18 Thyroid eye disease

Background

Thyroid eye disease (also known as dysthyroid eye disease, thyroid orbitopathy or thyroid ophthalmopathy) is a disease of the orbit that predominantly affects the extraocular muscles.1 It is the most common cause of unilateral or bilateral proptosis in adults, due to enlarged eye muscles and an increase in orbital fat. The term thyroid eye disease can be misleading. Although it is often related to Graves’ disease and thyroid autoimmunity, it can also occur in people who have normal thyroid gland function.

Thyroid eye disease most often affects young to middle aged adults, and is more common in females. It is considered to be an autoimmune inflammatory condition2,3 but the precise pathogenesis remains unclear. There is no laboratory test for thyroid eye disease, and the diagnosis is usually made clinically or radiologically. The classical signs are unilateral or bilateral proptosis, restricted eye movements, upper or lower eyelid retraction, eyelid and conjunctival oedema and, rarely, visual failure secondary to a compressive optic neuropathy.4

The natural history of thyroid eye disease is poorly documented in the literature, but it is often stated that there is an acute phase of disease with active orbital inflammation prior to an inactive fibrotic stage. A proportion of patients improve spontaneously, a factor that needs to be considered when assessing the effectiveness of any treatment.5 Recognised risk factors that may influence ocular prognosis include cigarette smoking,6 radioiodine treatment of thyrotoxicosis7 and uncontrolled thyroid dysfunction.8

Patients with thyroid eye disease are selected for treatment based on the activity and severity of the condition.9,10 In the absence of a treatment based on knowledge of the precise pathogenesis, a variety of therapeutic approaches have been proposed, chiefly various systemic immunosuppressive agents. Steroid therapy has been commonly used to manage thyroid eye disease for several decades, but many areas of controversy exist. Glucocorticoids have often been administered systemically in the initial stages of active orbital disease.11 Studies have tried to assess the benefit and side effects of intravenous pulsed high-dose steroids, followed by oral treatment12 or oral administration alone.13 There are, however, no clear guidelines regarding the best route, optimum dose or

duration of treatment, the role of uncontrolled risk factors or the effectiveness of steroids when combined with other immunosuppressive therapies.

Alternative methods exist that attempt to suppress active thyroid eye disease and reports of using orbital radiotherapy date back to 1936.14 The success rate associated with this treatment modality is also controversial, and the role of orbital radiotherapy in limiting the secondary effects of ocular inflammation remains poorly defined.15 This chapter concentrates on assessing what evidence exists for the use of steroid therapy and orbital radiotherapy in the clinical management of thyroid eye disease.

Question

What is the effectiveness of glucocorticoid therapy in reducing activity and severity of thyroid eye disease in patients when other risk factors have been controlled?

The evidence

A search of the Cochrane controlled trials register (CENTRAL) identified no randomised controlled trials for thyroid eye disease comparing steroids with a placebo group. Six published studies were found as prospective randomised controlled trials, but all looked at steroids versus, or in combination with, radiotherapy,16,17 immunosuppressive drugs,18,19 somatostatin analogues20 or intravenous immunoglobulins.21 Initial oral doses equivalent to 60–100 mg/day prednisone and tapered down for several months led to favourable responses within several weeks in about 60% of cases (range 40–100%). Ocular improvements include less soft tissue swelling, enhanced motility and an increase in optic nerve function, but benefit for proptosis is less evident. Combination therapies appear to be more effective in these trials.

Low dose oral prednisone (0·4–0·5 mg/kg/day for one month and tapering in three months) was shown in a randomised controlled study to be effective for preventing worsening ophthalmopathy after radioiodine treatment for hyperthyroidism.22 The eye changes after radioiodine are usually mild and transient, but it is worth considering oral steroids in high-risk cases.

Only one prospective, single-blind randomised study was found providing comparative data of high-dose intravenous and oral glucocorticoid treatment in association with orbital radiotherapy.23 The intravenous route seems to be more effective and better tolerated than the oral route.

Other routes of administration have been tried in an attempt to increase the efficacy and decrease the side effects of steroids. Local retrobulbar glucocorticoids were shown to be less effective than the systemic route in a randomised controlled study.24

Question

What evidence exists that orbital radiotherapy has a beneficial role in the treatment of active thyroid eye disease?

