Graves’ ophthalmopathy is the most common extra-thyroidal manifestation of Graves’ disease and is characterized by an inflammatory response of the orbital tissues, that is, an increase in the amount of fat due to abnormal synthesis of fibroblasts (preadipocytes), which leads to remodeling of the ocular muscles, orbital connective tissue and tissues. Immune cross-reactivity of thyroid and foveal surface antigens may be the pathogenesis of Graves’ ophthalmopathy, with thyrotropin receptor (TSH-R) and IGF-1 receptor (IGF-1R) on foveal fibroblasts playing a key role.
Most of the articles published within the last few years have been on the pathogenesis of Graves’ ophthalmopathy, and although they reflect the most recent research, the available reviews have focused on the treatment of active Graves’ ophthalmopathy, emphasizing the importance of immunosuppression. Recent relevant studies (mostly open-ended) have reported the potential efficacy of novel therapeutic approaches, and these biologic agents may serve as alternatives to steroidal immunosuppressive agents.
For decades, steroids have been the first-line agents for the treatment of active Graves’ ophthalmopathy, as there are no convincing data to support other drugs with equal or better anti-inflammatory and immunosuppressive effects than those available. Most studies have shown that corticosteroids can reduce inflammation and congestion in the eye socket.
Typically, improvement is seen within one week of oral prednisone (0.5-1 mg/kg/d), and the dose is then gradually reduced to the lowest dose needed to maintain improvement. However, if treatment is prolonged, long-term side effects may occur, including hepatotoxicity, Cushing’s syndrome, osteoporosis, cataracts, glaucoma, and diabetes.
Recently, a growing number of studies have shown that intravenous methylprednisolone (ivMP) shock therapy is more effective and causes fewer side effects than oral high-dose prednisone. However, a limitation of this therapy is that a significant proportion (20-30%) of patients with active Graves’ ophthalmopathy do not respond to ivMP, and another 10-20% of patients are prone to relapse after stopping treatment.
In a recent large, multicenter clinical trial of patients with active Graves’ ophthalmopathy conducted by the European Graves Eye Group Center, approximately 70% of patients treated with high-dose ivMP (cumulative dose of 7.5 g) shock therapy improved inflammation, and high-dose ivMP was more effective than medium-dose (5 g) and low-dose (2.5 g), but only 50% of patients had improvement in eye muscle function. The effect of high dose ivMP was stronger than that of medium dose (5g) and low dose (2.5g), but only 50% of patients had improvement in eye muscle function.
Up to 20% of patients did not respond to any dose of steroid therapy and, more importantly, more than 4% of patients showed disease progression and were prone to develop thyroid-related ophthalmopathy optic neuropathy (DON) due to suppression of the optic nerve in the eye socket.
For these reasons, within the last few years, alternative immunosuppressive therapies have been discovered based on the hypothesis that the available novel drugs target different antigens in the pathogenesis of Graves’ ophthalmopathy.
Targets of immunotherapy for Graves’ ophthalmopathy
The main factors associated with the inflammatory response phase of Graves’ ophthalmopathy (i.e., the active phase, in which disease progression leads to enlargement of the eye socket, degrading the patient’s visual function and affecting the patient’s quality of life) are as follows: first, antigens expressed on inflammatory target organs, namely fibroblast surface TSH-R and IGF-1R; second, inflammatory cytokines and other humoral factors involved in multiple stages of disease progression factors; and again, immune effector cells, B cells and T cells.
Targeting TSH receptors
Currently available substances are TSH-R small molecules, and two groups of researchers have investigated their role in thyroid cells and eye socket fibroblasts. Their studies provide important clues for the development of TSH-R antagonists. These small molecules can function as TSH-R agonists (activating the receptor), neutral antagonists (inhibiting agonist-induced receptor activation), and inverse agonists (inhibiting agonist-induced receptor activation, as well as basal and constitutive activation).
Reverse TSH-R agonists may be effective in the treatment of Graves’ hyperthyroidism, particularly in those patients most likely to achieve remission and those with Graves’ ophthalmopathy. It was shown that in a TSH-R-expressing Fischer rat thyroid cell line (FRTL-5), the compound Org274179-0 was able to inhibit basal, TSH-activated as well as thyroid-stimulating antibody-activated signaling.
Thus, TSH-R antagonists are also able to inhibit TSH-R activation on Graves’ eye fossa fibroblasts, which represents a novel treatment for Graves’ eye disease. In addition to this, another small molecule TSH-R antagonist, NCGC00229600, inhibits TSH-R ligands on foveal fibroblasts, which in turn allows hyaluronic acid to accumulate in the fovea. These findings support the hypothesis that a potent TSH-R antagonist may be beneficial in the treatment of Graves’ disease in the future.
