Chloroquine has an affinity for pigmented (melanin-containing) structures, which may explain its toxic properties in the eye. Melanin serves as a free-radical stabilizer and can bind toxins. Although it binds potentially retinotoxic drugs, it is unclear whether the effect is beneficial or harmful.

2.  Chloroquine and hydroxychloroquine belong to the quinolone family.
They are related drugs with similar clinical indications for use and
similar manifestations of retinal toxicity, although their therapeutic and
toxic doses differ.
 Initially, chloroquine was given for malaria prophylaxis and treatment.
Subsequently, it was used by rheumatologists for treating rheumatoid
arthritis, systemic/discoid lupus erythematosus, and other connective
tissue disorders. Dermatologists use these drugs for cutaneous lupus.
Expanded use of these drugs for nonmalarial disease entities has
resulted in prolonged duration of therapy and higher daily dosages
than those used in antimalarial therapy.
 Since it is far less toxic to the retina, hydroxychloroquine has replaced
chloroquine, except for individuals who travel in areas endemic with
malaria. Many reports on chloroquine retinopathy exist. In contrast,
only a few cases of hydroxychloroquine toxicity have been reported.

3.  Chloroquine has an affinity for pigmented (melanin-
containing) structures, which may explain its toxic
properties in the eye. Melanin serves as a free-radical
stabilizer and can bind toxins. Although it binds potentially
retinotoxic drugs, it is unclear whether the effect is
beneficial or harmful.
 Chloroquine and its principal metabolite have been found
in the pigmented ocular structures at concentrations much
greater than in any other tissue in the body. With more
prolonged exposure, the drug accumulates in the retina.
The drug remains in the pigmented structures long after its
use is stopped. In patients with retinopathy, traces of
chloroquine have been found in plasma, erythrocytes, and
urine 5 years or more after discontinuation of the drug.

5.  Both due to its efficacy and favorable side effect profile when compared
with alternative drugs for rheumatologic conditions,
hydroxychloroquine is an important agent in rheumatologists’
armamentarium. However, one barrier to hydroxychloroquine use can
be its effects on the eye .
 Ocular side effects of hydroxychloroquine can include impact on:-
 the cornea,
 ciliary body,
 lens and retina.
 Corneal deposits, fortunately, rarely affect vison.2 However, the
concern of retinal toxicity and the need for monitoring must be
reviewed with patients prior to and during its use.
 Monitoring is intended to identify separate ocular disease that would
interfere with identifying changes or baseline
 retinal disease that could increase hydroxychloroquine’s risk, as well as
to detect the earliest changes related to hydroxychloroquine. The
concern with retinal toxicity is that this may be irreversible and may
progress even after hydroxychloroquine discontinuation. Identifying
toxicity prior to changes affecting the fundus limits potential for further
deterioration.
 Despite this, a significant proportion of individuals receive
hydroxychloroquine without eye examinations.

7.  Estimates of prevalence are variable among studies, with differences likely
representing the increasing availability of more sensitive testing and case
ascertainment by the studies. Further, the impairment experienced by
patients was variable.
 Initial studies demonstrated the risk as low as 0.5% and no events of
retinal toxicity when dosing was below 6.5 mg/kg/day of ideal body weight.
Further a prospective cohort demonstrated incidence of 0.5% in patients
all treated with less than 6.5 mg/kg/day with no events occurring until
after six years of treatment.
 Wolfe et al, in a study of patient-reported toxicity with review of medical
records by experts, identified overall prevalence as 0.65%. However, the
probability of toxicity was 0.29% after five years and further increased after
10 years (1%) and 15 years (2.1%).
 In a study published in 2014 by Melles and Marmor that included only
patients who had been assessed with visual field examination or Spectral
Domain-Optical Coherence Tomography (SDOCT), the prevalence was 7.5%.
 Fortunately, thus far, studies have not identified clear risk to children who
had an in utero exposure. In certain scenarios particularly systemic lupus
erythematosus, hydroxychloroquine is felt to be an important treatment
option for pregnant women.

