E-Poster Presentation ESA-SRB-ANZBMS 2021

Alemtuzumab-induced Graves' disease (#408)

Varun Manoharan 1 2 , Divya Namboodiri 1 , Hamish Russell 1 2 , Vincent Wong 1 2
  1. Diabetes and Endocrine Service, Liverpool Hospital, NSW
  2. South Western Sydney Clinical School, University of New South Wales, Sydney, NSW

A 22 year old female was diagnosed with Graves’ disease (GD) with ocular manifestations eight months following her first dose of alemtuzumab prescribed for refractory relapsing-remitting multiple sclerosis (RRMS).  She underwent a total thyroidectomy, and her TSH receptor antibody (TSHrAb) levels remained elevated. She had progression of her ocular disease with marked proptosis and associated exposure keratopathy.

Alemtuzumab is a humanised monoclonal antibody targeting CD52, a transmembrane protein expressed in T and B cells, which reduces relapse rate and disability progression among patients with RRMS.(1-2)  Shifts in lymphocyte kinetics lead to undesirable reconstitution autoimmunity.(3-5) The profound lymphopaenia within days of infusion depletes CD4+ T regulatory cells (80%), CD8+ T lymphocytes (>80%) and mature B lymphocytes (>85%). This is followed by repopulation of B-cells, CD8+ T-cells, and CD4+ T-cells in sequence over time (Figure 1).(6-7) The marked hyper-repopulation (180%) of immature B-cells and the slower repopulation of memory CD4+ T-cells and T regulatory cells predisposes to autoimmunity.(6-7)

Autoimmune thyroid disease is the most common reconstitution autoimmune disorder that develops in patients treated with alemtuzumab; up to 70% of patients who develop thyroid dysfunction have GD.(3) Treatment options for alemtuzumab-induced GD include anti-thyroid medications, radioactive iodine therapy and surgery.

The TSHrAb occurs in 30-40% of these patients, and interestingly, TSHrAb in patients with alemtuzumab-induced GD can be stimulatory, inhibitory or neutral, making the disease course difficult to predict.(3) Up to 15% of these patients have a fluctuating course of disease, transitioning from a hyperthyroid to a hypothyroid state and vice versa.(3)

Graves’ eye disease is rare; only seventeen cases have been reported in the literature (2 moderate; 6 severe).(5) However, this could be an underestimate as routine ophthalmological assessment was not performed in all patients.

Figure-1. Time-course repopulation of lymphocytes in patients treated with alemtuzumab.

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  1. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28.
  2. Alasdair J Coles, Cary L Twyman, Douglas L Arnold, Jeff rey A Cohen, Christian Confavreux, Edward J Fox, Hans-Peter Hartung, Eva Havrdova, Krzysztof W Selmaj, Howard L Weiner, Tamara Miller, Elizabeth Fisher, Rupert Sandbrink, Stephen L Lake, David H Margolin, Pedro Oyuela, Michael A Panzara, D Alastair S Compston, for the CARE-MS II investigators Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380: 1829–39.
  3. Scappaticcio L, Castellana M, Virili C, Bellastella G, Centanni M, Cannavò S, Campennì A, Ruggeri RM, Giovanella L, Trimboli P. Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis. J Endocrinol Invest. 2020 Feb;43(2):219-229.
  4. Daniels, Gilbert & Vladic, Anton & Brinar, Vesna & Zavalishin, Igor & Valente, William & Oyuela, Pedro & Palmer, Jeffrey & Margolin, David. Alemtuzumab-Related Thyroid Dysfunction in a Phase 2 Trial of Patients With Relapsing-Remitting Multiple Sclerosis. The Journal of clinical endocrinology and metabolism. 2013; 99(1):80-89.
  5. Roos JCP, Moran C, Chatterjee VK, Jones J, Coles A, Murthy R. Immune reconstitution after alemtuzumab therapy for multiple sclerosis triggering Graves' orbitopathy: a case series. Eye (Lond). 2019 Feb;33(2):223-229.
  6. Freedman MS, Kaplan JM, Markovic-Plese S. Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis. Journal of Clinical & Cellular Immunology. 2013; 4(4): 1-9.
  7. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurology. 2017;74(8):961-969.