Retinotoxicity of hydroxychloroquine: is it possible to demonstrate by spectral domain optical coherence tomography before development? A Cross Sectional Investigation.
Optical coherence tomography (OCT) is the primary technique for the evaluation of retinal diseases. It has been recently evolved into the spectral-domain OCT (SD-OCT), which has a 43-100 times faster imaging capacity and higher signal-to noise ratio compared to the time-domain OCT. The inner segment and outer segment lines, external limiting membrane and the inner retinal structure including retinal nerve fiber layer (RNFL) and plexiform layer can be visualized more clearly by SD-OCT with 5 pm axial resolution. Spectral-domain OCT also allows for automatic and manual measurement of the retinal layers and RNFL. (6-8)
In this study, we aimed to measure the retinal layer thicknesses in patients using HCQ and to investigate whether retinal alterations were able to be detected before symptoms and/or signs of retinotoxicity became evident by using SD-OCT.
PATIENTS AND METHODS
A total of 114 female patients on HCQ for the treatment of RA (n=40), SjS (n=47) and CTDs (n=27), including systemic lupus erythematosus and other undefined connective tissue disorders were enrolled in this study. They were selected according to the following inclusion criteria: being 18 years old or older, having less than [+ or -] 6 diopter sphere of refractive error and having the ability to perform visual field testing. Exclusion criteria were as follows: history of CQ consumption, presence of diabetes mellitus, thyroid dysfunction, cataracts, glaucoma, and a history of uveitis or vascular disease which might compromise the ocular structures. Additionally, patients who had any macular autofluorescent abnormality demonstrated by 45 degree fundus autoflorescence imaging and/or any central or paracentral scotoma in central visual field testing were excluded. The SD-OCT database of the Ophthalmology Department of our Institution was used to identify a healthy control group of 87 age-matched females. The mean age of the healthy controls was 46.7 (95% CI: 45.6-47.9) years. On the other hand, the mean ages of HCQ-users were 46.7 (95% CI: 43.8-49.6); 48.7 (95% CI: 46.5-50.8) and 44.9 (95% CI: 41.348.5) years for the RA, SjS and CTD groups, respectively.
Demographic data including age, preliminary diagnosis, dose and total duration of HCQ, weight and height of all patients were recorded. The cumulative dose of consumed HCQ and the dose per kilogram of actual body weight and of lean body mass (1) were calculated. All patients were informed about the study protocol, and their informed consents were obtained. The study was approved by the local ethics committee of the Antalya Training and Research Hospital. A comprehensive ophthalmologic examination was applied for all patients. This examination protocol included the best corrected visual acuity using snellen chart, measurement of intraocular pressure by Goldmann applanation tonometry, 12-degree visual field perimetry with a white stimulus by using Octopus 900 (Interzeag AG, Schlieren- Zurich, Swiss). Fundus autofluorescence imaging and color fundus photography were recorded by using the Visucam NM FA (Carl Zeiss Meditec AG., Jena, Germany) with 45 degree fundus camera mode. The limits for the wavelength of the excitation light were between 510 nm and 580 nm; and those for the wavelength of the barrier filter were between 650 nm and 735 nm. At least five autofluorescence imaging shots were taken with a pupil width of at least 6 mm to obtain high-quality images.
Spectral-domain OCT imaging was applied by using the Cirrus HD OCT (Cirrus Carl Zeiss Meditec Inc., Dublin CA, USA). SD-OCT examination was performed according to three different protocols: the first one was the "macular cube 512x128 protocol" in which retinal thickness was measured in each of the nine regions quantitatively (Figure 1). The second one was the "optic disc cube protocol" in which the peripapillary retinal nerve fiber thickness was measured in each of four (superior, inferior, nasal, temporal) quadrants. The third protocol was the "horizontal and vertical HD five line raster scan" which comprised of 4,096 axial scan in each line. The distance between each individual scan was 0.5 mm. In this protocol, manual measurement of the outer retinal layer thickness (OLT) was performed at a point in the central fovea from internal limiting membrane (ILM) to the apex of retinal pigmented epithelium (RPE) by an ophtalmologist who was blinded to the primary diagnosis and drug consumption properties of the subjects. Additional measurements were performed at points 1 and 2 mm distance to the central fovea (from the outer plexiform layer to the apex of the retina with pigmented epithelium) in each quadrant by using computer-based caliper measurement tool of the SD-OCT system. The measured thicknesses at 1 and 2 mm distances from central fovea were named parafovea and perifovea, respectively (Figure 2). The arithmetic means of these two measurements were calculated.
