Thyroid Eye Disease

Thyroid eye disease (TED), also known as Graves’ophthalmopathy (GO), is the most serious complication of Graves’ disease. It is an autoimmune disorder affecting orbital fat, extra ocular muscles, and lacrimal gland, causing inflammation, tissue expansion, and fibrosis. Although TED is self-limited, it may cause permanent cosmetic and visual morbidity, impacting quality of life more than diabetes mellitus or chronic pulmonary disease¹

Epidemiology

The incidence of TED is reported to be 16 per 100,000 females and 2.9 per 100,000 males with an approximate prevalence of 0.25% with no significant ethnic predisposition. The higher preponderance in females relates to the higher incidence of hyperthyroidism in females. However, for severe TED, the ratio of females to males reverses to approximately 1:4².

Pathogenesis

The exact pathogenesis of TED remains unclear. Thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) have been identified as targets involved in TED development or progression. Autoantibodies against TSH-R (TRAbs) are elevated in TED patients, and increased adipogenesis in orbital fibroblasts have been attributed to a concomitant increase in TSH-R expression in the orbital tissue. Similarly, increased expression of IGF-1R has also been found in the orbital fibroblasts. A combination of these factors leads to an increase in hyaluronan production by orbital fibroblasts, and combined with T-cell trafficking and its activation in the orbit, result in inflammation of the eye.³ (Figure 1).

Figure 1. Pathogenesis of TED

The inflammation of the orbit leads to the first phase of TED, the inflammatory, active phase which then subsides into the variably fibrotic, inactive phase after a period of one to two years (range of 6 months to 5 years) demonstrates in Rundle’s curve with biphasic course. ⁴ Figure 2.

Figure 2. Rundle’s curve

Presentation

In approximately 40% of patients with TED, the ocular and systemic symptoms have a simultaneous onset. Approximately 60% of patients with hyperthyroidism will develop TED. For those with TED, 85% have hyperthyroidism, 10% have hypothyroidism and 5% are euthyroid².

The most common clinical sign is eyelid retraction (occurs in 90% of patients with TED), followed by exophthalmos (60%) and eye movement restrictions (40%). The most serious signs are optic neuropathy and exposure keratopathy as both can abruptly lead to blind- ness and are therefore ocular emergencies².

Risk Factors

Risk factors for developing TED include smoking, life stressor, poorly controlled hypothyroidism following radioactive iodine, and a positive family history of orbitopathy. Diabetics may have a higher risk of developing compressive optic neuropathy⁴.

Thyrotropin receptor stimulating immunoglobulins (TSI) influence thyroid function and mediate extra thyroidal manifestations of Graves’ disease. In the controlled trial reported by Lytton SD 2010(5), all patients including both GD and GO, the vast majority of the GO patients, independent of their thyroid function, were TSI-positive. All TSI-positive/TRAb-negative subjects had GO, whereas all TRAb-positive/TSI-negative subjects had GD only. TSI also have strong positive correlation with clinical activity score (CAS) and severity whereas TRAb has weaker correlations with CAS and severity⁵.

Management

Treatment of TED should be multidisciplinary with the ophthalmologist, endocrinologist and radiologist. There are several actions reported to prevent the occurrence and to avoid the progression of TED, which include stop smoking, keeping euthyroidism, and selenium.

Stopping smoking seems to play an important role in reducing the risk of having and aggravating TED. Since tobacco decreases the effect of immunosuppressive drugs, smokers have a weaker and slower response to treatment. Passive smokers are also harmed, mostly children. It seems be related to hypoxia and/or increased production of free radicals.⁶

There are three main options in the treatment of hyperthyroidism: medical (carbimazole and propylthiouracil), radioactive iodine and surgery (thyroidectomy). Medical treatment blocks the production of thyroid hormones and is used until the patient is euthyroid. The drug is then tapered whilst maintaining normal free T4 levels. Alternatively a ‘block and replace’ regime may be used where higher drug doses are used along with thyroxine replacement. Radioactive iodine is an effective alternative option but subsequent hypothyroidism is common. This treatment can cause progression of TED by a leakage of antigens from the thyroid gland, again eliciting an autoimmune response. This risk can be reduced with the simultaneous use of corticosteroids. Surgery is less commonly performed but may be used for patients with a large goiter.²

