How can we prevent disease relapse in Graves’ orbitopathy after immunosuppressive treatment?

Figures & data

Table 1. (a) Classifications of GO activity according to clinical activity score (CAS) [3]; b) Classifications of GO severity according to the EUGOGO score [4]; c) Composite index for the assessment of clinical response to treatment [6].

A. Clinical activity score (CAS) This score is calculated as the sum of each item has the same value of 1 GO is defined as active when CAS ≥3 at first assessment and CAS ≥3 at follow-up	B. EUGOGO score Mild GO: conservative treatment, lifestyle changes, selenium supplementation Moderate-to-severe GO: immunosuppression (if active) or elective surgical intervention (if inactive). Sight-threatening (very severe) urgent medical and/or surgical decompression	C. Composite index (2020 revision) Objective measures of treatment outcome Positive response to treatment: improvement in ≥2 features in one eye without deterioration in the other eye
Spontaneous orbital pain Gaze evoked orbital pain Eyelid swelling * Eyelid erythema* Conjunctival redness* Chemosis Inflammation of caruncle OR plica Follow-up (1–3 months) (8) Increase of >2 mm in proptosis (9) Decrease in ocular ductions in any one direction (>8°) (10) Decrease of acuity equivalent to 1 Snellen line	Mild GO lid retraction (<2 mm) mild soft-tissue involvement exophthalmos (<3 mm above normal for race and gender) absent/intermittent diplopia corneal exposure responsive to lubricants Moderate-to-severe GO lid retraction ≥ 2 mm moderate or severe soft-tissue involvement exophthalmos (≥3 mm above normal for race and gender) inconstant or constant diplopia Sight-threatening (very severe) GO Patients with dysthyroid optic neuropathy and/or corneal breakdown	≥2-mm reduction of lid aperture ≥1 point reduction in five-item CAS (item 3 to 7) ≥2 mm reduction in exophthalmos ≥8° increase of eye muscle duction
A color atlas for objective assessment is avaliable at the website of the EUGOGO group: https://www.eugogo.eu/en/home/		A positive response to treatment is defined as the improvement in 2 or more items in one eye without deterioration in the fellow eye

Figure 1. The biphasic course of GO according to the model of Rundle (Panel A). The shaded area represents the severity of GO graded according with the EUGOGO score (right axes). The black continuous line represents GO activity measured by the clinical activity score (CAS) (left axes). Dotted arrows and text in regular font outline the recommended therapies for each stage (active/inactive) and grade (mild, moderate to severe and sight-threatening). In italics fonts the treatments that might be useful in the future, but for which data are insufficient to support a recommendation. The gray arrow is the 6- weeks-follow up assessment and thereafter not-responders undergo a second line treatment. Patients developing sight-threatening GO (DON, corneal breakdown and sublussation of the eye globe) require urgent medical/surgical decompression.

Panel B A GO patient is fully responsive to treatment. The successful immunosuppressive therapy reduced either activity or the degree of residual disease, avoiding rehabilitative surgery. Patients who relapse undergo to an early (Panel C) or late recurrence (Panel D) after a variable period of inactive disease and require additional treatments. Known (bold regular font) or supposed (italic font) risk-factors/triggers are represented by arrows pointing up, while protective measures are outlined by arrows pointing down. TFTs = thyroid function tests; Se = selenium; RAI radioactive iodine therapy; GD Graves’ disease; GO = Graves’ orbitopathy; ivMP intravenous methylprednisolone; RX = orbital radiotherapy; CYA cyclosporine; OC oral corticosteroids; AZP = azathioprine; RTX = rituximab; MMF mycophenolate mofetil; DON dysthyroid optic neuropathy.

Table 2. Efficacy of available treatments for GO. The response and relapse rate and efficacy in preventing dysthyroid optic neuropathy (DON) are reported.

Treatment	N of patients	Type of study	Responders	Not responders	DON occurrence	Relapses	Long term outcome	Reference
ivMP alone	>250	5 RCT	70–88%	10–20% (dose dependent)	Variable (<10%)	15–30%	Effect on proptosis and diplopia variable	[30]; Kahaly GJ, Lancet Diabetes Endocrinol. 2018 and J Clin Endocrinol Metab 2005; Bartalena J Clin Endocrinol Metab 2012; Marcocci J Clin Endocrinol Metab 2001
Mycophenolate +ivMP	73	RCT vs ivMP alone	>75%	≈20%	<7%	<10%	Residual disease significantly less severe than after IVMP alone	Kahaly GJ, Lancet Diabetes Endocrinol. 2018
Teprotumumab	84	pooled data of 2 RCT	>80%	<10%	≈1%	≈20%	Durability of the response still unclear	[9]
Rituximab	141 (24 steroid resistant)	3 RCT (1 vs placebo; 2 vs ivMP) and 3 open studies	>85%	≈10%	<3%	<1%	Effect on proptosis and diplopia variable (probably equal to ivMP)	[30,31]; Li J, Pharmacology 2017; Khanna D, Ophthalmology, 2010; Du Pasquier-Fediaevsk L Ocul Immunol Inflamm. 2019 and Vannucchi G Thyroid. 2021 (low dose)
Tocilizumab	63	RCT vs placebo 1 open study	≈90%	≈10%	Not reported	Not reported	Ongoing definition	Perez-Moreiras JV, Am J Ophthalmol. 2018; Sánchez-Bilbao L, J Clin Med. 2020
RX alone	92	RCT	50–60%	30–40%	Unclear	Unclear	Effective on recent onset ocular motility impairment, less effective on proptosis	Mouritz MP Lancet 2000, Prummel MF J Clin Endocrinol Metab. 2004, Marcocci J Endocrinol Invest. 1991
RX + OC	56	2 RCT	≈65%	≈35%	Unclear	Unclear	Combination therapy improves final outcome	Marcocci J Endocrinol Invest. 1991, Marcocci J Clin Endocrinol Metab 2001
RX + ivMP	41	1 RCT	>85%	<15%

RCT = randomized controlled trials, ivMP = intravenous methylprednisolone, OC = oral corticosteroids, RX = orbital radiotherapy

Mourits MP, Prummel MF, Wiersinga WM, et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clinical Endocrinol. 1997;47:9–14.

 PubMed Web of Science ®Google Scholar

Bartalena L, Baldeschi L, Dickinson A, et al. Consensus statement of the european group on graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008;158:273–275.

 PubMed Web of Science ®Google Scholar

Currò N, Covelli D, Vannucchi G, et al. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid. 2014;24:897–905.

 PubMed Web of Science ®Google Scholar

Salvi M, Vannucchi G, Currò N, et al. 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;100:422–431.

 PubMed Web of Science ®Google Scholar

Kahaly GJ, Douglas RS, Holt RJ, et al. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials. Lancet Diabetes Endocrinol. 2021;9:360–372.

 PubMed Web of Science ®Google Scholar

Stan MN, Salvi M. MANAGEMENT OF ENDOCRINE DISEASE: rituximab therapy for Graves’ orbitopathy - lessons from randomized control trials. Eur J Endocrinol. 2017;176:R101–R109.

 PubMed Web of Science ®Google Scholar