{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:15:13Z","timestamp":1789748113013,"version":"4.0.1"},"reference-count":121,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,29]],"date-time":"2023-10-29T00:00:00Z","timestamp":1698537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Methotrexate (MTX), sulfonamides, hydroxychloroquine, and leflunomide have consistently resulted in remission with relatively mild to moderate adverse effects in patients with rheumatoid arthritis (RA). Modern medications outperform traditional treatments in that they target the pathological processes that underlie the development of RA. Methods: Following PRISMA guidelines, the authors accomplished a systematic review of the clinical efficacy of RA drugs, including the biologics such as Tumor Necrosis Factor-alpha inhibitors (TNF-\u03b1 i) like Etanercept, Infliximab, Golimumab, and Adalimumab, kinase inhibitors (JAK inhibitors including Baricitinib and Tofacitanib), SyK inhibitors like Fos-tamatinib, MAPK inhibitors such as Talmapimod, T-cell inhibitors (Abatacept), IL6 blockers (Tocilizumab), and B cells depleters (Rituximab). These drugs have been found to increase remission rates when combined with MTX. A bioinformatics-based network was designed applying STRING-MODEL and the DrugBank database for the aforementioned drugs and MTX and, finally, employed for this systematic review. Results: Current research demonstrates that non-TNF-\u03b1 inhibitor biologicals are particularly helpful in treating patients who did not respond well to conventional medications and TNF-\u03b1 inhibitors. Despite being effective, these innovative drugs have a higher chance of producing hazardous side effects. The in silico investigations suggested an uncovered molecular interaction in combining MTX with other biological drugs. The STRING-MODEL showed that DHFR, TYMS, and ATIC, as the receptors of MTX, interact with each other but are not connected to the major interacted receptors. Conclusions: New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy.<\/jats:p>","DOI":"10.3390\/jpm13111550","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T12:07:45Z","timestamp":1698667665000},"page":"1550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Network-Based In Silico Analysis of New Combinations of Modern Drug Targets with Methotrexate for Response-Based Treatment of Rheumatoid Arthritis"],"prefix":"10.3390","volume":"13","author":[{"given":"Marjan","family":"Assefi","sequence":"first","affiliation":[{"name":"Marie Curie Science Research Center, Greensboro, NC 27407, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-2914","authenticated-orcid":false,"given":"Kai-Uwe","family":"Lewandrowski","sequence":"additional","affiliation":[{"name":"Center for Advanced Spine Care of Southern Arizona, 4787 E Camp Lowell Drive, Tucson, AZ 85712, USA"},{"name":"Department of Orthopaedics, Fundaci\u00f3n Universitaria Sanitas, Bogot\u00e1 111321, Colombia"},{"name":"Department of Orthopedics, Hospital Universit\u00e1rio Gaffre e Guinle, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Lorio","sequence":"additional","affiliation":[{"name":"Advanced Orthopaedics, 499 E. Central Pkwy, Ste. 130, Altamonte Springs, FL 32701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5236-0903","authenticated-orcid":false,"given":"Rossano Kepler Alvim","family":"Fiorelli","sequence":"additional","affiliation":[{"name":"Department of General and Specialized Surgery, Gaffr\u00e9e e Guinle University Hospital, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro 22290-240, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Landgraeber","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Orthop\u00e4die und Orthop\u00e4dische Chirurgie Geb\u00e4ude 37, EG, Zimmer 56, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Sharafshah","sequence":"additional","affiliation":[{"name":"Marie Curie Science Research Center, Greensboro, NC 27407, USA"},{"name":"Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht P.O. Box 4144654839, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102735","DOI":"10.1016\/j.autrev.2020.102735","article-title":"Beyond the joints, the extra-articular manifestations in rheumatoid arthritis","volume":"20","author":"Conforti","year":"2021","journal-title":"Autoimmun. Rev."