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Graves' Orbitopathy


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polymorphism in the promoter region, has also shown an association with GO (odds ratio 1.70). Moreover, exon 1 and intron 1 polymorphisms are in linkage disequilibrium with each other [67]. These findings are in line with the fact that, as for several other autoimmune disorders, the exon polymorphism of CTLA4 is associated with more severe forms. Concerning TSHR, recent work using single-nucleotide polymorphisms has identified an association of the TSHR region with GD, but not autoimmune thyroiditis. However, no data concerning GO were reported in this work [68], and the genes implicated in GO are generally assumed to be the same as for GH. Thyroid peroxidase gene polymorphism has been recently associated with serum levels of thyroid peroxidase antibody in 2 independent genome-wide association studies, and a strong association between the rs11675434 single-nucleotide polymorphism located near thyroid peroxidase and the presence of clinically evident GO has been observed, especially in males [69].

      Smoking (1) increases the incidence and the severity of GO, (2) confers a current risk, with former smokers having a lower risk than current smokers of developing GO, even for comparable lifetime tobacco consumption, (3) influences the course of GO, with the response to treatment being poorer and delayed in smokers, and (4) increases the risk of progression of GO after 131I treatment. GD patients who smoke have 5 times the risk of developing GO than those who do not. The effect of smoking is dose dependent: the relative risk of diplopia or proptosis has been reported to be 1.8 at 1–10 cigarettes/day, 3.8 for 11–20 cigarettes/day and 7.0 for more than 20 cigarettes/day. In ex-smokers, the risk is no longer significant even at >20 cigarettes/day. This suggests a direct and immediate effect of smoking. Serum levels of cytokines do not differ in smoking and non-smoking GO patients. Essentially, stopping smoking is the only GO-preventive measure.

      How smoking affects GO is conjectural, but several mechanisms have been discussed:

      •superoxide radicals generated by smoking can induce orbital fibroblasts to proliferate;

      •nicotine and tar can increase class II HLA molecule expression by orbital fibroblasts in the presence of IFN-γ;

      Current understanding of the pathophysiology of GO views the orbital fibroblast as the main target of the autoimmune process. On stimulation by proinflammatory cytokines, orbital fibroblasts are induced to interact with activated autoreactive immune cells present within orbital tissues. As a consequence, they produce an excess of GAG, proliferate and can differentiate into adipocytes, as well as secrete cytokines, chemoattractants and an excess of prostaglandin E2.

      At this point, several possible therapeutic routes could theoretically be explored:

      •Interfering with upregulated functions of orbital fibroblasts. While glucocorticoids interfere with the production of both GAG and prostaglandin E, more specific agents could be considered, for instance cyclo-oxygenase inhibitors and non-steroid anti-inflammatory drugs. Due to its central role in adipogenesis, the use of antagonists of PPAR-γ or of selective PPAR-γ modulators represents a logical route to be considered. However, because of the pleiotropic effects of PPAR-γ on metabolism, inflammation, fibrosis, etc., preliminary studies using reliable experimental models of GO are mandatory.