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Review

Endokrynologia Polska

DOI: 10.5603/EP.a2022.0040

ISSN 0423–104X, e-ISSN 2299–8306

Volume/Tom 73; Number/Numer 4/2022

Submitted: 11.01.2022

Accepted: 17.03.2022

Early publication date: 18.07.2022

Optimization of the treatment of moderate to severe and active thyroid orbitopathy considering the recommendations of the European Group on Graves’ Orbitopathy (EUGOGO)

Mariusz Nowak1Bogdan Marek1Beata Kos-Kudła2Lucyna Siemińska1Magdalena Londzin-Olesik2Joanna Głogowska-Szeląg1Wojciech Nowak3Dariusz Kajdaniuk1
1Pathophysiology Division, Department of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
2Department of Endocrinology and Neuroendocrine Tumours, Department of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
3Science Students’ Association, Pathophysiology Division, Department of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland

Mariusz Nowak, Pathophysiology Division, Department of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Jordana 19 str., 41–808 Zabrze, Poland; e-mail: nowak-mar@wp.pl; mnowak@sum.edu.pl

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract
Graves’ disease (GB), also known as Basedow’s disease, is the most common cause of hyperthyroidism, and thyroid orbitopathy (TO) is its most common non-thyroid manifestation with an incidence of 42.2/million people/year.
Based on the guidelines of the European Graves’ Orbitopathy Group (EUGOGO), certain management standards presented in our publication should be used to optimize and improve the efficacy of TO treatment. Deciding on the optimal treatment for both hyperthyroidism and TO requires a cooperative team of specialists: endocrinologist, ophthalmologist, radiation therapist, and surgeon, as well as consideration of the risk of relapse and possible complications of the treatment method.
The inflammatory activity and severity of TO should be diagnosed based on the investigator’s own experience and according to standard diagnostic criteria. Assessment of the inflammatory activity of TO can be performed using the clinical activity score (CAS) and using imaging methods — mainly MRI. The severity of TO is assessed using a seven-grade NOSPECS classification and a three-grade EUGOGO scale.
In moderate to severe and active TO, i.v. methylprednisolone pulses are the treatment of choice. It is important to maintain the standard and regimen of treatment. The recommended standard as first-line treatment in most patients with moderate to severe and active TO is the combined use of methylprednisolone i.v. (cumulative dose of 4.5 g over 12 weeks) with concurrent administration of mycophenolate sodium 0.72 g per day for 24 weeks.
In more severe forms of moderate to severe and active TO, a higher cumulative dose of methylprednisolone i.v. is recommended as an alternative first-line treatment (7.5 g) as monotherapy starting with a dose of 0.75 g once a week for 6 weeks and 0.5 g for a further 6 weeks.
EUGOGO guidelines recommend that in cases of no clinical response after 6 weeks of first-line treatment with i.v. methylprednisolone and mycophenolate, after 3–4 weeks, a second course of i.v. methylprednisolone monotherapy should be started with a higher cumulative dose of 7.5 g. Other second-line treatment options are orbital radiotherapy with or without oral or i.v. systemic glucocorticosteroid therapy, cyclosporine, or azathioprine in combination with p.o. glucocorticosteroid, methotrexate monotherapy, and a group of biologic drugs rituximab, tocilizumab, teprotumumab).
Keeping in mind that TO is a sight-threatening disease, we expect, through the treatment applied, to maintain full visual acuity, pain relief, single vision in the useful part of the visual field, and a positive cosmetic effect. (Endokrynol Pol 2022; 73 (4): 756–767)
Key words: Graves’ disease; Basedow’s disease; thyroid orbitopathy; assessment of thyroid orbitopathy; first-line treatment; second-line treatment

Introduction

Graves’ (or Basedow’s) disease (GB) is the most common cause of hyperthyroidism, with an incidence rate of 210/million/year, and thyroid orbitopathy (TO) is the most common extra-thyroid manifestation of GB, with an incidence rate of 42.2/million/year [1]. TO belongs to a group of rare diseases. Laurnberg et al. found that moderate to severe TO, according to the European Group on Graves’ Orbitopathy (EUGOGO) classification, occurs with a prevalence of 16.1/million/year (women: 26.7; men: 5.5) in 4.9% of patients with GB, regardless of iodized salt supplementation [2]. A similar prevalence of moderate to severe TO has been confirmed by other authors [3, 4].

Ocular symptoms associated with hyperthyroidism were first described in 1840 [5]. However, the pathogenesis of TO is still not fully understood, and treatments are still only symptomatic and not always satisfactory.

TO is a combination of symptoms resulting from inflammation of the soft tissues of the orbit, and less commonly the pathology of the eyeball itself, which occur mainly in patients with GB, but also in patients with thyroiditis in the course of Hashimoto’s disease and less commonly without thyroid disease [6]. TO usually develops during hyperthyroidism, but it can also develop in euthyroidism or even hypothyroidism.

