Optic Neuritis Associated With Tumor Necrosis Factor-Alpha Inhibitor Certolizumab

Tumor necrosis factor-a (TNF-a) inhibitors are effective in treating a variety of autoimmune diseases; however, these pharmacologic agents also can induce or exacerbate central nervous system demyelination (1). In this article, we describe a case of certolizumab-associated optic neuritis.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Optic Neuritis Associated With Tumor Necrosis Factor– Alpha Inhibitor Certolizumab Ariel Chen, MD, Neil R. Miller, MD, Thomas M. Bosley, MD T umor necrosis factor-a (TNF-a) inhibitors are effective in treating a variety of autoimmune diseases; however, these pharmacologic agents also can induce or exacerbate central nervous system demyelination (1). In this article, we describe a case of certolizumab-associated optic neuritis. A 38-year-old woman with rheumatoid arthritis and a history of intermediate uveitis complicated by glaucoma and recurrent macular edema presented with 2 days of decreased vision in the right eye associated with painful eye movements. Seven months before, she had been diagnosed with rheumatoid arthritis and started on methotrexate. Because of minimal improvement, she received an initial injection of certolizumab 23 days before presentation and a second injection 13 days later (10 days before presentation). At presentation, the patient’s visual acuity was 20 of 125 with the right eye and 20 of 40 with the left eye, with baseline vision in the right eye having been 20 of 70 because of macular edema. The patient could identify 4 of 4 gross colors with each eye; however, the colors appeared darker when viewed with the right eye than when viewed with the left eye. Visual fields performed by confrontation were grossly full. Pupils were nonreactive because of extensive bilateral posterior synechiae; however, the patient reported a marked (90%) reduction in light brightness in the right eye compared with the left eye. Neither the anterior chamber nor the vitreous cavity showed evidence of inflammation. Both optic discs had increased cup-to-disc ratios; there was no disc swelling or pallor. Optical coherence tomography revealed an average retinal nerve fiber layer thickness of 96 mm in both eyes and an intact foveal contour with trace macular edema and an epiretinal membrane in the right eye. Fluorescein angiography of the right eye showed a temporal area of mottled staining from pigmentary changes and sclerotic vessels consistent with an old central retinal vein occlusion that did not involve the macula. Brain and spine MRI revealed right optic nerve enhancement on contrast-enhanced, T1weighted images (Fig. 1). In addition, there were multiple periventricular and thoracic spinal cord white-matter lesions on T2-weighted images; however, none of these lesions enhanced on T1 images (Fig. 2). Lumbar puncture revealed normal protein and glucose concentrations and no cells, but there were multiple oligoclonal bands. Given the lack of an obvious intraocular cause for the patient’s acute visual loss in the right eye as well as the MRI and cerebrospinal fluid findings, the acute reduction in vision was attributed to an optic neuropathy—specifically, demyelinating optic neuritis induced by the initiation of certolizumab with associated pre-existing but asymptomatic multifocal demyelination. Certolizumab was discontinued, and the patient was treated with 1 g of intravenous methylprednisolone for 5 days. Despite treatment, her vision decreased to bare hand motion on Day 3 after initial presentation, at which time her color vision was 0 of 4 with the right eye but still 4 of 4 with the left eye. Because of this visual decline, consideration was given to treating the patient with either plasmapheresis or intravenous immunoglobulin therapy; however, because the optic neuropathy was believed to be related to the effects of certolizumab or was related to underlying multiple sclerosis, it was decided not to institute either therapy, and 2 months later, the patient’s right eye visual acuity had improved to 20 of Wilmer Eye Institute (AC, NRM, TMB), Johns Hopkins University School of Medicine, Baltimore, Maryland. The authors report no conflicts of interest. Address correspondence to Ariel Chen, MD, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Baltimore, MD 21287; E-mail: [e-mail] Chen et al: J Neuro-Ophthalmol 2021; 41: e713-e714 FIG. 1. Axial (A) and coronal (B) T1-weighted, contrastenhanced magnetic resonance images show enhancement of the right optic nerve. e713 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Axial T2-weighted MRI shows multiple periventricular hyperintense lesions of the brain, consistent with demyelination (A). Corresponding contrast-enhanced T1weighted image shows no lesions, indicating that the lesions are chronic (B). Sagittal T2-weighted MRI of the thorax shows multiple hyperintense lesions of the thoracic spinal cord (C) that are not evident on a corresponding T1weighted, contrast-enhanced image (D). 200. This improvement was believed to be limited because of recurrent macular edema. TNF-a inhibitors target inflammatory cytokines and are effective for the treatment of a variety of systemic and ocular autoimmune diseases, including rheumatoid arthritis and uveitis. Although TNF-a inhibitors have significant benefits, they can induce new demyelination or exacerbate preexisting demyelination. For example, in a randomized clinical trial, TNF-a inhibitors were found to cause a dosedependent increase in relapse rate, attack duration, and severity of exacerbation of pre-existing multiple sclerosis (MS) (1). In addition, in a review of 122 published cases of TNF-a inhibitor-associated, new-onset demyelinating disease, this phenomenon occurred about 1.5 years after initiation of treatment (1). Optic neuritis has been the most commonly observed TNF-a inhibitor-associated visual complication. The National Registry of Drug-Induced Ocular Side Effects contained 358 cases of optic neuritis in 2013 associated with a variety of TNF-a inhibitors, including certolizumab (2), and Alexandre et al reported a case of certolizumabassociated optic neuritis with concomitantly diagnosed MS (3). Our case of certolizumab-associated optic neuritis occurred in a patient with pre-existing but asymptomatic multifocal demyelination. Based on our review of the PubMed database, this is the only reported case of certolizumab-associated optic neuritis with a well- e714 documented history, visual and neurological assessment, treatment, and clinical course. Certolizumab is one of the newer TNF-a inhibitors, created by conjugation of an IgG monoclonal antibody fragment to polyethylene glycol (4). Compared with other TNF-a inhibitors, certolizumab has a longer half-life, resulting in a lower frequency of dosing while maintaining a comparable efficacy (4). Nevertheless, as is the case with other TNF-a inhibitors, certolizumab seems to be able to at least exacerbate pre-existing demyelinating disease and has been associated not only with optic neuritis but also an acute oculomotor nerve demyelination (5). Thus, we recommend adding certolizumab to the list of TNF-a inhibitors that should not be prescribed for patients with a personal or family history of demyelinating diseases. Furthermore, given the association of intermediate uveitis and multiple sclerosis, we believe that patients with a history of apparently isolated intermediate uveitis who are being considered for treatment with a TNF-a inhibitor such as certolizumab, undergo an MRI to determine if there is any evidence of asymptomatic demyelinating disease. If the MRI reveals evidence of central nervous system demyelination, it would seem prudent to treat the patient with an alternative agent. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Chen, N. R. Miller, and T. M. Bosley; b. Acquisition of data: A. Chen, N. R. Miller, and T. M. Bosley; c. Analysis and interpretation of data: A. Chen, N. R. Miller, and T. M. Bosley. Category 2: a. Drafting the manuscript: A. Chen, N. R. Miller, and T. M. Bosley; b. Revising it for intellectual content: A. Chen, N. R. Miller, and T. M. Bosley. Category 3: a. Final approval of the completed manuscript: A. Chen, N. R. Miller, and T. M. Bosley. 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Cochrane Database Syst Rev. 2017;9:CD007649. 5. Ban BH, Crowe JL. Oculomotor nerve demyelination secondary to certolizumab pegol. J Clin Rheumatol. 2018;24:234–236. Chen et al: J Neuro-Ophthalmol 2021; 41: e713-e714 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.