Introduction
Hydroxychloroquine is an immunomodulator drug often used as a disease-modifying antirheumatic drug (DMARDs) and acts by inhibition and modulation of immune responses. Hydroxychloroquine also used in many conditions including diabetes mellitus, heart disease, graft-versus-host disease, adjunctive cancer therapy, systemic vasculitis and Coronavirus Disease 2019 (COVID-19).1, 2, 3, 4
Hydroxychloroquine retinal toxicity is a serious condition with potential retinal damage and has a higher prevalence than previously documented.5 The mechanism involved binding of hydroxychloroquine to the melanin of retinal pigmented epithelium, inhibits its activity over a prolonged period,6 causing thinning to both the inner and outer retina.7 Other mechanism is retinal vasculitis with retinal microinfarcts initiating the RNFL and macular thinning (inner retina), and arteriolar narrowing and disc pallor in higher concentration.8 Rare mechanism with early toxicity occurred with genetic predisposition to hydroxychloroquine9 and polymorphisms in the cytochrome P450 gene that increased hydroxychloroquine blood concentration.10
Visual acuity is usually good until the development of severe toxicity, so any efficient screening should detect structural changes (retina damage) before functional deterioration. Spectral Domain Optical Coherence Tomography (SD-OCT) is an important addition for early detection of hydroxychloroquine toxicity. The SD-OCT cross-section images at mild toxicity are subtle or unremarkable. Moderate toxicity has a distinctive discontinuity of the photoreceptor inner segment/outer segment.11 With time, the outer nuclear layer thinning occurred.12 However, the outer retinal thickness remains normal despite the destruction of outer segment photoreceptors creating the “flying saucer’’ or sombrero sign.13 Severe toxicity includes disruption of the outer retina and RPE.
The recommended dose of hydroxychloroquine, ophthalmology baseline, and follow-ups plus the screening tools changes over the years was summarized in (Table 1). The paradigm shift of these guidelines tally with discoveries of increased prevalence and the reversible retinal changes with early detection and intervention using SD-OCT. The current recommended dose is 5mg/kg real body weight per day with a baseline SD-OCT and re-imaging at 5 years of hydroxychloroquine usage to most patients classified as a low-risk group.5
Many cross-sectional studies using SD-OCT have shown earlier retina damages, but none had measured continuously from the beginning of hydroxychloroquine usage. Thus, the purpose of this pilot prospective cohort study is to evaluate the sequential changes of retina thickness in patients newly treated with hydroxychloroquine using the latest guideline recommendations.
Materials and Methods
This study was conducted after obtaining approvals from the Ethical Committee of Universiti Sains Malaysia and the Ministry of Health of Malaysia per the Declaration of Helsinki for Human Research (USM/JEPeM/ l6060209 and NMRR-16-116-28987 (IIR)). The sample size was calculated using closest studies using G*Power version 3.1.9.2 for Windows available at http://www.gpower.hhu.de We have summarized the methodology in (Figure 1). Written consent was obtained from all patients.
These patients underwent complete ocular and systemic history with the full ocular examination via slit lamp biomicroscope (Topcon Corp, Japan) and Volk Super 66 stereo fundus lens and then OCT macula and Optic disc (Cirrus-HD OCT 4000 software version 5.0, Carl Zeiss Meditec, Inc, Dublin, CA) pre, and 6 months of hydroxychloroquine treatment. At 3 months of hydroxychloroquine treatment, only OCT measurements were obtained in patients except for any visual symptoms where a complete ocular examination was conducted. Only tests that yielded signal strength of at least 6 and above were taken for interpretation to ensure the accuracy of the result.
A total of 33 patients were recruited. Two patients did not fulfill the selection criteria and five patients were lost to follow up. 26 patients were studied as per the protocol and included for analysis. Data collection and analysis were performed using the Statistical Package for the Social Sciences (SPSS) version 24 (SPSS, Chicago, IL, USA). Descriptive statistics were used to summarize the basic characteristics of the patients. Normally distributed data were expressed as mean ± standard deviation. All values were tested for normal distribution in all groups. Repeated Measured ANOVA test used to compare the macular thickness and RNFL thickness pre, 3 months, and 6 months. A P value of less than 0.05 (P<0.05) was considered significant.