The natural history of TO includes 2 phases of disease: an active (infiltrative) phase and an inactive (fibrotic) phase. The receptor for TSH (TSHR), located mainly on thyrocytes but also on orbital fibroblasts, is the autoantigen responsible for hyperthyroidism in GB and is considered a major pathogenetic factor of TO. Antibodies to the receptor for TSH (TRAb) are present in all patients with GB, and the severity and activity of TO correlates positively with blood TRAb levels [7, 8].

The site of ongoing inflammation in the orbit is the connective tissue, and within it are fibrocytes, a group of marrow-derived progenitor cells with immunomodulatory characteristics that exhibit high TSHR expression comparable to thyroid cells. These cells migrate to the orbit (only in TO patients) and develop into specific fibroblasts, characterized by overexpression of surface receptors and hyperreactivity to proinflammatory stimuli.

Another potential target autoantigen in TO is the IGF-1 receptor (IGF-1R) [9], and it appears that the interaction between TSHR and IGF-1R is more important than the action of individual molecules [10–12]. Stimulation of TSHR on fibrocytes and fibroblasts, with concomitant stimulation of IGF-1R, results in the release of pro-inflammatory cytokines and initiation of inflammation. Furthermore, patients may have one or both types of autoantibodies, and alternative production of other types of autoantibodies is not excluded. Studies suggest that autoantibodies to carbonic anhydrase 1 and alcohol dehydrogenase 1B were more prevalent in orbital fat in TO compared to controls [13].

A test that allows for the definitive diagnosis of GB and its differentiation from other causes of hyperthyroidism is the determination of serum TRAb, which are a specific biomarker of GB [14]. Most immunoassays only report the presence or absence of TRAb and their concentrations, but do not indicate their functional activity [15]. These antibodies can mimic [14] or block [16] the action of TSH or be functionally neutral [17]. TSHR-stimulating antibodies (TSI-Ab) are responsible for many of the clinical manifestations of GB and are an appropriate specific biomarker of the disease [18–20].

A more accurate assay, which unlike the TRAb assay does not detect blocking antibodies, is to evaluate the concentration of TSHR-stimulating antibodies (TSI-Ab) alone [12].

Antibodies to the IGF-1R seem to play an important role, as shown by cases of mild TO despite high or very high TRAb concentrations, and sometimes, conversely, by a dynamic and severe course of TO with low TRAb concentrations. We have high expectations for the inclusion of an anti-IGF-1 receptor antibody (Teprotumumab) in the treatment of moderate to severe and clinically active TO [21, 22].

Some researchers suggest the involvement of oxidative-reductive system disorders and angiogenesis in the pathogenesis of GB and probably also TO, although the results are inconclusive and often contradictory [23–31].

Since the publication of the European Thyroid Association (ETA) and European Graves’ Orbitopathy Group (EUGOGO) guidelines for the management of TO in 2016 [32], several new studies have been published, including randomized clinical trials (RCT) evaluating the use of new drugs, including biological drugs, in the treatment of moderate to severe and active TO [21, 22, 33–38]. Therefore, new recommendations for the assessment and treatment of TO were developed and published in 2021 [39].

TO represents a major therapeutic challenge in moderate to severe and clinically active forms that are often not fully or even poorly responsive to available treatments [4, 40, 41].

To the best of our knowledge and based on EUGOGO guidelines, certain standards of management should be applied to optimize and improve the efficacy of TO treatment.

Diagnose and classify the patient — optimal qualification for the appropriate treatment course

Selecting the optimal treatment for hyperthyroidism and OT requires a cooperative team of specialists: endocrinologist, ophthalmologist, radiation therapist, and surgeon, as well as taking into consideration the risk of recurrence and possible complications of the treatment method.

Achieving and maintaining thyroid balance

Control of thyroid function has a profound impact on the course and efficacy of TO treatment. Both hyperthyroidism and hypothyroidism have a negative impact on its course [42, 43]. Antithyroid drugs (ATD) and thyroidectomy per se do not seem to have a negative effect on the natural course of TO whereas radioiodine treatment is associated with a small but definite risk of exacerbation or de novo development of TO, especially in smokers [44].

Therefore, the EUGOGO guidelines [39] recommend that the priority in patients with TO should be rapid restoration and stable maintenance of euthyroidism, but importantly in patients with moderate to severe and active TO, the priority should be TO treatment and euthyroidism should be restored with ATD and stably maintained if possible.

There are 3 methods used to treat hyperthyroidism: 1. pharmacological, using ATD; 2. isotopic, using 131J radioactive iodine (RAI); and 3. surgical, using sub-total near-total or total thyroidectomy [45, 46]. Currently, 2 ATD agents are available: thiamazole, which is the drug of choice, and propylthiouracil, used much less frequently and preferred in the first trimester of pregnancy. In hyperthyroidism in the course of GB thiamazole is used p.o. for 12–18 months [47, 48]. After this duration of treatment, the highest remission rate of 50–55% is achieved. In patients with persistently elevated TRAb levels after 12-18 months of treatment, a recurrence of hyperthyroidism may be expected after completion of drug therapy; to avoid this, treatment with thiamazole may be continued and antibody determination repeated after another 12 months, or radical RAI treatment or thyroidectomy may be used [47, 48]. In the case of recurrence of hyperthyroidism in GB patients who have undergone the first cycle of treatment with ATD, radical treatment with RAI or thyroidectomy is recommended.

