BACKGROUND: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. OBJECTIVE: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. METHODS: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. RESULTS: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. CONCLUSION: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients.ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553).

1st Medical Faculty Department of Neurology Charles University Prague Czech Republic

Advanced Neurosciences Institute Franklin TN USA

Cardiff University School of Medicine Cardiff UK

Cardiff University School of Medicine Cardiff UK Fondazione IRCCS Ca' Granda Ospedale Policlinico Maggiore Milan Italy University of Milan Milan Italy

Center of Clinical Neuroscience Carl Gustav Carus University Hospital Dresden Germany

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany Brain and Mind Centre University of Sydney Sydney Australia Department of Neurology Medical University of Vienna Vienna Austria Department of Neurology Palacky University Olomouc Olomouc Czech Republic

Department of Neurology University of Warmia and Mazury Olsztyn Poland

La Paz University Hospital Universidad Autónoma de Madrid Madrid Spain

North Central Neurology Associates Cullman AL USA

Sanofi Cambridge MA USA

Universitair MS Centrum Hasselt Pelt Belgium

University of Alberta Edmonton Alberta Canada

Zobrazit více v PubMed

Genzyme Corporation LEMTRADA (alemtuzumab). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103948s5158lbl.pdf. Accessed 8 January 2020.

Sanofi Belgium LEMTRADA summary of product characteristics. Accessed 8 January 2020.

Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380: 1819–1828. PubMed

Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology 2017; 89: 1117–1126. PubMed PMC

Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839. PubMed

Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 2017; 89: 1107–1116. PubMed PMC

Coles AJ, Arnold DL, Bass AD, et al. Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial. Ther Adv Neurol Disord 2021; 14: 175628642098213. PubMed PMC

Comi G, Alroughani R, Boster AL, et al. Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: pooled analysis of the CARE-MS, extension, and TOPAZ studies. Mult Scler 2020; 26: 1866–1876. PubMed PMC

Freedman MS, Kaplan JM, Markovic-Plese S. Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in multiple sclerosis. J Clin Cell Immunol 2013; 4: 1000152. PubMed PMC

Hu Y, Turner MJ, Shields J, et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128: 260–270. PubMed PMC

Wiendl H, Carraro M, Comi G, et al. Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab. Neurol Neuroimmunol Neuroinflamm 2020; 7: e635. PubMed PMC

Durelli L, DeMercanti S, Rolla S, et al. Alemtuzumab long-term immunological study: the immunosuppressive effect does not last more than 48 months. Neurology 2016; 86: S2.008.

De Mercanti S, Rolla S, Cucci A, et al. Alemtuzumab long-term immunologic effect: treg suppressor function increases up to 24 months. Neurol Neuroimmunol Neuroinflamm 2016; 3: e194. PubMed PMC

Hartung H, Arnold D, Cohen J, et al. Lymphocyte subset dynamics following alemtuzumab treatment in the CARE-MS I study. Mult Scler 2012; 18: 935.

Kasper L, Arnold D, Coles A, et al. Lymphocyte subset dynamics following alemtuzumab treatment in the CARE-MS II study. Mult Scler 2013; 18: 531.

Bertolotto A, Arroyo R, Celius EG, et al. Quality of life improves with alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients with or without autoimmune thyroid adverse events: post hoc analysis of the CARE-MS studies. Neurol Ther 2020; 9: 443–457. PubMed PMC

Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 2017; 10: 343–359. PubMed PMC

Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 2015; 86: 208–215. PubMed

Cuker A, Bass AD, Nadj C, et al. Immune thrombocytopenia in alemtuzumab-treated MS patients: incidence, detection, and management. Mult Scler 2020; 26: 48–56. PubMed PMC

Phelps R, Winston JA, Wynn D, et al. Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis. Mult Scler 2019; 25: 1273–1288. PubMed PMC

Sanofi Genzyme LEMTRADA REMS (Risk Evaluation and Mitigation Strategy) program. Accessed 19 November 2020.

