Risk of Retinal Toxicity in Longterm Users of Hydroxychloroquine.
Kim Ji-Won,Kim Yoon Young,Lee Hwajeong,Park Sung-Hoon,Kim Seong-Kyu,Choe Jung-Yoon
The Journal of rheumatology
OBJECTIVE:Several studies have reported risk factors for hydroxychloroquine (HCQ) retinal toxicity, but data are limited for patients of Asian ancestry. The aim of this study was to investigate the rate of and factors for HCQ retinal toxicity in the Korean population. METHODS:There were 123 patients enrolled in this study who were using or had used HCQ. Retinal toxicity was detected using spectral domain optical coherence tomography, fundus autofluorescence, multifocal electroretinography, and automated visual field testing. Binary logistic regression analysis was performed to identify factors associated with HCQ retinal toxicity. RESULTS:Mean duration of HCQ use and mean HCQ dose in study participants was 10.1 years and 6.4 mg/kg, respectively. We found 17 patients (13.8%) with HCQ retinal toxicity among 123 patients. Patients with retinal toxicity took HCQ ranging from 6.7-21.9 years and daily dosage ranging from 4.9-9.1 mg/kg. Only 1 patient had retinal toxicity among patients with daily dose < 5.0 mg/kg. These factors increased the risk of HCQ retinal toxicity: longer duration of HCQ use [adjusted OR (aOR) = 4.71, 95% CI 2.18-10.15 for duration of HCQ use in 5-yr increments], higher daily HCQ dose (aOR = 3.34, 95% CI 1.03-10.80 for daily HCQ dose in 100-mg increments), and the presence of kidney disease (aOR = 8.56, 95% CI 1.15-64.00). CONCLUSION:HCQ retinal toxicity is associated with duration of HCQ use, daily HCQ dose, and presence of kidney disease. Proper dosing of maximum 5 mg/kg and regular screening according to risk factors are important in HCQ use.
Macular ganglion cell-inner plexiform layer thickness for detection of early retinal toxicity of hydroxychloroquine.
Kan Emrah,Yakar Konuralp,Demirag Mehmet Derya,Gok Mustafa
PURPOSE:This study evaluated the macular ganglion cell-inner plexiform layer (GC-IPL) thickness using spectral-domain (SD) optical coherence tomography (OCT) in patients with chronic exposure to hydroxychloroquine (HCQ). METHODS:A total of 90 patients (90 eyes) treated with HCQ for at least 5 years and normal controls were included in the study. A fundus examination, automated threshold perimetry, and GC-IPL thickness measurements using the Cirrus high-definition OCT ganglion cell analysis algorithm were performed in all patients treated with HCQ. Average, minimum, and sectorial macular GC-IPL thicknesses were compared between the patients and controls. RESULTS:There was no statistically significant difference in age or sex between the groups. The anterior segment and fundoscopy were normal in all patients and controls. Visual field (VF) testing was normal in all patients. The average, minimum, and sectorial macular GC-IPL thicknesses were significantly lower in patients than those in control subjects. CONCLUSIONS:There was significant thinning of the macular GC-IPL in the absence of clinically evident HCQ-related retinopathy and VF abnormalities. Measurements of the macular GC-IPL thickness using SD-OCT may therefore be useful in the early diagnosis and in monitoring the progression of retinal changes in patients receiving long-term HCQ therapy.
Use of OCT Retinal Thickness Deviation Map for Hydroxychloroquine Retinopathy Screening.
Kim Ko Eun,Ahn Seong Joon,Woo Se Joon,Park Kyu Hyung,Lee Byung Ro,Lee Yeon-Kyung,Sung Yoon-Kyoung
PURPOSE:To investigate the use of a retinal thickness deviation map generated from swept-source (SS) OCT images for hydroxychloroquine retinopathy screening. DESIGN:Retrospective cohort study. PARTICIPANTS:This study included 1192 Korean patients with a history of hydroxychloroquine treatment: 881 patients (1723 eyes) in the discovery set and 311 patients (591 eyes) in the validation set. Patients were screened for retinal toxicity using SS OCT, fundus autofluorescence, and standard automated perimetry. METHODS:According to the 2016 American Academy of Ophthalmology guidelines, hydroxychloroquine retinopathy was diagnosed by the presence of abnormalities on ≥1 objective structural tests alongside corresponding visual field defects. The 12 × 9-mm macular volume SS OCT scan was performed, and the retinal thickness deviation map was generated automatically using the built-in software. On this map, yellow (retinal thickness, <5% of the normative level) or red (<1% of the normative level) pixels were defined as abnormal. Abnormal findings were evaluated, and diagnostic criteria were developed based on the discovery set data; criteria were validated using the validation set data. MAIN OUTCOME MEASURES:The rate and patterns of abnormalities on the retinal thickness deviation map and sensitivity and specificity of the diagnostic criteria. RESULTS:The retinal thickness deviation map showed the following abnormal patterns in eyes with hydroxychloroquine retinopathy: pericentral (36.0%) or parafoveal (6.1%) ring, mixed-ring (34.2%), central island (13.2%), and whole macular thinning (10.5%). The criterion of ≥5 contiguous red pixels showing 1 of the 5 characteristic patterns in both eyes yielded the greatest diagnostic performance (sensitivity and specificity of 98.2% and 89.1% and of 100% and 87.5% in the discovery and validation set data, respectively). Moreover, the area of abnormal pixels on the map was correlated significantly with the mean deviation (P < 0.001) and pattern standard deviation (P < 0.001) on the Humphrey 30-2 test in eyes with hydroxychloroquine retinopathy. CONCLUSIONS:The retinal thickness deviation map may facilitate the objective evaluation of hydroxychloroquine retinopathy because it does not require subjective, morphologic evaluation of the outer retinal layers. The map has the potential to enhance hydroxychloroquine retinopathy screening when used in conjunction with conventional screening methods.
The Diagnostic Utility of Multifocal Electroretinography in Detecting Chloroquine and Hydroxychloroquine Retinal Toxicity.
Tsang Adrian C,Ahmadi Sina,Hamilton John,Gao Jennifer,Virgili Gianni,Coupland Stuart G,Gottlieb Chloe C
American journal of ophthalmology
PURPOSE:To evaluate multifocal electroretinography (mfERG) as a screening test for detecting hydroxychloroquine and chloroquine toxicity. DESIGN:Diagnostic accuracy study. METHODS:Patients referred to the University of Ottawa for hydroxychloroquine or chloroquine retinopathy screening during 2011-2014 underwent 10-2 automated visual field, spectral domain optical coherence tomography, and mfERG testing. Patients with amblyopia, high myopia or hyperopia, coexisting retinal disease, or prior surgery were excluded. Abnormalities in parafoveal ring amplitudes or ring ratios were considered a positive mfERG result. We used the definition for hydroxychloroquine and chloroquine toxicity provided by the 2016 American Academy of Ophthalmology recommendations. Area under the curve (AUC) for each mfERG parameter and the sensitivity and specificity of mfERG were calculated. Logistic regression was used to model the effect of covariates in receiver operating characteristic (ROC) analyses. RESULTS:In total, 63 patients (47 female, 16 male) were included. Of 120 eyes, 16 (13.3%) had toxicity according to the American Academy of Ophthalmology guidelines, and 39 (32.5%) had positive mfERG findings. mfERG was found to have a sensitivity of 1.00 (95% CI 0.79-1.00) and a specificity of 0.78 (95% CI 0.69-0.85). Ring 2 amplitude had the best performance among all parameters (AUC 0.97, 95% CI 0.94-1.00). Ring 2 amplitude decreased linearly with increasing cumulative dose and daily dose. CONCLUSIONS:The high sensitivity of parafoveal depression on mfERG and its relationship to cumulative and daily dose illustrates an important role for objective functional testing. The high false-positive rate suggests a potential period where physiologic dysfunction is detected objectively on mfERG before structural change on spectral domain optical coherence tomography.
TOXIC EFFECTS OF HYDROXYCHLOROQUINE ON THE CHOROID: Evidence From Multimodal Imaging.
Ahn Seong Joon,Ryu So Jung,Lim Han Woong,Lee Byung Ro
Retina (Philadelphia, Pa.)
PURPOSE:To investigate the choroidal changes that occur in hydroxychloroquine (HCQ) retinopathy using multimodal imaging including fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT) angiography and to correlate these changes with retinal findings obtained using OCT and fundus autofluorescence. METHODS:In 20 patients (n = 40 eyes) with systemic lupus erythematosus or rheumatoid arthritis diagnosed to have HCQ retinopathy, imaging modalities including swept-source OCT, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and OCT angiography were used to evaluate retinal and choroidal changes associated with retinopathy. The assessments included specific findings such as presence of hyperfluorescent or hypofluorescent lesions on angiography and signal void zones on OCT angiography, their frequencies, and the correlations among the retinal and choroidal findings. These findings were also correlated with the severity of retinopathy. Retinopathy progression was defined using fundus autofluorescence and OCT and correlated with the retinal/choroidal findings. RESULTS:Fluorescein angiography demonstrated a hyperfluorescent area, which reflects a defective retinal pigment epithelium, with multiple tiny dark spots within the area. Indocyanine green angiography showed a hypofluorescent area with dark spots, which was matched to the hypoautofluorescent area on fundus autofluorescence. Although there were no specific morphologic abnormalities in the choroid layers using en face choroidal imaging, OCT angiography demonstrated signal void areas on the choriocapillaris in the areas of the retinal pigment epithelium defect. Even after cessation of HCQ, there was progression of retinopathy in eyes with choroidal involvement, particularly on the area of choroidal findings. CONCLUSION:Multimodal imaging demonstrates choriocapillaris degeneration in eyes with HCQ retinopathy, particularly those with severe retinopathy. The choroidal change was associated with outer retinal toxicity of HCQ.