Statistical analysis was performed using SPSS (SPSS Inc., Chicago, IL, USA) for Windows v13.0 software. The Student's t-test was used to compare the means of continuous variables between the two different groups. One-way analysis of variance (ANOVA) with post-hoc Bonferroni correction was used to compare the means of measured parameters among three or more different groups. The Pearson's correlation analysis was used to define the relationship of retinal thicknesses with drug dose and duration of drug consumption. A cut-off value of 0.05 was considered statistically significant.
There was no significant difference between the mean ages of the study and healthy control groups. The cumulative dose of consumed drug and total duration of drug consumption were higher among the subjects with CTD than in the others (Table 1).
Statistical analysis was performed by considering the measurements of both eyes of each subjects. Therefore, the number was doubled for each subjects enrolled in the study. Comparison of the foveal thickness among healthy controls and HCQ-users revealed that the outer foveal segments, in particular, tended to be significantly higher in the healthy control group. The central part of the outer fovea was 169.8 [+ or -] 14.8 [micro]m for healthy controls, while that of HCQ-users was 166.0 [+ or -] 14.6 [micro]m (p = 0.013). Measurement of the parafovea revealed 117.5 [+ or -] 10.1 vs. 110.5 [+ or -] 11.0 [micro]m for the former and latter groups, respectively (p = 0.000001) (Table 2). Measurement of the foveal layers revealed that the central area of full foveal thickness was not different among the disease groups. In contrast, the foveal layers were thinner in subjects with CTD compared to healthy controls (Table 3). There was no inner segment/ outer segment band discontinuation in any of the subjects.
Retinal nerve fiber layers of the superior and inferior quadrants were thicker in healthy control subjects compared to HCQ-users (Table 2). When comparison was made among disease groups, RNFL thickness in the superior and inferior quadrants of CTD subjects were 114.7 [micro]m (95% Cl: 110.2-119.3) and 117.0 [micro]m (95% Cl: 112.0-122.0), respectively. These figures were statistically significantly different from the other groups (Table 4).
The cumulative dose of HCQ was found to be correlated with the parafoveal region thickness of OLT (r = -0.192, p<0.001) and inferior quadrant of RNFL (r = -0.104, p<0.05). The OLT in the parafoveal region was found to be correlated with drug dose per kg of actual body weight and per kg of lean body mass (r = -0.159 and -0.173 respectively, p<0.001). Similarly, the OLT in the perifoveal region was found to be correlated with the same parameters (Table 5).
Although the exact pathogenesis of HCQ-induced retinopathy has not been well-established yet, the similarity of the chemical structure and induced-retinopathy of HCQ to CQ suggest that the mechanisms may be analogous. (9) CQ binds to melanin of retinal pigmented epithelium with a high concentration and remains there for a prolonged period of time, even after cessation of therapy. (10) A study demonstrated that CQ disrupted the lysosomal function in retinal neurons and RPE. (11) The retinopathy caused by anti-malarial drugs consists of bilateral macular pigmentary alterations and functional abnormalities in the visual field. Ophthalmoscopic examination may reveal granular pigmentary changes in the form of bull's-eye maculopathy with a circle of RPE atrophy surrounding the central fovea. (12) It was demonstrated that high-speed ultra-high resolution OCT was able to detect the loss of the perifoveal photoreceptor inner segment/ outer segment junction and thinning of the outer nuclear layer in patients receiving HCQ. (13) Retinal thinning was considered to be the earliest indicator of retinopathy. (14) Two histopathological studies performed in humans with advanced CQ-induced retinopathy revealed destruction of the cone and rods, sparing the foveal cones. (15,16) Kahn et al. (17) compared retinal thicknesses at points 0.5 and 1 mm from the foveal center in patients with electroretinogram alterations without fundoscopic signs of retinotoxicity, and in age-matched controls. They found significant differences in measurements performed at 1 mm distance but not at 0.5 mm distance from the foveal center between the groups. In previous studies, measurements of the retinal structures were applied by accepting all layers as a whole. (5,17) In the present study, we measured the outer nuclear layer (photoreceptor nucleus layer), inner and outer segments. The layers did not contain any ganglion or nerve fiber. No difference was found in full thickness evaluation. The measurements performed by isolation indicated significant differences between drug users and controls. This might be interpreted as a possible decline in the thickness of these anatomical layers, before the fundoscopic alterations of retinotoxicity became apparent.
