Outcomes in Autoimmune Retinopathy Patients Treated With Rituximab SAMANEH DAVOUDI, NAZANIN EBRAHIMIADIB, CAGLA YASA, DAMLA D. SEVGI, RAMAK ROOHIPOOR, EVANGELIA PAPAVASILIEOU, JASON COMANDER, AND LUCIA SOBRIN PURPOSE: To evaluate clinical and ancillary testing, UTOIMMUNE RETINOPATHY (AIR) RESULTS FROM A including adaptive optics, outcomes in autoimmune presumed immunologic attack on the retina by retinopathy (AIR) patients treated with rituximab. antibodies against retinal antigens. The spectrum A DESIGN: Retrospective, interventional case series. of AIR includes nonparaneoplastic AIR (npAIR), METHODS: PATIENTS: Sixteen AIR patients treated with cancer-associated retinopathy (CAR), melanoma- rituximab. OBSERVATION PROCEDURES: All patients were associated retinopathy (MAR), and autoimmune-related treated with a loading and maintenance dose schedule of retinopathy and optic neuropathy (ARRON). There is intravenous rituximab. Visual acuity (VA), electroreti- no established treatment protocol for AIR, and the nography (ERG), and spectral-domain optical coherence evidence base for therapeutic intervention includes only tomography (SDOCT) and visual field (VF) results a few retrospective case series and case reports.1 The largest were recorded. A subset of patients was also imaged using retrospective series assessed therapeutic effects of immuno- adaptive optics scanning laser ophthalmoscopy suppressive medications including cyclosporine, predni- (AO-SLO). MAIN OUTCOME MEASURES: Rates of VA sone, infliximab, azathioprine, and mycophenolate in 30 change before vs after rituximab initiation were compared consecutive patients with AIR.2 They found potential ben- with mixed-model linear regression. efits from using immunosuppression to treat AIR, but this RESULTS: The rate of visual decline was significantly series did not include any patients treated with rituximab. less after rituximab initiation compared with the rate of Given the proposed antibody-mediated nature of AIR, a visual decline prior to rituximab initiation (P [ .005). therapeutic agent that targets B cells and thus reduces sys- Seventy-seven percent of eyes had stable or improved temic antibody levels would seem reasonable. Rituximab is VA 6 months after rituximab initiation. Amplitudes a monoclonal antibody that targets CD20þ Bcells.This and implicit times on ERG, mean deviation on VF, central medication has Food and Drug Administration approval subfield mean thickness, and total macular volume did not for treatment of several rheumatologic and hematologic dis- decrease to a significant degree over the rituximab eases.3 There are 6 individual case reports that have treatment period. Six eyes had serial AO-SLO imaging. described the treatment of AIR with rituximab, with varying Cone densities did not change significantly over the levels of success.3–8 These 6 patients include 1 patient with treatment period. npAIR in the setting of systemic lupus erythematosus and 5 3–8 CONCLUSION: VA was stable or improved in a majority patients with CAR. The primary aim of the current study of AIR patients while they were being treated with ritux- is to report outcomes for the treatment of AIR with imab. OCT and ERG parameters, as well as AO-SLO rituximab in a larger, consecutive series of patients. cone densities, were stable during treatment. Studies A secondary aim of the study is to report on the use of with additional patients and longer follow-up periods adaptive optics scanning laser ophthalmoscopy are needed to further explore the utility of rituximab in (AO-SLO) to monitor AIR. Patients with AIR often do the management of AIR. (Am J Ophthalmol not have visible retinal pathology that can be monitored 2017;180:124–132. Ó 2017 Elsevier Inc. All rights to judge progression and response to treatment. Therefore, reserved.) ancillary testing including electroretinography (ERG), visual field (VF), and spectral-domain optical coherence tomography (SDOCT) are typically used to monitor AIR patients.9 However, some patients present with advanced Supplemental Material available at AJO.com. disease and sparing of function in only a small area of See Accompanying Editorial Article on page xv. retina centrally. These patients have severely reduced Accepted for publication Apr 26, 2017. ERGs and VFs at baseline as well as OCTs with only a From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts (S.D., N.E., small amount of intact ellipsoid zone. It is difficult to judge C.Y., D.D.S., R.R., E.P., J.C., L.S.); and Department of Ophthalmology, progression in these cases. AO-SLO is a new technique Farabi Eye Hospital, Eye Research Center, Tehran University of that allows for quantitation of the central photoreceptors Medical Sciences, Tehran, Iran (N.E., R.R.). 