Retinal Toxicity Due to Antimalarials: Frequency and Risk Factors

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(B) Fundus with very slight changes in electroretinography. (C) The visual field showed a dense central scotoma. (D) Fluorescein angiography was unchanged." ] ] ] "textoCompleto" => "IntroductionHobbs in 1959 first reported retinal toxicity due to long term use of chloroquine (CQ).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Currently, sulfate hydroxychloroquine (HCQ) is the most widely used antimalarial agent in the treatment of autoimmune diseases because of its lower incidence of adverse reactions although, like CQ, may produce ocular toxicity due to corneal and retinal deposition. Retinal involvement produces irreversible changes in vision and the patient may not perceive this, so regular eye tests are recommended.Due to the difference found in the various studies and their frequent use in rheumatology, we is study to analyze the frequency of retinal toxicity and to identify associated risk factors in patients treated with antimalarials in the rheumatology clinic.MethodsPatientsWe performed a retrospective study of 40 patients treated with antimalarials (CQ and HCQ) in the Rheumatology clinic and who were referred for consultation to Ophthalmology in 2011 followed systematically after a year of treatment to rule out ocular toxicity.Inclusion criteria were: patients older than 18 years, current treatment with antimalarial due to rheumatic disease and who underwent an ophthalmologic examination in 2011. 2 patients were excluded prior to retinal disease (one was a drug user and another had a macular pseudoulcer), so the sample was 38 patients.All patients signed informed consent and the study was conducted according to the Declaration of Helsinki.Measurements and Data CollectionThe primary endpoint was defined as retinal toxicity secondary to drug damage, detected by alterations in at least 2 of the following tests: fundus examination, visual field with a macular pattern, optical coherence spectral domain tomography (SD-OCT) and full-field electroretinography or full-field (ERG), following the recommendations of the American Academy of Ophthalmology published in 2011.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>All patients were assessed for visual acuity in both eyes and underwent a slit lamp examination of the fundus under dilation and optical coherence tomography. In patients with suspected antimalarial toxicity using fundus examination and/or SD-OCT, we performed a visual field pattern covering the 10° macular central areas and ERG.The secondary variables considered were: type of drug, daily and accumulated dose of CQ and HCQ, duration of treatment and renal function by serum creatinine determination.AnalysisThe analysis of the association between retinal toxicity and antimalarial use was assessed by Chi-square test for qualitative variables and Student's t test for quantitative variables, with a confidence interval (CI) of 95%. The subanalysis of patients with retinal toxicity was performed using Fisher's exact test. Statistical analysis was performed using SPSS version 15.0 (Chicago). Statistical significance was considered at P<.05.ResultsThe sociodemographic characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. 81.6% of patients were treated with HCQ, average daily dose 254mg mean cumulative dose±SD 251.3±182.2g. The average daily dose of CQ was 250mg and the mean cumulative dose was 371.5±377.2g. The mean treatment duration was 3.17±2.5 years. In all cases creatinine levels were normal.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Retinal toxicity was detected in 5 of the patients evaluated (13.1%, 95%, 5%–21%). Three were treated with HCQ, with an average daily dose of 333mg and cumulative dose of 111g, and 2 treated with CQ, with an average daily dose of 250mg and cumulative dose of 230g. Four patients with retinal toxicity had a history of hypertension and 3 were taking corticosteroids at a dose less than 10mg or equivalent of prednisone/day. The 5 patients had an impaired SD-OCT while only 2 cases had the typical fundus image of bull's-eye maculopathy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In the other 3 patients we detected alterations in the visual field and only 2 of these 3 had alterations in the ERG.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Using the SD-OCT we found alterations in the inner layers of the retina at the IS/OS line (junction of inner and outer segments of photoreceptors) consisting subfoveal hyperreflectivity with a double image line parallel to retinal pigment epithelium. In the visual field, the observed defect was variable depending on the degree of involvement, finding sensitivity decreased in the Bebie curve in the central visual field and an increase in mean defect and loss of variance. Using the ERG we observed low amplitude bilaterally in the electrical response of the retina.No statistically significant association was found between retinal toxicity and type of drug. However, when analyzing separately the 7 patients treated with CQ we observed that 42.9% of them had an altered SD-OCT, P=.06.We found a positive relationship between retinal toxicity and hypertension (P<.05). No significant association between retinal involvement and corticosteroid use, diabetes mellitus, age and sex of the patient, baseline rheumatic disease, duration and cumulative daily dose or treatment with antimalarials was seen.DiscussionOur study showed a frequency of retinal toxicity in patients treated with antimalarials of 13.1%, with a greater tendency in patients treated with CQ. This frequency was higher than that found in most previous studies except<a class="elsevierStyleCrossRefs" href="#bib0005">1,3,4</a> Kobak et al.