{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:04Z","timestamp":1787028424952,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T00:00:00Z","timestamp":1587340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"publisher","award":["MOST108-2320-B-039-065"],"award-info":[{"award-number":["MOST108-2320-B-039-065"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"publisher","award":["MOST 108-2320-B-039-064-"],"award-info":[{"award-number":["MOST 108-2320-B-039-064-"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-109-208"],"award-info":[{"award-number":["DMR-109-208"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012544","name":"China Medical University, Taiwan","doi-asserted-by":"publisher","award":["CMU108-MF-14"],"award-info":[{"award-number":["CMU108-MF-14"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is an inflammatory joint disorder characterized by synovial proliferation and inflammation, with eventual joint destruction if inadequately treated. Modern therapies approved for RA target the proinflammatory cytokines or Janus kinases that mediate the initiation and progression of the disease. However, these agents fail to benefit all patients with RA, and many lose therapeutic responsiveness over time. More effective or adjuvant treatments are needed. Melatonin has shown beneficial activity in several animal models and clinical trials of inflammatory autoimmune diseases, but the role of melatonin is controversial in RA. Some research suggests that melatonin enhances proinflammatory activities and thus promotes disease activity in RA, while other work has documented substantial anti-inflammatory and immunoregulatory properties of melatonin in preclinical models of arthritis. In addition, disturbance of the circadian rhythm is associated with RA development and melatonin has been found to affect clock gene expression in joints of RA. This review summarizes current understanding about the immunopathogenic characteristics of melatonin in RA disease. Comprehensive consideration is required by clinical rheumatologists to balance the contradictory effects.<\/jats:p>","DOI":"10.3390\/ijms21082877","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T04:49:38Z","timestamp":1587444578000},"page":"2877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Reconsidering the Role of Melatonin in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"21","author":[{"given":"Iona J.","family":"MacDonald","sequence":"first","affiliation":[{"name":"School of Medicine, China Medical University, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Chung","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin 65152, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7113-8352","authenticated-orcid":false,"given":"Chih-Hsin","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan"},{"name":"Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mian, A., Ibrahim, F., and Scott, D.L. (2019). A systematic review of guidelines for managing rheumatoid arthritis. BMC Rheumatol., 3.","DOI":"10.1186\/s41927-019-0090-7"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/acr.22783","article-title":"2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis","volume":"68","author":"Singh","year":"2016","journal-title":"Arthritis  Rheumatol. (Hoboken, N.J.)"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1136\/annrheumdis-2016-210715","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update","volume":"76","author":"Smolen","year":"2017","journal-title":"Ann. Rheum Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11742","DOI":"10.3390\/ijms140611742","article-title":"Modulation by melatonin of the pathogenesis of inflammatory autoimmune diseases","volume":"14","author":"Lin","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2019.07.002","article-title":"Potential role of melatonin in autoimmune diseases","volume":"48","author":"Zhao","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.0959-9673.2006.00474.x","article-title":"The role of melatonin in immuno-enhancement: Potential application in cancer","volume":"87","author":"Miller","year":"2006","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1210\/er.2018-00084","article-title":"Melatonin as a Hormone: New Physiological and Clinical Insights","volume":"39","author":"Amaral","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1007\/s00018-017-2617-7","article-title":"Melatonin, mitochondria, and the skin","volume":"74","author":"Slominski","year":"2017","journal-title":"Cell Mol. Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.jid.2017.10.025","article-title":"Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions","volume":"138","author":"Slominski","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e12626","DOI":"10.1111\/jpi.12626","article-title":"Characterization of serotonin and N-acetylserotonin systems in the human epidermis and skin cells","volume":"68","author":"Slominski","year":"2020","journal-title":"J. Pineal Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1096\/fj.12-224691","article-title":"Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells","volume":"27","author":"Kim","year":"2013","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/exd.13208","article-title":"Metabolism of melatonin in the skin: Why is it important?","volume":"26","author":"Slominski","year":"2017","journal-title":"Exp. