Professional Documents
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Introduction
Systemic lupus erythematosus (SLE) is a multisystem and safety profile, and describe how patients taking these
autoimmune disease with varying patterns of organ agents should be monitored.
involvement. Lupus nephritis is one of the most common,
and most important, manifestations of SLE, and can lead A history of antimalarial drug use
to permanent renal damage and chronic kidney disease. Antimalarials are among the oldest drugs still used in
The mainstay of therapy for renal involvement in patients practice today. The first use of antimalarial drugs in a
with SLE is corticosteroids, immunosuppressive agents patient with SLE is thought to have occurred in 1630
and antihypertensive medications. when the wife of a Peruvian Viceroy, the Countess of
The role of antimalarial medications in the treatment Chinchon, was treated successfully for ‘tertian fever’
of patients with SLE is, perhaps, underappreciated in the (malaria) with powdered cinchona bark supplied by Jesuit
renal community. A study published in 2010 demon‑ priests. In 1894, J. S. Payne described features of the lupus
strated that the probability of a patient with SLE receiving rash and prescribed quinine to induce pallor, which was
an antimalarial agent was substantially decreased (OR successful. Following the First World War, the formula for
0.51, 95% CI 0.31–0.84) if their primary physician was a quinacrine was turned over to the US military. Atabrine
nephrologist rather than a rheumatologist.1 Antimalarial (the proprietary name for quinacrine) was used by many
Department of
drugs, specifically chloroquine and hydroxychloroquine, soldiers in the Second World War, principally as malaria
Pediatrics, Division of have been gaining increased prominence in the treat‑ prophylaxis; however, soldiers with various rheumatic
Rheumatology, The ment of patients with SLE—either with or without renal complaints (including inflammatory arthritis and cutane‑
Hospital for Sick
Children, 555 involvement—as a result of their excellent safety profile ous lupus) experienced symptomatic improvement while
University Avenue, and increasing evidence of efficacy. A systematic review taking this agent. These observations led to studies on
Toronto, ON M5G 1X8,
Canada (S‑J. Lee,
of antimalarial use in patients with SLE, published in the use of antimalarial drugs in patients with rheumatic
E. Silverman). 2010, showed that treatment with these agents resulted diseases, which demonstrated improvements in arthritis
Department of in improved disease control, reduced accrual of damage, and cutaneous lupus among patients treated with quina‑
Medicine, Division of
Nephrology, University and a beneficial effect on survival.2 crine. Chloroquine was subsequently introduced in 1953,
Health Network, This Review focuses on the role of chloroquine and and hydroxychloroquine in 1955. Both have greater effi‑
Toronto General
Hospital, 200 Elizabeth
hydroxychloroquine in the treatment of patients with cacy and better tolerability than quinacrine,3 and are still
Street, Toronto, SLE, specifically those with lupus nephritis. We discuss the two most commonly used antimalarial medications
ON M5G 2C4, Canada the current knowledge regarding the mechanisms of administered to patients with SLE.
(J. M. Bargman).