10 Inquiries to Lucia Sobrin, Massachusetts Eye and Ear Infirmary, 243 that remain in these patients, and thus has the potential Charles St, Boston, MA 02114; e-mail: [email protected] to be a useful tool to monitor patients with AIR. There is 124 © 2017 ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2017.04.019 1 case report of a patient with MAR in whom adaptive function, hepatitis B and C, tuberculosis, and complete optics imaging was used to detect cone density reduction blood counts before starting rituximab. before any detectable structural changes on SDOCT at Two different loading regimens of rituximab were used. the time of initial diagnosis,11 but this is the first study From 2010 to 2014, all patients were treated with a loading in which AO-SLO has been used to monitor AIR patients regimen of 1000 mg every other week for 2 doses, which is longitudinally. the most common dose used for rheumatologic conditions. More recently, we used a loading dose of 375 mg/m2 (eg, 675 mg for a 1.8 m2 body surface area) weekly for 4 weeks. This dose is used more commonly for hematologic malignancies, and we switched to this dosing based on METHODS encouraging results from 2 patients treated with this regimen. Treatment was repeated every 6 months, or PARTICIPANTS: This retrospective case series was sooner if the patient had worsening of symptoms earlier. approved by the Massachusetts Eye and Ear Infirmary The rationale for regular retreatment every 6 months in (MEEI) Institutional Review Board and was compliant the absence of worsening symptoms is that the peripheral with the Health Insurance Portability and Accountability CD20þ B cells begin to recover about 6–9 months after Act. We reviewed the medical records of all AIR patients rituximab infusion.12 Retreatment consisted of 1 rituximab who were examined on the MEEI Retina/Uveitis Services 1000 mg infusion. Patients were monitored with CD20 sub- from 2010 to 2016 and were treated with rituximab. The sets, complete blood counts, liver function tests, and a com- diagnosis was based on characteristic symptoms (sudden plete metabolic profile at each infusion and every 3 months or subacute painless loss of vision, photopsias, scotomas, between infusions. Total immunoglobulin levels were photoaversion, nyctalopia) and findings, abnormal ERG monitored every 6 months. Side effects were recorded at findings including abnormal rod and/or cone responses on each visit. Some patients were treated with rituximab as full-field testing and/or any abnormality on multifocal monotherapy. Others had rituximab added to other immu- testing, presence of antiretinal antibodies, exclusion of nosuppression. Intravenous methylprednisolone sodium other diagnoses, absence of overt inflammation, and no his- succinate 100 mg and hydroxyzine 25 mg were given as tory of hereditary retinal disease.9 An evaluation for malig- part of the pretreatment regimen before each rituximab nancy was done for all patients who did not already have a infusion to decrease the chance of infusion reactions. diagnosis of cancer. All patients had blood sent for antire- tinal antibody testing by Western blot to the Ocular Immu- ASSESSMENT OF QUANTITATIVE AND QUALITATIVE nology Laboratory, Casey Eye Institute, Oregon Health and CHARACTERISTICS IN OPTICAL COHERENCE TOMOGRA- Science University. Snellen visual acuity (VA), visual PHY: SDOCT images were obtained every 3 months. symptoms, ERG, fundus autofluorescence, VF, and Central subfield mean thickness (CSMT) and total macu- SDOCT results were recorded. OCT imaging was lar volume (TMV) were recorded from each visit from a performed with an SDOCT instrument (Spectralis, Heidel- horizontal foveal scan image. They were measured within berg, Germany). Fovea-centered images were acquired (25 the central 1-mm-diameter circle surrounding the fovea lines within a 20-degree horizontal scan and 25 lines within and the central 6-mm-diameter circle surrounding the a 20-degree vertical scan). Full-field ERGs were performed fovea, respectively. A masked ophthalmologist-grader with Burian-Allen electrodes (Hansen Labs, Coralville, ensured that the scans from which CSMT and TMV Iowa, USA) according to International Society for Clinical were recorded were of good quality and without artifact. Electrophysiology of Vision standard protocols. Multifocal electroretinography was performed with the Veris instru- FULL-FIELD AND MULTIFOCAL ELECTRORETINOG- ment (Electro-Diagnostic Imaging, Burlingame, Califor- RAPHY: Full-field and multifocal electroretinography nia, USA) and a stimulus array of 103 hexagons. A were obtained every 6 months. For the full-field electroret- subset of patients was also imaged using a prototype