|Ahead of print publication
Detection and correlation of changes on perimetry and optical coherence tomography in patients on chronic usage of hydroxychloroquine: A Cross-Sectional StudyDetection and Correlation of changes on Perimetry and Optical coherence tomography in patients on Chronic Usage of Hydroxychloroquine: A cross-sectional study
Yamini Priya1, Puneeth Isloor1, Usha Vasu1, Sumithra Selvam2, Vineeta Shobha3
1 Department of Ophthalmology, St. John's Medical College Hospital, Bengaluru, Karnataka, India
2 Division of Epidemiology and Biostatistics, St. John's Research Institute, St. John's Medical College Hospital, Bengaluru, Karnataka, India
3 Department of Clinical Immunology and Rheumatology, St. John's Medical College Hospital, Bengaluru, Karnataka, India
|Date of Submission||09-Nov-2021|
|Date of Acceptance||16-Jun-2022|
|Date of Web Publication||20-Sep-2022|
Department of Clinical Immunology and Rheumatology, St. John's Medical College Hospital, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Early detection of retinal toxicity in patients on chronic usage of hydroxychloroquine (HCQ) and thereby the prevention of irreversible visual loss is an important goal.
Methods: We performed a comprehensive ophthalmologic examination, visual field testing and macular scanning using spectral-domain optical coherence tomography (SD-OCT) and Humphrey Visual Field (HVF) 10-2 perimetry in chronic HCQ users (>1 year). Participants were grouped based on the duration of HCQ exposure (<2 years, 2–5 years; and >5 years) and compared all the ophthalmologic parameters between the groups.
Results: We included 110 patients (68 rheumatoid arthritis and 42 systemic lupus erythematosus), mean age being 38.5 ± 8.9 years, and median cumulative HCQ dose was 292 (interquartile range: 146,438) g. There were significant differences in parafoveal and perifoveal thickness between the three study groups <2 years (n = 42), 2–5 years (n = 55), and >5 years (n = 13) (P < 0.05) which were evident as early as 2 years of usage. Further, the OCT parameters showed a significant correlation with perimetry changes (P < 0.001), macular thinning, color vision, and fundus changes.
Conclusion: We demonstrate that SD-OCT and HVF 10-2 perimetry are complementary to each other and can be used to detect early retinal toxicity as early as 2 years of HCQ exposure.
Keywords: Humphrey visual field, hydroxychloroquine, optical coherence tomography, retinal toxicity, screening tests
|How to cite this URL:|
Priya Y, Isloor P, Vasu U, Selvam S, Shobha V. Detection and correlation of changes on perimetry and optical coherence tomography in patients on chronic usage of hydroxychloroquine: A Cross-Sectional StudyDetection and Correlation of changes on Perimetry and Optical coherence tomography in patients on Chronic Usage of Hydroxychloroquine: A cross-sectional study. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 3]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=356480
| Introduction|| |
Hydroxychloroquine (HCQ), an anti-malarial drug, is used in the treatment of many immunologically mediated rheumatologic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory myositis, and dermatologic conditions., Ocular toxicity to HCQ was initially described in 1967. The occurrence of ocular toxicity is approximated as 1% after 5–7 years of use or a cumulative dose of 1000 g of HCQ., The classical clinical picture of HCQ toxicity had been bilateral bull's eye maculopathy (BEM) caused by a ring of parafoveal retinal pigment epithelial (RPE) depigmentation and marked by paracentral and/or central scotoma with altered color vision. In Asians, initial damage may be located outside the central macula, near the arcades.
The exact mechanism of HCQ retinal toxicity is still unclear. Some preclinical studies have shown that pathological changes were seen in photoreceptor and retinal pigment epithelial cells., In addition, retinal toxicity may be irreversible and may progress even after its discontinuation.
