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Managing acute Graves’ disease ranges from immunosuppression to surgical intervention
Engineered TSH-receptor neutralizing antibodies that target T cells are being investigated.
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“The immune reaction from Graves’ disease results in the accumulation of activated T-cell lymphocytes within the orbital tissues,” said Jonathan J. Dutton, MD, PhD, an ocular ophthalmic plastic and reconstructive surgeon in private practice here. A variety of cytotoxic TH-1 type cytokine profiles, such as IL-2, interferon gamma and tissue necrosis factor alpha, are also released. “These cytokine profiles mediate the immune reaction that we see in the orbit,” he said.
The inflammatory mediators cause lymphatic relaxation and valve incompetence with stasis, vascular dilatation with increased blood flow and permeability increases in the vasculature that leads to tissue edema. There are a variety of cytokines released “which then feed back onto the fibroblasts and cause them to secrete glucosaminoglycans that accumulate in the tissues. These are hydrophilic and result in increased orbital edema,” he said. Additional cytokines act on the fibroblasts directly, causing collagen synthesis and in creased orbital fibrosis.
Chemokines
Chemokines, a subset of cytokines, act as chemo-attractants. They act on the vasculature and help attract the activated T cells and antigen presenting cells (mostly monocytes) into the area of inflammation. Presumably, this is accomplished by their ability to reorganize the receptor sites’ directions and polarity.
A series of transforming growth factors are also secreted because of this immune reaction. These act on T cells, which enter the area to undergo T-cell proliferation, and can also act directly on the connective tissue in the orbit to induce orbital fibrosis.
“There is growing evidence from a number of research laboratories that some of these selected cytokines can have an effect on pre-adipocytes found in the orbit, allowing them to grow into mature adipocytes. This increases the actual volume of fat in the orbit, enhancing proptosis and presenting as anterior prolapse of fat into the eyelids,” Dr. Dutton said.
Current therapies
Until now, the rationale for treatment of Graves’ disease has been symptomatic treatment while the disease is actively evolving. The inflammatory process in the orbit usually ends after running a course lasting anywhere from months up to 5 years.
Immunosuppression can be offered for significant symptoms, while radiotherapy is reserved for severe orbital congestion and for early stages of optic nerve compression. According to Dr. Dutton, surgery at this stage is generally reserved for patients who have vision-threatening situations. Definitive surgery is commonly delayed until the disease is stable.
Corticosteroids have been used to modulate the disease because they can block the cytokine release.
“They can also block the inflammatory mediators and transforming growth factors. The problem with steroids, though, is that they cannot be used long-term due to potential complications,” Dr. Dutton said.
Radiotherapy may be useful in early stages of Graves’ disease by up-regulating certain inhibitory cytokines, which then reduce the active inflammatory process. Radiotherapy also “can lead to orbital fibrosis and senescence from the accumulation of DNA breaks. It may reduce the size of the extraocular muscle slightly, but generally has very little effect on muscle size,” he said. Still, such reduction in cytokine activity may be “useful for early stages of optic nerve compression; however, it can take up to 3 months to achieve a full effect.”
Surgical therapy entails a staged approach: orbital decompression followed by strabismus surgery and then eyelid recession and blepharoplasty.
Into the future
Dr. Dutton is excited about future therapies for Graves’ disease.
“A tremendous amount has been written over the past decade on the immunology of Graves’ disease. More knowledge has been accumulated in the last few years alone than in all the previous 160 years since the disease was first described,” he said.
One area under active investigation is targeting immunomodulation to the specific receptor sites on the circulating anti-TSH receptor T cells.
“Antigen-presenting cells, which are necessary to activate these T cells, also sit on those receptor sites. One goal is the engineering of several soluble human TSH-receptor neutralizing antibodies, which then can circulate in the systemic circulation and presumably bind up these T cells,” Dr. Dutton said.
Mechanisms for up-regulating certain inhibitory cytokines (in particular, IL-13) can act on this complex, and block the pro-inflammatory mediators so crucial to the overall orbital process.
“Within a few years, it will be possible to specifically block the chemokine receptor sites on the peripheral lymphocytes, macrophages and monocytes. This will inhibit them from attracting new inflammatory cells into the orbital tissues. Cytokine modulation is also now being targeted specifically against cytokines,” he said.
In the next decade, “I think we’ll be able to control the inflammatory manifestations of Graves’ disease at a significantly earlier stage than currently, and certainly before the permanent scarring and anatomic changes occur,” Dr. Dutton said.
For Your Information:
- Jonathan J. Dutton, MD, can be reached at 2501 Weston Parkway, Cary, NC 27513; (919) 678-2620; fax: (919) 678-2676; e-mail: jon.dutton@atlanticeyeface.com.