The Risk of Toxic Retinopathy - University of Louisville Department

Research
Original Investigation
The Risk of Toxic Retinopathy in Patients
on Long-term Hydroxychloroquine Therapy
Ronald B. Melles, MD; Michael F. Marmor, MD
IMPORTANCE Hydroxychloroquine sulfate is widely used for the long-term treatment of
autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk
were low but were based largely on short-term users or severe retinal toxicity (bull’s eye
maculopathy). The risk may be much higher because retinopathy can be detected earlier
when using more sensitive screening techniques.
Invited Commentary
page 1460
Supplemental content at
jamaophthalmology.com
OBJECTIVES To reassess the prevalence of and risk factors for hydroxychloroquine retinal
toxicity and to determine dosage levels that facilitate safe use of the drug.
DESIGN, SETTING, AND PARTICIPANTS Retrospective case-control study in an integrated health
organization of approximately 3.4 million members among 2361 patients who had used
hydroxychloroquine continuously for at least 5 years according to pharmacy records and who
were evaluated with visual field testing or spectral-domain optical coherence tomography.
EXPOSURE Hydroxychloroquine use for at least 5 years.
MAIN OUTCOMES AND MEASURES Retinal toxicity as determined by characteristic visual field
loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk
factors and prevalence.
RESULTS Real body weight predicted risk better than ideal body weight and was used for all
calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied
with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration
of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0
mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use
but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease
(odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio,
4.59; 95% CI, 2.05-10.27).
CONCLUSIONS AND RELEVANCE These data suggest that hydroxychloroquine retinopathy is
more common than previously recognized, especially at high dosages and long duration of
use. While no completely safe dosage is identified from this study, daily consumption of 5.0
mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge
of these data and risk factors should help physicians prescribe hydroxychloroquine in a
manner that will minimize the likelihood of vision loss.
Author Affiliations: Kaiser
Permanente, Redwood City Medical
Center, Redwood City, California
(Melles); Byers Eye Institute, Stanford
University, Palo Alto, California
(Marmor).
JAMA Ophthalmol. 2014;132(12):1453-1460. doi:10.1001/jamaophthalmol.2014.3459
Published online October 2, 2014.
Corresponding Author: Ronald B.
Melles, MD, Kaiser Permanente,
Redwood City Medical Center, 1150
Veterans Blvd, Redwood City, CA
94063 ([email protected]).
1453
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Research Original Investigation
Toxic Retinopathy With Hydroxychloroquine Therapy
H
ydroxychloroquine sulfate is used by physicians in
many specialties for the long-term treatment of lupus erythematosus, rheumatoid arthritis, and other
autoimmune conditions and is being considered for wider applications, such as the management of diabetes mellitus. While
hydroxychloroquine has few systemic adverse effects, longterm use may lead to irreversible and potentially blinding retinal toxicity.1 This adverse effect has been considered rare (estimated occurrence in 0.5%-2.0% of long-term users2-4), but
the risk may in fact be considerably greater. Most existing data
about the prevalence of hydroxychloroquine retinal toxicity
come from studies2,3 based primarily on short duration of use
and on diagnosis at an advanced stage of visible retinal damage. However, retinopathy can be detected much earlier by central visual field testing and modern techniques, such as spectral-domain optical coherence imaging (SD-OCT).5
Because hydroxychloroquine distributes poorly in fatty
tissues,6 it was suggested earlier7,8 (and reinforced by current
American Academy of Ophthalmology screening guidelines9)
that dosage should be calculated by ideal body weight to reduce the theoretical risk of overdosing obese patients. A daily
dose of 6.5 mg/kg of ideal body weight has been generally recommended based on studies7,8 that found few cases of severe retinal toxicity below 6.5 mg/kg of real body weight, but
this value has never been evaluated to our knowledge.
We studied a large population of long-term hydroxychloroquine users whose retina was evaluated with sensitive diagnostic techniques. The data suggest that hydroxychloroquine retinopathy is not rare and that alternative dosing criteria
and awareness of specific risk factors may enhance the safe use
of this drug.
Methods
Kaiser Permanente Northern California (KPNC) is an integrated
health organization with a diverse population of approximately
3.4 million members. The organization has used electronic medical records for more than 20 years, and digital ophthalmic images have been reviewable on all patients since 2009. After KPNC
institutional review board approval, we queried the pharmacy
database for patients (n = 3482) taking hydroxychloroquine as
of January 1, 2009, for a minimum of 5 continuous years, with
a maximum gap in therapy of less than 1 year. Because we are
reporting only on aggregate data obtained by medical record reviews, informed consent from individual patients was not
deemed necessary by the institutional review board.
