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Immunopharmacol Immunotoxicol, 2013; 35(3): 434–442
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DOI: 10.3109/08923973.2013.780078

REVIEW ARTICLE

Chloroquine cardiomyopathy – a review of the literature

Ernst Tönnesmann1, Reinhard Kandolf2, and Thorsten Lewalter3
1
Department of Internal Medicine, Kaiser-Karl-Klinik, Bonn, Germany, 2Institute for Pathology, University Hospital Tübingen, Tübingen, Germany,
Immunopharmacology and Immunotoxicology Downloaded from informahealthcare.com by York University Libraries on 10/18/13

and 3Isar Heart Center Munich, Munich, Germany

Abstract Keywords
Chloroquine and hydroxychloroquine are still used for the prevention and treatment of malaria. Antimalarials, cardiomyopathy, cardiotoxicity,
Moreover, they are experiencing a renaissance in the long-term therapy of connective tissue chloroquine, hydroxychloroquine,
diseases (particularly in systemic lupus erythematosus). They induce a lysosomal dysfunction rheumatoid arthritis, systemic lupus
with an accumulation of pathologic metabolic products, which can be seen in ultrastructural erythematosus
histology as pathognomonic cytoplasmic inclusion bodies. Due to its lower toxicity,
hydroxychloroquine is the form used predominantly today. Retinopathy as a toxic result of History
this medication is well known. Cardiac side effects are rarely reported, but in some cases can be
severe and irreversible – two cases of organ transplantation have been described in the Received 2 January 2013
literature. They comprise conduction disturbances (bundle-branch block, atrioventricular block) Revised 7 February 2013
and cardiomyopathy – often with hypertrophy, restrictive physiology and congestive heart Accepted 22 February 2013
failure. As the clinical features of cardiotoxicity are unspecific, the identification and follow-up Published online 30 April 2013
of potentially affected patients is of utmost importance. Confirming the diagnosis of this toxic
storage disease requires histological examination of the myocardium in conjunction with
For personal use only.

electron microscopy. The primary clinical parameters (diagnostic criteria for this cardiomyo-
pathy, differential diagnostics, incidence, risk factors, prognosis) as well as the diagnostic
procedures are discussed against the background of the available literature.

History neuromyopathy in 19638,9, cardiomyopathy in 197110 and

Chloroquine, which was first synthesized in 1934 by
Andersag in Germany, was administered for the prophylaxis
and treatment of malaria during World War II. Later, other
indications for use included skin diseases, sarcoidosis,
extraintestinal amoebiasis, chronic Q fever and rheumatoid
disorders. Hydroxychloroquine was introduced in 1955.
The substance has been available (as chloroquine phos-
phate and chloroquine sulfate) as a medication for over
60 years and is still prescribed today for the prophylaxis
and treatment of malaria. In the field of rheumatology, the
substance is administered – primarily as hydroxychloroquine
sulfate, due to greater tolerability – for the long-term
treatment of rheumatoid arthritis and systemic lupus erythe-
matosus (SLE); its use as a treatment for SLE is once again
on the rise1,2. Its efficacy in rheumatic diseases is based on
a number of immunomodulating effects, the detailed descrip-
tion of which is beyond the scope of this paper3,4.
As early as 1948, reports of toxic effects stemming from
long-term administration were published in the literature
describing findings in animal experiments5 and testing of
voluntary subjects6. Initial publications detailing specific
toxic effects followed, including retinopathy in 19577,
Address for correspondence: Dr. med. Ernst Tönnesmann, Kaiser-Karl-
Klinik, Graurheindorfer Str. 137, D-53117 Bonn, Germany. Tel: 0049
2241 923617. Fax: 0049 2241 923666. E-mail: e.toennesmann@
t-online.de
third-degree atrioventricular (AV) block in 197811.
Pharmacokinetics/pathophysiology
Administered orally, chloroquine/hydroxychloroquine (both
substances have identical pharmacokinetic properties) are
resorbed at a rate of 90% and exhibit high bioavailability.