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> This may be due to the absence of standardized assessments to detect retinal toxicity, unlike our study where we followed the recommendations of the American Academy of Ophthalmology regarding screening of patients treated with antimalarials, and the use of new diagnostic methods of high precision (SD-OCT, ERG) which allow early detection. Thus, all patients underwent a fundus exam and SD-OCT, making it possible to identify a greater number of patients with retinal involvement. Moreover, Kobak et al. recognize that their study population may present a greater severity coming from a clinical research environment, which would explain why the frequency of retinopathy is greater.Compared to patients in terms of the antimalarial used, we observed that patients treated with CQ tended to have an increased risk of retinal toxicity, and if the group had undergone a broader study it is likely that the difference had reached significance.Among the factors associated with retinal toxicity, the most important were antimalarial treatment duration and daily dose, although we found conflicting results in different studies. In our study only found a positive association between retinal toxicity and hypertension. The induction of oxidative stress and endothelial dysfunction when there was hypertension<a class="elsevierStyleCrossRef" href="#bib0030">6</a> could explain this finding, as it has been demonstrated that the two processes act as promoters of vascular damage and progressive atherosclerotic and thrombotic complications in vascular walls.Regarding the clinical implications of our findings, all patients in whom retinal toxicity was detected were removed from antimalarial treatment, changing to other immunosuppressive drug for the underlying disease. In the 3 cases we detected early stage retinal toxicity by SD-OCT, without the typical bulls-eye maculopathy, with no significant changes in visual acuity that could affect the quality of life of patients.Our study is not without limitations. First is the retrospective design. And, second is the sample size, which could condition the failure to identify risk factors associated with retinal toxicity secondary to antimalarial drugs.However, the ophthalmologic evaluation sets our study apart from previous studies. Furthermore, in 3 of the 5 patients with retinal toxicity, SD-OCT was crucial because there were no other significant changes. Therefore, early changes in the outer layers of the retina assist the early detection of retinal toxicity and is particularly useful as SD-OCT is available in most hospitals and is highly sensitive and easy to perform in the clinical practice. In patients with SD-OCT and an altered visual field, the ERG helped confirm early stage toxicity.In summary, the frequency of antimalarial retinal toxicity in our study was high, with a tendency to an increased risk in patients treated with CQ. An associated risk factor was hypertension, although this finding should be confirmed in future studies. We believe that standardized screening of patients treated with antimalarials is essential for early detection of retinal toxicity, although prospective studies are needed with larger sample sizes with new techniques available to confirm the results obtained.Ethical ResponsibilitiesProtection of people and animalsThe authors declare that procedures conformed to the ethical standards of the committee responsible for human experimentation and were in accordance with the World Medical Association Declaration of Helsinki.Data confidentialityThe authors declare that they have followed the protocols of their workplace regarding the publication of data from patients and all patients included in the study have received sufficient information and gave their written informed consent to participate in this study.Right to privacy and informed consentThe authors have obtained informed consent from patients and/or subjects referred to in the article. This document is in the possession of the author of correspondence.Conflicts of InterestThe authors have no disclosures to make." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres326519" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objective" 2 => "Material and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec308024" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres326520" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivo" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec308025" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Measurements and Data Collection" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:3 [ "identificador" => "sec0040" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Protection of people and animals" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Data confidentiality" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-07-27" "fechaAceptado" => "2012-10-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec308024" "palabras" => array:4 [ 0 => "Chloroquine" 1 => "Hydroxychloroquine" 2 => "Retinal toxicity" 3 => "Antimalarial" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec308025" "palabras" => array:4 [ 0 => "Cloroquina" 1 => "Hidroxicloroquina" 2 => "Toxicidad retiniana" 3 => "Antipalúdicos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ObjectiveTo study the frequency of retinal toxicity and associated risk factors in a cohort of patients treated with antimalarials and seen at a tertiary level hospital. Material and methodsRetrospective study of 40 patients treated with antimalarials, who were referred to ophthalmology for the study of retinal toxicity during 2011. Data collection included type of antimalarial prescribed, daily and cumulative doses, presence of rheumatic disease, corticosteroid use, associated diseases and ophthalmologic examination. Retinal toxicity was confirmed if two of the following tests were altered: fundus examination, visual field with a macular pattern, changes in spectral domain optical coherence tomography (SD-OCT) and full-field electroretinography (ERG). ResultsToxic retinopathy was detected in 13.1% of patients (95% confidence interval 5%–21%) and a trend for a higher risk was observed in case of chloroquine (CQ) treatment. Among the patients with retinopathy, the mean cumulative dose was 229g for CQ and 111g for Hydroxychloroquine (HCQ), and the mean daily dose of CQ was 250mg and 333mg for HCQ. Arterial hypertension had a statistically significant effect on retinopathy development. ConclusionsToxic retinopathy defined by ophthalmological evaluation was detected in 13.1% of patients. A trend for a higher risk was observed in case of chloroquine treatment." