{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:31:28Z","timestamp":1787027488763,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T00:00:00Z","timestamp":1653091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["323530_199386"],"award-info":[{"award-number":["323530_199386"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_192738"],"award-info":[{"award-number":["310030_192738"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["31003A_182105"],"award-info":[{"award-number":["31003A_182105"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["IZCOZ0_177070"],"award-info":[{"award-number":["IZCOZ0_177070"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1\/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding Nrf2 modulate the risk of Hashimoto\u2019s thyroiditis (HT), suggesting that pharmacological activation of Nrf2 might also be protective. However, a patient with acute exacerbation of HT after starting DMF for MS was recently reported, raising questions about the thyroidal safety of Nrf2 activators. Methods: In a retrospective observational study, we investigated the prevalence and incidence of thyroid disorders (TD) among 163 patients with MS treated with DMF. Results: Only 7\/163 patients (4.3%) were diagnosed with functional TD; most (5\/163, 3.0%) were diagnosed before DMF treatment. Functional TD were diagnosed under or after DMF in only 2 patients (1.2%). Under DMF, one patient developed transient mild hypothyroidism with negative thyroid autoantibodies. After DMF discontinuation, another patient developed hyperthyroidism due to Graves\u2019 disease. No patient developed thyroid structural disease under or after DMF. Conclusions: The very low incidence of functional TD indicates an overall very good thyroid tolerance of DMF, arguing against screening for TD in MS patients considered for or treated with DMF, and supporting the further study of Nrf2 activators for the prevention and treatment of TD.<\/jats:p>","DOI":"10.3390\/antiox11051015","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T09:18:08Z","timestamp":1653124688000},"page":"1015","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Thyroid Disorders in Patients Treated with Dimethyl Fumarate for Multiple Sclerosis: A Retrospective Observational Study"],"prefix":"10.3390","volume":"11","author":[{"given":"C\u00e9dric O.","family":"Renaud","sequence":"first","affiliation":[{"name":"Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos G.","family":"Ziros","sequence":"additional","affiliation":[{"name":"Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amandine","family":"Mathias","sequence":"additional","affiliation":[{"name":"Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1146-3129","authenticated-orcid":false,"given":"Caroline","family":"Pot","sequence":"additional","affiliation":[{"name":"Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9565-4941","authenticated-orcid":false,"given":"Gerasimos P.","family":"Sykiotis","sequence":"additional","affiliation":[{"name":"Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nrneurol.2014.37","article-title":"Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis","volume":"10","author":"Friese","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.pharep.2017.02.017","article-title":"Mechanism of action of three newly registered drugs for multiple sclerosis treatment","volume":"69","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00109-019-01761-5","article-title":"Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis","volume":"97","author":"Yadav","year":"2019","journal-title":"J. Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"re3","DOI":"10.1126\/scisignal.3112re3","article-title":"Stress-Activated Cap\u2019n\u2019collar Transcription Factors in Aging and Human Disease","volume":"3","author":"Sykiotis","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.molmed.2004.09.003","article-title":"Nrf2\u2013Keap1 defines a physiologically important stress response mechanism","volume":"10","author":"Motohashi","year":"2004","journal-title":"Trends Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1073\/pnas.0308347100","article-title":"Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes","volume":"101","author":"Kang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"510","DOI":"10.3389\/fendo.2019.00510","article-title":"Keap1\/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer","volume":"10","author":"Renaud","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Thanas, C., Ziros, P.G., Chartoumpekis, D.V., Renaud, C.O., and Sykiotis, G.P. (2020). The Keap1\/Nrf2 Signaling Pathway in the Thyroid-2020 Update. Antioxidants, 9.","DOI":"10.3390\/antiox9111082"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1089\/thy.2018.0018","article-title":"NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland","volume":"28","author":"Ziros","year":"2018","journal-title":"Thyroid"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1089\/thy.2018.0480","article-title":"Interaction of Genetic Variations in NFE2L2 and SELENOS Modulates