[T] How should hyperthyroidism be managed in patients with Graves' ophthalmopathy?

[T] How should hyperthyroidism be managed in patients with Graves' ophthalmopathy?

GO is an inflammatory eye disease that develops in the orbit in association with autoimmune thyroid disorders (309).

In the majority of cases, it occurs in patients with current or past GD. Thyroid-associated orbitopathy, thyroid eye disease, and Graves' orbitopathy are other names used for GO. Approximately half of patients with Graves' hyperthyroidism have signs and/or symptoms of GO, and 5% suffer from severe disease.

TABLE 10. ASSESSMENT OF GRAVES' OPHTHALMOPATHY: CLINICAL ACTIVITY SCORE ELEMENTS

Elementsa

Each visit

Comparison with previous visit

Score

Painful feeling behind the globe over last 4 weeks

X

 

1

Pain with eye movement during last 4 weeks

X

 

1

Redness of the eyelids

X

 

1

 Redness of the conjunctiva

X

 

1

Swelling of the eyelids

X

 

1

Chemosis (edema of the conjunctiva)

X

 

1

Swollen caruncle (flesh body at medial angle of eye)

X

 

1

Increase in proptosis ≥ 2 mm

 

X

1

Decreased eye movements ≥ 5° any direction

 

X

1

Decreased visual acuity ≥ 1 line on Snellen chart

 

X

1

aA 7-point scale (excluding the last three elements) is used when no previous assessment is available. GO is considered active in patients with a CAS > 3.
Sources: Adapted from Mourits et al., 1989 (310); and Mourits et al., 1997 (311).

[T1] Assessment of disease activity and severity

The natural history of the disease is one of rapid deterioration followed by gradual improvement toward the baseline. This active phase is best described by the Clinical Activity Score (CAS) (310,311). The CAS is generated by the addition of one point for each of the following features if present: pain in primary gaze, pain with eye movement, chemosis, eyelid swelling, eyelid erythema, conjunctival redness, caruncula swelling, and, over the prior 3 months, decreased visual acuity, increased diplopia, and proptosis (Table 10). The score ranges from 0 to 10 and predicts response to anti-inflammatory therapies (310,311). A 7-point scale, lacking the last three elements, is used when no previous assessment is available. GO is considered active in patients with a CAS ≥  3. Therefore, hyperthyroid patients having only lid retraction alone, or in conjunction with mild conjunctival erythema and eyelid swelling, are not considered to have active GO.

The severity of the disease is best assessed using objective, quantifiable parameters and is a useful tool for directing therapy. The main gradations of disease severity are mild, moderate to severe, and sight threatening (312). Table 11 lists the elements as agreed upon in a consensus statement by the European Group on Graves' Orbitopathy (EUGOGO) (312). Both activity and severity of the disease must be considered in therapeutic decisions regarding treatment of the eye disease itself, as well as treatment of hyperthyroidism. The overall evaluation and management of GO is best done in a multidisciplinary clinic combining endocrinologists and ophthalmologists with expertise in the condition and other specialties in consultation (e.g., ENT, radiation therapy, plastic surgery, and endocrine surgery).

QoL is clearly impaired by the disease, but only a limited number of articles have been published in this area. The U.S. Food and Drug Administration has endorsed QoL information as a component of any therapeutic application. The QoL correlation with disease severity has been fair to excellent for the one instrument published to date in a North American population (316), though it lacks prospective data. Two new validated instruments assessing QoL in the U.S. population are soon to be published and will be useful, as the instrument commonly used in Europe (317) has not been tested in the North American population.