action of these drugs, highlight their favorable efficacy
Correspondence to: Metabolism of antimalarial drugs
J. M. Bargman
joanne.bargman@ Competing interests Hydroxychloroquine and chloroquine are both
uhn.ca The authors declare no competing interests. 4‑amino-quinolines; hydroxychloroquine is an analog
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 et al. Longitudinal 518 patients: 291 HCQ users, 227 nonusers Reduction in accrual of new disease damage (HR 0.68, 95% CI
(2005)35 cohort 0.53–0.93, P = 0.014)
LUMINA
Ruiz-Irastorza Prospective 232 patients: 62 HCQ users, 46 CQ users, 42 HCQ Increased cumulative 15-year survival in drug users vs nonusers
et al. (2006)63 cohort and CQ users, 82 nonusers (0.95 vs 0.6, HR 0.14, 95% CI 0.04–0.48, P <0.001)
Calvo-Alén Nested 32 patients with SLE and osteonecrosis vs 59 Possible protection against osteoporosis
et al. (2006)94 case–control controls without osteonecrosis matched for age, SLE Cases: less % HCQ exposure time (40% vs 59%, P = 0.026); higher
LUMINA duration, ethnicity and center; all exposed to HCQ, mean glucocorticoid dose (22.7 mg vs 14.8 mg, P = 0.011);
glucocorticoids and cytotoxic drugs cytotoxic drugs received more often (59% vs 32%, P = 0.015)
Wozniacka Cohort 25 patients with SLE treated with CQ vs 25 sex and Improved reduction in SLAM scores (9.47 to 4.92 after CQ,
et al. (2006)14 age-matched healthy controls P <0.001)
Costedoat- Longitudinal 143 patients with SLE: 120 inactive disease vs 23 Reduced serum HCQ levels in patients with flares (OR 0.4, 95% CI
Chalumeau cohort active disease; HCQ users 0.18–9.85, P = 0.01)
et al. (2006)93
Alarcón et al. Case–control 608 patients with SLE: 61 deaths (cases), 547 live Increased survival with HCQ use (OR 0.128, 95% CI 0.054–0.300,
(2007)34 (controls); HCQ users P <0.0001)
LUMINA
Ruiz-Irastorza Observational 235 patients with SLE: 156 HCQ and/or CQ users vs Protection against neoplasia (1.3% vs 13%, P <0.001); improved
et al. (2007)61 prospective 79 nonusers cumulative cancer-free survival (OR 0.98 vs 0.73, P <0.001)
cohort
James et al. Retrospective 130 US military patients with SLE: 26 patients Time between onset of first clinical signs or symptoms and SLE
(2007)95 chart review treated with HCQ before SLE classification classification was prolonged in patients treated with HCQ before
diagnosis vs not pretreated group (Wilcoxon signed-rank test,
P = 0.018)
Sisó et al. Cohort 206 patients with lupus nephritis: 56 previously Protection against infection (11% vs 29%, P = 0.006); increased
(2008)62 taking HCQ, 150 nonusers survival (2% vs 13%, P = 0.029)
Ruiz-Irastorza Nested 249 patients with SLE: 83 patients with infections Protection against infection (OR 0.06, 95% CI 0.02–0.18)
et al. (2009)96 case–control (cases) vs 166 with no infections (controls);
antimalarial users (agent not specified)
Shinjo et al. Retrospective 57 patients with SLE ≥65 years old: 43 with disease Disease remission strongly associated with CQ use (OR 12.9,
(2009)97 cohort remission, 14 with disease activity; CQ users 95% CI 2.9–58.1, P <0.001)
Pons-Estel Longitudinal 580 patients; HCQ users Possible delayed onset of integument damage (HR 0.23, 95% CI
et al. (2010)98 observational 0.12–0.47, P <0.0001)
LUMINA cohort
Shinjo et al. Longitudinal 1,480 patients: 1,141 CQ and/or HCQ users vs 339 Increased survival (4.4% vs 11.5%, HR 0.62, 95% CI 0.39–0.99,
(2010)37 cohort nonusers P <0.001)
GLADEL
Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; SLAM, systemic lupus activity measure; SLE, systemic lupus erythematosus.
benefit was noted with prolonged antimalarial agent Administration of these drugs also leads to significantly
use. 37 Some researchers have hypothesized that the reduced levels of apolipoprotein B in patients with either
widespread use of chloroquine to treat and/or prevent rheumatoid arthritis or SLE, and to increased levels of
malaria in West Africa might at least partially explain the apolipoprotein A in patients with rheumatoid arthritis.
