Content uploaded by Joanne M Bargman
Author content
All content in this area was uploaded by Joanne M Bargman on Jun 10, 2016
Content may be subject to copyright.
718
|
DECEMBER 2011
|
VOLUM E 7 www.nature.com/nrneph
Department of
Pediatrics, Division of
Rheumatology, The
Hospital for Sick
Children, 555
University Avenue,
Toronto, ON M5G 1X8,
Canada (S‑J. Lee,
E.Silverman).
Department of
Medicine, Division of
Nephrology, University
Health Network,
Toronto General
Hospital, 200 Elizabeth
Street, Toronto,
ONM5G 2C4, Canada
(J.M. Bargman).
Correspondence to:
J. M. Bargman
joanne.bargman@
uhn.ca
The role of antimalarial agents in the
treatment of SLE and lupus nephritis
Senq‑J Lee, Earl Silverman and Joanne M. Bargman
Abstract | Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various
organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE.
Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however,
their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially
by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will
focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe
the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents
chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their
use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations
regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall,
antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a
good safety profile.
Lee, S-J. etal. Nat. Rev. Nephrol. 7, 718–729 (2011); published online 18 October 2011; doi:10.1038/nrneph.2011.150
Introduction
Systemic lupus erythematosus (SLE) is a multisystem
autoimmune disease with varying patterns of organ
involvement. Lupus nephritis is one of the most common,
and most important, manifestations of SLE, and can lead
to permanent renal damage and chronic kidney disease.
The mainstay of therapy for renal involvement in patients
with SLE is corticosteroids, immunosuppressive agents
and antihypertensive medications.
The role of antimalarial medications in the treatment
of patients with SLE is, perhaps, underappreciated in the
renal community. A study published in 2010 demon‑
strated that the probability of a patient with SLE receiving
an antimalarial agent was substantially decreased (OR
0.51, 95% CI 0.31–0.84) if their primary physician was a
nephrologist rather than a rheumatologist.1 Antimalarial
drugs, specifically chloroquine and hydroxychloroquine,
have been gaining increased prominence in the treat‑
ment of patients with SLE—either with or without renal
involvement—as a result of their excellent safety profile
and increasing evidence of efficacy. A systematic review
of antimalarial use in patients with SLE, published in
2010, showed that treatment with these agents resulted
in improved disease control, reduced accrual of damage,
and a beneficial effect on survival.2
This Review focuses on the role of chloroquine and
hydroxychloroquine in the treatment of patients with
SLE, specifically those with lupus nephritis. We discuss
the current knowledge regarding the mechanisms of
action of these drugs, highlight their favorable efficacy
and safety profile, and describe how patients taking these
agents should be monitored.
A history of antimalarial drug use
Antimalarials are among the oldest drugs still used in
practice today. The first use of antimalarial drugs in a
patient with SLE is thought to have occurred in 1630
when the wife of a Peruvian Viceroy, the Countess of
Chinchon, was treated successfully for ‘tertian fever’
(malaria) with powdered cinchona bark supplied by Jesuit
priests. In 1894, J.S. Payne described features of the lupus
rash and prescribed quinine to induce pallor, which was
successful. Following the First World War, the formula for
quinacrine was turned over to the US military. Atabrine
(the proprietary name for quinacrine) was used by many
soldiers in the Second World War, principally as malaria
prophylaxis; however, soldiers with various rheumatic
complaints (including inflammatory arthritis and cutane‑
ous lupus) experienced symptomatic improvement while
taking this agent. These observations led to studies on
the use of antimalarial drugs in patients with rheumatic
diseases, which demonstrated improvements in arthritis
and cutaneous lupus among patients treated with quina‑
crine. Chloroquine was subsequently introduced in 1953,
and hydroxychloroquine in 1955. Both have greater effi‑
cacy and better tolerability than quinacrine,3 and are still
the two most commonly used antimalarial medications
administered to patients with SLE.
Metabolism of antimalarial drugs
Hydroxychloroquine and chloroquine are both
4‑amino‑quinolines; hydroxychloroquine is an analog
Competing interests
The authors declare no competing interests.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
NEPHROLOGY VOLUME 7
|
DECEMBER 2011
|
719
of chloroquine formed by β‑hydroxylation of one of
the N‑ethyl substituents. Both agents are well absorbed,
with 70–80% bioavailability after oral administration,
and half‑lives of 40–50days. Owing to this long half‑
life, 96% of steady‑state levels are not achieved until
after approximately 6months of continuous treatment.4
After similar doses given to healthy individuals (volun‑
teers) and to patients with rheumatoid arthritis, drug
concentrations vary between indivi duals up to 11‑fold.5
Both drugs are deposited in tissue at concentrations of
200–20,000 times above blood levels, with the highest
concentrations found in pigmented cells of the skin and
retina, but also in mono nuclear cells and muscle.6 In
animal models, chloroquine is 2–3 times more toxic
than hydroxychloroquine, whereas the latter drug is
only 60–70% as potent. Three times as much chloro‑
quine as hydroxychloroquine is excreted in the urine,
and three times as much hydroxychloroquine as chloro‑
quine is excreted in the feces.7 Inviv o studies show that
approximately 25% of hydroxychloroquine is excreted
by the kidneys; the rest is hepatic excretion and there‑
fore liver dysfunction may lead to higher concentrations
of the drug invivo. Renal excretion of both hydroxychlo‑
roquine and chloro quine is augmented by acidification
of the urine. The extensive sequestration of both drugs
within tissue limits their removal by hemo dialysis.4
Decreased glomerular filtration rate increases the risk
of toxic effects of both of these agents, in particular
cardio toxic effects and retinopathy.8
Mechanisms of action
The mechanisms of action of antimalarial drugs in
reducing inflammation remain unclear, although under‑
standing of the underlying pathways is improving. Both
hydroxychloroquine and chloroquine are lipophilic,
weak bases that easily pass across cell membranes and
into acidic intracellular vesicles, including lysosomes.
Their immunomodulatory effects are mediated by
mechanisms that are anti‑inflammatory, immuno‑
suppressive and photoprotective. Specifically, these
agents might alter lysosome stability, suppress antigen
presentation, inhibit prostaglandin and cytokine synthe‑
sis, and influence both Toll‑like receptor (TLR) signaling
and leukocyte activation.
Another use of antimalarial agents, of particular
interest to nephrologists, is the ability of hydroxychloro‑
quine to reduce 1‑hydroxylation of 25‑hydroxyvitamin
D3, which reduces elevated levels of 1,25 dihydroxy‑
vitaminD in patients with sarcoidosis and can be useful
for the hypercalcemia seen in this condition.9
Suppression of autoantigen presentation
Within the lysosomes of antigen‑presenting cells, anti‑
malarial agents cause functional alterations by increasing
the pH within lysosomal vesicles. This process results in
altered peptide loading and decreased binding of auto‑
antigenic peptides to classII MHC molecules (a low‑
affinity interaction); however, high‑affinity binding of
exogenous antigens (such as bacteria) to these molecules
is not affected. Antimalarial agents do not, therefore,
Key points
■Antimalarial therapy for patients with systemic lupus erythematosus (SLE) is
associated with improved survival and reduced disease activity, as well as
cardioprotective and anticancer effects
■In lupus nephritis, antimalarial therapy is associated with reduced
corticosteroid use, reduced disease activity, extended time to end-stage renal
disease, and, with adjunctive immunomodulatory treatment, improved duration
of renal remission
■Treatment with antimalarial agents should be continued in pregnant women
with SLE; the beneficial effects may include a reduction in the risk of cardiac
manifestations of neonatal SLE
■Antimalarial drugs have a good safety profile; gastrointestinal symptoms are
the most common adverse effect
■Baseline monitoring for retinopathy is required, but regular monitoring is
recommended by the American Academy of Ophthalmology guidelines only for
patients who have taken antimalarial agents for >5years
■In patients with impaired renal function, caution with dosing of antimalarial
agents is recommended and careful monitoring for adverse events should be
undertaken
cause substantial suppression of immune responses
directed against foreign antigens.10
Blockade of Toll‑like receptor signaling
TLRs are pattern‑recognition cellular receptors that
induce inflammatory responses by activating the innate
immune system.6 TLR activation causes dendritic cells
to produce large amounts of IFN‑α, and stimulates
Bcells to increase their production of immunoglobulins
and cyto kines, and to upregulate their expression of co‑
stimulatory molecules.11 Inv itro and invivo studies of
antimalarial agents in both rheumatoid arthritis and SLE
show that these drugs reduce inflammatory responses
by inhibiting TLR activation. The alkalinization of lyso‑
somes by antimalarial agents also interferes with endo‑
somal TLR signaling, primarily on antigen‑presenting
cells, thereby inhibiting TLR activation and reducing
inflammatory responses resulting from activation of the
innate immune system.6,11 The delay in onset of the clini‑
cal actions of antimalarial drugs may be explained by the
observation that the primary immunosuppressive effect is
on antigen‑ presenting cells, and not pre‑existing activated
T or Bcells; this delay may also be caused by the long
duration of time required to achieve steady‑state levels.
Reduced cytokine and prostaglandin synthesis
Inv itro and invivo studies of patients with SLE treated
with chloroquine show that this agent inhibits produc‑
tion of the cytokines, tumor necrosis factor (TNF), IL‑6,
IFN‑γ, IL‑1β, and IL‑18.12–15 Macrophages and monocytes
are the major cells affected. Some of these effects might be
lysosome‑independent,16,17 and are thought to be caused
by altered phosphorylation of mitogen‑ activated protein
kinases 3 and 1 (also known as MAPK3/ERK1 and
MAPK1/ERK2), and dual‑ specificity mitogen‑activated
protein kinase kinases 1 and 2 (also known as MAP2K1/
MEK1 and MAP2K2/MEK2).18 Finally, anti malarial
agents are prostaglandin antagonists. They inhibit
phospho lipase A2, with resultant alteration of arachidonic
acid metabolism and decreased inflammation.19
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
720
|
DECEMBER 2011
|
VOLUM E 7 www.nature.com/nrneph
Antiproliferative effects
Hydroxychloroquine promotes apoptosis by activating
caspase‑3, and might also sensitize cells to Fas‑mediated
apoptosis.20,21 Apoptosis of synoviocytes, antiprolifera‑
tion of endothelial cells and suppression of lymphocyte
function by antimalarial therapy, might lead to immuno‑
suppression and decreased angiogenesis.21 In v itro
studies show that chloroquine has inhibitory effects on
human endothelial cell proliferation and induces apop‑
tosis of these cells.22 This mechanism might have impor‑
tant consequences in patients with rheumatic diseases,
in whom upregulation of antiangiogenic pathways and
inhibition of pannus formation are important thera‑
peutic approaches. Antimalarials also inhibit neutro‑
phil superoxide release through lysosome‑independent
effects.23
Photoprotection
Multiple mechanisms have been proposed to explain the
clinically recognized effect of chloroquine and hydroxy‑
chloroquine on dermatological manifestations of SLE.