Targeting the IGF-1 receptor
IGF-1R is co-expressed with TSH-R on foveal fibroblasts in patients with Graves’ ophthalmopathy. Tietumumab (RV001), a fully humanized monoclonal antibody that binds to the IGF-IR extracellular subunit structural domain, has been used as a treatment for a variety of solid tumors and lymphomas. Recent studies have demonstrated its ability to reduce the proliferation of normal cells and Graves’ ophthalmopathy fibroblasts. Tietumumab is currently in a Phase 2 randomized placebo-controlled clinical trial in patients with active Graves’ ophthalmopathy. The study is being conducted in the United States and Europe with a planned enrollment of 80-100 patients and is expected to be completed in 2016.
Targeting inflammatory cytokines
1. Tumor necrosis factor-alpha
Inflammatory cytokines play a major role in triggering and maintaining the inflammatory response. Studies have shown that tumor necrosis factor-α (TNF-α) has an important role in Graves’ eye disease and other autoimmune diseases. The anti-TNF drug etanercept is a dimeric fusion protein containing the extracellular ligand binding domain of the human 75 kDa TNF-α receptor. Etanercept binds specifically to TNF and blocks TNF binding to cell surface receptors. paridaens et al. treated 10 patients with active Graves’ ophthalmopathy with etanercept and six patients did not respond. Moreover, to date, no study has reported that the efficacy and side effects of etanercept are superior to those of ivMP.
2. Interleukin-6 (IL-6)
Studies have shown that IL-6 and soluble IL-6 receptors are activated and serum soluble IL-6 receptor concentrations are elevated in patients with Graves’ ophthalmopathy. Tolimumab is an FDA-approved humanized IL-6 receptor monoclonal Ig
G1 antibody for the treatment of moderately to severely active rheumatoid arthritis (RA), has shown better promise in a recent clinical trial in patients with ivMP-resistant Graves’ eye disease.
The study showed improvement in clinical activity scores in 18 patients after treatment with tolimumab, reduced ocular prominence in 13 patients, improved ocular mobility in 15 patients, and improved compressive optic neuropathy in one patient who did not require foveal decompression. These preliminary positive results warrant an in-depth clinical trial.
3. Interleukin-1 (IL-1)
Early studies by Cawood et al. showed that IL-1 stimulated the proliferation of foveal fibroblasts in vitro and that activity was enhanced by the addition of tobacco extract to the culture medium, but this effect was able to be inhibited by anti-IL-1 antibodies. Although these data suggest that blocking the IL-1 signaling pathway may be beneficial in the treatment of active Graves’ ophthalmopathy, this hypothesis has not been tested in clinical trials.
Targeting B cells
The therapeutic benefits of B-cell depletion therapies highlight the role of B cells in promoting autoimmune diseases in humans. B cells are involved in a variety of immune responses. Following antigen-specific proliferation, B cells enter the germinal center, altering antigen receptors and generating long-lived memory B cell aggregates responsible for generating and maintaining serum antibody levels.
In autoimmune diseases, autoantibodies may be the cause of the disease by binding directly to specific receptors (e.g. TSH receptors on thyroid cell membranes in Graves’ disease) or by forming immune complexes in the tissues, locally activating complement responses and thus inducing inflammation.B cells are also important antigen-presenting cells that contribute to the triggering of autoimmune responses.
Rituximab
Rituximab (RTX) is FDA-approved for the treatment of non-Hodgkin’s lymphoma, RA, and sarcoidosis verruciformis, but is also used to treat a variety of autoimmune diseases outside of its indication. rituximab is a human-mouse chimeric monoclonal antibody that targets B-lymphocyte antigens, which are human B-lymphocyte-specific antigens. b-lymphocyte antigens are expressed on at least 95% of B cells (immature to mature B cells), but not in antibody-producing plasma cells.
Thus, RTX therapy removes B lymphocytes and short-lived plasma cells, leaving long-lived plasma cells behind. Antibody production is thus maintained, and levels remain unchanged even when peripheral B cells are depleted.
In humans, the mechanism of action of RTX in the treatment of autoimmune diseases remains unclear and is said to be mainly related to its direct B-cell depletion effect or its indirect effect on autoantibody production. Notably, response to treatment is not always associated with complete B-cell depletion, and RTX may not affect autoantibodies in the blood. In clinical trials of RTX for RA, RTX was effective in reducing symptoms, with improvement typically occurring within 8-16 weeks.
This effect was maintained during B-cell depletion (usually 16-24 weeks.) RTX may act through both Fc-mediated and Fab-mediated pathways, which involve the activation of two distinct immune effector pathways: induction of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, respectively. Antibody-dependent cell-mediated cytotoxicity emerges through the recruitment of potent effector cells expressing the Fc receptor (i.e., natural killer cells and polymorphonuclear granulocytes). Monocytes and macrophages also play an important role in a variety of murine B-cell depletion models, where they are able to recruit to sites of inflammation.