However, when retinal toxicity is recognized early, significant damage threatening fovea and thereby vision loss can be prevented. Thus, the American Academy of Ophthalmology (AAO) has recently revised recommendations for HCQ screening and has recommended that screening should include a comprehensive ophthalmic examination with Spectral Domain-optical coherence tomography (SD-OCT) and Humphrey Visual Field (HVF) 10-2 Perimetry as primary screening tests., Therefore, it is important for ophthalmologists to identify the patterns on SD-OCT and HVF that indicate HCQ toxicity. Furthermore, the additional tests which are recommended for screening of retinal toxicity include multifocal electroretinogram (mfERG) and fundus autofluorescence.,,,,, Moreover, mfERG is available only in large specialized ophthalmic centers.
Limited data are available for the correlation of SD-OCT and HVF in RA and SLE patients for HCQ retinal toxicity from our country.,,,, Thus, we have evaluated the correlation of SD-OCT and HVF in chronic users of HCQ intending to detect early retinal alterations before any significant RPE damage and permanent visual loss.
| Methods|| |
This was a cross-sectional study conducted at the Department of Ophthalmology in association with the Department of Clinical Immunology and Rheumatology, at a referral teaching hospital in Southern India. One hundred and ten consecutive adult patients with autoimmune disorders were included who were on continued treatment with HCQ for at least 1 year. All patients were recommended HCQ dosing adjusted as per their body weight.
Patients with pre-existing retinal diseases such as glaucoma, diabetic retinopathy, age-related macular degeneration, central serous retinopathy, retinitis pigmentosa, optic atrophy, and retinal detachment were excluded. Furthermore, those with media opacities such as corneal opacity, mature cataract, vitreous hemorrhage which hinders OCT examination were excluded. Patients with high refractive errors such as high axial myopia of -6D and above and high axial hypermetropia of + 6D and above were also excluded. Data were collected using a predefined structured case record form, which included dosage and duration of HCQ usage, in addition to ocular and medical history. Concomitant disease modifying antirheumatic drugs and immunosuppressants for underlying autoimmune disorders was continued as per the discretion of the treating rheumatologist.
Patients were stratified into three groups based on the duration of HCQ usage, <2 years (Group 1), 2–5 years (Group 2), and a period of >5 years (Group 3). All patients underwent comprehensive ophthalmologic examination of both eyes including the external ocular examination (slit lamp), visual acuity (illuminated early treatment diabetic retinopathy study chart scored as per the LogMAR scale), near vision (times new Roman chart), color vision (Ishihara's charts), and macular function (Amsler's Grid). In addition, slit lamp and fundus examinations were performed using a 90D lens, direct and indirect ophthalmoscopy. Evaluation for dry eye was performed by Schirmer's test on both eyes. Intraocular pressure was measured using Perkins Applanation Tonometry.
Macular Cube testing of 512 × 128 was carried out for both the eyes using Cirrus HD-OCT (4000-1720) SD technology version 18.104.22.168© Carl Zeiss Meditec Inc. The map of macular thickness which is composed of three concentric circles was assessed. The central circle comprises the fovea with a radius of 1 mm, an inner circle comprises the parafoveal region with a radius of 3 mm, and the outer circle comprises the perifoveal region with a radius of 5 mm. The macular thickness was measured from the internal limiting membrane to the retinal pigment epithelium basement membrane in all four quadrants – temporal, nasal, superior, and inferior in the perifoveal and parafoveal regions. The average thickness of the four quadrants was calculated to obtain average perifoveal and average parafoveal thickness. The presence or absence of thinning of the whole macula or part of the macula was noted using color coding of the retinal thickness map obtained on the OCT printout. A color coding of red or yellow on the macular thickness map printout was considered to indicate the presence of macular thinning.
HVF testing with the central 10-2 program (HFA II-750i) was carried out on both eyes of the participants. The presence of a paracentral or total ring scotoma between 2° and 6° with central sparing was taken as positive evidence of early HCQ-related changes and considered a qualitative parameter. The mean deviation (MD) value on perimetry was taken as a quantitative parameter. The procedures performed were following the Declaration of Helsinki. The Institutional Ethics Committee approved the study.
