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Long-term Progression of Pericentral Hydroxychloroquine Retinopathy

Seong Joon Ahn, MD, PhD, Eoi Jong Seo, MD, PhD, Ko Eun Kim, MD, PhD, Yu
Jeong Kim, MD, PhD, Byung Ro Lee, MD, PhD, June-Gone Kim, MD, PhD, Young
Hee Yoon, MD, PhD, Joo Yong Lee, MD, PhD

PII: S0161-6420(20)31031-9
DOI: https://doi.org/10.1016/j.ophtha.2020.10.029
Reference: OPHTHA 11530

To appear in: Ophthalmology

Received Date: 1 May 2020

Revised Date: 21 October 2020
Accepted Date: 26 October 2020

Please cite this article as: Ahn SJ, Seo EJ, Kim KE, Kim YJ, Lee BR, Kim J-G, Yoon YH, Lee JY, Long-
term Progression of Pericentral Hydroxychloroquine Retinopathy, Ophthalmology (2020), doi: https://
doi.org/10.1016/j.ophtha.2020.10.029.

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© 2020 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology

 Progression of Pericentral HCQ Retinopathy 1

1 Long-term Progression of Pericentral Hydroxychloroquine Retinopathy

3 Seong Joon Ahn, MD, PhD1; Eoi Jong Seo, MD, PhD2,3; Ko Eun Kim, MD, PhD4; Yu

4 Jeong Kim, MD, PhD1; Byung Ro Lee, MD, PhD1; June-Gone Kim, MD, PhD3; Young

5 Hee Yoon, MD, PhD3; Joo Yong Lee, MD, PhD3

1
7 Department of Ophthalmology, Hanyang University Hospital, Hanyang University

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8 College of Medicine, Seoul, Republic of Korea

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2
9 Department of Ophthalmology, Chungbuk National University Hospital, Chungbuk

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National University College of Medicine, Cheongju, Republic of Korea
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3
11 Department of Ophthalmology, Asan Medical Center, Ulsan University College of
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12 Medicine, Seoul, Republic of Korea

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4
13 Department of Ophthalmology, Nowon Eulji Medical Center, Eulji University College

14 of Medicine, Seoul, Republic of Korea

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15
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16 Short Title: Progression of Pericentral HCQ Retinopathy

17

18 Corresponding Author:

19 Joo Yong Lee, MD, PhD

20 Department of Ophthalmology, Asan Medical Center, Ulsan University College of

21 Medicine, 88 Olympic-ro 43 Gil, Songpa-gu, Seoul 05505, Republic of Korea

22 Tel: (82)-2-3010-3976

23 Fax: (82)-2-470-6440

24 E-mail: jooyong.lee@amc.seoul.kr
 Progression of Pericentral HCQ Retinopathy 2

25 Byung Ro Lee, MD, PhD

26 Department of Ophthalmology, Hanyang University Hospital, Hanyang University

27 College of Medicine, 222-1 Wangsipli-ro, Seongdong-gu, Seoul 04763, Republic of

28 Korea

29 Tel: (82)-2-2290-8570

30 Fax: (82)-2-2291-8517

31 E-mail: brlee@hanyang.ac.kr

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32

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33 Financial Support: This work was supported by a research grant from the Korean

34
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Retina Society issued in 2020 and a grant (2013-0826) from the Asan Institute for
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35 Life Sciences, Seoul, Korea. The sponsor or funding organization had no role in the
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36 design or conduct of this research.

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37 Conflict of interest: No conflicting relationship exists for any author.

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38 Abbreviations
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39 AMC: Asan Medical Center; BCVA: best-corrected visual acuity; EZ: ellipsoid zone;

40 FAF: fundus autofluorescence; GPA: guided progression analysis; HCQ:

41 hydroxychloroquine; HUH: Hanyang University Hospital; MD: mean deviation;

42 mfERG: multifocal electroretinography; OCT: optical coherence tomography; PSD:

43 pattern standard deviation; RPE: retinal pigment epithelium; VF: visual field

44

45 This article contains an online-only material. The following should appear online only:

46 Figures S1, S2, and S3 and Tables S1 and S2.

 Progression of Pericentral HCQ Retinopathy 3

47 ABSTRACT

48 Objective: To investigate the long-term progression of pericentral

49 hydroxychloroquine (HCQ) retinopathy.

50 Design: Multicenter, retrospective cohort study

51 Subjects: Eighty eyes (60 with pericentral pattern) of 41 Korean patients with HCQ

52 retinopathy who were followed up for ≥2 years after drug cessation.

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53 Methods: Patients were screened for HCQ retinopathy using spectral-domain or

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swept-source optical coherence tomography (OCT), fundus autofluorescence (FAF),
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55 and Humphrey visual field (VF) tests. Follow-up periods were divided into short-term

56 (≤2 years) and subsequent periods, and progression was evaluated in each of the
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57 periods and severity groups. Retinopathy progression on OCT was defined as

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58 increased length of the ellipsoid zone defect, decreased distance from the fovea to
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59 the photoreceptor defects, or newly developed or enlarged retinal pigment epithelium

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60 defects. On FAF, progression was defined as an increase in the area of

61 hyperautofluorescence or hypoautofluorescence. Functional progression was

62 defined as a regression coefficient of <0 dB/year for mean deviation and >0 dB/year

63 for pattern standard deviation, based on linear regression analysis of ≥3 VF tests.

