Puzzling Late Relapse of Thyroid Eye Disease: A Case Series

Abstract

Thyroid eye disease (TED) is a self-limiting autoimmune inflammatory condition that lasts an average of 18 to 36 months. Late recurrence of TED, defined as new onset of active orbitopathy after 5 years of quiescence, is rarely reported.

We retrospectively audited all patients with TED relapse between 2016 and 2024. Case 1, a 69-year-old female individual, presented with recurrent TED 40 years after the initial episode. Case 2, an 86-year-old female individual, reactivated initially 20 years, and then again 34 years, after the primary TED presentation. Case 3, a 52-year-old male individual, relapsed 9 years after the initial episode.

In all cases, TED relapse was confirmed with clinical examination, elevated thyrotropin receptor antibodies (TRAb) and characteristic radiological features. All 3 cases were managed with various combinations of rituximab, intravenous methylprednisolone, oral mycophenolate mofetil, ciclosporin, oral methotrexate, orbital radiotherapy, and orbital decompression surgery. All achieved quiescent disease.

This case series highlights the potential for late-onset relapse, sometimes several decades after the initial presentation and illustrates the potential severity of TED and need for multimodal treatment. Clinicians should be aware of the possibility of TED relapse and warn patients at discharge.

Introduction

Thyroid eye disease (TED) typically follows a self-remitting course, lasting an average of 18 to 36 months [1], with an initial inflammatory phase followed by an inactive phase. Late recurrence, defined as new onset of active orbitopathy after more than 5 years of quiescence, is uncommon [1, 2] and the possibility of late flare-up is not familiar to clinicians. Epidemiological evidence is scant about late relapse, and predisposing risk factors are unclear. We present a retrospective locally approved audit identified from the electronic patient record database seen between 2016 and 2024 in a UK-based tertiary referral TED multidisciplinary clinic. Relapse was defined as TED that recurred after a 5-year period of quiescence. It was confirmed with clinical examination, elevated thyrotropin receptor antibodies (TRAb), and characteristic radiological features. The Vision, Inflammation, Strabismus, and Appearance (VISA) score [3] was used to classify the degree of disease activity and severity. Three cases (1%) of relapsed TED were identified out of a total of 271 TED patients seen in the Oxford TED clinic.

This case series highlights the possibility of TED relapse decades after initial presentation, even in euthyroid patients, raising clinician and patient awareness.

Case Presentation

Case 1

A 69-year-old woman presented with recurrent TED with new onset bilateral proptosis, diplopia, and subjective visual deterioration 40 years after initial presentation. She first presented with hyperthyroidism TED aged 29. Initial treatment was with radioactive iodine (RAI) and the TED resolved spontaneously. She was an ex-smoker (stopping 9 years prior) with hypertension and a past history of transient ischemic attack.

Case 2

An 86-year-old woman presented during her second relapse of TED, with reduction of vision in her left eye. She was previously diagnosed with active TED at 52 years of age. She developed her first relapse at the age of 72 which required bilateral medial wall orbital decompression. She was an ex-smoker (stopping 1 year prior to her last relapse) and was hypertensive with ischemic heart disease. The patient was biochemically euthyroid on levothyroxine 75 µg at presentation.

Case 3

A 52-year-old man presented with late recurrent TED with worsening of both longstanding intermittent diplopia and eyelid edema, occasional bilateral ocular redness, and associated severe retrobulbar ache. He was an ex-smoker (discontinued 12 years previously) and had a history of diabetes mellitus type 2. He took levothyroxine 75 µg once daily and a statin.

His first presentation of TED was 9 years previously and was associated with a left optic neuropathy, orbital muscle swelling on imaging, and hypothyroidism on biochemistry (previously having Graves hyperthyroidism [TRAb 18.4 U/L] which had settled spontaneously).

Initial management of TED included weekly pulsed intravenous methylprednisolone (IVMP) (4 g in total) in conjunction with oral methotrexate (MTX) and orbital radiotherapy. He subsequently underwent bilateral medial rectus recession.

Diagnostic Assessment

Case 1

The patient was clinically and biochemically euthyroid on levothyroxine 75 µg once daily at re-presentation. Examination confirmed normal vision in the right eye and reduced vision in the left (Snellen visual acuity of 6/9). Ishihara color vision was significantly reduced (3/17) in the left eye, there was no relative afferent pupillary defect (RAPD), and the optic discs appeared healthy. There was evidence of bilateral proptosis with a significant bilateral ophthalmoplegia. VISA activity score was 5/10 with conjunctival injection, eyelid edema, chemosis, and retrobulbar ache. VISA severity score was 10/20.

TRAb titer was >30 IU/L (normal reference range, <0.40 IU/L). CT orbits revealed tendon-sparing enlargement of extra-ocular muscles with bilateral apical crowding (Fig. 1). The working diagnosis was severely active TED 40 years after initial presentation associated with left compressive optic neuropathy.

