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March 2022, Volume 72, Issue 3

Recent Advances In Endocrinology

Recent advances in the management of thyroid associated orbitopathy: A promising roadmap

Deepthi Elizabeth Kurian  ( Department of Ophthalmology, Schell eye hospital, Christian Medical College, Vellore ,India )
Sanjay Kalra  ( Department of Endocrinology, Bharti Hospital, Karnal, India. )
Nitin Kapoor  ( Department of Endocrinology, Christian Medical College, Vellore, india )

Abstract

Thyroid associated orbitopathy (or Graves’ orbitopathy) is the most common extrathyroidal manifestation of Graves’ disease; an auto-immune entity that has precarious visual consequences as well as psychological morbidity even in its milder stages. The treatment is largely based on the ‘activity’ and ‘severity’ of the disease; however, outcome can vary between patients depending on certain known and unknown risk factors. While there are certain guidelines on managing the orbitopathy, there are multiple lacunae in our knowledge of its pathophysiology. The current era is one where our mainstay of treatment of the active disease is still glucocorticoids, albeit a few good immunomodulatory drugs that have shown promising outcomes are in our armamentarium. In this article we present a compendium of the current consensus in the management of Graves’ orbitopathy, its evidence based rationale and crucial constraints along with the details of emerging biological agents.

 

Keywords: Graves, thyroid associated orbitopathy, immunomodulation

 

DOI: https://doi.org/10.47391/JPMA.22-018

 

Introduction

 

Thyroid associated orbitopathy (TAO) is a sight threatening disease entity associated with Graves’ disease (GD). We have come a long way in understanding the autoimmune process as well as the risk factors. However, the search is still on for better predictors of the course of the disease and its final outcome. The thyroid stimulating hormone (TSH) receptors present both in the thyroid gland as well as orbital fibroblasts (OF) respond to TSH receptor antibodies (TRAb) by inciting an inflammatory cascade ultimately resulting in accumulation of glycosaminoglycans (GAG) in the extraocular muscles and orbital fat. This is responsible for the various clinical signs and symptoms seen in TAO.1-3 Most of the medical management strategies are to tide over the initial active phase of TAO as described by Rundle.4,5 But are there factors that can worsen orbitopathy in GD? Can the course of the disease be modified? To answer these questions we present a brief overview of the existing treatment strategies and some of the recent advances in targeted research.

 

Clinical spectrum

 

The incidence of TAO is around 16 per 100,000 women and 2.9 per 100,000 men and the incidence in children is about 0.79 to 6.5 cases per 100,000 children.1,6 Mild orbitopathy occurs in about 50% of those with GD. Clinically significant (moderate) orbitopathy develop in 10 – 15% and they classify as type 1 disease (non infiltrative). Severe orbitopathy develop in 5 to 6 % and comprises mainly of corneal breakdown, orbital apex syndrome and dysthyroid optic neuropathy (DON) that manifest with severe proptosis, increase in strabismus, decrease in visual acuity, relative afferent papillary defect, disc oedema or a visual field defect. This classifies as type 2 disease (infiltrative). The orbitopathy can present ahead of (20%), along with (40%) or following (40%) the occurrence of thyroid abnormality.2,7 Sub-clinical orbitopathy can occur in about 70 to 90% where there are no eye signs or symptoms but there is typical tendon sparing enlargement of extra-ocular muscles (coke bottle appearance) on orbital imaging.7

 

 

 

 

Preferred management approach

 

The management of TAO requires a combined approach by an endocrinologist, ophthalmologist, optometrist, nuclear medicine physician, radiation therapist and an otorhinolaryngologist.

