Summer 2022 (Volume 32, Number 2)
Can We Individualize the Prevention
By Ruud H.J. Verstegen, MD, PhD; and Deborah M. Levy, MD, MS, FRCPC
A 15-year-old female presents with a two-month history of joint pain and fatigue. Over the past two
weeks, she developed a malar rash and, on examination, has a painless palatal ulcer, mild bifrontal
alopecia and two swollen joints. Investigations demonstrate lymphopenia, mild anemia and hypocomplementemia.
She is anti-nuclear antibody (ANA) positive (high titre) and positive for anti-Sm
antibodies. The remainder of her investigations are negative, and a diagnosis of systemic lupus
erythematosus (SLE) is made. Hydroxychloroquine (HCQ) is initiated at the first visit following a
discussion of possible adverse effects including retinal toxicity. The patient and her caregiver want
to know what should be done to prevent retinopathy, given that she may require this medication
for many years, if not decades.
HCQ, originally used for the treatment and prophylaxis
of malaria, has been used in SLE since the early 1950s
because of its excellent safety profile and multiple benefits
including improved disease control, survival and decreased
damage accrual. Long-term HCQ maintenance has
been standard of care since the landmark study by The Canadian
Hydroxychloroquine Study group demonstrated an
increased risk of disease flare after HCQ discontinuation.1
HCQ has a favourable safety profile with gastrointestinal
symptoms including decreased appetite, nausea, abdominal
pain, and diarrhea commonly cited.2 Retinopathy
following prolonged treatment with chloroquine and hydroxychloroquine
was described in 1959 and 1967, respectively.
3,4 It was initially thought to occur rarely, but
more recently a prevalence of 7.5% by more sensitive techniques
such as spectral-domain optical coherence imaging
(SD-OCT) was observed.5
HCQ retinopathy is irreversible and specific treatment is
currently lacking. Also, severe toxicity at diagnosis can further
progress for at least three years after treatment discontinuation,
whereas those with early and moderate toxicity generally
have no progression.6 Therefore, annual SD-OCT screening
should start five years after treatment initiation, or earlier in
the presence of additional risk factors.7
Prevention of Hydroxychloroquine-induced
The identification of risk factors has helped to develop
strategies for prevention. Melles and Marmor
showed that the risk of HCQ retinopathy is associated
with higher HCQ doses (>5.0 mg/kg/day [actual body
weight]), prolonged treatment duration (>10 years), cumulative
HCQ dose, chronic kidney disease (estimated
glomerular filtration rate [eGFR] <60 mL/min per
1.73 m2) and concomitant treatment with tamoxifen.5
Based on these data, the current recommendations
are to use a HCQ dose of 5 mg/kg actual body weight
per day (no absolute daily maximum).7,8 At this dose,
the risk of HCQ retinopathy is <2% within the first 10
years of treatment.5 Compared to prior guidelines that
recommended a dose of 6.5 mg/kg ideal body weight
per day (maximum 400 mg/day), the new dosing regimen
results in lower drug exposure in patients with
a low-normal BMI, which may decrease treatment efficacy.
In contrast, patients with a BMI >25 will have a
relatively higher HCQ exposure than before, which has
been shown to result in increased HCQ blood concentrations,9 and thus may increase toxicity. Besides these
general dosing recommendations, there is no clear guidance
on HCQ dosing for patients with concurrent renal
disease and those treated with tamoxifen.8
Therapeutic drug monitoring (TDM) and pharmacogenetic
testing (PGx) may allow for treatment individualization
and reduce risks for adverse drug reactions, while optimizing
treatment efficacy. TDM is the practice where drug
concentration measurements in serum or blood are performed
to guide pharmacotherapeutic management, whereas
PGx guides treatment decisions by identifying targeted
genetic variants that are associated with specific clinical
Although HCQ concentrations have been studied
for at least 30 years, this test has not seen widespread
clinical implementation. There is a large variability in
the HCQ blood concentrations achieved for a specific
dose,10 which in part can be explained by (partial)
non-adherence in combination with the long halflife
(i.e., 30-60 days). Garg et al. recently published a
meta-analysis of 17 studies that have explored the optimal
HCQ blood concentration in SLE.11 They found
a strong association between low HCQ blood concentrations
and non-adherence. In addition, among 1,223
individuals, those with HCQ blood concentrations
≥ 750 ng/mL had a 58% lower risk of active disease, as
well as a Systemic Lupus Erythematosus Disease Activity
Index (SLEDAI) score that was 3.2 points lower.11
In 2020, Petri et al. published their work on the association
between HCQ blood concentrations and the development
of retinopathy in SLE.12 Of 537 patients, 23
developed retinopathy (4.3%). Looking at those who had
developed retinopathy, more than half had a HCQ blood
concentration in the highest tertile (mean >1,177 ng/mL
or maximum >1,753 ng/mL). Unfortunately, this study did
not relate blood concentration to the time of HCQ administration
(i.e., peak, trough).
