Visual Recovery of Dysthyroid Optic Neuropathy With Teprotumumab

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Visual Recovery of Dysthyroid Optic Neuropathy With Teprotumumab Michael J. Lopez, Jordan L. Herring, MD, Ciera Thomas, Bradley A. Bertram, MD, Dilip A. Thomas, MD T hyroid-associated orbitopathy (TAO) is an autoimmune condition affecting the orbital soft tissues. The disease affects up to 50% of patients with Graves disease. A proportion of patients affected may develop disfigurement, disability, and visual loss. In the most severe cases of TAO, the orbital tissue expansion can cause optic nerve compression and injury known as dysthyroid optic neuropathy (DON), which may lead to irreversible visual loss (1,2). Current therapy for DON consists of systemic corticosteroids, orbital irradiation, and/or surgical decompression. Patients with contraindications to steroids or patients with refractory TAO may benefit from alternate therapies. Teprotumumab, an insulin-like growth factor I receptor (IGF-IR) blocker, was approved by the Food and Drug Administration in 2020 and showed promising results. In the phase-3 clinical trials, patients with optic neuropathy were specifically excluded from treatment (3). A recent case report, Sears 2020, demonstrated the successful use of teprotumumab in a patient with unilateral DON, refractory to intravenous (IV) steroids and radiation therapy (4). In our case, we present the first use of teprotumumab as a primary treatment in a patient with bilateral DON. A 61-year-old man was referred for 4 months of visual loss in the setting of newly discovered hyperthyroidism. On initial examination, his visual acuity was count finger at 4 feet in the right eye and 20/50 in the left eye. Pupils were equal, sluggish with a trace right RAPD (relative afferent pupillary defect). Automated visual fields showed bilateral central scotomas and nerve fiber layer bundle defects in the right eye . left eye. Ishihara color plates score was 0/15 in the right eye and 7/15 in the left eye. Bilateral exophthalmos was present with Hertel measurements of 25 mm right eye and 27 mm left eye, respectively. Extraocular movements were reduced bilaterally in all directions. There was no significant corneal exposure, and the remainder of anterior and posterior segment examinations were unremarkable. Department of Ophthalmology (MJL, JLH, DAT), Medical College of Georgia, Augusta University, Augusta, Georgia; and Franklin College of Arts and Sciences (CT), University of Georgia, Athens, Georgia. The authors report no conflict of interest. Address correspondence to Michael J. Lopez, BS, Medical College of Georgia, Augusta University, 1120 15th Street, BA-2720, Augusta, GA 30912; E-mail: [e-mail]. Lopez et al: J Neuro-Ophthalmol 2022; 42: e491-e493 The patient was started on oral prednisone 80 mg daily initially with some improvement in visual acuity to 20/150 in the right eye and 20/40 at 1-week follow-up. An initial dose of teprotumumab was given 13 days after the initial presentation and every 3 weeks thereafter. There was rapid and steady improvement after the initiation of treatment. At 1-month follow-up, having received 2 doses of teprotumumab and on 40-mg prednisone, uncorrected visual acuity had improved to 20/50 + 1 in the right eye and 20/30 in the left eye. Pupillary light reaction was improved in both eyes, and the RAPD in the right eye had resolved. Color plates were now 15/15 in both eyes, and exophthalmometry showed improvement to 21 mm in the right eye and 24 mm in the left eye, respectively (Fig. 1.). Corticosteroids were completely tapered off over the next 1 month with continued improvement of his clinical examination and automated visual fields, as seen in Figure 2. Repeat orbital imaging done 2 months after the treatment showed marked reduction of EOM volume and apical FIG. 1. Pretreatment MRI and 4-week posttreatment external photograph (left) vs. the 8-week posttreatment CT and most recent 16-week external photograph (right). The patient’s proptosis, lid retraction, and periorbital all improved following infusions of teprotumumab. e491 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. HVF at the initial presentation (top), and at 4-month follow-up (below), showing improvement in central scotoma and arcuate defects. crowding. At 4-month follow-up, having received his fifth dose of teprotumumab, best-corrected acuity returned to 20/25 in the right eye and 20/20 in the left eye with mild nasal steps only on VF testing. Exophthalmometry diminished further to 18 mm in the right eye and 21 mm in the left eye, and the patient remained off corticosteroids. At his most recent 6-month follow-up, having received his final dose of teprotumumab 1 month earlier, his bestcorrected acuity remained stable at 20/25 in the right eye and 20/20 in the left eye with mild nasal steps