They accumulate in melanin-containing cells (eye, skin), in
parenchymal organs (lung, liver, kidney), in the heart and in
the skeletal muscle. Their pharmacokinetics are characterized
by a long half-life (30–60 days) and a high volume of
distribution (116–285 L/kg); they follow a multi-compartment
13
20
model with very slow distribution between plasma and
tissue12,13. Steady state is not achieved until after a period
of months (accordingly, clinical improvement in the patients
appears only slowly), and the level of organ sequestration is
extremely high (and reversible only to a limited extent). Even
after administration of the compound has been discontinued,
it remains detectable in urine for years14.
Chloroquine and hydroxychloroquine are 4-aminoquino-
lines and (like amiodarone) belong to the class of ‘‘cationic
amphiphilic drugs’’, which are characterized by a hydropho-
bic ring structure and a hydrophilic side chain with a charged
cationic amine group15 (Figure 1). Preferential binding to
phospholipids, the accumulation in lysosomes with a shift in
pH, and the direct inhibition of lysosomal enzymes lead to the
impairment of intracellular degradation processes in conjunc-
tion with the accumulation of pathological metabolic products
 DOI: 10.3109/08923973.2013.780078
Figure 1. Structural formula of chloroquine.
(especially phospholipids and glycogen). These appear
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histologically as granulovacuolar cell mutations and ultra-
structurally as lamellar membranous inclusion bodies and as
‘‘curvilinear bodies’’ in cytoplasm16–19.
Side effects
At the beginning and over the course of treatment, side
effects include primarily gastrointestinal, neurological and
dermatological disorders, but these do not result in permanent
damage3,4.
Among the side effects that can occur in conjunction with
long-term treatment, eye damage (with irreversible retino-
pathy), in particular, has been both well-known and feared
since the 1950s; corresponding recommendations by profes-
sional associations regarding modalities of administration and
patient monitoring are generally accepted20.
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In contrast, neuromyopathy and especially cardiac damage
receive scant mention in the scientific literature, particularly
when considered in relation to the substance’s widespread
dissemination. Approximately 60 publications addressing
myopathies and neuropathies10,19,21–24 and reviews 18,25,26 have
appeared since the initial reports by Loftus8 and Whisnant9.
Clinical findings discussed in the literature generally involve
proximal muscle weakness in the lower extremities in
conjunction with diminished tendon reflexes yet with retained
sensation. Clinical manifestations typically resolve rapidly
after the medication is discontinued – even when this involves
long-term treatment and high cumulative dosages27.
Cardiac toxicity manifests itself in the form of conduction
disorders and cardiomyopathy (in conjunction with hypertro-
phy and often with restrictive physiology), whereby a third-
degree AV block frequently occurs years before clinical
manifestations of congestive heart failure. To date, reports
have been published on 47 patients with cardiomyo-
pathy10,28–62 and on 30 patients with total AV
block11,31,34,52,63–72. The substance exhibits quinidine-like
effects73; QT interval prolongation and malignant ventricular
arrhythmias have also been discussed in individual
cases57,74,75. Therapeutic doses cause ST-segment depression,
T wave inversion and QT interval prolongation in resting
electrocardiogram76.
Atrioventricular block
Complete AV block as the first manifestation of chloroquine/
hydroxychloroquine-induced cardiac damage is reported in
the literature, and several cases have been described in which
the medication continued to be administered due to improper
evaluation of the pathogenesis35,37,44,47,59. There is no known
Chloroquine cardiomyopathy 435
accumulation of higher-grade AV conduction disorders in
conjunction with rheumatic diseases77. The literature also
reports on findings of septal hypertrophy in echocardio-
graphy33,38,39,44–46,48,54,55,57,59 and in the analysis of an
autopsy specimen30 and an explant47. Furthermore, magnetic
resonance imaging revealed a septal delayed gadolinium
enhancement44,46,54,59, thereby suggesting direct, chloro-
quine-induced damage to the AV conduction system. This is
consistent with findings in animal experiments, which show
cardiac damage primarily in the interventricular septum
following chloroquine administration78. Electrophysiological
studies carried out on some patients show an infra-His
localization of the conduction disorder31,39,41. A total of 30
patients with third-degree AV block, but with no cardiomy-
opathy, are discussed in the literature11,31,34,52,63–72; the
indication for treatment was malaria for 17 of these patients,
and rheumatoid arthritis or SLE for 13. In addition, 14 of the
cardiomyopathy patients exhibited third-degree AV block
(Table 1). The evolution of the conduction disorder follows a
typical pattern, with the development of a complete right
bundle branch block and left anterior fascicular block prior to
the development of complete AV block31,59,65.