TABLE 11. GRAVES' OPHTHALMOPATHY SEVERITY ASSESSMENT

Gradea

Lid retraction

Soft tissues

Proptosisb

Diplopia

Corneal exposure

Optic nerve status

Mild

< 2 mm

Mild involvement

< 3 mm

Transient or absent

Absent

Normal

Moderate

≥ 2 mm

Moderate involvement

≥ 3 mm

Inconstant

Mild

Normal

Severe

≥ 2 mm

Severe involvement

≥ 3 mm

Constant

Mild

Normal

Sight threatening

Severe

Compression

Upper limits of normal

 

 

 

 

 

 

   African  American

 

F/M = 23/24 mm

   White

 

F/M = 19/21 mm

   Asian

 

F/M = 16/17 mm (Thai) or 18.6 mm (Chinese)

aMild GO: patients whose features of GO have only a minor impact on daily life, generally insufficient to justify immunosuppressive or surgical treatment. Moderate-to-severe GO: patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Sight-threatening GO: patients with dysthyroid optic neuropathy and/or corneal breakdown. This category warrants immediate intervention.
bProptosis refers to the variation compared to the upper limit of normal for each race/sex or the patient's baseline, if available.
Sources: Adapted from de Juan et al., 1980 (313); Sarinnapakorn et al., 2007 (314); Tsai et al., 2006 (315); and Bartalena et al., 2008 (312).

TABLE 12. USE OF ORAL GLUCOCORTICOIDS FOR PREVENTION OF GRAVES' OPHTHALMOPATHY DEVELOPMENT OR PROGRESSION WHEN RADIOACTIVE IODINE IS USED TO TREAT GRAVES' HYPERTHYROIDISM

 

RAI without glucocorticoids

RAI with oral glucocorticoids

No GO (nonsmoker)

Recommend

Recommend against

No GO (smoker)

Insufficient data to recommend for or against

 

GO present-active and mild (nonsmoker)

Acceptablea

Acceptablea

GO present-active and mild (smoker)

Recommend against

Recommend

GO present-active and moderate-to-severe or sight-threatening (smoker or nonsmoker)

Recommend against

Insufficient data to recommend for or against

GO present-inactive (smoker or nonsmoker)

Recommend

Recommend against

Methimazole or thyroidectomy are also recommended treatment options in each of these scenarios, and they are the preferred choice of therapy in patients with active and moderate-to-severe or sight-threatening GO.
aThe decision regarding use of concurrent glucocorticoids should be made in light of the risk-benefit ratio relative to the patient's overall health. Risk factors for GO deterioration (high T3 level, high TRAb level, smoking) increase the benefit of glucocorticoids in preventing GO deterioration. Poorly controlled diabetes, osteoporosis, psychiatric illness, high risk for infections increase the likelihood of complications from glucocorticoids.

In the remainder of section T, we discuss the prevention of GO and the management of hyperthyroidism in patients having established GO. In particular, we focus on recommendations regarding the concurrent use of corticosteroids in patients choosing radioactive iodine as treatment for hyperthyroidism (Table 12).

[T2] Prevention of GO

Current therapeutic approaches to GO, including local measures, corticosteroids, orbital radiation, and surgery (312), often fail to significantly improve the QoL of patients with this debilitating condition. Therefore, efforts should be made to prevent the development or progression of GO in patients with Graves’ hyperthyroidism. Identified risk factors for GO include radioiodine therapy for hyperthyroidism (318,319), smoking, high pretreatment T3 values (≥ 325 ng/dL or ≥ 5 nmol/L) (319), high serum pretreatment TRAb levels (>50% TBII inhibition or TSI >8.8 IU/Liter) (320), and hypothyroidism following radioiodine treatment (321).

RECOMMENDATION 80
Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with GO or risk factors for the development of ophthalmopathy. 1/++0

A number of studies have suggested that development of persistent, untreated hypothyroidism after therapy for hyperthyroidism plays a detrimental role in the progression of GO. An early study noted that patients who were either hypo-or hyperthyroid had more severe GO than euthyroid patients (322). Subsequently, two cohort studies in which patients received levothyroxine therapy early after radioactive iodine with the specific intent of preventing hypothyroidism noted that deterioration of GO rarely occurred (0%–2%) (321,323). A randomized study of newly diagnosed GD found that radioactive iodine did not increase the risk of worsening GO compared to therapy with MMI (RR of 0.95) in the setting where hypothyroidism was actively prevented by administration of thyroid hormone at 2 weeks after radioactive iodine administration (49).

