Ronald B. Melles

Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision)

BACKGROUND The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools. PATTERN OF RETINOPATHY Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. DOSE: We recommend a maximum daily HCQ use of ≤5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using ≤2.3 mg/kg real weight. RISK OF TOXICITY The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year. MAJOR RISK FACTORS High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen. SCREENING SCHEDULE A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors. SCREENING TESTS The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus. TOXICITY Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication. COUNSELING Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening.

The Risk of Toxic Retinopathy in Patients on Long-term Hydroxychloroquine Therapy

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 (bulls 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.

Comparative Effectiveness of Antibiotic Prophylaxis in Cataract Surgery.

PURPOSE Intracameral injection is an effective method for preventing infection, but no controlled study has been published in the United States. DESIGN We conducted an observational, longitudinal cohort study to examine the effect of topical and injected antibiotics on risk of endophthalmitis. PARTICIPANTS We identified 315 246 eligible cataract procedures in 204 515 members of Kaiser Permanente, California, 2005-2012. METHODS The study used information from the membership, medical, pharmacy, and surgical records from the electronic health record. MAIN OUTCOME MEASURES The adjusted odds ratio (OR) and 95% confidence interval (CI) for the association of antibiotic prophylaxis (route and agent) with risk of endophthalmitis was estimated using logistic regression analysis. RESULTS We confirmed 215 cases of endophthalmitis (0.07% or 0.7/1000). Posterior capsular rupture was associated with a 3.68-fold increased risk of endophthalmitis (CI, 1.89-7.20). Intracameral antibiotic was more effective than topical agent alone (OR, 0.58; CI, 0.38-0.91). Combining topical gatifloxacin or ofloxacin with intracameral agent was not more effective than using an intracameral agent alone (compared with intracameral only: intracameral plus topical, OR, 1.63; CI, 0.48-5.47). Compared with topical gatifloxacin, prophylaxis using topical aminoglycoside was ineffective (OR, 1.97; CI, 1.17-3.31). CONCLUSIONS Surgical complication remains a key risk factor for endophthalmitis. Intracameral antibiotic was more effective for preventing post-cataract extraction endophthalmitis than topical antibiotic alone. Topical antibiotic was not shown to add to the effectiveness of an intracameral regimen.

Metipranolol-associated Granulomatous Iritis

PURPOSE Topical metipranolol therapy for primary open-angle glaucoma has been associated with anterior granulomatous uveitis in the United Kingdom. We studied granulomatous uveitis reactions to topical metipranolol 0.3% therapy for primary open-angle glaucoma in two patients in the United States. METHODS Two patients, aged 71 and 81 years, were given topical metipranolol 0.3% therapy for primary open-angle glaucoma. RESULTS Both developed granulomatous uveitis. The iritis was associated with an increase in intraocular pressure in both patients and resolved on discontinuation of the drug. One patient was inadvertently rechallenged with metipranolol, and the iritis recurred. CONCLUSIONS Topical metipranolol 0.3% therapy may be associated with the development of granulomatous uveitis and a paradoxical increase in intraocular pressure.

Disparity between Visual Fields and Optical Coherence Tomography in Hydroxychloroquine Retinopathy

PURPOSE American Academy of Ophthalmology recommendations for screening for hydroxychloroquine (HCQ) retinopathy advise objective measures, such as spectral-domain optical coherence tomography (SD-OCT) and multifocal electroretinography (mfERG) along with visual fields. However, the relative sensitivity and specificity of screening tests have not been fully resolved. We characterize a subset of patients with toxicity who show unusual disparity between fields and SD-OCT and thus have implications for screening practice. DESIGN Review of charts and clinical data. PARTICIPANTS Patients at Stanford and Kaiser Permanente who had used HCQ with greater than 1000 g cumulative exposure. There were more than 2000 such individuals, among whom 150 had clear evidence of toxicity. METHODS Patients were evaluated by visual fields (10-2 white Swedish Interactive Threshold Algorithm pattern deviation plots), SD-OCT, and sometimes mfERG or fundus autofluorescence. MAIN OUTCOME MEASURES Relative findings on visual fields in comparison with SD-OCT. RESULTS There were 11 patients among those with HCQ toxicity who had parafoveal ring scotomas but a normal-appearing SD-OCT. None had a history of macular disease or evidence for any other cause of bulls eye maculopathy. Conversely, all cases with a clear degree of parafoveal damage on SD-OCT showed at least some focal spots of parafoveal field loss. CONCLUSIONS Approximately 10% of patients with early HCQ toxicity showed prominent ring scotomas on field testing without obvious SD-OCT abnormality. This should encourage the inclusion of visual fields as a key screening tool, even when SD-OCT (a more specific and objective test) also is performed. The combination of visual fields and SD-OCT gives both sensitivity and specificity while avoiding unnecessary stoppage of the drug.

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10−8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

Pericentral Hydroxychloroquine Retinopathy in Korean Patients

PURPOSE A pericentral pattern of hydroxychloroquine (HCQ) retinopathy recently has been recognized in the United States in patients of Asian heritage. We report on an investigation of this pericentral retinopathy within a Korean population. DESIGN Retrospective, observational study. PARTICIPANTS Patients taking HCQ who were referred to ophthalmology for screening of HCQ retinopathy. METHODS The medical records of patients were reviewed, including spectral domain optical coherence tomography, fundus autofluorescence, and visual fields. MAIN OUTCOME MEASURES Frequency of pericentral pattern of HCQ retinopathy and features of progression. RESULTS Among 218 patients referred, 9 (4.1%) were diagnosed with toxicity. Of these, 8 had a predominantly pericentral pattern of retinal change, whereas only 1 had the classic parafoveal distribution of retinal damage. Progression of retinopathy was documented in 3 patients followed more than 12 months while taking HCQ. No progression was seen in 2 patients without retinal pigment epithelial (RPE) damage who were followed for at least 12 months after discontinuation of HCQ. CONCLUSIONS We found that a pericentral pattern of HCQ retinopathy was predominant among Korean patients, rather than the traditional (bulls eye) parafoveal pattern of damage. Retinopathy progressed while on the drug, but the progression stopped in patients with toxicity detected before RPE damage. These observations suggest the need for new approaches when screening for HCQ toxicity in Asian patients.