Despite the finding of no difference in full foveal thicknesses between drug users and nonusers, a negative and significant correlation was present between the thickness of these structures and the dose of drug per kilogram of body weight. However, the clinical implication of this finding remains unknown.
Histological investigations reported that receptors located in the parafoveal region were affected by drug consumption earlier and more intense than in the other parts of the retina. (10,16,18) Our findings were consistent with these implications. It is known that the parafoveal and perifoveal layers are preferentially involved by anti-malarial-induced retinotoxicity than the foveal layer. The factors, considered as being responsible for this distribution are unknown. In a study performed on retinal structures of non-primate rats, the external limiting membrane was found to have a barrier-function against diffusion of proteins. (19) Additionally, loss or weakness of the junctions performing this barrial function was found in fovea centralis. (20) Therefore, it is reasonable to speculate that there may be diffusion of HCQ in this barrier-free area. However, this claim needs to be clarified by further investigations.
In a previous study which was performed through measurement of the peripapillary RNFL by scanning laser polarimetry, CQ-users were found to have thinner layers compared to healthy controls. (21) However, it was emphasized that using fixed corneal compensator during this measurement could not eliminate the birefringence, which might impair the acuity of the RNFL measurement. In addition, Pasadhika et al. (4) reported that the difference in thickness of RNFL was found only in the nasal quadrant of patients treated with CQ compared to healthy controls. In contrast, the thinning of RNFL was localized in the superior and inferior quadrants of HCQ-users in our study. This difference may be a consequence of the methodologic differences and of the analyzed drugs between these studies, in particular.
Although several risk factors as responsible for the development of HCQ-retinotoxicity, there are controversies concerning the role and dominancy of these factors. (5) In our study, despite being with lower coefficiency values, we found negative and significant correlations between the thicknesses of retinal layer measured at 1 mm distant to fovea centralis and drug consumption duration, cumulative dose of drug, dose of drug per kilogram of actual and lean body masses. We excluded the subjects with fundoscopic abnormalities. In addition, HCQ was officially permitted for sale by the government in 2008 in Turkey. Previously, some of the patients bought the drug through importation from other European countries. Therefore, many of the drug-user subjects in our study had a history of drug consumption for less than five years, which was considered as a risk factor for the development of retinotoxicity. As a consequence, we were unable to compare the results of SD-OCT measurements between subjects with and without HCQ-induced retinotoxicity. It is not, thus, reasonable to speculate about factors which may provoke retinotoxicity in the light of our findings.
Although there is a tendency to attribute the higher actual dose, higher cumulative dose and longer duration of drug consumption to the development of retinotoxicity, the fact that shorter duration and lower dose of drug consumption may lead to development of retinotoxicity should not be ignored. (21-25)
On the other hand, there is a controversy about which of the methods is the golden standard for the evaluation of retinotoxicity. (26,27) In our study, determination of the diminution of the retinal layers by SD-OCT without fundoscopic alterations may lead to drawing attention to evaluation of the role of SD-OCT in further studies. The SD-OCT seems to be an advantageous technique for the evaluation, since it is an easy and fast-applicable technique, gives precise results of entire retinal layers in detail thanks to the high-degree of compatibility among repetitive testing and that it is not affected by the patient-dependent factors. However, it is necessary to standardize and define the cut-off values for the measured thicknesses to define values to be determined in favor of retinotoxicity. Based on the present findings, it is reasonable to evaluate the parafoveal layer by serial SD-OCT.
In our study, patients with connective tissue disease had thinner retinal layers. Whether the reason for these findings was the natural course of the disease or the effect of HCQ treatment was unable to be identified. We believe that the ideal control group for this evaluation should be patients with connective tissue disease who are not under treatment with anti-malarial drugs.
