Risk Factors for Hydroxychloroquine Retinopathy and Its Subtypes.

Importance: The major toxic effect of hydroxychloroquine is retinopathy. Thus, current guidelines recommend limiting the dose and screening annually for retinopathy among all long-term users, but individual patient factors may be associated with retinopathy risk. Objective: To identify risk factors beyond hydroxychloroquine dose and duration of use for hydroxychloroquine retinopathy. Design, Setting, and Participants: This cohort study of 4677 patients in the Kaiser Permanente Northern California integrated health network who initiated hydroxychloroquine, continued treatment, and underwent retinopathy screening after 5 years of use was conducted from July 1, 1997, to December 31, 2020, with up to 15 years of follow-up. Statistical analysis was performed in August 2023. Exposure: Candidate risk factors included age at hydroxychloroquine initiation, sex, race and ethnicity, indications, chronic kidney disease (CKD), liver disease, diabetes, tamoxifen use, and medications that interact with hydroxychloroquine metabolism. Hydroxychloroquine dose was assessed from pharmacy dispensing records. Main Outcome and Measures: Incident hydroxychloroquine retinopathy was adjudicated from masked review of guideline-recommended screening studies and classified as parafoveal or pericentral pattern. Multivariable Cox proportional hazards regression was used to assess potential risk factors for hydroxychloroquine retinopathy within 15 years of initiation. Results: Of 4677 long-term hydroxychloroquine users (mean [SD] age at initiation, 52.4 [14.1] years; 3877 women [82.9%]), 125 patients developed hydroxychloroquine retinopathy within 15 years (102 parafoveal, 23 pericentral). Older age at time of hydroxychloroquine initiation was associated with retinopathy risk, with adjusted hazard ratios (HRs) of 2.48 (95% CI, 1.28-4.78) for those aged 45 to 54 years, 3.82 (95% CI, 2.05-7.14) for those aged 55 to 64 years, and 5.68 (95% CI, 2.99-10.79) for those aged 65 years or older compared with those younger than 45 years. The risk of retinopathy was higher among females than males (HR, 3.83 [95% CI, 1.86-7.89]), among patients with CKD stage 3 or greater (HR, 1.95 [95% CI, 1.25-3.04]), and among individuals with tamoxifen use (HR, 3.43 [95% CI, 1.08-10.89]). The likelihood of pericentral retinopathy was higher among Asian patients (HR, 15.02 [95% CI, 4.82-46.87]) and Black patients (HR, 5.51 [95% CI, 1.22-24.97]) compared with non-Hispanic White patients. Conclusions and Relevance: This study suggests that increasing age, female sex, CKD stage 3 or greater, and tamoxifen use were associated with a higher risk of hydroxychloroquine retinopathy, whereas being younger than 45 years at hydroxychloroquine initiation and male sex were associated with a lower risk. Race and ethnicity were also associated with the pattern of retinopathy. These factors should be incorporated into hydroxychloroquine dosing decisions.

Hydroxychloroquine Dose and Risk for Incident Retinopathy : A Cohort Study.

BACKGROUND: Hydroxychloroquine is recommended for all patients with systemic lupus erythematosus and is often used for other inflammatory conditions, but a critical long-term adverse effect is vision-threatening retinopathy. OBJECTIVE: To characterize the long-term risk for incident hydroxychloroquine retinopathy and examine the degree to which average hydroxychloroquine dose within the first 5 years of treatment predicts this risk. DESIGN: Cohort study. SETTING: U.S. integrated health network. PARTICIPANTS: All patients aged 18 years or older who received hydroxychloroquine for 5 or more years between 2004 and 2020 and had guideline-recommended serial retinopathy screening. MEASUREMENTS: Hydroxychloroquine dose was assessed from pharmacy dispensing records. Incident hydroxychloroquine retinopathy was assessed by central adjudication of spectral domain optical coherence tomography with severity assessment (mild, moderate, or severe). Risk for hydroxychloroquine retinopathy was estimated over 15 years of use according to hydroxychloroquine weight-based dose (>6, 5 to 6, or ≤5 mg/kg per day) using the Kaplan-Meier estimator. RESULTS: Among 3325 patients in the primary study population, 81 developed hydroxychloroquine retinopathy (56 mild, 17 moderate, and 8 severe), with overall cumulative incidences of 2.5% and 8.6% at 10 and 15 years, respectively. The cumulative incidences of retinopathy at 15 years were 21.6% for higher than 6 mg/kg per day, 11.4% for 5 to 6 mg/kg per day, and 2.7% for 5 mg/kg per day or lower. The corresponding risks for moderate to severe retinopathy at 15 years were 5.9%, 2.4%, and 1.1%, respectively. LIMITATION: Possible misclassifications of dose due to nonadherence to filled prescriptions. CONCLUSION: In this large, contemporary cohort with active surveillance retinopathy screening, the overall risk for hydroxychloroquine retinopathy was 8.6% after 15 years, and most cases were mild. Higher hydroxychloroquine dose was associated with progressively greater risk for incident retinopathy. PRIMARY FUNDING SOURCE: National Institutes of Health.