dramatically lower prevalence of SLE in this region than Hydroxychloroquine treatment might decrease the
in people of West African origin who migrated to Europe risk of atherosclerosis by improving binding (and inhib‑
or North America.38 A systematic review 2 of articles pub‑ iting dissociation) of insulin to its receptor, thereby
lished from 1982 to 2007 found a number of beneficial improving glucose tolerance (Table 2).45 In patients with
effects of antimalarial use in patients with SLE, includ‑ rheumatoid arthritis and SLE, use of hydroxychloroquine
ing improved survival, reduced disease activity, and was found to improve glucose profiles, lower fasting
organ-specific effects (Table 1). In the following subsec‑ insulin levels, lower insulin resistance, and lower hemo
tions we will focus on literature published from 2005 to globin A1c (HbA1c) levels.46–48 The favorable metabolic
2010 and discuss the effects of use of chloroquine and effect of hydroxychloroquine was also found in non-
hydroxychloroquine in patients with SLE. insulin-dependent diabetic patients without rheumatic
disease.49 The use of hydroxychloroquine is also associ‑
Dyslipidemia, glycemia and atherosclerosis ated with a reduced frequency of metabolic syndrome
The use of chloroquine and hydroxychloroquine is among patients with SLE.50
associated with significantly decreased levels of tri Data on the effects of antimalarial therapy on vascu‑
glycerides, LDL cholesterol and/or VLDL choles‑ lar disease are conflicting (Table 2). In a mouse model of
terol, and increased levels of HDL cholesterol. 39–44 atherosclerosis, chloroquine therapy decreased plaque
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 Prospective 232 patients with SLE: 62 HCQ users, 46 CQ Protection against thrombosis (HR 0.28, 95% CI 0.08–0.90)
et al. (2006)63 cohort users, 42 HCQ and CQ users, 82 nonusers
de Leeuw et al. Cross- 38 patients with SLE taking HCQ: 7 with CVD, 31 No significant change in cardiovascular risk (54% with CVD vs 53% without
(2006)99 sectional without CVD CVD, P = NS)
Sachet et al. In vivo 30 individuals: 10 patients with SLE taking CQ, Improved clearance of total cholesterol (CQ group 156 ± 16 mg/dl;
(2007)43 10 patients with SLE on no antimalarial therapy, no antimalarial group 174 ± 15 mg/dl; control group 200 ± 24 mg/dl,
10 healthy controls 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 Cohort 67 antiphospholipid-antibody-positive patients Decreased risk of thrombosis (OR 0.18, 95% CI 0.04–0.88, P = 0.034);
et al. (2008)100 with SLE treated with CQ or HCQ the subgroup of patients with lupus nephritis had an increased risk of
venous thrombosis (OR 6.2, P = 0.005)
Sisó et al. Cohort 206 patients with lupus nephritis: 56 had Reduced risk of developing hypertension (32% vs 50%, P = 0.027);
(2008)62 previously taken CQ or HCQ; 150 were nonusers protection against thrombosis (5% vs 17%, P = 0.039)
Kaiser et al. 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)
(2009)101
Tektonidou Longitudinal 288 patients with SLE: 144 antiphospholipid- Protection against thrombosis in both groups
et al. (2009)102 cohort antibody-positive patients, matched with 144 Antibody-positive: HR per month of treatment 0.99, 95% CI 0.98–1.0,
antiphospholipid-antibody-negative patients; HCQ P = 0.05
users Antibody-negative: HR per month of treatment 0.98, 95% CI 0.95–0.99,
P = 0.04
Jung et al. Nested 54 patients with SLE who experienced Protection against thrombosis (OR 0.32, 95% CI 0.14–0.74, P <0.01)
(2010)64 case– thromboembolic events vs 108 event-free
control patients with SLE (controls); HCQ users
Penn et al. Cross- 149 patients with SLE and 177 patients with Reduced fasting glucose levels in nondiabetic women (potentially
(2010)48 sectional rheumatoid arthritis; HCQ users vs nonusers 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.