In conclusion, we found that some of the retinal layers were affected by HCQ even without any signs of retinotoxicity by other modalities. This study is a cross-sectional investigation to obtain general data about retinal involvement by HCQ consumption. The major methodologic flaw is the inability to compare results of retinotoxicity-developed subjects with HCQ users with intact retina. In this concept, we consider the findings of our study as the background data for the next stage of investigation by which we plan to evaluate the effects of drugs on higher cumulative doses and longer duration of consumption in the coming years. Evaluation of a larger group of subjects compared to previous studies is the major superiority of this investigation. Further investigations, which should be performed by longer-duration of drug consuming subjects, preferentially with larger series are necessary to define probable risk factors for the development of retinotoxicity.
Received: August 01, 2013 Accepted: December 16, 2013
We have special thanks to nurse teams of our Rheumatology and Ophthalmology departments due to their valuable contributions during the management of patients evaluation.
Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
The authors received no financial support for the research and/or authorship of this article.
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Hasan Fatih CAY , Muhammet Kazim EROL , Deniz TURGUT COBAN , Mehmet BULUT , Hhan SEZER , Tuncay CAKIR , Naciye Fusun TORAMAN 
 Department of Physical Medicine and Rehabilitation, Antalya Training and Research Hospital, Division of Rheumatology, Antalya, Turkey
 Department of Ophthalmology, Antalya Training and Research Hospital, Antalya, Turkey
 Department of Physical Medicine and Rehabilitation, Antalya Training and Research Hospital, Antalya, Turkey
Correspondence: Muhammet Kazim Erol, M.D. Antalya Egitim ve Arastirma Hastanesi Goz Hastaliklari Klinigi, 07100 Antalya, Turkey.
Tel: +90 242-249 44 00 e-mail: firstname.lastname@example.org
Table 1. Mean ages and drug consuming properties of subjects according to the disease groups Age (years) Mean [+ or -] SD 95% CI Rheumatoid arthritis 46.7 [+ or -] 13.2 43.8-49.6 (n = 40) Sjogren's syndrome 48.7 [+ or -] 10.6 46.5-50.8 (n = 47) Connective tissue 44.9 [+ or -] 13.2 41.3-48.5 disease (n = 27) Healthy controls 46.7 [+ or -] 7.7 45.6-47.9 (n = 87) Treatment duration (months) Mean [+ or -] SD 95% CI Rheumatoid arthritis 13.8 [+ or -] 13.2 10.8-16.8 (n = 40) Sjogren's syndrome 14.1 [+ or -] 14.4 11.0-17.2 (n = 47) Connective tissue 24.4 [+ or -] 29.0 15.9-32.8 * disease (n = 27) Healthy controls NA (n = 87) Cumulative dose (g) Mean [+ or -] SD 95% CI Rheumatoid arthritis 114.8 [+ or -] 103.9 91.1-138.6 (n = 40) Sjogren's syndrome 103.1 [+ or -] 89.0 84.2-121.9 (n = 47) Connective tissue 180.3 [+ or -] 186.4 126.1-234.4 ** disease (n = 27) Healthy controls NA (n = 87) Dose/body weight (mg/kg) Mean [+ or -] SD 95% CI Rheumatoid arthritis 3.6 [+ or -] 1.5 3.3-3.9 (n = 40) Sjogren's syndrome 3.9 [+ or -] 1.8 3.6-4.4 (n = 47) Connective tissue 3.6 [+ or -] 1.3 3.2-3.9 disease (n = 27) Healthy controls