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Abstract

Background:

Dysthyroid optic neuropathy (DON) is a rare but serious complication of Graves’ orbitopathy (GO) that can lead to permanent vision loss. In a previous study, medical and surgical treatment of DON according to EUGOGO guidelines resulted in partial or no recovery in 30% of patients. Insulin growth factor-1 receptor inhibitor teprotumumab has shown significant improvement of GO symptoms, but little is known about its effect on DON. The aim of this study was to evaluate the efficacy of teprotumumab in treating steroid- and surgery-resistant DON.

Methods:

This retrospective case series included 6 patients (8 eyes; median age 58 years) with confirmed DON resistant to steroids and orbital decompression (median duration of DON 2 months, interquartile range [IQR 2.0–6.5]) treated at the Hospices Civils de Lyon. Median time from the end of first-line treatment was 34.5 days (IQR: 8.0–61.7). The treatment protocol was 8 intravenous infusions of teprotumumab administered every 3 weeks. Definition of DON recovery was based on changes in best-corrected visual acuity (BCVA) and visual field mean deviation (VF-MD).

Results:

At the end of teprotumumab treatment, DON recovered in 7/8 (87.5%) of affected eyes, with BCVA improvement in all patients (median 0.30 logMAR [0.24–0.42], p = 0.004) and a median VF-MD improvement of 66% (46–90) (p = 0.024). In 3/6 patients, DON improved after one infusion. All patients showed improvements in clinical activity score and proptosis. Improvements persisted over the follow-up (median from first infusion, 73.8 weeks), with no DON relapse but inflammatory relapse in two patients. Due to adverse events, two patients did not complete all infusions.

Conclusions:

The data suggest teprotumumab as a promising treatment for steroid- and surgery-resistant DON with rapid symptom improvement and long-lasting recovery. However, these only preliminary results need to be better evaluated by specific clinical trials.

Summary of the Research Problem

Dysthyroid optic neuropathy (DON) is a rare sight-threatening complication of thyroid eye disease (TED), affecting approximately 5–8% of patients with Graves’ orbitopathy (GO) which can lead to permanent vision loss.¹

Traditional management includes immediate high-dose steroid treatment (0.5–1 g of methylprednisolone daily for either three consecutive days or on every second day, which can be repeated after one week) and, if unsuccessful, surgical decompression of the optic nerve within 1–2 weeks.² A previous study from our group showed that treatment according to EUGOGO guidelines resulted in partial or no recovery in 30% of patients³ who are left with no other officially recommended treatment options. Nevertheless, other possible therapeutic strategies have been evaluated, such as surgical reintervention,⁴ orbital radiotherapy⁵ and tocilizumab.⁶

In GO, orbital fibroblasts are stimulated by autoantibodies targeting the IGF-1R/TSHR signaling complex, leading to inflammation and enlargement of extra-ocular muscles and intra-orbital fat.⁷ Teprotumumab is a human monoclonal inhibitor of insulin growth factor-1 receptor (IGF-1R) and has shown significant results in the remission of inflammation and orbit remodeling in placebo-controlled trials.^8,9 These studies, however, excluded patients with DON. A few small observational case studies have assessed teprotumumab treatment in these patients, and they have shown promising results.^10

–16

The aim of this study was to specifically investigate the effect of teprotumumab treatment on the recovery of steroid- and surgery-resistant DON.

Methods

This retrospective observational study, conducted at the Hospices Civils de Lyon between 2021 and 2023, included consecutive patients of at least 18 years of age who had a confirmed diagnosis of DON resistant to steroid treatment and neurosurgical apical orbital decompression, with a technique reported in a previous work.¹⁷ Diagnosis of resistant DON was validated by a multidisciplinary team, as previously described.³ Sex, age, smoking status, and baseline thyrotropin receptor antibody levels of included patients were documented.

Teprotumumab was administered every three weeks for a total of 8 infusions (first infusion: 10 mg/kg; subsequent infusions: 20 mg/kg if well tolerated). In the absence of marketing authorization, Teprotumumab treatment was temporarily authorized by French health authorities in selected cases due to the severity of the disease. From May 2022 onwards, a national multidisciplinary GO meeting validated indications for the treatment. The costs were covered by the national healthcare system.