Effect of disease stage on progression of hydroxychloroquine retinopathy.
Marmor Michael F,Hu Julia
IMPORTANCE:Hydroxychloroquine sulfate retinopathy can progress after the drug is stopped. It is not clear how this relates to the stage of retinopathy or whether early screening with modern imaging technology can prevent progression and visual loss. OBJECTIVE:To determine the relationship between progression of retinopathy and the severity of disease using objective data from optical coherence tomography and assess the value of early screening for the toxic effects of hydroxychloroquine. DESIGN, SETTING, AND PARTICIPANTS:Clinical findings in patients with hydroxychloroquine retinopathy were monitored with repeated anatomical and functional examinations for 13 to 40 months after the drug was stopped in a referral practice in a university medical center. Eleven patients participated, with the severity of toxic effects categorized as early (patchy parafoveal damage shown on field or objective testing), moderate (a 50%-100% parafoveal ring of optical coherence tomography thinning but intact retinal pigment epithelium), and severe (visible bull's-eye damage). MAIN OUTCOMES AND MEASURES:Visual acuity, white 10-2 visual field pattern density plots, fundus autofluorescence, spectral-density optical coherence tomography cross sections, thickness (from cube diagrams), and ellipsoid zone length. RESULTS:Visual acuity and visual fields showed no consistent change. Fundus autofluorescence showed little or no change except in severe cases in which the bull's-eye damage expanded progressively. Optical coherence tomography cross sections showed little visible change in early and moderate cases but progressive foveal thinning (approximately 7 μm/y) and loss of ellipsoid zone (in the range of 100 μm/y) in severe cases, which was confirmed by quantitative measurements. The measurements also showed some foveal thinning (approximately 4 μm/y) and deepening of parafoveal loss in moderate cases, but the breadth of the ellipsoid zone remained constant in both early and moderate cases. A few cases showed a suggestion of ellipsoid zone improvement. CONCLUSIONS AND RELEVANCE:Patients with hydroxychloroquine retinopathy involving the retinal pigment epithelium demonstrated progressive damage on optical coherence tomography for at least 3 years after the drug was discontinued, including loss of foveal thickness and cone structure. Cases recognized before retinal pigment epithelium damage retained foveal architecture with little retinal thinning. Early recognition of hydroxychloroquine toxic effects before any fundus changes are visible, using visual fields and optical coherence tomography (along with fundus autofluorescence and multifocal electroretinography as indicated), will greatly minimize late progression and the risk of visual loss.
Evolution of retinal changes measured by optical coherence tomography in the assessment of hydroxychloroquine ocular safety in patients with systemic lupus erythematosus.
Martín-Iglesias D,Artaraz J,Fonollosa A,Ugarte A,Arteagabeitia A,Ruiz-Irastorza G
OBJECTIVE:The objective of this report is to analyse retinal changes over a five-year period, assessed by spectral domain-optical coherence tomography (SD-OCT), in patients from the Lupus-Cruces cohort treated with hydroxychloroquine (HCQ). METHODS:SD-OCT screening was performed annually between 2012 and 2017. Average macular thickness (AMT), ganglion cell layer thickness (GCLT) and qualitative data of retinal pigment epithelium (RPE) and external retina (ExtR) were collected prospectively. We compared data from 2012 (first) and 2017 (second) SD-OCT. RESULTS:We studied 110 patients and 195 eyes. No cases of HCQ toxicity were detected. At the time of the second SD-OCT, 99% patients had taken a daily dose of HCQ ≤5 mg/kg/day. The median time on HCQ was 133 months. The mean AMT and GCLT were significantly lower in both eyes at the second SD-OCT; however, all the differences were clinically insignificant at less than 1%. Qualitative analysis of RPE and ExtR showed no significant changes. Similar results were found among patients with risk factors for retinopathy. The comparison of patients with and without risk factors showed no differences. CONCLUSIONS:This study shows clinically irrelevant retinal changes in an SLE cohort on HCQ treatment over a five-year follow-up. Our findings support the safety of long-term HCQ at doses ≤5 mg/kg/day.
Intravitreal dexamethasone implant therapy for the treatment of cystoid macular Oedema due to hydroxychloroquine retinopathy: a case report and literature review.
Ahn Seong Joon,Joung Jooyoung,Lee Sang Hyup,Lee Byung Ro
BACKGROUND:Cystoid macular oedema (CMO) is an uncommon complication associated with hydroxychloroquine (HCQ) retinopathy threatening central vision. We report a patient with HCQ retinopathy and CMO, for which an intravitreal dexamethasone implant was used, which led to complete resolution of oedema. CASE PRESENTATION:A 57-year-old woman with systemic lupus erythematosus (SLE) complaining of blurred vision in both eyes was diagnosed with bilateral HCQ retinopathy and CMO based on characteristic photoreceptor defects and cystoid spaces on optical coherence tomography, hypo-autofluorescence on fundus autofluorescence, and corresponding visual field defects. After treatment with systemic acetazolamide and topical dorzolamide, CMO showed partial resolution in the right eye. Owing to worsening renal function, an intravitreal dexamethasone implant was placed in the right eye, which resulted in resolution of CMO and visual improvement from 20/50 to 20/30. CONCLUSION:Intravitreal dexamethasone implant may be effective for the treatment of CMO in HCQ retinopathy, particularly for the cases refractory to systemic or topical carbonic anhydrase inhibitors.
[Update on recommendations for screening for hydroxychloroquine retinopathy].
Couturier A,Giocanti-Aurégan A,Dupas B,Girmens J-F,Le Mer Y,Massamba N,Barreau E,Audo I,
Journal francais d'ophtalmologie
INTRODUCTION:Recommendations for screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy have recently been changed by the American Academy of Ophthalmology, taking into account new published data on toxicity prevalence, risk factors, location of onset in the retina and the efficacy of screening tests. METHODS:Literature review. RESULTS AND DISCUSSION:The risk of developing CQ or HCQ retinopathy depends on the daily dose and duration of treatment. At recommended doses, the risk is<1 % at 5 years, <2 % at 10years but increases to about 20 % after 20years of treatment. The maximum recommended daily dose is 5.0mg/kg for HCQ and 2.3mg/kg for CQ. The two main risk factors are the daily dose and duration of treatment. The presence of kidney failure and treatment with tamoxifen are also significant risk factors. A baseline examination should be performed at the initiation of treatment to rule out pre-existing maculopathy. The screening is then annual and starts from the 5th year of treatment. The two tests recommended for screening are the automated visual field and spectral domain OCT. Multifocal ERG and autofluorescence fundus imaging are only carried out secondarily to confirm the pathology.
Early hydroxychloroquine retinopathy: optical coherence tomography abnormalities preceding Humphrey visual field defects.
Garrity Sean T,Jung Joo Yeon,Zambrowski Olivia,Pichi Francesco,Su Daniel,Arya Malvika,Waheed Nadia K,Duker Jay S,Chetrit Yaïr,Miserocchi Elisabetta,Giuffrè Chiara,Kaden Talia R,Querques Giuseppe,Souied Eric H,Freund K Bailey,Sarraf David
The British journal of ophthalmology
BACKGROUND/AIMS:Hydroxychloroquine (HCQ) retinopathy may result in severe and irreversible vision loss, emphasising the importance of screening and early detection. The purpose of this study is to report the novel finding of early optical coherence tomography (OCT) abnormalities due to HCQ toxicity that may develop in the setting of normal Humphrey visual field (HVF) testing. METHODS:Data from patients with chronic HCQ exposure was obtained from seven tertiary care retina centres. Ten patients with HCQ-associated OCT abnormalities and normal HVF testing were identified. Detailed analysis of the OCT findings and ancillary tests including colour fundus photography, fundus autofluorescence, multifocal electroretinography and microperimetry was performed in these patients. RESULTS:Seventeen eyes from 10 patients illustrated abnormalities with OCT and normal HVF testing. These OCT alterations included (1) attenuation of the parafoveal ellipsoid zone and (2) loss of a clear continuous interdigitation zone. Several eyes progressed to advanced parafoveal outer retinal disruption and/or paracentral visual field defects. CONCLUSION:Patients with high risk HCQ exposure and normal HVF testing may develop subtle but characteristic OCT abnormalities. This novel finding indicates that, in some cases of early HCQ toxicity, structural alterations may precede functional impairment. It is therefore important to employ a screening approach that includes OCT to assess for these early findings. Ancillary testing should be considered in cases with suspicious OCT changes and normal HVFs.
The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.
Melles Ronald B,Marmor Michael F
IMPORTANCE:Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques. OBJECTIVES:To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug. DESIGN, SETTING, AND PARTICIPANTS:Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography. EXPOSURE:Hydroxychloroquine use for at least 5 years. MAIN OUTCOMES AND MEASURES:Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence. RESULTS:Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27). CONCLUSIONS AND RELEVANCE:These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss.
Choroidal Thinning Associated With Hydroxychloroquine Retinopathy.