Inclusion criteria were a reliable central visual field examination or SD-OCT (2361 patients [67.8%]), techniques that
can demonstrate retinopathy before any visible fundus change.
Excluded were 654 patients (18.8%) who were screened only
by fundus examination (photography or ophthalmoscopy) and
348 patients (10.0%) who had no evidence of screening. Also
excluded were 119 patients (3.4%) with prior chloroquine use
or significant retinal comorbidity, such as macular degeneration or diabetic retinopathy. Demographic characteristics of the
included and excluded populations were similar (eTable in the
Supplement).
1454
A sequence of findings with visual field testing and SDOCT, from mild to severe, is shown in Figure 1. Fields could
use white or red targets,10 and all were performed using standard equipment (Humphrey perimeter; Carl Zeiss Meditec). The
SD-OCT recordings were performed with a standard instrument (Spectralis; Heidelberg Engineering). Retinal toxicity was
judged by characteristic damage on visual field testing or SDOCT (Figure 1) and was confirmed to be unequivocal by both
of us. For visual field testing, toxicity meant partial or full ring
scotomas mainly involving the parafoveal region.10,11 For SDOCT, this meant predominantly parafoveal thinning of the outer
retina and loss of photoreceptor outer segment marker lines
(ellipsoid zone and interdigitation zone).5,12,13
Most patients (2020 [85.6%]) had started taking hydroxychloroquine after the computerized pharmacy system was
implemented, and their medication use was calculated from
the number of tablets dispensed. The remainder (341 [14.4%])
started taking hydroxychloroquine a mean of 4.5 years before joining KPNC or before implementation of the pharmacy
system. Their use for the additional years was calculated from
prescribed amounts and was adjusted by their mean compliance rate when tracked by the pharmacy database. Throughout this article, dosage is expressed as use (ie, consumption
rather than prescribed dosage) relative to real body weight unless explicitly stated as ideal body weight. Ideal body weight
was calculated using a simplified formula: for women, 100 lb
for the first 5 ft of height, plus 5 lb for every inch of height over
5 ft; and for men, 110 lb for the first 5 ft of height, plus 5 lb for
every inch of height over 5 ft (for women, 45 kg for the first 1.5
m of height, plus 2.3 kg for each 2.5 cm of height over 1.5 m;
and for men, 50 kg for the first 1.5 m of height, plus 2.3 kg for
each 2.5 cm of height over 1.5 m).14
We estimated the mean glomerular filtration rate (GFR)
during the course of hydroxychloroquine therapy using the
4-variable Modification of Diet in Renal Disease equation:
GFR = 175 × Serum Creatinine Level−1.154 × Age−0.203 × (0.742
if Female) × (1.210 if Black).15 A patient was considered to have
kidney disease from a notation of stage 3, 4, or 5 disease on
their problem list or if their mean GFR was less than 60 mL/
min per 1.73 m2. Significant liver disease was determined by a
diagnosis of chronic hepatitis in the patient’s medical record
or by the mean liver enzyme levels (aspartate aminotransferase and alanine aminotransferase) being more than twice the
normal upper limit.
Comparisons between groups were performed using t test
for continuous measures and χ2 test for categorical measures, and all reported probability values are 2-sided. Odds ratios were derived using logistic regression analysis.
Results
Study Findings
Our results show that the prevalence of hydroxychloroquine
retinopathy is much higher than previously recognized and depends on risk factors such as daily dose, duration of use, and
kidney disease. The results also suggest the need to revise the
way that dosage is calculated to minimize risk. We identified
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Toxic Retinopathy With Hydroxychloroquine Therapy
Original Investigation Research
Figure 1. Progressive Stages of Hydroxychloroquine Retinopathy
Fundus photograph
Spectral-domain OCT
10-2 Pattern deviation and threshold
A
10
B
10
C
10
D
10
Clinical images (left to right): fundus photography, spectral-domain optical
coherence tomography (OCT), and 10-2 white target visual fields (pattern
deviation plot and threshold plot). Levels of retinal toxicity (top to bottom):
A, Normal fundus. B, Mild retinal toxicity, with distinctive parafoveal thinning of
the outer retina (arrowhead) and fragments of a ring scotoma. C, Moderate
retinal toxicity, with marked outer retinal thinning on both sides of the fovea
(arrowheads) and a prominent ring scotoma (but still no pigmentary changes
visible in the fundus). D, Severe retinal toxicity, with bull’s eye maculopathy on
the fundus image, disruption of the retinal pigment epithelium on
spectral-domain OCT, and severe visual field defects.
a new risk factor of concurrent tamoxifen citrate use. These
data have important implications for medical and ophthalmologic practice to maximize the availability of hydroxychloroquine to patients while avoiding retinal toxicity.
droxychloroquine therapy were significantly associated with
an increased prevalence of retinal toxicity. A multivariable logistic regression analysis was performed (Table 1) on those factors that showed significant differences by univariate analysis, along with age (which has been postulated to increase risk).