Results
Demographic data
We summarize demographic characteristics of the patients in (Table 2). Our patients were young with a mean age of 33.92 years. Females were predominant (76.9%). Malay race was the most (50%). SLE is the most common disease (57.7%). Generally, all the patients having good visual acuity and vision remain unchanged for the period of this study except the 3 patients with 6/12 visual acuity who improved with glasses prescription and/or artificial tears.
Table 1
Paradigm shifts in the recommendation of guidelines on hydroxychloroquine screening
|
|
RCOphth, 199314 |
RCOphth, 199815 |
AAO, 200216 |
RCOphth, 200417 |
RCOphth, 200918 |
AAO, 201119 |
AAO, 201720 |
RCOphth, 201821 |
|
Recommended dosage |
6.5 mg/kg lean weight |
6.5 mg/kg lean weight |
6.5 mg/kg lean weight |
6.5 mg/kg lean weight |
6.5 mg/kg lean weight |
6.5 mg/kg lean weight |
5.0 mg/kg real weight |
5.0 mg/kg real weight |
|
Baseline screening |
Recommended ophthalmology examination when starting, with VA, fundus and HVF 10-2 |
Respective discipline monitor with renal and liver function, history of visual symptoms, near VA Referral to ophthalmology if vision derangement or reduced VA |
Assessment should be done by an ophthalmologist within 1 year, of starting therapy High risk: |
Respective disciplines monitoring Suggested for ophthalmology assessment Referral to ophthalmology if vision derangement or reduced VA |
Respective disciplines monitoring with Amsler Chart (preferably red on black) and/or HVF 10-2
Referral to an optometrist if any visual complains Suggested for ophthalmology assessment |
Advised for an ophthalmologist assessment when starting High and Low risk as AAO 2002 |
Assessment should be done by an ophthalmologist within 1 year, of starting therapy Major toxicity factors:
Lesser toxicity factors: |
Assessment should be done by an ophthalmologist within six months, but not more than 12 months, of starting therapy with a colour retinal photograph and SD-OCT scans of the macula Major and Lesser toxicity factors as AAO 2017 |
|
Ophthalmology further screening |
Nil |
Nil |
After 5 years if low risk (earlier based on age) or annual if high risk |
At 5 years |
At 5 years |
At 5 years or cumulative dose of 1000 g of hydroxychloro -quine |
After 5 years if low risk (earlier based on age) or annual if presence of major risk |
After 5 years if low risk (earlier based on age) or annual if presence of major risk |
|
Important tools for screening |
VA and Amsler Test |
VA and Amsler Test |
VA, Amsler Chart and/or HVF 10-2 Multi focal ERG is still in investigation |
VA and Amsler Chart |
Fundus photography. Amsler Chart (red on black) Suggested OCT, FAF imaging and visual electrophysiological tests |
HVF 10-2 with white target Suggested SD-OCT, FAF and/or multi focal ERG |
SD-OCT and HVF (10-2 for Caucasian and 24-2 or 30-2 for Asian) |
SD-OCT, widefield FAF and HVF 10-2 HVF 30-2 if abnormal FAF HVF defect with normal SD-OCT and FAF require multi focal ERG |
|
Not recommended for screening |
Nil |
Nil |
Nil |
Nil |
Nil |
Fundus Photography, Time Domain OCT, Fluorescein angiograph, Full field ERG, Amsler grid, Colour testing and EOG |
Fundus Photography, Time Domain OCT, Fluorescein angiography, Full field ERG, Amsler grid, Colour testing and EOG |
VA, Fundus Photography, Time Domain OCT, Fluorescein angiography, Full field ERG, Amsler grid, Colour testing and EOG |
|
Long term follow-up |
No further ophthalmic examination is necessary unless the patient becomes symptomatic |
Individual arrangements after 5 years |
None for low risk, Annual for high risk |
May not be required in patients taking low (6.5 mg/kg) doses of hydroxychloro -quine |
Most patient does not require follow-ups after check at 5 years |
Annual screening in all patient after 5 years |
Annual screening in all patient after 5 years |
Annual screening in all patient after 5 years |
[i] RCOphth: Royal College of Ophthalmologists; AAO: American Academy of Ophthalmology; HVF: Humphrey visual field; ERG: Electro-retinogram; EOG: Electro-oculogram; VA: Visual Acuity; SD-OCT: Spectral Domain Optical Coherence Tomography; FAF: Fundus Autofluorescence; Italic words: Updated in the latest guidelines; Bold & Italic words: Removed from the latest guideline
Table 2
Demographic characteristics of patients, (n=26)
Comparing the central macular thickness and optic disc retinal nerve fiber layer thickness (RNFL) using Cirrus SD-OCT in patients with connective tissue diseases on hydroxychloroquine pre-treatment, 3 months, and 6 months post-treatment.