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1111\/bph.13898","article-title":"Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: Involvement of circadian clock genes","volume":"175","author":"Mehrzadi","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12416","DOI":"10.1111\/jpi.12416","article-title":"Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways","volume":"63","author":"Majidinia","year":"2017","journal-title":"J. Pineal. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/jpi.12224","article-title":"Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain","volume":"58","author":"Lacoste","year":"2015","journal-title":"J. Pineal. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/j.1749-6632.2002.tb04226.x","article-title":"Melatonin in rheumatoid arthritis: Synovial macrophages show melatonin receptors","volume":"966","author":"Maestroni","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1600-079X.2005.00237.x","article-title":"Positive relationship between melatonin receptor type 1B polymorphism and rheumatoid factor in rheumatoid arthritis patients in the Korean population","volume":"39","author":"Ha","year":"2005","journal-title":"J. Pineal. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e12560","DOI":"10.1111\/jpi.12560","article-title":"Melatonin attenuates TNF-alpha and IL-1beta expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis","volume":"66","author":"Huang","year":"2019","journal-title":"J. Pineal. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1002\/bies.201600204","article-title":"RORalpha is not a receptor for melatonin (response to DOI 10.1002\/bies.201600018)","volume":"38","author":"Slominski","year":"2016","journal-title":"Bioessays"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1096\/fj.13-242040","article-title":"RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D","volume":"28","author":"Slominski","year":"2014","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1749-6632.2000.tb05403.x","article-title":"Gene regulation by melatonin","volume":"917","author":"Carlberg","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1007\/BF01923947","article-title":"The melatonin rhythm: Both a clock and a calendar","volume":"49","author":"Reiter","year":"1993","journal-title":"Experientia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1600-079X.2005.00265.x","article-title":"Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: Regulation of pro-\/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects","volume":"39","author":"Lardone","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"282495","DOI":"10.1155\/2014\/282495","article-title":"Involvement of the circadian rhythm and inflammatory cytokines in the pathogenesis of rheumatoid arthritis","volume":"2014","author":"Yoshida","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/nrrheum.2016.93","article-title":"The brain-joint axis in osteoarthritis: Nerves, circadian clocks and beyond","volume":"12","author":"Berenbaum","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/jpi.12360","article-title":"Melatonin as an antioxidant: Under promises but over delivers","volume":"61","author":"Reiter","year":"2016","journal-title":"J. Pineal. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/jpi.12362","article-title":"Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin","volume":"61","author":"Hosseinzadeh","year":"2016","journal-title":"J. Pineal. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/S1567-5769(02)00088-7","article-title":"Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis rat","volume":"2","author":"Chen","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00296-010-1641-9","article-title":"Melatonin attenuates clock gene cryptochrome1, which may aggravate mouse anti-type II collagen antibody-induced arthritis","volume":"32","author":"Bang","year":"2012","journal-title":"Rheumatol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1600-079X.2004.00175.x","article-title":"Dual effect of melatonin as proinflammatory and antioxidant in collagen-induced arthritis in rats","volume":"38","author":"Molinero","year":"2005","journal-title":"J. Pineal. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/j.1749-6632.1999.tb07645.x","article-title":"Melatonin influences interleukin-12 and nitric oxide production by primary cultures of rheumatoid synovial macrophages and THP-1 cells","volume":"876","author":"Cutolo","year":"1999","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.3923\/pjbs.2007.1471.1476","article-title":"Serum melatonin in juvenile rheumatoid arthritis: Correlation with disease activity","volume":"10","author":"Saleh","year":"2007","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1111\/j.1365-2125.2007.02911.x","article-title":"Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin","volume":"64","author":"Forrest","year":"2007","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s00296-013-2930-x","article-title":"Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: A cross-sectional study","volume":"34","author":"Afkhamizadeh","year":"2014","journal-title":"Rheumatol. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13075-018-1770-1","article-title":"The circadian regulator Bmal1 in joint mesenchymal cells regulates both joint development and inflammatory arthritis","volume":"21","author":"Hand","year":"2019","journal-title":"Arthritis. Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kouri, V.P., Olkkonen, J., Kaivosoja, E., Ainola, M., Juhila, J., Hovatta, I., Konttinen, Y.T., and Mandelin, J. (2013). Circadian timekeeping is disturbed in rheumatoid arthritis at molecular level. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054049"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0165-5728(90)90139-E","article-title":"Constant darkness enhances autoimmunity to type II collagen and exaggerates development of collagen-induced arthritis in DBA\/1 mice","volume":"27","author":"Hansson","year":"1990","journal-title":"J. Neuroimmunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0165-5728(92)90171-G","article-title":"The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice","volume":"39","author":"Hansson","year":"1992","journal-title":"J. Neuroimmunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/j.1365-2249.1993.tb03416.x","article-title":"Pinealectomy ameliorates collagen II-induced arthritis in mice","volume":"92","author":"Hansson","year":"1993","journal-title":"Clin Exp. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1600-079X.1997.tb00338.x","article-title":"Circadian rhythm in experimental granulomatous inflammation is modulated by melatonin","volume":"23","author":"Lopes","year":"1997","journal-title":"J. Pineal. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/j.1749-6632.2002.tb04227.x","article-title":"Melatonin serum levels in rheumatoid arthritis","volume":"966","author":"Sulli","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1136\/ard.2005.038588","article-title":"The melatonin-cytokine connection in rheumatoid arthritis","volume":"64","author":"Cutolo","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1196\/annals.1351.027","article-title":"Circadian rhythms: Glucocorticoids and arthritis","volume":"1069","author":"Cutolo","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/jpi.12034","article-title":"Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site","volume":"54","author":"Rudra","year":"2013","journal-title":"J. Pineal. Res."},{"key":"ref_47","first-page":"3048","article-title":"Immunolocalization of MMP-2 and MMP-9 in human rheumatoid synovium","volume":"7","author":"Zhou","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1600-079X.2009.00689.x","article-title":"Melatonin inhibits human fibroblast-like synoviocyte proliferation via extracellular signal-regulated protein kinase\/P21(CIP1)\/P27(KIP1) pathways","volume":"47","author":"Nah","year":"2009","journal-title":"J. Pineal. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1365-2125.2007.03088.x","article-title":"Melatonin treatment does not improve rheumatoid arthritis","volume":"65","author":"Maestroni","year":"2008","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1111\/j.1365-2125.2008.03181.x","article-title":"Melatonin as an adjuvant therapy in patients with rheumatoid arthritis","volume":"66","author":"Korkmaz","year":"2008","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1159\/000014582","article-title":"Protective effect of melatonin on zymosan-induced cellular damage","volume":"8","author":"Cuzzocrea","year":"1999","journal-title":"Biol. Signals Recept."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jneuroim.2005.05.002","article-title":"Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages","volume":"165","author":"Mayo","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Yu, G.M., Kubota, H., Okita, M., and Maeda, T. (2017). The anti-inflammatory and antioxidant effects of melatonin on LPS-stimulated bovine mammary epithelial cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178525"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1600-079X.1997.tb00342.x","article-title":"Protective effect of melatonin in carrageenan-induced models of local inflammation: Relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity","volume":"23","author":"Cuzzocrea","year":"1997","journal-title":"J. Pineal. Res."},{"key":"ref_55","first-page":"7202","article-title":"miR-590-3p mediates melatonin-induced cell apoptosis by targeting septin 7 in the human osteoblast cell line hFOB 1.19","volume":"17","author":"Meng","year":"2018","journal-title":"Mol. Med. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:21:32Z","timestamp":1760361692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,20]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21082877"],"URL":"https:\/\/doi.org\/10.3390\/ijms21082877","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,20]]}}}