Table 3 | The effects of antimalarial drug use in patients with lupus nephritis
Study Design Population and treatment Outcomes in users
Tsakonas et al. Cohort 47 patients: 25 continued HCQ, Possible reduction in risk of and time to renal disease flare (RR 0.26, 95% CI
(1998)65 (randomized 22 withdrew 0.03–2.54, P = 0.25)
drug withdrawal)
Fessler et al. Longitudinal 518 patients: 291 started HCQ at Lower incidence of renal disease at baseline (25% vs 53%, P <0.0001)
(2005)35 LUMINA observational study enrollment, 227 were nonusers
cohort
Kasitanon et al. Cohort 29 patients: 11 used both HCQ and Patients with membranous lupus nephritis who were taking both drugs had
(2006)69 Hopkins MMF, 18 used MMF only improved rates of renal remission within 12 months (64% vs 22%, P = 0.036)
Lupus Cohort
Barber et al. Retrospective 35 patients with lupus nephritis: Improved sustained remission rates (93.8% vs 52.6%, P = 0.01)
(2006)103 cohort 15 out of 16 patients with sustained
remission taking HCQ vs 10 out of
19 patients with no sustained
remission (controls) taking HCQ
Sisó et al. Cohort 206 patients: 56 were taking CQ or Reduced percentage of patients with creatinine elevations >354 µmol/l (2%
(2008)62 HCQ before diagnosis of lupus vs 11%, P = 0.029); prolonged time to end-stage renal failure (2% vs 11%,
nephritis, 150 were nonusers P = 0.044); reduced frequency of hypertension (32% vs 50%, P = 0.027);
reduced mortality (2% vs 13%, P = 0.029)
Pons-Estel et al. Longitudinal 203 patients: 161 HCQ users, Reduced frequency of class IV glomerulonephritis (9.9% vs 33.3%, P <0.01);
(2009)66 LUMINA observational 42 nonusers protection against ESRD and/or diminished GFR (HR 0.38, 95% CI 0.13–
cohort 1.06, P = 0.065 [full model]; HR 0.38, 95%CI 0.16–0.86, P = 0.0206 [reduced
(prospective) 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% [5 years] or 38% [10 years]; nonusers 47% [5 years] or 70%
[10 years], P <0.0001)
Shinjo et al. Observational 1,480 patients: 1,141 CQ and/or Reduced prevalence of renal disease (28.4% vs 42.8%, P <0.001)
(2010)37 GLADEL inception cohort HCQ users, 339 nonusers
Abbreviations: CQ, chloroquine; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; RR, relative risk.
is low. Nevertheless, these findings provided early evi‑ P = 0.02).68 However, these findings are difficult to gen‑
dence that hydroxychloroquine treatment might reduce eralize to other populations, as the cohort consisted of
nephritic flares.65 only three ethnic groups.
In 2005, the investigators of the LUMINA study A substudy of 29 patients from the Hopkins Lupus
reported that hydroxychloroquine use was associ‑ Cohort who had either membranous nephritis or mixed
ated with a reduced risk of developing renal disease in membranous nephritis and proliferative nephritis treated
patients with SLE.35 In the subgroup of 203 patients with with mycophenolate mofetil, showed that concurrent use
lupus nephritis, 79.3% of patients had received hydroxy‑ of hydroxychloroquine led to a statistically significant
chloroquine treatment. Those who received hydroxy‑ improvement in the rate of renal remission at 12 months.
chloroquine had a lower frequency of World Health This finding persisted after controlling for the presence
Organization class IV glomerulonephritis, lower SLE of antibodies to double-stranded DNA.69
disease activity scores, and lower glucocorticoid doses A Spanish long-term, observational, cohort study of
than those patients not taking hydroxychloroquine. 206 patients showed that those with biopsy-proven lupus
Hydroxychloroquine treatment was also associated with nephritis taking chloroquine or hydroxychloroquine
a reduced cumulative probability of renal damage.66 The had a reduced incidence of elevated creatinine levels
magnitude of these effects was remarkable, leading to (>354 μmol/l), hypertension, infections, thrombotic events,
suggestions that the study results reflected confound‑ and death, as well as a prolonged time to development of
ing by indication, immortal person-time bias (meaning end-stage renal disease, compared to the incidence in
that the time between study enrollment and initiation those not taking antimalarial agents.62 These findings were
of hydroxychloroquine treatment should have been, significant despite the fact that only 27% of the 206 patients
but was not, excluded from the follow-up period, even were taking antimalarial agents. Although this study
though patients who developed renal damage during included a large cohort of patients, the analysis demon
this period were not treated with hydroxychloroquine), strates potential methodological limitations, including
and other potential (unknown) sources of bias.67,68 The confounding bias and immortal person-time bias.