Comparison of mean central macular thickness and optic disc RNFL thickness were summarized in (Table 3). Generally, the macula and RNFL were thinner post-treatment. Significant thinning occurred at superior, temporal, and inferior parafoveal areas and at temporal quadrant RNFL.
Comparison of the mean central macularand optic disc retinal nerve fiber layer (RNFL) thickness using Repeated Measured ANOVA test, n=26.
Table 3
Comparison of the mean central macular and optic disc retinal nerve fiber layer (RNFL) thickness using Repeated Measured ANOVA test, n=26
Post-hoc Bonferroni correction was done to establish changes of the significant retina thinning from (Table 3) over 3 months and 6 months and is summarized in (Table 4). The inferior parafoveal area showed significant retinal thinning at 3 months and 6 months when compared with the pre-treatment group.
Table 4
Post-hoc Bonferroni correction to establish changes of the significant retina thinning from Table 4
Linear Regression analysis to predict future thinning in the mean optic disc RNFL and the perifoveal areas based on parafoveal thinning from (Table 4) is summarized in (Table 5). All areas showed significant findings with the mean optic disc RNFL thickness significantly affected lesser (p =0.004, r2 =0.302) than the perifoveal area (p =0.001, r2 =0.784) when compared to the parafoveal thinning. Correlation analysis (Not Shown in the table) between parafoveal thinning and the mean optic disc RNFL also showed a significant result (p =0.004, r=0.55).
Table 5
Linear Regression analysis to predict future thinning in the perifoveal areas and mean optic disc RNFL on parafoveal thinning from Table 4.
Discussion and Conclusion
This study showed that there were significant thinning in mean macular thickness at parafoveal superior, temporal, and inferior areas. (Table 3). These changes could be the precursor to a future localized area of photoreceptor loss noted in moderate toxicity by SD-OCT. Our timelines are much earlier than Eric Chen et al13 who showed that the perifoveal thinning can be identified by SD-OCT in patients receiving hydroxychloroquine by 2 years. Likewise, SD-OCT cross-section quantitative analysis of the macula by Pasadhika et al22 found significant thinning of mean inner retinal thickness with the usage of hydroxychloroquine as early as 6 years even before ophthalmoscopic fundus changes. However, a recent study of hydroxychloroquine among SLE patients had shown that there are insignificant retinal changes with SD-OCT over 5 years duration.23 But, over 99% of their patients take less than 5 mg/kg/day of HCQ and more than 92% prescribed a dose 250 mg/day which differs enormously in daily practice. Thus, repeated measurements of macular thickness to detect early thinning is relevant while quantitative analysis (such as HD Raster with 6mm Vertical x 9mm Horizontal scan area) would only be fruitful at a later stage.
The parafoveal inferior area showed significant retinal thinning at 3 months and 6 months after hydroxychloroquine usage (Table 4) which corresponded to the typical pattern of this toxicity and coincided with a recent large study of patients using hydroxychloroquine for less than 5 years duration.24 However, two studies had documented that the typical parafoveal distribution of toxicity is not common in Asians, who show a pericentral pattern of foveal thinning.25, 26 But this perifoveal pattern in the first study was observed in Korean patients while the second study although include East Asian, Southeast Asian, and Filipinos, the total percentage of Asian was only 18%. They also found that 76% of patients had typical parafoveal changes, while only 12% each showed a perifoveal or mixed pattern. In our study, focusing on Asian patients, we found parafoveal involvement to be the first sign of toxicity. Similarly, the latest review in Korean patients showed predominantly parafoveal and mixed patterns.27 Another study showed that Hydroxychloroquine initially involves the parafovea, but becomes diffuse across the macula as damage progresses.28 With parafoveal thinning being a typical pattern, repeat of SD-OCT prior to 5 years should be done and compared to baseline values and once there is thinning should prompt for HVF 10-2 in Asians (instead of HVF 24-2) as it has better resolution and still able to detect the perifoveal defect.
