Figure 1. The patient here is seen as he first presented to the clinic in December 2018. The following montage shows him at several points throughout treatment for thyroid eye disease.
Figure 2. The patient, seen here a month after first presenting and being prescribed steroids.
Figure 3. At month 6 the patient's left eye was treated with orbital decompression surgery.
Figure 4. At 2 months postoperative, the patient wass again treated with steroids.
Figure 5. At 10 months from initial presentation (4 months postoperative) the patient was treated with radiation.
Figure 6. At 1 year since initial presentation, the patient was prescribed rituximab.
Figure 7. Here, the patient is at 14 months since initial presentation and before being started on teprotumumab.
Figure 8. The patient is seen here 5 months after starting teprotumumab.
Figure 9. At month 22 since initial presentation, the patient underwent strabismus surgery
Every day, patients report to ophthalmologists exhibiting signs or symptoms of thyroid eye disease (TED). Some of these patients arrive with an established diagnosis, referred by an endocrinologist, with new onset hyperthyroidism. Other patients may arrive with no diagnosis and more subtle ocular symptoms, such as intermittent diplopia or even simple tearing or red eye. In either case, prompt diagnosis and proper early treatment can obviate a lifetime of disability for these patients. It is crucial for ophthalmologists to recognize TED and understand the most current concepts in its treatment.
Thyroid eye disease, also known as Graves’ ophthalmopathy (GO) or thyroid associated orbitopathy (TAO), is an orbital inflammatory condition which can have devastating consequences including pain, strabismus, disfigurement, and vision loss. More than 30,000 new cases of TED are diagnosed in the United States annually.1 Hyperthyroidism is the most commonly associated dysthyroid condition, occurring in more than 80% of TED patients, but patients can exhibit hypothyroidism (~10%) or euthyroidism (~5% to 10%).2 The incidence of TED is more than 5 times greater in females than males, but males are more likely to progress to more severe disease, as are patients who smoke cigarettes.
Understanding the pathophysiology of TED informs our management decisions for this condition. The orbital fibroblast is a key target in the development of TED. In TED, bone marrow derived fibrocytes infiltrate the orbital tissues and mature into fibroblasts, capable of eventually differentiating into either myofibroblasts or adipocytes. These fibroblasts express abnormal levels of thyroid stimulating hormone receptor (TSHR) and insulin-like growth factor receptor (IGF-1R). In response to autoantibody stimulation of these receptors, fibroblasts release inflammatory cytokines which attract T- and B-cells to the orbit further inciting an inflammatory cascade which ultimately results in the final fibroblast-mediated inflammatory characteristics of the disease.3,4
The active inflammatory phase of the disease process can last several months to years. If untreated, the inflammation can eventually scar extraocular muscles restricting their mobility, hyaluron production by the stimulated fibroblasts can collect in the orbital tissues causing permanent edematous enlargement of the muscles and fat, and adipogenesis can further congest the orbital volume. The end result is a chronic inactive phase of the disease comprising proptosis of the globe, restrictive strabismus, retraction of the eyelids, and in its most severe manifestations, corneal damage from overexposure or compressive optic neuropathy.1
Surgical options are available in the chronic phase of TED to compensate for the permanent structural changes ensuing from the inflammatory phase. These include removal or repositioning of the bony orbit walls or reduction of orbital fat to reduce proptosis and optic nerve compression, strabismus surgery to loosen restricted muscles, and eyelid surgery to release retracted eyelids. As only a minority of TED patients end up with sequelae severe enough to require these surgical interventions, prior consensus was that the treating ophthalmologist should wait out the inflammatory phase to determine which patients would need surgery. However, with the development of more effective options for medical treatment of the active phase, the goal has shifted to minimizing the chronic sequelae and need for surgery through early anti-inflammatory treatment in the active phase for any patient at risk for significant progression.
Therapeutic options exist to suppress the orbital inflammatory process at several steps within this process. For many years, the mainstay of treatment has been general suppression of the overall immune system with glucocorticosteroids. This diminishes the population of circulating T-cells and B-cells systemically, thus curtailing the autoimmune infiltration of the orbit. Other general immunosuppressive agents, including cyclophosphamide, azathioprine and methotrexate, have been utilized as well, but usually are reserved for patients with severe inflammation not sufficiently responsive to steroids.5
External beam radiation to the orbit can provide lymphocyte-directed immune suppression similar in concept to glucocorticosteroid treatment, but localized specifically to the orbit. This is a commonly employed treatment modality, but clinical studies have had mixed findings regarding its efficacy.6 It appears to be most effective early in the active phase for patients with moderate to severe manifestations including progressive strabismus or optic neuropathy and to be minimally effective for mild or chronic phase disease.7 Its onset of action is slower than that of steroid treatment, but its result can be more permanent.