Daily use, duration of use, concurrent tamoxifen therapy, kidney disease, and lower weight were correlated with retinal toxicity, but age and sex were not. Additional univariate logistic
regression analysis showed the effect of factors that have frequently been used to estimate the risk of retinal toxicity for
individual patients (Table 2). Of 177 patients diagnosed as hav-
Overall Risk
Table 1 lists the clinical characteristics of our patient population. Of 2361 patients who had taken hydroxychloroquine continuously for at least 5 years and who had 10-2 visual fields or
SD-OCT, 177 (7.5%) showed clear signs of retinal toxicity
(Figure 1). None of the primary medical indications for hyjamaophthalmology.com
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Research Original Investigation
Toxic Retinopathy With Hydroxychloroquine Therapy
Table 1. Demographics and Statistical Overview
Variable
Table 2. Logistic Regression Analyses
Retinal
Toxicity
(n = 177)
No Retinal
Toxicity
(n = 2184)
163 (92.1)
1800 (82.4)
Patient Characteristics, No. (%)
Female sex
Race/ethnicity
P Value
Daily use in 100-mg increments
5.11 (3.83-6.83)
<.001
Duration of use in 5-y increments
2.03 (1.72-2.40)
<.001
Tamoxifen citrate therapy
4.59 (2.05-10.27)
<.001
Multivariable analysis
Asian
30 (16.9)
263 (12.0)
Kidney disease
2.08 (1.44-3.01)
<.001
Black
11 (6.2)
202 (9.2)
Weight
0.96 (0.95-0.97)
<.001
Female sex
1.80 (0.95-3.36)
.08
Age at start of therapy
1.01 (0.99-1.02)
.64
Hispanic
17 (9.6)
194 (8.9)
White
112 (63.3)
1429 (65.4)
Other
7 (4.0)
96 (4.4)
Daily use >5.0 mg/kg
5.67 (4.14-7.79)
<.001
Connective tissue diseasea
12 (6.8)
114 (5.2)
Cumulative use >20 g/kg
8.13 (5.61-11.76)
<.001
Lupus erythematosus
44 (24.9)
494 (22.6)
Duration of use >10 y
3.22 (2.20-4.70)
<.001
8 (4.5)
168 (7.7)
Rheumatoid arthritis
96 (54.2)
1284 (56.6)
Sjögren syndrome
11 (6.2)
90 (4.1)
Primary indication
Polyarthritis
Otherb
Kidney diseasec
Liver disease
Tamoxifen citrate therapyd
Anastrozole therapyd
6 (3.4)
82 (3.8)
66 (37.3)
495 (22.7)
2 (1.1)
61 (2.8)
12 (6.8)
26 (1.2)
4 (2.3)
23 (1.1)
Population Characteristics, mean (SD)
Age at start of therapy, y
52.2 (13.3)
52.3 (13.8)
Weight, kg
67.2 (16.7)
76.9 (19.5)
Ideal body weight, kg
53.6 (8.3)
57.2 (9.3)
BMI
25.8 (5.8)
28.3 (6.5)
Drug usee
Daily use, mg
344.6 (66.5)
290 (73.8)
Daily use per weight, mg/kg
5.4 (1.4)
4.0 (1.2)
Daily use per ideal body weight,
mg/kg
6.6 (1.7)
5.2 (1.5)
Cumulative use, g
1856 (668)
1275 (585)
Cumulative use per weight, g/kg
28.8 (11.7)
17.4 (8.8)
Duration of use, y
15.1 (5.5)
12.0 (5.0)
Tamoxifen citrate cumulative use if
taken, g
36.8 (17.4)
24.8 (10.5)
Abbreviation: BMI, body mass index (calculated as weight in kilograms divided
by height in meters squared).
a
Including mixed connective tissue disease, undifferentiated connected tissue
disease, and scleroderma.
b
Other primary indications included alopecia, psoriatic arthritis, sarcoidosis,
and urticaria.
c
Kidney disease was defined as a mean glomerular filtration rate of less than 60
mL/min per 1.73 m2 (stage 3, 4, or 5 chronic kidney disease).
d
Concurrent tamoxifen or anastrozole breast cancer chemotherapy for a
minimum of 6 months’ duration.
e
Estimated use based on tablets dispensed (refers to hydroxychloroquine
sulfate unless otherwise indicated).
ing retinal toxicity, 98 had color fundus photographs available for review, and only 31 (31.6%) showed a visible bull’s eye
depigmentation (Figure 1, bottom), confirming the higher sensitivity of our screening techniques.