64 Structural and functional progression rates were calculated using the slopes of

65 retinal thicknesses on the Early Treatment Diabetic Retinopathy Study grid and

66 perimetric parameters over time, respectively.

67 Main Outcome Measures: Structural and functional progression of retinopathy

68 Results: Approximately one-third of eyes with early pericentral retinopathy showed

 Progression of Pericentral HCQ Retinopathy 4

69 limited progression during the short-term period after drug cessation, but they

70 subsequently had stable or improved photoreceptors. Most eyes with moderate

71 pericentral retinopathy showed continuous progression, particularly when converted

72 to the severe stage. Severe eyes showed progressive damage throughout the follow-

73 up period. In all severity groups, the rates of retinal thinning decreased over time. In

74 eyes with pericentral retinopathy showing progression, circumferential enlargement

75 of retinal damage was prominent in earlier stages, whereas centripetal enlargement

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76 of the ring-shaped lesion was noted in advanced stages. Functional progression,

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77 noted in 58.7% of the pericentral eyes, corresponded with structural progression.
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78 Conclusions: Pericentral HCQ retinopathy showed severity-dependent progression.
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79 Moderate pericentral retinopathy usually progressed, but centripetal progression
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80 threatening the fovea was remarkable mostly in severe retinopathy. Our results
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81 suggest that early detection of retinopathy may minimize the risk of progression to
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82 foveal involvement in pericentral retinopathy.

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83
 Progression of Pericentral HCQ Retinopathy 5

84 Hydroxychloroquine (HCQ) is a drug widely used for the treatment of rheumatic and

85 dermatological diseases, such as systemic lupus erythematosus and rheumatoid

86 arthritis.1, 2 HCQ retinopathy is a retinal toxicity caused by the drug, usually occurring

87 in patients undergoing long-term treatment. It is characterized by photoreceptor

88 and/or retinal pigment epithelium (RPE) defects. Its prevalence has been reported to

89 be between 0.08%3 (among 1207 patients taking HCQ) and 7.5%4 (among 2361 with

90 >5 years of HCQ use),3-6 although recent studies using modern retinal imaging have

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91 suggested that the prevalence is higher than that reported previously.2, 7

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HCQ retinopathy can present in two distinct patterns: parafoveal and

93 pericentral.2, 8, 9 Parafoveal retinopathy is defined by the presence of outer retinal

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94 defects 2–8 degrees from the fovea.2, 10
The bull’s eye maculopathy is a late
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95 manifestation of this pattern, characterized by a parafoveal ring of RPE degeneration

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96 sparing a foveal island. Pericentral retinopathy, which is defined as retinal damage

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97 occurring in the area outside 8 degrees from the fovea.8 This is typically recognized
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98 at more advanced stages of the disease8; thus, particular attention is required for its

99 early detection. Selection of appropriate examinations that can cover the spatial

100 extent of retinal toxicity is important for the detection of the disease and its

101 progression.8-11 However, data regarding the progression of pericentral retinopathy

102 are relatively insufficient as several longitudinal studies have been conducted in

103 groups consisting primarily of patients with parafoveal retinopathy.12, 13

104 There has been no consensus regarding the definition of progression of HCQ

105 retinopathy.12-15 This has led to variability in the methods and results of progression

106 studies, which makes it impossible to draw significant conclusions. Accordingly, we

107 aimed to specify the definition of progression of HCQ retinopathy and to evaluate
 Progression of Pericentral HCQ Retinopathy 6

108 long-term structural and functional changes in our patient cohorts with HCQ

109 retinopathy, mostly with pericentral retinopathy. Through the use of wide-field retinal

110 imaging and visual field tests, we assessed the patterns of retinopathy progression

111 and associated risk factors. Based on the results obtained by separating the eyes

112 with HCQ retinopathy according to retinopathy pattern and severity, we aimed to

113 provide distinguishing features of progression in eyes with pericentral retinopathy.

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114

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115 METHODS

116 Study Population

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117 We identified 59 and 20 patients with HCQ retinopathy from Hanyang University
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118 Hospital (HUH) and Asan Medical Center (AMC), respectively, among the 1528 and
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119 581 patients who visited the hospitals from January 2012 to December 2019 for
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120 HCQ retinopathy screening. Among these patients, we included those who had been
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121 followed up for 2 or more years (with at least three visits) after HCQ retinopathy

122 diagnosis: a total of 30 from the HUH and 11 from AMC. We excluded two eyes in

123 which comorbid retinal diseases developed during the follow-up period (one eye with

124 branch retinal artery occlusion and one with central retinal artery occlusion). Finally,

125 80 eyes of 41 Korean patients were included in our analyses. This study was

126 approved by the Institutional Review Boards of both hospitals and adhered to the

127 tenets of the Declaration of Helsinki.