 

Assessing risks, activity and severity

 

The first step in management is to identify the patient’s risk factors and predict the probable course of the disease. The high risk factors are older age, female gender, Caucasian race, hyperthyroidism, subacute onset of concurrent thyroid abnormality, severe TAO at initial presentation, radioactive iodine therapy (RAI), hypothyroidism within six to eight weeks of RAI, radiation to the head and neck and smoking. Smoking also has a bearing on treatment response and disease recurrence. One needs to note that although TAO is more common in younger women, men tend to develop TAO at an older age and have a more severe disease.7

The next step is to address the modifiable risk factors and treat the active phase in order to prevent sight threatening events, simultaneously addressing the psychological and cosmetic damage. The ‘activity’ is assessed by various described scores such as NOSPECS (No physical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle signs, Corneal involvement, and Sight loss), VISA (Vision, Inflammation, Strabismus, Appearance) or the CAS (Clinical Activity Score) which is not only easy to use, but also has a good predictive value of response to immunosuppression.8,9 In the CAS system, one point each is given for presence of spontaneous retrobulbar pain, pain on attempted up or down gaze, redness of eyelids, redness of conjunctiva, swelling of caruncle/plica, swelling of eyelids and swelling of conjunctiva. On follow-up between 1 to 3 months, increase in proptosis (≥2 mm), decrease in visual acuity and decrease in eye movements (≥ 8°) are also given one point each if present. A patient with a score of three or more at initial presentation or four or more on a follow-up visit is considered to have an active disease.

Next, the ‘severity’ is to be established for which VISA or the more popular EUGOGO (European Group on Graves' Orbitopathy) system is used. EUGOGO classifies disease severity as mild, moderate and severe as given below.8

i)        Mild: Presence of (≥1 out of) mild lid retraction (<2mm), proptosis (<3mm), mild soft tissue involvement, corneal exposure responsive to lubricants, no or intermittent diplopia, minor impact on activities of daily living.

ii)       Moderate: Presence of (≥2 out of) lid retraction (≥2mm), proptosis (≥3mm), moderate to severe soft tissue involvement, constant or inconstant diplopia, sufficient impact activities of daily living.

iii)      Severe: Sight threatening proptosis with compressive optic neuropathy and/or corneal ulceration

Immunomodulation works only in the active phase and is of little use in the inactive/stable phase.

Treatment of active disease –Conventional therapeutic options

i)        Optimising thyroid hormone status: Hyperthyroidism should be treated with antithyroid drugs and based on the response, definite treatment like RAI or thyroidectomy should be planned; whereas hypothyroidism should be corrected promptly as well with eltroxin. RAI may be contra-indicated in younger children.6,10 Although correction of hyperthyroidism is needed for physiological homeostasis, it may not correlate directly with reducing severity of orbitopathy.8 It is suggested to treat patients who present with orbitopathy at the time of diagnosis of hyperthyroidism with corticosteroid along with anti-thyroid drugs especially if it is an infiltrative orbitopathy.

ii)       Cessation of smoking: This helps to reduce the reactive oxygen species in the inflamed micro-enviroment. A physician’s or psychiatrist’s consult may be sought for chronic smokers.

iii)      Selenium: Sodium selenite is recommended for its anti-oxidative effects, especially in mild disease as it improved quality of life and reduces progression to more severe disease (table 1).

 

 

Diabetes is a possible side effect.10

iv)      Lubricants and nonsteroidal anti-inflammatory drugs (NSAIDS): Topical lubricants should be prescribed for all patients irrespective of severity as there is risk of not just exposure but also reduced tear secretion due to inflammatory infiltration of the lacrimal gland. NSAIDS can be given for periocular pain in those who do not warrant steroids.

v)       Glucocorticoids (GC): They are the mainstay of treatment in moderate to severe and sight threatening TAO (table 1). Intravenous route is better tolerated and more effective than oral administration. Dosage should be based on severity. It should be cautiously used in those with diabetes, hypertension and osteoporosis; and should not be given to those with recent hepatitis, significant hepatic dysfunction, severe cardiovascular co-morbidities or psychiatric disorders. The mechanism of action of GC is non-specific and recurrences can occur after stopping treatment.11  Response to steroids is usually seen within 2 weeks and if there are severe side effects outweighing the benefits, it should be withdrawn and a second line treatment should be considered (table 1).

vi)      Adjunct immunomodulators: Cyclosporin, azathioprine and mycophenolate mofetil (MMF) are second line drugs that have shown to improve CAS and reduce recurrence of activity when used in combination with corticosteroids. Intravenous immunoglobulins are comparable to high doses of oral GC but its high cost and possible viral transfer limits its use.12

vii)     Orbital radiotherapy: Radiation is considered if there is suboptimal response to GC (table 1). Side effects may include immediate worsening of orbitopathy which may be prevented by giving concomitant glucocorticoids, especially to those at risk like smokers.8

viii)    Biologics: These are target specific immuno-modulators that block the downstream inflammatory process, used mainly in moderate to severe orbitopathy, some of which are discussed below and are given in table 2.

