Arslan Raja
Introduction
Hydroxychloroquine is an antimalarial agent with immunomodulatory properties, widely used in UK clinical practice for chronic inflammatory diseases. Its favourable safety profile and cost-effectiveness have led to increasing long-term use within the NHS (1).
However, hydroxychloroquine retinopathy is a recognised complication that may lead to permanent visual loss. Importantly, retinal toxicity may progress even after cessation of therapy, highlighting the need for early detection (2). UK-specific guidance has evolved in response to evidence suggesting that toxicity is more common than previously thought, necessitating systematic screening pathways (1).
Pathophysiology
Hydroxychloroquine accumulates within the retinal pigment epithelium (RPE), where it binds to melanin and remains for prolonged periods (3). This accumulation disrupts lysosomal function and impairs autophagy, leading to degeneration of photoreceptors and RPE cells.
Damage typically begins in the parafoveal region, resulting in thinning of the outer retina and disruption of the ellipsoid zone. In advanced disease, this produces the characteristic bull’s eye maculopathy, reflecting widespread RPE damage (4).
The toxic effects are dose-dependent and cumulative, with prolonged exposure increasing the likelihood of irreversible structural damage.
Epidemiology and Risk Factors
Recent UK-aligned data suggest that hydroxychloroquine retinopathy occurs in approximately 7.5% of long-term users, with prevalence increasing significantly with duration of therapy and cumulative dose (5).
Major Risk Factors
- Daily dose >5 mg/kg (real body weight) (1)
- Duration of therapy >5 years (1)
- Concomitant tamoxifen use
- Renal impairment (reduced drug clearance)
Additional Risk Factors
- Pre-existing retinal disease
- Increasing age
The “5 × 5 rule” (dose <5 mg/kg and screening after 5 years) is commonly used in UK practice as a practical framework for minimising risk (6).
Clinical Presentation and Diagnosis
Hydroxychloroquine retinopathy is typically asymptomatic in its early stages, reinforcing the importance of structured screening programmes.
When symptomatic, patients may report:
- Paracentral scotomas
- Blurred or reduced central vision
- Difficulty reading
Fundoscopy is often normal early on, with bull’s eye maculopathy appearing only in advanced disease.
Diagnostic Modalities
The Royal College of Ophthalmologists recommends a combination of structural and functional tests:
- Spectral-domain Optical Coherence Tomography (SD-OCT)
- Widefield Fundus Autofluorescence (FAF)
- Automated visual field testing (10-2 Humphrey)
OCT is particularly sensitive for detecting early parafoveal thinning and photoreceptor disruption before clinical symptoms arise (1).
Screening Guidelines
The RCOphth 2020 recommendations form the basis of UK practice:
Baseline Assessment
- Conducted within the first year of starting HCQ
- Includes risk factor assessment and baseline imaging
Annual Monitoring
- After 5 years of therapy for standard-risk patients
- From 1 year if high-risk (e.g., high dose, renal disease, tamoxifen use) (1)
Screening Tests
- SD-OCT + widefield FAF (core tests)
- Visual field testing as adjunct
Screening is typically delivered via hospital eye services or virtual clinics, with results communicated to the prescribing clinician and GP (6).
Importantly, community optometry alone is not considered sufficient for formal monitoring under current UK guidance (5).
Management and Treatment
Drug Cessation
The primary management of confirmed toxicity is cessation of hydroxychloroquine, in collaboration with the prescribing physician. This decision must balance ocular risk with systemic disease control.
Retinal damage may continue to progress after discontinuation, particularly in advanced cases (2).
Monitoring and Follow-Up
Patients with early or suspected toxicity require ongoing ophthalmic monitoring to assess progression.
No Reversal Therapy
Currently, there is no effective treatment to reverse established retinal damage, reinforcing the importance of early detection.
Prevention
Preventative strategies align closely with RCOphth guidance:
- Prescribe ≤5 mg/kg/day (real body weight) (1)
- Ensure timely referral for screening via NHS pathways
- Identify high-risk patients early
- Promote communication between:
- Ophthalmology
- Rheumatology
- General Practice
Patient education is also critical, particularly regarding adherence to screening programmes.
Conclusion
Hydroxychloroquine retinopathy is an increasingly recognised cause of preventable visual impairment in the UK. With growing long-term use of hydroxychloroquine, adherence to national screening guidelines is essential.
The introduction of structured monitoring programmes by the Royal College of Ophthalmologists represents a significant step toward reducing avoidable vision loss. Early identification of at-risk patients, appropriate dosing, and regular screening using sensitive imaging modalities are key to preventing irreversible damage.
As NHS services continue to evolve, multidisciplinary collaboration and robust screening pathways will remain central to minimising the burden of this condition.
References
- Yusuf IH, Foot B, Galloway J, et al. The Royal College of Ophthalmologists recommendations on screening for hydroxychloroquine and chloroquine users in the United Kingdom: executive summary. Eye (Lond). 2018;32(7):1168–1173.
- Mititelu M, Wong BJ, Brenner M, et al. Progression of hydroxychloroquine toxic effects after cessation. JAMA Ophthalmol. 2013;131(9):1187–1197.
- Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol. 1991;23(8):292–296.
- Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386–1394.
- Association of Optometrists (AOP). Hydroxychloroquine retinopathy guidance. London: AOP; 2020.
- The Royal College of Ophthalmologists. Hydroxychloroquine and Chloroquine Retinopathy Monitoring Guidelines (2020 Revision). London: RCOphth; 2020.