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ObjetivoEstudiar la frecuencia de toxicidad retiniana y factores de riesgo asociados en una cohorte de pacientes tratados con antipalúdicos de un hospital comarcal. Material y métodosEstudio retrospectivo de 40 pacientes. Se recogieron: tipo de antipalúdico, dosis diaria y acumulada, enfermedad reumatológica de base, patología concomitante y estudio oftalmológico. Se definió toxicidad retiniana como alteración en 2 de las 4 siguientes pruebas: examen de fondo de ojo, campo visual con patrón macular, tomografía de coherencia óptica de dominio espectral (SD-OCT) y electroretinografía de campo completo (ERG). ResultadosLa frecuencia de toxicidad retiniana fue 13.1% (95% intervalo de confianza [IC] 5-21%) con tendencia a un mayor riesgo en los pacientes en tratamiento con cloroquina. En estos pacientes con toxicidad retiniana, la dosis media acumulada de Cloroquina (CQ) fue de 229g y la de Hidroxicloroquina (HCQ) de 111g. La dosis media diaria de CQ fue de 250mg y la de HCQ fue de 333mg. Encontramos asociación positiva entre toxicidad retiniana e hipertensión arterial. ConclusionesLa frecuencia de toxicidad retiniana, valorada objetivamente mediante técnicas oftalmológicas, fue alta, con una mayor tendencia en pacientes en tratamiento con cloroquina." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Palma Sánchez D, et al. Toxicidad retiniana por antipalúdicos: frecuencia y factores de riesgo. Reumatol Clin. 2013;9:259–262." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1570 "Ancho" => 3000 "Tamanyo" => 429510 ] ] "descripcion" => array:1 [ "en" => "(A) OCT: loss of foveal depression and separation of the outer layers of the retina. (B) Fundus with very slight changes in electroretinography. (C) The visual field showed a dense central scotoma. (D) Fluorescein angiography was unchanged." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "MCTD, mixed connective tissue disease; ERG, electroretinogram; g, grams; SLE, systemic lupus erythematosus; mg, milligram; SD-OCT, spectral domain optical coherence tomography.Quantitative variables are expressed as mean±standard deviation (SD) and qualitative variables as n (%)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Total sample \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Retinal toxicity \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean age, years±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53.2±14.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.0±10.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gender; n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women, 31 (81.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women, 5 (100) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No. treatments of hydroxychloroquine, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (81.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (40) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chloroquine average daily dose, mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">250 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">250 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean cumulative dose of chloroquine, g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">371.6±377.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">229.9±455.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Average daily dose of hydroxychloroquine, mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">254 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">333 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean cumulative dose of hydroxychloroquine, g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">251.3±182.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110.0±106.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Duration of treatment, years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.2±2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.8±4.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rheumatic disease</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rheumatoid arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (41) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (60) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLE, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (33.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (40) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Osteoarthritis, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (7.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sjögren syndrome, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (5.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MCTD, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (5.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (5.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Concomitant corticosteroid treatment, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (60) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypertension, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (28.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (80) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes mellitus, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (13.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic/renal disease, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complementary examinations</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive SD-OCT, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (15.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (100) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive ERG, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (7.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (60) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive fundus, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (13.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (40) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab477075.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline Characteristics of Patients." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ocular side effects of antirheumatic medications: what a rheumatologist should know" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "V. 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Original Article