Recently, the case of a patient with sick sinus syndrome as
a result of hydroxychloroquine therapy was also reported54.
Cardiomyopathy
The following analysis of publications that have appeared
to date on cardiomyopathy under long-term treatment with
chloroquine/hydroxychloroquine refers to the patients with
cardiac histology [case 110,31,34,43/ case 230,52/
32,33,35–42,44–51,53–62 43,47
/ reviews ]. This group of 40 patients
(Table 1) consists primarily of women. Age (31–81 years),
cumulative dose (15–5040 g) and duration of treatment (2–35
years) vary greatly. All except one of them (who had recurrent
malaria) suffered from connective tissue diseases (predomin-
antly rheumatoid arthritis and SLE). Most patients were
treated with chloroquine, but in recent years there has been a
clear trend toward hydroxychloroquine.
With regard to clinical symptoms, the literature describes
chronic congestive heart failure in 29 cases, syncope in six
cases and acute heart failure in three cases (Table 1).
Enzyme elevation (creatine kinase, lactate dehydrogenase,
troponin) was reported in 13 patients24,36–38,43,45,46,49,54,56,59,62,
but frequently no findings are mentioned.
Cardiac diagnostics
Confirming an etiology for organ damage caused by chloro-
quine/hydroxychloroquine is a difficult differential diagnostic
task, partially because, on one hand, the underlying diseases –
primarily SLE and rheumatoid arthritis – often involve the
cardiovascular system33,79,80, and on the other hand, no
particular symptoms are specific enough to establish the
diagnosis. This problem is accentuated by the frequent
prescription of cortisone preparations with the risk of steroid
myopathy masking the clinical symptoms of chloroquine
toxicity.
With reference to diagnostic tools, the determination of
chloroquine blood levels is not accurate for the detection
of chloroquine toxicity, due to the complex pharmacokinetics
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Table 1. Details of patients with chloroquine/hydroxychloroquine-induced cardiomyopathy (including histologic studies of the myocardium).
436

Author/Ref. Age/Sex Diagnosis Drug Years CD (g) R/NM cAVB Cardiac diagnostics Histology EM CLB Symptoms Follow-up
a
Hughes /10 62 f RA CQ 2.5 330 M n.a. A AHF y
Motanb/30 68 f RA CQ 14 1900 þ n.a. A n.a. y
Godeaua/31 36 f SLE CQ n.a. 700 R þ n.a. EMB þ þ n.a. y
Ratliff/32 58 f dLE HCQ 10 730 NMR þ hypertrophy, rCMP EMB þ þ CHF "
CQ 6 1100
59 m SLE HCQ 2 290 n.a. EMB þ þ CHF "
McAllister/33 33 f SLE CQ 11 1100 NM hypertrophy EMB þ þ CHF n.a.
E. Tönnesmann et al.

73 f SLE CQ 8 730 hypertrophy A þ þ CHF y

Vernya/34 56 f SLE CQ 16 1170 NM þ echo: normal EMB þ  Syn !
Iglesias C./35 59 f dLE CQ 25 2280 M þ hypertrophy, rCMP A þ þ CHF y
August/36 81 f RA CQ 25 n.a. R hypertrophy A þ þ AHF y
Veinot/37 60 f RA CQ 10 912 NM þ hypertrophy, systolic dysfunction A þ þ CHF y
Baguet/38 58 f SLE HCQ 25 4380 NM hypertrophy, rCMP EMB þ þ CHF "
CQ 2 660
Teixeira/39 58 f RA CQ 9 820 þ echo: normal EMB þ þ Syn n.a.
Roos/40 53–73, ffm 1 SLE ! CQ n.a.(3) n.a.(3) M (1) dCMP (1) A/A/EMB þþþ þþ CHF yy n.a.
