Update on Graves Disease

Advances in Treatment of Mild, Moderate and Severe Thyroid Eye Disease

Diego Strianese

Disclosures

Curr Opin Ophthalmol. 2017;28(5):505-513. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: To report the most recent therapeutic advances of thyroid eye disease (TED) and offer general recommendations for management of TED.

Recent findings: Treatment of Graves ophthalmopathy is traditionally based on the use of high doses of corticosteroids and/or radiotherapy (RT) to decrease the activity of the disease, with the subsequent proptosis, strabismus and eyelid deformites treated with different surgical procedures. In recent years, the evidence that oxidative stress plays a relevant role in exacerbating TED severity has encouraged the use of antioxydative agents such as selenium, which has shown a capacity in limiting the disease progression. In addition, reports have shown the effectiveness of biological immunosuppressive agents in the management of TED. The main advantage of these medications seems to be the long lasting effects, which may reduce recurrence, and effectiveness in steroid-resistant cases. The reported increased accuracy of imaging techniques in evaluating fat and muscle volumes may provide useful information for surgical management.

Summary: The use of selenium, in mild TED, seems to limit disease progression without carrying the risk of relevant side-effects. Biological agents may provide an effective and long lasting block of the inflammatory activity of TED, with a possible lower risk of recurrence and reduction in the need for surgical intervention in moderate-to-severe disease. The accurate evaluation of fat and muscle volume, using a recently published algorithm for imaging, gives relevant information for preoperative assessment, allowing the customization of orbital decompression.

Introduction

Thyroid eye disease (TED) is the most common extra-thyroid manifestation of Grave's disease.[1] The prevalence has been estimated at 16 cases per 100 000 population for women.[2] Up to 50% of patients with autoimmune thyroid disease develop TED, and of those, as many as 10–20% develop severe inflammation, orbital congestion, impaired ocular motility or compressive optic neuropathy (CON).[3] Risk factors include smoking and poor control of thyroid dysfunction. Considerable progress has been made in unraveling the pathogenetic mechanisms leading to development of TED; however, the exact mechanism has yet to be understood, and the disease remains a therapeutic challenge and dilemma.

Autoimmune reactions in the orbit of TED patients are probably triggered by recognition of the thyroid-stimulating hormone receptor (TSHR), presented to autoreactive T-lymphocytes infiltrating the orbit by antigen-presenting cells, including B lymphocytes and macrophages. TSHR is expressed on orbital fibroblasts and adipocytes after differentiation from preadipocytes. The insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) may also be involved in the initiation or maintenance of orbital autoimmunity. Autoimmunity to the TSHR may trigger TED, and autoimmunity to IGF-1R might play a relevant role in maintaining ongoing reactions. Eventually, a number of reactions occur leading to proliferation of orbital fibroblasts, differentiation of preadipocytes into adipocytes, production of autoantibodies, secretion of cytokines, infiltration of extraocular muscles and increased synthesis and secretion of glycosaminoglycans. The expansion of the fibroadipose tissue and the infiltration of extraocular muscles lead to the clinical manifestations of TED.[3]

Ocular manifestation includes eyelid retraction, proptosis and ocular motility disturbance with a wide spectrum of inflammatory signs and soft tissue congestion and occasionally vision loss from CON. Severe proptosis, ocular motility restriction and eyelid retraction may lead to a corneal breakdown, which together with CON represents an emergency. The grading of the soft tissue changes and the inflammatory symptoms and signs, defined as 'disease activity', can be assessed by using clinical activity score (CAS) criteria or vision, inflammation, strabismus, and appearance (VISA) classification.[4] The spectrum of ocular findings is graded as 'disease severity': mild disease has minimal eyelid swelling, lid retraction or proptosis with little or no extraocular muscle dysfunction, with a minor impact on daily life. Moderate disease implies inflammatory features interfering with the ability to function, possible ocular motility dysfunction with diplopia, lid retraction greater than 2 mm and variable proptosis; at this grade, the disease has sufficient impact on daily life to justify the risks of immunosuppression, if active, or surgical intervention, if inactive. Severe disease refers to sight-threatening conditions such as CON or corneal ulceration, often necessitating some form of surgical intervention.[4] Broadly, TED follows a biphasic course, with a progressive or active phase lasting up to 1½ years, followed by a stable or inactive phase. The plot of the natural history of orbital disease over time (Rundle's curve) with a steeper slope in the active phase reflects a more acute onset and the possibility of more serious sequelae.[3,4]

The range of TED treatment options varies depending upon severity, from topical palliative treatments including artificial tears, ointments or prisms, to immunosuppressive agents such as steroids, RT and surgical decompression in more severe cases. Novel approaches to treatment have been recently reported; below, we discuss how they may change the current guidelines for treatment of TED.

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