128

129 Patient Evaluation

 Progression of Pericentral HCQ Retinopathy 7

130 We performed comprehensive ophthalmic examinations for all patients at baseline

131 and follow-up visits, including best-corrected visual acuity (BCVA) assessment, slit-

132 lamp examination, pneumatic tonometry, and fundus examination. We performed

133 spectral-domain (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and

134 swept-source OCT (DRI-OCT; Topcon Inc., Tokyo, Japan) in the AMC and HUH,

135 respectively. For each individual patient, we used the same OCT device throughout

136 the follow-up period. To obtain fundus autofluorescence (FAF) images, we used

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137 confocal scanning laser ophthalmoscopes: the Heidelberg Retina Angiograph

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138 (Heidelberg Engineering, Heidelberg, Germany) and/or Optos 200 Tx (Optos PLC,

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Dunfermline, United Kingdom) in the AMC and the F-10 (Nidek, Gamagori, Japan)
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140 and/or Optos 200 Tx in the HUH. We performed standard automated perimetry using
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141 the 30-2 and/or 10-2 strategies (Humphrey Field Analyzer; Carl Zeiss Meditec,
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142 Dublin, CA) in both hospitals. Based on the most recent guidelines issued by the

143 American Academy of Ophthalmology,2 we made a diagnosis of HCQ retinopathy

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144 when the findings from at least one objective test confirmed a subjective finding
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145 indicative of visual field defects. In all the patients, disruption or loss of the

146 photoreceptor layers in the parafoveal or pericentral areas on OCT and

147 corresponding central/parafoveal or pericentral scotoma on Humphrey 10-2 or 30-2

148 tests were confirmed. Hyper- or hypoautofluorescence in the parafoveal or

149 pericentral areas on FAF or amplitude reduction and prolonged implicit time in the

150 damaged area on multifocal electroretinography (mfERG) were additionally used for

151 our diagnosis.16

152 We divided eyes with HCQ retinopathy into the following three groups:

153 parafoveal (outer retinal defects in the area 2–8 degrees from the fovea), pericentral
 Progression of Pericentral HCQ Retinopathy 8

154 (defects more than 8 degrees from the fovea), and mixed (both patterns)

155 retinopathy.2, 10 Regarding severity, we classified eyes as early (patchy photoreceptor

156 defects without RPE involvement), moderate (photoreceptor defects without RPE

157 involvement in an area ≥180 degrees around the fovea), and severe (combined RPE

158 damage).10, 14, 17

159 We used all the FAF and OCT images and visual field test results obtained at

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160 baseline and follow-up visits for our analyses. To measure the distance from the

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161 fovea to photoreceptor defects, we used calipers embedded in the image viewer

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software provided by the OCT manufacturers and also confirmed the location of the

163 fovea on the scan to ensure that follow-up scans were centered at precisely the
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164 same location as baseline scans. Central macular thickness was measured using
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165 either a circular map analysis protocol provided by the spectral-domain OCT
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166 manufacturer or the macular volume scan of swept-source OCT, which measures the
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167 distance between the internal limiting membrane and the RPE and calculates the
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168 average thickness in a 1-mm-diameter circle centered on the fovea. Parafoveal

169 (defined as within a 0.5- to 1.5-mm radius from the fovea on the Early Treatment

170 Diabetic Retinopathy Study [ETDRS] grid) and perifoveal (within a 1.5- to 3-mm

171 radius from the fovea) retinal thicknesses were also automatically measured using

172 the same protocols in the temporal, nasal, superior, and inferior areas. As the two

173 hospitals in this study used different OCT devices, we assessed retinal thickness

174 changes obtained by subtracting the baseline thickness values from the follow-up

175 values.

176 We assessed the structural progression of retinopathy using FAF and OCT.

177 On FAF, we considered the appearance of new hypoautofluorescent or

 Progression of Pericentral HCQ Retinopathy 9

178 hyperautofluorescent lesions or the enlargement of existing lesions to indicate

179 progression.17, 18 In each eye showing retinopathy progression, we compared FAF

180 images obtained during the follow-up period to evaluate the patterns of progression.

181 On OCT, considering the diversity of features indicating the progression of outer

182 retinal damage, we defined three criteria for evaluating structural progression based

183 on the degree or extent of outer retinal defects: (1) a gradual increase over the

184 follow-up period in the length of the defect in the ellipsoid zone (EZ) line observed on

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185 horizontal or vertical scans crossing the fovea (i.e., length at baseline < length at 1

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186 year < length at 2 years); (2) a gradual decrease in the distance from the fovea to the

187
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photoreceptor defects on horizontal or vertical scans over the follow-up period, if the
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188 length of the EZ line defect could not be determined because its peripheral margins
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189 were not identifiable due to the relatively limited scan length in eyes with pericentral
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190 retinopathy; and (3) the new appearance or enlargement of disruption (attenuation

191 and thinning) of the RPE/Bruch’s complex on horizontal or vertical scans. We

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192 considered that OCT progression had occurred if at least one of these three criteria
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193 was met. The two investigators (SJA and EJS), while blinded to clinical information,

194 such as details on HCQ use and its severity, independently evaluated the images

195 and performed measurements to determine structural progression on OCT and FAF

196 during the first 2-year period after drug cessation and subsequent period. Any

197 discrepancy was resolved by consensus through discussion.

198 To evaluate the functional progression of HCQ retinopathy, we performed

199 linear regression to assess the changes in visual field indices, mean deviation (MD),

200 and pattern standard deviation (PSD) over time, using at least three reliable visual

201 field test results obtained during the follow-up period (e.g., baseline, 1 year, 2 years,
 Progression of Pericentral HCQ Retinopathy 10

202 and/or final visit). The regression coefficients were used to assess the rates of

203 functional progression, and those for MD less than 0 dB/year and those for PSD

204 greater than 0 dB/year were considered as visual field progression.

205 The rates for structural progression (retinal thinning) were also calculated by

206 linear regression of the central foveal, parafoveal, and perifoveal thicknesses on the

207 ETDRS grid over time. Parafoveal and perifoveal retinal thicknesses were obtained

208 by averaging the temporal, superior, nasal, and inferior parafoveal and perifoveal

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209 thicknesses on the ETDRS grid, respectively.

