British Journal of Rheumatology 1997;36:599–601

SCIENTIFIC REVIEWOPHTHALMOLOGICAL MONITORING FOR HYDROXYCHLOROQUINE TOXICITY:

A SCIENTIFIC REVIEW OF AVAILABLE DATAA. SILMAN and M. SHIPLEY*

ARC Epidemiology Research Unit, University of Manchester and *Clinical Affairs Committee, British Societyfor Rheumatology, 41 Eagle Street, London

T Clinical Affairs Committee of the British Societyfor Rheumatology and the Rheumatology Committeeof the Royal College of Physicians sought a scientificreview of available data from the Arthritis andRheumatism Council Epidemiology Research Unit atManchester. Its contents are published below.

1. NATURE OF EYE LESIONS1.1 Corneal deposits are the most frequently

described ophthalmological lesion following hydroxy-chloroquine therapy. Although dose related, they arenot related to retinal problems. The existence ofcorneal opacities alone would not be considered asufficient justification for ophthalmological monitoringgiven their benign significance.

1.2 The major problem is a maculopathy orretinopathy which can lead to visual field defects anda reduction in visual acuity.

1.3 The classical hallmark of hydroxychloroquine-related retinopathy is a ring of depigmentationsurrounded by a ring of mild increased pigmentation:the so-called bull’s eye appearance.

1.4 Other signs of retinal disease include decreasedacuity, decreased colour vision and scotomata whichare reported to be either central, paracentral or evenperipheral and particularly detectable with a red object.

2. HAS RETINOPATHY EVER BEEN NOTED INPATIENTS TAKING LOW-DOSE

HYDROXYCHLOROQUINE?2.1 There have been a number of case reports and

results from case series of patients receiving low-dosehydroxychloroquine (400 mg per day or less) who havedeveloped retinopathy [1–5].

2.2 It is, by contrast, difficult to find reports wherethe retinal toxicity has been so severe as to result invisual loss, and most retinal changes appear to bereversible [1].

2.3 This reversibility might be a result of bias in thatretinal toxicity is detected by ophthalmologicalmonitoring at an early stage and the drug stopped priorto further damage.

2.4 Early reports suggest that cases of hydroxy-chloroquine-induced retinopathy with loss of visualacuity do occur, though in such reports details of thedose used are frequently lacking and combined data are

frequently presented for chloroquine and hydroxy-chloroquine [4, 6]. One report [5] describes two cases ofirreversible retinopathy amongst 360 patients examinedprospectively, of whom 58 had received hydroxy-chloroquine for q6 yr. In one case of retinopathy, thedose of hydroxychloroquine was 400 mg daily for 3 yr,then 200 mg for 3.5 yr (cumulative dose 700 g), atwhich time she developed fundoscopic lesions andcentral scotomata. Visual acuity was 6/6. Theseabnormalities remain 4.5 yr after stopping the drug.The second patient had received 400 mg daily for 2 yr,then 200 mg daily for 6 yr (cumulative dose 730 g), atwhich time she developed fundoscopic lesions, slightlyreduced visual acuity (6/7.5) and paracentral scoto-mata. The abnormalities were still present 3 yr afterstopping the drug.

2.5 There are a small number of reported cases ofretinopathy with loss of visual acuity in patients treatedwith chloroquine at a daily dose of 250 mg (theequivalent of 400 mg hydroxychloroquine). Such casesare infrequent both in the literature and by directsurveying of both rheumatologists and ophthalmolo-gists [7].

3. ARE THE RETINAL LESIONS INHYDROXYCHLOROQUINE-TREATED

PATIENTS CAUSED BY THEHYDROXYCHLOROQUINE?

3.1 There is much evidence to suggest that none ofthe lesions described is unique to hydroxychloroquineuse.

3.2 More specifically, cases of retinopathy includingthe classical bull’s eye appearance occur in the absenceof any predisposing cause [8].

