transcription factors (FOXOs) also showed potential [82]. Likewise, inhibition of HIF-1 decreased VEGF secretion and adipogenesis which could prevent hypoxia-dependent tissue remodelling and expansion [46].
•Inhibition of cytokine actions. GO appears as a cytokine-driven disease; therefore, anticytokine approaches could be considered as in other autoimmune/inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease. Anti-TNF-α (etanercept, TNF-α receptor ectodomain fusion protein antagonist), which neutralizes the expression of other proinflammatory cytokines, has been tested in a small open-label trial in 10 patients with some improvement in the clinical activity score (from moderate to marked in 60% of the patients) [83]; tolerance was satisfactory. Controlled trials are obviously needed. The use of anti-IL-1 and anti-IL-6 could also be considered. The use of anti-IL-1 has been suggested in in vitro studies, to inhibit fibroblast proliferation [84]. The anti-IL-6 receptor monoclonal antibody tocilizumab has been tried in an open-label study with promising results [85].
•Deletion or downregulation of activated autoreactive lymphocytes. Several approaches are possible. The CTLA-4 agonist (abatacept), a potent inhibitor of T-cell proliferation, has been tested in psoriasis and rheumatoid arthritis. A non-mitogenic humanized anti-CD3 monoclonal antibody, the effect of which is to induce CD8+ and CD4+CD25+ T regulator cells, has been beneficial in two large controlled trials in type 1 diabetes. After initial reports indicating the potential beneficial effect of B-cell depletion by anti-CD20 monoclonal antibody (rituximab) [39, 40], 2 randomized controlled trials, 1 placebo-controlled conducted in the USA and 1 challenging intravenous steroids in the control arm in Italy, have recently been published [86]. Whilst one study found that rituximab was not superior to placebo, the other indicated that rituximab was significantly better than steroids in persistent GO inactivation. The lack of efficacy in the US trial may depend on a much longer duration of disease in treated patients compared to the very short duration (4.5 months) of patients in the Italian trial. A most interesting finding in patients treated with rituximab is the lack of disease relapse after 1 single dose of treatment, which suggests that the anti-CD20 monoclonal antibody probably depletes the target tissues from B cells that act as antigen-presenting cells at the very early stage of disease. This observation was unexpected and points to B cells playing an important role in the pathogenesis of GO not only in producing antibodies, but also as antigen-presenting cells (as mentioned above) and in secreting cytokines. Other B-cell-depleting pathways are available, through blockade of ligands from the TNF family, such as BAFF and APRIL. A randomized controlled trial challenging belimumab, an anti-BAFF monoclonal antibody, versus steroids is currently under way, after preliminary evidence of BAFF and its receptor being expressed on the thyrocyte [87] and serum BAFF concentrations being elevated in GD and GO [88].
However, a word of caution is necessary. Not only is the pathogenic antigenic system of GO still uncertain, but it is obvious that modulation of the cytokine network (as well as that of the number and functional state of T or B cells) might induce deleterious consequences disproportionate with the usual morbidity of GO.
A recent novel approach which uses TSH-R antagonists, either TSH-R-blocking antibodies or small molecules with TSH-R-blocking activity, may be an option to treat GH and GO. Antagonizing TSH-R in vitro decreased HA secretion of orbital fibroblasts [89].
As with cytokine therapy, clarification of the possible benefits, using in vitro or, rather, in vivo models of GO, is badly needed.
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