Retinal Toxicity Due to Antimalarials: Frequency and Risk Factors

Toxicidad retiniana por antipalúdicos: frecuencia y factores de riesgo

Deseada Palma Sáncheza,

Corresponding author

d_esiree@hotmail.com

Corresponding author.

, Elena Rubio Velazquezb, Sandra Soro Marína, Rebeca Reyes Garcíac

a Servicio de Reumatología, Rafael Mendez, Lorca, Murcia, Spain

b Servicio de Oftalmología, Hospital Rafael Mendez, Lorca, Murcia, Spain

c Unidad de Endocrinología, Hospital Rafael Mendez, Lorca, Murcia, Spain

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        "titulo" => "Toxicidad retiniana por antipal&#250;dicos&#58; frecuencia y factores de riesgo"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; OCT&#58; loss of foveal depression and separation of the outer layers of the retina&#46; &#40;B&#41; Fundus with very slight changes in electroretinography&#46; &#40;C&#41; The visual field showed a dense central scotoma&#46; &#40;D&#41; Fluorescein angiography was unchanged&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hobbs in 1959 first reported retinal toxicity due to long term use of chloroquine &#40;CQ&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Currently&#44; sulfate hydroxychloroquine &#40;HCQ&#41; is the most widely used antimalarial agent in the treatment of autoimmune diseases because of its lower incidence of adverse reactions although&#44; like CQ&#44; may produce ocular toxicity due to corneal and retinal deposition&#46; Retinal involvement produces irreversible changes in vision and the patient may not perceive this&#44; so regular eye tests are recommended&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Due to the difference found in the various studies and their frequent use in rheumatology&#44; we is study to analyze the frequency of retinal toxicity and to identify associated risk factors in patients treated with antimalarials in the rheumatology clinic&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0015" class="elsevierStylePara elsevierViewall">We performed a retrospective study of 40 patients treated with antimalarials &#40;CQ and HCQ&#41; in the Rheumatology clinic and who were referred for consultation to Ophthalmology in 2011 followed systematically after a year of treatment to rule out ocular toxicity&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Inclusion criteria were&#58; patients older than 18 years&#44; current treatment with antimalarial due to rheumatic disease and who underwent an ophthalmologic examination in 2011&#46; 2 patients were excluded prior to retinal disease &#40;one was a drug user and another had a macular pseudoulcer&#41;&#44; so the sample was 38 patients&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">All patients signed informed consent and the study was conducted according to the Declaration of Helsinki&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Measurements and Data Collection</span><p id="par0030" class="elsevierStylePara elsevierViewall">The primary endpoint was defined as retinal toxicity secondary to drug damage&#44; detected by alterations in at least 2 of the following tests&#58; fundus examination&#44; visual field with a macular pattern&#44; optical coherence spectral domain tomography &#40;SD-OCT&#41; and full-field electroretinography or full-field &#40;ERG&#41;&#44; following the recommendations of the American Academy of Ophthalmology published in 2011&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">All patients were assessed for visual acuity in both eyes and underwent a slit lamp examination of the fundus under dilation and optical coherence tomography&#46; In patients with suspected antimalarial toxicity using fundus examination and&#47;or SD-OCT&#44; we performed a visual field pattern covering the 10&#176; macular central areas and ERG&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The secondary variables considered were&#58; type of drug&#44; daily and accumulated dose of CQ and HCQ&#44; duration of treatment and renal function by serum creatinine determination&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The analysis of the association between retinal toxicity and antimalarial use was assessed by Chi-square test for qualitative variables and Student&#39;s <span class="elsevierStyleItalic">t</span> test for quantitative variables&#44; with a confidence interval &#40;CI&#41; of 95&#37;&#46; The subanalysis of patients with retinal toxicity was performed using Fisher&#39;s exact test&#46; Statistical analysis was performed using SPSS version 15&#46;0 &#40;Chicago&#41;&#46; Statistical significance was considered at <span class="elsevierStyleItalic">P</span>&#60;&#46;05&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">The sociodemographic characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; 81&#46;6&#37; of patients were treated with HCQ&#44; average daily dose 254<span class="elsevierStyleHsp" style=""></span>mg mean cumulative dose&#177;SD 251&#46;3&#177;182&#46;2<span class="elsevierStyleHsp" style=""></span>g&#46; The average daily dose of CQ was 250<span class="elsevierStyleHsp" style=""></span>mg and the mean cumulative dose was 371&#46;5&#177;377&#46;2<span class="elsevierStyleHsp" style=""></span>g&#46; The