8.  In terms of daily dose, initial studies emphasized a cut-off of 6.5
mg/kg of ideal body weight in terms of toxicity risk. However, due to
the typical dosing of either 200 or 400 mg of hydroxychloroquine, it is
rare for individuals to receive higher than this cut-off. More recent
studies suggest that real body weight predicts retinal toxicity better
than ideal body weight.
 Further, a cut-off of 5 mg/kg/day based on real body weight has
been proposed.
 In the study by Melles and Marmor, doses higher than 5 mg/kg/day
had rates of retinal toxicity of 10% within 10 years, which increased
further after 20 years to 40%. In contrast, between 4 and 5 mg/kg,
the risk was as low as 2% within 10 years and 20% after 20 years.
 This has been reflected in the most recent American Academy of
Ophthalmology (AAO) retinal toxicity monitoring recommendations.
Utilizing real body weight, typically up to a maximum of 400 mg, also
has the advantage of being more convenient in the clinic.

9.  An individualized approach for assessment of risk of toxicity
must be utilized. Age must be considered, in part because
ocular diseases that accumulate with age could pose difficulty in
terms of monitoring.
 Hydroxychloroquine is metabolized by the kidney and liver.
Kidney disease has been demonstrated to increase the risk of
toxicity (odds ratio 2.08) in the most recent study by Melles and
Marmor.
 Liver disease in this same study was not identified to be
associated with risk, but must be considered due its role in
metabolism.
 Concurrent tamoxifen use has also been identified as a
significant risk factor for retinal toxicity (odds ratio 4.59).
 However, blood level monitoring of hydroxychloroquine thus far
has not been able to be used in the clinical setting to predict risk
for retinal toxicity.
 Genetic factors are also being increasingly evaluated for their
association with risk. Clinical trials are currently in process to
further evaluate the role of genetics and hydroxychloroquine
toxicity

11.  The American Academy of Ophthalmology (AAO)
published updated retinal toxicity monitoring for
hydroxychloroquine/chloroquine recommendations
in 2016.
 The dreaded consequence of hydroxychloroquine
is “bull’s eye retinopathy,” which results in a ring
scotoma.
 Ideally, earlier changes can be identified to prevent
progression to this stage, which emphasizes the
importance of screening.

16.  The emphasis of baseline testing is the fundus evaluation of the macula. If
abnormalities of the macula are noted, AAO would recommend proceeding
with baseline visual fields and SD-OCT.
 The visual field testing should take into account a patient’s race/ethnicity
as patients with Asian background can have toxicity that is not limited to
the macula.
 For follow-up, automated visual fields and SD-OCT testing are
recommended. The use of additional testing, including multifocal
electroretinogram (mfERG) or fundus autofluorescence (FAF), is
recommended when available at a patients’ eye care provider. SD-OCT
generates images of the retina to the resolution level of cell layers.
 mfERG measures the electrical response to stimuli in order to identify
damage.
 Fundus autofluorescence technology detects fluorescence that can be the
consequence of damage.
 Older forms of screening, including fundus photography, time-domain
OCT, fluorescein angiography, full-field ERG,

17.  Amsler grid, color testing and electro-oculogram are
not preferred because they are less sensitive and/or
too subjective.
 The first examination should occur at baseline (near,
but not necessarily be prior to beginning therapy) and
then, if no other risk factors are present, should be
repeated after five years and annually thereafter. If
additional risk factors are identified, then screening
should occur annually.
 Although this specifically refers to screening in the
asymptomatic setting, if a patient experiences vision
changes
 including color vision then the patient should be
referred to their eye care provider.

18.  The presence of damage necessitates
discussion of discontinuation of
hydroxychloroquine because there is no
 treatment. The patient, rheumatologist and
ophthalmologist must collaborate to make
the best decision for the
 individual patient. Equivocal results of testing
can be followed up with repeat testing.

19.  Hydroxychloroquine can be an incredibly efficacious
medication. Fortunately, retinal toxicity is uncommon, but
assessment of risk and ophthalmic monitoring with
objective tests is essential to reduce the impact.
 Rheumatologists must communicate with their patients to
assure that monitoring is taking place. Risk factors should
be taken into account when assessing the timing for
surveillance including more recently identified concurrent
tamoxifen use.
 Real body weight dosing is a more convenient option in
the clinic, and doses less than 5 mg/kg/day have been
demonstrated to correlate with lower risk.
 The ACR has approved an updated position statement on
screening for hydroxychloroquine retinopathy to
emphasize the importance of screening and incorporation
of a patient’s risk factors into screening.