RAI treatment is contraindicated in patients with moderate to severe and active TO. It is accepted in mild and clinically active TO or with established risk factors for TO, with the addition of glucocorticosteroid prophylaxis [39, 47, 48]. RAI is associated with a risk of progression and/or de novo onset of TO. Risk factors for worsening ocular lesions after RAI treatment include smoking, high TRAb levels, the presence of active TO prior to treatment, subsequent RAI therapy, short duration of GB, whereas worsening is less possible in patients with long-standing and inactive TO [49–51].

The progression or development of RAI-related TO can be prevented by glucocorticosteroid prophylaxis (initial daily dose of 0.3–0.5 mg prednisone/kg body weight, gradually reduced over a period of 3 months) [39, 52, 53].

The alternative method of radical treatment — thyroidectomy — is more demanding for the patient than RAI treatment. Ophthalmic improvement is observed in 69–81% of patients treated with subtotal thyroidectomy [54–56].

Quit active smoking and avoid passive smoking

All patients with GB, independently of the presence of TO, should be advised to quit smoking. Smoking increases the risk of TO in patients with GB, and it may cause a more severe course of TO and the de novo onset or progression of TO after RAI treatment [4]. Smokers have a delayed or worse outcome from immunosuppressive treatment, and quitting smoking may have a beneficial effect on the course of TO [44].

The pathomechanism of this relationship is not fully understood. Cigarette smoke promotes oxidation and therefore increases oxygen free radical levels, which contributes to the development of TO. Tsai et al. showed that smokers or people who smoked in the past had significantly higher levels of 8-OHdG than never-smoking patients [57]. In another study, cigarette smoke extract was shown to significantly increase adipogenesis and glycosaminoglycan accumulation (mainly hyaluronic acid) synergistically with IL-1 [58].

Assessment of the inflammatory process activity of TO and its severity based on standardized scales and imaging methods

The clinical activity and severity of TO should be determined based on the examiner’s own experience and according to standard diagnostic criteria. TO should be classified as clinically active or inactive, and the degree of clinical severity should be assessed as mild, moderate to severe, or sight threatening, also taking into account the patient’s quality of life (QoL) assessment [59].

It is recommended that primary care physicians as well as ophthalmologists and endocrinologists refer patients with symptomatic TO, even in the mild stage but at risk of rapid deterioration (smokers, severe/unstable hyperthyroidism, high TRAb titres), to referral centres experienced and specialized in the diagnosis and treatment of TO, which improves the efficacy of treatment and the patient’s prognosis.

The inflammatory activity of TO can be assessed using a clinical activity score (CAS) and imaging modalities, mainly MRI.

CAS is used to assess typical features of inflammation such as pain, swelling, and congestion. It has some limitations due to the subjective assessment of, e.g., pain, although the experience of the examiner allows for its optimization [60]. CAS consists of 7 examined inflammatory parameters (spontaneous extraocular pain — a feeling of tightness in the orbit, pain on eye movements [it is the pain that the examiner “sees” — the eye automatically returns to the straight position when trying to look in a given direction], swelling of the eyelids, swelling of the conjunctivae, swelling and redness of the caruncle and plica, redness of the eyelids, conjunctival injection), and TO is defined as active if CAS ≥ 3 [39].

When examining a patient several times, we can also use the CAS scale supplemented with three additional parameters, i.e. increase in exophthalmos, increase in eye movement disorders and double vision, and deterioration of visual acuity over a period of 3 months. Using a 10-point scale, CAS ≥ 4 points is considered an inflammation-active OT [60].

At this ratio, we expect the benefit of the treatment to outweigh the side effects of its use. The authors consider as extremely important not only the examiner’s own experience, but also the reference of the clinical picture to reference pictures and schemes published in atlases because a good assessment of activity determines the decision on further management and the percentage of effectiveness of immunosuppressive treatment [61, 62]. This allows us to optimize the TO assessment and to decide on the initiation of immunosuppression or local observation strategy.

Orbital MRI is widely used not only to detect other pathologies, such as orbital tumours or vascular lesions, but also to identify oedema and distinguish active from inactive TO.

This is due to the high contrast resolution of MRI, allowing the signal intensity of fibrous and inflammatory tissue to be distinguished on strong fat-suppressed T2-weighted images derived from TIRM (turbo-inversion recovery-magnitude) sequences. In addition, many studies report the ability to quantify different signals using STIR protocols or T2 relaxation time measurements, which allows objective assessment of inflammation independently of muscle measurements and positively correlates with CAS [63, 64]. Orbital MRI is indicated in patients with unilateral or severely asymmetric exophthalmos, suspected optic nerve neuropathy, and euthyroid TO, while orbital CT is indicated before orbital decompression surgery [34, 65].