2 RA ! HCQ
Charlier/41 42 f RA CQ 7 756 þ echo: normal A þ þ Syn y
Freihage/42 50 f RA CQ 6 1100 hypertrophy, rCMP EMBþExpl. þ þ CHF TX
Norda/43 31 f SLE HCQ 12 1750 NM dCMP AþEMB þ  CHF y
Naqvi/44 61 f SLE CQ 23 2300 þ hypertrophy, rCMP, MRI: DE EMB þ  CHFþSyn "
Keating/45 39 f SLE HCQ 4 580 hypertrophy, systolic dysfunction EMB þ þ Syn n.a.
Reffelmann/46 67 f RA CQ 20 1825 hypertrophy, diast. EMB þ  CHF n.a.
dysf., MRI: DE
Costedoat- 59 f dLE CQ 8 680 NMR þ hypertrophy, rCMP Expl. þ þ CHF TX
Chalumeau/47 HCQ 4 580
Cotroneo/48 51 f jRAþSLE HCQ 31 3400 R hypertrophy, rCMP EMB þ þ CHF "
Hernández J./49 56 m RA CQ 6 550 hypertrophy, rCMP EMB þ þ CHF "
Soong/50 55 f SLE HCQ 10 1460 systolic dysfunction EMB þ  CHF þ ARF y
65 f ScleroþSS HCQ 25 3650 diastolic dysfunction EMB þ þ CHF "
Manohar/51 64 f SLE HCQ 10 n.a. hypertrophy, syst.þdiast. dysf. EMB þ þ CHF "
Saussineb/52 48 f LE CQ 3 225 þ echo: normal EMB Syn n.a.
Fragasso/53 74 m Malaria CQ (10) 15 systolic dysfunction EMB CHF "
Lee/54 52 f RA HCQ 13 1898 hypertrophy, rCMP, MRI: DE EMB þ þ Syn "
Pieroni/55 64 f MCTD CQ 5 1095 hypertrophy, rCMP EMB þ þ CHF n.a.
Muthukrishnan/56 66 f SLE HCQ 10 1460 þ hypertrophy, rCMP EMB CHF y
Newton-Cheh/57 47 m SLE HCQ 14 2190 hypertrophy, rCMP EMB þ þ CHF !
Hartmann/58 75 f RA HCQ 10 n.a. hypertrophy, syst. þ diast. dysf. EMB þ þ AHF "
Tönnesmann/59 65 f RA CQ 35 3195 R þ hypertrophy, diast. EMB þ þ (CHF) !
dysf., MRI: DE
Frustaci/60 39 m dLE HCQ 14 2555 hypertrophy, dCMP, MRI: DE EMB þ þ CHF "
Abbasi/61 52 f SLE HCQ 15 n.a. systolic dysfunction EMB þ  CHF "
Azimian/62 64 f RA HCQ 20 2920 M hypertrophy, rCMP A þ  CHF y
38 f dLE CQ 7 1277 M þ dCMP A þ þ CHF þ Syn y
a b
Case 1. Case 2. ": Improvement; !: Unchanged; y: Death.
Abbreviations:
A – autopsy; AHF – acute heart failure; ARF – acute renal failure; cAVB – complete AV-Block; CD – cumulative dose; CHF – congestive heart failure; CLB – curvilinear bodies; CQ – chloroquine ; DE – delayed
enhancement; diast. – diastolic; dCMP – dilated cardiomyopathy; dLE – discoid lupus erythematosus; dysf. – dysfunction; echo – echocardiography; EM – electron microscopy; EMB – endomyocardial biopsy;
Expl. – explanted heart; HCQ – hydroxychloroquine; M – myopathy; MCTD – mixed connective tissue disease; MRI – magnetic resonance imaging; n.a. – not available; NM – neuro-/myopathy;
Immunopharmacol Immunotoxicol, 2013; 35(3): 434–442

R – retinopathy; (j)RA – (juvenile) rheumatoid arthritis; rCMP – restrictive cardiomyopathy; Sclero – scleroderma; (S)LE – (systemic) lupus erythematosus; SS – Sjögren syndrome; Syn – syncope; syst. –
systolic; TX – heart transplantation.