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211 Statistical Analyses
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212 We calculated descriptive statistics regarding patient demographics and clinical

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213 characteristics. Values for continuous variables are presented as mean  ±  standard

214 deviation. Rates for structural progression were compared between the short-term
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215 and subsequent periods in each severity group. We performed univariate and
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216 multivariate logistic regression analyses to identify the clinical factors significantly

217 associated with structural and functional progression. After univariate logistic

218 regression analysis, variables with P < 0.10 were selected for subsequent

219 multivariate analysis using the stepwise selection method. The variables with

220 significant correlation were not analyzed simultaneously to avoid multicollinearity.

221 Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in regression

222 analyses. For all our analyses, we considered a P value of less than 0.05 to be

223 statistically significant. Statistical analyses were performed using SPSS software

224 version 23 (IBM Corp., Armonk, NY, USA).

 Progression of Pericentral HCQ Retinopathy 11

225

226 RESULTS

227 Demographic Data and Clinical Characteristics

228 The demographic data and clinical characteristics of the 41 patients (all Korean),

229 whose HCQ treatments were discontinued after the diagnosis of retinopathy, are

230 presented in Table 1. The mean follow-up period was 47.0 ± 22.1 months, and a total

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231 of 60 (75.0%) eyes, including 21 early, 16 moderate, and 23 severe eyes, had

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232 pericentral retinopathy. In these pericentral eyes, the median (range) follow-up

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periods in the early, moderate, and severe groups were 40 (24-91), 49 (33-84), and
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234 36 (24-109) months, respectively.
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235
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236 Structural Progression of Hydroxychloroquine Retinopathy

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237 Table 2 indicates the proportions of structural progression in eyes with pericentral
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238 retinopathy during the short-term and subsequent long-term periods after drug

239 cessation. During the first 2 years, 26.3% of eyes with early pericentral retinopathy

240 showed progression on FAF (Figure 1B), whereas none of the eyes showed

241 progression during the subsequent period. On OCT, 33.3% of the eyes showed only

242 short-term progression. Among eyes with moderate pericentral retinopathy, 81.3%

243 showed progression during the first 2 years. In contrast to early retinopathy, most

244 eyes (81.3%) with moderate pericentral retinopathy showed progression in the

245 subsequent period, as exemplified in Figure 1C and D. All eyes with severe

246 pericentral retinopathy showed continuous progression over the entire follow-up
 Progression of Pericentral HCQ Retinopathy 12

247 period (Figure 1E). However, eyes with parafoveal retinopathy showed long-term

248 stability in the early or moderate stage, whereas progressive changes were noted in

249 severe parafoveal eyes (Figure S1, available online at http://www.aaojournal.org).

250 Among the 16 eyes with moderate pericentral retinopathy, 9 (56.3%)

251 progressed to severe stages: 7 eyes showed severity conversion during the short-

252 term period (Figure 1D), and 2 showed severity conversion during the subsequent

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253 period. The eyes showing severity conversion usually had an extensive ring-shaped

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254 area of hyperautofluorescence, from the perifovea to the vascular arcade or beyond,

255 on FAF at diagnosis. -p

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256 Changes in quantitative parameters over time also differed according to the
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257 severity of retinopathy at baseline. Although eyes with early and moderate

258 pericentral retinopathy showed minimal change in the mean distances from the fovea
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259 to the nasal and temporal photoreceptor defects between baseline and the final visit,
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260 those with severe retinopathy showed a gradual decrease in the distances (Figure
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261 S2, available online at http://www.aaojournal.org). This indicates continuous

262 enlargement of retinal damage toward the fovea in severe pericentral retinopathy,

263 different from early/moderate stage (FAF images in Figure 1A to D). The rates of

264 change in retinal thickness over time (µm/year) in the central fovea (Figure 2A),

265 parafovea, and perifovea of the eyes with pericentral retinopathy (Figure 2B) were

266 generally greater in eyes with more advanced stages. The rates of retinal thinning

267 during the short-term period were mostly greater than those during the subsequent

268 period in each severity group. This difference was statistically significant in the

269 parafovea (P = 0.032) and perifovea (P = 0.027) of the eyes with moderate

270 pericentral retinopathy.

 Progression of Pericentral HCQ Retinopathy 13

271 Remarkably, partial recovery of photoreceptor damage was noted during the

272 follow-up period after drug cessation (Figure 3). Such partial improvement of

273 retinopathy was observed in 10.0% of the eyes: 7 eyes (29.2%) with early

274 retinopathy (5 pericentral, 2 parafoveal) and 1 eye (5.6%) with moderate pericentral

275 retinopathy. However, none of the eyes with severe retinopathy showed such

276 improvement.

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277

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278 Pattern of Structural Progression

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In pericentral eyes with structural progression, serial FAF images showed
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280 characteristic expansion of the lesion after drug cessation (Figure 4). Although the
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281 progression rate and pattern varied individually, eyes with earlier stages at disease
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282 recognition usually advanced in a circumferentially dominant manner after drug

283 cessation and either rarely or very slowly progressed in a centripetal direction
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284 (Figures 1A to 1D and 4). In severe eyes, hypoautofluorescence advanced

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285 circumferentially, and the expanded area also showed centripetal/centrifugal

286 progression, as shown in Figures 1E and 4. In eyes with extensive, ring-shaped

287 severe retinopathy, centripetal progression toward the fovea was remarkable (bottom

288 of Figure 4).