Chloroquine reduces levels of mRNA for IL‑1β, IL‑6 and
TNF in skin irradiated with ultraviolet‑B (UVB) light.
This agent might, therefore, have an inhibitory effect on
the production of proinflammatory cytokines induced
by UVB radiation.22 The intracellular mechanism pro‑
posed for photoprotection is activation of the transcrip‑
tion factor AP‑1, which subsequently transactivates the
immediate‑early genes, including JUN (which encodes
AP‑1 itself).24 Treatment with chloroquine decreases
serum levels of IL‑6, IL‑18 and TNF, and increases the
minimal erythemal dose (the amount of UVB light
required to induce cutaneous reddening) in patients
with SLE.14 Hence, chloroquine and hydroxychloroquine
have immunomodulatory properties that could lead to
protection against the skin damage associated with expo‑
sure to ultraviolet light. However, accumulation of these
agents within keratinocytes can lead to the sun‑induced
pigmenta tion changes associated with their use.
Decreased metalloproteinase activity
Metalloproteinases are involved in both inflammatory
and immune responses. Chloroquine reduces serum
levels of matrix metalloproteinase‑9 in patients with
SLE, and increases levels of metalloproteinase inhibitor 1,
which inhibits the activity of various metalloproteinases
and also maintains the balance between extracellular
matrix formation and destruction.25 Altered produc‑
tion of multiple metalloproteinases might also occur
via decreased expression of mitogen‑activated protein
kinase3 and p38 mitogen‑activated protein kinase within
the TLR or TNF pathways.26
Decreased leukocyte activation
Serum levels of the leukocyte activation markers, soluble
CD8 and soluble IL‑2 receptors are decreased after
6weeks of hydroxychloroquine treatment.27 Mean serum
levels of B‑cell activating factor are also significantly
reduced (6.3 ± 0.5 mg/ml to 3.0 ± 0.56 mg/ml, P = 0.0001)
following hydroxychloroquine use.28
Clinical benefits in patients with SLE
In 1894, quinine was used in the treatment of discoid
lupus, and in 1928 the beneficial effects of pamaquine on
discoid and subacute cutaneous lupus were suggested.29
The first study investigating withdrawal of amodiaquine
treatment, published in 1954, showed that all five patients
experienced a flare within 1–3months of stopping the
medication.30 The first controlled study on the efficacy of
chloroquine in patients with SLE appeared in 1975. This
retrospective study compared the symptoms of a group
of patients when they were on and off therapy, respec‑
tively. An overall benefit of chloroquine use was demon‑
strated, as measured by decreased flare rates, improved
skin disease and reduced glucocorticoid doses.31
In 1991, the Canadian Hydroxychloroquine Study
Group performed a prospective, randomized, trial,
which showed that compared with patients who contin‑
ued to take hydroxychloroquine, those who discontin‑
ued this treatment had a sixfold greater rate of severe
SLE exacerbation requiring withdrawal from the study
(4% versus 23%, P = 0.06), and a significantly higher rate
of SLE flare (73% versus 36%, P = 0.02), defined as the
development of specific clinical manifestations of SLE or
an increase in their severity, as well as a shorter time to
flare (P = 0.02).32 In 1996, a placebo‑controlled Spanish
study demonstrated that patients on chloroquine had
significantly lower flare rates and prednisone doses, and
lower overall disease activity, as scored by the Systemic
Lupus Erythematosus Disease Activity Index (SLEDAI)
at 1year.33 Subsequent cohort studies have continued
to reinforce these findings. In the USA, the Hopkins
Lupus Cohort and the LUMINA (Lupus in Minorities:
Nature Versus Nurture) nested case–control study,
which was conducted in adults of Hispanic (Mexican
and Central American), African American and white
European popula tions, showed that hydroxychloro‑
quine use was associated with a long‑term protective
effect on end‑organ damage and improved survival.34,35
The improvement in survival associated with the use of
these medications was still evident even after account‑
ing for confounding factors, including disease severity,
major organ involvement and socioeconomic class.34 In
both studies,34,35 the researchers attributed the increased
survival to beneficial cardioprotective effects of the anti‑
malarial used and a reduction in SLE flares, accrual of
chronic damage and neoplasms. Hydroxychloroquine
use is associated with reduced overall damage scores
in patients either with or without damage before
starting this drug, and also increased time to accrual
of new damage. Researchers who studied a cohort of
151 Israeli patients also found that those on hydroxy‑
chloroquine had reduced scores on the Systemic Lupus
International Collaborating Clinics–American College
of Rheumatology Damage Index for SLE.36
The GLADEL study, which involved a large observa‑
tional cohort of 1,480 patients from 34 centers in nine
Latin‑American countries, demonstrated that the use of
hydroxychloroquine and/or chloroquine for >6months
led to a 38% reduction in overall mortality (hazard ratio
[HR] 0.62, 95% CI 0.39–0.99).37 The greatest survival
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
NEPHROLOGY VOLUME 7
|
DECEMBER 2011
|
721
benefit was noted with prolonged antimalarial agent
use.37 Some researchers have hypothesized that the
widespread use of chloroquine to treat and/or prevent
malaria in West Africa might at least partially explain the
dramatically lower prevalence of SLE in this region than
in people of West African origin who migrated to Europe
or North America.38 A systematic review2 of articles pub‑
lished from 1982 to 2007 found a number of beneficial
effects of antimalarial use in patients with SLE, includ‑
ing improved survival, reduced disease activity, and
organ‑specific effects (Table1). In the following subsec‑
tions we will focus on literature published from 2005 to
2010 and discuss the effects of use of chloroquine and
hydroxychloroquine in patients with SLE.
Dyslipidemia, glycemia and atherosclerosis
The use of chloroquine and hydroxychloroquine is
associ ated with significantly decreased levels of tri‑
glycerides, LDL cholesterol and/or VLDL choles‑
terol, and increased levels of HDL cholesterol.39–44
Administration of these drugs also leads to significantly
reduced levels of apo lipoprotein B in patients with either
rheumatoid arthritis or SLE, and to increased levels of
apolipoproteinA in patients with rheumatoid arthritis.
Hydroxychloroquine treatment might decrease the
risk of atherosclerosis by improving binding (and inhib‑
iting dissociation) of insulin to its receptor, thereby
improving glucose tolerance (Table2).45 In patients with
rheumatoid arthritis and SLE, use of hydroxychloroquine
was found to improve glucose profiles, lower fasting
insulin levels, lower insulin resistance, and lower hemo‑
globinA1c (HbA1c) levels.46–48 The favorable metabolic
effect of hydroxychloroquine was also found in non‑
insulin‑dependent diabetic patients without rheumatic
disease.49 The use of hydroxychloroquine is also associ‑
ated with a reduced frequency of metabolic syndrome
among patients with SLE.50
Data on the effects of antimalarial therapy on vascu‑
lar disease are conflicting (Table2). In a mouse model of
atherosclerosis, chloroquine therapy decreased plaque
Table 1 | Overall and organ-specific effects of antimalarial drugs in patients with SLE and lupus nephritis
Study Design Population and treatment Outcomes in users
Fessler etal.
(2005)35
LUMINA
Longitudinal
cohort
518 patients: 291 HCQ users, 227 nonusers Reduction in accrual of new disease damage (HR 0.68, 95% CI
0.53–0.93, P = 0.014)
Ruiz-Irastorza
etal. (2006)63
Prospective
cohort
232 patients: 62 HCQ users, 46 CQ users, 42 HCQ
and CQ users, 82 nonusers
Increased cumulative 15-year survival in drug users vs nonusers
(0.95 vs 0.6, HR 0.14, 95% CI 0.04–0.48, P <0.001)
Calvo-Alén
etal. (2006)94
LUMINA
Nested
case–control
32 patients with SLE and osteonecrosis vs 59
controls without osteonecrosis matched for age, SLE
duration, ethnicity and center; all exposed to HCQ,
glucocorticoids and cytotoxic drugs
Possible protection against osteoporosis
Cases: less % HCQ exposure time (40% vs 59%, P = 0.026); higher
mean glucocorticoid dose (22.7 mg vs 14.8 mg, P = 0.011);
cytotoxic drugs received more often (59% vs 32%, P = 0.015)
Wozniacka
etal. (2006)14
Cohort 25 patients with SLE treated with CQ vs 25 sex and
age-matched healthy controls
Improved reduction in SLAM scores (9.47 to 4.92 after CQ,
P <0.001)
Costedoat-
Chalumeau
etal. (2006)93
Longitudinal
cohort
143 patients with SLE: 120 inactive disease vs 23
active disease; HCQ users
Reduced serum HCQ levels in patients with ares (OR 0.4, 95% CI
0.18–9.85, P = 0.01)
Alarcón etal.
(2007)34
LUMINA
Case–control 608 patients with SLE: 61 deaths (cases), 547 live
(controls); HCQ users
Increased survival with HCQ use (OR 0.128, 95% CI 0.054–0.300,
P <0.0001)
Ruiz-Irastorza
etal. (2007)61
Observational
prospective
cohort
235 patients with SLE: 156 HCQ and/or CQ users vs
79 nonusers
Protection against neoplasia (1.3% vs 13%, P <0.001); improved
cumulative cancer-free survival (OR 0.98 vs 0.73, P <0.001)
James etal.
