{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T12:05:52Z","timestamp":1793880352040,"version":"4.7.0"},"reference-count":99,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2019M661312"],"award-info":[{"award-number":["2019M661312"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["YQ2019H005"],"award-info":[{"award-number":["YQ2019H005"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013254","name":"National College Students Innovation and Entrepreneurship Training Program","doi-asserted-by":"publisher","award":["202010226204"],"award-info":[{"award-number":["202010226204"]}],"id":[{"id":"10.13039\/501100013254","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013254","name":"National College Students Innovation and Entrepreneurship Training Program","doi-asserted-by":"publisher","award":["202010226206"],"award-info":[{"award-number":["202010226206"]}],"id":[{"id":"10.13039\/501100013254","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81903763"],"award-info":[{"award-number":["81903763"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Clinical Immunology"],"published-print":{"date-parts":[[2021,9]]},"DOI":"10.1016\/j.clim.2021.108793","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T11:29:14Z","timestamp":1625570954000},"page":"108793","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":198,"special_numbering":"C","title":["Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis"],"prefix":"10.1016","volume":"230","author":[{"given":"Shuang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjie","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"6","key":"10.1016\/j.clim.2021.108793_bb0005","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1056\/NEJMoa1109071","article-title":"ORAL solo investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis","volume":"367","author":"Fleischmann","year":"2012","journal-title":"N. Engl. J. Med."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0010","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/ar4593","article-title":"The disease formerly known as rheumatoid arthritis","volume":"16","author":"Firestein","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"10.1016\/j.clim.2021.108793_bb0015","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.biopha.2017.02.099","article-title":"Anti-arthritic effect of berberine on adjuvant-induced rheumatoid arthritis in rats","volume":"89","author":"Wang","year":"2017","journal-title":"Biomed. Pharmacother."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0020","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1097\/BOR.0000000000000470","article-title":"What are the dominant cytokines in early rheumatoid arthritis?","volume":"30","author":"Ridgley","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0025","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s00281-017-0633-1","article-title":"Cellular and molecular perspectives in rheumatoid arthritis","volume":"39","author":"Veale","year":"2017","journal-title":"Semin. Immunopathol."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0030","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1128\/MMBR.00031-10","article-title":"Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases","volume":"75","author":"Cargnello","year":"2011","journal-title":"Microbiol. Mol. Biol. Rev."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0035","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1152\/physrev.00028.2011","article-title":"Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update","volume":"92","author":"Kyriakis","year":"2012","journal-title":"Physiol. Rev."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0040","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1124\/mol.113.090365","article-title":"Mitogen-activated protein kinase-activated protein kinase 2 in neuroinflammation, heat shock protein 27 phosphorylation, and cell cycle: role and targeting","volume":"85","author":"Gurgis","year":"2014","journal-title":"Mol. Pharmacol."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0045","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.smim.2014.02.009","article-title":"TNF and MAP kinase signalling pathways","volume":"26","author":"Sabio","year":"2014","journal-title":"Semin. Immunol."},{"key":"10.1016\/j.clim.2021.108793_bb0050","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fcell.2015.00088","article-title":"MAPK-activated protein kinases (MKs): novel insights and challenges","volume":"3","author":"Gaestel","year":"2016","journal-title":"Front. Cell Dev. Biol."