Measurement of Real vs Ideal Body Weight
We calculated receiver operating characteristic curves
(Figure 2A) to assess the sensitivity and specificity of real vs
1456
Odds Ratio (95% CI)
Variable
Univariate analysis
ideal body weight in predicting retinal toxicity and found that
real body weight is a better predictor of retinal toxicity (receiver operating characteristic curve area, 0.78 for real body
weight vs 0.75 for ideal body weight; P = .03). Because current dosing recommendations advise 6.5 mg/kg of ideal body
weight,9 it is important to have a comparable value in real body
weight to aid in the interpretation of population data. If one
looks at the distribution of patients comparing use by real body
weight with use by ideal body weight (eFigure 1 in the Supplement), 6.5 mg/kg of ideal body weight corresponds approximately to 5.0 mg/kg of real body weight along the regression
line (patients were typically approximately 25%-30% heavier
than ideal body weight). This value is also realistic in terms of
rheumatologic practice because most of our patients (1828 of
2361 [77.4%]) were in fact consuming less than 5.0 mg/kg of
real body weight. Furthermore, the prevalence of retinal toxicity relative to real body weight is essentially independent of
body habitus (Figure 2B), whereas the risk is much higher in
thin individuals using ideal body weight (Figure 2C). Because
of these findings, we have used real body weight for all subsequent presentations in this article and 5.0 mg/kg of real body
weight as a division between judicious and excessive use.
Dosage and Duration
Kaplan-Meier curves in Figure 3A show the cumulative risk in
the population for 3 different ranges of dosage per kilogram.
Patients with a mean daily use exceeding 5.0 mg/kg had approximately a 10% risk of retinal toxicity within 10 years of
treatment and an almost 40% risk after 20 years. Patients using
an intermediate amount of 4.0 to 5.0 mg/kg had risk of less than
2% within the first 10 years of use but almost 20% risk after 20
years. These medication use values are based on pharmacy dispensing information and were on average approximately 20%
lower than the prescribed dosage because of variable patient
compliance.
The smoothed hazard estimates in Figure 3B show the incremental risk of retinal toxicity (annual risk) that a patient
without retinal toxicity faces in each ensuing year. For use of
5.0 mg/kg or less, this annual risk is less than 1% in the first
decade of use but rises to almost 4% after 20 years and is 2 to
3 times higher at use exceeding 5.0 mg/kg.
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Toxic Retinopathy With Hydroxychloroquine Therapy
Figure 3C shows more directly the continuous interaction of use and duration of use in determining the prevalence
of retinal toxicity. No dosage is completely safe, but regulation of either factor will greatly reduce the risk from the other.
Original Investigation Research
Figure 2. Hydroxychloroquine Retinal Toxicity and Daily Use by Real
Body Weight vs Ideal Body Weight
A Prediction by real vs ideal body weight
1.00
Other Risks
0.75
Sensitivity
Effect of Kidney and Liver Function
The kidneys are the main mechanism for clearance of
hydroxychloroquine,8 and decreased renal function leads to
higher serum concentration.16 Kidney disease markedly increases the risk of retinal toxicity (Table 2), and eFigure 2 in
the Supplement shows the relationship between retinal toxicity and the GFR. A drop in kidney function by 50% leads to
an approximate doubling of the risk of retinopathy. Although
hydroxychloroquine is partially cleared by the hepatic system,7
we found no increase in the risk of retinal toxicity from liver
disease.
Use per real body weight
(ROC curve area, 0.78)
Use per ideal body weight
(ROC curve area, 0.75)
Reference
0.50
0
0
0.50
0.75
1.00
1 – Specificity
B
Risk vs body habitus based on real body weight (5.0 mg/kg cutoff)
0.6
Predicted Toxic Retinopathy
Exposure to Tamoxifen
Patients who had concurrent tamoxifen therapy for breast cancer were at greatly increased risk of the development of retinal toxicity (Table 2), and retinal toxicity correlated with greater
cumulative tamoxifen intake (P = .03). In contrast, patients
treated for estrogen receptor–positive breast cancer with concurrent anastrozole did not appear to have a similar increase
in risk. None of the patients who took hydroxychloroquine and
tamoxifen concurrently showed crystalline deposits or macular edema that is characteristic of tamoxifen retinopathy,17 but
they all had parafoveal outer retinal damage and were classified as having hydroxychloroquine retinopathy.