Figure 1.

Axial computed tomography scan; marked tendon-sparing extra-ocular muscles thickening (→) and bilateral orbital apex crowding (►).

Case 2

Clinically, there was bilateral reduction of vision of 2/60 and 6/18 in the right and left eye respectively. Positive findings included bilateral proptosis and ophthalmoplegia, eyelid retraction, and prominent eyelid orbital fat prolapse. Ishihara color vision was reduced at 10/17 plates in the left eye. There was no RAPD or optic disc swelling. VISA activity score was 1/10 with conjunctival injection. VISA severity score was 8/20.

Investigations confirmed a raised TRAb at 8.5 IU/L. Magnetic resonance imaging of the orbits revealed marked proptosis, increased orbital fat volume bilaterally, tendon-sparing extra-ocular muscle hypertrophy (in the posterior orbit), and bilateral optic nerve compression at the orbital apices (Fig. 2). The diagnosis was reactivation of TED 34 years following the original presentation, associated with mild disease activity and high severity.

Figure 2.

Axial magnetic resonance imaging; marked proptosis, enhancement of marked extra-ocular muscles enlargement (→), orbital apices crowding (►).

Case 3

The patient was biochemically euthyroid at presentation and eye examination confirmed visual acuities of 6/6 and 6/7.5 in the right and left eye respectively. Positive findings included significant bilateral ophthalmoplegia and a hyperemic left optic disc. Ishihara color vision was full bilaterally with no RAPD. VISA activity score was 5/10 with chemosis, conjunctival injection, eyelid swelling, and retrobulbar ache with diurnal variation. VISA severity score was 13/20. TRAb were raised, at 5.4 IU/L. Computed tomography of the orbits showed proptosis, extra-ocular muscle thickening, and orbital apex crowding (Fig. 3). The diagnosis was reactivation of TED 9 years following initial presentation, with severely active, moderately severe disease.

Figure 3.

Coronal computed tomography scan; extra-ocular muscles thickening (→) with orbital apex crowding (►).

Treatment

Case 1

Immunosuppression was initiated with 3 infusions of IVMP at weekly intervals (500 mg, 250 mg, 250 mg) alongside a single 100-mg rituximab (RTX) infusion. Also, 500 mg oral mycophenolate mofetil (MMF) was commenced at 500 mg daily, incrementing to 2 grams daily. Two weeks post-treatment, vision in both eyes had improved to 6/7.5, but Ishihara remained 11/17 in the left eye, indicating ongoing optic nerve compression and a left 3-wall orbital decompression was performed. Two weeks post-decompression, there was good visual acuity bilaterally with normal color vision. Two months later, the patient’s VISA activity score was 2/10 and VISA severity score 7/20. A further dose of 100-mg RTX infusion was administered and the patient remained on MMF 2 g/day.

Case 2

Immunosuppression was initiated with weekly 500-mg IVMP infusions for 6 weeks and oral MTX 20 mg once-weekly as maintenance treatment. Visual acuity improved bilaterally to 6/12 and Ishihara plates to 16/17 in the left eye at 2 weeks post-treatment. However, symptoms worsened between IVMP infusions (discomfort and left visual blurriness), suggesting persistent activity refractory to standard treatment. Weekly IVMP infusions were started again for 7 weeks. The patient underwent bilateral 3-wall orbital decompression due to residual bone seen along the postero-medial orbital walls bilaterally. Adjuvant orbital radiotherapy was administered as a concurrent intervention to stabilize the inflammatory disease. A single infusion of RTX (1 g) and 4 further infusions of IVMP (125-500 mg) were given. Oral ciclosporin (175-200 mg daily) was commenced for 5 months in addition to MTX.

Case 3

Immunosuppression was initiated with 100-mg RTX and 500-mg IVMP infusion followed by a further 500-mg IVMP infusion a week later.

Outcome and Follow-Up

Case 1

Six months following presentation the patient remained quiescent (VISA activity score 1/10) with residual binocular diplopia (VISA severity score 6/20) and was therefore referred for squint surgery.

Case 2

Bilaterally, vision improved to 6/9 and the Ishihara plates to 16/17 (left eye). The disease became inactive and oral MTX 20 mg weekly was continued.

Case 3

At the follow-up assessment 2 months later, the diplopia and retroorbital pain had significantly improved. At 4 months, the patient’s VISA activity score had reduced to 1/10 and VISA severity score to 4/20.

Table 1 summarizes the pre- and post-reactivation management, which was well tolerated with no significant persistent adverse effects.

Table 1.