},{"key":"10.1016\/j.clim.2021.108793_bb0055","doi-asserted-by":"crossref","first-page":"330","DOI":"10.3389\/fendo.2019.00330","article-title":"The MAPK pathway-based drug therapeutic targets in pituitary adenomas","volume":"10","author":"Lu","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"10.1016\/j.clim.2021.108793_bb0060","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.cca.2017.08.021","article-title":"MicroRNAs and bioactive compounds on TLR\/MAPK signaling in rheumatoid arthritis","volume":"473","author":"Sujitha","year":"2017","journal-title":"Clin. Chim. Acta"},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0065","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.apsb.2018.01.008","article-title":"Targeting ERK, an Achilles\u2019 heel of the MAPK pathway, in cancer therapy","volume":"8","author":"Liu","year":"2018","journal-title":"Acta Pharm. Sin. B"},{"issue":"11","key":"10.1016\/j.clim.2021.108793_bb0070","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nrm1498","article-title":"The RAF proteins take Centre stage","volume":"5","author":"Wellbrock","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"10","key":"10.1016\/j.clim.2021.108793_bb0075","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrc4000","article-title":"MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road","volume":"15","author":"Caunt","year":"2015","journal-title":"Nat. Rev. Cancer"},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0080","doi-asserted-by":"crossref","first-page":"a033746","DOI":"10.1101\/cshperspect.a033746","article-title":"Ras-mediated activation of the Raf family kinases","volume":"9","author":"Terrell","year":"2019","journal-title":"Cold Spring Harb. Perspect Med."},{"issue":"15","key":"10.1016\/j.clim.2021.108793_bb0085","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.4155\/fmc.15.132","article-title":"JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases","volume":"7","author":"Kumar","year":"2015","journal-title":"Future Med. Chem."},{"key":"10.1016\/j.clim.2021.108793_bb0090","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3389\/fphys.2017.00829","article-title":"The JNK signaling pathway in renal fibrosis","volume":"8","author":"Grynberg","year":"2017","journal-title":"Front. Physiol."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0095","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1128\/MMBR.00043-14","article-title":"JNK signaling: regulation and functions based on complex protein-protein partnerships","volume":"80","author":"Zeke","year":"2016","journal-title":"Microbiol. Mol. Biol. Rev."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0100","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1074\/jbc.M111.281915","article-title":"Distinct signaling properties of mitogen-activated protein kinase kinases 4 (MKK4) and 7 (MKK7) in embryonic stem cell (ESC) differentiation","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.clim.2021.108793_bb0105","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3389\/fcell.2016.00067","article-title":"Redundancy in the world of MAP kinases: all for one","volume":"4","author":"Saba-El-Leil","year":"2016","journal-title":"Front. Cell Dev. Biol."},{"key":"10.1016\/j.clim.2021.108793_bb0110","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.canlet.2016.10.008","article-title":"Targeting p38 MAP kinase signaling in cancer through post-translational modifications","volume":"384","author":"Zou","year":"2017","journal-title":"Cancer Lett."},{"issue":"33","key":"10.1016\/j.clim.2021.108793_bb0115","doi-asserted-by":"crossref","first-page":"55684","DOI":"10.18632\/oncotarget.18264","article-title":"The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells","volume":"8","author":"Corre","year":"2017","journal-title":"Oncotarget"},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0120","first-page":"27","article-title":"Cardiac fibroblast p38 MAPK: a critical regulator of myocardial remodeling","volume":"6","author":"Turner","year":"2019","journal-title":"J. Cardiovasc. Dev. Dis."},{"key":"10.1016\/j.clim.2021.108793_bb0125","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.3389\/fimmu.2020.01630","article-title":"Circadian control of inflammasome pathways: implications for circadian medicine","volume":"11","author":"Pourcet","year":"2020","journal-title":"Front. Immunol."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0130","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.immuni.2019.03.021","article-title":"The IL-17 family of cytokines in health and disease","volume":"50","author":"McGeachy","year":"2019","journal-title":"Immunity."