the Risk of Hashimoto\u2019s Thyroiditis","volume":"29","author":"Santos","year":"2019","journal-title":"Thyroid"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e15185","DOI":"10.1097\/MD.0000000000015185","article-title":"Acute exacerbation of Hashimoto\u2019s thyroiditis in a patient treated with dimethyl fumarate for multiple sclerosis: A case report","volume":"98","author":"Ciurleo","year":"2019","journal-title":"Medicine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1210\/jc.2013-2409","article-title":"The incidence and prevalence of thyroid dysfunction in Europe: A meta-analysis","volume":"99","author":"Galofre","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1034\/j.1600-0404.2003.02009.x","article-title":"Multiple sclerosis, interferon beta and clinical thyroid dysfunction","volume":"107","author":"Kreisler","year":"2003","journal-title":"Acta Neurol. Scand."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1002\/med.21567","article-title":"Dimethyl fumarate, a two-edged drug: Current status and future directions","volume":"39","author":"Saidu","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_15","first-page":"555","article-title":"Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis","volume":"8","author":"Orlando","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.clinbiochem.2012.11.021","article-title":"Enhanced oxidative stress in Hashimoto\u2019s thyroiditis: Inter-relationships to biomarkers of thyroid function","volume":"46","author":"Rostami","year":"2013","journal-title":"Clin. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e401","DOI":"10.1212\/NXI.0000000000000401","article-title":"Impaired T-cell migration to the CNS under fingolimod and dimethyl fumarate","volume":"4","author":"Mathias","year":"2017","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1016\/S0140-6736(99)02429-0","article-title":"Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis","volume":"354","author":"Coles","year":"1999","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.5455\/annalsmedres.2019.07.420","article-title":"Autoimmune polyglandular syndrome type iii which accompanies to multiple sclerosis: A case report","volume":"26","author":"Gorgel","year":"2019","journal-title":"Ann. Med. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases","volume":"18","author":"CCuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5907","DOI":"10.4049\/jimmunol.168.11.5907","article-title":"Enhanced iodination of thyroglobulin facilitates processing and presentation of a cryptic pathogenic peptide","volume":"168","author":"Dai","year":"2002","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.fct.2019.02.004","article-title":"Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: Results of a 12-week randomized trial","volume":"126","author":"Chartoumpekis","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1126\/science.aan4665","article-title":"Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity","volume":"360","author":"Kornberg","year":"2018","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5736","DOI":"10.1038\/s41467-021-25466-x","article-title":"Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera","volume":"12","author":"Poganik","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1089\/thy.2020.0044","article-title":"Mice Hypomorphic for Keap1, a Negative Regulator of the Nrf2 Antioxidant Response, Show Age-Dependent Diffuse Goiter with Elevated Thyrotropin Levels","volume":"31","author":"Ziros","year":"2021","journal-title":"Thyroid"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1001\/jama.2017.4011","article-title":"Screening for Thyroid Cancer: US Preventive Services Task Force Recommendation Statement","volume":"317","author":"Grossman","year":"2017","journal-title":"JAMA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"622","DOI":"10.4158\/EP161208.GL","article-title":"American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules\u20142016 Update","volume":"22","author":"Gharib","year":"2016","journal-title":"Endocr. Pract."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s40618-019-01105-7","article-title":"Alemtuzumab-induced thyroid events in multiple sclerosis: A systematic review and meta-analysis","volume":"43","author":"Scappaticcio","year":"2020","journal-title":"J. Endocrinol. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.2478\/enr-2021-0018","article-title":"Graves\u2019 disease with spontaneous resolution following ocrelizumab in primary progressive multiple sclerosis","volume":"55","author":"Duarte","year":"2021","journal-title":"Endocr. Regul."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/5\/1015\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:16:03Z","timestamp":1760138163000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/5\/1015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,21]]},"references-count":30,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["antiox11051015"],"URL":"https:\/\/doi.org\/10.3390\/antiox11051015","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,21]]}}}