Ahn Seong Joon,Ryu So Jung,Joung Joo Young,Lee Byung Ro
American journal of ophthalmology
PURPOSE:To investigate choroidal thickness in patients using hydroxychloroquine (HCQ) and compare choroidal thickness between eyes with and without HCQ retinopathy. DESIGN:Retrospective case series. METHODS:Setting: Institutional. PATIENTS:We included 124 patients with systemic lupus erythematosus or rheumatoid arthritis who were treated with HCQ. The patients were divided into an HCQ retinopathy group and a control group, according to the presence or absence of HCQ retinopathy. OBSERVATION:Total choroidal thickness and choriocapillaris-equivalent thickness were measured manually by 2 independent investigators using swept-source optical coherence tomography (SS-OCT; DRI-OCT, Topcon Inc, Tokyo, Japan). These measurements were made at the fovea and at nasal and temporal locations 0.5, 1.5, and 3 mm from the fovea. Medium-to-large vessel layer thickness was calculated accordingly. The thicknesses were compared between the HCQ retinopathy and control groups. We performed correlation analyses between choroidal thicknesses and details regarding HCQ use. MAIN OUTCOME MEASURES:Total choroidal thickness and choriocapillaris-equivalent thickness. RESULTS:Choroidal thicknesses were significantly decreased (P < .05) in the HCQ retinopathy group compared to the control group, except at the temporal choroid 1.5 mm from the fovea. Choriocapillaris-equivalent thicknesses were significantly different in all choroidal locations between the groups. In contrast, the medium-to-large vessel layer thickness was only significantly different at a few locations. The cumulative dose/body weight was significantly correlated with subfoveal choroidal and choriocapillaris-equivalent thicknesses (both P = .001). The association between presence of HCQ retinopathy and choroidal thicknesses was also statistically significant after adjusting for age, diagnosis for HCQ use, refractive errors, and duration of HCQ use (P = .001 and P = .003 for subfoveal choroidal and choriocapillaris-equivalent thickness, respectively). CONCLUSIONS:These results all suggest that HCQ retinopathy is associated with choroidal thinning, especially in the choriocapillaris. Our results may suggest choroidal involvement of HCQ toxicity.
En Face Optical Coherence Tomography Imaging of the Photoreceptor Layers in Hydroxychloroquine Retinopathy.
Ahn Seong Joon,Joung Jooyoung,Lee Byung Ro
American journal of ophthalmology
PURPOSE:To investigate the application of en face optical coherence tomography (OCT) imaging in eyes with hydroxychloroquine (HCQ) retinopathy. DESIGN:Retrospective case series. METHODS:Setting: Institutional. PATIENT POPULATION:Sixty-two eyes of 31 Asian patients with HCQ retinopathy. OBSERVATION PROCEDURES:Macular volume scanning using swept-source OCT was performed in 6 × 6-mm and 9 × 9-mm areas centered on the fovea. Segmentation of the photoreceptor layers was automatically performed between the inner border of the ellipsoid zone and that of the retinal pigment epithelium-Bruch membrane complex to obtain en face OCT images. Findings from the en face images were qualitatively and quantitatively evaluated; they were analyzed and correlated with the fundus autofluorescence and visual field findings. MAIN OUTCOME MEASURES:En face OCT findings. RESULTS:All eyes with HCQ retinopathy had a beaten-bronze appearance in the areas with photoreceptor defects, whereas those with intact photoreceptors had areas with smooth surfaces, which were occasionally demarcated by hyporeflective margins, on the en face OCT images. The presence and extent of the retinopathy could be quickly determined using the images. They also provided quantitative information on the progression based on the areas of intact photoreceptors compared over several visits. Furthermore, the area of central intact photoreceptors significantly correlated with the mean deviation, pattern standard deviation, and visual field index of 30-2 visual field examinations (all P < .001). CONCLUSIONS:En face OCT may be useful for visualizing the presence and extent of HCQ retinopathy and its progression. The area of central intact photoreceptors measured on en face OCT images showed a significant association with functional visual field defects. This imaging may be a helpful adjunct for screening and follow-up examinations of HCQ retinopathy.
Rethinking the Hydroxychloroquine Dosing and Retinopathy Screening Guidelines.
Browning David J,Yokogawa Naoto,Greenberg Paul B,Perlman Elliot
American journal of ophthalmology
PURPOSE:To describe the rationale for revising the hydroxychloroquine (HCQ) dosing and screening guidelines and to identify the barriers to more effective guidelines in the future. DESIGN:Literature review. METHODS:A PubMed query of studies on HCQ dosing and HCQ retinopathy (HCQR) screening was conducted with a selective review of the English language literature. RESULTS:Three iterations of the American Academy of Ophthalmology HCQ dosing and HCQR screening guidelines have been published without including prescribing physicians on the writing committees. This may contribute to prescribing physicians' low adherence to the guidelines. As ancillary tests have improved, asymptomatic HCQR is being detected earlier, leading to a higher reported prevalence of HCQR and a drop in the ceiling for safe dosing. These trends put stricter constraints on prescribers and their patients, who may have had well-controlled autoimmune disease on HCQ doses that were previously considered to be below the high-risk threshold for HCQR. Indeed, stopping HCQ at the earliest sign of HCQR should be reconsidered; for cases of early HCQR, dose reduction and more intensive monitoring for retinopathy may strike a more appropriate balance between HCQ risk and benefits. A prospective study using the Diabetic Retinopathy Clinical Research Retina Network with standardized collection of data, HCQ blood levels, centralized grading of ancillary tests, and community and academic ophthalmologists would provide a stronger evidence base for future HCQ guidelines. CONCLUSIONS:The HCQ dosing and screening guidelines should be updated and a prospective study of HCQ dosing and HCQR should be initiated with the joint efforts of ophthalmologists and prescribing physicians.
Structural and Functional Characterization of the Retinal Effects of Hydroxychloroquine Treatment in Healthy Eyes.
Gil Pedro,Nunes André,Farinha Cláudia,Teixeira Dora,Pires Isabel,Silva Rufino
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde
PURPOSE:To evaluate the influence of hydroxychloroquine in visual field and retinal layer thickness. METHODS:This is a retrospective cross-sectional study. Patients taking hydroxychloroquine without signs of hydroxychloroquine retinopathy were included. Optical coherence tomography segmentation was used to obtain the ETDRS map thickness of each retinal layer. Groups were divided into short-term (< 5 years) and long-term (≥5 years) drug use. RESULTS:We included 93 eyes of 93 patients (short-term: 25 eyes; long-term: 68 eyes). The inner nuclear layer (INL) was thinner in the long-term group (32.86 ± 2.12 vs. 34.14 ± 2.37 μm; p = 0.014). Considering long-term cases, the parafoveal ganglion cell layer (GCL) showed an inverse correlation with cumulative dose (r = -0.37; p < 0.001). After adjusting for confounders, parafoveal ganglion cell complex thickness was associated with cumulative dose (β = -0.239; p = 0.011). The parafoveal outer retina and visual field indices were similar between groups and did not correlate with cumulative dose. CONCLUSION:Hydroxychloroquine leads to progressive thinning of the parafoveal inner retina, particularly the INL and GCL. Visual field indices do not reflect the long-term effects of the drug.
Optical Coherence Tomography Protocols for Screening of Hydroxychloroquine Retinopathy in Asian Patients.
Ahn Seong Joon,Joung Jooyoung,Lim Han Woong,Lee Byung Ro
American journal of ophthalmology
PURPOSE:To investigate the distribution of outer retinal changes in hydroxychloroquine (HCQ) retinopathy and explore optical coherence tomography (OCT) protocols to maximize the sensitivity of HCQ retinopathy detection in Asian patients. DESIGN:Diagnostic validity assessment. METHODS:Setting: Institutional. PATIENT POPULATION:Forty-eight eyes (24 patients) with HCQ retinopathy underwent 6-mm horizontal and vertical line scans and 6 × 6-mm volume scans using spectral-domain OCT (SD-OCT), and 9-mm line scans and 6 × 6-mm and 12 × 9-mm volume scans using swept-source OCT (SS-OCT). OBSERVATION PROCEDURES:Distances from the fovea to the defective photoreceptors were measured in the temporal, nasal, superior, and inferior directions from line scan OCT images. The sensitivity of retinopathy detection, indicated by photoreceptor defects, was compared among protocols. MAIN OUTCOME MEASURES:Detection of photoreceptor defects and distances from the fovea to the defects. RESULTS:The average minimum distance from the fovea to an area of photoreceptor defects was 1.84 ± 1.26 mm (mean ± standard deviation). The distances were greater than 3 mm horizontally and vertically in 15 (31.3%) and 17 (35.4%) eyes with HCQ retinopathy, respectively, and only wide-field line or volume scans could detect defects in the eyes. The 9-mm line scans detected HCQ retinopathy significantly better than 6-mm scans (P < .001); the sensitivity of the wide volume scan was significantly greater than the standard volume scan (P = .001). The 12 × 9-mm volume scan detected retinopathy with the greatest sensitivity (100%). CONCLUSIONS:Our study recommends a wide-field OCT scan to screen Asian patients taking HCQ medications.
SEQUENTIAL CHANGES IN HYDROXYCHLOROQUINE RETINOPATHY UP TO 20 YEARS AFTER STOPPING THE DRUG: Implications for Mild Versus Severe Toxicity.
Pham Brandon H,Marmor Michael F
Retina (Philadelphia, Pa.)