Treatments are available to block the cytokine mediation of the orbital inflammatory response. Cyclosporine blocks cytokine production by T-cells; infliximab, adalimumab and etanercept block tumor necrosis factor α; and tocilizumab blocks interleukin 6; all of which have been reported effective in improving active phase TED.5
The production of autoantibodies by B-cells is a crucial link in the orbital inflammatory chain. For years, the literature advocated using plasmapheresis or plasma exchange, physically removing antibodies from circulation, to treat TED, usually as an initial adjunct to steroid immunosuppression.8 Present-day versions of this antibody-reduction concept utilize monoclonal antibodies rather than physical plasma filtering. Rituximab treatment removes B-cells from circulation, thus inhibiting the production of these antibodies.9 IMVT-1401 is a newly-developed monoclonal antibody which augments the body’s antibody clearance mechanism. This new agent is presently being tested to determine its effectiveness in treating TED.10
The final link in the orbital inflammatory chain is the action of the stimulated fibroblast, and there are treatments targeted here as well. Antioxidant therapy with nicotinamide, allopurinol, or selenium have been reported to improve the outcome of TED, presumably by blunting the fibroblast reaction to the oxidative stress of the orbital imflammation.11 Perhaps the most promising therapy targeted at the fibroblast is teprotumumab, recently given FDA indication specifically for TED. This monoclonal antibody blocks the autoimmune stimulation of orbital fibroblasts by binding the IGF-1R. Teprotumumab has shown promise not only in halting the active progression of TED, but also in reversing the resultant proptosis, strabismus, and compressive optic neuropathy.12
With numerous options available for the treatment of TED, it is crucial that we evaluate TED patients early in the course of their disease, and that this evaluation include a dual-pronged analysis for both the severity of the disease and the risk of progression for each patient. Only then can clinicians make rational choices as to the optimal management of that individual patient’s disease.
A good history is the first step in evaluating TED. A simple patient survey of 5 questions, reporting on upper eyelid swelling or fullness, lower lid bags, redness of the eyes or eyelids, eyes too wide open, and blurred vision can identify 80% of TED patients with 75% specificity, according to an Investigative Ophthalmology & Visual Sciences study.13 Symptoms of TED most often start fairly coincident with a patients’ dysthyroid symptoms, but this is not reliably true in all cases. Often enough the patient notices the ophthalmic symptoms before recognizing the systemic ones, and sometimes the ophthalmic symptoms don’t start until the patient is well along in the treatment of dysthyroidism. A patient interview should document the course of TED symptoms as distinct from the timeframe of dysthyroidism.
Ophthalmic examination can identify not only obvious signs, such as proptosis or strabismus, but also more subtle signs such as chemosis, caruncle swelling, sub-brow fullness, lid lag or lagophthalmos, and subtle visual field deficits. The VISA evaluation scheme provides a useful guide to a complete ophthalmic examination of the TED patient.14 In this scheme, each letter of the acronym identifies an aspect of the evaluation in decreasing hierarchical order of clinical urgency. Vision (V) is evaluated for evidence of optic neuropathy, including assessment of visual acuity, afferent pupil defect, color vision, and visual field sensitivity. Inflammation (I) is scored to give an inflammation index, or clinical activity score, based on variables of pain, erythema of eyelid or injection of conjunctiva or caruncle, and edema of eyelid or chemosis of conjunctiva. Strabismus (S) is measured directly by prism correction or scored by severity of diplopia. Appearance (A) and corneal exposure is evaluated regarding globe proptosis, eyelid retraction, and corneal appearance.
Diagnostic testing is used both to confirm a diagnosis of TED and to predict a patient’s risk of progression. Thyroid function testing is most often handled by the patient’s endocrinologist or primary medical physician, but it is important for the ophthalmologist treating TED as well, as thyroid stabilization is an important factor in TED stabilization. Furthermore, the choice of thyroid treatment employed affects the course of the patient’s TED: radioactive iodine destruction of the thyroid gland can release antigen and exacerbate TED, while surgical thyroidectomy can alleviate inflammation. Thyrotropin receptor antibody, and specifically a subset of this antibody, thyroid stimulating immunoglobulin (TSI), reflects the rise and fall of the active phase of TED, providing a key indicator of the course of the disease process. Diagnostic imaging can provide evidence of muscle enlargement, even in cases where clinical signs are not obvious, and radiologic characteristics can help discern active from chronic disease.15
Make A Plan
Good early treatment decision-making is the goal of early evaluation of TED. While there is no single test to determine clinical treatment, the combination of patient history, VISA evaluation, and TSI testing can guide a prudent decision that can potentially save a patient from a lifetime of debilitating consequences. In evaluating a new TED patient, my goal is typically to garner enough information within the initial evaluation visit to propose a treatment plan at that visit, or at latest the next visit if additional testing is warranted. If disease is mild and risk of progression low, the patient may opt for conservative symptom amelioration only, for example lubricating eye drops or cold compresses as needed. If active phase disease appears at all likely, the patient is typically offered a course of intravenous pulsed-dose corticosteroid. This can serve not only to treat the disease process, but also as an empiric test of disease activity. Alternatively, if the patient opts against steroid treatment, early follow-up within 1-3 months can be used to judge disease progression. Patients responsive to corticosteroid treatment but with incomplete resolution or early recurrence of disease activity are offered alternative secondary therapy against active disease. Rheumatologic consultation is employed for most of these treatments, due to the systemic monitoring needed for serious possible side effects. Early experience with teprotumumab treatment suggests that it may develop a primary role in treatment of early active disease with a relatively low side effect profile, and benefit patients in the chronic phase of disease as well.
To effectively treat patients early, TED patients need to be seen early. Awareness must be high among optometrists, medical primary care providers, and endocrinologists for the need for early referral for ophthalmic evaluation. “Wait and see” is not an appropriate strategy for TED; early diagnosis and treatment can and is allowing TED patients to avoid a lifetime of ophthalmic issues.
Thomas J. Joly. MD, PhD, is a board-certified ophthalmic plastic surgeon with more than 20 years of specialized experience. He is currently head of oculoplastics at Eastern Virginia Medical School Department of Ophthalmology and holds an assistant professorship in that department.
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