Abstract
Purpose
To study post-interventional findings in patients with dysthyroid optic neuropathy (DON) treated with teprotumumab.
Observations
In this multicenter observational Case series , patients with DON were treated with teprotumumab, an insulin-like growth factor I receptor inhibitor (10 mg/kg for the first infusion then 20 mg/kg for subsequent infusions, every three weeks for a total 8 infusions). This study included patients with acute and chronic thyroid eye disease (TED) with DON who had failed conventional therapies and were not candidates for surgical decompression. Data collected included best corrected visual acuity (BCVA), color vision, RAPD when present, and orbital CT or MRI. Proptosis, clinical activity score (CAS), Gorman diplopia score (GDS), and Humphrey visual fields (HVF) were also evaluated.
Ten patients (6 women, 4 men) with an average age 64 years old were included in this study. Mean follow up after completion of infusions was 15 weeks. Baseline visual acuity (VA) impairment ranged from hand motion (HM) to 20/25 in affected eyes. All patients had pre-treatment orbital CT or MRI that confirmed orbital apex compression. Seventy percent of patients had objective improvement in DON after 2 infusions of teprotumumab measured as significant improvement in visual acuity, resolution of RAPD, or both. After completion of treatment, affected eyes had a mean BCVA improvement of 0.87 logMAR (p=0.0207), proptosis reduction of 4.7 mm (p<0.00001), CAS improvement of 5.25 points (p<0.00001), and GDS improvement of 0.75 points (p=0.160). All 6 patients who presented with an RAPD had resolution or improvement of RAPD. All 7 patients who presented with color vision deficits had normalization or improvement of color vision.
Conclusions and Importance
Teprotumumab infusions resulted in medical decompression and objective resolution or improvement of dysthyroid optic neuropathy. Most patients had rapid improvement of visual acuity and reversal of RAPD. Post-infusion imaging demonstrated reduction in extraocular muscle size that correlated with improvement in visual dysfunction. However, patients who presented with longstanding severe visual loss had limited improvement. There was no recurrence of DON after completion of teprotumumab in our cohort.
Highlights
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Teprotumumab is effective for the treatment of dysthyroid optic neuropathy.
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Most patients demonstrated rapid objective improvement after 2 infusions.
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Visual acuity improved and relative afferent pupillary defect resolved after treatment.
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Orbital imaging showed improvement of orbital apex crowding after treatment.
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Patients with longstanding severe vision loss had limited improvement in visual acuity.
1
Introduction
Thyroid eye disease (TED) frequently results in volumetric expansion of the extraocular muscles and orbital fat. These factors may lead to dysthyroid optic neuropathy (DON) secondary to compression of the optic nerve, a rare but serious complication of TED that can lead to permanent vision loss if not treated in a timely manner. In DON, orbital imaging may demonstrate expansion of orbital fat volume, as well as effacement of the normal orbital fat separating the optic nerve and extraocular muscles. Although the extraocular muscles are frequently enlarged, it is also common to detect orbits with high orbital fat volume and relatively normal extraocular muscles. In addition to apical compression, the optic nerve may also appear stretched (thinner and straightened with tenting of the globe posteriorly). , DON occurs in 1–8% of patients with TED. DON can present with decreased visual acuity, relative afferent pupillary defect (RAPD) if unilateral or asymmetric, red desaturation, color vision abnormalities, visual field defects, and loss of nerve fiber layer on optical coherence tomography (OCT). DON is traditionally managed with a variety of modalities, often in combination, including oral or intravenous (IV) high-dose corticosteroids, orbital radiation, and urgent surgical decompression.
Teprotumumab, a human monoclonal antibody directed against the insulin-like growth factor I receptor (IGF-IR), was approved by the U.S. Food and Drug Administration (FDA) for the treatment of TED on January 21st, 2020. Although patients with optic neuropathy were excluded from the two original clinical efficacy trials, the trial data showed significant reduction in proptosis, clinical activity score (CAS), diplopia, and improvement in quality-of-life score in the treatment arm compared to placebo. Furthermore, orbital imaging in the Phase 3 trial demonstrated a reduction in extraocular muscle size (including at the orbital apex) making teprotumumab a potential therapeutic option for patients with DON.
The purpose of this Case series was to study post-interventional findings in patients with dysthyroid optic neuropathy (DON) treated with teprotumumab.
2
Methods
In this observational Case series, patients with DON were treated with teprotumumab (10 mg/kg for the first infusion then 20 mg/kg for subsequent infusions) every three weeks for a total of 8 infusions per the protocol in clinical trials. , DON was defined as visual loss secondary to thyroid eye disease related compression and/or stretching of the optic nerve. Patients either had acute (9 months or less duration) progressive active TED or chronic (10 months or greater duration) active TED. Patients were treated with teprotumumab because they were poor surgical candidates and had failed other interventions including oral prednisone, IV methylprednisolone, orbital radiation, and/or surgical orbital decompression with progression of DON despite prior interventions.
Patient gender, ethnicity, baseline thyroid status, and smoking status were documented. A complete eye examination was performed. Data collected included best corrected visual acuity (BCVA), color vision, RAPD or disc edema when applicable, Humphrey visual field (HVF), and orbital imaging with evidence of apical crowding or optic nerve stretch. Proptosis (Hertel exophthalmometer), CAS and Gorman diplopia score (GDS) were also evaluated. Baseline thyroid function tests included thyroid-stimulating hormone (TSH) and thyroid stimulating immunoglobulin (TSI). The change in the data from baseline to most recent post-treatment visit is reported for all patients.