(2007)95
Retrospective
chart review
130 US military patients with SLE: 26 patients
treated with HCQ before SLE classication
Time between onset of rst clinical signs or symptoms and SLE
classication was prolonged in patients treated with HCQ before
diagnosis vs not pretreated group (Wilcoxon signed-rank test,
P = 0.018)
Sisó etal.
(2008)62
Cohort 206 patients with lupus nephritis: 56 previously
taking HCQ, 150 nonusers
Protection against infection (11% vs 29%, P = 0.006); increased
survival (2% vs 13%, P = 0.029)
Ruiz-Irastorza
etal. (2009)96
Nested
case–control
249 patients with SLE: 83 patients with infections
(cases) vs 166 with no infections (controls);
antimalarial users (agent not specied)
Protection against infection (OR 0.06, 95% CI 0.02–0.18)
Shinjo etal.
(2009)97
Retrospective
cohort
57 patients with SLE ≥65years old: 43 with disease
remission, 14 with disease activity; CQ users
Disease remission strongly associated with CQ use (OR 12.9,
95% CI 2.9–58.1, P <0.001)
Pons-Estel
etal. (2010)98
LUMINA
Longitudinal
observational
cohort
580 patients; HCQ users Possible delayed onset of integument damage (HR 0.23, 95% CI
0.12–0.47, P <0.0001)
Shinjo etal.
(2010)37
GLADEL
Longitudinal
cohort
1,480 patients: 1,141 CQ and/or HCQ users vs 339
nonusers
Increased survival (4.4% vs 11.5%, HR 0.62, 95% CI 0.39–0.99,
P <0.001)
Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; SLAM, systemic lupus activity measure; SLE, systemic lupus erythematosus.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
722
|
DECEMBER 2011
|
VOLUM E 7 www.nature.com/nrneph
burden.51 Treatment with hydroxychloroquine has been
associated with a lower prevalence of carotid artery
plaques compared with not taking this agent in some,
but not all studies.52,53 However, in three cohort studies,
neither the use of nor the duration of use of chloroquine
or hydroxychloroquine correlated with plaque forma‑
tion.54–56 Measures of arterial stiffness were significantly
lower in patients taking hydroxychloroquine than in
patients who were not taking this drug.57,58 The results of
a case–control study of 29 patients with SLE demonstrated
that individuals with cardiovascular diseases were signifi‑
cantly less likely than those without such diseases to have
received hydroxychloroquine.59 However, a 2010 report
from the Systemic Lupus Erythematosus International
Collaborating Clinics international inception cohort study,
which included 1,249 patients, did not find any difference
in the rate of atherosclerotic vascular events after 2years of
follow‑up between patients who were taking antimalarials
and those who were not on this treatment. However, such
events occurred in only 1.8% of the whole cohort.60
Malignancy
Antimalarial drug use in patients with SLE could reduce
the risk of malignancy. In one study, the prevalence of
neoplasia was lower in patients treated with anti malarials
(1.3%) than in those not taking such medications (13%).61
In another study, the prevalence of malignancy in chloro‑
quine or hydroxychloroquine users was 0%, versus 3%
in nonusers.62
Thrombosis
Antimalarial drug use is thromboprotective (Table2).
A significantly reduced risk of thrombosis is evident
in patients on chloroquine and hydroxychloroquine
versus the risk in those not receiving this treatment.62,63
In another study, a 68% reduction in the risk of thrombo‑
embolism was found in patients with SLE on hydroxy‑
chloroquine therapy, as compared to individuals with
SLE who were not taking these medications.64
Clinical benefits in lupus nephritis
Antimalarial therapy has several potential benefits in
patients with lupus nephritis (Table3). Antimalarial
therapy is recommended in patients with lupus nephri‑
tis with preserved renal function, even though they may
have a risk of renal impairment later on. Strategies such
as dose reduction and monitoring for adverse effects
of antimalarial treatment should be implemented in
patients who have renal impairment.
The Canadian Hydroxychloroquine Study Group was
one of the first to examine the effects of antimalarial drug
use on renal outcomes. This randomized withdrawal
study with 3‑year follow‑up demonstrated that contin‑
ued hydroxychloroquine treatment was associated with
a 74% reduction in the risk of nephritic flares compared
with withdrawal (placebo) (4% in the hydroxychloro‑
quine group versus 14% in the placebo group, relative
risk 0.26, 95% CI 0.03–2.54). Owing to the small cohort
of 47 patients included in this study, its statistical power
Table 2 | The effects of antimalarial agents on cardiovascular disease, thrombosis and glycemic control in patients with SLE and lupus nephritis
Study Design Population and treatment Outcomes in users
Ruiz-Irastorza
etal. (2006)63
Prospective
cohort
232 patients with SLE: 62 HCQ users, 46 CQ
users, 42 HCQ and CQ users, 82 nonusers
Protection against thrombosis (HR 0.28, 95% CI 0.08–0.90)
de Leeuw etal.
(2006)99
Cross-
sectional
38 patients with SLE taking HCQ: 7 with CVD, 31
without CVD
No signicant change in cardiovascular risk (54% with CVD vs 53% without
CVD, P = NS)
Sachet etal.
(2007)43
Invivo 30 individuals: 10 patients with SLE taking CQ,
10 patients with SLE on no antimalarial therapy,
10 healthy controls
Improved clearance of total cholesterol (CQ group 156 ± 16 mg/dl;
no antimalarial group 174 ± 15 mg/dl; control group 200 ± 24 mg/dl,
P <0.001) and low-density lipoproteins (CQ group 88 ± 16 mg/dl;
no antimalarial group 108 ± 17 mg/dl; control group 118 ± 23 mg/dl,
P <0.001)
Choojitarom
etal. (2008)100
Cohort 67 antiphospholipid-antibody-positive patients
with SLE treated with CQ or HCQ
Decreased risk of thrombosis (OR 0.18, 95% CI 0.04–0.88, P = 0.034);
the subgroup of patients with lupus nephritis had an increased risk of
venous thrombosis (OR 6.2, P = 0.005)
Sisó etal.
(2008)62
Cohort 206 patients with lupus nephritis: 56 had
previously taken CQ or HCQ; 150 were nonusers
Reduced risk of developing hypertension (32% vs 50%, P = 0.027);
protection against thrombosis (5% vs 17%, P = 0.039)
Kaiser etal.
(2009)101
Cohort 1,930 patients with SLE: 1,534 (80%) HCQ users Protection against thrombosis (OR 0.67, 95% CI 0.5–0.9, P = 0.008)
Tektonidou
etal. (2009)102
Longitudinal
cohort
288 patients with SLE: 144 antiphospholipid-
antibody-positive patients, matched with 144
antiphospholipid-antibody-negative patients; HCQ
users
Protection against thrombosis in both groups
Antibody-positive: HR per month of treatment 0.99, 95% CI 0.98–1.0,
P = 0.05
Antibody-negative: HR per month of treatment 0.98, 95% CI 0.95–0.99,
P = 0.04
Jung etal.
(2010)64
Nested
case–
control
54 patients with SLE who experienced
thromboembolic events vs 108 event-free
patients with SLE (controls); HCQ users
Protection against thrombosis (OR 0.32, 95% CI 0.14–0.74, P <0.01)
Penn etal.
(2010)48
Cross-
sectional
149 patients with SLE and 177 patients with
rheumatoid arthritis; HCQ users vs nonusers
Reduced fasting glucose levels in nondiabetic women (potentially
improved glycemic control)
SLE: 85.9 mg/dl vs 89.3 mg/dl, P = 0.04; rheumatoid arthritis: 82.5 mg/dl
vs 86.6 mg/dl, P = 0.05
Abbreviations: CQ, chloroquine; CVD, cardiovascular disease; HCQ, hydroxychloroquine; NS, not significant; SLE, systemic lupus erythematosus.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
NEPHROLOGY VOLUME 7
|
DECEMBER 2011
|
723
is low. Nevertheless, these findings provided early evi‑
dence that hydroxychloroquine treatment might reduce
nephritic flares.65
In 2005, the investigators of the LUMINA study
reported that hydroxychloroquine use was associ‑
ated with a reduced risk of developing renal disease in
patients with SLE.35 In the subgroup of 203 patients with
lupus nephritis, 79.3% of patients had received hydroxy‑
chloroquine treatment. Those who received hydroxy‑
chloroquine had a lower frequency of World Health
Organization classIV glomerulonephritis, lower SLE
disease activity scores, and lower glucocorticoid doses
than those patients not taking hydroxychloroquine.
Hydroxychloroquine treatment was also associated with
a reduced cumulative probability of renal damage.66 The
magnitude of these effects was remarkable, leading to
suggestions that the study results reflected confound‑
ing by indication, immortal person‑time bias (meaning
that the time between study enrollment and initiation
of hydroxychloroquine treatment should have been,
but was not, excluded from the follow‑up period, even
though patients who developed renal damage during
this period were not treated with hydroxychloroquine),
and other potential (unknown) sources of bias.67,68 The
authors of the 2005 paper subsequently responded by
performing time‑dependent analyses using a longitudi‑
nal approach, and still found that hydroxychloroquine
use reduced the occurrence of renal disease, albeit to
a lesser extent (adjusted OR 0.51, 95% CI 0.29–0.91,
P = 0.02).68 However, these findings are difficult to gen‑
eralize to other populations, as the cohort consisted of
only three ethnic groups.
A substudy of 29 patients from the Hopkins Lupus
Cohort who had either membranous nephritis or mixed
membranous nephritis and proliferative nephritis treated
with mycophenolate mofetil, showed that concurrent use
of hydroxychloroquine led to a statistically significant
improvement in the rate of renal remission at 12months.
This finding persisted after controlling for the presence
of antibodies to double‑stranded DNA.69
A Spanish long‑term, observational, cohort study of
206 patients showed that those with biopsy‑proven lupus
nephritis taking chloroquine or hydroxy chloroquine
had a reduced incidence of elevated creatinine levels
(>354 μmol/l), hypertension, infections, thrombotic events,
and death, as well as a prolonged time to develop ment of
end‑stage renal disease, compared to the incidence in
those not taking antimalarial agents.62 These findings were
signifi cant despite the fact that only 27% of the 206 patients
were taking antimalarial agents. Although this study
included a large cohort of patients, the analysis demon‑
strates potential methodological limitations, including
confounding bias and immortal person‑time bias.