SPSS (Version 25, SPSS Inc. Chicago, USA) program was used for the statistical analysis. Descriptive statistics were calculated using mean ± standard deviation for quantitative variables. For categorical variables, frequency and percentages were calculated. The assumption of normality was assessed using the Q-Q plot. One-way ANOVA was used to compare the perifoveal, parafoveal, and foveal thickness between the study groups. Bonferroni post hoc analysis was used to test the multiple comparisons. Kruskal–Wallis test was used to compare the MD on perimetry values between the study groups. A Chi-square test was used to test the association between perimetry changes, color vision, and visual acuity among the study groups. Analysis of covariance was performed to compare perifoveal, parafoveal, and foveal thickness between the study groups adjusted for age, sex, and cumulative dose. Spearman rank or Kendall's tau correlation analysis was performed in the determination of a relationship between the parameters and a P < 0.05 was considered to be statistically significant. The correlations were done considering eyes while the demographics and descriptive were done considering individual patients.
| Results|| |
A total of 220 eyes of 110 patients were evaluated, the mean cumulative dose of HCQ was 382.91 g (range- 73–1460 g). Their demographic characteristics and HCQ usage are tabulated in [Table 1]. Of them, 68 patients were RA, 42 had SLE and all had used HCQ for a minimum period of 1 year. There were 42 (38.2%) patients in Group 1, 55 (50%), and 13 (11.8%) in Group 2 and Group 3 respectively corresponding to HCQ exposure of <2 years, 2–5 years, and >5 years.
The parafoveal, perifoveal, and foveal thickness in the three groups is presented in [Table 2]. The mean parafoveal and perifoveal thickness was significantly lower in Groups 2 and 3 compared to Group 1 (P < 0.001); however, there was no significant difference between the values in Groups 2 and 3. This difference between the three study groups remained significant after adjusting for age, sex, and the cumulative dose of HCQ (P < 0.01). Although there was no significant difference in the foveal thickness (P = 0.09) between the three groups, it was observed that in Group 3 foveal thickness was numerically lower. The percentage of eyes with macular thinning was significantly more in Group 3 (69.23%) and Group 2 (63.63%) as compared to Group 1 (32.14%) (P < 0.001).
|Table 2: Comparison of age, gender, and outcome parameters between the three study groups|
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Normal perimetry findings were most frequent in Group 1 relative to Groups 2 and 3. The frequency of eyes with paracentral scotomas was higher in Group 2 compared to Group 1 and Group 3. The percentage of eyes with ring scotomas was higher in Group 3 (15.38%) compared to the other two groups (1.19% and 7.27%, respectively). It was observed that the field defect increases with an increase in the duration of HCQ usage.
The OCT parameters (parafoveal, perifoveal, and foveal thickness) showed a significant correlation (P < 0.001) with other parameters such as perimetry changes, MD on 10-2 HVF, macular thinning, color vision, and fundus changes [Supplementary Table 1]. The fundus changes were mainly dull foveal reflex (33 of 220 eyes) and BEM (4 of 220 eyes) [Supplementary Figure 1] & [Supplymentary Figure 2]. BEM was seen in two patients (4 eyes), both belonging to Group 3 with a duration of >5 years and cumulative dose of 730 mg and 1168 mg. Abnormal color vision was seen in only one patient (2 eyes) of Group 3 who had BEM.
| Discussion|| |
This cross-sectional study aimed to detect and correlate the changes in SD-OCT and HVF 10-2 perimetry among chronic HCQ users at an early stage before the occurrence of significant irreversible retinal damage. We found significant differences in parafoveal and perifoveal thickness, macular thickness on SD-OCT, and perimetry changes among the three groups categorised based on the duration of HCQ exposure. The difference in duration of HCQ exposure between Group 1 and Group 3 is a minimum of 4 years. Further, the parafoveal, perifoveal and foveal thickness showed a significant correlation with other parameters such as perimetry changes, MD on 10-2 HVF, macular thinning, color vision, and fundus changes.
