Perspective Novel Immunomodulating Agents for Graves Orbitopathy Luigi Bartalena, M.D.*, Adriana Lai, M.D.*, Emanuele Compri, M.D.*, Claudio Marcocci, M.D.†, and Maria Laura Tanda, M.D.* *Department of Clinical Medicine, University of Insubria, Division of Endocrinology, Ospedale di Circolo, Varese; and †Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy G raves orbitopathy (GO), the major extrathyroidal expression of Graves disease, is a disorder of auto- immune origin. 1 Although its natural history is incom- pletely understood, it undergoes an initial period of inflammation (active phase), then stabilizes (plateau or static phase), and finally spontaneously remits (inactiva- tion phase). 2 Remission is, however, inevitably partial, and residual cosmetic and/or functional ocular abnormal- ities are responsible for a marked impairment in the quality of life of affected individuals. 3 The ideal situation would be to prevent GO occurrence, but this is impos- sible under most circumstances. Nevertheless, an active control of factors such as cigarette smoking and thyroid dysfunction, which are known to be associated with an increased risk of GO occurrence and exacerbation (Table 1), is essential. 4 When GO is mild and its activity is low, an expectant strategy (“wait-and-see”) may be justified, and treatment may be limited to topical agents (artificial tears, ointments, prisms). 5 When GO is full-blown, ac- tive, and moderate to severe, its management still relies after many decades on the use of glucocorticoids, most commonly given intravenously, with or without associ- ated orbital radiotherapy. 6 Inactive (burnt-out) GO is not responsive to immunosuppressive therapy and may re- quire orbital decompression, if exophthalmos is severe with corneal exposure, or dysthyroid optic neuropathy is present. 6 Because many patients ultimately are unhappy with treatment outcome, rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) for cos- metic and/or functional disturbances is needed in at least one third of patients. 1 Thus, medical therapy of GO has changed very little in the last 30 to 40 years and still is based on “jurassic” treatments. What are the reasons for this disappointing lack of progress? Several factors contribute to it, includ- ing the incomplete understanding of GO pathogenesis, and late intervention, the latter often being related to the lack of a “global” strategy for the management of thyroid disease and eye disease. Early intervention is a major issue, because medical treatment is effective only in the active phase of the disease and should possibly be ap- plied within 1 year from the onset of GO. 7 The pathogenesis of GO is incompletely understood. The leading pathogenic hypothesis, which takes in ac- count the association and temporal link of thyroid dis- ease and orbital disease, is that GO is an autoimmune disorder triggered by autoreactive T-lymphocytes react- ing with 1 or more antigens shared by thyroid and orbital tissues. 1 According to this hypothesis, intrathyroidal au- toreactive T-lymphocytes might reach the orbit, where they recognize the common antigen (or antigens) pre- sented by antigen-presenting cells, such as dendritic cells, macrophages and B-lymphocytes. After antigen recognition, a cascade of events would be triggered, leading to secretion of a number of cytokines, which, in turn, stimulate fibroblast proliferation, preadipocyte dif- ferentiation in adipocytes, and secretion of glycosamino- glycans from fibroblasts. The latter, in view of their hydrophilic features, attract water leading to edema of periocular tissue. The increased orbital content (fibroadi- pose tissue, extraocular muscles infiltrated by inflammatory cells) explain mechanically most clinical manifestations of GO. 8 Experimental evidence supports this hypothesis. For example, autologous T-lymphocytes of GO patients can stimulate proliferation of orbital fibroblasts, and this effect requires overexpression of class II major histocompatibility complex antigens and costimulators on antigen-presenting cells, because it can be abrogated by coexposure to anti- bodies to class II major histocompatibility complex or CD40. 9 Different patterns of cytokine production from orbital T-cells have been reported, with a prevalent T-helper (Th)1 pattern [secretion of interleukin (IL)-2, interferon-, Accepted for publication January 9, 2008. Presented by Professor Bartalena as a plenary lecture at the 38th Annual Fall Meeting of the American Society of Ophthalmic Plastic and Reconstructive Surgery, New Orleans, LA, November 9 –10, 2007. This work was partially supported by grants from the Italian Ministry of University and Research (MUR, Rome) and the University of Insubria at Varese to Luigi Bartalena. Address correspondence and reprint requests to Luigi Bartalena, Department of Clinical Medicine, University of Insubria, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. E-mail: l.bartalena@libero.it or luigi.bartalena@uninsubria.it DOI: 10.1097/IOP.0b013e318179f8a5 Ophthalmic Plastic and Reconstructive Surgery Vol. 24, No. 4, pp 251–256 ©2008 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. 251