},{"issue":"15","key":"10.1016\/j.clim.2021.108793_bb0135","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.3390\/ijms20153792","article-title":"Extracellular signal-regulated kinase: a regulator of cell growth, inflammation, chondrocyte and bone cell receptor-mediated gene expression","volume":"20","author":"Lu","year":"2019","journal-title":"Int. J. Mol. Sci."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0140","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00296-009-0976-6","article-title":"Epidermal growth factor increases prostaglandin E2 production via ERK1\/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis","volume":"30","author":"Nah","year":"2010","journal-title":"Rheumatol. Int."},{"key":"10.1016\/j.clim.2021.108793_bb0145","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.intimp.2017.07.019","article-title":"Is macrophage polarization important in rheumatoid arthritis?","volume":"50","author":"Wang","year":"2017","journal-title":"Int. Immunopharmacol."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0150","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."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0155","first-page":"735","article-title":"Brucine inhibits TNF-\u03b1-induced HFLS-RA cell proliferation by activating the JNK signaling pathway","volume":"18","author":"Tang","year":"2019","journal-title":"Exp. Ther. Med."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0160","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.jaci.2019.06.019","article-title":"Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis","volume":"144","author":"Sakurai","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"issue":"6","key":"10.1016\/j.clim.2021.108793_bb0165","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.3390\/ijms20061346","article-title":"Roles of cyclic AMP response element binding activation in the ERK1\/2 and p38 MAPK Signalling pathway in central nervous system, cardiovascular system, osteoclast differentiation and Mucin and cytokine production","volume":"20","author":"Koga","year":"2019","journal-title":"Int. J. Mol. Sci."},{"issue":"5","key":"10.1016\/j.clim.2021.108793_bb0170","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/art.24485","article-title":"Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies","volume":"60","author":"Damjanov","year":"2009","journal-title":"Arthritis Rheum."},{"issue":"5","key":"10.1016\/j.clim.2021.108793_bb0175","doi-asserted-by":"crossref","first-page":"846","DOI":"10.3899\/jrheum.100602","article-title":"A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis","volume":"38","author":"Genovese","year":"2011","journal-title":"J. Rheumatol."},{"key":"10.1016\/j.clim.2021.108793_bb0180","article-title":"Inhibition against p38\/MEF2C pathway by Pamapimod protects osteoarthritis chondrocytes hypertrophy","author":"Zhang","year":"2020","journal-title":"Panminerva Med."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0185","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/art.24266","article-title":"Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis","volume":"60","author":"Cohen","year":"2009","journal-title":"Arthritis Rheum."},{"issue":"5","key":"10.1016\/j.clim.2021.108793_bb0190","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nrd.2018.21","article-title":"Kinase inhibitors: the road ahead","volume":"17","author":"Ferguson","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"issue":"14","key":"10.1016\/j.clim.2021.108793_bb0195","doi-asserted-by":"crossref","first-page":"4596","DOI":"10.1021\/jm0310986","article-title":"Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase","volume":"48","author":"Gaillard","year":"2005","journal-title":"J. Med. Chem."},{"issue":"Pt A","key":"10.1016\/j.clim.2021.108793_bb0200","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.arr.2015.01.003","article-title":"DAMPs as mediators of sterile inflammation in aging-related pathologies","volume":"24","author":"Feldman","year":"2015","journal-title":"Ageing Res. Rev."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0205","doi-asserted-by":"crossref","first-page":"a006049","DOI":"10.1101\/cshperspect.a006049","article-title":"Signaling in innate immunity and inflammation","volume":"4","author":"Newton","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0210","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2008.01.020","article-title":"Shared principles in NF-kappaB signaling","volume":"132","author":"Hayden","year":"2008","journal-title":"Cell."