The investigators of the GLADEL study reported that
77% of the participants had received chloroquine and/or
hydroxychloroquine, defined as use of these agents for >6
consecutive months. In addition to prolonged survival,
the researchers demonstrated that renal disease was less
Table 3 | The effects of antimalarial drug use in patients with lupus nephritis
Study Design Population and treatment Outcomes in users
Tsakonas etal.
(1998)65
Cohort
(randomized
drug withdrawal)
47 patients: 25 continued HCQ,
22 withdrew
Possible reduction in risk of and time to renal disease are (RR 0.26, 95% CI
0.03–2.54, P = 0.25)
Fessler etal.
(2005)35 LUMINA
Longitudinal
observational
cohort
518 patients: 291 started HCQ at
study enrollment, 227 were nonusers
Lower incidence of renal disease at baseline (25% vs 53%, P <0.0001)
Kasitanon etal.
(2006)69 Hopkins
Lupus Cohort
Cohort 29 patients: 11 used both HCQ and
MMF, 18 used MMF only
Patients with membranous lupus nephritis who were taking both drugs had
improved rates of renal remission within 12months (64% vs 22%, P = 0.036)
Barber etal.
(2006)103
Retrospective
cohort
35 patients with lupus nephritis:
15 out of 16 patients with sustained
remission taking HCQ vs 10 out of
19 patients with no sustained
remission (controls) taking HCQ
Improved sustained remission rates (93.8% vs 52.6%, P = 0.01)
Sisó etal.
(2008)62
Cohort 206 patients: 56 were taking CQ or
HCQ before diagnosis of lupus
nephritis, 150 were nonusers
Reduced percentage of patients with creatinine elevations >354 µmol/l (2%
vs 11%, P = 0.029); prolonged time to end-stage renal failure (2% vs 11%,
P = 0.044); reduced frequency of hypertension (32% vs 50%, P = 0.027);
reduced mortality (2% vs 13%, P = 0.029)
Pons-Estel etal.
(2009)66 LUMINA
Longitudinal
observational
cohort
(prospective)
203 patients: 161 HCQ users,
42 nonusers
Reduced frequency of classIV glomerulonephritis (9.9% vs 33.3%, P <0.01);
protection against ESRD and/or diminished GFR (HR 0.38, 95% CI 0.13–
1.06, P = 0.065 [full model]; HR 0.38, 95%CI 0.16–0.86, P = 0.0206 [reduced
model]); decreased glucocorticoid (prednisone) dose (11.3 ± 12.0 mg vs
16.8 ± 20.5 mg, P = 0.025); protection against renal damage (HR 0.12, 95%
CI 0.02–0.97, P = 0.0464 [full model]; HR 0.29, 95% CI 0.13–0.68,
P = 0.0043 [reduced model]); reduced cumulative probability of renal damage
(HCQ users 20% [5years] or 38% [10years]; nonusers 47% [5years] or 70%
[10years], P <0.0001)
Shinjo etal.
(2010)37 GLADEL
Observational
inception cohort
1,480 patients: 1,141 CQ and/or
HCQ users, 339 nonusers
Reduced prevalence of renal disease (28.4% vs 42.8%, P <0.001)
Abbreviations: CQ, chloroquine; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; RR, relative risk.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
724
|
DECEMBER 2011
|
VOLUM E 7 www.nature.com/nrneph
frequent in antimalarial drug users than in nonusers
(28.4% versus 42.8%).37
Antimalarial drugs are postulated to reduce the
severity of renal disease through immunomodulatory,
anti‑inflammatory and antithrombotic effects. All such
effects act beneficially on the vascular endothelium
and reduce renal inflammation. The studies discussed
above provide intriguing evidence that chloroquine and
hydroxy chloroquine might retard the progression of
renal disease, increase the duration of renal remission
when combined with other immunosuppressive medica‑
tions, and reduce cumulative dose of glucocorticoids.
However, caution must be exercised with generalizing
these results to specific populations, as the majority
of studies included only Hispanic or Latin American,
African American, and Caucasian populations.
Pregnancy and fetal outcomes
Antimalarials are safe and effective for pregnant patients
with lupus (Table4). Hydroxychloroquine readily crosses
the placenta, and blood levels of this drug are similar
between mother and fetus.6 However, studies have
revealed no increased risk of retinopathy or ototoxic
effects in infants born to women taking hydroxychloro‑
quine at the recommended (reduced) dose of <4 mg/kg
(lean body weight) per day during the pregnancy.70,71 A
review published in 2005 of >250 pregnancies also sup‑
ported the lack of teratogenic effects associated with
hydroxychloroquine use.72
Pregnancy increases disease activity in many patients
with SLE. Flares can potentially worsen renal function,
hypertension and/or proteinuria, leading to an increased
risk of maternal and fetal complications.73 These adverse
outcomes can also occur as a consequence of stopping
commonly used immuno suppressive therapies, includ‑
ing antimalarial drugs, owing to fears of potential fetal
or neonatal complica tions. Two studies in 2001 and 2006
suggested that hydroxychloroquine use in pregnant
patients with lupus is associated with decreased overall
disease activity and flare rates.74,75 The 2006 study found
that women with SLE who stopped hydroxychloroquine
when they became pregnant had worse disease activity
and higher glucocorticoid requirements than women
with SLE who continued taking hydroxychloroquine
during the pregnancy, or women who were not taking
this drug at the time of conception.74 These results
suggest that withdrawal of hydroxychloroquine during
pregnancy exacerbates the risk of developing increased
disease activity, as occurs in nonpregnant patients. The
results of a case–control study that analyzed data from
the American Neonatal Lupus Registry suggest that the
use of hydroxychloroquine during pregnancy in mothers
with antinuclear antibodies (anti‑Ro/SSA and/or anti‑La/
SSB antibodies) decreases the risk of cardiac manifesta‑
tions of neonatal lupus erythematosus in a multi variable
analysis (OR 0.46, 95% CI 0.18–1.18, P = 0.10). The
researchers concluded that use of anti malarial drugs
resulted in decreased TLR signaling, which led to
Table 4 | An overview of studies on antimalarial drug use in pregnant patients with SLE
Study Study type Population and treatment Outcomes of users
Buchanan etal.
(1996)104
Cohort 36 pregnant women with SLE taking HCQ
and 53 pregnant women with SLE not
taking HCQ
No signicant difference in live birth rates with and without HCQ (86% vs
83%); no signicant difference in rates of fetal death or spontaneous abortion
with and without HCQ (14% vs 17%); no signicant difference in premature
births with and without HCQ (55% vs 48%); no signicant difference in
intrauterine growth failure with and without HCQ (19% vs 41%)
Levy etal.
(2001)75
Prospective
cohort
20 pregnant women with SLE randomized
with 10 to treatment with HCQ and 10 to
placebo
Lower SLEPDAI scores at delivery (P = 0.0356); may reduce ares (0% vs 30%,
P = 0.21); reduced prednisone requirements (6.0 ± 6.2 mg vs 15.5 ± 24.5 mg
at 18weeks, P = 0.07; 4.5 ± 4.3 mg vs 13.7 ± 27.9 mg , P <0.05 at delivery); no
congenital abnormalities, and no retinopathy or ototoxic effects in children
1.5–3.0years of age born to mothers who used antimalarial drugs
Costedoat-
Chalumeau
etal. (2003)105
Nested
case–control
90 women with SLE (133 pregnancies)
taking HCQ and 53 women with SLE
(70 pregnancies) not taking HCQ
No difference in live-birth rates with and without HCQ (88% vs 84%); no
difference in rate of congenital abnormalities with HCQ compared with rates
in the general population (2.26% vs 2.3%); no visual, hearing, growth, or
developmental abnormalities associated with HCQ treatment
Clowse etal.
(2006)74
Prospective
cohort
257 pregnancies in 3 groups: (1) 56
pregnancies in women with SLE taking
HCQ; (2) 163 pregnancies in women with
SLE not taking HCQ; (3) 38 women
stopped taking HCQ either in the
3months before pregnancy or during the
rst trimester
No difference in rates of miscarriage, stillbirth, pregnancy loss, congenital
abnormalities with and without HCQ; stillbirths: 6% vs 8% vs 9%, P = 0.85;
preterm (20–28weeks): 12% vs 10% vs 6%, P = 0.83; preterm (28–
37weeks): 27% vs 31% vs 47%, P = 0.87; full-term: 61% vs 59% vs 47%,
P = 0.98; reduced overall SLE disease activity; SLEDAI score >4: 52% vs 62%
vs 84%, P = 0.0075; are rates: 30% vs 36% vs 55%, P = 0.053; reduced
doses of prednisone during pregnancy (16 ± 12 mg vs 23 ± 19 mg vs
21 ± 16 mg, P = 0.056)
Carvalheiras
etal. (2010)106
Retrospective
cohort
43 women with SLE who had 51
pregnancies over 14years; 20 patients
treated with HCQ
No cases of maternal mortality; no cases of fetal malformations
Izmirly etal.
(2010)76
Case–control 50 women with SLE whose infants
developed NLE (14% HCQ users) vs 151
women with SLE whose infants did not
develop NLE (controls: 37.1% HCQ users)
HCQ use might reduce the risk of fetal development of cardiac NLE in
pregnant women with SLE and either anti-Ro/SSA or anti-La/SSB antibodies
(OR 0.46, 95% CI 0.18–1.18, P = 0.10)
Abbreviations: HCQ, hydroxychloroquine; NLE, neonatal lupus erythematosus; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SLEPDAI,
Systemic Lupus Erythematosus Pregnancy Disease Activity Index.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
NEPHROLOGY VOLUME 7
|
DECEMBER 2011
|
725
reduced cardiac inflammation and scarring.76 We con‑
clude that hydroxychloroquine use should be maintained
during pregnancy.
