{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T15:12:23Z","timestamp":1783955543542,"version":"3.55.0"},"reference-count":60,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Rheumatic diseases encompass various autoimmune and inflammatory conditions affecting the joints, muscles, and connective tissues. Recent studies have advanced our understanding of the molecular pathogenesis of rheumatic diseases and have led to the identification of several promising therapeutic targets, paving the way for the development of novel drug interventions. This review highlights the latest molecular advances in rheumatoid arthritis, with a particular focus on innovative therapeutic strategies, and presents new perspectives on their management, including cytokines, intracellular signaling pathways, immune checkpoints, and novel cell-based therapies. A better understanding of these targets is essential for developing effective and personalized treatments.<\/jats:p>","DOI":"10.3390\/jcm14165827","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T15:34:53Z","timestamp":1755531293000},"page":"5827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Promising Molecular Therapeutic Targets for Drug Development in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3449-696X","authenticated-orcid":false,"given":"Sang Wan","family":"Chung","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul 02453, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nrrheum.2014.6","article-title":"Pathogenesis and prevention of rheumatic disease: Focus on preclinical RA and SLE","volume":"10","author":"Deane","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1136\/ard-2022-223356","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update","volume":"82","author":"Smolen","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e004987","DOI":"10.1136\/rmdopen-2024-004987","article-title":"Switching to biological DMARDs versus cycling among JAK inhibitors in patients with rheumatoid arthritis and with inadequate response to JAK inhibitors: From FIRST registry","volume":"11","author":"Miyazaki","year":"2025","journal-title":"RMD Open"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2147\/ITT.S288550","article-title":"Bruton\u2019s tyrosine kinase inhibition for the treatment of rheumatoid arthritis","volume":"10","author":"Arneson","year":"2021","journal-title":"ImmunoTargets Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1136\/annrheumdis-2020-eular.3804","article-title":"OP0234 MBS2320, a novel selective modulator of immune metabolism, in patients with severe rheumatoid arthritis: Safety, tolerability and efficacy results of a phase 2 study","volume":"79","author":"Patel","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_7","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_8","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_9","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1056\/NEJMoa2209856","article-title":"A phase 2 trial of peresolimab for adults with rheumatoid arthritis","volume":"388","author":"Tuttle","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103291","DOI":"10.1016\/j.jaut.2024.103291","article-title":"Telitacicept: A novel horizon in targeting autoimmunity and rheumatic diseases","volume":"148","author":"Zeng","year":"2024","journal-title":"J. Autoimmun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.4049\/jimmunol.2100820","article-title":"SM03, an anti-CD22 antibody, converts cis-to-trans ligand binding of CD22 against \u03b12, 6-linked sialic acid glycans and immunomodulates systemic autoimmune diseases","volume":"208","author":"Wong","year":"2022","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1093\/rheumatology\/keab699","article-title":"SM03, an anti-human CD22 monoclonal antibody, for active rheumatoid arthritis: A phase II, randomized, double-blind, placebo-controlled study","volume":"61","author":"Li","year":"2022","journal-title":"Rheumatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1172\/JCI119781","article-title":"Functional CD40 ligand is expressed by T cells in rheumatoid arthritis","volume":"100","author":"MacDonald","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_14","first-page":"1035","article-title":"Ligation of CD40 induced tumor necrosis factor-alpha in rheumatoid arthritis: A novel mechanism of activation of synoviocytes","volume":"26","author":"Harigai","year":"1999","journal-title":"J. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"van Kooten, C. (2000). Immune regulation by CD40-CD40-l interactions-2; Y2K update. Front. Biosci., 5.","DOI":"10.2741\/kooten"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/art.10856","article-title":"A short course of BG9588 (anti\u2013CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis","volume":"48","author":"Boumpas","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaar6584","DOI":"10.1126\/scitranslmed.aar6584","article-title":"A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity","volume":"11","author":"Karnell","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/72162","article-title":"Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand","volume":"6","author":"Kawai","year":"2000","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.4049\/jimmunol.0903888","article-title":"Anti-CD40L immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A transgenic mice","volume":"185","author":"Meyer","year":"2010","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1160\/TH04-12-0774","article-title":"The role of CD40 in CD40L-and antibody-mediated platelet activation","volume":"93","author":"Amirkhosravi","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1136\/annrheumdis-2024-eular.1536","article-title":"Op0036 efficacy, safety, and pharmacokinetics of anti-cd40 antibody abiprubart (Kpl-404) in patients with rheumatoid arthritis: A phase 2, randomized, placebo-controlled 12-week-treatment proof-of-concept study","volume":"83","author":"Jenkins","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1007\/s12016-015-8498-3","article-title":"OX40, OX40L and autoimmunity: A comprehensive review","volume":"50","author":"Webb","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13075-017-1261-9","article-title":"OX40 signaling is involved in the autoactivation of CD4+ CD28\u2212 T cells and contributes to the pathogenesis of autoimmune arthritis","volume":"19","author":"Jiang","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cai, X., Zhang, M., Ren, F., Fei, W., Zhang, X., Zhao, Y., Yao, Y., and Lin, N. (2022). Synovial macrophages expression of OX40L is required for follicular helper T cells differentiation in the joint microenvironment. Cells, 11.","DOI":"10.3390\/cells11203326"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.1073\/pnas.1035999100","article-title":"IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist","volume":"100","author":"Nakae","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1016\/S0140-6736(23)01619-7","article-title":"Efficacy of rocatinlimab for moderate-to-severe atopic dermatitis","volume":"402","author":"Devjani","year":"2023","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0140-6736(22)02037-2","article-title":"An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: A multicentre, double-blind, placebo-controlled phase 2b study","volume":"401","author":"Simpson","year":"2023","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1093\/bjd\/ljad240","article-title":"Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: Results of a phase IIa randomized placebo-controlled trial","volume":"189","author":"Weidinger","year":"2023","journal-title":"Br. J. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100195","DOI":"10.1016\/j.jacig.2023.100195","article-title":"Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis","volume":"3","author":"Rewerska","year":"2024","journal-title":"J. Allergy Clin. Immunol. Glob."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1002\/art.23992","article-title":"Treatment of rheumatoid arthritis with a Syk kinase inhibitor: A twelve-week, randomized, placebo-controlled trial","volume":"58","author":"Weinblatt","year":"2008","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/art.30114","article-title":"An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: A three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents","volume":"63","author":"Genovese","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1093\/rheumatology\/keaa732","article-title":"Safety and efficacy of fostamatinib in rheumatoid arthritis patients with an inadequate response to methotrexate in phase II OSKIRA-ASIA-1 and OSKIRA-ASIA-1X study","volume":"60","author":"Tanaka","year":"2021","journal-title":"Rheumatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"184","DOI":"10.2174\/1573397116666201113085444","article-title":"Safety and efficacy of mavrilimumab for rheumatoid arthritis: A systematic review and meta-analysis","volume":"17","author":"Shamseldin","year":"2021","journal-title":"Curr. Rheumatol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"For the NEXUS Study Group, Taylor, P.C., Saurigny, D., Vencovsky, J., Takeuchi, T., Nakamura, T., Matsievskaia, G., Hunt, B., Wagner, T., and Souberbielle, B. (2019). Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: A randomized, controlled trial. Arthritis Res. Ther., 21, 101.","DOI":"10.1186\/s13075-019-1879-x"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1136\/ard-2023-224482","article-title":"Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: Two phase 3 randomised trials (contRAst 1 and contRAst 2)","volume":"82","author":"Fleischmann","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.intimp.2016.03.038","article-title":"Iguratimod (T-614) suppresses RANKL-induced osteoclast differentiation and migration in RAW264. 7 cells via NF-\u03baB and MAPK pathways","volume":"35","author":"Gan","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_37","first-page":"1097","article-title":"The SMILE study: Study of long-term methotrexate and iguratimod combination therapy in early rheumatoid arthritis","volume":"10","author":"Du","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.hoc.2021.03.006","article-title":"Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: Beyond ibrutinib","volume":"35","author":"Lasica","year":"2021","journal-title":"Hematol. Oncol. Clin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1136\/annrheumdis-2019-eular.2794","article-title":"THU0186 Safety, tolerability and pharmacokinetics of MBS2320, a selective modulator of immune metabolism, in healthy volunteers and patients with rheumatoid arthritis","volume":"78","author":"Patel","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nri.2016.58","article-title":"Inflammasomes: Mechanism of assembly, regulation and signalling","volume":"16","author":"Broz","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102299","DOI":"10.1016\/j.jaut.2019.06.010","article-title":"Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review","volume":"103","author":"Shin","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kl\u00fcck, V., A Jansen, T.L.T., Janssen, M., Comarniceanu, A., Efd\u00e9, M., Tengesdal, I.W., Schraa, K., Cleophas, M.C.P., Scribner, C.L., and Skouras, D.B. (2020). Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: An open-label, dose-adaptive, proof-of-concept, phase 2a trial. Lancet Rheumatol., 2.","DOI":"10.1016\/S2665-9913(20)30065-5"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.joca.2018.02.901","article-title":"NLRP3 as a potentially novel biomarker for the management of osteoarthritis","volume":"26","author":"McAllister","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.immunol.021908.132612","article-title":"Immunological and inflammatory functions of the interleukin-1 family","volume":"27","author":"Dinarello","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"782382","DOI":"10.1155\/2015\/782382","article-title":"The role of IL-1\u03b2 in the bone loss during rheumatic diseases","volume":"2015","author":"Ruscitti","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41590-018-0120-4","article-title":"Regulatory T cells in autoimmune disease","volume":"19","author":"Hafler","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_47","first-page":"3297","article-title":"Elevated expression of PD-1 on T cells correlates with disease activity in rheumatoid arthritis","volume":"17","author":"Luo","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"17050","DOI":"10.1002\/jcp.28445","article-title":"The role of BAFF and APRIL in rheumatoid arthritis","volume":"234","author":"Shabgah","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s40265-021-01591-1","article-title":"Telitacicept: First approval","volume":"81","author":"Dhillon","year":"2021","journal-title":"Drugs"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"691","DOI":"10.5414\/CP203907","article-title":"An open-label, multiple-dose study to assess the preliminary pharmacokinetics, pharmacodynamics, clinical activity, and safety of human mouse chimeric anti-CD22 monoclonal antibody (SM03) in patients with rheumatoid arthritis","volume":"59","author":"Zhao","year":"2021","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev-immunol-030409-101243","article-title":"Control of immunity by the TNFR-related molecule OX40 (CD134)","volume":"28","author":"Croft","year":"2010","journal-title":"Annu. Rev. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S1074-7613(01)00191-1","article-title":"OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells","volume":"15","author":"Rogers","year":"2001","journal-title":"Immunity"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1002\/1521-4141(200010)30:10<2815::AID-IMMU2815>3.0.CO;2-#","article-title":"Contribution of OX40\/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis","volume":"30","author":"Yoshioka","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.immuni.2015.05.012","article-title":"OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response","volume":"42","author":"Jacquemin","year":"2015","journal-title":"Immunity"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1600-065X.2009.00766.x","article-title":"The significance of OX40 and OX40L to T-cell biology and immune disease","volume":"229","author":"Croft","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1080\/13543784.2022.2075340","article-title":"Investigational drugs for immune thrombocytopenia","volume":"31","author":"Provan","year":"2022","journal-title":"Expert Opin. Investig. Drugs."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1124\/jpet.111.188441","article-title":"Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis","volume":"340","author":"Coffey","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chen, Y., Liu, H., Tian, Y., Luo, Z., Yin, G., and Xie, Q. (2022). Neoplasm risk in patients with rheumatoid arthritis treated with fostamatinib: A systematic review and meta-analysis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.768980"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1186\/s13018-021-02603-2","article-title":"Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: A systematic review and meta-analysis of RCTs","volume":"16","author":"Hu","year":"2021","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Nozaki, Y. (2021). Iguratimod: Novel Molecular Insights and a New csDMARD for Rheumatoid Arthritis, from Japan to the World. Life, 11.","DOI":"10.3390\/life11050457"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/16\/5827\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:29:53Z","timestamp":1760034593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/16\/5827"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,18]]},"references-count":60,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["jcm14165827"],"URL":"https:\/\/doi.org\/10.3390\/jcm14165827","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,18]]}}}