NA (n = 87) Dose/lean body mass (mg/kg) Mean [+ or -] SD 95% CI Rheumatoid arthritis 5,5 [+ or -] 2.1 5.1-6.0 (n = 40) Sjogren's syndrome 5.4 [+ or -] 1.9 4.9-5.8 (n = 47) Connective tissue 5.0 [+ or -] 1.7 4.5-5.5 disease (n = 27) Healthy controls NA (n = 87) SD: Standard deviation; CI: Confidence interval; * p = 0.006 both vs. Rheumatoid arthritis and Sjogren's syndrome groups (ANOVA with Post hoc Bonferroni test); ** p = 0.012 and 0.002 vs. Rheumatoid arthritis and Sjogren's syndrome groups respectively (ANOVA with Post hoc Bonferroni Test); NA: Not applicable. Table 2. Foveal layer thicknesses and retinal nerve fiber layer measurements among healthy controls and hydroxychloroquine users Healthy controls Hydroxychloroquine (n = 174) users (n = 228) Mean [+ or -] SD Mean [+ or -] SD Full thickness fovea ([micro]m) Central thickness 249.9 [+ or -] 20.0 249.5 [+ or -] 22.5 First quadrants 322.3 [+ or -] 14.2 319.5 [+ or -] 16.7 Second quadrants 281.3 [+ or -] 11.0 279.45 [+ or -] 16.9 Outer fovea ([micro]m) Central thickness 169.8 [+ or -] 14.8 166.0 [+ or -] 14.6 Parafovea 117.5 [+ or -] 10.1 110.5 [+ or -] 11.0 Perifovea 103.8 [+ or -] 7.6 100.0 [+ or -] 8.5 Retinal nerve fiber layer ([micro]m) Superior quadrant 122.3 [+ or -] 13.8 118.1 [+ or -] 15.9 Inferior quadrant 127.1 [+ or -] 15.2 121.3 [+ or -] 18.4 Nasal quadrant 73.1 [+ or -] 11.9 74.3 [+ or -] 14.8 Temporal quadrant 64.0 [+ or -] 9.5 65.2 [+ or -] 10.6 p * Full thickness fovea ([micro]m) Central thickness 0.839 First quadrants 0.084 Second quadrants 0.209 Outer fovea ([micro]m) Central thickness 0.013 Parafovea < 0.001 Perifovea < 0.001 Retinal nerve fiber layer ([micro]m) Superior quadrant 0.007 Inferior quadrant 0.001 Nasal quadrant 0.384 Temporal quadrant 0.243 SD: Standard deviation; * Student t-test. Table 3. Foveal layer thicknesses among disease groups Healthy controls (n = 174) Mean [+ or -] SD 95% CI Full thickness fovea ([micro]m) Central 249.9 [+ or -] 20.0 246.8-253.1 First quadrants 322.3 [+ or -] 14.2 320.2-324.4 * Second quadrants 281.3 [+ or -] 11.0 279.7-283.0 ** Outer fovea ([micro]m) Central 169.8 [+ or -] 14.8 167.5-171.9 Parafovea 117.5 [+ or -] 10.1 116.0-119.0 Perifovea 103.8 [+ or -] 7.6 102.7-104.9 Rheumatoid arthritis (n = 80) Mean [+ or -] SD 95% CI Full thickness fovea ([micro]m) Central 251.4 [+ or -] 19.4 247.1-255.8 First quadrants 322.0 [+ or -] 20.6 318.5-325.5 ([section]) Second quadrants 283.1 [+ or -] 13.4 280.1-286.1 ([section] [section]) Outer fovea ([micro]m) Central 167.1 [+ or -] 16.9 163.2-171.0 Parafovea 111.5 [+ or -] 9.3 109.3-113.6 ([infinity]) Perifovea 101.1 [+ or -] 7.3 99.4-102.7 Sjogren's syndrome (n = 94) Mean [+ or -] SD 95% CI Full thickness fovea ([micro]m) Central 248.5 [+ or -] 21.0 243.7-252.8 First quadrants 320.9 [+ or -] 16.6 317.4-324.4 ([psi]) Second quadrants 279.3 [+ or -] 21.1 274.9-283.7 Outer fovea ([micro]m) Central 167.0 [+ or -] 13.5 164.1-169.9 Parafovea 110.7 [+ or -] 12.9 108.0-113.5 ([SIGMA]) Perifovea 99.9 [+ or -] 9.8 97.9-102.0 (a) Connective tissue disease (n = 54) Mean [+ or -] SD 95% CI Full thickness fovea ([micro]m) Central 249.3 [+ or -] 29.2 241.2-257.3 First