authors of the 2005 paper subsequently responded by The investigators of the GLADEL study reported that
performing time-dependent analyses using a longitudi‑ 77% of the participants had received chloroquine and/or
nal approach, and still found that hydroxychloroquine hydroxychloroquine, defined as use of these agents for >6
use reduced the occurrence of renal disease, albeit to consecutive months. In addition to prolonged survival,
a lesser extent (adjusted OR 0.51, 95% CI 0.29–0.91, the researchers demonstrated that renal disease was less
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 et al. Cohort 36 pregnant women with SLE taking HCQ No significant difference in live birth rates with and without HCQ (86% vs
(1996)104 and 53 pregnant women with SLE not 83%); no significant difference in rates of fetal death or spontaneous abortion
taking HCQ with and without HCQ (14% vs 17%); no significant difference in premature
births with and without HCQ (55% vs 48%); no significant difference in
intrauterine growth failure with and without HCQ (19% vs 41%)
Levy et al. Prospective 20 pregnant women with SLE randomized Lower SLEPDAI scores at delivery (P = 0.0356); may reduce flares (0% vs 30%,
(2001)75 cohort with 10 to treatment with HCQ and 10 to P = 0.21); reduced prednisone requirements (6.0 ± 6.2 mg vs 15.5 ± 24.5 mg
placebo at 18 weeks, 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
1.5–3.0 years of age born to mothers who used antimalarial drugs
Costedoat- Nested 90 women with SLE (133 pregnancies) No difference in live-birth rates with and without HCQ (88% vs 84%); no
Chalumeau case–control taking HCQ and 53 women with SLE difference in rate of congenital abnormalities with HCQ compared with rates
et al. (2003)105 (70 pregnancies) not taking HCQ in the general population (2.26% vs 2.3%); no visual, hearing, growth, or
developmental abnormalities associated with HCQ treatment
Clowse et al. Prospective 257 pregnancies in 3 groups: (1) 56 No difference in rates of miscarriage, stillbirth, pregnancy loss, congenital
(2006)74 cohort pregnancies in women with SLE taking abnormalities with and without HCQ; stillbirths: 6% vs 8% vs 9%, P = 0.85;
HCQ; (2) 163 pregnancies in women with preterm (20–28 weeks): 12% vs 10% vs 6%, P = 0.83; preterm (28–
SLE not taking HCQ; (3) 38 women 37 weeks): 27% vs 31% vs 47%, P = 0.87; full-term: 61% vs 59% vs 47%,
stopped taking HCQ either in the P = 0.98; reduced overall SLE disease activity; SLEDAI score >4: 52% vs 62%
3 months before pregnancy or during the vs 84%, P = 0.0075; flare rates: 30% vs 36% vs 55%, P = 0.053; reduced
first trimester doses of prednisone during pregnancy (16 ± 12 mg vs 23 ± 19 mg vs
21 ± 16 mg, P = 0.056)
Carvalheiras Retrospective 43 women with SLE who had 51 No cases of maternal mortality; no cases of fetal malformations
et al. (2010)106 cohort pregnancies over 14 years; 20 patients
treated with HCQ
Izmirly et al. Case–control 50 women with SLE whose infants HCQ use might reduce the risk of fetal development of cardiac NLE in
(2010)76 developed NLE (14% HCQ users) vs 151 pregnant women with SLE and either anti-Ro/SSA or anti-La/SSB antibodies
women with SLE whose infants did not (OR 0.46, 95% CI 0.18–1.18, P = 0.10)
develop NLE (controls: 37.1% HCQ users)
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.
