Graves' ophtalmopathy Translated title: Oftalmopatía de Graves

Environmental, genetic, and immune factors are at play in the development of the variable clinical manifestations of Graves' ophthalmopathy (GO). Among the environmental contributions, smoking is the risk factor most consistently linked to the development or worsening of the disease. The close temporal relationship between the diagnoses of Graves' hyperthyroidism and GO have long suggested that these 2 autoimmune conditions may share pathophysiologic features. The finding that the thyrotropin receptor (TSHR) is expressed in orbital fibroblasts, the target cells in GO, supported the notion of a common autoantigen. Both cellular and humeral immunity directed against TSHR expressed on orbital fibroblasts likely initiate the disease process. Activation of helper T cells recognizing TSHR peptides and ligation of TSHR by TRAb lead to the secretion of inflammatory cytokines and chemokines, and enhanced hyaluronic acid (HA) production and adipogenesis. The resulting connective tissue remodeling results in varying degrees extraocular muscle enlargement and orbital fat expansion. A subset of orbital fibroblasts express CD34, are bone-marrow derived, and circulate as fibrocytes that infiltrate connective tissues at sites of injury or inflammation. As these express high levels of TSHR and are capable of producing copious cytokines and chemokines, they may represent an orbital fibroblast population that plays a central role in GO development. In addition to TSHR, orbital fibroblasts from patients with GO express high levels of IGF-1R. Recent studies suggest that these receptors engage in cross-talk induced by TSHR ligation to synergistically enhance TSHR signaling, HA production, and the secretion of inflammatory mediators.

Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder associated with thyroid disease which affects ocular and orbital tissues. GO follows a biphasic course in which an initial active phase of progression is followed by a subsequent partial regression and a static inactive phase. Although the majority of GO patients have a mild, self-limiting, and nonprogressive ocular involvement, about 3–7% of GO patients exhibit a severe sight-threatening form of the disease due to corneal exposure or compressive optic neuropathy. An appropriate assessment of both severity and activity of the disease warrants an adequate treatment. The VISA (vision, inflammation, strabismus, and appearance), and the European Group of Graves' Orbitopathy (EUGOGO) classifications are the two widely used grading systems conceived to assess the activity and severity of GO and guide the therapeutic decision making. A critical analysis of classification, assessment, and management systems is reported. A simplified “GO activity assessment checklist” for routine clinical practice is proposed. Current treatments are reviewed and management guidelines according to the severity and activity of the disease are provided. New treatment modalities such as specific monoclonal antibodies, TSH-R antagonists, and other immunomodulatory agents show a promising outcome for GO patients.

Graves' ophthalmopathy is defined as autoimmune inflammation of extraocular muscles and orbital fat or connective tissue, usually in patients with Graves' disease. About one in 20 patients with Graves' hyperthyroidism has moderate-to-severe Graves' ophthalmopathy. Corticosteroids have been the mainstay of treatment, but new evidence about immune mechanisms has provided a basis to explore other drug classes. Intravenous methylprednisolone pulses are more effective and better tolerated than oral prednisone in the treatment of active, moderate-to-severe Graves' ophthalmopathy. Rituximab has also been suggested as a possible replacement for intravenous corticosteroids. Two randomised controlled trials of rituximab reached seemingly contradictory conclusions-rituximab was not better with respect to the primary outcome (clinical activity score) than placebo in one trial (which, however, was confounded by rather long Graves' ophthalmopathy duration), but was slightly better than intravenous methylprednisolone pulses in the other (disease flare-ups occurred only in the latter group). On the basis of evidence published so far, rituximab cannot replace intravenous methylprednisolone pulses, but could have a role in corticosteroid-resistant cases. Open-label studies of tumour-necrosis-factor-α blockade had limited efficacy, but other studies showed that interleukin-6 receptor antibodies were effective. Results of randomised controlled trials investigating the efficacy of the IGF-1 receptor antibody teprotumumab and the interleukin-6 receptor antibody tocilizumab are expected shortly. Approaches that target the causal mechanism of Graves' ophthalmopathy (antibodies or antagonists that block thyroid-stimulating-hormone receptors) also look promising.