Several classifications are used to assess the severity of OT, the most common being the NOSPECS classification [66] and the currently recommended three-grade EUGOGO severity scale [39].

The NOSPECS classification (an acronym from the first letter of the English words) is a 7-grade classification from grade “0” meaning no objective or subjective symptoms of OT to grade “6” meaning OT causing various degrees of visual impairment [66] .

The severity classification of TO according to EUGOGO guidelines includes 3 grades:

1. Mild TO — TO symptoms having little impact on daily life. Retraction < 2 mm, mild soft-tissue inflammation, exophthalmos < 3 mm above normal, no or only intermittent diplopia, corneal symptoms resolving after moisturizers;
2. Moderate to severe TO: without sight-threatening TO symptoms but with the presence of symptoms that make daily life difficult: eyelid retraction > 2 mm, moderate to severe soft tissue symptoms, exophthalmos > 3 mm above normal, intermittent or persistent diplopia.
3. Sight-threatening TO (very severe): optic nerve neuropathy and/or corneal abnormality up to corneal rupture (ulceration/perforation) [39].

For the purposes of their own and clinical practice, the authors of this article also classify TO into the so-called “anterior orbitopathy” — with a clear and dominant manifestation of oedematous and inflammatory changes in the eyelids and conjunctiva, caruncle, or plica, and “posterior orbitopathy” with dominant inflammatory symptoms in the oculomotor muscles and orbital fat, especially in the area of the muscular cone.

Patient’s problems reported to the doctor

Patients with TO report to the doctor the following symptoms:

— change in appearance (exophthalmos, asymmetry of eye position, retraction of the eyelids, lagophthalmos, swelling of the eyelids, conjunctivae, redness of the eyelids and conjunctiva) — discomfort (feeling of “tightness of the orbit”, pushing out of the eyeballs, pain, feeling of a foreign body under the eyelids, dry eyes);
— “psychosocial” (non-acceptance of one’s own appearance, limitation of ability to perform work);
— visual disturbances (neuropathy, keratopathy, pain, feeling of a foreign body under the eyelids, doubling, decrease of visual acuity and/or visual field) [59].
The role of the ophthalmologist in the diagnostic and therapeutic process

Assessment of the presence and differentiation of ocular symptoms of TO — differential diagnosis of other causes of eyelid and conjunctiva oedema and their redness.

Assessment of the inflammatory activity of TO using the CAS scale and assessment of the severity of the disease based on available classification tests and shared decision about the form of treatment (observation or initiation of first-line treatment).

Rehabilitative strabismus surgery in clinically inactive cases of TO with primary gaze position diplopia and eyelid oculoplastic surgery.

Atypical TO presentations include unilateral TO, unilateral or bilateral TO in patients without prior or coexisting symptoms of thyroid disorders, absence of symptoms of eyelid retraction, divergent strabismus, diplopia as the only symptom of the disease, or diplopia increasing at the end of the day.

The differential diagnosis of TO includes the following: allergic conjunctivitis or blepharoconjunctivitis, anterior or posterior eyelid margin inflammation (the most common cause of eyelid hyperaemia), myasthenia gravis, isolated periorbital myositis, orbital tumours (primary and secondary), carotid artery to cavernous sinus fistula, orbital cavernous haemangioma, orbital venous anomalies such as orbital varicosities, non-inflammatory orbitopathies (Wegener’s disease), and head and neck limited clinical phenotype of IgG4-related disease [67-69].

Mild TO — EUGOGO guidelines

Selenium supplementation (200 mg/day) has been shown to have beneficial effects in GB patients with symptoms of mild TO. It has been shown to reduce inflammation of the periocular soft tissues, improve quality of life, and reduce the risk of TO progression [70]. However, it is not known whether selenium is effective in all patients regardless of selenium levels or only in cases of selenium deficiency, because the studies did not assess selenium levels at baseline, prior to the inclusion of selenium supplementation. Kucharzewski et al. investigating selenium concentrations in patients with various thyroid disorders showed the lowest selenium concentration in blood in the GB group, and the highest selenium concentration in the thyroid gland tissue [71].

EUGOGO investigators recommend a six-month selenium supplementation period in patients with mild or moderate to severe TO [32, 39].

Most patients (up to 60%) with mild TO may have a spontaneous regression of ocular symptoms up to a year after thyroid function is restored. Therefore, control of local ophthalmic status and topical treatment appear to be sufficient [32, 39]. The following symptoms should be decreased or eliminated: photophobia by wearing dark glasses, foreign body sensation with the use of “artificial tears” solutions; in the case of increased intraocular eye pressure we recommend topical beta-blocker drops; in the case of exophthalmos and related lagophthalmos — a moist chamber with “artificial tears” solutions; in the case of double vision we use alternate covering of the eyes or prism glasses in the case of constant double vision when looking straight ahead. Smoking is always forbidden, and selenium prophylaxis is recommended [32, 39, 41].