frequent in antimalarial drug users than in nonusers Pregnancy increases disease activity in many patients
(28.4% versus 42.8%).37 with SLE. Flares can potentially worsen renal function,
Antimalarial drugs are postulated to reduce the hypertension and/or proteinuria, leading to an increased
severity of renal disease through immunomodulatory, risk of maternal and fetal complications.73 These adverse
anti-inflammatory and antithrombotic effects. All such outcomes can also occur as a consequence of stopping
effects act beneficially on the vascular endothelium commonly used immunosuppressive therapies, includ‑
and reduce renal inflammation. The studies discussed ing antimalarial drugs, owing to fears of potential fetal
above provide intriguing evidence that chloroquine and or neonatal complications. Two studies in 2001 and 2006
hydroxychloroquine might retard the progression of suggested that hydroxychloroquine use in pregnant
renal disease, increase the duration of renal remission patients with lupus is associated with decreased overall
when combined with other immunosuppressive medica disease activity and flare rates.74,75 The 2006 study found
tions, and reduce cumulative dose of glucocorticoids. that women with SLE who stopped hydroxychloroquine
However, caution must be exercised with generalizing when they became pregnant had worse disease activity
these results to specific populations, as the majority and higher glucocorticoid requirements than women
of studies included only Hispanic or Latin American, with SLE who continued taking hydroxychloroquine
African American, and Caucasian populations. during the pregnancy, or women who were not taking
this drug at the time of conception. 74 These results
Pregnancy and fetal outcomes suggest that withdrawal of hydroxychloroquine during
Antimalarials are safe and effective for pregnant patients pregnancy exacerbates the risk of developing increased
with lupus (Table 4). Hydroxychloroquine readily crosses disease activity, as occurs in nonpregnant patients. The
the placenta, and blood levels of this drug are similar results of a case–control study that analyzed data from
between mother and fetus. 6 However, studies have the American Neonatal Lupus Registry suggest that the
revealed no increased risk of retinopathy or ototoxic use of hydroxychloroquine during pregnancy in mothers
effects in infants born to women taking hydroxychloro‑ with antinuclear antibodies (anti-Ro/SSA and/or anti-La/
quine at the recommended (reduced) dose of <4 mg/kg SSB antibodies) decreases the risk of cardiac manifesta
(lean body weight) per day during the pregnancy.70,71 A tions of neonatal lupus erythematosus in a multivariable
review published in 2005 of >250 pregnancies also sup‑ analysis (OR 0.46, 95% CI 0.18–1.18, P = 0.10). The
ported the lack of teratogenic effects associated with researchers concluded that use of antimalarial drugs
hydroxychloroquine use.72 resulted in decreased TLR signaling, which led to
reduced cardiac inflammation and scarring.76 We con‑ levels in the retinal pigmented epithelium; these agents,
clude that hydroxychloroquine use should be maintained therefore, accumulate disproportionately in these cells
during pregnancy. and are more likely to alter the lysosomal pH of melanin-
containing cells than those of melanin-free cells.78 The
Adverse effects of antimalarial agents earliest symptom of retinal damage is loss of paracentral
Both hydroxychloroquine and chloroquine are well- visual fields, with loss of color vision; these losses prog‑
tolerated medications with good safety profiles. The ress as the lesion spreads into the fovea and over the
most commonly reported adverse effects of treatment fundus. The very early stages of functional loss may be
are gastrointestinal (nausea, vomiting, diarrhea, anorexia reversible with cessation of antimalarial therapy, but
and, rarely, elevated levels of liver enzymes) or neurologi‑ most cases with maculopathy are irreversible.79
cal (headache and dizziness). Retinopathy is an uncom‑ It was originally suggested that ophthalmological
mon, but very important adverse effect associated with examinat ions should be performed every 3 months
antimalarial use (Table 5).77 in patients receiving antimalarial agents, but by 1996
examinations every 6–12 months were considered ade‑
Retinopathy quate.80,81 The American Academy of Ophthalmology
The retinal toxic effects associated with antimalarial (AAO) published revised recommendations in 2011 after
use are the result of disrupted metabolism of the retinal reviewing literature surrounding screening methods,
pigmented epithelium, which results in the degenera‑ implications of screening, and risk factors for devel‑