  • RECOMMENDATION 81
    In nonsmoking patients with Graves' hyperthyroidism who have no clinically apparent ophthalmopathy, 131I therapy without concurrent steroids, methimazole, or thyroidectomy should be considered equally acceptable therapeutic options. 1/++0

Several retrospective cohort studies and randomized trials have identified the risk of GO development or progression after therapy for hyperthyroidism to be between 15% and 33%. Two randomized controlled trials found that risk to be 23/150 (15%) for radioactive iodine, compared with 4/148 (3%) for ATDs (318) in one study, and 13/39 (33%) for radioactive iodine compared with 4/38 (10%) for ATDs and 6/37 (16%) for surgery (319) in the other study. In contrast, one prospective but nonrandomized cohort study identified no difference among ATD, surgery, and radioactive iodine treatment, with an overall 4.9%–7.1% frequency of GO development (324). The higher risk of GO worsening after radioactive iodine therapy in the majority of studies may be related to the unique increase in TRAb levels observed following this therapy (222). Experimental evidence suggests that these antibodies may be directly involved in GO pathogenesis (309).

There is evidence that corticosteroids given concurrently with radioiodine therapy may prevent worsening of GO in patients with mild active eye disease (318). However, there is insufficient evidence to recommend prophylactic treatment with corticosteroids in nonsmoking patients who do not have clinically apparent GO. The relatively low absolute risk of nonsmokers developing new-onset severe GO suggests that GO prevention should not be a factor in the selection of therapy for hyperthyroidism in this group of patients (318).

There is insufficient evidence to recommend for or against the use of prophylactic corticosteroids in smokers who have no evidence of GO. However, in two different studies, active smokers who received radioactive iodine represented the group with the highest incidence (23%–40%) of new GO or deterioration of pre-existing GO during 1 year of follow-up (49,318).

  • RECOMMENDATION 82
    Clinicians should advise patients with GD to stop smoking and refer them to a structured smoking cessation program. Patients exposed to secondhand smoke should be identified and advised of its negative impact. 1/++0

Smoking is the most important known risk factor for the development or worsening of GO, unrelated to type of therapy for GO (322), and consistent data from several studies show a detrimental effect of smoking on GO in patients treated with radioactive iodine (49,318). The risk is proportional to the number of cigarettes smoked per day and former smokers have significantly lower risk than current smokers, even after adjusting for lifetime cigarette consumption (325).

Technical remarks: Clinicians should consult guidelines on effective and evidence-based approaches to aid in smoking cessation and avoidance of second hand smoke (326,327).

[T3] Treatment of hyperthyroidism in patients with active GO of mild severity (see Tables 10 and11 for definitions of disease activity and severity)

  • RECOMMENDATION 83
    In patients with Graves' hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease, 131I therapy, methimazole, and thyroidectomy should be considered equally acceptable therapeutic options. 1/++0
     
  • RECOMMENDATION 84
    Patients with Graves' hyperthyroidism and mild active ophthalmopathy who have no other risk factors for deterioration of their eye disease and choose radioactive iodine therapy should be considered for concurrent treatment with corticosteroids. 2/++0

Technical remarks:  The decision whether or not to administer concurrent glucocorticoids in a particular patient choosing 131I therapy should be made in light of the risk–benefit ratio (i.e., their personal risk of worsening GO, balanced against their risk of developing glucocorticoid side effects). Risk factors for side effects of oral corticosteroids include poorly controlled diabetes, hypertension, osteoporosis, psychiatric disease, and predisposition to infections. Smokers in whom the risk–benefit ratio for the concurrent use of corticosteroids is high may be better treated with methimazole or surgery. Besides smoking, risk factors for deterioration of GO following radioiodine therapy include high pretreatment T3 values (325 ng/dL or 5 nmol/L) (319), active and progressive GO over the preceding 3 months, high serum pretreatment thyrotropin antibody levels (>50% TBII inhibition or TRAb >8.8 IU/L), and development of hypothyroidism following the treatment (321).