 DOI: 10.3109/08923973.2013.780078
and the large inter-individual fluctuation range in the
metabolism of the substance12,81. Thus, two of the cardio-
myopathy patients had normal serum levels34,59. Nonetheless,
there are indications that the clinical effectiveness of the
treatment correlates to the blood levels81.
Hemodynamic measurements (echocardiography, cardiac
catheterization) in 27 of the patients cited revealed restrictive
cardiomyopathy and/or relevant diastolic dysfunction in 16
cases, systolic functional impairment (including dilated
cardiomyopathies) in nine and combined systolic–diastolic
dysfunction in two cases (Table 1).
Pieroni reported the interesting case of a patient who
suffered from dilated cardiomyopathy and then was treated for
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mixed connective tissue disease with 600 mg of chloroquine
daily. Five years later severely restrictive cardiomyopathy as
the result of chloroquine damage was diagnosed55.
Cardiac imaging
The most common pathological result in cardiac imaging is –
often biventricular – myocardial hypertrophy, which is some-
times accompanied by an abnormal pattern of the ventricle
wall in echocardiography35,38,51,62/case 2 and, considering the
differential diagnostics, can resemble amyloidosis or Fabry
disease38,40,47.
Tissue viability testing via magnetic resonance imaging
was reported in five publications44,46,54,59,60, which revealed
delayed gadolinium enhancement in a non-coronary distribu-
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tion. Whether the sampling error can be circumvented and
the histological accuracy increased by an MR-guided biopsy
is a controversial issue82,83.
Histology
In view of the large number of variables in the clinical
hypothesis, the histological examination plays an extremely
important role. In the 40 patients on chloroquine/hydroxy-
chloroquine studied, the myocardial tissue was obtained
during autopsy (n ¼ 12), organ removal in conjunction with
heart transplants (n ¼ 2) and endomyocardial biopsy using
cardiac catheters (n ¼ 26; see Table 1), two of which were
Figure 2. Endomyocardial biopsy in a patient with rheumatoid arthritis and long-term treatment with chloroquine: lamellar and curvilinear inclusion
bodies in the myocytes (electron microscopy)59.
Chloroquine cardiomyopathy 437
55,59
taken from the left ventricle , and the rest presumably
from the right ventricle. As a rule, the morphology of the
tissue damage caused by chloroquine/hydroxychloroquine
is identical in all organs involved. Light microscopic
study reveals partly extended vacuoles in the cytoplasm
with inclusions of granular material with PAS positivity,
which gives the cells the appearance of hypertrophy and
leads to disorganization of the myofibrillar architecture.
Ultrastructurally, lamellar (in the case of concentric arrange-
ment, known as ‘‘myeloid bodies’’) and so-called ‘‘curvilin-
ear’’ inclusion bodies are found, which are made up of
autophagolysosomes with poorly digested cytoplasmic organ-
elles and membranes16,19 (Figure 2). The curvilinear bodies
are comma-shaped structures which in human pathology
occur only in cases of chloroquine damage and in ‘‘neuronal
ceroid lipofuscinosis’’, a group of hereditary neurodegenera-
tive disorders in children84,85. The detection of curvilinear
bodies requires electron microscopic study at higher magni-
fications (430 000) and a pathologist who is familiar with
these structures33,86. They were described for the first time
in 1965 by Rewcastle in a muscle biopsy of a 33-year-old
female patient with SLE, who had taken a cumulative dose
of 900 g of chloroquine phosphate over a period of 5 years19.
Subsequently, identical inclusion bodies were found in the
retina87, in peripheral nerve cells21 and in the heart31,86.
Finally, we refer to the description of megamitochondria
in two patients with hydroxychloroquine-induced cardiomyo-
pathy, the significance of which is as yet unclear50,60.