mean treatment duration was 3&#46;17&#177;2&#46;5 years&#46; In all cases creatinine levels were normal&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Retinal toxicity was detected in 5 of the patients evaluated &#40;13&#46;1&#37;&#44; 95&#37;&#44; 5&#37;&#8211;21&#37;&#41;&#46; Three were treated with HCQ&#44; with an average daily dose of 333<span class="elsevierStyleHsp" style=""></span>mg and cumulative dose of 111<span class="elsevierStyleHsp" style=""></span>g&#44; and 2 treated with CQ&#44; with an average daily dose of 250<span class="elsevierStyleHsp" style=""></span>mg and cumulative dose of 230<span class="elsevierStyleHsp" style=""></span>g&#46; Four patients with retinal toxicity had a history of hypertension and 3 were taking corticosteroids at a dose less than 10<span class="elsevierStyleHsp" style=""></span>mg or equivalent of prednisone&#47;day&#46; The 5 patients had an impaired SD-OCT while only 2 cases had the typical fundus image of bull&#39;s-eye maculopathy &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In the other 3 patients we detected alterations in the visual field and only 2 of these 3 had alterations in the ERG&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Using the SD-OCT we found alterations in the inner layers of the retina at the IS&#47;OS line &#40;junction of inner and outer segments of photoreceptors&#41; consisting subfoveal hyperreflectivity with a double image line parallel to retinal pigment epithelium&#46; In the visual field&#44; the observed defect was variable depending on the degree of involvement&#44; finding sensitivity decreased in the Bebie curve in the central visual field and an increase in mean defect and loss of variance&#46; Using the ERG we observed low amplitude bilaterally in the electrical response of the retina&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">No statistically significant association was found between retinal toxicity and type of drug&#46; However&#44; when analyzing separately the 7 patients treated with CQ we observed that 42&#46;9&#37; of them had an altered SD-OCT&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;06&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">We found a positive relationship between retinal toxicity and hypertension &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;05&#41;&#46; No significant association between retinal involvement and corticosteroid use&#44; diabetes mellitus&#44; age and sex of the patient&#44; baseline rheumatic disease&#44; duration and cumulative daily dose or treatment with antimalarials was seen&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Our study showed a frequency of retinal toxicity in patients treated with antimalarials of 13&#46;1&#37;&#44; with a greater tendency in patients treated with CQ&#46; This frequency was higher than that found in most previous studies except<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;4</span></a> Kobak et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This may be due to the absence of standardized assessments to detect retinal toxicity&#44; unlike our study where we followed the recommendations of the American Academy of Ophthalmology regarding screening of patients treated with antimalarials&#44; and the use of new diagnostic methods of high precision &#40;SD-OCT&#44; ERG&#41; which allow early detection&#46; Thus&#44; all patients underwent a fundus exam and SD-OCT&#44; making it possible to identify a greater number of patients with retinal involvement&#46; Moreover&#44; Kobak et al&#46; recognize that their study population may present a greater severity coming from a clinical research environment&#44; which would explain why the frequency of retinopathy is greater&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Compared to patients in terms of the antimalarial used&#44; we observed that patients treated with CQ tended to have an increased risk of retinal toxicity&#44; and if the group had undergone a broader study it is likely that the difference had reached significance&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Among the factors associated with retinal toxicity&#44; the most important were antimalarial treatment duration and daily dose&#44; although we found conflicting results in different studies&#46; In our study only found a positive association between retinal toxicity and hypertension&#46; The induction of oxidative stress and endothelial dysfunction when there was hypertension<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> could explain this finding&#44; as it has been demonstrated that the two processes act as promoters of vascular damage and progressive atherosclerotic and thrombotic complications in vascular walls&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding the clinical implications of our findings&#44; all patients in whom retinal toxicity was detected were removed from antimalarial treatment&#44; changing to other immunosuppressive drug for the underlying disease&#46; In the 3 cases we detected early stage retinal toxicity by SD-OCT&#44; without the typical bulls-eye maculopathy&#44; with no significant changes in visual acuity that could affect the quality