quadrants 313.5 [+ or -] 17.2 308.8-318.3 Second quadrants 274.4 [+ or -] 11.3 271.2-277.5 Outer fovea ([micro]m) Central 162.5 [+ or -] 12.2 158.9-166.1 (@) Parafovea 108.7 [+ or -] 9.7 105.8-111.5 ([OMEGA]) Perifovea 98.3 [+ or -] 7.6 96.1-100.6 (b) SD: Standard deviation; CI: Confidence interval; *: p = .002; vs. CTD group; ([section]): p = 0.014; vs CTD group; ([psi]): p = 0.0375 vs. CTD group; **: p = 0.014; vs. CTD group; ([section]) ([section]): p = 0.004 vs. CTD group; (@) p = 0.017 vs. Healthy controls; ([infinity]) ; p = 0.00027 vs. Healthy controls; ([OMEGA]): p = 0.000009 vs. Healthy = controls; Q: p = 0.000004 vs. Healthy controls; (a): p = 0.002 vs. Healthy controls; (b): p = 0.0003 vs. Healthy controls; One-way ANOVA with Post hoc Bonferroni test. Table 4. Retinal nerve fiber layer thickness of subjects in different disease groups Healthy controls (n = 174) Mean [+ or -] SD 95% CI RNFL ([micro]m) Superior quadrant 122.3 [+ or -] 13.8 120.2-124.4 Inferior quadrant 127.1 [+ or -] 15.2 124.8-129.5 Nasal quadrant 73.1 [+ or -] 11.9 71.3-75.0 Temporal quadrant 64.0 [+ or -] 9.5 62.5-65.4 Rheumatoid arthritis (n = 80) Mean [+ or -] SD 95% CI RNFL ([micro]m) Superior quadrant 117.4 [+ or -] 16.7 113.6-121.3 Inferior quadrant 123.8 [+ or -] 18.7 119.5-128.1 Nasal quadrant 73.9 [+ or -] 13.0 70.9-76.9 Temporal quadrant 64.8 [+ or -] 10.0 62.6-67.1 Sjogren's syndrome (n = 94) Mean [+ or -] SD 95% CI RNFL ([micro]m) Superior quadrant 120.7 [+ or -] 14.5 117.7-123.7 Inferior quadrant 121.8 [+ or -] 18.0 118.0-125.5 Nasal quadrant 75.7 [+ or -] 14.6 72.7-78.7 Temporal quadrant 65.7 [+ or -] 10.1 63.6-67.8 Connective tissue diseases (n = 54) Mean [+ or -] SD 95% CI RNFL ([micro]m) Superior quadrant 114.7 [+ or -] 16.6 110.2-119.3 * Inferior quadrant 117.0 [+ or -] 18.1 112-0-122.0 ** Nasal quadrant 72.4 [+ or -] 17.4 67.6-77.2 Temporal quadrant 64.9 [+ or -] 12.4 61.4-68.3 SD: Standard deviation; CI: Confidence interval; RNFL: Retinal nerve fiber layer; * p = 0.009 vs healthy controls; ** p = 0.001 vs healthy controls (One-way ANOVA with post hoc Bonferroni text). Table 5. Correlations between ocular coherence tomography measurements and drug consumption parameters Dose/body Dose/lean Cumulative Treatment weight body mass dose duration Correlation coefficients (r) Full thickness fovea Central -0.108 -0.091 0.10 0.060 First quadrants -0.119 * -0.071 -0.081 -0.002 Second quadrants -0.120 * -0.053 -0.039 0.016 Outer fovea Central -0.140 * -0.133 * -0.035 -0.039 Parafovea -0.159 ** -0.173 ** -0.192 ** -0.127 * Perifovea -0.159 ** -0.149 * -0.09 0.018 RNFL Superior quadrant -0.027 -0.018 -0.073 -0.073 Inferior quadrant -0.055 -0.031 -0.104 * -0.135 ** Nasal quadrant 0.008 0.046 0.050 0.030 Temporal quadrant -0.022 -0.041 -0.085 -0.028 * p < 0.05 (Pearson's correlations); ** p < 0.01 (Pearson's correlations); RNFL: Retinal nerve fiber layer.
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Cay, Hasan Fatih; Erol, Muhammet Kazim; Coban, Deniz TURGUT; Bulut, Mehmet; Sezer, Hhan; Cakir, Tunc|
|Publication:||Turkish Journal of Rheumatology|
|Date:||Sep 1, 2014|
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