Moderate to severe and clinically active TO — EUGOGO guidelines

Methylprednisolone

Since the 1950s, glucocorticoids have been used in the treatment of TO. They can be used topically (as periocular or extraocular and subconjunctival injections) and by oral and intravenous routes [72–75].

The intravenous route of weekly pulses of methylprednisolone is more effective and safer than high doses of p.o. prednisone, and the limitation is that it must be administered in health care facilities after contraindications to its use have been excluded [76].

It should be considered whether the benefits of ongoing immunosuppressive therapy outweigh the potential side effects of steroid therapy as a first-line treatment of active TO. In certain cases of so-called “posterior orbitopathy” or a significant decrease in quality and comfort of life, systemic therapy should be considered even with a CAS lower than 3 points.

The potential complications of i.v. intensive glucocorticoids therapy, including life-threatening ones, such as acute cardiac syndromes or piriform hepatic failure, should be kept in mind [77].

Hepatic toxicity of intravenous glucocorticoids has been described by many authors. This complication is rare, most often in the form of mild, drug-induced liver damage, with an increase in liver enzyme values, resolving after a pause in the administration of i.v. methylprednisolone and the use of drugs regenerating liver cells, but it may also cause acute liver failure and lead to death [78–80]. Several cases of myocardial necrosis and acute coronary syndromes have been documented in patients without prior cardiac disorders, hypertension leading to myocardial infarction, ischaemic stroke, and pulmonary embolism after treatment with intravenous pulses of methylprednisolone [81–83].

Patients with viral hepatitis, impaired liver function, severe cardiovascular disease, and psychiatric disease should not be qualified for high-dose i.v. methylprednisolone therapy.

Despite the risks described above, i.v. glucocorticoids remain the first-line treatment in patients with TO, although new therapies such as mycophenolate, biologics, or anti-thymocyte globulin administration are being tried [84–87]. In moderate to severe and active TO i.v. methylprednisolone pulses are the treatment of choice.

The use of the same i.v. dose of methylprednisolone in different administration regimens dramatically changes the effectiveness of the treatment.

A treatment regimen of methylprednisolone infusions once a week is more effective and safer than a regimen of daily or every-other-day methylprednisolone infusions in patients with active moderate to severe TO.

Kahaly et al. [88], using a regimen consistent with current EUGOGO recommendations, i.e. a cumulative dose of 4.5 g of methylprednisolone divided into 12 weekly infusions (6 weeks at 0.5 g and 6 weeks at 0.25 g), demonstrated a positive response to treatment in 77% of patients, which is in agreement with the results of other authors’ studies [89].

Zhu et al. [89] published the results of a RCT designed to compare the efficacy and safety of 2 protocols of intravenous administration of the same cumulative dose of 4.5 g of methylprednisolone i.v. administered weekly or daily. The authors demonstrated a significantly higher rate of positive response to the weekly vs. daily protocol at week 12 (76.92 vs. 41.03%; p = 0.0025).

It is currently recommended to start treatment with a medium dose of methylprednisolone (cumulative dose 4.5 g) 0.5 g once a week for 6 weeks then 0.25 g once a week for another 6 weeks (12 weeks in total). In severe cases of moderate to severe GO, a high dose (cumulative dose of 7.5 g) of 0.75 g once a week for 6 weeks then 0.5 g once a week for another 6 weeks is recommended [32, 39].

Based on a RCT [38, 84] conducted in patients with moderate to severe and active OT using methylprednisolone in combination with mycophenolate, it was shown that combination treatment is significantly more effective while maintaining treatment safety [90, 91] compared to methylprednisolone monotherapy; new first-line treatment guidelines were introduced in 2021 [39].

Mycophenolate

Mycophenolate competitively and reversibly inhibits inosine monophosphate dehydrogenase, resulting in decreased antibody production by B lymphocytes and dual antiproliferative effects on both B and T lymphocytes [92]. Mycophenolate inhibits fibroblast proliferation and function [93].

A multicentre clinical trial [38,91] in patients with moderate to severe and active TO compared 2 immunosuppressive regimens, i.e. weekly methylprednisolone i.v. for 12 weeks (the current standard of treatment) and combination treatment with methylprednisolone i.v. for 12 weeks and mycophenolate sodium 0.72 g per day for 24 weeks. Researchers demonstrated a 49% response rate with monotherapy versus 63% efficacy with combination treatment at week 12 (p = 0.089); at week 24 the combination treatment group demonstrated a statistically significantly higher response rate (71% vs. 53%, p = 0.026) and maintenance of effect at week 36 (67% vs. 45.5%).

Another study compared the efficacy of three weekly i.v. infusions of methylprednisolone, and continued treatment with prednisolone p.o. or mycophenolate mofetil (1 g daily), both for 24 weeks [84]. The use of mycophenolate increased treatment efficacy to 79% at week 12 and 91% at week 24, compared to the first regimen with efficacy of 51% and 68%, respectively.