New diagnostic methods
Two reports were recently published which described
new examination techniques that could play a significant
role in alternative methods of establishing a diagnosis. In
one case of a patient with hydroxychloroquine-induced
cardiomyopathy confirmed by biopsy, seven lysosomal
enzymes were measured in the cardiomyocytes and in the
peripheral blood lymphocytes. Three of these (alpha-galacto-
sidase A, beta-galactosidase, arylsulfatase A) showed identi-
cal, reversible formation inhibition for both cell series, which
 438 E. Tönnesmann et al.
was regressive in the lymphocytes 6 months after discontinu-
ation of hydroxychloroquine as evidenced by a follow-up
cardiac biopsy60. Lee et al. have developed immunohisto-
chemical diagnostic markers for the detection of autophagic
vacuolar myopathy in patients under treatment with hydro-
xychloroquine, which, given the required sensitivity to and
specificity for individual drugs, could possibly later replace
the ultrastructural study, but not the cardiac biopsy88.
Differential diagnostics
While curvilinear bodies definitively document the patho-
genesis of chloroquine/hydroxychloroquine damage, the pres-
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ence of lamellar inclusion bodies is also described after the
administration of amiodarone or disobutamide and in cases
of storage diseases such as Niemann–Pick disease or Fabry
disease15,21 (Table 2). In particular, Fabry disease, which is
also accompanied by myocardial hypertrophy, can make the
differential diagnosis difficult. Roos40 reported on the case of
a patient who was diagnosed with Fabry disease based on an
endomyocardial biopsy (without knowledge of the medication
she was taking); the correct diagnosis of chloroquine cardio-
myopathy was made only at autopsy. Soong50 presented a
similar case. The range of differential diagnoses in the case of
the vacuolar myopathy revealed under light microscopy is
considerably larger and includes SLE, rheumatoid arthritis,
polymyositis, dermatomyositis, steroid myopathy, carcinoma,
hypokalemia, periodic paralysis and thyrotoxicosis9,18,19.
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Particularly with regard to the rheumatic diseases and the
drugs used to treat them, overlaps can occur, so that an
ultrastructural tissue analysis with documentation of the
curvilinear bodies is essential.
Furthermore, the following differential diagnoses must be
ruled out, among other things (Table 2): coronary artery
disease, vasculitis (due to the underlying rheumatic disease),
acute or reactivated viral myocarditis and amyloidosis.
There is no correlation between the different organ toxi-
cities which would permit analogous diagnostic conclusions.
Thus, of the 40 patients with cardiomyopathy – regardless of
the cumulative dose – neuromyopathy was observed in 12 and
retinopathy in six. However, the combination of both was
Table 2. Differential diagnoses of chloroquine/hydroxychloroquine-
induced cardiomyopathy59.
 Connective tissue SLE
diseases: Rheumatoid arthritis
Dermatomyositis
Polymyositis
 Varia: Steroid myopathy
Other causes for conduction disturbances
Hypertensive heart disease
Hypertrophic cardiomyopathy sui generis
Coronary artery disease
 Storage diseases: Fabry disease
Niemann–Pick disease
Amiodarone-induced cardiomyopathy
Other lysosomal storage diseases
Amyloidosis
 Inflammation: Viral myocarditis
Lupus myocarditis
Vasculitis
Immunopharmacol Immunotoxicol, 2013; 35(3): 434–442
found only in two patients (Table 1). Accordingly, the use of a
histologic sample from the (more easily accessible) peripheral
muscle for diagnostic purposes in the case of suspected
cardiomyopathy as proposed by several authors appears to be
problematic. Rather, an endomyocardial biopsy should be
preferred, especially since numerous differential diagnoses
can be excluded as described above. This is of considerable
importance in determining further management.
Incidence
Due to the small number of cases, the incidence of
chloroquine/hydroxychloroquine toxicity is difficult to deter-
mine. With regard to retinopathy, in the case of long-term
treatment with standard dosages, it is stated as 2.6%
for chloroquine and 0.3% for hydroxychloroquine2,89,90.
With respect to neuromyopathy, an incidence of 1 in 100
patient years was reported for chloroquine25 and 1.9 in 1000
patient years for hydroxychloroquine22. The only prospective
study by Casado [23] revealed an annual incidence of
1.2%; however, an elevation of muscle enzyme levels in
the serum was selected as the primary screening tool.
No information was given about cardiotoxicity in any of the
literature cited.
The incidence of cardiac damage is almost impossible
to calculate due to the lack of systematic studies, but a
considerable number of undetected cases can be assumed.