289

290 Functional Progression of Hydroxychloroquine Retinopathy

291 Functional progression was observed in 60.0% of the 50 eyes with HCQ retinopathy,

292 for which at least three reliable 30-2 visual field tests were performed over a follow-
 Progression of Pericentral HCQ Retinopathy 14

293 up period of at least 2 years. Functional progression was noted in 58.7% of eyes with

294 pericentral retinopathy and generally corresponded with FAF and OCT progression

295 within the entire follow-up period (Table S1, available online at

296 http://www.aaojournal.org).

297 Figure 5 shows a representative case of pericentral retinopathy showing

298 functional progression and the overall results on the rate of changes in MD and PSD

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299 in eyes with pericentral retinopathy. In this case, Humphrey 30-2 and 10-2 tests

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300 revealed ring scotoma and peripheral constriction, respectively, in both grayscale

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and pattern deviation maps, which corresponded to hypoautofluorescent lesions on

302 FAF. The maps showed gradual expansion of scotoma and worsening of MD and
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303 PSD, despite intervisit variabilities (Figure 5A). Overall, the rate of MD change over
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304 time (Figure 5B) revealed that eyes with severe pericentral retinopathy showed the
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305 highest rate of change (-0.52 ± 1.09 dB/year) compared to eyes with early (-0.22 ±
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306 0.96 dB/year) or moderate pericentral retinopathy (-0.40 ± 0.46 dB/year). However,
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307 for PSD, eyes with moderate retinopathy showed the greatest rate of change (0.66 ±

308 1.14 dB/year).

309 As shown in Figure S3 (available online at http://www.aaojournal.org), mean

310 BCVA remained stable over the follow-up period in each severity group of pericentral

311 retinopathy. Blindness was not observed among the eyes with pericentral retinopathy,

312 whereas 5 eyes with severe parafoveal or mixed retinopathy showed blindness at

313 the final visit. Among the severe eyes, vision loss was particularly remarkable in

314 those with baseline foveal involvement.

315
 Progression of Pericentral HCQ Retinopathy 15

316 Risk Factors for Progression

317 We assessed risk factors for structural and functional progression by logistic

318 regression analyses using demographic and clinical factors such as age, follow-up

319 duration, cumulative dose/body weight, daily dose/body weight, severity of

320 retinopathy, and retinopathy pattern (Table S2, available online at

321 http://www.aaojournal.org). The severity of retinopathy was the only factor

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322 significantly associated with structural progression on FAF (P = 0.001) and OCT (P =

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323 0.001). However, none of the clinical factors showed a significant association with

324 functional progression (all P > 0.05). -p

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325
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326 DISCUSSION
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327 The rates of progression of HCQ retinopathy assessed by the modern imaging
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328 modalities such as spectral-domain OCT and FAF were variable in the literature,
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329 ranging from 36.8% to 81.8%.12-15, 17, 19-23 We hypothesize that this variability was

330 due to differences in the follow-up periods, severity and pattern of retinopathy in the

331 included eyes, and definitions of progression (or test sensitivities) between the

332 studies. The present study aimed to address the progression of HCQ retinopathy

333 after drug cessation in Asian patients mostly with pericentral retinopathy, for which

334 the long-term course is relatively unknown. We divided eyes with HCQ retinopathy

335 according to retinopathy pattern and the entire follow-up period into short-term

336 (within 2 years) and subsequent long-term ones and separately evaluated the long-

337 term post-cessation behavior of HCQ retinopathy. Our study showed that

338 progression of HCQ retinopathy was dependent on disease pattern, severity, and the
 Progression of Pericentral HCQ Retinopathy 16

339 time after drug cessation.

340 In particular, eyes with pericentral retinopathy showed different clinical

341 courses from those with parafoveal retinopathy in the moderate stage. Eyes with

342 early or moderate parafoveal retinopathy in our study showed long-term stability,

343 consistent with that in the existing literature.13, 14 In contrast, approximately 80% of

344 eyes with moderate pericentral retinopathy, including 56.3% progressing to severe

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345 stage, showed continuous progression over the entire follow-up period. However, the

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346 progression rates decreased over time, and the inward advancement toward the

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fovea was minimal in the eyes with moderate pericentral retinopathy over a long-

348 term period compared to severe eyes.

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349 For the high conversion rate from moderate to severe stage in pericentral

350 retinopathy, it is unclear whether pericentral eyes are different from parafoveal eyes
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351 in terms of susceptibility to RPE damages considering that there were no parafoveal
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352 cases in our cohort with extent of retinal damage and follow-up period comparable to
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353 our pericentral eyes. The high rate in the moderate eyes could be attributed to the

354 missed detection of RPE damage. However, the absence of hypoautofluorescence

355 and intact RPE/Bruch’s membrane line was confirmed in most (14 of 16) of the

356 moderate eyes using wide-field FAF (Optos) and OCT (9- or 12-mm) in addition to

357 standard imaging (6-mm scan or 30- to 50-degree retinal imaging). In eyes with

358 severity conversion, extensive lesions were detected at disease recognition,

359 suggesting the possibility of combined RPE damage. The damage could have been

360 either missed or undetectable using the currently available imaging modalities,

361 particularly given the difficulty in interpreting peripheral OCT.