The evidence

A Cochrane systematic review on the role of radiotherapy in thyroid eye disease is currently underway. This review will include randomised controlled trials in which orbital radiotherapy was compared to sham orbital radiotherapy or to no intervention.25 The primary outcomes used were to evaluate changes in standardised indices of clinical activity before and after intervention, and to assess the time from treatment to the end of the active phase of the disease. Only one trial26 was deemed to meet the inclusion criteria for the review. The study was a double-blind, randomised trial in which consecutive patients referred to the study centre were assessed using predefined criteria for inclusion. Allocation concealment of those patients enrolled appears to have been adequate. The radiotherapist providing the treatment was not masked, but was not involved in the preor post-treatment outcome measurements. The recipients of care and the persons responsible for outcome assessments were both unaware of the assigned therapy. There were no apparent systematic differences in care provided apart from the treatment being evaluated, nor were there differences in outcome assessments for the two groups.

Sixty patients judged to have moderate thyroid eye disease, who had been euthyroid for at least three months, were enrolled. Thirty were assigned retrobulbar radiotherapy using a dose of 20 Gy in ten fractions over 12 days, and 30 to receive sham irradiation. All patients were examined one day before and four, 12 and 24 weeks after treatment by the same ophthalmologist.

The qualitative treatment outcome was successful in 18 of 30 (60%) irradiated patients versus nine of 29 (31%) sham irradiated patients at 24 weeks (relative risk (RR) 1·9, 95% confidence interval (CI) 1·0–3·6, P = 0·04). This difference was chiefly due to a motility improvement in the

radiotherapy group (14/17 = 82%) compared to the sham irradiated patients (4/15 = 27%) (RR = 3·1, CI 1·3–7·4, P = 0·004). Other clinical outcome measures, such as eyelid swelling and proptosis, were not significantly different between the two groups. Apart from the exclusion of one patient from the analysis at 12 weeks because of recurrence of hyperthyroidism, the study quality was considered to be at low risk of bias.

A double-blind trial of prednisone versus radiotherapy in patients with moderately severe eye disease confirmed findings from uncontrolled studies that these two treatment modalities are equally effective.17

Discussion

Thyroid eye disease provides many challenges for researchers assessing the impact of various treatment modalities. It remains relatively uncommon, the natural history is not well documented and large variations can occur in disease duration and activity. Clinical evaluation, in a reproducible manner, can be difficult, with no existing standard objective or subjective technique.

Despite being established therapies for thyroid eye disease, the role and effectiveness of steroids and retrobulbar irradiation is unclear. The literature is littered with conclusions and statements from mainly uncontrolled open clinical trials. The complexities involved in studying patients with thyroid eye disease make an evidence-based approach essential. There are no formal randomised controlled trials comparing steroids with a placebo. The paper by Mourits et al.26 is the only double-blind, randomised clinical trial assessing the success associated with retrobulbar irradiation identified from an extensive search. The methodology and study design suggest that the risk of bias is low and therefore their conclusions that radiotherapy improves, but does not cure, motility impairment in patients with moderate Graves’ orbitopathy, are likely to be valid.

Implications for practice

The intravenous administration of glucocorticoids seems to be more effective and better tolerated than the oral route in the treatment of severe thyroid eye disease, although there is only one published randomised study comparing oral and intravenous glucocorticoid treatment associated with orbital radiotherapy.23 One patient with transient noninfectious hepatitis was described in this study and in another report there was a case of fatal liver damage.27 There is a need to carefully monitor patients’ liver status before and during treatments and to establish new

intravenous steroid schedules in severe thyroid eye disease to prevent liver toxicity or exacerbation of previous asymptomatic autoimmune chronic hepatitis.

Implications for research

Many issues in the treatment of moderately severe thyroid eye disease remain unclear. The impact of steroid therapy, including the optimum dose and route, is not clearly established. Similarly little is known regarding the best radiation dose, most appropriate timing for the treatment and the success of using irradiation in combination with other modalities. In an era of evidencebased medicine the use of steroids and orbital irradiation for thyroid eye disease require further evaluation, using prospective randomised trials, in order that best practice can be further established.

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