LAUSR

Graves’ orbitopathy (GO) is an autoimmune orbital disease mostly associated with Graves’ hyperthyroidism, causing disfiguring signs (exophthalmos, periorbital swelling, strabismus) and relevant symptoms (diplopia, tearing, photophobia, and [rarely] sight loss) [1]. While the majority of cases are mild and require only local measures (topic treatments with artificial tears during the day and ocular gel at nighttime) and control of modifiable risk factors (especially smoking) [2], active moderate-to-severe forms represent a major therapeutic dilemma and challenge. High-dose systemic glucocorticoids, as monotherapy or combined with other treatments (mycophenolate, orbital radiotherapy, cyclosporine) and preferably administered intravenously, represent a mainstay in the management of these forms for their potent anti-inflammatory effects and immunosuppressive actions [2], but often have limited efficacy on exophthalmos. Recent promising results have been reported with targeted therapies based on biologics, such as rituximab, tocilizumab, and, particularly, teprotumumab. The latter is a fully humanized monoclonal antibody acting as insulin-like growth factor-1 (IGF-1) receptor antagonist, which has been shown in two randomized placebo-controlled multicenter trials to be highly effective on GO, with an unprecedented reduction in exophthalmos, improvement of diplopia and overall ophthalmic involvement, and a less convincing effect on quality of life [3, 4]. These results have been so impressive to convince the Food and Drug Administration (FDA) to approve teprotumumab (TepezzaTM) in 2020 for the treatment of GO. Surprisingly, the FDA-approved teprotumumab without limitations related to activity or severity of the disease, despite the fact that evidence from randomized clinical trials is limited to active moderate-to-severe forms of GO, but lacking for mild and/or inactive forms of GO, as well for sight-threatening dysthyroid optic neuropathy. In addition to problems related to accessibility (e.g., the drug has not been approved yet by the European Medicines Agency) and its exceedingly high price of more than one hundred thousands USD per cycle of treatment, there are still unanswered questions regarding durability of the favorable response, as in longer follow-up (72 weeks, i.e., 48 weeks after treatment withdrawal) 33% of patients had a relapse of exophthalmos, 31% showed a recurrence of diplopia, and 17% could be considered as overall responders any longer [5]. A relevant and unsettled issue regarding this novel drug is its safety. Teprotumumab is described as a relatively safe drug, although numerous adverse events, usually mild-tomoderate, have been reported in the two randomized clinical trials that led to registration, including muscle spasms, diarrhea, hyperglycemia, alopecia, and dysgeusia [3, 4]. One case of “Hashimotos’ encephalopathy” [3] might be viewed in a different way, considering a recent well-described case of teprotumumab-induced amyloid encephalopathy, reverted only by plasmapheresis after teprotumumab discontinuation [6]. Two newly diagnosed cases of inflammatory bowel disease (ulcerative colitis) have also been reported [7, 8]. Among other adverse events described in the two randomized clinical trials [3, 4] and the recent open-label clinical-extension OPTIC-X study [9] from the same investigators, hearing impairment seems to be a frequent untoward effect. A recent consensus paper from investigators of the two randomized clinical trials mentioned this important * L. Bartalena [email protected]