0.25
Use per real body weight
≤5.0 mg/kg
Use per real body weight
>5.0 mg/kg
0.4
0.2
0
Discussion
15
jamaophthalmology.com
25
30
35
BMI
C
Risk vs body habitus based on ideal body weight (6.5 mg/kg cutoff)
0.6
Predicted Toxic Retinopathy
We found that 7.5% of long-term hydroxychloroquine users
screened with modern techniques showed evidence of retinal toxicity. This prevalence is approximately 3 times higher
than previously reported,2-4 but the risk to an individual depends on dosage and duration of use. Prior studies2,3 included patients with shorter duration of use and depended
mainly on the development of bull’s eye maculopathy to detect retinal toxicity. In contrast, most of our patients diagnosed as having retinal toxicity were detected before bull’s eye
maculopathy was visible.
A limitation of our study is that approximately 30% of
long-term hydroxychloroquine users initially identified were
excluded because of a lack of sensitive screening studies or
for comorbid retinopathy. However, the excluded group
showed demographic characteristics similar to those of the
included group (eTable in the Supplement), and we do not
believe a major difference would exist in their prevalence of
retinopathy.
Our data show that, although no hydroxychloroquine use
is completely safe, the risk of retinal toxicity can be kept low
with careful dosage adjustment and with shorter periods of use.
However, the risk rises markedly with concurrent kidney disease, and the prevalence can exceed 50% with use above 5.0
mg/kg and with duration beyond 20 years.
20
Use per ideal body weight
≤6.5 mg/kg
Use per ideal body weight
>6.5 mg/kg
0.4
0.2
0
15
20
25
30
35
BMI
A, Receiver operating characteristic (ROC) curve of the prediction of retinal
toxicity by real body weight compared with ideal body weight. The difference in
the area under the ROC curves is significant (P = .03). B and C, Effect of body
habitus on the rate of retinal toxicity, comparing a daily use cutoff level of 5.0
mg/kg real body weight (B) to a cutoff level of 6.5 mg/kg ideal weight (C). Body
habitus is indicated by body mass index (BMI, calculated as weight in kilograms
divided by height in meters squared).The lines show adjusted predictions after
logistic regression analysis of BMI and retinal toxicity with 95% CIs.
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Research Original Investigation
Toxic Retinopathy With Hydroxychloroquine Therapy
Figure 3. Cumulative and Yearly Risk of Retinal Toxicity
A Cumulative risk at 3 use levels
B
0.20
<4.0 mg/kg
4.0-5.0 mg/kg
>5.0 mg/kg
0.60
0.50
0.40
0.30
0.20
0.10
0
5
10
15
20
25
Yearly Risk of Toxic Retinopathy
Risk of Toxic Retinopathy
0.70
Yearly risk at 3 use levels
0.15
0.10
0.05
Duration of Hydroxychloroquine Therapy, y
No. at risk
<4.0 mg/kg
1196
4.0-5.0 mg/kg 632
>5.0 mg/kg
533
C
766
386
310
387
190
139
136
61
41
34
12
6
0
5
10
15
20
25
30
Duration of Hydroxychloroquine Therapy, y
Risk at different levels of daily and cumulative use
Risk of Toxic Retinopathy, %
60
50
Duration of
treatment, y
40
10-14
30
15-19
5-9
≥20
20
10
0
<3.0
3.0-3.9
4.0-4.9
5.0-5.9
≥6.0
Hydroxychloroquine Daily Use, mg/kg
A, Kaplan-Meier curves showing the cumulative risk of hydroxychloroquine retinal toxicity at 3 use levels. B, Smoothed hazard estimates showing yearly risk of toxic
retinopathy at 3 use levels. C, Interaction of use and duration of use in the prevalence of retinal toxicity.
We propose the use of real body weight for dosage calculation because it correlates better with retinal toxicity than ideal
body weight and allows estimations of risk that are independent
of body habitus. A recent study18 found that serum levels of hydroxychloroquine also correlate better with real body weight.
