title: Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis.
abstract: BACKGROUND
  Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis.
  
  
  OBJECTIVE
  The objective of the study was a detailed description of thyroid dysfunction in CAMMS223.
  
  
  METHODS
  Relapsing-remitting multiple sclerosis patients (n=334) were randomized 1:1:1 to 44 μg sc interferon-β-1a (SC IFNB-1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; antithyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist.
  
  
  RESULTS
  During a median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB-1a patients had thyroid dysfunction (P<.0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had more than one episode of thyroid dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves' hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII positive. The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year.
  
  
  CONCLUSIONS
  Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves' hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism after overt Graves' hyperthyroidism, and a high prevalence of TBII-positive overt hypothyroidism.
authors.affiliation: Department of Medicine and Thyroid Unit (G.H.D.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Neurology (A.V.), General Hospital 'Sveti Duh,' and Department of Neurology (V.B.), Zagreb Medical School and University Hospital Center, Zagreb HR-10000, Croatia; Scientific Research Institute of Neurology of Russian Academy of Medical Sciences (I.Z.), Moscow 123367, Russia; Division of Endocrinology, Diabetes, and Nutrition (W.V.), University of Maryland School of Medicine, Baltimore, Maryland 21201; and Genzyme Corporation, a Sanofi Company (P.O., J.P., D.H.M.), Cambridge, Massachusetts 02142.
authors.forename: Gilbert H
authors.initials: GH
authors.lastname: Daniels
authors.forename: Anton
authors.initials: A
authors.lastname: Vladic
authors.forename: Vesna
authors.initials: V
authors.lastname: Brinar
authors.forename: Igor
authors.initials: I
authors.lastname: Zavalishin
authors.forename: William
authors.initials: W
authors.lastname: Valente
authors.forename: Pedro
authors.initials: P
authors.lastname: Oyuela
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Palmer
authors.forename: David H
authors.initials: DH
authors.lastname: Margolin
authors.forename: Jenna
authors.initials: J
authors.lastname: Hollenstein
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects*; D001323:Autoantibodies / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D013959:Thyroid Diseases / Q000097:blood / Q000453:epidemiology / Q000209:etiology*; D013960:Thyroid Function Tests; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D018828:Immunoglobulins, Thyroid-Stimulating; C056626:thyroid microsomal antibodies; C094372:thyrotropin-binding inhibitory immunoglobulin; D000074323:Alemtuzumab; D016899:Interferon-beta; D000068556:Interferon beta-1a