We observed a significant reduction in para and perifoveal thickness and noted the presence of paracentral scotomas in more than half on perimetry even in the group with 2–5 years of HCQ exposure which signifies the importance of screening earlier than 5 years which is the cut-off suggested by AAO. Similar finding of significant thinning of the perifoveal retina in the group with 1–5 years of HCQ usage when compared to normal controls was found in a study by Ulviye et al.
Our cohort was much younger, mean age being <40 years, as compared to other similar studies which were conducted by Ulviye et al. (49 years), Pasadhika and Fishman (54 years), Chen et al. (55 years), and Melles and Marmor (52.2 years) [Table 3].,,, Despite this, our cohort had a significant reduction in para and perifoveal thickness even after adjusting for age among all the groups.
|Table 3: Comparison of key baseline and ophthalmic parameters with that of previous similar publications|
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In our study, as suggested by AAO for the early detection of retinal toxicity, we used two primary screening modalities SD-OCT and HVF 10-2 perimetry. Perimetry revealed paracentral scotoma in 92 eyes and ring scotoma in 13 eyes, which is similar to previous publications.,, Same authors have demonstrated that with <5 years of HCQ exposure, perimetry may be normal while there may be perifoveal thinning on SD-OCT, which further substantiates its complementary role in screening for early retinal toxicity.
The OCT parameters such as average foveal, perifoveal, and parafoveal thickness showed a significant correlation with perimetry changes and also with macular thinning, color vision, and fundus changes. This stresses upon us the need to carry out both SD-OCT and HVF in patients on HCQ as one of them is subjective and functional while the other is objective and structural. Both can be complementary to each other when an attempt is made to pick up early abnormalities. A similar correlational analysis between the two investigational modalities (OCT and perimetry) was reported by Chen et al. Browning and Lee reported relative sensitivity and specificity of 10-2 visual fields, mf-ERG, and SD-OCT in detecting HCQ retinopathy. They found that the retinal thickness measurements on SD-OCT were reproducible and of particular worth compared to the other two ancillary tests. Therefore, all these studies re-iterate that a combination of the two or more investigative modalities is more effective than a single one alone. However, the availability of mf-ERG is limited at most centers even in comprehensive ophthalmology setup in our geographic region. Therefore, a combination of SD-OCT and HVF can be used to detect the early features of HCQ toxicity as shown in our study.
We report dull foveal reflex in 33 eyes which was similar to findings seen in other similar studies [Table 3]. However, this interpretation is subjective and situational. Ulviye et al. have reported normal fundoscopy in those with a duration of treatment <5 years. Therefore, retinal changes on fundoscopy can be subtle and a late finding when significant RPE loss would have occurred and so it is not recommended as a screening tool.
Strengths of our study include large sample size and wide spectrum of patients with duration of treatment ranging from 1 to 10 years; more than 2/3rd had used HCQ for longer than 2 years. Furthermore, we have used both the primary screening tests recommended by AAO, i.e., SD-OCT and HVF 10-2 perimetry. We were limited by the inability to include wider field HVF (24-2 and 30-2) which is more likely to detect extramacular disease known to occur in the Asian population, and that we have not included a control group. Further attempts are required in a larger sample to determine the ideal time at which surveillance for HCQ ocular toxicity should be performed and provide guidance specific to geographic regions and various autoimmune rheumatic disease subsets.
| Conclusion|| |
This study reconfirms SD-OCT changes and demonstrates a decline in retinal thickness as early as 2–5 years of HCQ exposure which constitutes almost half of the study population. We also confirmed the correlation between OCT parameters such as foveal, perifoveal, and parafoveal thickness and perimetry changes (P < 0.001), macular thinning, color vision, fundus changes. SD-OCT and HVF which are available at most ophthalmology outpatient settings can be effectively utilized for the early detection of HCQ toxicity.
Procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Declaration of Helsinki. The study is approved by the Institutional Ethics Committee St. John's Medical College, St. John's National Academy of Medical Sciences. All participants consented to participation.
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We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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[Table 1], [Table 2], [Table 3]