The empirical use limit of 5.0 mg/kg of real body weight that we
suggest should be sufficiently high to provide medical relief for
most patients because it is in fact equivalent to the current dosing recommendation of 6.5 mg/kg of ideal body weight for patients of ordinary habitus9 (eFigure 1 in the Supplement), and
most of our patients were being maintained medically on less
than 5.0 mg/kg of hydroxychloroquine sulfate. It is important
to emphasize that our data represent pills dispensed, and many
of our patients who were prescribed at a dosage of 6.5 mg/kg
of ideal body weight were using a lower amount because of imperfect compliance. Dosing by real body weight will be simpler
to calculate than by ideal body weight, and the main effect clinically will be a reduction of dosage for thin patients (many of
whom may be receiving high dosages by the criteria of this
study). However, it will be incumbent on physicians to consider
compliance in the prescription of this drug. Maintaining daily
use at 5.0 mg/kg or less would keep both the cumulative risk and
annual risk of retinal toxicity low, especially for the first 10 years
1458
of use. Because hydroxychloroquine takes several months to
reach stable blood levels,19 dosing can be adjusted to weight by
omitting or splitting tablets on certain days of the week. In
theory, it would be ideal if hydroxychloroquine dosing could
be guided by blood levels, but studies19,20 have found wide variations, and the results suggest that blood concentrations in an
individual do not correlate closely with dosage, weight, or clinical effectiveness. However, blood levels may aid in judging noncompliance or the effects of kidney disease.16,18,21
Our prevalence data apply to the overall population of longterm hydroxychloroquine users, and risk rises markedly after
10 years of use. However, in rheumatologic practices, many patients benefit from the use of the drug for much longer periods, and it is important to know the annual risk as they stay
on the drug regimen. The smoothed hazard estimates
(Figure 3B) show that a patient who shows no signs of retinal
toxicity at a given point in time and is not overdosed will have
a risk of developing retinal toxicity during the ensuing year of
approximately 1% after 10 years of use and an annual risk of
less than 4% after 20 years of use. These data should serve to
reassure medical specialists that the drug can be prescribed
safely for extended periods with understanding of the ocular
risks and with effective screening.
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Toxic Retinopathy With Hydroxychloroquine Therapy
Original Investigation Research
If we extrapolate the use of long-term hydroxychloroquine at KPNC to the entire US population, approximately
350 000 patients should receive annual eye screening by current guidelines.9 Therefore, screening for hydroxychloroquine retinal toxicity is an important economic and patient
safety issue. Retinal toxicity from hydroxychloroquine use cannot be completely prevented, but effective screening should
recognize retinal toxicity before symptoms or significant risk
of central visual field loss appear (ie, before the appearance of
bull’s eye maculopathy). Screening requires the use of tests,
such as 10-2 visual fields and SD-OCT (and other modern techniques, such as autofluorescence imaging and multifocal
electroretinography22,23), to demonstrate early retinal damage. We have shown that 10-2 visual fields are sometimes more
sensitive than SD-OCT in revealing retinal toxicity.24 However, SD-OCT is more specific and objective, and we suggest
the use of both tests when available. With effective screening, retinal toxicity can be recognized at an early stage when
patients are typically asymptomatic and disease is unlikely to
progress.25
Our results confirm the basic principles of screening recommended by the American Academy of Ophthalmology.9
However, we propose the use of real body weight rather than
ideal body weight to calculate daily dose, along with possible
ARTICLE INFORMATION
Submitted for Publication: May 1, 2014; final
revision received July 11, 2014; accepted July 12,
2014.
Published Online: October 2, 2014.
doi:10.1001/jamaophthalmol.2014.3459.
Author Contributions: Dr Melles had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: All authors.
Administrative, technical, or material support:
Marmor.
Study supervision: Melles.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Additional Contributions: Eric Jorgenson, PhD,
Division of Research, Kaiser Permanente Northern
California, and Frederick Wolfe, MD, National Data
Bank for Rheumatic Diseases, gave advice
regarding statistical methods.
Correction: This article was corrected on October
30, 2014, to fix an error in Table 2.
REFERENCES
1. Michaelides M, Stover NB, Francis PJ, Weleber
RG. Retinal toxicity associated with
hydroxychloroquine and chloroquine: risk factors,
screening, and progression despite cessation of
therapy. Arch Ophthalmol. 2011;129(1):30-39.
jamaophthalmology.com
adjustment for patient compliance. Our data show that age is
not a risk factor, but our findings emphasize the importance
of kidney disease, which raises the effective blood level of
hydroxychloroquine.16 Unexpectedly, we also found a strong
relationship between retinal toxicity and tamoxifen use. Tamoxifen is a retinal toxin in its own right, although most cases
of tamoxifen retinopathy were reported early in the history of
the drug when higher dosages were prescribed.26 Our data indicate that chronic low-dosage administration of tamoxifen has
an adverse synergism with hydroxychloroquine, and the effect is related to the cumulative dose.
Conclusions
These data suggest that hydroxychloroquine retinopathy is
more common than previously recognized, especially at high
daily intake and with long durations of use or in the presence
of kidney disease or concurrent tamoxifen therapy. Daily use
of 5.0 mg/kg of real body weight or less is associated with a low
risk for up to 10 years of use. We anticipate that these data will
help physicians develop prescribing patterns that maintain patients on this valuable medication while minimizing the risk
of retinal toxicity.
