The Royal College of Ophthalmologists recently published recommendations for retinal screening in users of hydroxychloroquine and chloroquine in the United Kingdom . This article forms a summary of the key components of the guideline. These recommendations involve a range of stakeholders including patients, Ophthalmologists and the hospital eye service, Rheumatologists, Dermatologists, General Practitioners, community optometry services, healthcare commissioners, and patient groups/ voluntary organisations who have had input into the development of the guideline.
The full guideline can be found online at: https://www.rcophth.ac.uk/standards-publications-research/clinical-guidelines/. The criteria used for grading evidence is specified in Table 1, and the recommendations and grade of evidence supporting them are detailed in Table 2a, 2b, 2c, 2d, 2e, 2f, 2g. (Fig. 1).Table 2c is a standardised screening protocol that applies to all patients.
A comprehensive non-systematic review of hydroxychloroquine retinopathy which summarises the evidence at the time of guideline development is available .
The need for an update to guidance
Hydroxychloroquine is a drug increasingly used in the treatment of systemic lupus erythematosus, rheumatoid arthritis and other autoimmune disorders . Emerging evidence from clinical studies indicates that hydroxychloroquine confers a survival benefit in patients with systemic lupus erythematosus , and is often used in combination with other disease modifying agents in rheumatoid arthritis . The use of hydroxychloroquine is increasing with an estimated 11,000 new treatment initiations per year in England and Wales . Hydroxychloroquine retinopathy was previously considered rare (prevalence of 0.5% on in patients taking the drug for 6 years ) probably because the diagnosis was made when patients became symptomatic with fundus abnormalities visible on clinical examination. Previous recommendations (RCOphth, 2009) did not support screening as evidence at the time suggested that the disease was very rare and there was no reliable test for detecting disease at a reversible stage . However, modern retinal imaging techniques have been shown to be reliable in detecting pre-symptomatic retinopathy. Moreover, new data using modern retinal imaging techniques identify the prevalence of hydroxychloroquine retinopathy at around 7.5% in patients taking the drug for more than 5 years, increasing to 20–50% after 20 years . These data suggest a large patient cohort with detectable pre-symptomatic hydroxychloroquine retinopathy in the United Kingdom who continue to take the medication.
It is recognised that most hospital eye services have modern retinal imaging technology (optical coherence tomography and fundus autofluorescence) and automated visual field testing which makes local screening possible. Such tests are generally acceptable to patients. Some ophthalmologists have recognised an increasing number of patients diagnosed with advanced hydroxychloroquine retinopathy who have developed symptoms . It is also recognised that some opportunistic screening takes place in the hospital eye service led by clinicians in patients considered at risk of toxicity and in some motivated patients who seek referral for screening. Current screening protocols are likely to vary between centres with varying efficacy in detecting disease.
These factors in combination highlighted a need for an update to the guidance on screening for retinal toxicity in hydroxychloroquine and chloroquine users.
Hydroxychloroquine is a safe and effective medication used to treat a variety of disorders. Long-term use of hydroxychloroquine can cause hydroxychloroquine retinopathy, a condition in which harmful effects on the retina can lead to permanent loss of vision affecting both eyes (retinopathy). Specialised retinal tests are able to detect early evidence of retinopathy before a patient notices visual changes. However, once hydroxychloroquine retinopathy results in noticeable loss of vision, the damage to the retina is permanent and often continues to get worse even if the medication is stopped. Hydroxychloroquine retinopathy becomes more likely the longer any individual is taking the medication and with higher doses of the medication. Looking for a particular condition in a person thought to be at risk, in order to detect it before symptoms develop to minimise the risk of harm is a process called “screening”. The aim of screening for hydroxychloroquine retinopathy is to detect the earliest definite signs of the condition to allow those individuals to seek alternative medications in consultation with their prescribing doctor whilst allowing those unaffected to continue to benefit from the medication. Although most patients taking hydroxychloroquine will not develop retinopathy, around 7.5% of individuals taking hydroxychloroquine for more than 5 years may have signs of retinal damage detected on specialised tests.
The methods used in developing this guideline followed those specified in the RCOphth Clinical Guidelines Process manual and are outlined in full in the published guideline.
Key research questions
Research questions relevant to screening for hydroxychloroquine retinopathy were defined by the guideline development group:
How many patients are currently receiving treatment and how many new patients are prescribed treatment each year?
What is the risk of toxicity retinopathy for patient sub-groups (by disease and ethnic groupings)?
What is the risk of progression of toxicity retinopathy for patient sub-groups?
Who should initiate the screening process?
Which patients require screening for hydroxychloroquine retinopathy?
When should patients be screened for hydroxychloroquine retinopathy?
What tests should be performed on patients as part of the screening schedule?
In what setting should screening for hydroxychloroquine retinopathy be performed?
What are the signs from screening tests that indicate hydroxychloroquine retinopathy?
