Ocular Toxicity

Ocular toxicity is a common manifestation of long-term hydroxychloroquine use, therefore baseline and annual ocular monitoring is required during treatment. In this section we will be focusing on retinal toxicity since it is the most prevalent ocular toxicity associated with hydroxychloroquine.

4-aminoqinolines such as hydroxychloroquine (HCQ) and chloroquine (CQ) can have adverse effects on the eyes. There are numerous ocular toxicities that may occur during treatment with 4-AQ including choroid toxicity (alongside thinning of the choroid) as well as accumulation of 4-AQ in the cornea causing haloes and glare¹. Deposits of 4-AQ within the cornea are usually reversible upon cessation of treatment¹. However the most prevalent ocular toxicity which is commonly associated with use of 4-AQ's is retinopathy¹.

Retinal Toxicity (Retinopathy)

Retinal toxicity is currently characterised by the progressive degeneration of the photoreceptors and other cells of the retinal pigment epithelium (RPE) of the eye¹. Degeneration of the retina can be classified into 4 different stages¹:

"Preclinical" phase with a normal eye fundus and normal visual acuity,
"Clinical" maculopathy with anomalies within the eye fundus or visual acuity,
Bull's eye maculopathy (shown in video)
Blindness

In cases where retinal toxicity is diagnosed early, treatment with 4-AQ can be ceased and this may reduce or reverse some of the effects seen, however sometimes damage to the retina is irreversible¹.

Mechanism of Retinal Toxicity

Daily high doses (>5mg/kg/day) of CQ or HCQ can lead to irreversible retinopathy and ototoxicity (see ENT toxicity for more details about ototoxicity)^2-3. This is because 4-AQ such as CQ and HCQ accumulate in melanin-rich tissues such as the eyes, inner ears, and substantia nigra in the brain⁴.

The exact mechanism of retinal toxicity is currently unknown¹. The first proposed mechanism of toxicity is that, due to a build up of 4-AQ in the melanin-rich retinal pigment epithelium (RPE), there is an accumulation of lipofuscin and a loss of photoreceptor cells within the eye^1,5. 4-aminoquinolines inhibit the normal processes of recycling and destruction of organelles within the cells, and so therefore also inhibit the storage of lipofuscin leading to intracellular accumulation¹. 4-aminoquinolines are also alkalising agents, so inhibit pH-dependent activities of the cell including the activity of organic anion transporting polypeptide 1 A2 (OATP1A2), preventing the recycling of all-trans-retinol in the RPE - this also leads to an accumulation of lipofuscin^1,6.

There is also some suggestion that retinal damage by 4-AQ doesn't initially happen within the RPE, but actually within the ganglion cells first and that the retinal layers of the eye are affected afterwards¹.

Prevalence & Monitoring

Prevalence of retinal toxicity is still unknown, but estimated to currently be around 7.5%^1,7. There is hesitancy about the exact prevalence since until recently it was thought to be between 0.5 and 2%, and only increased due to advances in screening methods and technology¹. Broken down, toxicity is currently estimated to be <2% within the first 10 years of use, but about 20% after 20 years of use - dosage dependent¹.

Monitoring of the eyes and retina is essential to try to avoid any long-term effects of retinal toxicity. The current NICE guidelines recommend a baseline examination within the first year of drug treatment as well as annual monitoring for patients on long-term therapy (>5 years)⁸. The American Association of Ophthalmology (AAO) has more specific screening with varying recommendations based on patient ethnicity³. Find more information about retinal monitoring on the Toxicity Management page.

There are a number of risk factors for retinal toxicity including the daily dose, comorbidities such as chronic kidney disease, older age, female sex, high BMI, and genetic predisposition^1,3.

Explore other Toxicities & Adverse Effects

References:

1. Muller R. Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factor, prognostic and screening possibilities. Rheumatology International. 2021, 41, pp1189-1202.

2. Aduriz-Lorenzo P, Aduriz-Llaneza P, Araiz-Iribarren, & Khamashta M. Current opinion on hydroxychloroquine-related retinal toxicity screening: where do we stand now? Lupus. 2020, 29(7), pp671-674.

3. American Academy of Ophthalmology. Recommendations on screening for Chloroquine and Hydroxychloroquine retinopathy-2016 [Online]. 2016. [Date accessed: 21/11/2021]. Available from: https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h#top

4. Browning D. Pharmacology of Chloroquine and Hydroxychloroquine. Nature Public Health Emergency Collection. 2014. pp 35-55.

5. Ilowite N & Laxer R. PHARMACOLOGY AND DRUG THERAPY. In: Cassidy J, Laxer R, Petty R, & Lindsley C. eds. Textbook of Pediatric Rheumatology. Philadelphia. Saunders Elvesier, 2010, pp 76-126.

6. Yusuf I, Sharma S, Luqmani R, & Downes S. Hydroxychloroquine Retinopathy. Eye. 2017, 31, pp 828-845.

7. Goldman D. 10.1 - Hydrosychloroquine toxicity. In: Goldman R, Waheed N, & Duker J. eds. Atlas of Retinal OCT: Optical Coherence Tomography. Elvesier, 2017, pp 68-71.

8. NICE. What monitoring is required for hydroxychloroquine? [Online]. 2021. [Date accessed: 22/11/2021]. Available from: https://cks.nice.org.uk/topics/dmards/management/hydroxychloroquine/

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