3.3 It is necessary, therefore, to compare thefrequency of reported retinal pathology in hydroxy-chloroquine-treated patients with an age-matchedgroup of untreated individuals with the same diseaseyet who are untreated.

3.4 There have been few studies which haveundertaken extensive ophthalmological monitoring ofuntreated rheumatoid arthritis patients to address thisissue.

3.5 In the classic study on this question [9], theincidence of pigmentary retinopathy in 408chloroquine- and hydroxychloroquine-treated patientswas 0.5% compared to 0.9% in 333 untreatedrheumatoid arthritis patients. The maculopathy in bothgroups was reported as being indistinguishable.

Submitted 10 August 1996; revised version accepted 8 February1997.

= 1997 British Society for Rheumatology599

BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 5600

3.6 The electro-oculogram (EOG) is considered tobe a sensitive test of retinal function, though it appearsthat depression of the EOG score is also seen inrheumatoid arthritis, with 20% of untreated rheum-atoid arthritis patients having an abnormal result [10].

4. DO THE TESTS USED DETECTRETINOPATHY AT A REVERSIBLE STAGE?4.1 Like any other proposed screening test, the

proposed ophthalmological monitoring needs to detectretinal lesions at a stage where intervention (i.e.stopping the drug) can reverse the condition or preventdeterioration.

4.2 If the cases of retinopathy detected by monitor-ing fail to respond to cessation of therapy, themonitoring does not have a useful role.

4.3 The only definitive approach to addressing thisissue is a randomized trial of monitoring with drugcessation, with the end point being loss of visual acuity.Both ethical constraints and the rarity of the end pointpreclude such a trial ever being conducted.

4.4 Surrogate data come from case reports.Although some have shown that the retinal lesions arereversible (e.g. [1, 3]), others have suggested that drugcessation may be more likely to prevent furtherdeterioration. In some cases, deterioration even onstopping the drug occurs [11].

The problem of interpreting the data from such casereports is that the natural history of what would havehappened had the drug not been withdrawn isunknown. Indeed, in some instances restarting the drugdid not cause a recurrence of the retinopathy,suggesting that the two may not be causally related.

5. IS THE OPHTHALMOLOGICALMONITORING PROPOSED VALID FOR THE

DETECTION OF REVERSIBLE RETINALLESIONS?

5.1 Any proposed screening test should also bevalid: that is, both sensitive in detecting retinal lesionswhen they are present and specific in not falselyrecording abnormality in a normal retina. Theconsequences of the latter may be to cease the use ofan effective anti-rheumatic therapy as well as leading tounnecessary anxiety.

5.2 The assessment of validity requires a goldstandard for ophthalmological monitoring whichprobably does not exist.

5.3 Various screening tests have been proposed,including: (i) Amsler charts for self-detection of fieldloss; assessment of (ii) visual acuity, (iii) colour vision,(iv) visual fields using red and white objects, (v)fundoscopy, (vi) EOG and electroretinography.

5.4 Each of the above methods is problematic.Amsler charts require a degree of compliance that maybe difficult to achieve, and they may be both insensitiveand non-specific.

5.5 Abnormalities in colour testing are also difficultto interpret given that patients with rheumatoidarthritis also have an increased occurrence of colourdefects [12].

5.6 Even scotomata to a red object may benon-specific: their presence has been documented in6% of the normal population [13].

5.7 There is no consensus as to which test(s) shouldbe used and comparative data are sparse. The intervalbetween testing is crucial, though again the appropriateinterval has not been critically assessed by comparativestudies, although there is a consensus based on opinion,rather than fact, that 6 monthly is appropriate.

5.8 It has been mentioned above that both themacular appearance and even the EOG result may notbe specific to hydroxychloroquine toxicity.

6. WHAT IS THE INCIDENCE OF RETINALTOXICITY?

6.1 Given the above points, it is clear that in theabsence of an agreed definition, plus the difficulty inattributing any retinopathy detected to drug use, datafrom different sources are not easily combined.