Although the available studies provide an important
basis to further explore the relationship between HCQ
dosing, drug disposition, clinical efficacy, and retinopathy
risk, there is significant overlap between the HCQ
blood concentrations found in patients with and without
a favourable outcome, making it difficult to establish a
target drug concentration and interpret individual HCQ
blood concentrations. In addition, these results cannot be
applied to the pediatric population as data are absent in
children (i.e., <12 years old), and very limited in adolescents
(12-18 years old).
The individual variation in pharmacokinetics as well
as an individual sensitivity to develop HCQ retinopathy
may be genetically determined. As of yet, pharmacogenomic
studies involving this topic are limited, but variants in
CYP2D6, CYP2C8, CYP3A4 and CYP3A5 may contribute
to individual pharmacokinetic differences and the risk
for adverse drug reactions.13,14 In addition, one variant in
ABCA4 may be protective of HCQ retinopathy.15
Hydroxychloroquine is a hallmark SLE treatment that is
usually well tolerated. However, irreversible HCQ retinopathy
is an important adverse drug reaction that requires
optimal efforts at prevention. Recent dosing recommendations
may decrease the rate of retinopathy in some patients,
but also impact treatment efficacy. TDM and PGx
are promising approaches to individualize HCQ treatment
in the future; however, currently, insufficient data exist to
guide clinical decision making, and prospective studies to
demonstrate their role are needed.
Ruud H.J. Verstegen, MD, PhD
Divisions of Clinical Pharmacology &
Toxicology and Rheumatology,
The Hospital for Sick Children
Department of Paediatrics,
University of Toronto
Deborah M. Levy, MD, MS, FRCPC
Division of Rheumatology,
The Hospital for Sick Children
Department of Paediatrics,
University of Toronto
1. The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing
hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine
Study Group. N Engl J Med. 1991; 324(3): 150-4.
2. Sanofi-Aventis Canada Inc. Hydroxychloroquine [Product Monograph]. Health Canada: Drug Product
Database [Available from: https://pdf.hres.ca/dpd_pm/00063288.pdf.]
3. Shearer RV, Dubois EL. Ocular changes induced by long-term hydroxychloroquine (plaquenil) therapy.
Am J Ophthalmol. 1967; 64(2): 245-52.
4. Hobbs HE, Sorsby A, Freedman A. Retinopathy following chloroquine therapy. Lancet. 1959;
5. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine
therapy. JAMA ophthalmology. 2014; 132(12):1453-60.
6. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA
ophthalmology 2014; 132(9):1105-12.
7. Marmor MF, Kellner U, Lai TY, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine
Retinopathy (2016 Revision). Ophthalmology 2016; 123(6):1386-94.
8. Rosenbaum JT, Costenbader KH, Desmarais J, et al. American College of Rheumatology, American
Academy of Dermatology, Rheumatologic Dermatology Society, and American Academy of Ophthalmology
2020 Joint Statement on Hydroxychloroquine Use With Respect to Retinal Toxicity. Arthritis
rheumatol. 2021; 73(6):908-11.
9. Pedrosa T, Kupa LVK, Pasoto SG, et al. The influence of obesity on hydroxychloroquine blood levels
in lupus nephritis patients. Lupus. 2021; 30(4): 554-9.
10. 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): 547-53.
11. Garg S, Unnithan R, Hansen KE, et al. Clinical Significance of Monitoring Hydroxychloroquine Levels
in Patients With Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis. Arthritis
Care Res (Hoboken). 2021; 73(5):707-16.
12. Petri M, Elkhalifa M, Li J, et al. Hydroxychloroquine Blood Levels Predict Hydroxychloroquine Retinopathy.
Arthritis rheumatol. 2020; 72(3):448-53.
13. Gao B, Tan T, Cao X, et al. Relationship of cytochrome P450 gene polymorphisms with blood concentrations
of hydroxychloroquine and its metabolites and adverse drug reactions. BMC medical
genomics 2022; 15(1): 23.
14. Lee JY, Vinayagamoorthy N, Han K, et al. Association of Polymorphisms of Cytochrome P450 2D6
With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus. Arthritis
rheumatol 2016; 68(1):184-90.
15. Grassmann F, Bergholz R, Mändl J, et al. Common synonymous variants in ABCA4 are protective
for chloroquine induced maculopathy (toxic maculopathy). BMC Ophthalmol 2015; 15: 18.