The typical parafoveal thinning could predict future thinning in other areas as shown in our study (Table 5). Among all, perifoveal area showed the highest impact as compared to fovea because fovea is protected by foveal avascular zone. Thus, repeat of SD-OCT prior to 5 years should look for new areas of thinning instead of looking for worsening of the value of the same area. Parafoveal area thinning could also influence the mean disc RNFL thickness and this new finding could be important in future studies to identify the nature of the toxicity and performing appropriate screening tests.
Our study also showed RNFL thinning (at temporal quadrant) (Table 3) in patients taking hydroxychloroquine but compared to the macula thinning we could not establish a significant change at 3 months or 6 months (Table 4). There are limited studies in this area. GY Liu et al.19 showed that there is significant retinal nerve layer thinning besides macula thinning in SLE patients with chronic hydroxychloroquine usage. Another study found the patients using hydroxychloroquine for a mean of 13.4 years had thinner mean retinal nerve fiber layers values than healthy patients.14 Interestingly, an older study found significant thinning of RNFL nasal quadrant using quantitative analysis at 5 years of usage and postulated that it because of significant retinal ganglion cell degeneration. Measurement of the macular ganglion cell-inner plexiform layer (GC-IPL) over time may establish a new link this toxicity.15
The main limitation of our study is a short time of observation as further follow-ups could show transformation into structural defects. We also cannot measure the blood hydroxychloroquine level to establish compliance as proper testing is unreliable or still in development.
The fundamental challenge in managing retinal hydroxychloroquine toxicity is the possibility of toxicity before 5 years of usage. A large population study conducted in the United Kingdom in 2018 showed excess dosing of hydroxychloroquine than the recommended ophthalmology level16 as it is quite commonly prescribed as 200mg or 400mg daily dose.17 Another study also revealed that half of the patients had weight documented before prescription but not used to determine the doses.18 Further, a safe dose of 5mg/kg real bodyweight places short, obese patients at unnecessarily increased risk for retinopathy.20 It is also not uncommon that patients may develop renal disease or experience weight loss (and a higher dose) after 1 year and these patients will probably not realize they are high risk and will go without follow-up for 4 more years.21 Meanwhile, only 86% were aware that they require eye checks after five years of hydroxychloroquine use, and even worse, 20% were not compliant.29 Also, these patients’ eye reports are likely hard to acquire after 5 years.
Addressing this challenge, SD-OCT is crucial for the detection of early hydroxychloroquine retinal toxicity. And once the toxicity was detected, and the drug withheld before RPE damage, the progression is mild and limited (Reversible toxicity).30 If the drug is continued, the area of functional disturbance expands with RPE involvement and encroach fovea and stopping the drug in this stage will not prevent further deterioration of vision (Irreversible toxicity).26 Second SD-OCT imaging performed before 5-years duration, after baseline assessment may detect potential earliest retina thinning and, once there is a thinning, other modalities such as HVF 10-2, FAF, or mfERG could be used. SD-OCT also easily available and could be a cost-effective way of screening. The future applications of OCT include OCT angiography to detect the earliest microvascular changes31 and the wide-angle mode swept source OCT(SS-OCT) for its accuracy and a wider area.32
In summary, SD-OCT could evaluate potential hydroxychloroquine retinal toxicity better, and we should perform it early and repeatedly.
Acknowledgments
We are indebted to the Rheumatological, Medical, and Dermatological departments of Hospital Raja Permaisuri Bainun contributing for the patients’ pool as well as to Dr. Siti Azrin Abdul Hamid and Liu Kien Ting from the Department of Biostatistics and Research Methodology who assisted us during proposal preparation and statistical analysis respectively.