only on VF testing. Exophthalmometry diminished further to 18 mm in the right eye and 19 mm in the left eye. A 25 PD comitant ET remains with improved diplopia. The patient has remained off corticosteroids. There is no current consensus on the optimal treatment for TAO or DON (1). Systemic corticosteroids and orbital decompression surgery are the current mainstays of therapy. However, in select patients, steroids may be contraindicated and have a wide side effect profile, including hepatic injury, hyperglycemia, and psychosis. Furthermore, recurrence of TAO is common following the withdrawal of steroid therapy (1,2). Prior studies have already found that immunosuppressive and biologic therapies, like rapamycin, azithromycin, mycophenolate, rituximab, and tocilizumab, may be effective alternatives to steroids in the treatment of TAO (1,2). Teprotumumab is the only Food and Drug Administration–approved biologic for the treatment of active TAO. It is a fully human monoclonal antibody that blocks the activation of the IGF-IR, a key player in the e492 pathogenesis of TAO that can lead to orbital soft tissue hypertrophy and optic nerve compression. In the OPTIC trial, teprotumumab resulted in better outcomes in patients with active TAO compared with placebo. However, the trial specifically excluded patients with decreasing visual acuity or optic neuropathy as found in our patient (3). In our patient, teprotumumab, in combination with oral prednisone, resulted in rapid improvement in visual acuity, visual fields, diplopia, and proptosis within 4 weeks of starting therapy. The combination therapy likely resulted in a faster response rate than the median response time of 6.4 weeks with teprotumumab monotherapy seen in the OPTIC trial (4). Indeed, visual acuity showed initial improvement with oral prednisone alone. Subsequently, our patient was able to be weaned off steroids completely before his 10-week follow-up and continued to demonstrate slow improvement in proptosis and lid retraction. We attribute our patient’s rapid initial improvement and steroid taper to the combination therapy, with continued improvement and sustained effect on teprotumumab monotherapy. We suggest that teprotumumab combined with corticosteroids may potentially be a primary treatment for DON, perhaps obviating orbital decompression or irradiation therapy in some cases. We do acknowledge that in select cases where expedient treatment is needed, orbital decompression may still be preferred. Our patient started expedited teprotumumab therapy 13 days after the initial presentation. Time-dependent factors for insurance approval, initiation of infusion, and onset of therapeutic effect must be individualized in treatment decisions. A similar report, Sears 2020, demonstrated the benefits of teprotumumab for DON refractory to IV steroids and radiation therapy in a patient with unilateral DON (4). Our case also demonstrates that teprotumumab, in combination with corticosteroids, may be effective as a primary therapy in a patient with DON and warrants further investigation. Our patient required treatment for hyperglycemia, a potentially augmented side effect of combination therapy with corticosteroids and teprotumumab, which needs to be considered. Whether teprotumumab monotherapy would provide an equally effective and rapid enough treatment response, while avoid potentiating side effect profiles, remains unknown. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. J Lopez, J. L Herring, C. Thomas, B. A. Bertram, and D. A. Thomas; b. Acquisition of data: M. J. Lopez, J. L. Herring, C. Thomas, and D. A. Thomas; c. Analysis and interpretation of data: M. J. Lopez, J. L. Herring, C. Thomas, and D. A. Thomas. Category 2: a. Drafting the manuscript: M. J. Lopez, J. L. Herring, C. Thomas, and D. A. Thomas; b. Revising it for intellectual content: M. J. Lopez, J. L. Herring, C. Thomas, and D. A. Thomas. Category 3: a. Final approval of the completed manuscript: M. J. Lopez, J. L. Herring, C. Thomas, and D. A. Thomas. Lopez et al: J Neuro-Ophthalmol 2022; 42: e491-e493 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence REFERENCES 1. Blandford AD, Zhang D, Chundury RV, Perry JD. Dysthyroid optic neuropathy: update on pathogenesis, diagnosis, and management. Expert Rev Ophthalmol. 2017;12:111–121. 2. Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM, Kahaly GJ, Ludgate M. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020;16:104–116. Lopez et al: J Neuro-Ophthalmol 2022; 42: e491-e493 3. Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marinò M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med. 2020;382:341–352. 4. Sears CM, Azad AD, Dosiou C, Kossler AL. Teprotumumab for dysthyroid optic neuropathy: early response to therapy. Ophthalmic Plast Reconstr Surg. 2020. e493 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.