tion of photoreceptors. Antimalarial drugs demonstrate oping retinotoxicity.79 Screening is not for prevention,
enhanced binding to melanin, which is present at high but rather to detect early toxicity in order to stabilize
maculopathy and stop further loss of visual acuity. The cardiotoxic effects of high-dose antimalarial therapy
AAO recommendations are to first perform a baseline include decreased myocardial contractility, hypotension
screen within the first year of antimalarial therapy. and conduction abnormalities. Chronic cardiotoxic
Previous literature suggests that the cumulative dose effects of this treatment are manifested by heart block,
of antim alarial agents has an important role in the biventricular hypertrophy and/or cardiomyopathy
development of toxic effects. The AAO recommenda‑ (usually constrictive or restrictive). These complica‑
tions suggest that annual screening may not be necessary tions are most frequently seen in patients receiving high
before 5 years of cumulative therapy, and therefore that doses of antimalarial agents and in those with renal
annual screening should be conducted after 5 years of impairment.88
cumulative therapy. However, caution must be exercised
when factors that increase the risk of retinopathy are Cutaneous toxic effects
present, including: high cumulative doses of these agents Both hydroxychloroquine and chloroquine sometimes
(hydroxychloroquine >1,000 g or chloroquine >460 g); cause oval patches of yellow-brown to slate-gray hyper‑
high daily doses (hydroxychloroquine >400 mg daily, or pigmentation that might enlarge. The hyperpigmenta‑
>6.5 mg/kg of lean body weight; chloroquine >250 mg tion can begin after 4 months of therapy and occurs in up
daily, or >3.0 mg/kg of lean body weight); older age; renal to 10% of patients treated with these agents. The lesions
or liver dysfunction; and pre-existing visual impair‑ tend to develop on mucosal areas, in particular the hard
ment, such as retinal disease or maculopathy. Obesity palate, although any area of the skin may be involved.89
is a risk factor for retinopathy because antimalarials are Antimalarial drugs might exacerbate psoriasis in a small
not deposited in fatty tissue; dosing should, therefore, be proportion (1–2%) of patients. However, a systematic
based on lean body weight.82,83 review published in 2006 revealed no strong evidence
Ophthalmologic examinations in patients taking anti‑ either supporting or refuting the hypothesis that anti
malarial drugs should include enquiries about visual malarial use worsens psoriasis. 90 Whether hydroxy
symptoms, a thorough ophthalmologic examination chloroquine has a role in the treatment of new-onset
and an automated visual field assessment (using the psoriasis in patients with SLE is, therefore, unclear.
Humphrey visual field 10–2 pattern testing).80 Other more
specific objective testing to be considered that may only Iatrogenic phospholipidosis
be available in specialist centers include the multifocal One case report described a woman with inflammatory
electroretinogram, spectral domain-optical coherence polyarthritis who was treated with hydroxychloroquine
tomography, and fundus autofluorescence.79,84 Evidence and went on to develop iatrogenic phospholipidosis
from large clinical studies of patients with rheumatic resembling Fabry disease. A renal biopsy sample obtained
diseases (enrolling 526–3,995 patients) supports these to investigate proteinuria revealed ‘classic’ Fabry
recommendations, as only 0.4–0.65% of patients devel‑ disease. However, DNA mutational analysis revealed
oped retinal toxic effects associated with antimalarial no abnormalities associated with Fabry disease in this
therapy. The majority of such adverse events occurred patient’s α‑galactosidase A gene. The authors of this report
after 6 years of antimalarial treatment and/or in patients postulated that long-term hydroxychloroquine use caused
taking >6.5 mg/kg hydroxychloroquine daily; some cases iatrogenic phospholipidosis secondary to inhibition
of retinopathy were also seen when the dose of anti of the activity of circulating α‑galactosidase.91
malarial agent was based on the patient’s overall weight,
rather than lean body weight.83,85,86 The guidelines pub‑ Drug level monitoring
lished by the British Royal College of Ophthalmologists Poor compliance with antimalarial therapy and other
and the British Society for Rheumatology in 2009 are medications for SLE can be a common problem. A study
similar to the AAO recommendations, stating that annual of hydroxychloroquine pharmacokinetics showed that
screening is not required until after 5 years of cumula‑ serum levels of this agent could be quantified by high-