Rapid Macular Thinning Is an Early Indicator of Hydroxychloroquine Retinal Toxicity.

PURPOSE: To demonstrate rapid macular thinning as an early and objective sign of hydroxychloroquine retinopathy. DESIGN: Retrospective case cohort. PARTICIPANTS: Cohort of 301 patients receiving long-term hydroxychloroquine therapy at Kaiser Permanente Northern California who underwent a minimum of 4 OCT studies that included Early Treatment Diabetic Retinopathy Study (ETDRS) retinal thickness values over a minimum of 4 years. METHODS: Creation of sequential retinal thickness plots to show the rate of change in macular thickness within ETDRS regions. MAIN OUTCOME MEASURES: Identification of rapid macular thinning, comparison of patients with rapid thinning to those with stable macular thickness, and comparison of rapid thinning patients with and without conventional OCT or 10-2 visual field signs of hydroxychloroquine toxicity. RESULTS: Retina thinning in 219 stable patients receiving long-term hydroxychloroquine therapy averaged (mean ± standard deviation) 0.62 ± 0.45 µm/year, whereas 82 patients showed a period of relatively linear rapid thinning with a loss of 3.75 ± 1.34 µm/year. Of the patients with rapid thinning, 38 eventually demonstrated conventional OCT or 10-2 visual field signs of hydroxychloroquine retinal toxicity. The cumulative retinal thinning in these patients was 25.1 ± 6.2 µm compared with 15.7 ± 4.0 µm in those without conventional toxicity (P < 0.01). CONCLUSIONS: Retinal thickness remains stable for many years in most patients receiving long-term hydroxychloroquine therapy, but after a critical point, the retina may begin to thin rapidly. Sequential plots of inner and outer ETDRS ring macular thickness provide objective evidence of this early structural change several years before conventional signs appear. This approach can alert patients and prescribing physicians to potential retinal damage and uses readily available OCT measurements that could be automated by manufacturers for use in comprehensive eye care settings.

TOPOGRAPHIC OPTICAL COHERENCE TOMOGRAPHY SEGMENTATION SHOWS LIMITED ELLIPSOID ZONE RECOVERY IN MILD HYDROXYCHLOROQUINE RETINOPATHY.

PURPOSE: Optical coherence tomography (OCT) cross-sections have shown limited ellipsoid zone (EZ) improvement in mild hydroxychloroquine (HCQ) retinopathy within a few years after drug cessation. However, the extent, functional significance, and stability of such changes over time remain unclear. METHODS: We created en face EZ maps using automated pixel-by-pixel segmentation for four patients with early-moderate HCQ toxicity followed for 6-8 years after drug cessation. These maps were compared with OCT cross-sections, fundus autofluorescence, and automated 10-2 visual fields. RESULTS: One patient had no EZ line loss; one had stable EZ loss throughout follow-up; two showed 30 to 40% reduction in the area of loss, largely in the first 2 years. This limited recovery mostly occurred in regions where the EZ line was only thinned or fragmented; other similar areas did not improve. Fundus autofluorescence hyperfluorescence and visual fields did not show consistent correlation with topography. CONCLUSION: Anatomic EZ recovery, when present, was restricted to regions of mild damage and did not correlate with fundus autofluorescence or improvement in visual fields. Topographic mapping seemed no more sensitive locally than cross-sectional OCT but may aid detection and longitudinal follow-up of toxicity by showing early damage or changes in the macula that could be missed with individual cross-sections.