},{"issue":"23","key":"10.1016\/j.clim.2021.108793_bb0215","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000010920","article-title":"Inhibition of NF-\u03baB signaling pathway induces apoptosis and suppresses proliferation and angiogenesis of human fibroblast-like synovial cells in rheumatoid arthritis","volume":"97","author":"Xia","year":"2018","journal-title":"Medicine (Baltimore)"},{"issue":"9","key":"10.1016\/j.clim.2021.108793_bb0220","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri.2017.52","article-title":"The non-canonical NF-\u03baB pathway in immunity and inflammation","volume":"17","author":"Sun","year":"2017","journal-title":"Nat. Rev. Immunol."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0225","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13075-015-0527-3","article-title":"Non-canonical NF-\u03baB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?","volume":"17","author":"Noort","year":"2015","journal-title":"Arthritis Res. Ther."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0230","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/rheumatology\/kew393","article-title":"Targeting non-canonical nuclear factor-\u03baB signalling attenuates neovascularization in a novel 3D model of rheumatoid arthritis synovial angiogenesis","volume":"56","author":"Maracle","year":"2017","journal-title":"Rheumatology (Oxford)"},{"issue":"24","key":"10.1016\/j.clim.2021.108793_bb0235","doi-asserted-by":"crossref","first-page":"6275","DOI":"10.3390\/ijms20246275","article-title":"NF-\u03baB signaling regulates physiological and pathological Chondrogenesis","volume":"20","author":"Jimi","year":"2019","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0240","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12016-015-8515-6","article-title":"Bone as a target organ in rheumatic disease: impact on osteoclasts and osteoblasts","volume":"51","author":"Baum","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0245","doi-asserted-by":"crossref","first-page":"a003350","DOI":"10.1101\/cshperspect.a003350","article-title":"Signaling to NF-kappaB: regulation by ubiquitination","volume":"2","author":"Wertz","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0250","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/cr.2010.159","article-title":"Role of NF-\u03baB in the skeleton","volume":"21","author":"Novack","year":"2011","journal-title":"Cell Res."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0255","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/art.38303","article-title":"Regulation of apoptosis and inflammatory responses by insulin-like growth factor binding protein 3 in fibroblast-like synoviocytes and experimental animal models of rheumatoid arthritis","volume":"66","author":"Lee","year":"2014","journal-title":"Arthritis Rheum."},{"issue":"11","key":"10.1016\/j.clim.2021.108793_bb0260","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1007\/s12272-014-0345-1","article-title":"Anti-inflammatory effects of methyl ursolate obtained from a chemically derived crude extract of apple peels: potential use in rheumatoid arthritis","volume":"37","author":"P\u00e1dua","year":"2014","journal-title":"Arch. Pharm. Res."},{"issue":"5","key":"10.1016\/j.clim.2021.108793_bb0265","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1007\/s10787-020-00741-3","article-title":"The advances of methotrexate resistance in rheumatoid arthritis","volume":"28","author":"Yu","year":"2020","journal-title":"Inflammopharmacology."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0270","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.rdc.2015.08.006","article-title":"Glucocorticoids and rheumatoid arthritis","volume":"42","author":"Ferreira","year":"2016","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"10.1016\/j.clim.2021.108793_bb0275","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3389\/fphar.2020.00073","article-title":"Iguratimod as a new drug for rheumatoid arthritis: current landscape","volume":"11","author":"Xie","year":"2020","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.clim.2021.108793_bb0280","doi-asserted-by":"crossref","first-page":"109704","DOI":"10.1016\/j.biopha.2019.109704","article-title":"Molecular mechanisms and clinical application of Iguratimod: a review","volume":"122","author":"Jiang","year":"2020","journal-title":"Biomed. Pharmacother."},{"issue":"8","key":"10.1016\/j.clim.2021.108793_bb0285","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1002\/acr.23133","article-title":"Repair of bone Erosion in rheumatoid arthritis by Denosumab: a high-resolution peripheral quantitative computed tomography study","volume":"69","author":"Yue","year":"2017","journal-title":"Arthritis Care Res."