PURPOSE:To characterize the stability or progression of different stages of hydroxychloroquine (HCQ) retinopathy up to 20 years after stopping the drug. METHODS:We reviewed findings from 13 patients with initial HCQ retinopathy classified as early (patchy photoreceptor damage), moderate (ring of photoreceptor thinning or scotoma), or severe (retinal pigment epithelial [RPE] damage). Patients had been off HCQ for as many as 14 years at initial examination and were subsequently followed for 5 years to 8 years with repeated fundus autofluorescence and spectral domain optical coherence tomography. RESULTS:Early and moderate cases stabilized in fundus autofluorescence appearance, foveal thickness, ellipsoid zone line length, and visual acuity for up to 9 years after stopping HCQ. By contrast, severe cases demonstrated a continual loss of these parameters for up to 20 years off the drug. The presence of RPE damage at initial examination predicted progressive retinopathy over many years. CONCLUSION:The steady progression of severe HCQ retinopathy in eyes showing RPE damage after drug cessation suggests a metabolic insult that chronically destabilizes rather than destroys cellular function, with a clinical course resembling that of genetic dystrophies. Our findings stress the importance of early detection to minimize progression and visual loss.
Pericentral retinopathy and racial differences in hydroxychloroquine toxicity.
Melles Ronald B,Marmor Michael F
PURPOSE:To describe patterns of hydroxychloroquine retinopathy distinct from the classic parafoveal (bull's eye) maculopathy. DESIGN:Retrospective case series. PARTICIPANTS:Patients from a large multi-provider group practice and a smaller university referral practice diagnosed with hydroxychloroquine retinopathy. Patients with widespread or "end-stage" retinopathy were excluded. METHODS:Review of ophthalmic studies (fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, multifocal electroretinography, visual fields) and classification of retinopathy into 1 of 3 patterns: parafoveal (retinal changes 2°-6° from the fovea), pericentral (retinal changes ≥ 8° from the fovea), or mixed (retinal changes in both parafoveal and pericentral areas). MAIN OUTCOME MEASURES:Relative frequency of different patterns of hydroxychloroquine retinopathy and comparison of risk factors. RESULTS:Of 201 total patients (18% Asian) with hydroxychloroquine retinopathy, 153 (76%) had typical parafoveal changes, 24 (12%) also had a zone of pericentral damage, and 24 (12%) had pericentral retinopathy without any parafoveal damage. Pericentral retinopathy alone was seen in 50% of Asian patients but only in 2% of white patients. Patients with the pericentral pattern were taking hydroxychloroquine for a somewhat longer duration (19.5 vs. 15.0 years, P < 0.01) and took a larger cumulative dose (2186 vs. 1813 g, P = 0.02) than patients with the parafoveal pattern, but they were diagnosed at a more severe stage of toxicity. CONCLUSIONS:Hydroxychloroquine retinopathy does not always develop in a parafoveal (bull's eye) pattern, and a pericentral pattern of damage is especially prevalent among Asian patients. Screening practices may need to be adjusted to recognize pericentral and parafoveal hydroxychloroquine retinopathy.
Evaluation of Retromode Imaging for Use in Hydroxychloroquine Retinopathy.
Ahn Seong Joon,Lee Sang Un,Lee Sang Hyup,Lee Byung Ro
American journal of ophthalmology
PURPOSE:To report on the application of retromode imaging using infrared lasers to eyes with hydroxychloroquine (HCQ) retinopathy, and to compare retromode images with those acquired via conventional objective screening imaging modalities-optical coherence tomography (OCT) and fundus autofluorescence (FAF). DESIGN:Diagnostic validity assessment. METHODS:Setting: Institutional. PATIENT POPULATION:Sixty-two eyes of 31 patients with systemic lupus erythematosus or rheumatoid arthritis who were treated with HCQ and developed HCQ retinopathy (patient group), 270 eyes of 135 patients with the same diseases who were treated with HCQ but exhibit no retinopathy (HCQ-taking control group), and 162 eyes of 81 normal controls (normal control group). OBSERVATION PROCEDURES:Diagnosis of HCQ retinopathy was performed with screening tests recommended by the American Academy of Ophthalmology, including OCT, FAF, and visual field examination. Retromode imaging, using confocal scanning laser ophthalmoscopy, was performed for the patient group and both control groups. The findings on retromode imaging were correlated with outer retinal changes on OCT B-scan images, then compared with the FAF findings. The sensitivity and specificity of retromode imaging were calculated. MAIN OUTCOME MEASURES:Findings of retromode imaging and sensitivity/specificity of the imaging. RESULTS:All patients with HCQ retinopathy showed a parafoveal or pericentral ring-shaped or round area of decreased reflectance with prominent deep choroidal vessels, resulting in 100% sensitivity for the detection of retinopathy. Specificity of the imaging was 73.0% and 76.4% in the HCQ-taking control group and both control groups, respectively. Compared to FAF, retromode imaging enabled the detection of photoreceptor defects with greater sensitivity, particularly in eyes with early retinopathy. However, FAF provided additional information on the status of the retinal pigment epithelium, which could not be discriminated from photoreceptor defects in retromode imaging. CONCLUSIONS:Retromode imaging may be useful for detecting HCQ retinopathy. However, its excellent sensitivity but limited specificity is suggestive of a supplementary role in screening HCQ retinopathy, particularly for early detection.
Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy.
Chandler Laurel C,Yusuf Imran H,McClements Michelle E,Barnard Alun R,MacLaren Robert E,Xue Kanmin
International journal of molecular sciences
Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed.
The effect of oral acetazolamide on cystoid macular edema in hydroxychloroquine retinopathy: a case report.
Hong Eun Hee,Ahn Seong Joon,Lim Han Woong,Lee Byung Ro
BACKGROUND:Hydroxychloroquine (HCQ) retinopathy can accompany other retinal complications such as cystoid macular edema (CME), which leads to central visual loss. We report a case of CME with HCQ retinopathy that improved with the use of oral acetazolamide, and discussed the possible mechanisms of CME in HCQ retinopathy using multimodal imaging modalities. CASE PRESENTATION:A 62-year-old patient with systemic lupus erythematosus (SLE) and HCQ retinopathy developed bilateral CME with visual decline. Fluorescein angiography (FA) showed fluorescein leakage in the macular and midperipheral area. After treatment with oral acetazolamide (250 mg/day) for one month, CME was completely resolved, best corrected visual acuity (BCVA) improved from 20/50 to 20/25, and FA examination showed decreased dye leakage in the macular and midperipheral areas. CONCLUSIONS:In cases of vision loss in HCQ retinopathy, it is important to consider not only progression of maculopathy, but also development of CME, which can be effectively treated with oral acetazolamide.
LONGITUDINAL CHANGES IN EYES WITH HYDROXYCHLOROQUINE RETINAL TOXICITY.
Allahdina Ali M,Chen Katherine G,Alvarez Jason A,Wong Wai T,Chew Emily Y,Cukras Catherine A
Retina (Philadelphia, Pa.)
PURPOSE:To characterize functional and structural changes in hydroxychloroquine (HCQ) retinal toxicity after drug cessation. METHODS:Twenty-two patients (91% female; mean age 58.7 ± 11.4 years; mean duration of HCQ treatment 161.1 ± 90 months; mean dose 5.9 ± 1.9 mg/kg) with detected HCQ retinopathy were monitored for 6 months to 82 months after HCQ cessation with multimodal imaging including spectral domain optical coherence tomography and fundus autofluorescence imaging at 488 nm (standard) and 787 nm (near-infrared autofluorescence). Tests of visual function including visual acuity, Humphrey visual field testing, and multifocal electroretinography (mfERG) were performed. Study eyes were categorized into four separate severity stages by qualitative grading of spectral domain optical coherence tomography macular scans taken at the time of HCQ cessation. Changes in outcome measures between drug cessation and last follow-up visit were computed and compared between eyes of different severity stages. RESULTS:Study eyes (n = 44) were categorized based on optical coherence tomography criteria into: Stage 1 (subtle changes confined to parafoveal region; n = 14), Stage 2 (clear localized changes in parafovea; n = 17), Stage 3 (extensive parafoveal changes; n = 7), and Stage 4 (foveal involvement, n = 6). Visual acuity measurements across follow-up were stable in Stage 1 and Stage 2 eyes but decreased significantly in Stage 3 and 4 eyes. Humphrey visual field measures were also stable in stages 1 and 2 but deteriorated in Stage 3 eyes. mfERG testing demonstrated significant improvement in the R1/R2 ratio after HCQ cessation in Stage 1 eyes (mean change = -0.86 ± 0.79, P = 0.03) but did not change significantly in eyes of higher stages. Decreases in macular thickness in ≥1 of 9 Early Treatment Diabetic Retinopathy Study subfields on spectral domain optical coherence tomography were found in eyes of all stages, with Stage 2 eyes demonstrating thinning in most subfields (eight of nine subfields). In eyes with a measurable central foveal ellipsoid zone band island (9 of 17 Stage 2 eyes and 7 of 7 Stage 3 eyes), progressive decrease in the foveal ellipsoid zone band length was observed in 6 of 9 (67%) Stage 2 eyes and 6 of 7 (86%) Stage 3 eyes. Changes indicative of progressing retinopathy were detected in 17% of Stage 1 eyes, 46% of Stage 2 eyes, and 43% of Stage 3 eyes on standard fundus autofluorescence imaging, and in 17% of Stage 1 eyes, 38% of Stage 2 eyes, and 14% of Stage 3 eyes on near-infrared autofluorescence imaging. CONCLUSION:Eyes with detected HCQ retinopathy do not demonstrate general stability in retinal structure and function after HCQ cessation but instead demonstrate a range of changes during follow-up whose magnitudes correlate with retinopathy severity at the time of cessation. After cessation, eyes with only subtle and localized retinopathy were mostly stable and may show some functional improvement, whereas more severely affected eyes continued to progress. These findings provide evidence that early detection and prompt cessation in HCQ retinopathy may be needed to arrest retinopathy progression and to optimize long-term outcomes.