},{"key":"ref_2","first-page":"286","article-title":"Extra-articular manifestations in rheumatoid arthritis","volume":"5","author":"Cojocaru","year":"2010","journal-title":"Maedica"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Xu, Y., and Wu, Q. (2021). Prevalence Trend and Disparities in Rheumatoid Arthritis among US Adults, 2005\u20132018. J. Clin. Med., 10.","DOI":"10.3390\/jcm10153289"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1136\/annrheumdis-2013-204627","article-title":"The global burden of rheumatoid arthritis: Estimates from the Global Burden of Disease 2010 study","volume":"73","author":"Cross","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1136\/ard.61.4.290","article-title":"Early referral recommendation for newly diagnosed rheumatoid arthritis: Evidence based development of a clinical guide","volume":"61","author":"Emery","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R42","DOI":"10.1186\/ar2951","article-title":"Work disability remains a major problem in rheumatoid arthritis in the 2000s: Data from 32 countries in the QUEST-RA Study","volume":"12","author":"Sokka","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"K\u00f6hler, B.M., G\u00fcnther, J., Kaudewitz, D., and Lorenz, H.-M. (2019). Current Therapeutic Options in the Treatment of Rheumatoid Arthritis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8070938"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.3346\/jkms.2017.32.7.1207","article-title":"A Case of Rheumatoid Vasculitis Involving Hepatic Artery in Early Rheumatoid Arthritis","volume":"32","author":"Lee","year":"2017","journal-title":"J. Korean Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.5114\/reum.2018.75523","article-title":"Cartilage and bone damage in rheumatoid arthritis","volume":"56","author":"Ostrowska","year":"2018","journal-title":"Rheumatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/rheumatology\/35.suppl_3.6","article-title":"Clinical and Laboratory Assessments in Rheumatoid Arthritis and Osteoarthritis","volume":"35","author":"Scott","year":"1996","journal-title":"Rheumatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1016\/S0720-048X(98)00038-2","article-title":"The clinical features of rheumatoid arthritis","volume":"27","author":"Grassi","year":"1998","journal-title":"Eur. J. Radiol."},{"key":"ref_12","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":"ref_13","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/art.1780390407","article-title":"Activation of the transcription factor nuclear factor-\u03baB in human inflamed synovial tissue","volume":"39","author":"Marok","year":"1996","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.cyto.2015.07.014","article-title":"The role of BAFF in the progression of rheumatoid arthritis","volume":"76","author":"Wei","year":"2015","journal-title":"Cytokine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1159\/000493390","article-title":"Rheumatoid Arthritis: A Brief Overview of the Treatment","volume":"27","author":"Bullock","year":"2018","journal-title":"Med. Princ. Pract."},{"key":"ref_18","unstructured":"Staheli, L.T., Hall, J.G., Jaffe, K.M., and Paholke, D.O. (1998). Arthrogryposis: A Text Atlas, Cambridge University Press."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3121\/cmr.2007.698","article-title":"An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs","volume":"5","author":"Ong","year":"2007","journal-title":"Clin. Med. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1136\/annrheumdis-2019-216655","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update","volume":"79","author":"Smolen","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","first-page":"8","article-title":"RHUMATOID ARTHRITIS: A REVIEW","volume":"21","author":"Devi","year":"2022","journal-title":"YMER"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ejmech.2018.09.027","article-title":"Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review","volume":"158","author":"Wang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/anr.1780320202","article-title":"Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A Prospective Study with Baseline and Sequential Biopsy Samples","volume":"32","author":"Kremer","year":"1989","journal-title":"Arthritis Rheum."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1002\/art.1780380904","article-title":"Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables","volume":"38","author":"Kremer","year":"1995","journal-title":"Arthritis Rheum."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1006\/clim.1999.4777","article-title":"Mechanism of Action for Leflunomide in Rheumatoid Arthritis","volume":"93","author":"Fox","year":"1999","journal-title":"Clin. Immunol."