Adverse effects of antimalarial agents
Both hydroxychloroquine and chloroquine are well‑
tolerated medications with good safety profiles. The
most commonly reported adverse effects of treatment
are gastro intestinal (nausea, vomiting, diarrhea, anorexia
and, rarely, elevated levels of liver enzymes) or neurologi‑
cal (headache and dizziness). Retinopathy is an uncom‑
mon, but very important adverse effect associated with
antimalarial use (Table5).77
Retinopathy
The retinal toxic effects associated with antimalarial
use are the result of disrupted metabolism of the retinal
pigmented epithelium, which results in the degenera‑
tion of photoreceptors. Antimalarial drugs demonstrate
enhanced binding to melanin, which is present at high
levels in the retinal pigmented epithelium; these agents,
therefore, accumulate disproportionately in these cells
and are more likely to alter the lysosomal pH of melanin‑
containing cells than those of melanin‑free cells.78 The
earliest symptom of retinal damage is loss of para central
visual fields, with loss of color vision; these losses prog‑
ress as the lesion spreads into the fovea and over the
fundus. The very early stages of functional loss may be
reversible with cessation of antimalarial therapy, but
most cases with maculopathy are irreversible.79
It was originally suggested that ophthalmological
examina tions should be performed every 3months
in patients receiving antimalarial agents, but by 1996
examina tions every 6–12months were considered ade‑
quate.80,81 The American Academy of Ophthalmology
(AAO) published revised recommendations in 2011 after
reviewing literature surrounding screening methods,
implications of screening, and risk factors for devel‑
oping retinotoxicity.79 Screening is not for prevention,
but rather to detect early toxicity in order to stabilize
Table 5 | Potential adverse effects associated with antimalarial agents
Adverse effect Agent Supporting studies Reported frequency
Retinopathy CQ Leecharonen etal. (2007)8
Marmor etal. (2002)82
Wang etal. (1999)77
Aviña-Zubieta etal. (1998)107
Finbloom etal. (1985)108
Retinopathy: 0.18–19%
Corneal deposits: 6–7%
Retinopathy HCQ Wolfe etal. (2010)85
Mavrikakis etal. (2003)83
Marmor etal. (2002)82
Wang etal. (1999)77
Aviña-Zubieta etal. (1998)107
Levy etal. (1997)86
Spalton etal. (1993)109
Finbloom etal. (1985)108
Retinopathy: 0–6%
Corneal deposits: 0.8%
Ototoxic effects HCQ Wang etal. (1999)77
Morand etal. (1992)110
0–0.6%
Cardiotoxic
effects
CQ and HCQ Costedoat-Chalumeau etal.
(2007)111,112
Wozniacka etal. (2006)113
Nord etal. (2004)88
Cervera etal. (2001)114
Heart conduction defect: 0–4%
Cardiomyopathy: <1%
Atrioventricular block: <1%
Case reports of cardiomyopathy, heart conduction disturbances,
congestive heart failure
Cutaneous
lesions
Quinacrine,
CQ and HCQ
Kalia etal. (2010)6
Di Giacomo etal. (2009)115
Puri etal. (2008)89
Herman etal. (2006)90
Wang etal. (1999)77
Aviña-Zubieta etal. (1998)107
Morand etal. (1992)110
Skin rash: 0.6–4.3%
Hyperpigmentation: 10–30% (most frequent with quinacrine)
Urticaria: 12%
Psoriasis: insufcient evidence to suggest these agent cause
ares
Gastrointestinal
symptoms
CQ and HCQ Bezerra etal. (2005)116
Van Beek & Piette (2001)117
Wang etal. (1999)77
Aviña-Zubieta etal. (1998)107
Morand etal. (1992)110
Gastrointestinal (overall): 0–30%
Nausea or vomiting: 12%
Diarrhea: 18%
Elevated levels of liver enzymes: 10%
Other CQ and HCQ Casado etal. (2006)118
Bezerra etal. (2005)116
Wang etal. (1999)77
Aviña-Zubieta etal. (1998)107
Morand etal. (1992)110
Headaches: 1.3–12%
Myopathy: 0–6.7%
Rare events
(case reports)
CQ and HCQ Kalia etal. (2010)6
Collins etal. (2008)119
Bracamonte etal. (2006)91
Hemolysis in patients with G6PD deciency; severe leukopenia
or aplastic anemia; acute CQ-induced psychosis (similar to
phencyclidine-induced psychosis); pseudo-Fabry disease
Abbreviations: CQ, chloroquine; G6PD, glucose-6-phosphate 1-dehydrogenase; HCQ, hydroxychloroquine.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
726
|
DECEMBER 2011
|
VOLUM E 7 www.nature.com/nrneph
maculopathy and stop further loss of visual acuity. The
AAO recommendations are to first perform a baseline
screen within the first year of antimalarial therapy.
Previous literature suggests that the cumulative dose
of anti malarial agents has an important role in the
develop ment of toxic effects. The AAO recommenda‑
tions suggest that annual screening may not be necessary
before 5years of cumulative therapy, and therefore that
annual screening should be conducted after 5years of
cumulative therapy. However, caution must be exercised
when factors that increase the risk of retino pathy are
present, including: high cumulative doses of these agents
(hydroxy chloroquine >1,000 g or chloro quine >460 g);
high daily doses (hydroxychloroquine >400 mg daily, or
>6.5 mg/kg of lean body weight; chloroquine >250 mg
daily, or >3.0 mg/kg of lean body weight); older age; renal
or liver dysfunction; and pre‑existing visual impair‑
ment, such as retinal disease or maculo pathy. Obesity
is a risk factor for retinopathy because anti malarials are
not deposited in fatty tissue; dosing should, therefore, be
based on lean body weight.82,83
Ophthalmologic examinations in patients taking anti‑
malarial drugs should include enquiries about visual
symptoms, a thorough ophthalmologic examination
and an automated visual field assessment (using the
Humphrey visual field 10–2 pattern testing).80 Other more
specific objective testing to be considered that may only
be available in specialist centers include the multi focal
electroretinogram, spectral domain‑optical coherence
tomography, and fundus autofluorescence.79,84 Evidence
from large clinical studies of patients with rheumatic
diseases (enrolling 526–3,995 patients) supports these
recommendations, as only 0.4–0.65% of patients devel‑
oped retinal toxic effects associated with anti malarial
therapy. The majority of such adverse events occurred
after 6years of antimalarial treatment and/or in patients
taking >6.5 mg/kg hydroxychloroquine daily; some cases
of retinopathy were also seen when the dose of anti‑
malarial agent was based on the patient’s overall weight,
rather than lean body weight.83,85,86 The guidelines pub‑
lished by the British Royal College of Ophthalmologists
and the British Society for Rheumatology in 2009 are
similar to the AAO recommendations, stating that annual
screening is not required until after 5years of cumula‑
tive therapy, as clinically significant maculopathy is rare
and no reliable test exists for detecting this retinopathy
within the reversible stage. The guidelines recommend
careful or earlier screening by an ophthalmologist if the
patient has baseline visual impairment or eye disease, if
visual disturbances are noticed during antimalarial treat‑
ment, or if the patient is receiving high doses (>6.5 mg/kg
daily) of hydroxychloroquine or continuous treatment
for >5years.87
Neuromyotoxic and cardiotoxic effects
Neuromyotoxic and cardiotoxic effects are rare but
potentially fatal complications of antimalarial therapy.
Patients with neuromyotoxic effects usually present with
bilateral and progressive muscle weakness of the legs,
which can be accompanied by a polyneuropathy. Acute
cardiotoxic effects of high‑dose antimalarial therapy
include decreased myocardial contractility, hypo tension
and conduction abnormalities. Chronic cardiotoxic
effects of this treatment are manifested by heart block,
biventricular hypertrophy and/or cardio myopathy
(usually constrictive or restrictive). These complica‑
tions are most frequently seen in patients receiving high
doses of antimalarial agents and in those with renal
impairment.88
Cutaneous toxic effects
Both hydroxychloroquine and chloroquine sometimes
cause oval patches of yellow‑brown to slate‑gray hyper‑
pigmentation that might enlarge. The hyperpigmenta‑
tion can begin after 4months of therapy and occurs in up
to 10% of patients treated with these agents. The lesions
tend to develop on mucosal areas, in particular the hard
palate, although any area of the skin may be involved.89
Antimalarial drugs might exacerbate psoriasis in a small
proportion (1–2%) of patients. However, a systematic
review published in 2006 revealed no strong evidence
either supporting or refuting the hypothesis that anti‑
malarial use worsens psoriasis.90 Whether hydroxy‑
chloroquine has a role in the treatment of new‑onset
psoriasis in patients with SLE is, therefore, unclear.
Iatrogenic phospholipidosis
One case report described a woman with inflammatory
polyarthritis who was treated with hydroxychloroquine
and went on to develop iatrogenic phospholipidosis
resembling Fabry disease. A renal biopsy sample obtained
to investigate proteinuria revealed ‘classic’ Fabry
disease. However, DNA mutational analysis revealed
no abnormali ties associated with Fabry disease in this
patient’s α‑galactosidase A gene. The authors of this report
postulated that long‑term hydroxychloroquine use caused
iatrogenic phospholipidosis secondary to inhibition
of the activity of circulating α‑galactosidase.91
Drug level monitoring
Poor compliance with antimalarial therapy and other
medica tions for SLE can be a common problem. A study
of hydroxychloroquine pharmacokinetics showed that
serum levels of this agent could be quantified by high‑
performance liquid chromatography.92 Five patients
had undetectable levels reflecting poor treatment
compliance. Patients with active SLE had significantly
lower serum hydroxy chloroquine concentrations than
those with inactive disease (694 ± 448 ng/ml versus
1,079 ± 526 ng/ml, P = 0.001). This may be due to poor
compliance, but more a result of large interindividual
variations in hydroxychloroquine bioavailability. A
low serum concentration of hydroxychloroquine was
a predictor of disease exacerbation (OR 0.4, 95% CI
0.18–0.85, P = 0.01), and a hydroxychloroquine concen‑
tration threshold of 1,000 ng/ml had a negative predic‑
tive value of 96% for exacerbations.93 Hence, measuring
serum levels of hydroxy chloroquine could prove bene‑
ficial in assessing compliance, as well as in predicting and
potentially reducing disease exacerbations. Serum levels
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
NEPHROLOGY VOLUME 7
|
DECEMBER 2011
|
727
of hydroxychloroquine are not measured in current clini‑
cal practice, however, as not all laboratories are able to
perform this test.