2. Wolfe F, Marmor MF. Rates and predictors of
hydroxychloroquine retinal toxicity in patients with
rheumatoid arthritis and systemic lupus
erythematosus. Arthritis Care Res (Hoboken). 2010;
62(6):775-784.
12. Chen E, Brown DM, Benz MS, et al. Spectral
domain optical coherence tomography as an
effective screening test for hydroxychloroquine
retinopathy (the “flying saucer” sign). Clin
Ophthalmol. 2010;4:1151-1158.
3. Levy GD, Munz SJ, Paschal J, Cohen HB, Pince
KJ, Peterson T. Incidence of hydroxychloroquine
retinopathy in 1,207 patients in a large multicenter
outpatient practice. Arthritis Rheum. 1997;40(8):
1482-1486.
13. Spaide RF, Curcio CA. Anatomical correlates to
the bands seen in the outer retina by optical
coherence tomography: literature review and
model. Retina. 2011;31(8):1609-1619.
4. Mavrikakis I, Sfikakis PP, Mavrikakis E, et al. The
incidence of irreversible retinal toxicity in patients
treated with hydroxychloroquine: a reappraisal.
Ophthalmology. 2003;110(7):1321-1326.
5. Marmor MF. Comparison of screening
procedures in hydroxychloroquine toxicity. Arch
Ophthalmol. 2012;130(4):461-469.
6. Mackenzie AH. Pharmacologic actions of
4-aminoquinoline compounds. Am J Med. 1983;75
(1A):5-10.
7. Mackenzie AH. Dose refinements in long-term
therapy of rheumatoid arthritis with antimalarials.
Am J Med. 1983;75(1A):40-45.
8. Bernstein HN. Ocular safety of
hydroxychloroquine. Ann Ophthalmol. 1991;23(8):
292-296.
9. Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler
WF; American Academy of Ophthalmology. Revised
recommendations on screening for chloroquine and
hydroxychloroquine retinopathy. Ophthalmology.
2011;118(2):415-422.
10. Marmor MF, Chien FY, Johnson MW. Value of
red targets and pattern deviation plots in visual
field screening for hydroxychloroquine retinopathy.
JAMA Ophthalmol. 2013;131(4):476-480.
11. Anderson C, Blaha GR, Marx JL. Humphrey
visual field findings in hydroxychloroquine toxicity.
Eye (Lond). 2011;25(12):1535-1545.
14. Pai MP, Paloucek FP. The origin of the “ideal”
body weight equations. Ann Pharmacother. 2000;
34(9):1066-1069.
15. Levey AS, Coresh J, Balk E, et al; National
Kidney Foundation. National Kidney Foundation
practice guidelines for chronic kidney disease:
evaluation, classification, and stratification
[published correction appears in Ann Intern Med.
2003;139(7):605]. Ann Intern Med. 2003;139(2):
137-147.
16. Lee JY, Luc S, Greenblatt DJ, Kalish R,
McAlindon TE. Factors associated with blood
hydroxychloroquine level in lupus patients: renal
function could be important. Lupus. 2013;22(5):
541-542.
17. Gualino V, Cohen SY, Delyfer MN, Sahel JA,
Gaudric A. Optical coherence tomography findings
in tamoxifen retinopathy. Am J Ophthalmol. 2005;
140(4):757-758.
18. Francès C, Cosnes A, Duhaut P, et al. Low blood
concentration of hydroxychloroquine in patients
with refractory cutaneous lupus erythematosus:
a French multicenter prospective study. Arch
Dermatol. 2012;148(4):479-484.
19. Tett SE, Cutler DJ, Day RO, Brown KF.
Bioavailability of hydroxychloroquine tablets in
healthy volunteers. Br J Clin Pharmacol. 1989;27(6):
771-779.
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1459
Research Original Investigation
Toxic Retinopathy With Hydroxychloroquine Therapy
20. Carmichael SJ, Day RO, Tett SE.
A cross-sectional study of hydroxychloroquine
concentrations and effects in people with systemic
lupus erythematosus. Intern Med J. 2013;43(5):547553.
21. Costedoat-Chalumeau N, Pouchot J,
Guettrot-Imbert G, et al. Adherence to treatment in
systemic lupus erythematosus patients. Best Pract
Res Clin Rheumatol. 2013;27(3):329-340.
22. Kellner U, Renner AB, Tillack H. Fundus
autofluorescence and mfERG for early detection of
retinal alterations in patients using
chloroquine/hydroxychloroquine. Invest
Ophthalmol Vis Sci. 2006;47(8):3531-3538.