American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and American Academy of Ophthalmology 2020 Joint Statement on Hydroxychloroquine Use With Respect to Retinal Toxicity.

Four major medical societies involved with hydroxychloroquine (HCQ) therapy concur on the need for common principles and cooperation to minimize the risk of ocular toxicity. At a daily dosage of ≤5 mg/kg/day actual body weight, the risk of retinal toxicity from HCQ is <2% for usage up to 10 years. Widespread adoption of more sensitive testing techniques, such as optical coherence tomography and automated visual fields, by eye care providers will allow the detection of early toxicity and thus preserve the patient's visual function. Baseline testing is advised to rule out confounding disease when a patient is started on HCQ. Annual screening with sensitive tests should begin no more than 5 years after treatment initiation. Providers should be sensitive to the medical value of HCQ, and not stop the drug for uncertain indications. It is important to note that effective communication among prescribing physicians, patients, and eye care providers will optimize the utility and safety of HCQ.

SEQUENTIAL RETINAL THICKNESS ANALYSIS SHOWS HYDROXYCHLOROQUINE DAMAGE BEFORE OTHER SCREENING TECHNIQUES.

PURPOSE: We sought to determine the earliest diagnostic signs of hydroxychloroquine retinopathy up to the point of clinical recognition. METHODS: Retrospective series of 6 patients (5 parafoveal disease; 1 pericentral disease) with at least 3 examinations over 3.5 years or more preceding diagnosis of HCQ retinopathy. Spectral domain optical coherence tomography (sdOCT) cross-sections, fundus autofluorescence (FAF) and visual fields were generated clinically. Stored sdOCT data were re-examined later to generate topographic ellipsoid zone (EZ) maps, minimum intensity (MI) analysis and sequential plots of regional retinal thickness. Retrospective series of six patients (5 parafoveal disease; one pericentral disease) with at least three examinations over 3.5 years or more preceding diagnosis of hydroxychloroquine retinopathy. RESULTS: Spectral domain optical coherence tomography cross-sections and fields showed similar sensitivity; fundus autofluorescence was not helpful. In parafoveal cases, EZ topography and minimum intensity analysis were no more reliable. Sequential thickness plots from four parafoveal cases showed dramatic retinal thinning across the posterior pole beginning 4 years to 5 years before clinical diagnosis, with parafoveal regions thinning even faster. The pericentral case showed thinning only outside the central macula. Peripheral EZ loss was more dramatic with EZ topography than sdOCT cross-sections. CONCLUSION: Sequential retinal thickness plots reveal definitive thinning years before current diagnostic procedures. We hope that OCT manufacturers will develop software to display such measurements. Ellipsoid zone topography was not more sensitive than sdOCT cross-sections, but important for recognizing pericentral disease.

The rapid N-wave as a potentially useful measure of the photopic negative response.

PURPOSE: The photopic negative response (PhNR) correlates with ganglion cell function and has previously been examined as an indicator of glaucomatous optic nerve damage. However, it is a prolonged response that is measured against baseline, and its clinical utility has been limited by extensive variability, poor repeatability, and baseline instability. We have observed a distinct brief negative wave ("N-wave") commonly present within the slow PhNR trough, which may provide practical and analytic advantages as a clinical measure. METHODS: We reviewed data from an interventional trial of 59 glaucoma patients who had 4 exams over an 8-month period. The PhNR was recorded with standard ISCEV stimuli (1 Hz and in some cases 4 Hz stimulation), and N-waves were measured manually, relative to return to baseline. RESULTS: N-waves, when present, could be measured easily despite shifting baselines and a degree of background noise. The PhNR median amplitude centered around 18 µV, while the N-wave median centered around 7 µV, with a distribution of responses skewed toward low or zero amplitudes. CONCLUSIONS: The N-wave appears to be a component of the longer PhNR, though its exact origin and significance remain unclear. As a rapid waveform that is independent of baseline, the N-wave is in many ways easier to measure accurately than the slower PhNR, which is highly dependent on baseline stability. The N-wave may prove useful clinically if further studies can optimize its stimulation, show its behavior in normal individuals and find correlation with markers of optic nerve disease.