 Progression of Pericentral HCQ Retinopathy 17

362 We found that the pattern of progression in pericentral retinopathy was also

363 dependent on the severity of retinopathy. Our findings presented in Figure 4 have

364 clinical implications that progression toward (or threatening) the fovea is significantly

365 more likely to occur in severe stages. Thus, early detection of HCQ retinopathy

366 before RPE defects is important. The circumferential progression in earlier stages

367 may also be related to the late diagnosis of pericentral retinopathy.8 More specifically,

368 early pericentral retinopathy can be missed by conventional (not wide-field) imaging

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369 until centripetal progression becomes more prominent in the advanced stages

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370 (Figure 6). To avoid late diagnosis in these patients, at least one imaging modality,

371
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OCT or FAF, should cover a wide-ranging area, or other types of OCT scans may be
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372 used to support the earlier detection of pericentral retinopathy.
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373 HCQ retinopathy is generally considered to be irreversible and progressive in

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374 nature.2, 24 Although complete recovery was not confirmed in any cases in our limited
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375 follow-up period, we noted partial healing of the photoreceptor defects in some eyes
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376 with early retinopathy; this was also observed in a study by Pham et al.13 Although

377 functional gain corresponding to photoreceptor recovery was not confirmed in the

378 patients, HCQ retinopathy can be reversible to some extent. However, it should be

379 noted that none of the patients with severe retinopathy, regardless of the pattern of

380 retinopathy, showed reversible damage. As RPE cell damage itself may lead to

381 secondary loss of photoreceptors,25 severe cases with RPE damage may show

382 progressive outer retinal degeneration despite drug cessation.

383 While the structural progression of HCQ retinopathy has been more widely

384 studied, functional progression has rarely been addressed in the literature. The

385 reported rate of functional progression was lower than that of structural
 Progression of Pericentral HCQ Retinopathy 18

386 progression,23 which was also observed in this study. Despite individual and intervisit

387 variability of perimetric parameters, the mean rate of change in MD showed a linear

388 trend according to the severity of retinopathy (Figure 5), with a greater decline in

389 more severe stages. This corresponded to the greater rate of structural progression

390 (retinal thinning) in severe stages, indicating a structure–function correlation in HCQ

391 retinopathy progression.

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392 Several limitations of our study must be carefully considered when

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393 interpreting our results. First, the OCT and FAF devices differed between the two

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study centers; it is therefore important to consider the possibility of bias resulting

395 from the use of different imaging devices. However, we assessed retinal thickness
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396 changes to minimize the effect of discrepancies between OCT devices. Second, the
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397 follow-up period (approximately 4 years on average) may not be sufficient to assess
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398 the long-term progression of HCQ retinopathy. In particular, it has not yet been
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399 determined whether pericentral retinopathy can finally involve or spare the fovea; to
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400 validate this, a longer follow-up period is needed. Third, mfERG data were not used

401 for our analyses due to the lack of sufficient follow-up data. However, mfERG, with

402 its excellent sensitivity26, may provide a better means to detect functional

403 progression. Additionally, follow-up loss in our study population may have affected

404 the progression rates. However, no significant difference was found in the potential

405 factors affecting the rate of progression, including the severity of retinopathy and

406 cumulative HCQ dose, between patients with and without follow-up loss. Thus, this

407 preferential follow-up loss may not have significantly affected our progression rates,

408 although we cannot fully exclude the potential bias. Finally, our patients were all

409 Koreans, and based on the ethnic differences in retinopathy presentation, the pattern
 Progression of Pericentral HCQ Retinopathy 19

410 and progression of retinopathy in our patients may differ from those in other

411 ethnicities.

412 In summary, this study found severity-dependent progression of HCQ

413 retinopathy. Moderate pericentral retinopathy usually progressed, which is the

414 distinguishing feature of progression of pericentral retinopathy compared to that of

415 parafoveal retinopathy, but at a slower rate over time after drug cessation. Either

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416 circumferentially dominant progression or no progression in earlier stages and

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417 centripetal progression remarkable in the severe stage suggest the importance of

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early detection of retinopathy for reducing the potential risk of fovea-threatening

419 progression and vision loss in pericentral retinopathy.

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 Progression of Pericentral HCQ Retinopathy 20

421 REFERENCES

422 1. Marmor MF, Kellner U, Lai TY, et al. Revised recommendations on screening

423 for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118:415-

424 422.

425 2. Marmor MF, Kellner U, Lai TY, et al. Recommendations on Screening for

426 Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology.

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427 2016;123:1386-1394.

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428 3. Levy GD, Munz SJ, Paschal J, et al. Incidence of hydroxychloroquine

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430 Rheum. 1997;40:1482-1486.

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431 4. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term
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433 5. Mikkelsen J. [Ocular complications after treatment with antimalarial agents in

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435 6. Finbloom DS, Silver K, Newsome DA, Gunkel R. Comparison of

436 hydroxychloroquine and chloroquine use and the development of retinal toxicity. J

437 Rheumatol. 1985;12:692-694.

438 7. Marmor MF, Melles RB. Disparity between visual fields and optical coherence

439 tomography in hydroxychloroquine retinopathy. Ophthalmology. 2014;121:1257-1262.

440 8. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in

441 hydroxychloroquine toxicity. Ophthalmology. 2015;122:110-116.

442 9. Lee DH, Melles RB, Joe SG, et al. Pericentral hydroxychloroquine

443 retinopathy in Korean patients. Ophthalmology. 2015;122:1252-1256.