},{"issue":"7","key":"10.1016\/j.clim.2021.108793_bb0290","doi-asserted-by":"crossref","first-page":"530","DOI":"10.18632\/oncotarget.188","article-title":"Targeting the PI3K\/Akt\/mTOR pathway--beyond rapalogs","volume":"1","author":"Markman","year":"2010","journal-title":"Oncotarget"},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0295","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.joca.2020.02.027","article-title":"The PI3K\/AKT\/mTOR signaling pathway in osteoarthritis: a narrative review","volume":"28","author":"Sun","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"10.1016\/j.clim.2021.108793_bb0300","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.vph.2015.05.008","article-title":"The critical role of Akt in cardiovascular function","volume":"74","author":"Abeyrathna","year":"2015","journal-title":"Vasc. Pharmacol."},{"issue":"7","key":"10.1016\/j.clim.2021.108793_bb0305","doi-asserted-by":"crossref","first-page":"530","DOI":"10.18632\/oncotarget.188","article-title":"Targeting the PI3K\/Akt\/mTOR pathway--beyond rapalogs","volume":"1","author":"Markman","year":"2010","journal-title":"Oncotarget"},{"key":"10.1016\/j.clim.2021.108793_bb0310","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3389\/fendo.2018.00338","article-title":"PTEN: tumor suppressor and metabolic regulator","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"10.1016\/j.clim.2021.108793_bb0315","first-page":"335","article-title":"Targeting the PI3K\/AKT\/mTOR pathway in bladder Cancer","volume":"2018","author":"Sathe","year":"1655","journal-title":"Methods Mol. Biol."},{"issue":"45","key":"10.1016\/j.clim.2021.108793_bb0320","doi-asserted-by":"crossref","first-page":"74217","DOI":"10.18632\/oncotarget.12487","article-title":"MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K-AKT signal pathway","volume":"7","author":"Qu","year":"2016","journal-title":"Oncotarget"},{"issue":"12","key":"10.1016\/j.clim.2021.108793_bb0325","doi-asserted-by":"crossref","first-page":"4288","DOI":"10.1096\/fj.09-135160","article-title":"PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis","volume":"23","author":"Hayer","year":"2009","journal-title":"FASEB J."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0330","doi-asserted-by":"crossref","first-page":"172","DOI":"10.4062\/biomolther.2019.153","article-title":"PBT-6, a novel PI3KC2\u03b3 inhibitor in rheumatoid arthritis","volume":"28","author":"Kim","year":"2020","journal-title":"Biomol. Ther. (Seoul)."},{"issue":"3","key":"10.1016\/j.clim.2021.108793_bb0335","doi-asserted-by":"crossref","first-page":"R92","DOI":"10.1186\/ar3019","article-title":"Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice","volume":"12","author":"Toyama","year":"2010","journal-title":"Arthritis Res. Ther."},{"issue":"19","key":"10.1016\/j.clim.2021.108793_bb0340","doi-asserted-by":"crossref","first-page":"9228","DOI":"10.1021\/acs.jmedchem.6b01169","article-title":"Discovery of orally efficacious Phosphoinositide 3-kinase \u03b4 inhibitors with improved metabolic stability","volume":"59","author":"Patel","year":"2016","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.clim.2021.108793_bb0345","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1146\/annurev-med-051113-024537","article-title":"The JAK-STAT pathway: impact on human disease and therapeutic intervention","volume":"66","author":"O\u2019Shea","year":"2015","journal-title":"Annu. Rev. Med."},{"issue":"16","key":"10.1016\/j.clim.2021.108793_bb0350","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1080\/14656566.2016.1241237","article-title":"Chemical JAK inhibitors for the treatment of rheumatoid arthritis","volume":"17","author":"Nakayamada","year":"2016","journal-title":"Expert. Opin. Pharmacother."},{"issue":"3\u20134","key":"10.1016\/j.clim.2021.108793_bb0355","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1080\/08977194.2018.1518324","article-title":"Understanding SOCS protein specificity","volume":"36","author":"Linossi","year":"2018","journal-title":"Growth Factors"},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0360","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/ni.3691","article-title":"Mechanisms and consequences of Jak-STAT signaling in the immune system","volume":"18","author":"Villarino","year":"2017","journal-title":"Nat. Immunol."