23. Lyons JS, Severns ML. Detection of early
hydroxychloroquine retinal toxicity enhanced by
ring ratio analysis of multifocal electroretinography.
Am J Ophthalmol. 2007;143(5):801-809.
25. Marmor MF, Hu J. Effect of disease stage on
progression of hydroxychloroquine retinopathy
[published online June 12, 2014]. JAMA Ophthalmol.
doi:10.1001/jamaophthalmol.2014.1099.
26. Kaiser-Kupfer MI, Lippman ME. Tamoxifen
retinopathy. Cancer Treat Rep. 1978;62(3):315-320.
24. Marmor MF, Melles RB. Disparity between
visual fields and optical coherence tomography in
hydroxychloroquine retinopathy. Ophthalmology.
2014;121(6):1257-1262.
Invited Commentary
We Need to Be Better Prepared
for Hydroxychloroquine Retinopathy
Hendrik P. N. Scholl, MD, MA; Syed Mahmood Ali Shah, MBBS
From the first discovery of chloroquine by Hans Andersag at
Bayer in 1939 and later development of its hydroxyl and less
toxic form hydroxychloroquine (HCQ), these medications have
been one of the most abundantly used around the world and
have been instrumental in saving countless lives from malaria. Hydroxychloroquine is
currently listed in the World
Related article page 1453
Health Organization Model
List of Essential Medicines as
a disease-modifying agent for rheumatoid arthritis. Its use is
becoming ubiquitous for a variety of autoimmune disorders
from lupus to rheumatoid arthritis and now finding its way into
dermatology and oncology.1 There are more than 50 studies
evaluating HCQ in various disorders including many tumors.
With the results of the LUMINA (Lupus in Minorities: Nature
vs Nurture) trial showing clear benefit of HCQ use by decreasing mortality and end organ damage, HCQ use has significantly increased and is being advocated by the rheumatology
community with clinical trials reporting its use in 50% of patients with lupus, with tertiary care centers reporting the rate
of up to 90% (Baltimore Lupus Cohort; Michele Petri, MD, MPH,
Johns Hopkins Hospital, written communication, June 25,
2014). Given the increasing use of HCQ and retinopathy being
the only absolute contraindication for its use, it is more critical than ever to advocate for screening, detection, and prevention of retinopathy. Of note, most of these screenings are
not performed by retina spec ialists but by general
ophthalmologists.2
The American Academy of Ophthalmology recently issued revised guidelines including the recommendation of more
sensitive tests such as multifocal electroretinography, spectraldomain optical coherence tomography, and fundus autofluorescence. Although advanced screening is not recommended
until 5 years of receiving HCQ, considering the number of patients receiving the medication and the actual practice of performing those tests every year adds significant cost to the overall health care system.2 In an article in JAMA Ophthalmology,
Melles and Marmor3 suggest that approximately 350 000 patients in the United States should receive an annual eye screen1460
ing when applying the current guidelines. However, that number may be much higher if we add the current use in both adult
and juvenile rheumatoid arthritis, not to mention the newly
found use in oncology, where it may end up being used in
higher than normal doses, and in some cases for maintenance, resulting in high cumulative doses.4
Melles and Marmor3 report retinopathy in 7.5% of longterm HCQ users screened with modern techniques, which is
about 3 times higher than previous estimates. Those previous estimates had been primarily based on clinical examination and visual fields. Current widespread presence and use
of optical coherence tomography as a sensitive and reproducible test, which even allows exact anatomical placement of follow-up scans, may prove to be more sensitive and allow detection of changes well before bull’s-eye maculopathy has
developed. Such precise investigation of the retinal morphology does not, however, make functional tests obsolete since
a recent study by Marmor and Melles5 suggests that visual field
loss can actually be a more sensitive marker than the loss of
the ellipsoid zone on optical coherence tomography.
There is extensive discussion in the literature (comprehensively summarized by Melles and Marmor3) about the use
of ideal and real body weight. Within the rheumatology community, there may be a new drive to guide the dose based on
blood levels, rather than body weight. Instead of using it as an
adjunct, it should be a primary method to achieve a steady
state, which would address both compliance and overdosing
in high-risk patients. Most of the discussion about body weight
is trying to find a balance between the safety and efficacy of
HCQ, but to our knowledge, no randomized studies have
shown that dosing based on either ideal or real body weight is
superior for the disease itself. The retrospective study of Melles
and Marmor3 suggests that the real body weight is a better predictor of toxic effects but not essentially better at striking the
best balance between safety and efficacy.
How do we deal as ophthalmologists with HCQ being increasingly used and finding new indications? We need to acknowledge that HCQ reduces mortality and decreases end organ damage in lupus6 and need to be prepared that HCQ will
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