Hydroxychloroquine Blood Levels Predict Hydroxychloroquine Retinopathy.
Petri Michelle,Elkhalifa Marwa,Li Jessica,Magder Laurence S,Goldman Daniel W
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:In 2016, the American Academy of Ophthalmology (AAO) changed the recommended daily dose of hydroxychloroquine (HCQ) from 6.5 mg/kg to <5 mg/kg. However, it is not clear that the lower prescribed dose of HCQ will have the same efficacy for systemic lupus erythematosus (SLE) activity or the same role in protecting against cardiovascular risk factors and thrombosis. This study was undertaken to address the frequency of HCQ retinopathy and the role of HCQ blood levels in identifying those individuals who are at a greater future risk of retinopathy. METHODS:HCQ blood levels in 537 patients with SLE from a large clinical cohort were repeatedly measured, and patients were tested for HCQ retinopathy. We assessed the risk of retinopathy according to clinical characteristics and blood levels of HCQ. RESULTS:The overall frequency of retinopathy was 4.3% (23 of 537 patients). There was a 1% risk of retinopathy in the first 5 years of HCQ treatment, 1.8% from 6 to 10 years, 3.3% from 11 to 15 years, 11.5% from 16 to 20 years, and 8.0% after 21 years of use. We found that older age (P < 0.0001), higher body mass index (P for trend = 0.0160), and longer duration of HCQ intake (P = 0.0024 and P for trend = 0.0006) were associated with a higher risk of HCQ toxicity. Higher blood levels of HCQ predicted later HCQ retinopathy (P = 0.0124 and P = 0.0340 for mean and maximum HCQ blood levels, respectively). CONCLUSION:Our data prove the utility of assessing blood levels of HCQ in the prediction of retinopathy. This would allow clinicians to either decrease the dose or increase monitoring in those patients with high HCQ blood levels.
Yusuf I H,Sharma S,Luqmani R,Downes S M
Eye (London, England)
Hydroxychloroquine (HCQ; Plaquenil) is used increasingly in the management of a variety of autoimmune disorders, with well established roles in dermatology and rheumatology and emerging roles in oncology. Hydroxychloroquine has demonstrated a survival benefit in patients with systemic lupus erythematosus; some clinicians advocate its use in all such patients. However, Hydroxychloroquine and chloroquine (CQ) have been associated with irreversible visual loss due to retinal toxicity. Hydroxychloroquine retinal toxicity is far more common than previously considered; an overall prevalence of 7.5% was identified in patients taking HCQ for greater than 5 years, rising to almost 20% after 20 years of treatment. This review aims to provide an update on HCQ/CQ retinopathy. We summarise emerging treatment indications and evidence of efficacy in systemic disease, risk factors for retinopathy, prevalence among HCQ users, diagnostic tests, and management of HCQ retinopathy. We highlight emerging risk factors such as tamoxifen use, and new guidance on safe dosing, reversing the previous recommendation to use ideal body weight, rather than actual body weight. We summarise uncertainties and the recommendations made by existing HCQ screening programmes. Asian patients with HCQ retinopathy may demonstrate an extramacular or pericentral pattern of disease; visual field testing and retinal imaging should include a wider field for screening in this group. HCQ is generally safe and effective for the treatment of systemic disease but because of the risk of HCQ retinal toxicity, modern screening methods and ideal dosing should be implemented. Guidelines regarding optimal dosing and screening regarding HCQ need to be more widely disseminated.
[Variability of chloroquine and hydroxychloroquine retinopathy among various ethnicities].
Giocanti-Aurégan A,Couturier A,Girmens J-F,Le Mer Y,Massamba N,Barreau E,Audo I,
Journal francais d'ophtalmologie
INTRODUCTION:Current screening recommendations for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are based on central 10°C static perimetry and a high-resolution SD-OCT with a special attention to the inferior part of the macula where the toxicity usually starts by ellipsoid zone disruption. However, Melles and Marmor, have recently shown a great variability in the topography of the initial toxicity observed among various ethnicities, which is important to keep in mind so as not to miss early toxicity in certain subgroups of patients. METHODS:Review of the literature. RESULTS:Ethnic differences have been shown regarding the topography of the initial retinal toxicity of CQ and HCQ, particularly between Caucasian and Asian subjects. In Caucasians, the first signs of toxicity are more often localized in the inferior para-foveal area associated with a decrease in retinal sensitivity in the upper 10°C visual field. However, in Asian subjects, the first signs of toxicity appear more pericentral (still inferior) with an extramacular pattern that could be missed by the usual 10°C visual field screening. DISCUSSION/CONCLUSION:The pathophysiology of these ethnic differences is unknown and may be due to distinct genetic predisposition to CQ and HCQ toxicity. Screening strategies should be adjusted to the ethnicity and performed in Asian subjects with larger visual fields (30°C), along with SD-OCT, looking for ellipsoid disruption≥8°C from the fovea. The recognition of this pericentral topography and an adjusted screening protocol should avoid late diagnosis in Asians treated with CQ and HCQ.
Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations.
Paniri Alireza,Hosseini Mohammad Mahdi,Rasoulinejad Ahmad,Akhavan-Niaki Haleh
European journal of pharmacology
Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.
Fluorescence Lifetimes in Patients With Hydroxychloroquine Retinopathy.
Solberg Yasmin,Dysli Chantal,Möller Burkhard,Wolf Sebastian,Zinkernagel Martin S
Investigative ophthalmology & visual science
Purpose:To investigate fundus autofluorescence lifetime features in patients with hydroxychloroquine (HCQ) retinopathy, and to identify early markers of retinal alterations in patients due to HCQ. Methods:Patients attending screening for HCQ retinopathy were imaged with a fluorescence lifetime imaging ophthalmoscope. Mean retinal fluorescence lifetimes (Tm) were obtained in a short spectral channel (SSC, 498-560 nm) and a long spectral channel (LSC, 560-720 nm). Screening modalities included fundus images, fundus autofluorescence intensity images (FAF), spectral-domain optical coherence tomography (SD-OCT), visual fields, and multifocal electroretinogram (mfERG). Results:Forty-two eyes of 21 patients on HCQ therapy and 40 eyes of 20 healthy age-matched controls were included. Fourteen eyes of 7 patients with HCQ retinopathy (mean age, 66.1 [SD, 7.7] years) and 28 eyes of 14 patients (mean age, 46.1 [SD, 7.9] years) receiving HCQ without retinopathy were identified. Patients with HCQ retinopathy showed a parafoveal ring-shaped or oval area of prolonged mean fluorescence lifetimes. In these areas, mean (±SEM) lifetimes were 374 ± 7 ps in the SSC, and on average 19.4% longer compared to the control group (P = 0.0001). Patients on HCQ without retinopathy had retinal fluorescence lifetimes that were similar to the control group. Conclusions:This study shows that HCQ retinopathy displays characteristic mean fluorescence lifetimes.
Evaluation of Hydroxychloroquine Retinopathy Using Ultra-Widefield Fundus Autofluorescence: Peripheral Findings in the Retinopathy.
Ahn Seong Joon,Joung Jooyoung,Lee Byung Ro
American journal of ophthalmology
OBJECTIVES:To investigate the application of ultra-widefield fundus autofluorescence (UWF-FAF) imaging in evaluating hydroxychloroquine (HCQ) retinopathy and to report peripheral autofluorescence findings in Asian patients with this condition. DESIGN:Retrospective case series. METHODS:Setting: institutional. PATIENT POPULATION:58 eyes of 29 patients with HCQ retinopathy. OBSERVATION PROCEDURES:UWF-FAF imaging was performed, and the images were compared to conventional FAF images obtained using a confocal digital ophthalmoscope. The sensitivities of detecting retinopathy using the 2 modalities were compared. Peripheral autofluorescence findings in the eyes with HCQ retinopathy were assessed, and their association with the Humphrey visual field test results obtained using the 30-2 and full-field 120 (FF-120) protocols was analyzed. Main outcome measurements were abnormal FAF findings. RESULTS:In 41 of 58 eyes (70.7%) with HCQ retinopathy, abnormal FAF findings were noted in the retinal periphery outside the field of view of conventional FAF as hypoautofluorescent (23 eyes, 39.7%) and hyperautofluorescent (38 eyes, 65.5%) lesions. In 5 eyes (8.6%), differences were revealed between conventional FAF and UWF-FAF in detecting retinopathy. Most of the eyes with severe retinopathy showed the most extensive hypoautofluorescence in the nasal peripheral retina. The areas with abnormal FAF findings were significantly correlated with the number of unseen spots on FF-120 results and mean deviation and pattern standard deviation of the 30-2 test results (all P < .001). CONCLUSIONS:Peripheral autofluorescence findings varied in eyes with HCQ retinopathy according to the severity of the retinopathy. The retinal findings with UWF-FAF were functionally correlated to visual field results. UWF-FAF may be useful for evaluating HCQ retinopathy, particularly in Asian patients.
Frequency and Clinical Characteristics of Hydroxychloroquine Retinopathy in Korean Patients with Rheumatologic Diseases.