None of the studies reported an increase in treatment-related adverse events. Combination treatment did not increase the risk of infection and hepatotoxicity compared with monotherapy with i.v. methylprednisolone pulses [90, 94, 95].

Therefore, the current recommended standard (according to EUGOGO) as first-line treatment in most patients with moderate to severe and active TO is the combined use of methylprednisolone i.v. (cumulative dose of 4.5 g over 12 weeks) with concomitant administration of mycophenolate sodium 0.72 g per day for 24 weeks [39].

In more severe forms of moderate to severe and active TO, (fixed/unstable diplopia, severe periorbital soft tissue inflammatory symptoms), a higher cumulative dose of methylprednisolone i.v. is recommended as an alternative first-line treatment: 7.5 g as monotherapy starting with a dose of 0.75 g once a week for 6 weeks and 0.5 g for another 6 weeks [39].

No response to treatment after 6 weeks — do we change the strategy or continue the treatment regimen?

A partial answer to the question of how to treat if there is no response to treatment after 6 weeks is found in the work of EUGOGO investigators [96]. We know from our own experience that standard treatment with i.v. methylprednisolone in the form of 12 weekly infusions is not always effective.

Perros et al. proposed an index (composite index) to assess the response to treatment in moderate to severe and active TO [97]. It consists of reduction in eyelid width by ≥ 2 mm, reduction by ≥ 1 point in the five-item CAS scale (excluding subjective, patient-reported spontaneous pain or pain with eye movements), reduction in exophthalmos by ≥ 2 mm, and improvement in eye movement by ≥ 8°. Improvement in 2 or more of the parameters tested in one eye without worsening in the other eye can be considered a positive response to treatment [98].

Bartalena et al. [96] showed in a study group of 159 patients that those who developed progression of TO despite treatment at week 6 remained in the same category at week 12 and also at week 24 of treatment. Thus, it is unlikely that patients who had worsening severity and clinical activity of TO within 6 weeks after starting the first-line i.v. methylprednisolone 0.5 g/week would benefit from continuing the standard treatment regimen. This group of patients, although small, remains the most challenging. If there has been a worsening of OT reclassifying it to severe, vision-threatening TO, treatment should be intensified with i.v. glucocorticoids therapy according to the treatment regimen for neuropathy. With no effect of one or two weeks of intensive steroid therapy, orbital decompression should be performed urgently. With progression of symptoms but remaining treated with moderate to severe TO, continuation of the i.v. methylprednisolone regimen with the addition of mycophenolate sodium, currently recommended as first-line, at a dose of 0.72 g/day for 24 weeks, and consideration of initiating orbital topical radiotherapy as second-line treatment [39]. Patients who do not respond to treatment at 6 weeks, but whose clinical pattern does not worsen, still have a significant opportunity to improve with continued treatment for 12 or 24 weeks and a cumulative dose of methylprednisolone up to 8.0 g. These patients (n = 100) with continued treatment have a 58% and 53% chance of improvement (as assessed by the CAS ratio) at 12 and 24 weeks of treatment, respectively [96]. Patients with clinical improvement after 6 weeks of treatment (n = 51) will remain in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively [96].

No response or recurrence of activity after the end of first-line treatment — second-line treatment

In the EUGOGO guidelines [39] it is recommended that in cases of no clinical response after 6 weeks of i.v. methylprednisolone treatment, following an ophthalmologic examination and laboratory assessment of treatment tolerance, after a 3–4-week break, a second course of i.v. methylprednisolone monotherapy should be initiated with a higher cumulative dose (7.5 g), starting the second cycle with doses of 0.75 g for 6 weeks and then 0.5 g for another 6 weeks. Because there are no studies evaluating the tolerance and side effects of combined treatment with 750 mg methylprednisolone and mycophenolate, steroid monotherapy is recommended. According to the authors of the current publication, a period of 6 weeks is too short for the decision to change the treatment strategy, which is in agreement with the results of other authors’ studies [96].

Orbital radiotherapy (ORT) with or without oral or i.v. systemic glucocorticoids therapy

Low doses of ORT exhibit immunosuppressive effects mainly by decreasing leukocyte adhesion to the endothelium, stimulating apoptosis of immune cells involved in inflammation, increasing the expression of anti-inflammatory cytokines, and decreasing the secretion of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF-a), interleukin 1b (IL-1b), and nitric oxide (NO) and reactive oxygen species (ROS) [97, 98].

Prummel et al. demonstrated that ORT is as effective as oral prednisone [99], and other studies have shown that orbital radiotherapy synergistically potentiates the effects of oral glucocorticoids [100, 101].