Night Blindness in a Healthy Middle-Class Child.

How do you clinically approach a night-blind child in a vegetarian family, with no obvious dystrophy and no obvious malnutrition? This case reviews some of the issues, and it reminds us of some of the cautions. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:286-288.].

The eyes of the angel of death: Ophthalmic experiments of Josef Mengele.

The infamous Schutzstaffel doctor Josef Mengele was known as the Angel of Death for choosing and condemning Jews, gypsies, and other prisoners to the gas chambers at the Auschwitz-Birkenau concentration camp. Less known was his active participation in ophthalmic research with equal disregard for life and ethical principles. Mengele was not an ophthalmologist, but he worked in close collaboration and complicity with two genetic researchers at the Kaiser-Wilhelm Institute in Berlin, Karin Magnussen and Otmar Von Verschuer. The objective of the eye color protocol was to demonstrate hereditary differences in iris structure determined by race and ostensibly to "cure" heterochromia. Mengele sent heterochromous Gypsy eyes to Magnussen, extracted from the bodies of inmates who died (or he killed). Mengele injected adrenaline into children's eyes in an attempt to change eye color and to study environmental influences. Mengele was undoubtedly influenced to conduct these human experiments by his great ambition to publish to obtain academic promotion. These ophthalmologic experiments not only solidify Mengele's reputation as an angel of death but also show the symbiosis that existed between the concentration camp physicians and others in the Nazi medical establishment. Ophthalmology, like all of medicine, has had its share of unethical experimentation, but none with more disregard for life and ethical principles than that of Mengele at Auschwitz.

DIFFUSE CHORIORETINOPATHY WITHOUT SEROUS DETACHMENT ASSOCIATED WITH CARDIAC TRANSPLANTATION.

PURPOSE: To analyze an unusual case of widespread chorioretinopathy after cardiac transplantation for its potential etiology and clinical significance. METHODS: Clinical examinations included widefield and macular color and fundus autofluorescence photography, spectral domain optical coherence tomography, fluorescein angiography and indocyanine green angiography, full-field electroretinography, and Goldmann visual fields. PATIENT: A 44-year-old Hispanic woman was referred to rule out retinitis pigmentosa. Medical history revealed cardiac transplantation 6 months previously for idiopathic cardiomyopathy. RESULTS: Visual acuity was 20/20 in both eyes. The fundi showed widespread gray mottling and little pigmentation, but fundus autofluorescence revealed black speckling broadly across the fundus, and geographic retinal pigment epithelium loss in the nasal midperiphery of the left eye. Spectral domain optical coherence tomography showed normal inner retina, and surprising preservation of outer nuclear layer, but the ellipsoid zone line was fragmented, and the interdigitation zone line was replaced with irregular debris. Retinal pigment epithelium was very thin with occasional excrescences. Electroretinography showed mild loss of both rods and cones, with mild flicker peak delay only in the left eye. Fluorescein angiography showed no leakage, but a reticular pigment pattern in the macula. Indocyanine green angiography showed irregular arteriolar remodeling, and few large arteries. DISCUSSION AND CONCLUSION: Serous retinopathy is well known after organ transplantations, but this patient had retinal pigment epithelium and retinal damage well into the periphery and no leakage. Retinal dystrophy was deemed unlikely given the relatively good electroretinography. The indocyanine green vascular changes raise the possibility of a transient choroidal ischemic event during or shortly after cardiac surgery. The event altered retinal pigment epithelium diffusely, but allowed for enough regeneration to sustain retinal function. Diffuse transplant chorioretinopathy may be discovered if postcardiac transplant patients get peripheral retinal examinations.