Eo Doo Ri,Lee Min Gyu,Ham Don Il,Kang Se Woong,Lee Jaejoon,Cha Hoon Suk,Koh Eunmi,Kim Sang Jin
Journal of Korean medical science
This study aimed to evaluate the frequency and clinical characteristics of hydroxychloroquine (HCQ) retinopathy in Korean patients with rheumatologic diseases. We retrospectively reviewed medical records of 310 patients taking HCQ. Ophthalmic examinations included spectral-domain optical coherence tomography (SD-OCT), automated visual field test, and fundus autofluorescence. The severity of retinopathy was categorized as early, moderate, or severe, and the location was categorized as parafoveal, pericentral, or mixed pattern. Among 310 patients, 9 patients (2.9%) were diagnosed as HCQ retinopathy. Among the patients with HCQ use ≥ 5 years (n = 174), the frequency was 5.2%. Only 1 (11.1%) of the 9 patients was symptomatic. The mean daily dose per kilogram of real body weight of the 9 patients was 5.6 mg, and only 3 had used 6.5 mg or more. Four of the 9 patients had severe HCQ retinopathy. Six of the 9 patients showed pericentral or mixed pattern of retinal damage. Consequently, the frequency of HCQ retinopathy in Korean patients was not low, especially when administered at a high cumulative dose and for a long duration. Screening of HCQ retinopathy by the recommended guidelines that include SD-OCT seems useful and should be done to detect retinal damage earlier in patients with chronic exposure to HCQ.
Quantitative assessment of outer retinal layers and ellipsoid zone mapping in hydroxychloroquine retinopathy.
Ugwuegbu Obinna,Uchida Atsuro,Singh Rishi P,Beven Lucas,Hu Ming,Kaiser Stephanie,Srivastava Sunil K,Ehlers Justis P
The British journal of ophthalmology
BACKGROUND:To quantitatively assess outer retinal layers in eyes with hydroxychloroquine (HCQ) toxicity. METHODS:A retrospective case-control study was performed to identify eyes with HCQ retinopathy/toxicity at Cleveland Clinic. A clinical diagnosis of HCQ retinopathy was made based on clinical and imaging features including the presence of parafoveal ellipsoid zone (EZ) loss on spectral-domain optical coherence tomography (OCT) and visual field defects. All participants underwent macular cube scan using the Cirrus HD-OCT (Zeiss, Oberkochen, Germany). Quantitative assessment of outer nuclear layer (ONL)/Henle fibre layer complex (HFL) metrics and EZ mapping were performed with a novel software platform and compared with age-matched controls. HCQ toxicity group was divided into three subgroups based on the severity. RESULTS:There were 14 eyes from 14 patients in HCQ toxicity group (mean age 57.0±18.6 years), and 14 eyes from 14 subjects in age-matched control group (mean age 59.4±18.6 years). Multiple outer retinal parameters including ONL/HFL-EZ volume, parafoveal ONL/HFL-EZ thickness and EZ-retinal pigment epithelium (RPE) volume were significantly reduced in all HCQ toxicity subgroups (early, moderate and advanced toxicity) compared with controls. Semiautomated layer segmentation tool produced en face representation of EZ-RPE mapping and allowed unique visualisation of EZ attenuation in eyes with HCQ toxicity. The longitudinal analysis of HCQ toxicity group demonstrated progressive decline in some outer retinal parameters. CONCLUSION:HCQ toxicity resulted in significant outer retinal layer volumetric thinning compared with controls. Quantitative assessment of outer retinal parameters and EZ mapping on SD-OCT may become a useful biomarker to identify and monitor HCQ toxicity.
Short-term, high-dose hydroxychloroquine corneal toxicity.
Savage Daniel E,Plotnik Ronald,Wozniak Rachel A F
American journal of ophthalmology case reports
Purpose:To describe the corneal findings and management of a 61-year-old female with vortex keratopathy following short term, high dose hydroxychloroquine used in the setting of a clinical trial for recurrent breast cancer. Observations:The patient was found to have significant corneal vortex keratopathy without retinal pathology within 3 months of 1200 mg daily hydroxychloroquine treatment as an adjuvant medication for cancer therapy. Cessation of the medication led to the resolution of the corneal verticillata within 1 month yet the vision did not return to baseline. Ultimately, remaining irregular astigmatism and ocular surface disease required a scleral contact lens to achieve a BSCVA of 20/25 OU. Conclusions and Importance:Hydroxychloroquine-induced vortex keratopathy is largely considered dose and duration dependent and is uncommon with most standard treatment algorithms. However, with increasing use of high-dose hydroxychloroquine in adjunct cancer therapy, corneal findings are likely to become more frequent. Persistent visual impairment may occur, thus increased understanding of this pathology can aid in counseling patients and guiding treatment recommendations.
Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS-evaluation of whole blood, plasma, and serum as sample matrices.
Carlsson Henrik,Hjorton Karin,Abujrais Sandy,Rönnblom Lars,Åkerfeldt Torbjörn,Kultima Kim
Arthritis research & therapy
BACKGROUND:Hydroxychloroquine (HCQ) is the standard of care in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other inflammatory rheumatic diseases and potentially for the treatment in COVID-19 patients. Determination of HCQ for therapeutic drug monitoring (TDM) can be performed in whole blood (WB), serum, and plasma. Direct comparisons of WB, serum, and plasma levels of HCQ in patients with SLE have not previously been reported. We describe a method for the determination of HCQ in human blood using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and compare the suitability of the three sample matrices. METHODS:A method for the determination of HCQ in human blood using LC-HRMS was developed, validated, and applied for the determination of HCQ levels in WB, serum, and plasma from 26 SLE patients. The reproducibility of the method, in the three matrices, was evaluated using quality control samples and repeated preparations and measurements of patient samples. The performance of the developed method for HCQ measurement in serum was further evaluated by comparison with two previously reported extraction methods. RESULTS:The performance of the presented method demonstrated high accuracy and precision. A large range of HCQ concentrations was observed for the SLE patients in all three matrices (WB, serum, and plasma). The mean levels in WB were approximately two-fold the levels in serum and plasma (813 ng/mL compared to 436 ng/mL and 362 ng/mL, respectively). Spiked quality controls showed high reproducibility for all matrices (coefficient of variation, CV, approx. 5%), whereas in patient samples, equally high-precision was only found using WB as the matrix (CV 3%). The CV for serum and plasma was 14% and 39%, respectively. Two alternative methods applied to serum samples did not demonstrate improved precision. CONCLUSIONS:A LC-HRMS method for the measurement of HCQ in human blood was developed and validated. Whole blood was found to be the superior sample matrix in terms of sample reproducibility. Thus, whole blood samples should be used for HCQ analysis when patients are monitored for HCQ treatment effects. The assay is in clinical use to monitor levels of HCQ in patients.
Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis.
Rempenault Claire,Combe Bernard,Barnetche Thomas,Gaujoux-Viala Cécile,Lukas Cédric,Morel Jacques,Hua Charlotte
Annals of the rheumatic diseases
OBJECTIVE:Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has been shown to improve survival rates in other inflammatory diseases. We aimed to assess the available literature on the cardiovascular impact of HCQ in patients with RA. METHODS:We systematically searched for studies evaluating the effects of HCQ on cardiovascular outcomes of known risk factors for CVD in patients with RA. Databases searched were MEDLINE (via PubMed), EMBase, Cochrane Library and the American College of Rheumatology and European League Against Rheumatism annual meetings. A meta-analysis was performed with a random-effects model, estimating mean differences (MDs), HRs and 95% CIs. Data were extracted by one investigator and independently checked by another. RESULTS:The literature search revealed 185 articles and abstracts of interest; further examination resulted in 16 studies fulfilling the criteria. The MDs between HCQ users and non-users in levels of total, low-density and high-density cholesterol and triglycerides were -9.8 (95% CI -14.0 to -5.6), -10.6 (95% CI -14.2 to -7.0), +4.1 (95% CI 2.2 to 6.0) and -19.2 (95% CI -27.2 to -11.1), respectively. Diabetes incidence was lower for HCQ ever users than never users (HR 0.59 (95% CI 0.49 to 0.70)). HCQ seemed to decrease insulin resistance and incidence of CVD, but data were too few for meta-analysis. CONCLUSION:Besides its limited efficacy for disease activity and progression, HCQ may benefit the metabolic profile and to a lesser extent cardiovascular events in patients with RA, which suggests its usefulness combined with other conventional synthetic disease-modifying antirheumatic drugs.
Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.
Schrezenmeier Eva,Dörner Thomas
Nature reviews. Rheumatology
Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic 'deep' volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug's chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose-response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors.
Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases.
Klinger G,Morad Y,Westall C A,Laskin C,Spitzer K A,Koren G,Ito S,Buncic R J
Lancet (London, England)
Chronic use of chloroquine and hydroxychloroquine inthe treatment of rheumatic disease carries a small risk of sight-threatening pigmentary retinopathy. To obtain safety data for its use in pregnancy, we did ophthalmic examinations in 21 children born to women who took these drugsduring pregnancy. Average daily maternal doses of the two drugs were 317 mg hydroxychloroquine and 332 mg chloroquine. The mean duration of gestational exposure was 7.2 months. No ophthalmic abnormality was detected in these children. Therapeutic use of these drugs during pregnancy may not pose a significant risk of ocular toxicity to offspring.
Hydroxychloroquine retinopathy - implications of research advances for rheumatology care.
Jorge April,Ung Cindy,Young Lucy H,Melles Ronald B,Choi Hyon K
Nature reviews. Rheumatology
Despite advances in therapy for rheumatic diseases, hydroxychloroquine remains almost universally recommended for the treatment of systemic lupus erythematosus (SLE), and is often used in the management of other rheumatic diseases such as rheumatoid arthritis (RA). However, the major dose-limiting toxicity of hydroxychloroquine is retinopathy that can lead to loss of vision. New highly sensitive screening methods can identify early stages of retinopathy, and studies that include these modalities have indicated a substantially higher prevalence of hydroxychloroquine retinopathy than was previously recognized, resulting in revisions to ophthalmology guidelines and the recommendation of a low dose of hydroxychloroquine for many patients. However, the efficacy of low-dose hydroxychloroquine for treating SLE and other rheumatic diseases is unknown. Further studies are required to establish the effectiveness and retinal safety of the latest hydroxychloroquine treatment recommendations.