},{"key":"ref_26","first-page":"CD002047","article-title":"Leflunomide for the treatment of rheumatoid arthritis","volume":"2010","author":"Osiri","year":"2002","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_27","first-page":"1182","article-title":"Leflunomide for the treatment of rheumatoid arthritis: A systematic review and metaanalysis","volume":"30","author":"Osiri","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"453","DOI":"10.4103\/idoj.IDOJ_280_20","article-title":"Hydroxychloroquine in dermatology and beyond: Recent update","volume":"11","author":"Sinha","year":"2020","journal-title":"Indian Dermatol. Online J."},{"key":"ref_29","first-page":"7","article-title":"Sulphasalazine: Mechanism of action in rheumatoid arthritis","volume":"34","year":"1995","journal-title":"Rheumatology"},{"key":"ref_30","first-page":"S14","article-title":"Biologic Agents in Rheumatoid Arthritis: An Update for Managed Care Professionals","volume":"17","author":"Agarwal","year":"2011","journal-title":"J. Manag. Care Pharm."},{"key":"ref_31","first-page":"i1777","article-title":"Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: Abridged Cochrane systematic review and network meta-analysis","volume":"353","author":"Hazlewood","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrrheum.2017.83","article-title":"The role of IL-6 in host defence against infections: Immunobiology and clinical implications","volume":"13","author":"Winthrop","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1056\/NEJMoa1310476","article-title":"Tofacitinib versus Methotrexate in Rheumatoid Arthritis","volume":"370","author":"Lee","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_34","first-page":"270","article-title":"Role of tumor necrosis factor-alpha in rheumatoid arthritis: A review","volume":"10","author":"Vasanthi","year":"2007","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.5114\/aoms.2014.47827","article-title":"State of the art paper Tumor necrosis factor inhibitors\u2013state of knowledge","volume":"6","author":"Lis","year":"2014","journal-title":"Arch. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.coph.2010.01.005","article-title":"Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases","volume":"10","author":"Taylor","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1002\/art.21814","article-title":"Guillain-Barr\u00e9 and Miller Fisher syndromes occurring with tumor necrosis factor \u03b1 antagonist therapy","volume":"54","author":"Shin","year":"2006","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrd1342","article-title":"Targeting IL-1 in inflammatory disease: New opportunities for therapeutic intervention","volume":"3","author":"Braddock","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1161\/CIRCRESAHA.116.302317","article-title":"Innate Immunity and the Failing Heart","volume":"116","author":"Mann","year":"2015","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.clinthera.2011.05.044","article-title":"Use of Biologics in Rheumatoid Arthritis: Current and Emerging Paradigms of Care","volume":"33","author":"Curtis","year":"2011","journal-title":"Clin. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"ii55","DOI":"10.1136\/ard.62.suppl_2.ii55","article-title":"B cell therapy for rheumatoid arthritis: The rituximab (anti-CD20) experience","volume":"62","author":"Shaw","year":"2003","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","first-page":"87","article-title":"Rituximab for the treatment of rheumatoid arthritis: An update","volume":"8","author":"Mok","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_43","first-page":"78","article-title":"Abatacept mechanism of action: Concordance with its clinical profile","volume":"8","author":"Calatrava","year":"2012","journal-title":"Reumatol. Clin."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.2146\/ajhp070449","article-title":"Tocilizumab: The first interleukin-6-receptor inhibitor","volume":"65","author":"Sebba","year":"2008","journal-title":"Am. J. Health Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s40265-017-0723-3","article-title":"Baricitinib: First Global Approval","volume":"77","author":"Markham","year":"2017","journal-title":"Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1136\/annrheumdis-2016-210094","article-title":"Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: Results from the RA-BUILD study","volume":"76","author":"Dougados","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1056\/NEJMoa1608345","article-title":"Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis","volume":"376","author":"Taylor","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/S0140-6736(18)31115-2","article-title":"Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): A