The recommended cumulative dose of 20 Gray (Gy) to the orbit is given for 2 weeks as 10 daily fractions of 2 Gy [102]. Also, a regimen of 1 Gy per week for 20 weeks has been shown to be equally effective [103]. Oeverhaus et al. [104] compared the efficacy of 2 treatment regimens: i.v. methylprednisolone with ORT and in monotherapy i.v. methylprednisolone in patients with moderate to severe and active TO. The researchers demonstrated a statistically significant improvement in ocular motility and a diplopia reduction (11.3 ± 10.9°) and a reduction in exophthalmos (2.5 ± 0.5 mm) after combination therapy. In the authors’ opinion, combination therapy is significantly more effective in reducing the severity and activity of TO and should therefore always be considered in moderate to severe and active TO, especially with ocular motility disorders present, which is also consistent with our own observations. According to our own experience, in justified cases we start ORT during i.v. steroid therapy (after the first 6 infusions) knowing that the beneficial effect of ORT is long term and will probably occur 6 to 12 months after its administration.

Cyclosporine in combination with a glucocorticoid p.o.

Cyclosporine inhibits T helper cell proliferation and cytotoxic lymphocyte activity, and suppresses cytokine (IL-2) secretion and antibody production. Prummel et al. [105] demonstrated that cyclosporine monotherapy (7.5 mg/kg body weight/day) compared with oral prednisone monotherapy (starting dose 60 mg/day) had a significantly lower efficacy (22% vs. 61%). In contrast, combination treatment with a daily dose of 5.0–7.5 mg/kg of cyclosporine (administered over a period of one year) in combination with 50-100 mg of prednisone daily (during the first 10 weeks of treatment) has an efficacy of approximately 90% [106].

Methotrexate

A beneficial effect of methotrexate at a dose of 7.5 to 10 mg/week depending on body weight for 12 months was demonstrated [107]. The authors demonstrated the absence of treatment-related side effects and that methotrexate treatment is effective in reducing inflammation assessed by the CAS scale as well as ocular motility disorders. Methotrexate may be an alternative treatment in TO in patients who cannot tolerate steroids [107]. Similar results have also been reported by other investigators [108].

Azathioprine

Azathioprine is an antiproliferative drug (with a similar mechanism of action to mycophenolate) used as an adjunct to glucocorticoids therapy in autoimmune and inflammatory diseases. Studies have not demonstrated a benefit of its use in monotherapy in active TO but have shown a beneficial effect when combined with low-dose glucocorticoids [109, 110].

Biological drugs
Rituximab

Rituximab, an anti-CD20 antibody, blocks B-lymphocyte activation and differentiation. Reports on its efficacy are ambiguous. Stan et al. [111] compared the efficacy of rituximab (2 × 1000 mg) compared to placebo. The authors showed no advantage of rituximab over placebo in reducing both inflammatory activity (CAS) and TO severity at 24 or 52 weeks of follow-up.

In another study, Salvi et al. [112] showed a significantly better response to rituximab compared to glucocorticoids i.v. (cumulative dose, 7.5 g). At week 24, all patients treated with rituximab showed a reduction in TO activity compared with 69% in the group receiving i.v. glucocorticoids. At week 52, no patient in the rituximab treatment group showed a recurrence of TO activity in contrast to 31% in the i.v. glucocorticoids group. Similar results have also been shown with very low rituximab dose (single 100 mg dose) [85].

Tocilizumab

Tocilizumab, a monoclonal antibody against the receptor for interleukin 6 (IL-6). Perez-Moreiras et al. reported the results of a clinical trial that included patients with moderate to severe and active OT, who had not responded to prior i.v. treatment with methylprednisolone (n = 32) [35]. Patients were treated with i.v. tocilizumab monotherapy at a dose of 8 mg/kg body weight/month, administered at weeks 0, 4, 8, and 12, and evaluating treatment through week 28. The researchers demonstrated a reduction in CAS (86% achieved CAS < 3 vs. 35% in the placebo group, p < 0.005) at week 16 of treatment. Tocilizumab was well tolerated, and the most common adverse symptoms were infections and headache [35].

In another study conducted in a group of patients who did not respond to the standard first-line i.v. methylprednisolone regimen, researchers demonstrated similar efficacy of tocilizumab. The drug was well tolerated, and most patients showed improvement (92%) [37]. Similarly, in a small study, 8 glucocorticoid-resistant patients with moderate to severe and active TO showed a beneficial effect of tocilizumab as assessed by CAS score and exophthalmos measurement [37].

Teprotumumab

Teprotumumab, a monoclonal antibody against the receptor for IGF-1 (IGF-1R) has been introduced as a promising treatment.

IGF-1R is overexpressed in fibroblasts and orbital lymphocytes in TO patients. It forms a functional complex and mediates signal transduction through TSHR [10, 113]. Teprotumumab is a fully humanized monoclonal immunoglobulin (Ig) G1 inhibitory antibody that binds to the extracellular domain of IGF-1R and blocks its activation and signalling by endogenous ligands. Binding of teprotumumab also leads to internalization and degradation of IGF-1R, resulting in up to 95% reduction of available receptor protein on the cell surface [113]. The safety and efficacy of teprotumumab has been studied in RCT in patients with moderate to severe and active TO [21, 22, 34]. Smith et al. showed that 73% of patients in the teprotumumab-treated group (vs. 14% in the placebo group) achieved a good response to treatment with improvements in both CAS and proptosis [22]. Similar results were reported by Dougles et al. [21], who, in a clinical trial, at week 24 showed a significantly higher percentage of patients who experienced a reduction in exophthalmos of more than 2 mm in the teprotumumab group than in the placebo group (83% vs. 10%, p < 0.001), and 53% of patients showed a complete disappearance of the double vision (compared to 25% of patients in the placebo group) and a mean CAS reduction of 3.4 points. Jain et al. demonstrated a reduction in oculomotor muscle and orbital fat volume in patients with moderate to severe and active TO after i.v. treatment with teprotumumab [34].