Selenium is incorporated into selenoproteins, most of which are expressed in the thyroid gland. Low levels of selenium seem to increase the risk of thyroid disease. Supplementation with selenium reduces the levels of oxygen free radicals that could induce or exacerbate TED. It was administered orally for 6 months (100 ug twice daily) and was found to improve quality of life, eyelid aperture and soft tissue changes and slow down disease progression.⁶

Treatment for active TED varies from conservative observation to active management requiring anti-inflammatory drugs and/ or surgical decompression. This can be done through the use of Clinical Activity Score (CAS), European Group on Graves’ Orbitopathy (EUGOGO), NOSPEC classification guidelines or VISA (vision, inflammation, strabismus and appearance) scoring guidelines.³

The mainstay of treatment is corticosteroids to potentially diminish or shorten the acute inflammatory phase; steroid sparing options include orbital irradiation, immunosuppressive drugs inhibiting T cell, B cells, cytokines, mono or polyclonal antibodies against tumor necrosis factor receptor, IGF-1 receptor, thyrotropin receptor, and CD40 pathway are also showing promising results.

Corticosteroids

This group of drugs reduces the production of GAG by orbital fibroblasts and modulates T- and B-cell function. These effects lead to an improvement in orbital inflammation. The most effective route of administration is intravenous. As intravenous administration achieves a greater decrease in the CAS and has fewer side effects than oral administration. The current recommended dose is IV administration is methylprednisolone 500 mg/week for 6 weeks followed by 250 mg/week for six additional weeks (EUGOGO regimen). The side effect of glucocorticoids is well-known and the use of corticosteroids cannot reverse the changes in orbital tissue nor the proptosis and strabismus.^{6, 7}

Targeted immunotherapy may shift the treatment paradigm from addressing acute and chronic complications as they occur to a more proactive approach that could ultimately diminish the significant morbidity currently still associated with TED.

Rituximab

This drug is a chimeric antibody against the antigen CD20 present on B cells. Rituximab could be useful in TED because it prevents antigen presentation by B cells, therefore reducing the production of TSRH antibodies and inflammatory cytokines. A randomized controlled trial comparing it with IVMP in active, moderate‐to‐severe TED showed a 100% response, with no reactivation at 24 weeks and fewer rehabilitative surgeries in the treated group. A controlled trial in North America comparing rituximab to placebo, however, did not show a significant difference. The contradictory results from these randomised controlled trials, rituximab currently cannot replace IVMP as primary treatment.^{7, 8}

Anti-TNF-a

TNF-a is a molecule produced by fibrocytes when they are stimulated by TSH or by thyroid-stimulating immunoglobulins. This molecule causes production of adhesion molecules and chemokines in fibroblasts and the recruitment of inflammatory cells to local tissues. There are three important drugs in this group, i.e., infliximab, etanercept, and adalimumab. Some case reports showed promising results of these drugs.^{7, 8}

Tocilizumab

This drug is a recombinant humanized monoclonal antibody to the IL-6 receptor. IL-6 is a pro-inflammatory cytokine present in Th1 immune response. Perez-Moreiras, Gomez-Reino 2018 9 reported the randomized trial that tocilizumab (8 mg/kg i.v. at weeks 0, 4, 8, and 12) is efficacious in reducing orbital inflammation in steroid-resistant cases with proptosis in 72%, extra ocular motility in 83%, and diplopia in 54%. Currently tocilizumab has a role in treating active, severe TED cases refractory to steroid treatment.⁹

