenovirus: Blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators","volume":"96","author":"Bondeson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.09.015","article-title":"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and in-duces T helper type 2-associated cytokines","volume":"23","author":"Schmitz","year":"2005","journal-title":"Immunity"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3389\/fimmu.2017.00475","article-title":"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines","volume":"24","author":"Griesenauer","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1002\/art.24305","article-title":"Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis","volume":"60","author":"Palmer","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jbspin.2011.02.011","article-title":"Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis","volume":"79","author":"McKee","year":"2012","journal-title":"Joint Bone Spine"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.3346\/jkms.2011.26.9.1132","article-title":"Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis","volume":"26","author":"Hong","year":"2011","journal-title":"J. Korean Med. Sci."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"985301","DOI":"10.1155\/2013\/985301","article-title":"Increased IL-33 in synovial fluid and paired serum is associated with disease activity and autoantibodies in rheumatoid arthritis","volume":"2013","author":"Tang","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.cyto.2011.12.010","article-title":"Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis","volume":"58","author":"Xiangyang","year":"2012","journal-title":"Cytokine"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"4297354","DOI":"10.1155\/2020\/4297354","article-title":"Blocking interleukin-33 alleviates the joint inflammation and inhibits the development of collagen-induced arthritis in mice","volume":"2020","author":"Li","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s12079-018-0464-4","article-title":"A network map of IL-33 signaling pathway","volume":"12","author":"Pinto","year":"2018","journal-title":"J. Cell Commun. Signal."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.immuni.2015.01.016","article-title":"The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway","volume":"42","author":"Endo","year":"2015","journal-title":"Immunity"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1006\/cimm.2001.1821","article-title":"Interleukin-2 promotes antigenic reactivity of rested T cells but prolongs the postactivational refractory phase of activated T cells","volume":"211","author":"Norris","year":"2001","journal-title":"Cell Immunol."},{"key":"ref_194","first-page":"239","article-title":"Serum IL-2 level in rheumatoid arthritis: Correlation with joint destruction and disease progression","volume":"2","author":"Tebib","year":"1991","journal-title":"Eur. Cytokine Netw."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"6108342","DOI":"10.1155\/2020\/6108342","article-title":"Increased serum Interleukin-2 levels are associated with abnormal peripheral blood natural killer cell levels in patients with active rheumatoid arthritis","volume":"2020","author":"Li","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0896-8411(88)90005-4","article-title":"Serum interleukin-2-receptor in rheumatoid arthritis: A prognostic indicator of disease activity?","volume":"1","author":"Wood","year":"1988","journal-title":"J. Autoimmun."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1084\/jem.168.5.1573","article-title":"Cytokines in chronic inflammatory arthritis","volume":"168","author":"Firestein","year":"1988","journal-title":"J. Exp. Med."},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Makuch, S., Wi\u0119cek, K., and Wo\u017aniak, M. (2021). The immunomodulatory and anti-inflammatory effect of curcumin on immune cell populations, cytokines, and in vivo models of rheumatoid arthritis. Pharmaceuticals, 4.","DOI":"10.3390\/ph14040309"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1136\/annrheumdis-2018-214229","article-title":"Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial","volume":"78","author":"Rosenzwajg","year":"2019","journal-title":"Ann Rheum. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/10922\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:11:13Z","timestamp":1760166673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/10922"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,10]]},"references-count":199,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222010922"],"URL":"https:\/\/doi.org\/10.3390\/ijms222010922","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,10]]}}}