All the patients had a complete ophthalmological evaluation¹⁸ at the start and at the end of teprotumumab, as well as at the last follow-up, including: clinical evaluation, fundus oculi and slit-lamp examination, visual acuity, visual field, and color vision assessment. Parameters included in this study were BCVA (best corrected visual acuity), VF-MD (visual field—mean deviation), clinical activity score (CAS), proptosis, and diplopia. BCVA was measured according to the Monoyer scale and was converted to logMAR for analysis (0.0 corresponding to normal BCVA and 2.6 to no light perception).

Recovery from DON was defined as follows:

significant: VF-MD improvement ≥50% AND final BCVA <0.2 and improvement of ≥0.1 logMAR, OR <0.1 logMAR, which did not deteriorate

partial: VF-MD improvement 25-50% AND/OR BCVA improvement <0.1

absent: VF-MD worsened, unchanged, or improvement <25%; OR no improvement in BCVA

Quantitative variables were expressed as median (interquartile range, IQR). A paired t-test was used to compare pre- and post-teprotumumab data where applicable.

The study was conducted in accordance with the ethical standards of the local Institutional Review Board and was approved by the local Institutional Review Board (IRB 20-047), and by the Ethics Committee of the Hospices Civils de Lyon. As required for observational studies, all patients received a non-opposition information letter concerning the protocol.

Results

Baseline characteristics

Six patients (5 females, 1 male; 8 eyes) were included in the study (Table 1). DON duration was 2 months (IQR: 2.0–6.5). Median time from end of first-line treatment was 34.5 days (IQR: 8.0–61.7). Prior to starting teprotumumab, all patients had received intravenous glucocorticoid, at least 3 grams, and apical decompression surgery, except for Patient 1, who had received medial wall decompression surgery because his DON was due to stretching of the optic nerve. Patient 3 underwent orbital radiation before surgical decompression.

Table 1.

Clinical Characteristics at the Start of Teprotumumab Treatment

Patient	1	2	3		4	5		6	Median (IQR)
Smoker^a	Yes	No	No		Yes	No		Yes
GO duration (months)	34	66	12		9	2		12	12 (9.8–8.5)
DON duration (months)	1	8	10		2	2		2	2 (2.0–6.5)
Prior treatment	ivGC, surgical decompression OU+OS	ivGC, strabismus + eyelid surgery OD, surgical decompression OS	ivGC, orbital radiation, surgical decompression OU		ivGC, surgical decompression OS	ivGC, surgical decompression OU		ivGC, surgical decompression OU
Days from the end of 1^st line treatments^b to the start of teprotumumab	14	107	64		6	6		55	34.5 (8.0–61.7)
TRAb (IU/l)	17.4	5.5	2.2		3.5	33.1		2.9	4.5 (3.1–4.4)
Eye	OS	OS	OD	OS	OS	OD	OS	OS
CAS	4	6	4	4	4	7	7	4	4 [4.0–6.3]
Proptosis (mm)	31	23	20	21	19	27	25	25	24 (20.8–25.5)
BCVA (logMAR)	0.60	0.22	0.52	0.70	0.70	0.05	0.00	0.30	0.41 (0.18–0.63)
VF MD (dB)	4.5^c	N/A^d	3.7	4.7	4.0	2.8	2.8	0.9	3.3 (2.8–3.9)

all patients stopped smoking at the start of the treatment, but Patient 1 resumed smoking during treatment.

steroid intravenous infusions and apical orbital decompression surgery.

VF measurement not reliable because of psychiatric comorbidities.

VF measurement not possible (important strabismus).

BCVA, best-corrected visual acuity; CAS, Clinical Activity Score; DON, dysthyroid optic neuropathy; GO, Graves’ orbitopathy, ivGC, intravenous glucocorticoids; IQR, interquartile range; logMAR, logarithm of the minimum angle of resolution; MD, mean deviation; N/A, not available; OD, oculus dexter (right eye); OS, oculus sinister (left eye); OU, oculus uterque (both eyes); TRAb, TSH receptor antibody; VF, visual field.

Visual acuity was impaired in 7/8 eyes, and the baseline BCVA was 0.41 LogMAR (IQR: 0.18–0.63); baseline visual field was available and reliable for 4/6 patients and impaired in all of them with a median MD value of 3.3 dB (2.8–3.9) (Table 1).

DON symptoms following teprotumumab treatment

Patients received 8 infusions of teprotumumab, except for Patients 4 and 6, who received 6 and 4 infusions, respectively, and stopped treatment because of side effects (invalidating tinnitus and diarrhea, respectively).

