LAUSR

discrepancy [8],because of these conflicting results, the role of rituximab for moderate-to-severe and active GO remains to be defined in larger, multicenter RCTs [9]. The recent guidelines published by the European Thyroid Association/ European Group on Graves’ Orbitopathy (EUGOGO) [3] indicate rituximab as a possible second-line treatment for patients poorly responsive to a first course of ivGCs. Likewise, evidence is lacking concerning other potential therapeutic agents, such as adalimumab, etanercept, infliximab, monoclonals or small molecules blocking the TSH receptor [9]. Results of an ongoing RCT on the use of the interleukin-6 receptor monoclonal antibody, tocilizumab, are awaited shortly. Few weeks ago the New England Journal of Medicine has published the results of an RCT on the use of an insulin-like growth factor-1 (IGF-1) receptor-blocking monoclonal antibody, teprotumumab [10]. The rationale for using this agent resides with in vitro evidence showing the important role in GO orbital tissue played by the IGF-1 receptor,which seems to cross-talk with the TSH receptor and, thereby, modulate and enhance the pathogenic actions of TSH-receptor antibodies on the TSH receptor [2]. Accordingly, blockade of the IGF-1 receptor might attenuate the pathogenic signaling associated with TSH receptor activation by TSH receptor antibodies. In this multicenter study involving 15 American and European centers (although the large majority of patients were recruited in only six centers), 45 patients were randomized to receive placebo for 24 weeks, and 42 patients to be treated with teprotumumab (eight intravenous infusions at 3-week intervals, the first using a dose of 10 mg per kg of body weight, the remaining seven using a dose of 20 mg per kg of body weight) [10]. The primary outcome to define response was a reduction in the 7-item Clinical Activity Score (CAS) of at least two points and a reduction Management of hyperthyroidism due Graves’ disease is imperfect because therapies targeting pathogenic mechanisms of the disease are lacking [1]. Even more complex is the treatment of moderate-to-severe and active Graves’ orbitopathy (GO), the most common extrathyroidal manifestation of Graves’ disease. Although recent years have witnessed a better understanding of its pathogenesis [2], GO remains a therapeutic challenge and dilemma. Intravenous glucocorticoids (ivGCs) represent the first-line treatment for these patients [3], but results are not always satisfactory, partial responses are frequent, relapses after drug withdrawal are not uncommon, adverse events do occur, and many patients eventually require rehabilitative surgery [4, 5]. Recently, attention has been focused on the use of biologicals, which might specifically intervene on the pathogenic mechanisms of GO. In 2015 two small, monocenter, randomized clinical trials (RCTs) were published in the same issue of the Journal of Clinical Endocrinology and Metabolism: these studies investigated the effects of rituximab, a CD20+ B cell-depleting agent, versus placebo [6] or ivGCs [7], respectively. Results were conflicting, negative (no differences with placebo) in the first trial, positive (beneficial effects compared to ivGCs) in the second one [6, 7]. Although an attempt was made by the authors of the two trials to reanalyze together their own data to reconcile this