of life of patients&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Our study is not without limitations&#46; First is the retrospective design&#46; And&#44; second is the sample size&#44; which could condition the failure to identify risk factors associated with retinal toxicity secondary to antimalarial drugs&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">However&#44; the ophthalmologic evaluation sets our study apart from previous studies&#46; Furthermore&#44; in 3 of the 5 patients with retinal toxicity&#44; SD-OCT was crucial because there were no other significant changes&#46; Therefore&#44; early changes in the outer layers of the retina assist the early detection of retinal toxicity and is particularly useful as SD-OCT is available in most hospitals and is highly sensitive and easy to perform in the clinical practice&#46; In patients with SD-OCT and an altered visual field&#44; the ERG helped confirm early stage toxicity&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In summary&#44; the frequency of antimalarial retinal toxicity in our study was high&#44; with a tendency to an increased risk in patients treated with CQ&#46; An associated risk factor was hypertension&#44; although this finding should be confirmed in future studies&#46; We believe that standardized screening of patients treated with antimalarials is essential for early detection of retinal toxicity&#44; although prospective studies are needed with larger sample sizes with new techniques available to confirm the results obtained&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ethical Responsibilities</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Protection of people and animals</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors declare that procedures conformed to the ethical standards of the committee responsible for human experimentation and were in accordance with the World Medical Association Declaration of Helsinki&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data confidentiality</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their workplace regarding the publication of data from patients and all patients included in the study have received sufficient information and gave their written informed consent to participate in this study&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Right to privacy and informed consent</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors have obtained informed consent from patients and&#47;or subjects referred to in the article&#46; This document is in the possession of the author of correspondence&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of Interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors have no disclosures to make&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To study the frequency of retinal toxicity and associated risk factors in a cohort of patients treated with antimalarials and seen at a tertiary level hospital&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective study of 40 patients treated with antimalarials&#44; who were referred to ophthalmology for the study of retinal toxicity during 2011&#46; Data collection included type of antimalarial prescribed&#44; daily and cumulative doses&#44; presence of rheumatic disease&#44; corticosteroid use&#44; associated diseases and ophthalmologic examination&#46; Retinal toxicity was confirmed if two of the following tests were altered&#58; fundus examination&#44; visual field with a macular pattern&#44; changes in spectral domain optical coherence tomography &#40;SD-OCT&#41; and full-field electroretinography &#40;ERG&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Toxic retinopathy was detected in 13&#46;1&#37; of patients &#40;95&#37; confidence interval 5&#37;&#8211;21&#37;&#41; and a trend for a higher risk was observed in case of chloroquine &#40;CQ&#41; treatment&#46; Among the patients with retinopathy&#44; the mean cumulative dose was 229<span class="elsevierStyleHsp" style=""></span>g for CQ and 111<span class="elsevierStyleHsp" style=""></span>g for Hydroxychloroquine &#40;HCQ&#41;&#44; and the mean daily dose of CQ was 250<span class="elsevierStyleHsp" style=""></span>mg and 333<span class="elsevierStyleHsp" style=""></span>mg for HCQ&#46; Arterial hypertension had a statistically significant effect on retinopathy development&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Toxic retinopathy defined by ophthalmological evaluation was detected in 13&#46;1&#37; of patients&#46; A trend for a higher risk was observed in case of chloroquine treatment&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudiar la frecuencia de toxicidad retiniana y factores de riesgo asociados en una cohorte de pacientes tratados con antipal&#250;dicos de un hospital comarcal&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio retrospectivo de 40 pacientes&#46; Se recogieron&#58; tipo de antipal&#250;dico&#44; dosis diaria y acumulada&#44; enfermedad reumatol&#243;gica de base&#44; patolog&#237;a concomitante y estudio oftalmol&#243;gico&#46; Se defini&#243; toxicidad retiniana como alteraci&#243;n en 2 de las 4 siguientes pruebas&#58; examen de fondo de ojo&#44; campo visual con patr&#243;n