444 10. Ahn SJ, Joung J, Lee BR. Evaluation of Hydroxychloroquine Retinopathy
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445 Using Ultra-Widefield Fundus Autofluorescence: Peripheral Findings in the

446 Retinopathy. Am J Ophthalmol. 2020;209:35-44.

447 11. Ahn SJ, Joung J, Lim HW, Lee BR. Optical Coherence Tomography

448 Protocols for Screening of Hydroxychloroquine Retinopathy in Asian Patients. Am J

449 Ophthalmol. 2017;184:11-18.

450 12. Allahdina AM, Chen KG, Alvarez JA, et al. LONGITUDINAL CHANGES IN

451 EYES WITH HYDROXYCHLOROQUINE RETINAL TOXICITY. Retina. 2019;39:473-

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453 13. Pham BH, Marmor MF. SEQUENTIAL CHANGES IN

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455 THE DRUG: Implications for Mild Versus Severe Toxicity. Retina. 2019;39:492-501.
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456 14. Marmor MF, Hu J. Effect of disease stage on progression of

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457 hydroxychloroquine retinopathy. JAMA Ophthalmol. 2014;132:1105-1112.

458 15. Mititelu M, Wong BJ, Brenner M, et al. Progression of hydroxychloroquine

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459 toxic effects after drug therapy cessation: new evidence from multimodal imaging.
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460 JAMA Ophthalmol. 2013;131:1187-1197.

461 16. Kim KE, Ahn SJ, Woo SJ, et al. Use of Optical Coherence Tomography

462 Retinal Thickness Deviation Map for Hydroxychloroquine Retinopathy Screening.

463 Ophthalmology. 2020.

464 17. Ahn SJ, Ryu SJ, Lim HW, Lee BR. TOXIC EFFECTS OF

465 HYDROXYCHLOROQUINE ON THE CHOROID: Evidence From Multimodal

466 Imaging. Retina. 2019;39:1016-1026.

467 18. Ahn SJ, Lee SU, Lee SH, Lee BR. Evaluation of Retromode Imaging for Use

468 in Hydroxychloroquine Retinopathy. Am J Ophthalmol. 2018;196:44-52.

 Progression of Pericentral HCQ Retinopathy 22

469 19. de Sisternes L, Hu J, Rubin DL, Marmor MF. Localization of damage in

470 progressive hydroxychloroquine retinopathy on and off the drug: inner versus outer

471 retina, parafovea versus peripheral fovea. Invest Ophthalmol Vis Sci. 2015;56:3415-

472 3426.

473 20. Kellner S, Weinitz S, Farmand G, Kellner U. Cystoid macular oedema and

474 epiretinal membrane formation during progression of chloroquine retinopathy after

475 drug cessation. Br J Ophthalmol. 2014;98:200-206.

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476 21. Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for

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477 early detection of retinal alterations in patients using chloroquine/hydroxychloroquine.

478 Invest Ophthalmol Vis Sci. 2006;47:3531-3538.

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479 22. Lally DR, Heier JS, Baumal C, et al. Expanded spectral domain-OCT findings
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480 in the early detection of hydroxychloroquine retinopathy and changes following drug
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481 cessation. Int J Retina Vitreous. 2016;2:18.

482 23. Scarinci F, Shaarawy A, Narala R, et al. LOSS OF EXTERNAL LIMITING

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483 MEMBRANE INTEGRITY PREDICTS PROGRESSION OF

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484 HYDROXYCHLOROQUINE RETINAL TOXICITY AFTER DRUG

485 DISCONTINUATION. Retina. 2016;36:1951-1957.

486 24. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine

487 retinopathy. Eye (Lond). 2017;31:828-845.

488 25. Golestaneh N, Chu Y, Xiao YY, et al. Dysfunctional autophagy in RPE, a

489 contributing factor in age-related macular degeneration. Cell Death Dis.

490 2017;8:e2537.

491 26. Tsang AC, Ahmadi Pirshahid S, Virgili G, et al. Hydroxychloroquine and

492 chloroquine retinopathy: a systematic review evaluating the multifocal

 Progression of Pericentral HCQ Retinopathy 23

493 electroretinogram as a screening test. Ophthalmology. 2015;122:1239-1251 e1234.

494

495

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 Progression of Pericentral HCQ Retinopathy 24

496 FIGURE LEGENDS

497 Figure 1. Fundus autofluorescence (FAF, top) and optical coherence tomography

498 (OCT, bottom) images showing progression of pericentral hydroxychloroquine

499 retinopathy over time in representative cases with early, moderate, and severe

500 stages. Eyes with early stages show stability throughout the follow-up period (A) or

501 progression (indicated by arrowhead) limited during the short-term period (2 years)

502 following drug cessation (B). The eyes with moderate severity (C and D) show

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503 enlargement of hyperautofluorescence (C, denoted by double arrows) and

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504 appearance/enlargement of hypoautofluorescence (D, dotted polygon or double

505
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arrows). The eye with severe stage (E) shows remarkable enlargement of
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506 hypoautofluorescence, both in circumferential (dotted polygon) and
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507 centripetal/centrifugal (from short to long double arrows) manners. Horizontal (H)
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508 and vertical (V) OCT cross-sections show progression consistent with FAF findings

509 as the decreased distances from the fovea to the borders of photoreceptor defects in
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510 structurally progressed eyes. Vertical white lines on OCT indicate the borders
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511 between the intact and defective ellipsoid zone. The numbers in gray boxes denote

512 the year of follow-up visit from baseline (drug cessation).

513

514 Figure 2. Rates of change of retinal thickness (µm/year) over time in the central

515 fovea, parafovea, and perifovea on the Early Treatment Diabetic Retinopathy Study

516 grid in severity groups of pericentral hydroxychloroquine retinopathy. Error bars

517 denote 95% confidence intervals. Asterisks (*) indicate statistical significance (P <

518 0.05).