The recommended corticosteroid dose for GO prophylaxis is the equivalent of prednisone 0.4–0.5 mg/kg/day, started 1– 3 days after radioactive iodine treatment, continued for 1 month, and then tapered over 2 months (312). However, a recent retrospective cohort study suggested that lower doses and shorter duration of oral prednisone (about 0.2 mg/kg/ day for 6 weeks) may be equally effective for prevention of GO exacerbation in patients with initially mild or absent eye disease, if supported by future randomized clinical trials (328).

  • RECOMMENDATION 85
    Patients with Graves' hyperthyroidism and mild active ophthalmopathy who are smokers or have other risk factors for GO and choose radioactive iodine therapy should receive concurrent corticosteroids. 1/++0

A randomized study of patients having pre-existing GO of mild severity found the relative risk for deterioration of eye disease to be 2.2 for surgery and 1.9 for radioactive iodine compared with ATDs, though the patients were not randomized with respect to their baseline GO status (319). An earlier prospective cohort (also not randomized as to baseline GO or smoking status and in which post-treatment hypothyroidism was not actively prevented) identified no difference in deterioration of pre-existing GO between the three modes of therapy (324). Neither surgery nor radioactive iodine therapy was associated with deterioration in pre-existing GO in 48 patients in another early study (329).

One large randomized controlled trial studying mainly patients with previously treated GD showed radioactive iodine therapy to be associated with an increased risk of GO progression (RR of 5.8 in comparison with ATDs) and found that risk to be eliminated with concurrent corticosteroid administration (318).

[T4] Treatment of hyperthyroidism in patients with active and moderate-to-severe or sight-threatening GO (see Tables 10 and 11 for definitions of disease activity and severity)

  • RECOMMENDATION 86
    Patients with Graves' hyperthyroidism and active moderate-to-severe or sight-threatening ophthalmopathy should be treated with either methimazole or surgery. 1/+00

We are aware of no trials in patients with moderate-to-severe and active eye disease that compare hyperthyroidism therapies for impact on GO. However, a comparison of two different surgical approaches (total thyroidectomy vs. subtotal thyroidectomy) for patients with moderate-to-severe GO showed that the eye disease improved over 3 years of follow-up in all patients (330). In another series of 42 patients with progressive GO treated with total thyroidectomy, exophthalmos was stable in 60% of cases and improved in the remainder (331), suggesting that surgery is not detrimental to GO and may be associated with improvement in some patients. Other studies suggest that ATDs may not adversely impact mild active GO, but do not address severe GO (318).

Technical remarks: Radioactive iodine therapy is a less desirable option in these patients and, if used, concurrent steroids should be administered.

[T5] Treatment of GD in patients with inactive GO (see Table 10 for definition of disease inactivity)

  • RECOMMENDATION 87
    In patients with Graves' hyperthyroidism and inactive ophthalmopathy, we suggest that 131I therapy without concurrent corticosteroids, methimazole, and thyroidectomy are equally acceptable therapeutic options. 2/++0

A series of 72 patients with inactive GO according to the CAS were treated with radioactive iodine without concurrent glucocorticoid administration (323). In those whom hypothyroidism was prevented by early thyroxine therapy, no deterioration in eye disease was reported (323). Smoking history did not impact GO outcome in this cohort.

A recent retrospective study examined the impact of concurrent oral or intravenous glucocorticoid therapy on the prevalence of reactivation of GO after radioiodine therapy in patients having inactive GO (332). They identified GO activation in approximately 7% of patients considered at low risk who were given no steroid prophylaxis. Despite prophylaxis, 33% of patients considered at high risk who were treated with oral glucocorticoids had worsening of GO. Only intravenous glucocorticoids were effective in preventing GO reactivation. However, because of the retrospective nature of this study and the lack of prespecified criteria for dose and route of steroid use in those considered at risk, we did not include these data in our deliberations regarding the above recommendation.