All patients had BCVA improvement, observed already after the first infusion in half of cases. Final median BCVA was 0.00 (IQR: 0.00–0.06) (Table 2). Median improvement in BCVA across all affected eyes following treatment was −0.30 logMAR (IQR: −0.42 to −0.24) versus pre-teprotumumab baseline (p = 0.004; logMAR absolute difference).

Table 2.

Markers of Neuropathy and Inflammation at Baseline (Pre) and at the End of Teprotumumab Infusions (Post) and at the Last Follow-up

Patient	1	2	3		4	5		6	Median (IQR)
Eye	OS	OS	OD	OS	OS	OD	OS	OS
DON symptoms
BCVA (logMAR)
Pre	0.60	0.22	0.52	0.70	0.70	0.05	0.00	0.30	0.41 (0.18–0.63)
Post	0.00	−0.08	0.05	0.40	0.30	0.00	0.00	0.00	0.00 (0.00–0.11)
Last FU	0.10	0.00	0.05	0.00	0.22	0.00	0.00	0.00	0.00 (0.00–0.06)
VF MD (dB)
Pre	4.5^a	N/A^b	3.7	4.7	4.0	2.8	2.8	0.9	3.3 (2.8–3.9)
Post	5.6^a	N/A^b	1.8	0.9	4.0	0.1	0.2	0.5	0.7 (0.3–1.6)
Last FU	4.3^a	N/A^b	2.4	1.2	4.6	0.1	0.0	0.1	0.7 (0.1–2.1)
1st best response (#infusions)	1	4^c	1		6^c	1^d		4^c
DON recovery	Significant	Significant	Significant	Partial/Significant^e	Absent	Significant	Significant	Partial/Significant^e
GO symptoms
CAS
Pre	4	6	4	4	4	7	7	4	4 (4.0–6.3)
Post	0	0	0	0	1	0	0	3	0 (0.0–0.3)
Last FU	1	0	0	0	1	1^f	1^f	2^g	1.0 (0.0–1.0)
Proptosis
Pre	31	23	20	21	19	27	25	25	24.0 (20.8–25.5)
Post	24	19	14	14	17	17	17	20	17.0 (16.3–19.3)
Last FU	21	17	15	14	17	23^f	21^f	22^g	19.0 (16.5–21.3)
FU (weeks)	55	155	36		69	79		83	73.8 (50.4–80.0)

VF measurement not reliable because of psychiatric comorbidities; not included in analysis.

VF measurement not possible (strabismus).

No earlier assessment completed.

Visual field improvement.

Partial DON recovery post teprotumumab treatment; significant DON recovery at last FU.

Received Tocilizumab during FU.

Received radiotherapy during FU.

BCVA, best-corrected visual acuity; CAS, Clinical Activity Score; DON, dysthyroid optic neuropathy; FU, follow-up; GO, Graves’ orbitopathy; IQR, interquartile range; logMAR, logarithm of the minimum angle of resolution; MD, mean deviation; N/A, not available; OD, oculus dexter (right eye); OS, oculus sinister (left eye); VF, visual field.

At the last follow-up, after 73.8 weeks (IQR: 50.4–80) the BCVA improvement was −0.39 logMAR (IQR: −0.48 to −0.18) versus pre-teprotumumab baseline (p = 0.005). One patient showed a deterioration in visual acuity at the last follow-up assessment compared to post-teprotumumab results (Patient 1: 55 weeks follow-up, +0,10 logMAR). However, recurrence of DON was excluded by the color vision test and the absence of pupillary deficit and papillary edema, despite his VF results not always being reliable because of psychiatric comorbidities.

Six eyes from four patients had complete, reliable pre- and post-teprotumumab VF measurements. MD following treatment was 0.7 dB (IQR: 0.3–1.6) (Table 2), and its improvement ranged from 0 to −96% (median −66%; p = 0.024).

Recovery from DON following teprotumumab treatment, compared to pre-teprotumumab baseline, was observed in 7/8 affected eyes (87.5%); 5 eyes from 4 patients had significant recovery, and 2 had partial recovery (Table 2). Results were maintained at the last follow-up (Table 2). The only patient for whom no recovery was observed had an improvement in BCVA of 0.4 logMAR but no improvement in VF.