Diabetes Pathology and Risk of Primary Open-Angle Glaucoma: Evaluating Causal Mechanisms by Using Genetic Information

Although type 2 diabetes (T2D) predicts glaucoma, the potential for unmeasured confounding has hampered causal conclusions. We performed separate sample genetic instrumental variable analyses using the Genetic Epidemiology Research Study on Adult Health and Aging cohort (n = 69,685; 1995-2013) to estimate effects of T2D on primary open-angle glaucoma (POAG; 3,554 cases). Genetic instrumental variables for overall and mechanism-specific (i.e., linked to T2D via influences on adiposity, β-cell function, insulin regulation, or other metabolic processes) T2D risk were constructed by using 39 genetic polymorphisms established to predict T2D in other samples. Instrumental variable estimates indicated that T2D increased POAG risk (odds ratio = 2.53, 95% confidence interval: 1.04, 6.11). The instrumental variable for β-cell dysregulation also significantly predicted POAG (odds ratioβ-cell = 5.26, 95% confidence interval: 1.75, 15.85), even among individuals without diagnosed T2D, suggesting that metabolic dysregulation may increase POAG risk prior to T2D diagnosis. The T2D risk variant in the melatonin receptor 1B gene (MTNR1B) predicted risk of POAG independently of T2D status, indicating possible pleiotropic physiological functions of melatonin, but instrumental variable effect estimates were significant even excluding MTNR1B variants. To our knowledge, this is the first genetic instrumental variable study of T2D and glaucoma, providing a novel approach to evaluating this hypothesized relationship. Our findings substantially bolster observational evidence that T2D increases POAG risk.

Hydroxychloroquine and the retina.

Hydroxychloroquine sulfate is widely prescribed in the treatment of systemic lupuserythematosus (SLE), rheumatoidarthritis, and related autoimmunediseases, and it has largely superseded the use of chloroquinephosphate for these conditions. Furthermore, hydroxychloroquine isnowbeingevaluated forothermedical uses, including controlofbloodglucose levelsandasanadjunct tochemotherapyfor cancer.Althoughhydroxychloroquinehas relatively fewsystemicadverse effects, a specter of potential retinal toxicity hangs over its use, and regular screening isnecessary todetectearly changes in the retina before vision is compromised.1 The study by Nika et al2 in JAMAOphthalmologyshowsthatdespitetheriskof toxicity,manypatientsusinghydroxychloroquine forSLEandrelateddisordersarestill not seeing eye care professionals or getting appropriate diagnostic tests. This is a wake-up call to physicianswho prescribe this drug. The American Academy of Ophthalmology (AAO) has published guidelines for screening that call for a baseline examination at the start of hydroxychloroquine therapy and then annual screening beginning after 5 years of use.3 Nika et al2 reviewed records from 6339 patients using hydroxychloroquine or chloroquine (98.6% took hydroxychloroquine) in a managed care network. Among new users of these drugs, less than half had a baseline examination (recommended to rule out other macular disease) within the first year of therapy. Among long-term users ( 5 years), one-quarter had no examinations in years 6 and 7. Many of those who did see an eye care professional did not receive visual field testing (a key procedure recommended for screening). Among patients classified to be at “high” risk, one-third had no diagnostic testing at all during the 5 years of the study. Patients under a rheumatologist’s care or with higher education receivedmore screening so that patient understanding appears to be an important component to the maintenance of screening. The disparity between eye care visits during which only basic examinations were performed JAMAOPHTHALMOLOGY

Accuracy of Intraocular Lens Calculation Formulas

PURPOSE To compare the accuracy of intraocular lens (IOL) calculation formulas (Barrett Universal II, Haigis, Hoffer Q, Holladay 1, Holladay 2, Olsen, and SRK/T) in the prediction of postoperative refraction using a single optical biometry device. DESIGN Retrospective consecutive case series. PARTICIPANTS A total of 13 301 cataract operations with an AcrySof SN60WF implant and 5200 operations with a SA60AT implant (Alcon Laboratories, Inc., Fort Worth, TX). METHODS All patients undergoing cataract surgery between July 1, 2014, and December 31, 2015, with Lenstar 900 optical biometry were eligible. A single eye per patient was included in the final analysis, resulting in a total of 18 501 cases. We compared the performance of each formula with respect to the error in predicted spherical equivalent and evaluated the effect of applying the Wang-Koch (WK) adjustment for eyes with axial length >25.0 mm on 4 of the formulas. RESULTS For the SN60WF, the standard deviation of the prediction error, in order of lowest to highest, was the Barrett Universal II (0.404), Olsen (0.424), Haigis (0.437), Holladay 2 (0.450), Holladay 1 (0.453), SRK/T (0.463), and Hoffer Q (0.473), and the results for the SA60AT were similar. The Barrett formula was significantly better than the other formulas in postoperative refraction prediction (P < 0.01) for both IOL types. Application of the WK axial length modification generally resulted in a shift from hyperopic to myopic outcomes in long eyes. CONCLUSIONS Overall, the Barrett Universal II formula had the lowest prediction error for the 2 IOL models studied.