Conclusions
Antimalarial agents have been the mainstay of treatment
for SLE, in combination with other immunomodula‑
tory drugs, but are underused by nephrologists. Their
immuno modulatory and anti‑inflammatory effects are
associated with numerous beneficial effects on the out‑
comes of patients with SLE, including improvements in
survival and remission rates, and reductions in disease
activity, accrual of new disease‑related damage, and
infection rates. Antimalarial therapy has antithrombotic
and vascular protective effects, and might also have a role
in preventing neoplasia. These drugs are beneficial and
safe to use in pregnant women, in whom they reduce
both disease activity and glucocorticoid requirements.
These benefits are crucial for pregnant patients with SLE,
as other immunomodulatory drugs must frequently be
stopped owing to their potential teratogenic effects. Strong
evidence also supports the use of antimalarial drugs
in patients with lupus nephritis: treatment with these
agents is associated with reductions in the prevalence
of renal disease (classIV glomerulonephritis, elevated
serum levels of creatinine and hypertension); disease
activity; glucocorticoid requirements; and progression
to chronic kidney disease.
Cautious monitoring for potential adverse effects
of antimalarial therapy is recommended, especially in
patients with concurrent renal or liver impairment. The
most important adverse effects are retinopathy, cardio‑
toxic effects, neuromyopathy, cutaneous hyperpigmenta‑
tion, and elevated liver enzyme levels and/or creatinine
levels. Baseline visual examination is required within
1year of commencing antimalarial therapy, but annual
screening is not recommended unless the patient has
clinical symptoms or findings of retinopathy or is at
a high risk of developing it. Annual screening should,
however, be implemented after 5years of cumulative
antimalarial therapy.
Overall, antimalarial drugs are generally safe and
have far more potential benefits than potential risks for
patients with SLE and lupus nephritis. Nephrologists
should not overlook this important class of drugs in the
management of patients with SLE.
Review criteria
The MEDLINE database was searched to identify papers
published in English between 2005 and 2011 on the
benefits or efficacy of antimalarial agents in SLE,
using the following MeSH terms: (“antimalarials” OR
“chloroquine” OR “hydroxychloroquine” OR “plaquenil”)
AND (“lupus erythematosus, systemic” OR “lupus”).
Papers published in English on the benefits of
antimalarial drug use in patients with lupus nephritis were
identified by a further MEDLINE search up to 2011 using
the above MeSH terms in combination with “nephritis”
OR “lupus nephritis” OR “renal” OR “kidney”. A PubMed
search was then conducted using all of the above terms
to identify additional relevant articles.
1. Schmajuk, G., Yazdany, J., Trupin, L. & Yelin, E.
Hydroxychloroquine treatment in a community-
based cohort of patients with systemic lupus
erythematosus. Arthritis Care Res. (Hoboken) 62,
386–392 (2010).
2. Ruiz-Irastorza, G., Ramos-Casals, M., Brito-
Zeron, P. & Khamashta, M.A. Clinical efficacy
and side effects of antimalarials in systemic
lupus erythematosus: a systematic review. Ann.
Rheum. Dis. 69, 20–28 (2010).
3. Wallace, D.J. The history of antimalarials. Lupus
5 (Suppl. 1), S2–S3 (1996).
4. Tett, S.E., Cutler, D.J., Day, R.O. & Brown, K.F.
Bioavailability of hydroxychloroquine tablets in
healthy volunteers. Br. J. Clin. Pharmacol. 27,
771–779 (1989).
5. Furst, D.E. Pharmacokinetics of
hydroxychloroquine and chloroquine during
treatment of rheumatic diseases. Lupus 5
(Suppl. 1), S11–S15 (1996).
6. Kalia, S. & Dutz, J.P. New concepts in
antimalarial use and mode of action in
dermatology. Dermatol. Ther. 20, 160–174
(2007).
7. McChesney, E.W. Animal toxicity and
pharmacokinetics of hydroxychloroquine sulfate.
Am. J. Med. 75, 11–18 (1983).
8. Leecharoen, S., Wangkaew, S. & Louthrenoo, W.
Ocular side effects of chloroquine in patients
with rheumatoid arthritis, systemic lupus
erythematosus and scleroderma. J. Med. Assoc.
Thai. 90, 52–58 (2007).
9. Barré, P.E., Gascon-Barré, M., Meakins, J.L. &
Goltzman, D. Hydroxychloroquine treatment of
hypercalcemia in a patient with sarcoidosis
undergoing hemodialysis. Am. J. Med. 82,
1259–1262 (1987).
10. Fox, R. Anti-malarial drugs: possible
mechanisms of action in autoimmune disease
and prospects for drug development. Lupus 5
(Suppl. 1), S4–S10 (1996).
11. Ermann, J. & Bermas, B.L. The biology behind
the new therapies for SLE. Int. J. Clin. Pract. 61,
2113–2119 (2007).
12. van den Borne, B.E., Dijkmans, B.A.,
deRooij,H.H., le Cessie, S. & Verweij, C.L.
Chloroquine and hydroxychloroquine equally
affect tumor necrosis factor-alpha, interleukin 6,
and interferon-gamma production by peripheral
blood mononuclear cells. J. Rheumatol. 24,
55–60 (1997).
13. Karres, I. etal. Chloroquine inhibits
proinflammatory cytokine release into human
whole blood. Am. J. Physiol. 274, R1058–R1064
(1998).
14. Wozniacka, A., Lesiak, A., Narbutt, J.,
McCauliffe,D.P. & Sysa-Jedrzejowska, A.
Chloroquine treatment influences
proinflammatory cytokine levels in systemic
lupus erythematosus patients. Lupus 15,
268–275 (2006).
15. Jang, C.H., Choi, J.H., Byun, M.S. & Jue, D.M.
Chloroquine inhibits production of TNF-alpha,
IL-1beta and IL-6 from lipopolysaccharide-
stimulated human monocytes/macrophages by
different modes. Rheumatology (Oxford) 45,
703–710 (2006).
16. Jeong, J.Y. & Jue, D.M. Chloroquine inhibits
processing of tumor necrosis factor in
lipopolysaccharide-stimulated RAW 264.7
macrophages. J. Immunol. 158, 4901–4907
(1997).
17. Sperber, K. etal. Selective regulation of cytokine
secretion by hydroxychloroquine: inhibition of
interleukin 1 alpha (IL-1-alpha) and IL-6 in human
monocytes and Tcells. J. Rheumatol. 20,
803–808 (1993).
18. Weber, S.M., Chen, J.M. & Levitz, S.M.
Inhibition of mitogen-activated protein kinase
signaling by chloroquine. J. Immunol. 168,
5303–5309 (2002).
19. Löffler, B.M., Bohn, E., Hesse, B. & Kunze, H.
Effects of antimalarial drugs on phospholipase A
and lysophospholipase activities in plasma
membrane, mitochondrial, microsomal and
cytosolic subcellular fractions of rat liver.
Biochim. Biophys. Acta 835, 448–455 (1985).
20. Kim, W.U. etal. Hydroxychloroquine potentiates
Fas-mediated apoptosis of rheumatoid
synoviocytes. Clin. Exp. Immunol. 144, 503–511
(2006).
21. Potvin, F., Petitclerc, E., Marceau, F. &
Poubelle,P.E. Mechanisms of action of
antimalarials in inflammation: induction of
apoptosis in human endothelial cells.
J.Immunol. 158, 1872–1879 (1997).
22. Wozniacka, A. etal. The influence of antimalarial
treatment on IL-1beta, IL-6 and TNF-alpha mRNA
expression on UVB-irradiated skin in systemic
lupus erythematosus. Br. J. Dermatol. 159,
1124–1130 (2008).
23. Hurst, N.P., French, J.K., Gorjatschko, L. &
Betts, W.H. Studies on the mechanism of
inhibition of chemotactic tripeptide stimulated
human neutrophil polymorphonuclear leucocyte
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
728
|
DECEMBER 2011
|
VOLUM E 7 www.nature.com/nrneph
superoxide production by chloroquine and
hydroxychloroquine. Ann. Rheum. Dis. 46,
750–756 (1987).
24. Nguyen, T.Q., Capra, J.D. & Sontheimer, R.D.
4-Aminoquinoline antimalarials enhance UV-B
induced c-jun transcriptional activation. Lupus
7, 148–153 (1998).
25. Lesiak, A. etal. Effect of chloroquine
phosphate treatment on serum MMP-9 and
TIMP-1 levels in patients with systemic lupus
erythematosus. Lupus 19, 683–688 (2010).
26. Lim, E.J. etal. Toll-like receptor 9 dependent
activation of MAPK and NF-kB is required for
the CpG ODN-induced matrix
metalloproteinase-9 expression. Exp. Mol. Med.
39, 239–245 (2007).
27. Wallace, D.J., Linker-Israeli, M., Metzger, A.L.
& Stecher, V.J. The relevance of antimalarial
therapy with regard to thrombosis,
hypercholesterolemia and cytokines in SLE.
Lupus 2 (Suppl. 1), S13–S15 (1993).
28. Toubi, E. etal. The reduction of serum
B-lymphocyte activating factor levels following
quinacrine add-on therapy in systemic lupus
erythematosus. Scand. J. Immunol. 63,
299–303 (2006).
29. Dubois, E.L. Antimalarials in the management
of discoid and systemic lupus erythematosus.
Semin. Arthritis Rheum. 8, 33–51 (1978).
30. Dubois, E.L. Quinacrine (atabrine) in treatment
of systemic and discoid lupus erythematosus.
AMA Arch. Intern. Med. 94, 131–141 (1954).
31. Rudnicki, R.D., Gresham, G.E. &
Rothfield,N.F. The efficacy of antimalarials in
systemic lupus erythematosus. J. Rheumatol.