Teprotumumab

This drug is the IGF-1R blockers bind to IGF-1R on fibrocytes and attenuate TSH-dependent signals, leading to a decrease in IL-6 and IL-8 expression. Smith, Kahaly 2017 ¹⁰ reported that eight infusions of teprotumumab over 24 weeks (10 mg/kg every 3 weeks, followed by 20 mg/kg for the remaining seven infusions), were associated with clinical improvement in patients with moderate‐to‐severe, active TED, shown by reductions in CAS, proptosis, subjective diplopia, and improved quality of life. The reduction in proptosis was comparable to orbital decompression. The results were further confirmed by phase 3 trial, OPTIC (Treatment of Graves’ Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo‐Controlled, Clinical Study), and the drug has received Food and Drug Administration (FDA) approval ^8,10. Figure 3

Figure 3. A complex interaction of the immune system, proinflammatory cytokines, and autoantibodies on orbital fibroblasts leading to the clinical characteristics of TED and sites of action of target therapy.

Orbital Radiation

The mechanism is mainly through the non-specific anti-inflammatory effects of radiotherapy, suppressing radiosensitive infiltrating lymphocytes, inhibiting fibroblast proliferation and mucopolysaccharide secretion. It is useful in treating TED patients who are not sensitive to or cannot tolerated corticoids, or those with recurrent symptoms after corticoids therapy. Radiotherapy dose is 20 Gy in 10 fractions within two to three weeks. Although the radiotherapy is slower to reveal therapeutic effects than corticoids, it could provide a more prolonged protection period. After radiopathy, satisfactory symptom control is possible. The complications are acceptable as the dose is lower than the dose that cause retinopathy (>35 Gy) and neuropathy (>50 Gy). Cataract formation and chronic xerophthalmias were found as long-term complications and can be well-managed.¹¹

Surgical Treatment

Surgical treatment in TED is orbital decompression in addressing rehabilitation like proptosis and tissue scarring along with squint correction and lid repair in chronological order. Orbital decompression can also be an urgent procedure in vision-threatening conditions like dysthyroid optic neuropathy (DON) to relieve pressure on the orbital apex and improve vascular/axonal flow within the optic nerve.⁴ Correction of upper eyelid retraction is generally undertaken in fibrotic or stable phase with various surgical techniques that can provide the better appearance and reduce the ocular surface exposure.

Conclusion

The manifestations of TED are multifactorial and are difficult to treat optimally with conventional modalities. While intravenous corticosteroid is still the first line of treatment for active, moderate and severe TED including DON, targeted immunotherapies afford additional benefits especially for partial and non-responders to corticosteroid treatment. Addition of immunomodulators has the potential to reduce disease severity by proptosis reduction, disease inactivation and improving treatment response in corticosteroid refractory cases; the benefit needs to be weighed against side effects and cost.

References

1. S.Bahn R. Graves’ Disease. New York Heidelberg Dordrecht London: Springer; 2015 2015.
2. McAlinden C. An overview of thyroid eye disease. Eye Vis (Lond). 2014;1:9.
3. Chin YH, Ng CH, Lee MH, Koh JWH, Kiew J, Yang SP, et al. Prevalence of thyroid eye disease in Graves’ disease: A meta-analysis and systematic review. Clin Endocrinol (Oxf). 2020.
4. Raymond S. Douglas AM, Shivani Gupta. Thyroid Eye Disease. Gupta RDAMS, editor. New York Heidelberg Dordrecht London: Springer 2015.
5. Lytton SD PK, Kanitz M, Matheis N, Kohn LD, Kahaly GJ. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metab. 2010;95(5)::2123-31.
6. Pouso-Diz JM, Abalo-Lojo JM, Gonzalez F. Thyroid eye disease: current and potential medical management. Int Ophthalmol. 2020;40(4):1035-48.
7. Khong JJ, McNab A. Medical treatment in thyroid eye disease in 2020. Br J Ophthalmol. 2020.
8. Honavar SG. Medical management of thyroid eye disease – A paradigm shift. Indian J Ophthalmol. 2020;68(8):1515-8.
9. Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodriguez Alvarez FM, et al. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol. 2018;195:181-90.
10. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017;376(18):1748-61.
11. Li YJ, Luo Y, He WM, Li P, Wang F. Clinical outcomes of graves’ ophthalmopathy treated with intensity modulated radiation therapy. Radiat Oncol. 2017;12(1):171.