Objective: To systematically review recent advances in the pharmacotherapy of Graves’ disease (GD) and provide evidence-based recommendations for individualized clinical management. Methods: We conducted a comprehensive literature search of PubMed, Cochrane Library, and CNKI databases for studies published within the past ten years focusing on antithyroid drugs (ATDs), biologics, and small-molecule targeted therapies. Results: Traditional ATDs remain first-line therapy for GD; however, relapse rates following discontinuation approach 50%. Novel targeted therapies—including anti-CD20 monoclonal antibodies (rituximab), anti-CD40 monoclonal antibodies (iscalimab), and neonatal Fc receptor (FcRn) antagonists—have demonstrated potential in reducing thyrotropin receptor antibody (TRAb) titers and improving remission rates in refractory GD. TSH receptor (TSHR) blocking antibodies and small-molecule antagonists represent promising etiological treatment strategies. Conclusion: GD pharmacotherapy is transitioning from empirical immunosuppression to precision-targeted interventions. Future therapeutic paradigms should emphasize individualized treatment protocols and discontinuation strategies guided by dynamic TRAb monitoring.
References
[1]
Lee, S.Y. and Pearce, E.N. (2023) Hyperthyroidism. Journal of the American Medical Association, 330, 1472-1483. https://doi.org/10.1001/jama.2023.19052
[2]
Li, Y., Teng, D., Ba, J., Chen, B., Du, J., He, L., et al. (2020) Efficacy and Safety of Long-Term Universal Salt Iodization on Thyroid Disorders: Epidemiological Evidence from 31 Provinces of Mainland China. Thyroid, 30, 568-579. https://doi.org/10.1089/thy.2019.0067
[3]
Chaker, L., Cooper, D.S., Walsh, J.P. and Peeters, R.P. (2024) Hyperthyroidism. The Lancet, 403, 768-780. https://doi.org/10.1016/s0140-6736(23)02016-0
[4]
Lanzolla, G., Marinò, M. and Menconi, F. (2024) Graves Disease: Latest Understanding of Pathogenesis and Treatment Options. Nature Reviews Endocrinology, 20, 647-660. https://doi.org/10.1038/s41574-024-01016-5
[5]
Lee, A.C.H. and Kahaly, G.J. (2025) Targeted Immunotherapies for Graves’ Thyroidal & Orbital Diseases. Frontiers in Immunology, 16, Article 1571427. https://doi.org/10.3389/fimmu.2025.1571427
[6]
Abdi, H., Amouzegar, A. and Azizi, F. (2019) Antithyroid Drugs. Iranian Journal of Pharmaceutical Research, 18, 1-12.
[7]
Li, J., Bai, L., Wei, F., Wei, M., Xiao, Y., Yan, W., et al. (2021) Effect of Addition of Thyroxine in the Treatment of Graves’ Disease: A Systematic Review. Frontiers in Endocrinology, 11, Article 560157. https://doi.org/10.3389/fendo.2020.560157
[8]
Ross, D.S., Burch, H.B., Cooper, D.S., Greenlee, M.C., Laurberg, P., Maia, A.L., et al. (2016) 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid, 26, 1343-1421. https://doi.org/10.1089/thy.2016.0229
[9]
Azizi, F., Amouzegar, A., Tohidi, M., Hedayati, M., Khalili, D., Cheraghi, L., et al. (2019) Increased Remission Rates after Long-Term Methimazole Therapy in Patients with Graves' Disease: Results of a Randomized Clinical Trial. Thyroid, 29, 1192-1200. https://doi.org/10.1089/thy.2019.0180
[10]
Park, S.Y., Kim, B.H., Kim, M., Hong, A.R., Park, J., Park, H., et al. (2021) The Longer the Antithyroid Drug Is Used, the Lower the Relapse Rate in Graves’ Disease: A Retrospective Multicenter Cohort Study in Korea. Endocrine, 74, 120-127. https://doi.org/10.1007/s12020-021-02725-x
[11]
Mohlin, E., Filipsson Nyström, H. and Eliasson, M. (2014) Long-Term Prognosis after Medical Treatment of Graves’ Disease in a Northern Swedish Population 2000–2010. European Journal of Endocrinology, 170, 419-427. https://doi.org/10.1530/eje-13-0811
[12]
Schott, M., Morgenthaler, N.G., Fritzen, R., et al. (2004) Levels of Autoantibodies against Human TSH Receptor Predict Relapse of Hyperthyroidism in Graves’ Disease. Hormone and Metabolic Research, 36, 92-96.