macular&#44; tomograf&#237;a de coherencia &#243;ptica de dominio espectral &#40;SD-OCT&#41; y electroretinograf&#237;a de campo completo &#40;ERG&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La frecuencia de toxicidad retiniana fue 13&#46;1&#37; &#40;95&#37; intervalo de confianza &#91;IC&#93; 5-21&#37;&#41; con tendencia a un mayor riesgo en los pacientes en tratamiento con cloroquina&#46; En estos pacientes con toxicidad retiniana&#44; la dosis media acumulada de Cloroquina &#40;CQ&#41; fue de 229<span class="elsevierStyleHsp" style=""></span>g y la de Hidroxicloroquina &#40;HCQ&#41; de 111<span class="elsevierStyleHsp" style=""></span>g&#46; La dosis media diaria de CQ fue de 250<span class="elsevierStyleHsp" style=""></span>mg y la de HCQ fue de 333<span class="elsevierStyleHsp" style=""></span>mg&#46; Encontramos asociaci&#243;n positiva entre toxicidad retiniana e hipertensi&#243;n arterial&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La frecuencia de toxicidad retiniana&#44; valorada objetivamente mediante t&#233;cnicas oftalmol&#243;gicas&#44; fue alta&#44; con una mayor tendencia en pacientes en tratamiento con cloroquina&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Palma S&#225;nchez D&#44; et al&#46; Toxicidad retiniana por antipal&#250;dicos&#58; frecuencia y factores de riesgo&#46; Reumatol Clin&#46; 2013&#59;9&#58;259&#8211;262&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; OCT&#58; loss of foveal depression and separation of the outer layers of the retina&#46; &#40;B&#41; Fundus with very slight changes in electroretinography&#46; &#40;C&#41; The visual field showed a dense central scotoma&#46; &#40;D&#41; Fluorescein angiography was unchanged&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">MCTD&#44; mixed connective tissue disease&#59; ERG&#44; electroretinogram&#59; g&#44; grams&#59; SLE&#44; systemic lupus erythematosus&#59; mg&#44; milligram&#59; SD-OCT&#44; spectral domain optical coherence tomography&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Quantitative variables are expressed as mean&#177;standard deviation &#40;SD&#41; and qualitative variables as n &#40;&#37;&#41;&#46;</p>"
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Retinal toxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">No&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Mean age&#44; years&#177;SD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;2&#177;14&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;0&#177;10&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Gender&#59; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Women&#44; 31 &#40;81&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Women&#44; 5 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">No&#46; treatments of hydroxychloroquine&#44; &#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;81&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Chloroquine average daily dose&#44; mg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Mean cumulative dose of chloroquine&#44; g</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">371&#46;6&#177;377&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">229&#46;9&#177;455&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Average daily dose of hydroxychloroquine&#44; mg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">254&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Mean cumulative dose of hydroxychloroquine&#44; g</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">251&#46;3&#177;182&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">110&#46;0&#177;106&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Duration of treatment&#44; years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;2&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;8&#177;4&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Rheumatic disease</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SLE&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Osteoarthritis&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;7&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sj&#246;gren syndrome&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;5&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>MCTD&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;5&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Other&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;5&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant corticosteroid treatment&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Hypertension&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;28&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Diabetes mellitus&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;13&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Hepatic&#47;renal disease&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Complementary examinations</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Positive SD-OCT&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;15&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Positive ERG&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;7&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2012.10.007