2, 323–330 (1975).
32. [No authors listed] A randomized study of the
effect of withdrawing hydroxychloroquine
sulfate in systemic lupus erythematosus. The
Canadian Hydroxychloroquine Study Group.
N.Engl. J. Med. 324, 150–154 (1991).
33. Meinão, I.M., Sato, E.I., Andrade, L.E.,
Ferraz,M.B. & Atra, E. Controlled trial with
chloroquine diphosphate in systemic lupus
erythematosus. Lupus 5, 237–241 (1996).
34. Alarcón, G.S. etal. Effect of
hydroxychloroquine on the survival of patients
with systemic lupus erythematosus: data from
LUMINA, a multiethnic US cohort (LUMINA L).
Ann. Rheum. Dis. 66, 1168–1172 (2007).
35. Fessler, B.J. etal. Systemic lupus
erythematosus in three ethnic groups: XVI.
Association of hydroxychloroquine use with
reduced risk of damage accrual. Arthritis
Rheum. 52, 1473–1480 (2005).
36. Molad, Y. etal. Protective effect of
hydroxychloroquine in systemic lupus
erythematosus. Prospective long-term study of
an Israeli cohort. Lupus 11, 356–361 (2002).
37. Shinjo, S.K. etal. Antimalarial treatment may
have a time-dependent effect on lupus survival:
data from a multinational Latin American
inception cohort. Arthritis Rheum. 62,
855–862 (2010).
38. Westlake, S.L. & Edwards C.J. Anti-malarials
and lupus in West Africa use and lupus in
Africans. Lupus 18, 193–195 (2009).
39. Hodis, H.N., Quismorio, F.P. Jr, Wickham, E. &
Blankenhorn, D.H. The lipid, lipoprotein, and
apolipoprotein effects of hydroxychloroquine in
patients with systemic lupus erythematosus.
J.Rheumatol. 20, 661–665 (1993).
40. Petri, M., Lakatta, C., Magder, L. & Goldman, D.
Effect of prednisone and hydroxychloroquine on
coronary arter y disease risk factors in
systemic lupus erythematosus: a longitudinal
data analysis. Am. J. Med. 96, 254–259
(1994).
41. Tam, L.S., Gladman, D.D., Hallett, D.C.,
Rahman, P. & Urowitz, M.B. Effect of antimalarial
agents on the fasting lipid profile in systemic
lupus erythematosus. J. Rheumatol. 27,
2142–2145 (2000).
42. Borba, E.F. & Bonfá, E. Longterm beneficial
effect of chloroquine diphosphate on lipoprotein
profile in lupus patients with and without steroid
therapy. J. Rheumatol. 28, 780–785 (2001).
43. Sachet, J.C. etal. Chloroquine increases low-
density lipoprotein removal from plasma in
systemic lupus patients. Lupus 16, 273–278
(2007).
44. Cardoso, C.R., Signorelli, F.V., Papi, J.A. &
Salles, G.F. Prevalence and factors associated
with dyslipoproteinemias in Brazilian systemic
lupus erythematosus patients. Rheumatol. Int.
28, 323–327 (2008).
45. Bevan, A.P., Christensen, J.R., Tikerpae, J. &
Smith, G.D. Chloroquine augments the binding
of insulin to its receptor. Biochem. J. 311,
787–795 (1995).
46. Petri, M. Hydroxychloroquine use in the
Baltimore Lupus Cohort: effects on lipids,
glucose and thrombosis. Lupus 5 (Suppl. 1),
S16–S22 (1996).
47. Rekedal, L.R. etal. Changes in glycosylated
hemoglobin after initiation of hydroxychloroquine
or methotrexate treatment in diabetes patients
with rheumatic diseases. Arthritis Rheum. 62,
3569–3573 (2010).
48. Penn, S.K. etal. Hydroxychloroquine and
glycemia in women with rheumatoid arthritis and
systemic lupus erythematosus. J. Rheumatol.
37, 1136–1142 (2010).
49. Gerstein, H.C., Thorpe, K.E., Taylor, D.W. &
Haynes, R.B. The effectiveness of
hydroxychloroquine in patients with type2
diabetes mellitus who are refractory to
sulfonylureas—a randomzed trial. Diabetes Res.
Clin. Pract. 55, 209–219 (2002).
50. Bellomio, V. etal. Metabolic syndrome in
Argentinean patients with systemic lupus
erythematosus. Lupus 18, 1019–1025 (2009).
51. Razani, B., Feng, C. & Semenkovich, C.F. p53 is
required for chloroquine-induced
atheroprotection but not insulin sensitization.
J.Lipid Res. 51, 1738–1746 (2010).
52. Roman, M.J. etal. Prevalence and correlates of
accelerated atherosclerosis in systemic lupus
erythematosus. N. Engl. J. Med. 349,
2399–2406 (2003).
53. Zhang, C.Y. etal. Evaluation of risk factors that
contribute to high prevalence of premature
atherosclerosis in Chinese premenopausal
systemic lupus erythematosus patients. J. Clin.
Rheumatol. 15, 111–116 (2009).
54. Souza, A.W., Hatta, F.S., Miranda, F. Jr &
Sato,E.I. Atherosclerotic plaque in carotid
arteries in systemic lupus erythematosus:
frequency and associated risk factors. Sao Paulo
Med. J. 123, 137–142 (2005).
55. Von Feldt, J.M. etal. Homocysteine levels and
disease duration independently correlate with
coronary arter y calcification in patients with
systemic lupus erythematosus. Arthritis Rheum.
54, 2220–2227 (2006).
56. Selzer, F. etal. Comparison of risk factors for
vascular disease in the carotid artery and aor ta
in women with systemic lupus erythematosus.
Arthritis Rheum. 50, 151–159 (2004).
57. Selzer, F. etal. Vascular stiffness in women with
systemic lupus erythematosus. Hypertension
37, 1075–1082 (2001).
58. Tanay, A. etal. Vascular elasticity of systemic
lupus erythematosus patients is associated with
steroids and hydroxychloroquine treatment. Ann.
NY Acad. Sci. 1108, 24–34 (2007).
59. Bessant, R. etal. Prevalence of conventional
and lupus-specific risk factors for
cardiovascular disease in patients with
systemic lupus erythematosus: a case-control
study. Arthritis Rheum. 55, 892–899 (2006).
60. Urowitz, M.B. etal. Atherosclerotic vascular
events in a multinational inception cohort of
systemic lupus erythematosus. Arthritis Care
Res. (Hoboken) 62, 881–887 (2010).
61. Ruiz-Irastorza, G. etal. Antimalarials may
influence the risk of malignancy in systemic
lupus erythematosus. Ann. Rheum. Dis. 66,
815–817 (2007).
62. Sisó, A. etal. Previous antimalarial therapy in
patients diagnosed with lupus nephritis:
Influence on outcomes and survival. Lupus 17,
281–288 (2008).
63. Ruiz-Irastorza, G. etal. Effect of antimalarials
on thrombosis and survival in patients with
systemic lupus erythematosus. Lupus 15,
577–583 (2006).
64. Jung, H. etal. The protective effect of
antimalarial drugs on thrombovascular events
in systemic lupus erythematosus. Arthritis
Rheum. 62, 863–868 (2010).
65. Tsakonas, E. etal. A long-term study of
hydroxychloroquine withdrawal on
exacerbations in systemic lupus
erythematosus. The Canadian
Hydroxychloroquine Study Group. Lupus 7,
80–85 (1998).
66. Pons-Estel, G.J. etal. Protective effect of
hydroxychloroquine on renal damage in patients
with lupus nephritis: LXV, data from a
multiethnic US cohort. Arthritis Rheum. 61,
830–839 (2009).
67. Vlad, S.C. Protective effect of
hydroxychloroquine on renal damage may be
biased: comment on the article by Pons-Estel
etal. Arthritis Rheum. 61, 1614 (2009).
68. Vinet, E., Bernatsky, S. & Suissa, S. Have some
beneficial effects of hydroxychloroquine been
overestimated? Potential biases in
observational studies of drug effects: comment
on the article by Pons-Estel etal. Arthritis
Rheum. 61, 1614–1615 (2009).
69. Kasitanon, N., Fine, D.M., Haas, M.,
Magder,L.S. & Petri, M. Hydroxychloroquine
use predicts complete renal remission within
12months among patients treated with
mycophenolate mofetil therapy for membranous
lupus nephritis. Lupus 15, 366–370 (2006).
70. Parke, A. Antimalarial drugs and pregnancy. Am.
J. Med. 85, 30–3 (1988).
71. Parke, A. & West, B. Hydroxychloroquine in
pregnant patients with systemic lupus
erythematosus. J. Rheumatol. 23, 1715–1718
(1996).
72. Costedoat-Chalumeau, N., Amoura, Z.,
Huong,D.L., Lechat, P. & Piette, J.C. Safety of
hydroxychloroquine in pregnant patients with
connective tissue diseases. Review of the
literature. Autoimmun. Rev. 4, 111–115 (2005).
73. Germain, S. & Nelson-Piercy, C. Lupus nephritis
and renal disease in pregnancy. Lupus 15,
148–155 (2006).
74. Clowse, M.E., Magder, L., Witter, F. & Petri, M.
Hydroxychloroquine in lupus pregnancy. Arthritis
Rheum. 54, 3640–3647 (2006).
75. Levy, R.A. etal. Hydroxychloroquine (HCQ) in
lupus pregnancy: double-blind and placebo-
controlled study. Lupus 10, 401–404 (2001).
76. Izmirly, P.M. etal. Evaluation of the risk of anti-
SSA/Ro-SSB/La antibody-associated cardiac
manifestations of neonatal lupus in fetuses of
mothers with systemic lupus erythematosus
exposed to hydroxychloroquine. Ann. Rheum.
Dis. 69, 1827–1830 (2010).
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS
|
NEPHROLOGY VOLUME 7
|
DECEMBER 2011
|
729
77. Wang, C. etal. Discontinuation of antimalarial
drugs in systemic lupus erythematosus.
J.Rheumatol. 26, 808–815 (1999).