randomised, double-blind, placebo-controlled phase 3 trial","volume":"391","author":"Burmester","year":"2018","journal-title":"Lancet"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1177\/1060028013512790","article-title":"Tofacitinib: The First Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthritis","volume":"47","author":"Vyas","year":"2013","journal-title":"Ann. Pharmacother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1002\/acr.20494","article-title":"Phase II study of tofacitinib (CP-690,550) combined with MTX in patients with rheumatoid arthritis and an inadequate response to MTX","volume":"63","author":"Tanaka","year":"2011","journal-title":"Arthritis Care Res."},{"key":"ref_51","first-page":"188","article-title":"Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis","volume":"18","author":"Singh","year":"1991","journal-title":"J. Rheumatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.3899\/jrheum.110207","article-title":"Canadian Rheumatology Association Recommendations for Pharmacological Management of Rheumatoid Arthritis with Traditional and Biologic Disease-modifying Antirheumatic Drugs","volume":"39","author":"Bykerk","year":"2012","journal-title":"J. Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1136\/annrheumdis-2021-220973","article-title":"EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis","volume":"81","author":"Nagy","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1002\/acr.24596","article-title":"2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis","volume":"73","author":"Fraenkel","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1001\/jama.2018.13103","article-title":"Diagnosis and Management of Rheumatoid Arthritis: A Review","volume":"320","author":"Aletaha","year":"2018","journal-title":"JAMA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.3899\/jrheum.201467","article-title":"Effectiveness of a Second Biologic After Failure of a Non\u2013tumor Necrosis Factor Inhibitor As First Biologic in Rheumatoid Arthritis","volume":"48","author":"Chatzidionysiou","year":"2021","journal-title":"J. Rheumatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1056\/NEJMe2026142","article-title":"What Next after Biologic Therapy Fails in Rheumatoid Arthritis?","volume":"383","author":"Goll","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2177\/jsci.32.149","article-title":"New biologic and non biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis","volume":"32","author":"Saito","year":"2009","journal-title":"Nihon Rinsho Men\u2019eki Gakkai Kaishi=Jpn. J. Clin. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Provan, S.A., Berg, I.J., Hammer, H.B., Mathiessen, A., Kvien, T.K., and Semb, A.G. (2015). The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab, Abatacept and Tociliziumab. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130709"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"211","DOI":"10.2147\/DDDT.S104233","article-title":"Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: Evidence to date","volume":"11","author":"Crotti","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/1756-185X.12293","article-title":"Kinase inhibitors: The next generation of therapies in the treatment of rheumatoid arthritis","volume":"17","author":"MacFarlane","year":"2014","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6158","DOI":"10.1073\/pnas.0401602101","article-title":"The immunomodulatory adapter proteins DAP12 and Fc receptor \u03b3-chain (FcR\u03b3) regulate development of functional osteo-clasts through the Syk tyrosine kinase","volume":"101","author":"Mocsai","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","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."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1136\/annrheumdis-2014-207178","article-title":"Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs","volume":"75","author":"Burmester","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1056\/NEJMoa2109927","article-title":"Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis","volume":"386","author":"Ytterberg","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1056\/NEJMoa2008250","article-title":"Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis","volume":"383","author":"Enejosa","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1136\/annrheumdis-2020-219214","article-title":"Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: A phase III randomised clinical trial","volume":"80","author":"Combe","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Chuang, S.