Institutional Review Board (IRB)/Ethics Committee approval was obtained. This study adheres to the tenets of the Declaration of Helsinki as amended in 2013 and the Health Insurance Portability and Accountability Act. Written informed consent was obtained from all patients for publication of this Case series and for use of all identifiable photographs.
3
Results
Participants included 6 women and 4 men, ages 36–84 years (mean age 64-years-old). There were four Caucasians, two Asians, two African Americans, one Hispanic, and one East Asian Indian. Two patients were prior tobacco smokers (cases 4, 5). TED duration ranged from several weeks to greater than 10 years ( Table 1 ). Average follow up was 15 weeks (range 0–33 weeks) after the last infusion.
| Case | Age | Sex | Tobacco use | TED Duration | Prior treatment | TSH | TSI |
|---|---|---|---|---|---|---|---|
| 1 | 76 | F | Never | 10 years | IV/oral steroids, surgical decompression OU | 0.07 | 509 |
| 2 | 84 | F | Never | 1 year | IV steroids | 0.01 | 483 |
| 3 | 62 | F | Never | 6 months | IV steroids | <0.0025 | 380 |
| 4 | 73 | F | Prior | 1 year | IV steroids, surgical decompression OD | 3.41 | 453 |
| 5 | 45 | M | Prior | 1.5 year | IV steroids, orbital radiation OD | 0.48 | 610 |
| 6 | 55 | F | Never | 2 months | IV/oral steorids, surgical decompression OD | 0.11 | 330 |
| 7 | 73 | F | Never | 2 months | Oral steroids | 0.88 | 408 |
| 8 | 57 | M | Never | 10 years | IV steroids, surgical decompression OU, orbital radiation OU | 0.68 | <89 |
| 9 | 40 | M | Never | 10 months | IV/oral steroids | 0.16 | 389 |
| 10 | 76 | M | Never | 5 years | IV/oral steroids, surgical decompression OD | 0.01 | 353 |
All patients had pre-treatment orbital CT or MRI that confirmed orbital apex compression and/or stretching of the optic nerve with tenting of the globe. All patients had diagnostic findings supporting diagnosis of DON with decline in visual acuity (VA), presence of RAPD (when asymmetric), decreased color vision, and/or visual field defects on HVF. All patients had evidence of active inflammation with CAS greater than 3.
Seventy percent of patients had objective improvement after 2 infusions including either significant improvement in visual acuity, resolution of RAPD, or both. Six patients had an RAPD prior to treatment with teprotumumab; all had resolution (n=5) or improvement (n=1) of RAPD after one to two infusions of teprotumumab. Three patients did not have an RAPD due to symmetric bilateral involvement. All seven patients who had color vision deficits had rapid normalization (n=6) or improvement (n=1) of color vision after 2 infusions. Three patients presented with severe vision loss due to longstanding compressive optic neuropathy and had minimal objective improvement from pre-treatment VA of hand motion (HM) ( Table 2 ).
| Case | Laterality of CON | RAPD | Resolution of RAPD | VA OD/OS Pre Infusion | VA OD/OS Post Infusion | Color vision deficit | Normalization of color vision |
|---|---|---|---|---|---|---|---|
| 1 | OU | No | n/a | HM | 20/800 | n/a a | n/a |
| HM | 20/800 | ||||||
| 2 | OU | No | n/a | HM | 20/800 | n/a a | n/a |
| HM | 20/800 | ||||||
| 3 | OU | No | n/a | 20/200 | 20/50 | OU | Yes |
| 20/200 | 20/30 | ||||||
| 4 | OS | No | n/a | 20/30 | 20/20 | OS | Yes |
| 20/30 | 20/20 | ||||||
| 5 | OU (OS > OD) | OS | Yes | 20/40 | 20/20 | OS | Yes |
| 20/125 | 20/20 | ||||||
| 6 | OS | OS | Yes | 20/25 | 20/25 | OS | Yes |
| 20/100 | 20/25 | ||||||
| 7 | OD | OD | Yes | 20/25 | 20/20 | n/a b | n/a |
| 20/25 | 20/20 | ||||||
| 8 | OU (OS > OD) | OS | Yes | 20/100 | 20/25 | OU | Yes |
| 20/60 | 20/30 | ||||||
| 9 | OS | OS | Yes | 20/30 | 20/20 | OS | Yes |
| 20/40 | 20/20 | ||||||
| 10 | OU (OS > OD) | OS | No c | 20/100 | 20/70 | OD | No d |
| HM | 20/200 |
a VA too poor to evaluate color vision.
Visual acuity ranged from hand motion (HM) to 20/25 in affected eyes at baseline. Snellen VA was converted to logMAR units for analysis. Average improvement of visual acuity was 0.64 (±0.58) logMAR (p=0.0190) in all eyes and 0.87 (±0.60) logMAR (p=0.0207) in affected eyes. Average reduction in proptosis at last follow up was 4.8 (±2.7) mm in all eyes (p<0.00001) and 4.7 (±2.7) mm in eyes affected by DON (p<0.00001). Average reduction in CAS was 5.25 (±1.2) (p<0.00001) and average reduction in GDS was 0.75 (±1.1) (p=0.160) ( Table 3 ). Only one patient (Case 8) who completed 8 infusions per protocol had only 1 mm reduction in proptosis; all others had at least 2 mm of proptosis reduction. Fifty percent of patients received post-infusion orbital CT or MRI that confirmed improvement in orbital crowding.