Pre- and post-reactivation management

Case number	1	2	3
Age, years	69	86	52
Primary treatment (at first presentation)
IVMP			✓
OD		✓
RT			✓
RAI	✓
MTX			✓
MMF
RTX
Treatment following TED relapse
IVMP	✓	✓	✓
OD	✓	✓
RT		✓
RAI
MTX		✓
MMF	✓
RTX	✓	✓	✓
Ciclosporin		✓
Maintenance treatment
MTX		✓
MMF	✓

Abbreviations: IVMP, intravenous methylprednisolone; MMF, mycophenolate mofetil; MTX, methotrexate; OD, orbital decompression; RAI, radioactive iodine; RT, orbital radiotherapy; RTX, rituximab.

Discussion

Thyroid eye disease (TED) is a relatively common condition among patients with Graves disease, with an overall prevalence of 40% [4]. However, TED is rarely reported to reactivate after the initial active phase. We report 3 patients (1%) with TED relapse from a cohort of 271 patients seen in the Oxford Joint Thyroid Clinic between 2016 and 2024 who developed relapsed TED at a mean of 20 years following the original presentation at an average age of 69 with a female to male ratio of 2:1. Case 1 relapsed once after 40 years, at age 69. Case 2 reactivated at 20 years after the initial presentation, at age 72, and again 14 years later at age 86. Case 3 relapsed 9 years after, at age 52. All 3 patients were biochemically euthyroid on levothyroxine with high TRAb titers at relapse. Although most TED patients are hyperthyroid, 10% of cases occur in patients with euthyroid or hypothyroid [5]. All cases who reactivated were ex-smokers and only 1 patient had undergone RAI at the time of initial treatment for Graves disease. They all had bilateral tendon-sparing enlargement of extra-ocular muscles which helped guide the diagnosis of TED reactivation. Patel et al reported that clinical and radiological features of reactive disease may mimic those seen in the initial episode [2].

To our knowledge, only 2 prior studies have examined TED recurrence rate. Selva et al identified 8 relapses (5%) in a cohort of 193 cases [1] with a mean recurrence age of 51, a 3:1 female to male ratio, and an average interval of 12 years between first and second event with only a single recurrence reported. All patients were euthyroid at the time of reactivation, none had ever received RAI, and the only identified trigger was smoking in 1 patient. Patel et al, in a further review of 415 cases, reported 65 cases (15.7%) of TED recurrence [2]. The mean age at first relapse was 49.1 years and at second relapse 52.6 years with a female to male ratio of 4.5:1.

Relapses occurred on average 10.3 years after initial presentation; 66.7% were euthyroid, 9% had multiple recurrences with smokers having a higher recurrence rate, and 34% had undergone RAI for their first TED event.

Risk factors for the development of the first TED episode are well recognized: male gender, increasing age, smoking, and a history of RAI [6]. However, their role in predisposing to late relapse is unclear. From the limited data available, elevated TRAb, a history of smoking, RAI, and periocular/orbital intervention may be relevant potential risk factors [1, 2, 7]. In our cohort, all patients were euthyroid despite high TRAb titers.

Previous studies similarly reported euthyroid patients as well, but not their TRAb titers at relapse. Patel et al noted that clinical and radiological features of reactive disease may mimic those seen in the initial episode [2].

This study has limitations. The 1% late reactivation rate reflects cases from a tertiary referral TED clinic, likely underestimating the recurrence rate as milder cases may have been managed elsewhere or may have not sought review. To establish recurrence rates more robustly, future larger multicenter studies are needed. Prospective assessment of TED recurrence with disease-modifying therapies, such as rituximab, mycophenolate, and teprotumumab, will also be crucial. Finaly, despite its retrospective nature, our study demonstrates that TED can relapse many decades after initial presentation. Importantly, our findings highlight the potential risk of severe relapses and underscore the need for clinician awareness.

Learning Points

• TED relapse can occur as a late manifestation, even several decades after initial disease onset, a phenomenon that is not well reported in the literature.

• Clinicians should consider the possibility of late reactivation in euthyroid patents and patients should be warned to report new symptoms.

• Elevated TRAb levels in euthyroidism may trigger recurrence.

• Smoking is a strong risk factor for recurrence, as outlined in other studies.

Contributors

All authors made individual contributions to authorship. E.O., N.M., H.E.T., J.H.N. were involved in the examination of the patients, diagnosis making, and medical management. E.O. and J.H.N. were responsible for the patients’ surgeries. All authors reviewed and approved the final draft.

Abbreviations

IVMP

intravenous methylprednisolone

MMF

mycophenolate mofetil

MTX

methotrexate

RAI

radioactive iodine

RAPD

relative afferent pupillary defect

TED

thyroid eye disease

TRAb

thyrotropin receptor antibody

VISA

Vision, Inflammation, Strabismus, and Appearance

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from all patients.

Data Availability Statement

Original data generated and analyzed during this study are included in this published article.