[13]
Otsuka, F., Noh, J.Y., Chino, T., Shimizu, T., Mukasa, K., Ito, K., et al. (2012) Hepatotoxicity and Cutaneous Reactions after Antithyroid Drug Administration. Clinical Endocrinology, 77, 310-315. https://doi.org/10.1111/j.1365-2265.2012.04365.x
[14]
Robinson, J., Richardson, M., Hickey, J., James, A., Pearce, S.H., Ball, S.G., et al. (2014) Patient Knowledge of Antithyroid Drug-Induced Agranulocytosis. European Thyroid Journal, 3, 245-251. https://doi.org/10.1159/000367990
[15]
Wang, M., Lee, W., Huang, T., Chu, C. and Hsieh, C. (2014) Antithyroid Drug-Related Hepatotoxicity in Hyperthyroidism Patients: A Population-Based Cohort Study. British Journal of Clinical Pharmacology, 78, 619-629. https://doi.org/10.1111/bcp.12336
[16]
Bahn, R.S., Burch, H.B., Cooper, D.S., Garber, J.R., Greenlee, M.C., Klein, I., et al. (2011) Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocrine Practice, 17, 456-520. https://doi.org/10.4158/ep.17.3.456
[17]
Noh, J.Y., Yasuda, S., Sato, S., Matsumoto, M., Kunii, Y., Noguchi, Y., et al. (2009) Clinical Characteristics of Myeloperoxidase Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Caused by Antithyroid Drugs. The Journal of Clinical Endocrinology & Metabolism, 94, 2806-2811. https://doi.org/10.1210/jc.2008-2700
[18]
Stagnaro-Green, A., Abalovich, M., Alexander, E., Azizi, F., Mestman, J., Negro, R., et al. (2011) Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and Postpartum. Thyroid, 21, 1081-1125. https://doi.org/10.1089/thy.2011.0087
[19]
Andersen, S.L., Olsen, J., Wu, C.S. and Laurberg, P. (2013) Birth Defects after Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study. The Journal of Clinical Endocrinology & Metabolism, 98, 4373-4381. https://doi.org/10.1210/jc.2013-2831
[20]
Abalovich, M., Amino, N., Barbour, L.A., Cobin, R.H., De Groot, L.J., Glinoer, D., etal. (2007) Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 92, S1-S7. https://doi.org/10.1210/jc.2007-0141
[21]
Mooij, C.F., Cheetham, T.D., Verburg, F.A., Eckstein, A., Pearce, S.H., Léger, J., et al. (2022) 2022 European Thyroid Association Guideline for the Management of Pediatric Graves’ Disease. European Thyroid Journal, 11, e210073. https://doi.org/10.1530/etj-21-0073
[22]
Ylli, D., Klubo-Gwiezdzinska, J. and Wartofsky, L. (2019) Thyroid Emergencies. Polish Archives of Internal Medicine, 129, 526-534. https://doi.org/10.20452/pamw.14876
[23]
Cheetham, T.D., Cole, M., Abinun, M., Allahabadia, A., Barratt, T., Davies, J.H., et al. (2022) Adjuvant Rituximab—Exploratory Trial in Young People with Graves Disease. The Journal of Clinical Endocrinology & Metabolism, 107, 743-754. https://doi.org/10.1210/clinem/dgab763
[24]
Huerva, V. (2011) Rituximab for Treatment of Graves Orbitopathy. Archivos de la Sociedad Española de Oftalmología (English Edition), 86, 162-163. https://doi.org/10.1016/j.oftale.2011.01.007
[25]
Heemstra, K.A., Toes, R.E., Sepers, J., Pereira, A.M., Corssmit, E.P., Huizinga, T.W.J., et al. (2008) Rituximab in Relapsing Graves’ Disease, a Phase II Study. European Journal of Endocrinology, 159, 609-615. https://doi.org/10.1530/eje-08-0084
[26]
Kahaly, G.J., Stan, M.N., Frommer, L., Gergely, P., Colin, L., Amer, A., et al. (2020) A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves Hyperthyroidism—A Proof-of-Concept Trial. The Journal of Clinical Endocrinology & Metabolism, 105, 696-704. https://doi.org/10.1210/clinem/dgz013
[27]
Lin, J., Wang, Y., Fang, W., Hsiao, C., Chagnaadorj, A., Lin, Y., et al. (2016) Serum BAFF and Thyroid Autoantibodies in Autoimmune Thyroid Disease. Clinica Chimica Acta, 462, 96-102. https://doi.org/10.1016/j.cca.2016.09.004
[28]
Tanaka, Y., Curtis, P., DeRose, K., Kurrasch, R., Kinoshita, K., Tanaka, R., et al. (2023) Long-Term Safety and Efficacy of Belimumab in Japanese Patients with SLE: A 7-Year Open-Label Continuation Study. Modern Rheumatology, 33, 122-133. https://doi.org/10.1093/mr/roab125
[29]
Lane, L.C., Cheetham, T.D., Perros, P. and Pearce, S.H.S. (2020) New Therapeutic Horizons for Graves’ Hyperthyroidism. Endocrine Reviews, 41, 873-884. https://doi.org/10.1210/endrev/bnaa022
[30]
Furmaniak, J., Sanders, J., Sanders, P., Li, Y. and Rees Smith, B. (2022) TSH Receptor Specific Monoclonal Autoantibody K1‐70TM Targeting of the TSH Receptor in Subjects with Graves’ Disease and Graves’ Orbitopathy—Results from a Phase I Clinical Trial. ClinicalEndocrinology, 96, 878-887. https://doi.org/10.1111/cen.14681
[31]
Jansson, L., Vrolix, K., Jahraus, A., Martin, K.F. and Wraith, D.C. (2018) Immunotherapy with Apitopes Blocks the Immune Response to TSH Receptor in HLA-DR Transgenic Mice. Endocrinology, 159, 3446-3457. https://doi.org/10.1210/en.2018-00306
[32]
McLachlan, S.M. and Rapoport, B. (2019) A Transgenic Mouse That Spontaneously Develops Pathogenic TSH Receptor Antibodies Will Facilitate Study of Antigen-Specific Immunotherapy for Human Graves’ Disease. Endocrine, 66, 137-148. https://doi.org/10.1007/s12020-019-02083-9
[33]
Neumann, S., Eliseeva, E., McCoy, J.G., Napolitano, G., Giuliani, C., Monaco, F., etal. (2011) A New Small-Molecule Antagonist Inhibits Graves’ Disease Antibody Activation of the TSH Receptor. The Journal of Clinical Endocrinology & Metabolism, 96, 548-554. https://doi.org/10.1210/jc.2010-1935