There are two studies on the cardiotoxicity of chloro-
quine91 and hydroxychloroquine92 in which no pathological
findings were documented with regard to changes in the
resting ECG, conduction disorders or arrhythmias. In another,
older study by Godeau31, there were AV conduction disorders
in 18 of 112 patients suffering from lupus erythematosus;
five of the 18 had a third-degree AV block (all patients were
being treated with chloroquine). Cardiomyopathy was also
documented by means of a biopsy in one of these patients.
Moreover, there are four studies that investigated the
efficacy and toxicity of long-term treatment with both
substances22,93–95 and reviews 2,4. However, one study dealt
only with hydroxychloroquine93 and one included only
patients with SLE22. No indications of cardiotoxicity induced
by the two substances were found. Thus, it is clear that all of
the knowledge and theories regarding this cardiomyopathy are
founded exclusively on descriptions of individual cases.
Based on strict ultrastructural criteria (documentation
of curvilinear bodies), the diagnosis of chloroquine/hydroxy-
chloroquine cardiomyopathy has been confirmed pathologic-
ally in only 27 patients up to now (see Table 1).
It is striking that neuromyopathy can already manifest
itself clinically after only a short treatment period (5–7
months) and low cumulative doses (70–80 g)24,96,97, while the
patients with cardiac damage show symptoms only at a later
stage with high cumulative doses (patients with AV block:
after an average of 7 years/720 g; cardiomyopathy patients:
after an average of 14 years/1640 g). It must be noted that
the cardiac process may be clinically asymptomatic for a
long period and that the symptoms of toxic damage are often
ascribed to the underlying rheumatic disease and its compli-
cations. Moreover, in cases of neuromyopathy, the rapid
clinical improvement after discontinuation of even high
 DOI: 10.3109/08923973.2013.780078
cumulative doses is well described in nearly all publica-
tions27. With regard to retinopathy, on the other hand,
progression of the changes after discontinuation of the
medication is frequently observed98,99.
The latter observation may be due to the extremely high
concentrations of chloroquine/hydroxychloroquine in tissues
containing melanin13. But otherwise the cause of these
varying dynamics in the pathological process in the affected
organs is unclear.
Prognosis
The prognosis for this cardiomyopathy appears to be
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mixed (Table 1): Freihage42 and Costedoat-Chalumeau47
describe two patients with refractory heart failure, in which
heart transplants had to be performed 3 to 4 months after
discontinuation of the medication. Fifteen patients died (most
of them soon after the diagnosis had been established),
whereby the cause of death was not clarified in all cases and
the correlation with the chloroquine/hydroxychloroquine
damage could not be confirmed. The course of the illness
was not clear for seven patients, and an improvement was
described in 13 cases (Table 1); this improvement was
histologically documented in three patients with a repeated
myocardial biopsy after six months32,60 and two years48,
respectively. Frustaci’s casuistics are particularly noteworthy,
with regression of the pathological changes in the electrocar-
diogram, in the echocardiogram and the magnetic resonance
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imaging as well as in the follow-up biopsy and the activity
of the lysosomal enzymes six months after discontinuation of
hydroxychloroquine60. The regression of a complete AV block
is not well-documented in any case.
It is striking that the cumulative dose (1100/1260 g) and
the duration of treatment (6/12 years) were not particularly
high in the two patients with heart transplants42,47 and that,
on the other hand, symptoms and cardiac function improved
in five of the nine patients with the highest cumulative doses
after the medication was discontinued38,44,48,50,60. These
contradictory findings make it impossible to forecast the
prognosis in individual cases and underscore the abundance
of unanswered questions.
Risk factors
The small number of patients with cardiac symptoms and
the scant clinical data in some of the reports cited make it
difficult to specify risk factors for chloroquine/
hydroxychloroquine cardiomyopathy. Up until now, it has
not been possible to define predictive values for any of the
parameters discussed (such as age, gender, duration of
treatment, cumulative dose, underlying illness) in order to
estimate toxicity in individual cases, so that other factors
could play a significant role in the individual disposition of
the patient (genetics, liver and kidney function, metabolism).
Genetic polymorphism was recently reported for the first time
as a cause of change in the enzyme activity in chloroquine
metabolism (cytochrome P450 2C8)52.