 

 

ix)      Local treatment: Periocular triamcinolone (40 mg/ ml) has been shown to safely reduce diplopia even in the active stage. Subconjunctival  and intra-levator administration has been shown to resolve eyelid swelling and lid retraction.12 Intra-ocular pressure needs to be monitored in these cases. Botulinum toxin injection or fillers can help treat eyelid retraction and lagophthalmos.

x)       Orbital decompression: Surgery in active phase may be required in the setting of acute DON, corneal breakdown, and acute globe subluxation under cover of GC.13 DON may be out of proportion to the proptosis as it occurs due to apical compression by the enlarged muscles. Hence, it warrants a posterior decompression of the optic canal rather than a wall decompression.7

Biologics – Beyond conventional treatment

i)        Rituximab, a humanized CD20 specific monoclonal antibody (1000mg, two weeks apart or single dose of 500mg), when compared to IVMP, has shown to have improvement in CAS and reduced recurrence rates in one randomized controlled trial (RCT), whereas  another smaller placebo controlled RCT did not show a significant difference.14,15 Nevertheless, the possible benefit of rituximab cannot be completely ruled out. It is currently an off label drug due to its B cell depleting side effect. Arthralgia, hypotension, aggravation of inflammatory bowel disease are other possible side effects.

ii)       Teprotumab, an IGF1 receptor antibody, was declared a breakthrough therapy, when it was shown to reduce CAS, have quicker response and improve quality of life in a placebo controlled RCT.16 Teprotumab additionally reduces proptosis which was not observed with other immunomodulators; and hyperglycaemia seems to be the only risk factor. The RCT used a dosage of eight intravenous infusions, one every three weeks (initial dose of 10 mg/kg of body weight, followed by 20 mg/kg for the remaining seven infusions) and did not include sight threatening orbitopathy or long standing active disease. Hence, the effect in these situations is unclear. Efficacy and safety were further proven in a placebo controlled RCT.17

iii)      Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody, which has shown promising effects. This is probable because IL-6 acts at multiple points including increasing expression of TSH receptors on newly laid down adipocytes. A multicentric observational study evaluated the effect of Tocilizumab in moderate to severe orbitopathy including DON. They used a dosage of 8 mg/kg intra-venously every four weeks or 162 mg subcutaneously every week and found a significant improvement in CAS, proptosis, symptoms as well as visual acuity by one month which was maintained even at the end of one year.18 There were no major side effects that warranted discontinuation of treatment. Effect of Tocilizumab compared to placebo in GC resistant TAO in an earlier RCT had demonstrated significant improvement in CAS, but no effect on proptosis; however patients with DON were not included.19

Table 1 shows a summary the various medications used in the management of active disease as per the guidelines of the European thyroid association 2016 and 2018.8,10 The mechanism of action of upcoming immunomodulators are listed in table 2. Research on animal models has revealed some isoform of peroxisome proliferator activated receptor γ, that are involved in adipogenesis, in fact have an inhibitory action on certain cytokines which forms the basis of various trials exploring its therapeutic effect. Newer studies have also explored the role of antigen- specific immunotherapy that is thought to reinstate auto-antigen tolerance. In vitro and in vivo mouse model studies have shown encouraging results with placenta derived mesenchymal stem cells.20

Treatment of inactive disease:

An inactive disease for more than 6 months with stable proptosis and strabismus can be considered for surgical procedures aimed for symptomatic and cosmetic rehabilitation. Diplopia caused by up to 12 to 15 prism dioptres of strabismus can be corrected with prisms both in active and inactive phase.13 Surgical rehabilitation is done for disfiguring proptosis, chronic pain/discomfort, congestion, and corneal exposure. The expected outcome of orbital decompression is relief of orbital pain, reduction in exophthalmos, eyelid puffiness and postural visual obscuration. The complication however is squint and diplopia which is corrected usually by recession of extraocular muscles, retroequatorial myopexies and conjunctival recession aiming mainly at abolishing diplopia at primary and inferior gaze. Lid retraction is then dealt with by mullerectomy or transconjunctival levator recession. Excess of lax skin is addressed with blepharoplasty. The order of surgery to be followed is as described above as orbital decompression drastically changes squint and eyelid measurements; and lid surgery needs a final corneal position as a landmark which is achieved only after the required squint surgery.7,13 One of the challenges in TAO is deciding whether congestion is due to activity or just venous congestion. In some patients these persistent venous congestion after treatment may resolve only with orbital decompression which makes it another indication for surgery.

 

Conclusion

 

There are multiple checkpoints in the inflammatory pathway that can be targeted to halt the disease; however the various interconnected autoimmune mechanisms make this challenging. While we await consensus guidelines on immunomodulatory therapy, further research will probably address the unmet need for better biomarkers that can guide management of TAO.

 

 References

 

1.       Bahn RS. Graves' ophthalmopathy. N Engl J Med. 2010;362:726-38.

2.       Turck N, Eperon S, De Los Angeles Gracia M, Obéric A, Hamédani M. Thyroid-Associated Orbitopathy and Biomarkers: Where We Are and What We Can Hope for the Future. Dis Markers. 2018;2018:7010196.

3.       Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med. 1993;329:1468-75.

4.       Bartley GB. Rundle and his curve. Arch Ophthalmol. 2011;129:356-8.

5.       Menconi F, Profilo MA, Leo M, Sisti E, Altea MA, Rocchi R, et al. Spontaneous Improvement of Untreated Mild Graves’ Ophthalmopathy: Rundle’s Curve Revisited. Thyroid. 2014 ;24:60–6.

6.       Szczapa-Jagustyn J, Gotz-Więckowska A, Kocięcki J. An update on thyroid-associated ophthalmopathy in children and adolescents.J. Pediatr. Endocrinol. Metab.2016 ;29:1115–22.

7.       Rootman, Jack. Diseases of the Orbit: A Multidisciplinary Approach. Philadelphia: Lippincott Williams & Wilkins, 2003.

8.       Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO). The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur Thyroid J. 2016;5:9-26.

9.       Dolman PJ. Evaluating Graves’ Orbitopathy. Best Pract. Res. Clin. Endocrinol. 2012;26:229–48.

10.     Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. ETJ. 2018;7:167–86.

11.     Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M, Daumerie C, et al. Efficacy and Safety of Three Different Cumulative Doses of Intravenous Methylprednisolone for Moderate to Severe and Active Graves’ Orbitopathy. J Clin Endocrinol Metab. 2012;97:4454–63.

12.     Honavar SG. Medical management of thyroid eye disease – A paradigm shift. Indian J Ophthalmol. 2020;68:1515–8.

13.     Rootman DB. Orbital decompression for thyroid eye disease. Surv.Ophthalmol.2018 ;63:86–104.

14.     Salvi M, Vannucchi G, Currò N, Campi I, Covelli D, Dazzi D, Simonetta S, Guastella C, Pignataro L, Avignone S, Beck-Peccoz P. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study. J Clin Endocrinol Metab. 2015;100:422-31.

15.     Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab. 2015 ;100:432-41.

16.     Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, et.al.Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017;376:1748-1761.

17.     Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R,et.al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med. 2020;382:341-352.

18.     Sánchez-Bilbao L, Martínez-López D, Revenga M, López-Vázquez Á, Valls-Pascual E, Atienza-Mateo B,et.al. Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients. J Clin Med. 2020;9:2816.

19.     Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez 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.

20.     Park M, Banga JP, Kim GJ, Kim M, Lew H. Human placenta-derived mesenchymal stem cells ameliorate orbital adipogenesis in female mice models of Graves' ophthalmopathy. Stem Cell Res Ther. 2019;10:246.

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