Читать книгу Graves' Orbitopathy - Группа авторов - Страница 79

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.

Current therapeutic approaches are based on non-specific immunosuppression by glucocorticoids and orbit radiotherapy. For years, more specific immunomodulatory treatments have been considered, and some have been tested [79, 80]. Among the classical immunosuppressants, only cyclosporine has shown some efficacy in combination with glucocorticoids. Somatostatin analogues, if assimilated to immunosuppressive agents because of the expression of somatostatin receptors by activated lymphocytes, have not proved to be of significant efficacy. However, the newer analogues – such as SOM230, which has a broader range of specificity than octreotide, for example – may potentially be of use in light of reports of expression of various somatostatin receptor subtypes in orbital fibroblasts [81].

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.

•Disruption of signal cascades regulating the tissue-remodelling processes which cause GO. Combined inhibition of PI3K-1A and mTORC1 signalling in vitro decreased both HA accumulation and adipogenesis [11] whilst targeting common downstream 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.