-Y., Lin, C.-H., Huang, T.-H., and Fang, J.-Y. (2018). Lipid-Based Nanoparticles as a Potential Delivery Approach in the Treatment of Rheumatoid Arthritis. Nanomaterials, 8.","DOI":"10.3390\/nano8010042"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1586\/1744666X.2015.1027151","article-title":"Iguratimod for the treatment of rheumatoid arthritis in Japan","volume":"11","author":"Tanaka","year":"2015","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1080\/14397595.2016.1265695","article-title":"Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: Interim analysis of a post-marketing surveillance study of 2679 patients in Japan","volume":"27","author":"Mimori","year":"2017","journal-title":"Mod. Rheumatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1002\/art.41275","article-title":"Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Blind, Phase II Trial","volume":"72","author":"Cohen","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nrrheum.2010.23","article-title":"Ethnogenetic heterogeneity of rheumatoid arthritis\u2014Implications for pathogenesis","volume":"6","author":"Kochi","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1002\/art.20553","article-title":"A gene\u2013environment interaction between smoking and shared epitope genes in HLA\u2013DR provides a high risk of seropositive rheumatoid arthritis","volume":"50","author":"Padyukov","year":"2004","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.intimp.2010.06.026","article-title":"Cigarette smoke condensate extracts augment collagen-induced arthritis in mice","volume":"10","author":"Chujo","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.bbrc.2010.12.118","article-title":"Etiological role of cigarette smoking in rheumatoid arthritis: Nasal exposure to cigarette smoke condensate extracts augments the development of collagen-induced arthritis in mice","volume":"404","author":"Okamoto","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/rheumatology\/ker257","article-title":"Intrinsic danger: Activation of Toll-like receptors in rheumatoid arthritis","volume":"51","author":"Goh","year":"2011","journal-title":"Rheumatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1002\/art.24140","article-title":"Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll-like receptor expression in early and longstanding arthritis","volume":"58","author":"Ospelt","year":"2008","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/S0002-9440(10)63918-1","article-title":"Expression and Regulation of Toll-Like Receptor 2 in Rheumatoid Arthritis Synovium","volume":"162","author":"Seibl","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.imlet.2007.03.004","article-title":"Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation","volume":"110","author":"Kim","year":"2007","journal-title":"Immunol. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1002\/art.21273","article-title":"RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via toll-like receptor 3","volume":"52","author":"Brentano","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1002\/art.21278","article-title":"The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7\/8 results in synergistic cytokine production by dendritic cells","volume":"52","author":"Roelofs","year":"2005","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1100\/tsw.2010.207","article-title":"New Therapeutic Approaches for the Treatment of Rheumatoid Arthritis may Rise from the Cholinergic Anti-Inflammatory Pathway and Antinociceptive Pathway","volume":"10","author":"Pan","year":"2010","journal-title":"Sci. World J."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1471-2474-10-46","article-title":"Disease modifying and antiangiogenic activity of 2-Methoxyestradiol in a murine model of rheumatoid arthritis","volume":"10","author":"Plum","year":"2009","journal-title":"BMC Musculoskelet. Disord."