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0365","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jphs.2016.12.001","article-title":"A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model","volume":"133","author":"Ito","year":"2017","journal-title":"J. Pharmacol. Sci."},{"issue":"18","key":"10.1016\/j.clim.2021.108793_bb0370","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.2174\/1389557519666190617152011","article-title":"Current status in the discovery of covalent Janus kinase 3 (JAK3) inhibitors","volume":"19","author":"Dai","year":"2019","journal-title":"Mini-Rev. Med. Chem."},{"issue":"5","key":"10.1016\/j.clim.2021.108793_bb0375","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1080\/19382014.2019.1650580","article-title":"JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys","volume":"11","author":"Kim","year":"2019","journal-title":"Islets."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0380","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.immuni.2019.03.011","article-title":"The immunobiology of the Interleukin-12 family: room for discovery","volume":"50","author":"Tait Wojno","year":"2019","journal-title":"Immunity."},{"key":"10.1016\/j.clim.2021.108793_bb0385","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.3389\/fimmu.2018.03047","article-title":"IRF and STAT transcription factors - from basic biology to roles in infection, protective immunity, and primary immunodeficiencies","volume":"9","author":"Mogensen","year":"2019","journal-title":"Front. Immunol."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0390","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.immuni.2012.03.013","article-title":"The JAK-STAT pathway at twenty","volume":"36","author":"Stark","year":"2012","journal-title":"Immunity."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0395","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/imr.12705","article-title":"JAK\/STAT signaling in regulation of innate lymphoid cells: the gods before the guardians","volume":"286","author":"Stabile","year":"2018","journal-title":"Immunol. Rev."},{"key":"10.1016\/j.clim.2021.108793_bb0400","doi-asserted-by":"crossref","first-page":"106210","DOI":"10.1016\/j.intimp.2020.106210","article-title":"The role of JAK\/STAT signaling pathway and its inhibitors in diseases","volume":"80","author":"Xin","year":"2020","journal-title":"Int. Immunopharmacol."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0405","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00394-015-0850-0","article-title":"Dietary extra-virgin olive oil prevents inflammatory response and cartilage matrix degradation in murine collagen-induced arthritis","volume":"55","author":"Rosillo","year":"2016","journal-title":"Eur. J. Nutr."},{"issue":"5","key":"10.1016\/j.clim.2021.108793_bb0410","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.3892\/etm.2016.3136","article-title":"Chlorogenic acid induces apoptosis to inhibit inflammatory proliferation of IL-6-induced fibroblast-like synoviocytes through modulating the activation of JAK\/STAT and NF-\u03baB signaling pathways","volume":"11","author":"Lou","year":"2016","journal-title":"Exp. Ther. Med."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0415","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3892\/ijmm.2016.2843","article-title":"Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen-induced arthritis by suppressing the activation of the JAK\/STAT signaling pathway","volume":"39","author":"Yang","year":"2017","journal-title":"Int. J. Mol. Med."},{"issue":"6","key":"10.1016\/j.clim.2021.108793_bb0420","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/rheumatology\/key339","article-title":"Clinical significance of Janus kinase inhibitor selectivity","volume":"58","author":"Choy","year":"2019","journal-title":"Rheumatology (Oxford)"},{"issue":"12","key":"10.1016\/j.clim.2021.108793_bb0425","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1177\/0091270010389469","article-title":"The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers","volume":"51","author":"Shi","year":"2011","journal-title":"J. Clin. Pharmacol."},{"issue":"10","key":"10.1016\/j.clim.2021.108793_bb0430","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":"Takeuchi","year":"2019","journal-title":"Ann. Rheum. Dis."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0435","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/1744666X.2019.1544892","article-title":"Upadacitinib for the treatment of rheumatoid arthritis","volume":"15","author":"Serhal","year":"2019","journal-title":"Expert. Rev. Clin. Immunol."