78. Sundelin, S.P. & Terman, A. Different effects of
chloroquine and hydroxychloroquine on
lysosomal function in cultured retinal pigment
epithelial cells. APMIS 110, 481–489 (2002).
79. Marmor, M.F., Kellner, U., Lai, T.Y., Lyons, J.S. &
Meiler, W.F. Revised recommendations on
screening for chloroquine and
hydroxychloroquine retinopathy. Ophthalmology
118, 415–422 (2011).
80. Rynes, R.I. Ophthalmologic considerations in
using antimalarials in the United States. Lupus
5(Suppl. 1), S73–S74 (1996).
81. Spalton, D.J. Retinopathy and antimalarial
drugs—the British experience. Lupus
5(Suppl.1), S70–S72 (1996).
82. Marmor, M.F., Carr, R.E., Easterbrook, M.,
Farjo,A.A. & Mieler, W.F. Recommendations on
screening for chloroquine and
hydroxychloroquine retinopathy: a report by the
American Academy of Ophthalmology.
Ophthalmology 109, 1377–1382 (2002).
83. Mavrikakis, I. etal. The incidence of irreversible
retinal toxicity in patients treated with
hydroxychloroquine: a reappraisal.
Ophthalmology 110, 1321–1326 (2003).
84. Lyons, J.S. & Severns, M.L. Using multifocal
ERG ring ratios to detect and follow Plaquenil
retinal toxicity: a review: review of mfERG ring
ratios in Plaqunil toxicity. Doc. Ophthal. 118,
29–36 (2008).
85. Wolfe, F. & Marmor, M.F. Rates and predictors of
hydroxychloroquine retinal toxicity in patients
with rheumatoid arthritis and systemic lupus
erythematosus. Arthritis Care Res. (Hoboken) 62,
775–784 (2010).
86. Levy, G.D. etal. Incidence of hydroxychloroquine
retinopathy in 1,207 patients in a large
multicenter outpatient practice. Arthritis Rheum.
40, 1482–1486 (1997).
87. The Royal College of Ophthalmologists.
Hydroxychloroquine and Ocular Toxicity
Recommendations on Screening [online], http://
www.rcophth.ac.uk/core/core_picker/download.
asp?id=165&filetitle=Ocular+Toxicity+and+Hydr
oxychloroquine%3A+Guidelines+for+Screen
ing+2009 (2009).
88. Nord, J.E., Shah, P.K., Rinaldi, R.Z. &
Weisman,M.H. Hydroxychloroquine
cardiotoxicity in systemic lupus erythematosus:
a report of 2 cases and review of the literature.
Semin. Arthritis Rheum. 33, 336–351 (2004).
89. Puri, P.K., Lountzis, N.I., Tyler, W. & Ferringer, T.
Hydroxychloroquine-induced hyperpigmentation:
the staining pattern. J. Cutan. Pathol. 35,
1134–1137 (2008).
90. Herman, S.M., Shin, M.H., Holbrook, A. &
Rosenthal, D. The role of antimalarials in the
exacerbation of psoriasis: a systematic review.
Am. J. Clin. Dermatol. 7, 249–257 (2006).
91. Bracamonte, E.R., Kowalewska, J., Starr, J.,
Gitomer, J. & Alpers, C.E. Iatrogenic
phospholipidosis mimicking Fabry disease. Am.
J. Kidney Dis. 48, 844–850 (2006).
92. Costedoat-Chalumeau, N. etal. Very low blood
hydroxychloroquine concentration as an
objective marker of poor adherence to treatment
of systemic lupus erythematosus. Ann. Rheum.
Dis. 66, 821–824 (2007).
93. Costedoat-Chalumeau, N. etal. Low blood
concentration of hydroxychloroquine is a marker
for and predictor of disease exacerbations in
patients with systemic lupus erythematosus.
Arthritis Rheum. 54, 3284–3290 (2006).
94. Calvo-Alén, J. etal. Systemic lupus
erythematosus in a multiethnic US cohort
(LUMINA): XXIV. Cytotoxic treatment is an
additional risk factor for the development of
symptomatic osteonecrosis in lupus patients:
results of a nested matched case-control study.
Ann. Rheum. Dis. 65, 785–790 (2006).
95. James, J.A. etal. Hydroxychloroquine sulfate
treatment is associated with later onset of
systemic lupus erythematosus. Lupus 16,
401–409 (2007).
96. Ruiz-Irastorza, G. etal. Predictors of major
infections in systemic lupus erythematosus.
Arthritis Res. Ther. 11, R109 (2009).
97. Shinjo, S.K. Systemic lupus erythematosus in
the elderly: antimalarials in disease remission.
Rheumatol. Int. 29, 1087–1090 (2009).
98. Pons-Estel, G.J. etal. Possible protective effect
of hydroxychloroquine on delaying the
occurrence of integument damage in lupus: LXXI,
data from a multiethnic cohort. Arthritis Care
Res. (Hoboken) 62, 393–400 (2010).
99. de Leeuw, K. etal. Traditional and non-traditional
risk factors contribute to the development of
accelerated atherosclerosis in patients with
systemic lupus erythematosus. Lupus 15,
675–682 (2006).
100. Choojitarom, K. etal. Lupus nephritis and
Raynaud’s phenomenon are significant risk
factors for vascular thrombosis in SLE patients
with positive antiphospholipid antibodies. Clin.
Rheumatol. 27, 345–351 (2008).
101. Kaiser, R., Cleveland, C.M. & Criswell, L.A. Risk
and protective factors for thrombosis in
systemic lupus erythematosus: results from a
large, multi-ethnic cohort. Ann. Rheum. Dis. 68,
238–241 (2009).
102. Tektonidou, M.G., Laskari, K.,
Panagiotakos,D.B. & Moutsopoulos, H.M. Risk
factors for thrombosis and primary thrombosis
prevention in patients with systemic lupus
erythematosus with or without antiphospholipid
antibodies. Arthritis Rheum. 61, 29–36 (2009).
103. Barber, C.E., Geldenhuys, L. & Hanly, J.G.
Sustained remission of lupus nephritis. Lupus
15, 94–101 (2006).
104. Buchanan, N.M. etal. Hydroxychloroquine and
lupus pregnancy: review of a series of 36 cases.
Ann. Rheum. Dis. 55, 486–488 (1996).
105. Costedoat-Chalumeau, N. etal. Safety of
hydroxychloroquine in pregnant patients with
connective tissue diseases: a study of one
hundred thirty-three cases compared with a
control group. Arthritis Rheum. 48, 3207–3211
(2003).
106. Carvalheiras, G. etal. Pregnancy and systemic
lupus erythematosus: review of clinical features
and outcome of 51 pregnancies at a single
institution. Clin. Rev. Allergy Immunol. 38,
302–306 (2010).
107. Aviña-Zubieta, J.A., Galindo-Rodriguez, G.,
Newman, S., Suarez-Almazor, M.E. &
Russell,A.S. Long-term effectiveness of
antimalarial drugs in rheumatic diseases. Ann.
Rheum. Dis. 57, 582–587 (1998).
108. Finbloom, D.S., Silver, K., Newsome, D.A. &
Gunkel, R. Comparison of hydroxychloroquine
and chloroquine use and the development of
retinal toxicity. J. Rheumatol. 12, 692–694
(1985).
109. Spalton, D.J., Verdon Roe, G.M. &
Hughes,G.R. Hydroxychloroquine, dosage
parameters and retinopathy. Lupus 2, 355–358
(1993).
110. Morand, E.F., McCloud, P.I. & Littlejohn, G.O.
Continuation of long term treatment with
hydroxychloroquine in systemic lupus
erythematosus and rheumatoid arthritis. Ann.
Rheum. Dis. 51, 1318–1321 (1992).
111. Costedoat-Chalumeau, N. etal. Cardiomyopathy
related to antimalarial therapy with illustrative
case report. Cardiology 107, 73–80 (2007).
112. Costedoat-Chalumeau, N. etal. Heart
conduction disorders related to antimalarials
toxicity: an analysis of electrocardiograms in
85 patients treated with hydroxychloroquine for
connective tissue diseases. Rheumatology
(Oxford) 46, 808–810 (2007).
113. Wozniacka, A., Cygankiewicz, I., Chudzik, M.,
Sysa-Jedrzejowska, A. & Wranicz, J.K. The
cardiac safety of chloroquine phosphate
treatment in patients with systemic lupus
erythematosus: the influence on arrhythmia,
heart rate variability and repolarization
parameters. Lupus 15, 521–525 (2006).
114. Cervera, A., Espinosa, G., Font, J. & Ingelmo,M.
Cardiac toxicity secondary to long term
treatment with chloroquine. Ann. Rheum. Dis.
60, 301 (2001).
115. Di Giacomo, T.B., Valente, N.Y. & Nico, M.M.
Chloroquine -induced hair depigmentation.
Lupus 18, 264–266 (2009).
116. Bezerra, E.L., Vilar, M.J., da Trindade
Neto,P.B. & Sato, E.L. Double-blind,
randomized, controlled clinical trial of
clofazimine compared with chloroquine in
patients with systemic lupus erythematosus.
Arthritis Rheum. 52, 3073–3078 (2005).
117. Van Beek, M.J. & Piette, W.W. Antimalarials.
Dermatol. Clin. 19, 147–160 (2001).
118. Casado, E. etal. Antimalarial myopathy:
an underdiagnosed complication? Prospective
longitudinal study of 119 patients. Ann.
Rheum. Dis. 65, 385–390 (2006).
119. Collins, G.B. & McAllister, M.S. Chloroquine
psychosis masquerading as PCP: a case
report. J. Psychoactive Drugs 40, 211–214
(2008).
Author contributions
S-J. Lee and E. Silverman researched the data for the
article. S-J. Lee and J. M. Bargman were the principal
contributors to writing the article and discussing its
content, although E. Silverman was also involved in
these aspects of the manuscript. J. M. Bargman, and
to a lesser extent S-J. Lee, participated in the review
and/or editing of the manuscript before submission.
REVIEWS
© 2011 Macmillan Publishers Limited. All rights reserved