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1007\/s12016-019-08742-z","article-title":"Toll-like Receptors, Infections, and Rheumatoid Arthritis","volume":"58","author":"Arleevskaya","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"R103","DOI":"10.1186\/ar3034","article-title":"Toll-like receptor 3 upregulation in macrophages participates in the initiation and maintenance of pristane-induced arthritis in rats","volume":"12","author":"Meng","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/med.20214","article-title":"Prophylactic and therapeutic implications of toll-like receptor ligands","volume":"32","author":"Hedayat","year":"2010","journal-title":"Med. Res. Rev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1080\/08923970902802926","article-title":"The potential use of toll-like receptor (TLR) agonists and antagonists as prophylactic and\/or therapeutic agents","volume":"31","author":"Makkouk","year":"2009","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1517\/14712598.2010.534080","article-title":"Modulation of toll-like receptor function has therapeutic potential in autoimmune disease","volume":"10","author":"Clanchy","year":"2010","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13075-020-2097-2","article-title":"Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug","volume":"22","author":"Samarpita","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"285","DOI":"10.2147\/ITT.S288547","article-title":"Contribution of Toll-Like Receptors and the NLRP3 Inflammasome in Rheumatoid Arthritis Pathophysiology","volume":"10","author":"Unterberger","year":"2021","journal-title":"ImmunoTargets Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1186\/s13075-015-0775-2","article-title":"Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis","volume":"17","author":"Choulaki","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/cei.13167","article-title":"NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis","volume":"194","author":"Guo","year":"2018","journal-title":"Clin. Exp. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1111\/j.1365-2567.2009.03174.x","article-title":"Expression and function of the NALP3 inflammasome in rheumatoid synovium","volume":"129","author":"Kolly","year":"2010","journal-title":"Immunology"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Lin, Y.-J., Anzaghe, M., and Sch\u00fclke, S. (2020). Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells, 9.","DOI":"10.3390\/cells9040880"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e7023","DOI":"10.7717\/peerj.7023","article-title":"Comparison of therapeutic effects of different mesenchymal stem cells on rheumatoid arthritis in mice","volume":"7","author":"Zhang","year":"2019","journal-title":"PeerJ"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3727\/096368915X688470","article-title":"Effects of Transplantation of CTLA4Ig-Overexpressing Adipose Tissue-Derived Mesenchymal Stem Cells in Mice with Sustained Severe Rheumatoid Arthritis","volume":"25","author":"Choi","year":"2016","journal-title":"Cell Transplant."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1007\/s12015-020-10000-1","article-title":"Genetically Modified Mesenchymal Stromal\/Stem Cells: Application in Critical Illness","volume":"16","author":"Varkouhi","year":"2020","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"39593","DOI":"10.1038\/srep39593","article-title":"Etanercept-Synthesising Mesenchymal Stem Cells Efficiently Ameliorate Collagen-Induced Arthritis","volume":"7","author":"Park","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"362","DOI":"10.5966\/sctm.2012-0135","article-title":"Comparison of Drug and Cell-Based Delivery: Engineered Adult Mesenchymal Stem Cells Expressing Soluble Tumor Necrosis Factor Receptor II Prevent Arthritis in Mouse and Rat Animal Models","volume":"2","author":"Liu","year":"2013","journal-title":"STEM CELLS Transl. Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Lopez-Santalla, M., Fernandez-Perez, R., and Garin, M.I. (2020). Mesenchymal Stem\/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications. Cells, 9.","DOI":"10.3390\/cells9081852"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/med.20045","article-title":"Rheumatoid arthritis, a complex multifactorial disease: On the way toward in-dividualized medicine","volume":"26","author":"Glocker","year":"2006","journal-title":"Med. Res. Rev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/acr.21641","article-title":"2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis","volume":"64","author":"Singh","year":"2012","journal-title":"Arthritis Care Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1056\/NEJMoa1303006","article-title":"Therapies for Active Rheumatoid Arthritis after Methotrexate Failure","volume":"369","author":"Mikuls","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Li, L., Pan, Z., Ning, D., and Fu, Y. (2021). Rosmanol and Carnosol Synergistically Alleviate Rheumatoid Arthritis through Inhibiting TLR4\/NF-\u03baB\/MAPK Pathway. Molecules, 27.","DOI":"10.3390\/molecules27010078"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"912933","DOI":"10.3389\/fimmu.2022.912933","article-title":"A Novel Drug Combination of Mangiferin and Cinnamic Acid Alleviates Rheumatoid Arthritis by Inhibiting TLR4\/NF\u03baB\/NLRP3 Activation-Induced Pyroptosis","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1078569","DOI":"10.3389\/fphys.2022.1078569","article-title":"Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation","volume":"13","author":"Werner","year":"2023","journal-title":"Front. Physiol."