519
 Progression of Pericentral HCQ Retinopathy 25

520 Figure 3. Partial photoreceptor recovery in an eye with early hydroxychloroquine

521 retinopathy. Over the 3-year follow-up period, the length of the defect in the ellipsoid

522 zone line on optical coherence tomography gradually decreased (white arrows), and

523 the distance from the fovea to the photoreceptor defects increased (yellow arrows),

524 indicating photoreceptor recovery. Fundus autofluorescence showed less remarkable

525 hyperautofluorescence at Year 3 than at previous visits. However, 30-2 and 10-2

526 Humphrey visual field examinations showed variable results on scotomas in

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527 grayscale (left) and pattern deviation (right) maps and also on perimetric parameters,

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528 without any definite evidence suggesting functional recovery. MD = mean deviation;

529 PSD = pattern standard deviation

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531 Figure 4. Patterns of progression of pericentral damage on fundus autofluorescence

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532 (FAF) images in eyes with hydroxychloroquine retinopathy. Yellow and white

533 arrowheads indicate hyperautofluorescence and hypoautofluorescence, respectively.

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534 The eye with localized hyperautofluorescence shows a more demarcated,

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535 hyperautofluorescent lesion (top). Hyperautofluorescence shows either no or minimal

536 centripetal progression in eyes with extensive hyperautofluorescence or

537 hypoautofluorescence, whereas hypoautofluorescence shows centripetal and

538 circumferential expansion. In particular, centripetal progression is remarkable in the

539 eye with extensive, ring-shaped hypoautofluorescence (bottom). The numbers in

540 gray boxes denote the year of follow-up visit from baseline.

541

542 Figure 5. Functional progression of hydroxychloroquine retinopathy in a

543 representative case with the severe stage (A) and overall rate of change in mean
 Progression of Pericentral HCQ Retinopathy 26

544 deviation and pattern standard deviation in subgroups of pericentral retinopathy

545 divided based on severity of retinopathy (B). Horizontal bars in each group indicate

546 mean (longer) and range (shorter).

547

548 Figure 6. An illustration showing the area scanned by different optical coherence

549 tomography protocols in relation to the pattern of retinopathy progression in a

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550 representative Asian patient with hydroxychloroquine retinopathy. At an earlier stage

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551 (left), retinopathy typically progresses in a circumferential manner around the

552
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vascular arcades. This is unlikely to be detected by standard horizontal or vertical
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553 line scans. However, at a later stage (right), retinopathy usually progresses toward
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554 the fovea, and this is more likely to be detected by all of the scans. Blue arrows

555 indicate the direction of retinopathy progression.

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Precis
Pericentral hydroxychloroquine retinopathy showed severity-dependent progression.
Moderate pericentral retinopathy usually progressed, but centripetal progression
threatening the fovea was remarkable in severe retinopathy. Early detection of
pericentral retinopathy may minimize the risk of fovea-threatening progression.

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Table 1. Demographic data and clinical characteristics of the patients with
hydroxychloroquine retinopathy included in this study

Number (%) or mean ± SD

Characteristics
(range)
Diagnosis, SLE:RA 30:11 (73.2:26.8)

Age, years 56.1 ± 10.4 (37–77)

Sex, female 40 (97.6)

Follow-up period, months 47.0 ± 22.1 (24–109)

Time from drug cessation to the first follow-up visit 5.8 ± 5.9 (1-24)

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Duration of HCQ use, years 13.3 ± 5.2 (3.5–24)

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Daily dose of HCQ, mg 258.0 ± 83.1 (131.3–400)

Daily dose of HCQ/BW, mg/kg -p 5.0 ± 1.8 (2.9–9.3)

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Daily dose of HCQ/BW > 5 mg/kg 14 (34.1)

Cumulative dose of HCQ, g 1307.1 ± 437.3 (397.6–2336)

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Cumulative dose of HCQ/BW, g/kg 25.5 ± 9.0 (8.1–43.8)

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Pattern of retinopathy, eyes with

9:60:11 (11.3:75:13.8)
parafoveal:pericentral:mixed patterns
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Severity of HCQ retinopathy, eyes with

24:18:38 (30:22.5:47.5)
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early:moderate:severe retinopathy
Continuous variables are presented as mean ± standard deviation.

BW: body weight; HCQ: hydroxychloroquine; RA: rheumatoid arthritis; SD: standard
deviation; SLE: systemic lupus erythematosus
Table 2. Proportions of structural progression during the short-term (2 years) and subsequent long-term periods after drug

cessation in eyes with pericentral retinopathy.

Short-term period, No. (%) Subsequent period, No. (%)

Group
FAF OCT FAF OCT
All 40/57 (70.2%) 42/59 (71.2%) 35/55 (63.6%) 36/55 (65.5%)
Severity groups*
Early† 5/19 (26.3%) 7/21 (33.3%) 0/17 (0) 0/17 (0)
†
Moderate 13/16 (81.3%) 13/16 (81.3%) 13/16 (81.3%) 14/16 (87.5%)
†
Severe 22/22 (100%) 22/22 (100%) 22/22 (100%) 22/22 (100%)
FAF: fundus autofluorescence; OCT: optical coherence tomography
*Subgroups were divided based on the severity of disease at the time of diagnosis (and also drug cessation).
†
Median (range) follow-up periods in the early, moderate, and severe groups were 40 (24-91), 49 (33-84), and 36 (24-109) months,
respectively.

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