Understanding the Autoimmune Link Behind Graves’ Disease and Thyroid Eye Disease

Graves’ disease and Thyroid eye disease (TED) are both associated with significant morbidity and impact on quality of life.[1][2][3] In fact, Graves’ disease is the most common cause of hyperthyroidism in the U.S.[4] Symptoms for both diseases can wax and wane, and sometimes prove challenging to control.[5][6]

What may be less well understood or appreciated is the fact that Graves’ disease and TED are related autoimmune conditions: Graves’ disease primarily affects the thyroid gland, but also may present with extrathyroidal manifestations, such as TED.[7] A deeper look at their shared pathophysiology may help explain the link between Graves’ hyperthyroidism and TED, as well as illuminate considerations for future treatment approaches.

 

The role of thyroid-stimulating hormone receptor (TSHR)

TSHR is important for intracellular signaling. TSHR is also present throughout the body and in the eye.[8]

In Graves’ disease, pathogenic immunoglobulin G (IgG) autoantibodies bind to and activate TSHR, resulting in the stimulation of excess thyroid hormone.[9] In TED, these autoantibodies target TSHR found in the muscle, tissue and fat around the eye.[10] In fact, elevated TSHR autoantibody (TRAb/TSI, or thyroid-stimulating immunoglobulin) levels in Graves’ disease correlate with increased risk of developing TED (approximately 30–40% of Graves’ disease patients develop TED[11][12]) and may predict TED severity and outcomes.[13] TED can also occur in people before thyroid-related symptoms appear.[14]

In addition, there is emerging scientific understanding that TSHR may influence the signaling of another protein, insulin-like growth factor 1 receptor (IGF-1R), expressed on orbital fibroblasts, through synergistic receptor crosstalk, which may also play a role in TED symptoms.[15][16]

TRAbs are the only specific biomarker for Graves’ disease and TED, correlating to both disease severity and clinical outcomes.[17] As a result, TRAb/TSI measurement is a sensitive and specific tool for diagnosis and ongoing management of Graves’ disease, including extrathyroidal manifestations such as TED.[18]

Key symptoms & impact

Graves’ disease [19][20]

  • Rapid heartbeat
  • Unexplained weight loss
  • Increased appetite / frequent bowel movements
  • Shortness of breath
  • Muscle weakness / fatigue
  • Irritability / anxiety
  • Heat intolerance
  • Changes in menstrual cycle / reduced libido
  • Goiter
  • Decreased attention span

Thyroid eye disease [21]

  • Red, irritated eyes
  • Proptosis
  • Chronic watery eyes
  • Blurred vision or diplopia
  • Difficulty or pain when moving the eyes 

Graves’ disease and TED can significantly impact quality of life. If left uncontrolled, Graves’ disease can lead to serious health complications, including cardiovascular complications while TED can result in irreversible vision damage or even blindness.[22][23][24]

The current treatment landscape in Graves’ disease

Treatment approaches in Graves’ disease – which include anti-thyroid drugs (ATDs), radioactive iodine (RAI) and surgery – have remained unchanged for approximately 70 years.[25] All target the thyroid to stabilize thyroid hormones, rather than the underlying disease driver: pathogenic IgG autoantibodies.[26]

While some patients with Graves’ disease may achieve thyroid hormone level normalization with ATDs, the treatment experience can be variable.

“Stable thyroid hormone levels are an important treatment goal for my patients.” – Mark A. Lupo, MD, founder and medical director, Thyroid & Endocrine Center of Florida

A recent chart review of 1,100 patients with Graves’ disease in the U.S. highlights a sizable proportion of patients who struggle to achieve normal thyroid hormone levels:

  • 23% of patients were unable to maintain disease control
  • 16% required significant titration to achieve control
  • While many patients receive a recommendation from their provider for definitive treatment, more than half have not undergone the procedure[27]

In this context, there remains an unmet medical need for those who cannot tolerate or struggle to achieve stable, long-lasting euthyroidism and who want to avoid definitive treatment. These patients often present with severe hyperthyroidism, large goiters and high TRAb levels.[28][29] Ongoing TRAb/TSI testing and enhanced provider-patient dialogue about symptoms may help identify Graves’ patients who struggle to achieve disease control.

The current treatment landscape for TED

Treatment approaches for TED include corticosteroids, orbital radiotherapy, non-biologic immunosuppressive therapies, biologics, and surgery.[30] Management of TED in the U.S. has shifted dramatically in recent years, due to the approval of a new biologic medication for moderate-to-severe disease, and subsequent burst of investigational therapies in development. Treatment selection should consider whether TED is mild, moderate-to-severe, or sight-threatening, and providers should also consider variable response rates and side effects in their decision-making process. Currently, there are no approved therapies for TED that target the underlying systemic autoimmune response.

“Given the current treatment options, I typically counsel my patients with TED that a complete restoration of visual function and a return to their previous appearance is unlikely.” -Giuseppe Barbesino, MD, Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Massachusetts General Hospital

Given the shared pathology of Graves’ disease and TED, there is a need for earlier therapeutic interventions that may potentially address the underlying autoimmune driver of both the thyroidal and ocular manifestations of Graves’ disease. 

The promise of emerging treatment approaches

Treatment advances that target the underlying autoimmune driver of Graves’ disease and TED – pathogenic IgG autoantibodies – offer the potential to help improve symptoms and quality of life for these patients.[31][32] The neonatal Fc receptor (FcRn) functions normally to keep IgG antibodies in circulation by preventing their lysosomal degradation.

“As a clinician treating people with both Graves’ disease and TED, I am excited about the potential to offer my patients more treatment options in the future,” said Dr. Barbesino.

Immunovant, a clinical-stage immunology company in anti-FcRn technology development, is pursuing a patient-focused development approach with a goal to develop additional treatment options in autoimmune disease. To learn more about Immunovant’s clinical research involving FcRn-targeted therapies and its dedication to enabling normal lives for people with autoimmune diseases, visit Immunovant.com.

Watch a free on-demand webinar sponsored by Immunovant, Inc., to hear from clinical experts Mark Lupo, MD, founder and medical director of the Thyroid & Endocrine Center of Florida, and Giuseppe Barbesino, MD, of Massachusetts General Hospital, for a moderated discussion about the treatment landscape in Graves’ disease, which has remained largely unchanged for the last 70 years.

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Disclaimer:

The statements and opinions expressed in the article and video are solely those of the authors and not of AACE. The information, opinions, and recommendations presented in the article and video are for general information only and any reliance on or use of the information provided is done at your own risk.


References

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