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Li, R.-N., Ou, T.-T., Lin, C.-H., Lin, Y.-Z., Fang, T.-J., Chen, Y.-J., Tseng, C.-C., Sung, W.-Y., Wu, C.-C., and Yen, J.-H. (2023). NLRP3 Gene Polymorphisms in Rheumatoid Arthritis and Primary Sjogren\u2019s Syndrome Patients. Diagnostics, 13.","DOI":"10.3390\/diagnostics13020206"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Liu, X., Chen, X., Zhang, C., Huang, M., Yu, H., Wang, Y., and Wang, Y. (2023). Mitochondrion-NLRP3 inflammasome activation in macrophages: A novel mechanism of the anti-inflammatory effect of Notopterygium in rheumatoid arthritis treatment. Biomed. Pharmacother., 167.","DOI":"10.1016\/j.biopha.2023.115560"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"179","DOI":"10.14715\/cmb\/2023.69.8.27","article-title":"Regulatory effect of zinc finger protein A20 on rheumatoid arthritis through NLRP3\/Caspase-1 signaling axis mediating pyroptosis of HFLS- RA cells","volume":"69","author":"Zhao","year":"2023","journal-title":"Cell. Mol. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Sun, H.-G., Jiang, Q., Fan, W.-J., Shen, X.-Y., Wang, Z.-W., and Wang, X. (2023). TAGAP activates Th17 cell differentiation by promoting RhoA and NLRP3 to accelerate rheumatoid arthritis development. Clin. Exp. Immunol., uxad084.","DOI":"10.1093\/cei\/uxad084"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Ye, Q., Yan, T., Shen, J., Shi, X., Luo, F., and Ren, Y. (2023). Sulforaphene targets NLRP3 inflammasome to suppress M1 polarization of macrophages and inflammatory response in rheumatoid arthritis. J. Biochem. Mol. Toxicol., 37.","DOI":"10.1002\/jbt.23362"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"154640","DOI":"10.1016\/j.phymed.2022.154640","article-title":"Osthole: A potential AMPK agonist that inhibits NLRP3 inflammasome activation by regulating mitochondrial homeostasis for combating rheumatoid arthritis","volume":"110","author":"Jiang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e306","DOI":"10.1002\/mco2.306","article-title":"Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming","volume":"4","author":"Zhang","year":"2023","journal-title":"Medcomm"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"101890","DOI":"10.1016\/j.trim.2023.101890","article-title":"Effect of autologous bone marrow derived mesenchymal stem cells in treatment of rheumatoid arthritis","volume":"80","author":"Elbasha","year":"2023","journal-title":"Transpl. Immunol."},{"key":"ref_116","first-page":"183","article-title":"The Effects of Mesenchymal Stem Cells on the Gene Expression of TGF-beta and IFN-gamma in Patients with Rheumatoid Arthritis","volume":"22","author":"Ghoryani","year":"2023","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/s13287-023-03523-0","article-title":"Exosomes derived from mesenchymal stem cells primed with disease-condition-serum improved therapeutic efficacy in a mouse rheumatoid arthritis model via enhanced TGF-\u03b21 production","volume":"14","author":"Choi","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"10612","DOI":"10.1038\/s41598-023-37741-6","article-title":"The effects of IL-1\u03b2 stimulated human umbilical cord mesenchymal stem cells on polarization and apoptosis of macrophages in rheumatoid arthritis","volume":"13","author":"Zeng","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s12010-022-04090-5","article-title":"Curcumin-Loaded Mesenchymal Stem Cell\u2013Derived Exosomes Efficiently Attenuate Proliferation and Inflammatory Response in Rheumatoid Arthritis Fibroblast-Like Synoviocytes","volume":"195","author":"He","year":"2022","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1089\/bio.2022.0003","article-title":"Genetically Engineered Exosomes as a Potential Regulator of Th1 Cells Response in Rheumatoid Arthritis","volume":"21","author":"Ren","year":"2023","journal-title":"Biopreservation Biobanking"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Rui, K., Tang, X., Shen, Z., Jiang, C., Zhu, Q., Liu, S., Che, N., Tian, J., Ling, J., and Yang, Y. (2023). Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis. J. 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