What action should be taken for patients with hydroxychloroquine retinopathy?
What are the costs or economic implications of screening for hydroxychloroquine retinopathy?
What is the efficacy of screening protocols for detecting early hydroxychloroquine retinopathy?
Who is responsible for monitoring patient participation in screening?
What information should be obtained from referring clinicians to ophthalmologists at the initiation of screening?
What information should be communicated by ophthalmologists after a screening episode has been undertaken?
What information should be given to patients at initial screening?
What information should be given to patients regarding treatment options at the point of detection of hydroxychloroquine retinopathy?
Grading the level of evidence
A pre-determined method for searching for evidence was followed, which involved Cochrane. The levels of evidence for each individual study were evaluated and graded by the guideline development group according to its strength using the Scottish Intercollegiate Guidelines Network framework (SIGN 50). The grade of each recommendation has been based upon the quality of the evidence and the potential for patient benefit (Table 1), rather than the clinical importance of the recommendation. This evidence was then evaluated in the context of the defined research questions to develop the recommendations and grade their strength. Using the evidence identified, the Guideline Development Group determined the guideline recommendations.
Key recommendations and Good Practice Points (GPP) for implementation
Tables 2a, 2b, 2c, 2d, 2e, 2f, 2g specify the key components of the recommendations made, although additional recommendations relating to work commitments, patients unable to participate in the screening programme and termination of screening are specified in the full guideline.
Current evidence suggests the highest risk of hydroxychloroquine retinopathy in patients taking a dose greater than 5 mg/kg per day . Many patients take 400 mg of hydroxychloroquine per day, which is a higher than recommended dose for any patient who weighs less than 80 kg . All prescribers should be aware of the good practice recommendation that a dose of less than 5 mg/kg per day will reduce the risk of hydroxychloroquine retinopathy, although no absolutely safe dose has been identified . Previous guidance suggested a safe dose defined on the basis of lean body weight . However, there are a variety of methods of calculating lean body weight  and current evidence favours absolute body weight in defining risk of retinopathy . Therefore, absolute body weight is both easier to measure and more informative. Safe dosing by general practitioners and hospital specialists is likely to reduce the incidence of hydroxychloroquine retinopathy in patients at risk . A useful aide memoir for these guidelines for hydroxychloroquine is the 5 × 5 rule: ideally keep dosage <5 mg/kg/day and screen after five years of drug use.
Considerations for patients
Education of patients at risk of hydroxychloroquine retinopathy is vital to ensure the risks of treatment are understood in the context of the significant benefits, the nature of screening tests, the screening schedule and how the outcome of screening is communicated and acted on. This will minimise any anxiety that may occur in patients at risk of retinopathy. In order to support the ongoing education of this patient group, the Macular Society has produced a patient information leaflet with input from the RCOphth guideline development group which is available online and should be distributed to all patients taking hydroxychloroquine and chloroquine . Prescribing physicians should be aware of the screening recommendations so that appropriate referral to the hospital eye service can be made and that information given to patients about screening remains consistent.
Imran H. Yusuf, Barny Foot, James Galloway, Michael R. Ardern-Jones, Sarah-Lucie Watson, Cathy Yelf, Michael A. Burdon, Paul N. Bishop, Andrew J. Lotery. Royal College of Ophthalmologists Guideline Development Group - Hydroxychloroquine and Chloroquine Retinopathy: Recommendations on Screening. https://www.rcophth.ac.uk/standards-publications-research/clinical-guidelines/ Accessed 3 March 2018.
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Richard Smith, Brian Bourke, Stephen Jones, Arul k Rajammal, Alan Silman. Hydroxychloroquine and Ocular Toxicity Recommendations on Screening. The Royal College of Ophthalmologists 2009.
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Imran H. Yusuf, Cathy Yelf. Eye screening for patients taking hydroxychloroquine (Plaquenil®): Macular Society. https://www.macularsociety.org/sites/default/files/resource/Hydroxychloroquine%20-%20access.pdf Accessed 1 March 2018.
We thank our expert reviewers, Dr Ron Melles and Mr Alastair Denniston, college members who provided feedback on these draft guidelines and Iris Gordon from the Cochrane Eyes and Vision Group for assistance in searching the evidence basis.
The Multidisciplinary guideline development group was chaired by AJL. IHY was involved in grading the evidence, writing the first draft of the guideline. BF represented The Royal College of Ophthalmologists and supported the guidance development process. PNB, MAB and S-LW provided ophthalmic specialist clinical input. JG represented the British Society for Rheumatology and provided rheumatological specialist clinical input. MRA-J represented the British Association of Dermatologists and provided dermatological specialist clinical input. CY contributed as a Patient and Carer representation.
Conflict of interest
The authors declare that they have no conflict of interest.
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Cite this article
Yusuf, I.H., 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 32, 1168–1173 (2018). https://doi.org/10.1038/s41433-018-0136-x
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