6.2 Most studies suggest that the risk of retinopathyis increased with increasing duration of drug use [5],though given the rarity of cases following hydroxy-chloroquine use, such data are extrapolated fromstudies of chloroquine [14]. The point is that anycumulative percentage quoted needs to be consideredagainst the stated treatment duration.

6.3 Despite these caveats, the frequency of severeretinopathy is very low. Combining seven case series[1, 3, 4, 5, 15] with a total of some 1800 patients treatedwith hydroxychloroquine, only one case of retinopathywith visual loss was observed.

6.4 In these series there was a very small number(Q10) of subjects who had other retinal problems,most of which were not thought to be due tohydroxychloroquine use.

6.5 Given the rarity of retinal toxicity, it is notpossible to comment usefully on any threshold either interms of treatment duration or in total cumulativedose, at which the risk level increases to an importantextent.

7. ARE THERE HAZARDS FROM APROGRAMME OF OPHTHALMOLOGICAL

MONITORING?7.1. It is likely that anxiety is created by the testing

itself and by the unnecessary further investigation ofscreening positives who turn out to be normal.

7.2 Some patients may decline to start therapybecause of anxiety, despite counselling, that thefrequency of serious visual impairment is unknown.

7.3 Cessation of therapy which is otherwise beingeffective may lead to a relapse of inflammatoryarthritis.

7.4 It has been suggested that such an increase ininflammatory activity could actually worsen pre-exist-ing retinopathy [10].

8. WHAT IS THE FINANCIAL COST OFACHIEVING ANY SUGGESTED BENEFIT?8.1 There are no data relating the costs of screening

to benefit, a deficiency which in other areas of medical

SILMAN AND SHIPLEY: MONITORING FOR HYDROXYCHLOROQUINE TOXICITY 601

practice would be considered a contraindication to theintroduction of a screening programme.

8.2 At its simplest level, the costs would need torelate to the costs of monitoring and of furtherinvestigation against the benefit of saving visual acuity.In practice, the latter is likely to be very difficult toquantify and its valuation in pound terms is verysubjective.

8.3 A more exact cost–benefit analysis would needto take account of the impact on the disease of stoppingthe drug and the costs of alternative therapies.

9. THE INFLUENCE OF LITIGATION9.1 Clearly, the threat, real or apparent, of litigation

is a powerful stimulus to continue ophthalmologicalmonitoring even if, in cost–benefit terms, the gains aremarginal or even negative.

9.2 Abolition of any existing programme ofscreening might fail to pass the ‘physician’s mothertest’, i.e. if the patient were the physician’s mother,would monitoring be advocated?

10. CONCLUSIONS10.1 There is no single distinctly identifiable retinal

pathology resulting from hydroxychloroquine use.10.2 Cases of retinopathy have been described

following hydroxychloroquine use and drug cessationseems to have prevented further deterioration.

10.3 There is no consensus as to the appropriateapproach for screening, and no method is ideal.

10.4 The incidence of sight-threatening retinopathyon hydroxychloroquine at the recommended dose of400 mg daily is extremely small and at a level which inother areas of medicine would preclude the initiation ofa screening programme.

10.5 The incidence of retinopathy may not be higherthan background population rates.

10.6 There are both direct and indirect costs ofophthalmological monitoring which have not beencalculated, even a small net benefit may not beassumed.

11. RECOMMENDATIONS11.1 If ophthalmological monitoring is to be

recommended on the basis of evidence, the followingneed to be undertaken before any guidelines can bedrawn up.

11.2 A comparison of the sensitivity and specificityof potential eye screening protocols should be

evaluated against a gold standard of consensusophthalmological opinion.

11.3 The cost of such monitoring should beevaluated and studies should be undertaken toascertain indirect costs.

11.4 The feasibility of monitoring comparative trialsof (i) different screening intervals and (ii) differentscreening approaches should be assessed.

11.5 By comparison with other screening tests inmedical practice, a good case could be made for notcontinuing with routine screening.

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