GO symptoms following teprotumumab treatment

Symptoms of inflammation improved in all patients during the treatment. A median CAS reduction of −4 (IQR: −6.3 to −3.8) from pre-teprotumumab baseline was observed across all DON eyes (p < 0.001) after completing teprotumumab and at the last follow-up: four patients (67%) achieved a CAS of 0 at the first follow-up after treatment (Table 2). Patient 5 and 6 had an inflammatory relapse respectively 7.5 and 3.0 months after the end of teprotumumab and required further treatments (tocilizumab and radiotherapy, respectively).

Improvement in proptosis was observed in all affected eyes (Table 2). Median proptosis reduction was −6.5 mm (IQR: −7.3 to −4.8) compared to baseline (p < 0.001).

Adverse effects

The most common side effect was mild alopecia, in 3/6 of patients. Gastrointestinal discomfort was reported by two patients and included diarrhea grades 1 and 2, (chronic inflammatory bowel disease was excluded). While hearing was not assessed before teprotumumab treatment, one patient complained of hearing loss around the seventh/eighth infusion, and one patient with preexisting hearing loss due to presbycusis had tinnitus and eustachian tube dysfunction but with a normal audiogram. New-onset hyperglycemia was observed in 1/6 patients, while Patient 5 reported a decompensation of her diabetes with HbA1c going from 5.8% to 7.1%.

Key concluding messages

The present study is the first one including only homogenous patients treated for DON resistant to steroid and surgery according to guidelines.²

Teprotumumab treatment led to DON recovery in 87.5% of eyes, with improvements in VA and/or VF in all patients, together with a significant improvement of CAS and proptosis.

Adverse events of teprotumumab require special attention, especially hyperglycemia and hearing impairment. Hyperglycemia occurred in two patients, one of whom was already affected by type 2 diabetes, whereas hearing impairment (hearing loss and tinnitus) was noted in two patients, one of whom had preexisting hearing loss.

Our data appear to be reassuring on a 73-week follow-up, but little is known about the long-term lasting benefit of teprotumumab treatment.^19,20 Indeed, two of our patients required further lines of treatment because of recurrence of proptosis and inflammation but without DON relapse. In this study, all patients had undergone surgical decompression before teprotumumab treatment; that probably prevented patients from recurrence of DON. Therefore, the treatment outcomes need to be carefully monitored in the future.

Its use as an earlier step of the treatment strategy to avoid surgical decompression has been suggested in two patients with a complete resolution of DON after teprotumumab therapy without prior intervention.^12,14 However, considering post teprotumumab inflammatory relapses, surgery remains the gold standard in the absence of specific clinical trials.

This study had several limitations due to its single-center retrospective design, in addition to the small sample size and the absence of a control group. However, it shows encouraging data on teprotumumab efficacy on resistant DON, with significant rapid and long-lasting improvement of this sight-threatening condition. Long-term efficacy and safety of this treatment require further investigations.

Footnotes

Acknowledgments

The authors thank Andrea Schumacher and Hannah Scott from IPG Health for their assistance with the medical writing of the original draft of this article.

Authors’ Contributions

A.L.C.: Data curation; writing—original draft, review and editing; G.K.: Data curation; formal analysis; writing—review and editing; F.B.-C.: Pre-final editing; M.P.: Data curation; T.B., K.T.-S.-T., and C.F.T.: Resources (visual assessment); H.L., S.C., J.A.P., and G.R.: Resources (endocrinological evaluation); R.M. and E.J.: Resources (surgical information), J.A.-d.P.: Conceptualization, supervision and critical review of the drafts. All authors revised and approved the article.

Author Disclosure Statement

The authors declare that the IPG Health medical writing assistance was financed by Amgen. J.A.P. declares the following conflicts of interests: consulting Horizon and Amgen, Principal Investigator Horizon, ArgenX. A.L.C., G.K., M.P., T.B., K.T., C.F.T., G.R., E.J., H.L., S.C., R.M. declare no other conflicts of interest.

Funding Information

No public or commercial funding.

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Teprotumumab Treatment in Patients with Steroid and Surgery-Resistant Dysthyroid Optic Neuropathy: A Case Series

Abstract

Background:

Methods:

Results:

Conclusions:

Summary of the Research Problem

Methods

Results

Baseline characteristics

DON symptoms following teprotumumab treatment

GO symptoms following teprotumumab treatment

Adverse effects

Key concluding messages

Footnotes

Acknowledgments

Authors’ Contributions

Author Disclosure Statement

Funding Information

References