The rationale for using RTX to treat Graves’ ophthalmopathy is to block the production of pathogenic autoantibodies, and B-cell depletion involves antigen presentation and production of inflammatory cytokines. Since the first report of a study in which RTX successfully treated one patient with moderate to severe Graves’ ophthalmopathy, RTX has been studied in 43 patients with Graves’ ophthalmopathy, and most were non-controlled studies.
Two recent reports highlight that RTX may be effective in patients with Graves’ ophthalmopathy, even at lower doses than current autoimmune rheumatoid arthritis therapy.Salvi et al. reported that after injecting only 100 mg of the drug, RTX titration was discontinued in 2 patients due to adverse effects from instantaneous cytokine release.The study showed that this RTX was able to induce all peripheral B-cell depletion and improve inactive Graves’ ophthalmopathy.
More recently, Mitchell et al. treated eight patients with active, steroid-resistant Graves’ ophthalmopathy and one patient with inactive Graves’ ophthalmopathy with RTX. The study showed that five patients (55%) presented with clinical manifestations of DON. Prior to peripheral B-cell depletion, although two patients received a full dose of RTX (1000 mg, 2 doses), six patients received only a 500 mg dose, 2 titrations, and another 3.
In patients with active disease, Graves’ ophthalmopathy improved rapidly, with only four patients experiencing mild side effects after the first injection. All patients with concomitant DON showed improvement in symptoms and a reduction in NOSPECS classification from grade 6 to grade 4.
Due to the lack of randomized clinical trials and quantitative efficacy studies, a suitable dose for the treatment of active Graves’ ophthalmopathy has still not been found. Preliminary results of two ongoing randomized clinical trials evaluating RTX for the treatment of Graves’ ophthalmopathy were recently reported. salvi et al. compared the efficacy of RTX with ivMP in patients with active moderate to severe Graves’ ophthalmopathy, with CAS reduction as the primary endpoint. after RTX treatment, CAS was significantly reduced, independent of the dose administered (1000 mg or 500 mg ).
At week 24, all patients in the RTX-treated group had improved symptoms compared to only 69% in the ivMP group (p<0.001). no disease recurrence was seen in patients in the rtx-treated group, and disease recurrence was seen in 5 patients in the ivmp-treated group. Data on secondary endpoints (total eye score, mortality, and quality of life) will help determine whether rtx is a disease-modifying therapy. <
p=””>And Stan et al found that RTX was not effective in treating active Graves’ ophthalmopathy compared with the placebo group. The study was conducted in 21 patients, and 2 developed optic neuropathy after treatment with RTX. Differences in recruitment criteria may be able to explain the bias between the results of these two studies.
Infusion-related adverse reactions, which usually occur during the first dose of RTX, are the most common side effect of RTX and may be related to the fact that it is a humanized monoclonal antibody. Pre-administration of antihistamines and low-dose hydrocortisone prior to dosing, as well as slowing the infusion rate during the first hour of dosing can mitigate side effects. Inflammatory cytokine release and complement activation are causes of acute infusion reactions, which may occur in 10% of patients but are usually reversible.
RTX has also been reported to increase the risk of infection, particularly hepatitis B recurrence. Elevated risk of disease is associated with the dose and duration of administration and is more common in oncology patients. A recent retrospective analysis of 3,000 RA patients showed comparable rates of serious infections with RTX compared with placebo and methotrexate over an observation period of 9.5 years. No elevated risk of malignancy was observed over time.
This analysis suggests that RTX was better tolerated over time, even after multiple courses of therapy. Progressive multifocal leukoencephalopathy (PML) has been reported in RTX-treated patients, but mainly in patients with systemic lupus erythematosus (SLE). At least 40% of PML cases occur in patients with SLE, including those with relatively little immunosuppression, suggesting that SLE itself may also be predictive of PML development.
Targeting T cells
Studies have shown that RTX is also able to affect peripheral blood T cells in patients with Graves’ ophthalmopathy. 8 patients with active severe Graves’ ophthalmopathy were treated with RTX at doses of 1000 mg and 500 mg every 2 weeks and were given anti-allergy medication after administration. Although B-cell depletion occurred in all patients, as expected, reduced levels of T-cell subsets expressing IGF-1R compared with pre-treatment were also associated with clinical improvement. reduced IGF-1R and T-cells after RTX treatment were secondary to reduced B-cells, which occurred following B-cell depletion. Whether this mechanism of action underlies the improvement in clinical symptoms of Graves’ ophthalmopathy with RTX or is simply an incidental phenomenon of treatment requires further studies to demonstrate.
Conclusion
Within the last few years, the use of novel immunosuppressive agents as potential future treatments for Graves’ ophthalmopathy has become a new area of research of considerable interest. The available data have shown some promise, but the sample sizes of these studies are too small. Therefore, large randomized, placebo-controlled clinical studies are expected to demonstrate the current treatment outcomes of all these biologic agents. In the meantime, it is hoped that data from RTX studies (the most extensively studied monoclonal antibody) will be published in the future. Initial results seem to suggest that RTX has an ameliorating effect on Graves’ eye disease.