Signs of hydroxychloroquine toxicity in a patient with rhegmatogenous retinal detachment.
Campos-Pavón J,Sambricio J,Redondo-García I
Archivos de la Sociedad Espanola de Oftalmologia
CLINICAL CASE:The case is presented of a 56 year-old patient diagnosed with rhegmatogenous retinal detachment and on treatment with hydroxychloroquine (HCQ). A Spectral Domain-Optical Coherence Tomography (SD-OCT) was performed that showed changes in the outer retina in the eye with macular detachment, as well as the «flying saucer» sign in the other eye. After a complete retinopexy the «flying saucer» sign was still present. DISCUSSION:SD-OCT could be used as a test in order to reveal HCQ toxicity in the event of retinal detachment. In this case, this technique shows abnormalities such as a hyper-reflective line in the outer retina layers.
Controlled, double-blind, randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in SARS CoV2 infection in healthcare personnel in the hospital setting: A structured summary of a study protocol for a randomised controlled trial.
Cuadrado-Lavín Antonio,Olmos José Manuel,Cifrian José Manuel,Gimenez Teresa,Gandarillas Marco Antonio,García-Saiz Mar,Rebollo Maria Henar,Martínez-Taboada Victor,López-Hoyos Marcos,Fariñas María Carmen,Crespo Javier
BACKGROUND:SARS-CoV-2 infection presents a high transmission in the group of health professionals in Spain (12-15% infected). Currently there is no accepted chemoprophylaxis but hydroxychloroquine (HDQ) is known to inhibit the coronavirus in vitro. Our hypothesis is that oral administration of hydroxychloroquine to healthcare professionals can reduce the incidence and prevalence of infection as well as its severity in this group. METHODS:Design: Prospective, single center, double blind, randomised, controlled trial (RCT). PARTICIPANTS:Adult health-care professionals (18-65 years) working in areas of high exposure and high risk of transmission of SARS-COV-2 (COVID areas, Intensive Care Unit -ICUs-, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. Exclusion criteria include previous infection with SARS CoV2 (positive SARS-CoV-2 PCR or IgG serology), pregnancy or lactation, any contraindication to hydroxychloroquine or evidence of unstable or clinically significant systemic disease. INTERVENTIONS:Patients will be randomized (1:1) to receive once-daily oral Hydroxychloroquine 200mg for two months (HC group) or placebo (P group) in addition to the protective measures appropriate to the level of exposure established by the hospital. A serological evaluation will be carried out every 15 days with PCR in case of seroconversion, symptoms or risk exposure. Primary outcome is the percentage of subjects presenting infection (seroconversion and/or PCR +ve) by the SARS-Cov-2 virus during the observation period. Additionally, both the percentage of subjects in each group presenting Pneumonia with severity criteria (Curb 65 ≥2) and that of subjects requiring admission to ICU will be determined. DISCUSSION:While awaiting a vaccine, hygiene measures, social distancing and personal protective equipment are the only primary prophylaxis measures against SARS-CoV-2, but they have not been sufficient to protect our healthcare professionals. Some evidence of the in vitro efficacy of hydroxychloroquine against this virus is known, along with some clinical data that would support the study of this drug in the chemoprophylaxis of infection. However, there are still no data from controlled clinical trials in this regard. If our hypothesis is confirmed, hydroxychloroquine can help professionals fight this infection with more guarantees. PARTICIPANTS:This is a single-center study that will be carried out at the Marqués de Valdecilla University Hospital. 450 health professionals working at the Hospital Universitario Marqués de Valdecilla in areas of high exposure and high risk of transmission of SARS COV2 (COVID hospital areas, Intensive Care Unit, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. INCLUSION CRITERIA:1) Health professionals aged between 18 and 65 years (inclusive) at the time of the first screening visit; 2) They must provide signed written informed consent and agree to comply with the study protocol; 3) Active work in high exposure areas during the last two weeks and during the following weeks. EXCLUSION CRITERIA:1) Previous infection with SARS CoV2 (positive coronavirus PCR or positive serology with SARS Cov2 negative PCR and absence of symptoms); 2) Current treatment with hydroxychloroquine or chloroquine; 3) Hypersensitivity, allergy or any contraindication for taking hydroxychloroquine, in the technical sheet; 4) Previous or current treatment with tamoxifen or raloxifene; 5) Previous eye disease, especially maculopathy; 6) Known heart failure (Grade III to IV of the New York Heart Association classification) or prolonged QTc; 7) Any type of cancer (except basal cell) in the last 5 years; 6) Refusal to give informed consent; 8) Evidence of any other unstable or clinically significant untreated immune, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric illness; 9) Antibodies positive for the human immunodeficiency virus; 10) Significant kidney or liver disease; 11) Pregnancy or lactation. INTERVENTION AND COMPARATOR:Two groups will be analyzed with a 1: 1 randomization rate. 1)Intervention: (n = 225): One 200 mg hydroxychloroquine sulfate coated tablet once daily for two months.2)Comparator (control group) (n = 225): One hydroxychloroquine placebo tablet (identical to that of the drug) once daily for two months MAIN OUTCOMES: The primary outcome of this study will be to evaluate: number and percentage of healthcare personnel presenting symptomatic and asymptomatic infection (see "Diagnosis of SARS CoV2 infection" below) by the SARS-Cov2 virus during the study observation period (8 weeks) in both treatment arms;number and percentage of healthcare personnel in each group presenting with Pneumonia with severity criteria (Curb 65 ≥2) and number and percentage of healthcare personnel requiring admission to the Intensive Care Unit (ICU) in both treatment arms. DIAGNOSIS OF SARS COV2 INFECTION: Determination of IgA, IgM and IgG type antibodies against SARS-CoV-2 using the Anti-SARS-CoV-2 ELISA kit (EUROIMMUN Medizinische Labordiagnostika AG, Germany) every two weeks. In cases of seroconversion, a SARS-CoV-2 PCR will be performed to rule out / confirm an active infection (RT-PCR in One Step: RT performed with mastermix (Takara) and IDT probes, following protocol published and validated by the CDC Evaluation of COVID-19 in case of SARS-CoV-2 infection RANDOMISATION: Participants will be allocated to intervention and comparator groups according to a balanced randomization scheme (1: 1). The assignment will be made through a computer-generated numeric sequence for all participants BLINDING (MASKING): Both participants and investigators responsible for recruiting and monitoring participants will be blind to the assigned arm. NUMBERS TO BE RANDOMISED (SAMPLE SIZE):Taking into account the current high prevalence of infection in healthcare personnel in Spain (up to 15%), to detect a difference equal to or greater than 8% in the percentage estimates through a two-tailed 95% CI, with a statistical power of 80% and a dropout rate of 5%, a total of 450 participants will need to be included (250 in each arm). TRIAL STATUS:The protocol approved by the health authorities in Spain (Spanish Agency for Medicines and Health Products "AEMPS") and the Ethics and Research Committee of Cantabria (CEIm Cantabria) corresponds to version 1.1 of April 2, 2020. Currently, recruitment has not yet started, with the start scheduled for the second week of May 2020. TRIAL REGISTRATION:Eudra CT number: 2020-001704-42 (Registered on 29 March 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Baseline Retinal Examinations in Patients With Systemic Lupus Erythematosus Newly Initiating Hydroxychloroquine Treatment in a US Medicaid Systemic Lupus Erythematosus Population, 2000-2010.
Lin Tzu-Chieh,Marmor Michael F,Barbhaiya Medha,Guan Hongshu,Chen Sarah K,Feldman Candace H,Costenbader Karen H
Arthritis care & research
OBJECTIVE:Baseline retinal examinations have long been recommended for patients beginning treatment with hydroxychloroquine (HCQ), but it is unknown how well this guideline is followed. We investigated baseline eye examinations among US SLE patients enrolled in Medicaid in whom HCQ treatment was newly initiated. METHODS:Using billing codes, we identified SLE patients ages 18-65 years who were enrolled in Medicaid and residing in the 29 most populated US states, from 2000 to 2010. New users of HCQ were identified by filled prescriptions, with none filled in the preceding 12 months. Retinal examinations that were performed within 30 days before to 1 year after the index prescription were identified. We examined the proportions of patients receiving retinal examinations over the study years and compared the characteristics of those who did and those who did not receive examinations, using bivariable and multivariable logistic regression models. RESULTS:Among 12,755 SLE patients newly starting HCQ treatment, 32.5% received baseline dilated eye examinations. The proportions of patients receiving baseline eye examinations did not significantly change from 2000 to 2010 (31.0-34.4%; P for linear trend = 0.12). Factors associated with an increased likelihood of having an examination included female sex, Asian versus white race, and a higher number of laboratory tests performed during the preceding year. Compared with white patients, lower proportions of black and Native American patients with SLE had baseline retinal examinations. CONCLUSION:Only one-third of patients with SLE enrolled in Medicaid and in whom HCQ was newly initiated received the recommended baseline retinal examinations, and this proportion did not significantly increase from 2000 to 2010. The sociodemographic variation in this recommended care has been observed for other recommended medical care in SLE and requires both further investigation and interventions to address it.
Are the Current Recommendations for Chloroquine and Hydroxychloroquine Screening Appropriate?