tive therapy, as clinically significant maculopathy is rare performance liquid chromatography. 92 Five patients
and no reliable test exists for detecting this retinopathy had undetectable levels reflecting poor treatment
within the reversible stage. The guidelines recommend compliance. Patients with active SLE had significantly
careful or earlier screening by an ophthalmologist if the lower serum hydroxychloroquine concentrations than
patient has baseline visual impairment or eye disease, if those with inactive disease (694 ± 448 ng/ml versus
visual disturbances are noticed during antimalarial treat‑ 1,079 ± 526 ng/ml, P = 0.001). This may be due to poor
ment, or if the patient is receiving high doses (>6.5 mg/kg compliance, but more a result of large interindividual
daily) of hydroxychloroquine or continuous treatment variations in hydroxychloroquine bioavailability. A
for >5 years.87 low serum concentration of hydroxychloroquine was
a predictor of disease exacerbation (OR 0.4, 95% CI
Neuromyotoxic and cardiotoxic effects 0.18–0.85, P = 0.01), and a hydroxychloroquine concen‑
Neuromyotoxic and cardiotoxic effects are rare but tration threshold of 1,000 ng/ml had a negative predic‑
potentially fatal complications of antimalarial therapy. tive value of 96% for exacerbations.93 Hence, measuring
Patients with neuromyotoxic effects usually present with serum levels of hydroxychloroquine could prove bene
bilateral and progressive muscle weakness of the legs, ficial in assessing compliance, as well as in predicting and
which can be accompanied by a polyneuropathy. Acute potentially reducing disease exacerbations. Serum levels
of hydroxychloroquine are not measured in current clini‑ most important adverse effects are retinopathy, cardio‑
cal practice, however, as not all laboratories are able to toxic effects, neuromyopathy, cutaneous hyperpigmenta‑
perform this test. tion, and elevated liver enzyme levels and/or creatinine
levels. Baseline visual examination is required within
Conclusions 1 year of commencing antimalarial therapy, but annual
Antimalarial agents have been the mainstay of treatment screening is not recommended unless the patient has
for SLE, in combination with other immunomodula‑ clinical symptoms or findings of retinopathy or is at
tory drugs, but are underused by nephrologists. Their a high risk of developing it. Annual screening should,
immunomodulatory and anti-inflammatory effects are however, be implemented after 5 years of cumulative
associated with numerous beneficial effects on the out‑ antimalarial therapy.
comes of patients with SLE, including improvements in Overall, antimalarial drugs are generally safe and
survival and remission rates, and reductions in disease have far more potential benefits than potential risks for
activity, accrual of new disease-related damage, and patients with SLE and lupus nephritis. Nephrologists
infection rates. Antimalarial therapy has antithrombotic should not overlook this important class of drugs in the
and vascular protective effects, and might also have a role management of patients with SLE.
in preventing neoplasia. These drugs are beneficial and
safe to use in pregnant women, in whom they reduce
both disease activity and glucocorticoid requirements. Review criteria
These benefits are crucial for pregnant patients with SLE,
as other immunomodulatory drugs must frequently be The MEDLINE database was searched to identify papers
stopped owing to their potential teratogenic effects. Strong published in English between 2005 and 2011 on the
benefits or efficacy of antimalarial agents in SLE,
evidence also supports the use of antimalarial drugs
using the following MeSH terms: (“antimalarials” OR
in patients with lupus nephritis: treatment with these “chloroquine” OR “hydroxychloroquine” OR “plaquenil”)
agents is associated with reductions in the prevalence AND (“lupus erythematosus, systemic” OR “lupus”).
of renal disease (class IV glomerulonephritis, elevated Papers published in English on the benefits of
serum levels of creatinine and hypertension); disease antimalarial drug use in patients with lupus nephritis were
activity; glucocorticoid requirements; and progression identified by a further MEDLINE search up to 2011 using
to chronic kidney disease. the above MeSH terms in combination with “nephritis”
OR “lupus nephritis” OR “renal” OR “kidney”. A PubMed
Cautious monitoring for potential adverse effects
search was then conducted using all of the above terms
of antimalarial therapy is recommended, especially in to identify additional relevant articles.
patients with concurrent renal or liver impairment. The
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