Pariani N, Willis M, Muller I, et al. Alemtuzumab-induced thyroid dysfunction exhibits distinctive clinical and immunological features. J Clin Endocrinol Metab 2018; 103: 3010–3018. PubMed PMC

Mohammed MS, Shoeib NS, Sabry IM, et al. Evaluation of thyroid functions in patients with multiple sclerosis before and after treatment with interferon beta. J Thyroid Disord Ther 2018; 7: 227.

Sloka JS, Phillips PW, Stefanelli M, et al. Co-occurrence of autoimmune thyroid disease in a multiple sclerosis cohort. J Autoimmune Dis 2005; 2: 9. PubMed PMC

Frisullo G, Calabrese M, Tortorella C, et al. Thyroid autoimmunity and dysfunction in multiple sclerosis patients during long-term treatment with interferon beta or glatiramer acetate: an Italian multicenter study. Mult Scler 2014; 20: 1265–1268. PubMed

Monzani F, Caraccio N, Casolaro A, et al. Long-term interferon beta-1b therapy for MS: is routine thyroid assessment always useful? Neurology 2000; 55: 549–552. PubMed

Ruck T, Barman S, Schulte-Mecklenbeck A, et al. Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity. Brain 2022; 145: 1711–1725. PubMed PMC

Daniels GH, Vladic A, Brinar V, et al. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab 2014; 99: 80–89. PubMed

Rotondi M, Molteni M, Leporati P, et al. Autoimmune thyroid diseases in patients treated with alemtuzumab for multiple sclerosis: an example of selective anti-TSH-receptor immune response. Front Endocrinol (Lausanne) 2017; 8: 254. PubMed PMC

Ruck T, Schulte-Mecklenbeck A, Pfeuffer S, et al. Pretreatment anti-thyroid autoantibodies indicate increased risk for thyroid autoimmunity secondary to alemtuzumab: a prospective cohort study. EBioMedicine 2019; 46: 381–386. PubMed PMC

Muller I, Moran C, Lecumberri B, et al. European Thyroid Association guidelines on the management of thyroid dysfunction following immune reconstitution therapy. Eur Thyroid J 2019; 8: 173–185. PubMed PMC

Gonzalez-Aguilera B, Betea D, Lutteri L, et al. Conversion to Graves disease from Hashimoto thyroiditis: a study of 24 patients. Arch Endocrinol Metab 2018; 62: 609–614. PubMed PMC

Muller I, Willis M, Healy S, et al. Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy: evidence that TRAb may precede thyroid dysfunction by many years. Thyroid 2018; 28: 1682–1693. PubMed

Sovetkina A, Nadir R, Scalfari A, et al. Development of autoimmune thyroid disease in multiple sclerosis patients post-alemtuzumab improves treatment response. J Clin Endocrinol Metab 2020; 105: e3392–e3399. PubMed

Humar M, Dohrmann H, Stein P, et al. Thionamides inhibit the transcription factor nuclear factor-kappaB by suppression of Rac1 and inhibitor of kappaB kinase alpha. J Pharmacol Exp Ther 2008; 324: 1037–1044. PubMed

Kahan BC, Feagan B, Jairath V. A comparison of approaches for adjudicating outcomes in clinical trials. Trials 2017; 18: 266. PubMed PMC

Barclay K, Carruthers R, Traboulsee A, et al. Best practices for long-term monitoring and follow-up of alemtuzumab-treated MS patients in real-world clinical settings. Front Neurol 2019; 10: 253. PubMed PMC

Decallonne B, Bartholomé E, Delvaux V, et al. Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management. Acta Neurol Belg 2018; 118: 153–159. PubMed PMC

Devonshire V, Phillips R, Wass H, et al. Monitoring and management of autoimmunity in multiple sclerosis patients treated with alemtuzumab: practical recommendations. J Neurol 2018; 265: 2494–2505. PubMed PMC

Zobrazit více v PubMed

ClinicalTrials.gov
NCT00548405, NCT00530348, NCT00930553