Publications

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.

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.[12] Ocular toxicity to HCQ was initially described in 1967.[3] The occurrence of ocular toxicity is approximated as 1% after 5–7 years of use or a cumulative dose of 1000 g of HCQ.[45] 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.[6]

The exact mechanism of HCQ retinal toxicity is still unclear.[7] Some preclinical studies have shown that pathological changes were seen in photoreceptor and retinal pigment epithelial cells.[89] In addition, retinal toxicity may be irreversible and may progress even after its discontinuation.[10]

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.[1112] 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.[131415161718] 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.[1920212223] 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 5.2.1.12© 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.