},{"issue":"6","key":"10.1016\/j.clim.2021.108793_bb0440","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1136\/annrheumdis-2016-210104","article-title":"Filgotinib (GLPG0634\/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)","volume":"76","author":"Westhovens","year":"2017","journal-title":"Ann. Rheum. Dis."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0445","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/art.39473","article-title":"VX-509 (Decernotinib), an Oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis","volume":"68","author":"Genovese","year":"2016","journal-title":"Arthritis Rheum."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0450","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3109\/03009742.2010.486767","article-title":"Expression of \u03b2-catenin in rheumatoid arthritis fibroblast-like synoviocytes","volume":"40","author":"Xiao","year":"2011","journal-title":"Scand. J. Rheumatol."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0455","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: from human mutations to treatments","volume":"19","author":"Baron","year":"2013","journal-title":"Nat. Med."},{"issue":"22","key":"10.1016\/j.clim.2021.108793_bb0460","doi-asserted-by":"crossref","first-page":"14004","DOI":"10.1074\/jbc.M114.628818","article-title":"WNT1-induced secreted Protein-1 (WISP1), a novel regulator of bone turnover and WNT signaling","volume":"290","author":"Maeda","year":"2015","journal-title":"J. Biol. Chem."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0465","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/art.38895","article-title":"Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: a potential target for abatacept therapy","volume":"67","author":"Iwata","year":"2015","journal-title":"Arthritis Rheum."},{"issue":"4","key":"10.1016\/j.clim.2021.108793_bb0470","doi-asserted-by":"crossref","DOI":"10.1002\/prp2.565","article-title":"ZYBT1, a potent, irreversible Bruton\u2019s tyrosine kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer","volume":"8","author":"Ghoshdastidar","year":"2020","journal-title":"Pharmacol. Res. Perspect."},{"issue":"6","key":"10.1016\/j.clim.2021.108793_bb0475","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.mehy.2012.08.022","article-title":"Combined therapeutic application of mTOR inhibitor and vitamin D(3) for inflammatory bone destruction of rheumatoid arthritis","volume":"79","author":"Kim","year":"2012","journal-title":"Med. Hypotheses"},{"key":"10.1016\/j.clim.2021.108793_bb0480","doi-asserted-by":"crossref","first-page":"102373","DOI":"10.1016\/j.jaut.2019.102373","article-title":"The immunobiology of mTOR in autoimmunity","volume":"110","author":"Suto","year":"2020","journal-title":"J. Autoimmun."},{"issue":"1","key":"10.1016\/j.clim.2021.108793_bb0485","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41584-018-0109-2","article-title":"Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis","volume":"15","author":"Chen","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"10.1016\/j.clim.2021.108793_bb0490","doi-asserted-by":"crossref","first-page":"105463","DOI":"10.1016\/j.phrs.2021.105463","article-title":"Properties of FDA-approved small molecule protein kinase inhibitors: a 2021 update","volume":"165","author":"Roskoski","year":"2021","journal-title":"Pharmacol. Res."},{"issue":"2","key":"10.1016\/j.clim.2021.108793_bb0495","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/jcph.1513","article-title":"Preferential inhibition of JAK1 relative to JAK3 by Upadacitinib: exposure-response analyses of ex vivo data from 2 phase 1 clinical trials and comparison to Tofacitinib","volume":"60","author":"Mohamed","year":"2020","journal-title":"J. Clin. Pharmacol."}],"container-title":["Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1521661621001303?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1521661621001303?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T16:05:33Z","timestamp":1761494733000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1521661621001303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9]]},"references-count":99,"alternative-id":["S1521661621001303"],"URL":"https:\/\/doi.org\/10.1016\/j.clim.2021.108793","relation":{},"ISSN":["1521-6616"],"issn-type":[{"value":"1521-6616","type":"print"}],"subject":[],"published":{"date-parts":[[2021,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis","name":"articletitle","label":"Article Title"},{"value":"Clinical Immunology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.clim.2021.108793","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"108793"}}