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Year/Month	Html	Pdf	Total

2024 November	6	17	23
2024 October	26	28	54
2024 September	33	22	55
2024 August	67	31	98
2024 July	54	28	82
2024 June	53	38	91
2024 May	60	28	88
2024 April	42	26	68
2024 March	42	25	67
2024 February	48	19	67
2024 January	41	21	62
2023 December	46	20	66
2023 November	42	25	67
2023 October	32	26	58
2023 September	55	36	91
2023 August	24	13	37
2023 July	26	28	54
2023 June	51	23	74
2023 May	36	28	64
2023 April	21	17	38
2023 March	56	41	97
2023 February	37	31	68
2023 January	46	23	69
2022 December	33	38	71
2022 November	38	34	72
2022 October	46	27	73
2022 September	26	28	54
2022 August	33	41	74
2022 July	45	39	84
2022 June	45	42	87
2022 May	60	41	101
2022 April	60	32	92
2022 March	39	44	83
2022 February	37	44	81
2022 January	35	34	69
2021 December	40	33	73
2021 November	43	48	91
2021 October	48	49	97
2021 September	37	42	79
2021 August	39	38	77
2021 July	29	33	62
2021 June	52	42	94
2021 May	51	42	93
2021 April	51	57	108
2021 March	56	23	79
2021 February	30	21	51
2021 January	50	26	76
2020 December	45	29	74
2020 November	30	18	48
2020 October	13	14	27
2020 September	26	23	49
2020 August	29	18	47
2020 July	23	18	41
2020 June	31	19	50
2020 May	31	20	51
2020 April	40	23	63
2020 March	14	10	24
2019 April	2	0	2
2019 January	1	0	1
2018 May	3	1	4
2018 April	39	6	45
2018 March	53	7	60
2018 February	26	4	30
2018 January	22	8	30
2017 December	28	6	34
2017 November	24	8	32
2017 October	35	4	39
2017 September	25	2	27
2017 August	28	7	35
2017 July	24	7	31
2017 June	40	10	50
2017 May	49	8	57
2017 April	29	7	36
2017 March	24	9	33
2017 February	21	3	24
2017 January	28	4	32
2016 December	52	14	66
2016 November	36	10	46
2016 October	42	18	60
2016 September	51	18	69
2016 August	54	20	74
2016 July	37	23	60

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