Most adverse events during the study were mild to moderate. The most common adverse effects reported with teprotumumab included muscle cramps (25%), nausea (17%), alopecia (13%), diarrhoea (13%), fatigue (10%), hearing worsening (10%), and hyperglycaemia (8%) [21, 22, 34]. The drug was registered by the FDA in January 2020 for the treatment of patients with active TO. Teprotumumab was also considered as a second-line treatment for moderate to severe and active OT in the latest EUGOGO recommendations [39]. Its introduction into routine clinical practice is currently limited by the lack of comprehensive long-term efficacy and safety data, the lack of head-to-head comparison with i.v. glucocorticoids, and the price of the drug.

Other drugs

The use of antithymocyte globulin in the treatment of unresponsive active TO has also been tried with good results [87] although systemic glucocorticotherapy and its combination with mycophenolate is still the mainstay of treatment for moderate to severe active TO.

RCTs have not shown a significantly beneficial effect of somatostatin analogues on the course of TO [114, 115]. Similarly, studies conducted on small groups of patients with active TO have not shown a significantly beneficial effect of anti-TNFa drugs on the course of the disease [116, 117].

Sight-threatening thyroid orbitopathy — EUGOGO guidelines

The following are indications for urgent TO treatment: decreased visual acuity unexplained by other causes, quantitative or qualitative colour vision disturbances, oedema of the optic disc with venous stasis in the retinal vessels, rapidly increasing exophthalmos, decreased corneal transparency, or a visible cornea when the eyelids are closed.

Impairment or loss of visual acuity can be caused by optic nerve neuropathy (DON) due to compression of the optic nerve in the muscular cone, less commonly by optic nerve stretching, severe corneal damage, and in rare cases, eyeball subluxation.

The treatment of choice in DON is the urgent initiation of large i.v. doses of methylprednisolone (500 to 1000 mg) for 3 consecutive days of the week or on alternate days with constant local control [39]. When symptoms stabilize or improve, which is usually observed, we continue this regimen on the following week as well. In the case of progression of symptoms despite the above-mentioned regimen, the patient should be referred for emergency orbital decompression — visual emergency.

It was shown that in patients with DON, immediate decompression did not result in better outcomes compared to glucocorticoids given i.v. as first-line treatment [118]. In the active phase of TO, decompression surgery is indicated in patients with severe exposure keratopathy and, as second-line treatment, in patients with DON unresponsive to i.v. glucocorticoids.

Orbital decompression is a procedure performed to reduce intra-orbital pressure by removing part of its bony walls in cases of excessive tissue volume in the orbit. For many years, only methods of external access to the orbit were used. Thanks to the development of skills and surgical techniques of otolaryngologists, neurosurgeons, and maxillofacial surgeons, endoscopic orbital decompression has become a developing, multidisciplinary field of surgery. More and more authors propose endoscopic surgical methods (with removal of medial and inferior medial orbital wall), less invasive than the so-called balanced decompression (removal of the medial and lateral walls with or without fat removal). Triple-wall decompression is chosen for a high degree of proptosis, but it is associated with a higher incidence of complications, especially postoperative diplopia. Additional ophthalmologic procedures, i.e. strabismus surgery and lowering of the upper eyelid position, are necessary to restore normal eye function and appearance [119, 120]. Topical treatment (lubricating drops, vitamin A eye ointments, moist chambers, tarsorrhaphy) can be used in active TO as an emergency treatment to shield the cornea in the case of corneal surface damage, thus reducing the risk of corneal perforation [121].

Chances of a complete cure for thyroid orbitopathy

Sabini et al. studied a group of 99 patients with TO diagnosed at least 10 years earlier, who had undergone various possible forms of treatment (immunosuppression, ORT, surgery) and had been without treatment for 5 years. The authors demonstrated the absence of objective TO symptoms in 8 patients (~ 8%), subjective symptoms in 24 patients (~ 24%), and complete cure of TO (absence of objective and subjective disease symptoms) in only 2 patients (~ 2%) [122].

It is important to remember that the expectations of the patient and the doctor are different. A patient with TO expects a rapid return of visual function and a return to the pre-disease state. The physician, remembering that TO is a vision-threatening disease, expects maintenance of full visual acuity, absence of pain, single vision in the useful part of the visual field, and a positive cosmetic effect. TO is a “chronic” disease, patients are ill for years rather than weeks, and patients’ eyes rarely return to their pre-TO state.

Funding

The authors report no financial support.

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