Schwartzman Sergio,Samson C Michael
Rheumatic diseases clinics of North America
Hydroxychloroquine and quinacrine are frequently used to treat rheumatic diseases. Ocular toxicity, although infrequent, is one of the potential side effects of antimalarial therapies. Current recommendations are unifocal in being developed by only ophthalmologists who do not treat patients for their rheumatic diseases. The data used to create the recommendations are meager and retrospective. Comanagement of patients with rheumatic disease who are exposed to antimalarial therapies requires a greater interaction between ophthalmologists and rheumatologists.
A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye.
Costedoat-Chalumeau Nathalie,Dunogué Bertrand,Leroux Gaëlle,Morel Nathalie,Jallouli Moez,Le Guern Véronique,Piette Jean-Charles,Brézin Antoine P,Melles Ronald B,Marmor Michael F
Clinical reviews in allergy & immunology
Hydroxychloroquine (HCQ) and chloroquine have been used for more than 50 years to treat systemic lupus erythematosus (SLE) and other rheumatic diseases. In general, these drugs are well tolerated and rarely need to be discontinued because of an adverse systemic reaction. However, both medications can be irreversibly toxic to the retina. A new study indicates that toxicity is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. With attention to dosage and other factors, and with proper screening for early signs of toxicity, HCQ can be prescribed with relative safety even over long periods of time.
Artificial Intelligence for Rapid Meta-Analysis: Case Study on Ocular Toxicity of Hydroxychloroquine.
Michelson Matthew,Chow Tiffany,Martin Neil A,Ross Mike,Tee Qiao Ying Amelia,Minton Steven
Journal of medical Internet research
BACKGROUND:Rapid access to evidence is crucial in times of an evolving clinical crisis. To that end, we propose a novel approach to answer clinical queries, termed rapid meta-analysis (RMA). Unlike traditional meta-analysis, RMA balances a quick time to production with reasonable data quality assurances, leveraging artificial intelligence (AI) to strike this balance. OBJECTIVE:We aimed to evaluate whether RMA can generate meaningful clinical insights, but crucially, in a much faster processing time than traditional meta-analysis, using a relevant, real-world example. METHODS:The development of our RMA approach was motivated by a currently relevant clinical question: is ocular toxicity and vision compromise a side effect of hydroxychloroquine therapy? At the time of designing this study, hydroxychloroquine was a leading candidate in the treatment of coronavirus disease (COVID-19). We then leveraged AI to pull and screen articles, automatically extract their results, review the studies, and analyze the data with standard statistical methods. RESULTS:By combining AI with human analysis in our RMA, we generated a meaningful, clinical result in less than 30 minutes. The RMA identified 11 studies considering ocular toxicity as a side effect of hydroxychloroquine and estimated the incidence to be 3.4% (95% CI 1.11%-9.96%). The heterogeneity across individual study findings was high, which should be taken into account in interpretation of the result. CONCLUSIONS:We demonstrate that a novel approach to meta-analysis using AI can generate meaningful clinical insights in a much shorter time period than traditional meta-analysis.
The eye as the discrete but defensible portal of coronavirus infection.
Coroneo Minas Theodore
The ocular surface
Oculo-centric factors may provide a key to understanding invasion success by SARS-CoV-2, a highly contagious, potentially lethal, virus with ocular tropism. Respiratory infection transmission via the eye and lacrimal-nasal pathway elucidated during the 1918 influenza pandemic, remains to be explored in this crisis. The eye and its adnexae represent a large surface area directly exposed to airborne viral particles and hand contact. The virus may bind to corneal and conjunctival angiotensin converting enzyme 2 (ACE2) receptors and potentially to the lipophilic periocular skin and superficial tear film with downstream carriage into the nasopharynx and subsequent access to the lungs and gut. Adenoviruses and influenza viruses share this ocular tropism and despite differing ocular and systemic manifestations and disease patterns, common lessons, particularly in management, emerge. Slit lamp usage places ophthalmologists at particular risk of exposure to high viral loads (and poor prognosis) and as for adenoviral epidemics, this may be a setting for disease transmission. Local, rather than systemic treatments blocking virus binding in this pathway (advocated for adenovirus) are worth considering. This pathway is accessible with eye drops or aerosols containing drugs which appear efficacious via systemic administration. A combination such as hydroxychloroquine, azithromycin and zinc, all of which have previously been used topically in the eye and which work at least in part by blocking ACE2 receptors, may offer a safe, cost-effective and resource-sparing intervention.
Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19.
Magagnoli Joseph,Narendran Siddharth,Pereira Felipe,Cummings Tammy H,Hardin James W,Sutton S Scott,Ambati Jayakrishna
Med (New York, N.Y.)
Background:Despite limited and conflicting evidence, hydroxychloroquine, alone or in combination with azithromycin, is widely used in COVID-19 therapy. Methods:We performed a retrospective study of electronic health records of patients hospitalized with confirmed SARS-CoV-2 infection in US Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 h of diagnosis were classified based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) or no HC as treatments. The primary outcomes were mortality and use of mechanical ventilation. Findings:A total of 807 patients were evaluated. Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group (adjusted hazard ratio [aHR], 1.83; 95% confidence interval [CI], 1.16-2.89; p = 0.009), but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80-2.15; p = 0.28). Both the propensity-score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group (aHR, 1.19; 95% CI, 0.78-1.82; p = 0.42 and aHR, 2.11; 95% CI, 0.96-4.62; p = 0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72-1.66; p = 0.69 and aHR, 1.25; 95% CI, 0.59-2.68; p = 0.56, respectively) compared to the no HC group. Conclusions:Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin. Funding:University of Virginia Strategic Investment Fund.
Systemic lupus erythematosus and ocular involvement: an overview.
Clinical and experimental medicine
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of undefined etiology and with remarkably heterogeneous clinical features. Virtually any organ system can be affected, including the eye. SLE-related eye involvement can be diagnosed in approximately one-third of the patients and is usually indicative of disease activity. An early diagnosis and the adoption of suitable therapeutic measures are necessary to prevent sight-threatening consequences, especially in patients with juvenile SLE. Periocular lesions, such as eyelid involvement and orbital inflammation, are relatively rare and, in case of orbital masses, may require a biopsy control. Keratoconjunctivitis sicca or secondary Sjögren's syndrome is the most frequent ophthalmic manifestation of SLE. According to its variable severity, lubricating tear drops may be sufficient in mild cases, whereas cyclosporine-A ophthalmic solution, glucocorticoids (GCs), methotrexate, and/or other immunosuppressive drugs may be required in the more severe cases. Partial occlusion of the lacrimal punctum by thermal cautery is rarely applied. Although uncommon, episcleritis and scleritis can sometimes be detected as an initial finding of SLE and reveal themselves as moderate to intense ocular pain, redness, blurred vision, and lacrimation. Unilateral or more often bilateral retinopathy is responsible for visual loss of variable severity and is ascribed to vasculitis of the retinal capillaries and arterioles. In addition to the combined treatment suitable for all patients with active SLE, intravitreal bevacizumab should be considered in cases of severe vaso-occlusive retinopathy and laser photocoagulation in cases of neovascularization. Purtscher-like retinopathy is likely ascribable to the formation of microemboli that results in retinal vascular occlusion and microvascular infarcts. Choroidal disease is characterized by monolateral or bilateral blurred vision. Because of the choroidal effusion, retinal detachment and secondary angle-closure glaucoma may occur. Ischemic optic neuropathy is characterized by acute-onset and progressive binocular visual impairment as a consequence of occlusion of the small vessels of the optic nerves due to immune complex vasculitis. Intravenous GC boluses followed by oral GCs and/or, in case of recurrence, intravenous cyclophosphamide and/or rituximab are commonly employed. Neovascularization can be treated by intravitreal bevacizumab and progression of retinal ischemic areas by retinal laser photocoagulation. Ocular adverse events (AE) have been described following the long-term administration of one or more of the drugs presently used for the treatment of SLE patients. Posterior subcapsular cataracts and secondary open-angle glaucoma are common AE of the prolonged GC administration. The long-term administration of hydroxychloroquine (HCQ) sulfate is well known to be associated with AE, such as vortex keratopathy and in particular the often irreversible and sight-threatening maculopathy. Length of administration > 5 years, > 1000 g total HCQ consumption, > 6.5 mg/kg daily dosing, coexistence of renal disease, and preexisting maculopathy are all considered risk factors for HCQ-induced retinopathy. Ocular AE of additional immunosuppressive and biological agents are still poorly known, given the worldwide more limited experience with their long-term use. A thorough ophthalmological control is strongly recommended at closer intervals for all SLE patients, in step with the total length of exposure to the drugs and the cumulative dose administered.
Ocular manifestations of systemic lupus erythematosus.
Sivaraj R R,Durrani O M,Denniston A K,Murray P I,Gordon Caroline
Rheumatology (Oxford, England)
Ocular manifestations of lupus are fairly common, may be the presenting feature of the disease and can be sight-threatening. Almost any part of the eye and visual pathway can be affected by inflammatory or thrombotic processes. Ocular pain and visual impairment require urgent assessment by an ophthalmologist. Infection should be excluded. Optic neuritis and ischaemic optic neuropathy may be difficult to distinguish. Scleritis and severe retinopathy require systemic immunosuppression but episcleritis, anterior uveitis and dry eyes can usually be managed with local eye drops. Vaso-occlusive disease, particularly in the presence of antiphospholipid antibodies, requires treatment with anticoagulation and proliferative retinopathy is treated with laser therapy. Hydroxychloroquine rarely causes ocular toxicity at doses under 6.5 mg/kg/day. When this has occurred, it has been associated with more than 5 years of drug exposure.