The risk factors for retinopathy defined by the American
Academy of Ophthalmology20 were revised in 201189 and
focus on treatment duration45 years and a cumulative dose of
41000/460 g for hydroxychloroquine/chloroquine. Whether
Chloroquine cardiomyopathy 439
they can be generalized to cardiotoxicity remains to be seen.
As both substances are metabolized primarily in the liver and
excreted via the kidneys, an accumulation in cases of hepatic
and renal insufficiency is likely. However, it is not clear what
the practical importance of this consideration might be,
especially as the high degree of sequestration and fixation
in the tissue (multi-compartment model) is deemed to be a
limiting factor for the excretion of the substances4. Moreover,
there are no specific dosage recommendations in the
literature43,100.
In general, the following standard dosages apply: 250 mg
chloroquine phosphate and 400 mg hydroxychloroquine sul-
fate daily. The weight and height of the patients are not
taken into account, and neither substance is stored in fatty
tissue. Thus, to prevent an overdose in overweight patients
and individuals of short stature, a dosage based on lean
body weight should be selected, whereby 3.5–4.0 mg/kg
(chloroquine) and 6.0–6.5 mg/kg (hydroxychloroquine) have
been established89,101.
Hydroxychloroquine
Hydroxychloroquine, which differs from chloroquine only in
a hydroxyl group at the end of the side chain, but not
in pharmacokinetics or metabolism, is described in the
literature as less effective, but also less toxic24,43,94. It has
been experiencing a comeback, particularly in the treatment
of SLE, especially as favorable effects on lipid, glucose and
bone metabolism and on hemostatic parameters have
been documented and the dosages of corticosteroids can be
lowered1–4. Although no reliable statistical data are available,
it is striking that the incidence of neuromyopathy appears
to be lower under hydroxychloroquine than under chloro-
quine22,25. The same is true for retinopathy, so that in the USA
chloroquine has largely been replaced by hydroxychloroquine
in the treatment of SLE and rheumatoid arthritis2,89,100.
Of the 12 cases of neuromyopathy and six of retinopathy
among the cardiomyopathy patients, only two of the former
and one of the latter occurred under treatment with
hydroxychloroquine43,48,62/case 1. A third-degree AV block
under treatment with hydroxychloroquine has been described
in only two patients in all 44 cases cited in the literature56,67.
This finding is supported by the two studies on conduction
disorders, which found AV blocks in patients treated
with chloroquine31, but not in patients treated with
hydroxychloroquine92.
Of 13 patients whose test results and symptoms improved
after discontinuation of a long-term medication, eight had
been treated with hydroxychloroquine, three with chloroquine
and two with both substances (Table 1).
Conclusion
It must be noted that cardiotoxicity is difficult to diagnose
under long-term treatment with chloroquine/hydroxychloro-
quine and is presumably often overlooked in everyday clinical
practice. Up to now, it has not been possible to define risk
factors or limit values for dosage and duration of treatment.
Early detection is of utmost importance, as no therapy is
available, the reversibility of organ damage is questionable
and severe courses of illness (including heart transplants)
 440 E. Tönnesmann et al.
have been described. In case of long-term treatment and high
cumulative doses, we propose at least annual follow-up
examinations. These should include a detailed medical history
with physical examination results (assessment for congestive
heart failure, accompanying visual dysfunction or neuromyo-
pathy), an electrocardiogram (assessment for conduction
disorder or abnormality of repolarization), a serum enzyme
count (lactate dehydrogenase, creatine kinase, troponin) and,
if required, echocardiography (assessment for hypertrophy,
abnormal myocardial texture, restrictive physiology). If
myocardial damage is suspected, further diagnostic measures
including an endomyocardial biopsy with an electron micro-
scopic examination are required. In addition, the chloroquine/
Immunopharmacology and Immunotoxicology Downloaded from informahealthcare.com by York University Libraries on 10/18/13
hydroxychloroquine medication should be discontinued
immediately.
Declaration of interest
The authors report no declarations of interest.
References
1. Costedoat-Chalumeau N, Leroux G, Amoura Z, Piette JC.
Hydroxychloroquine dans le traitement du lupus: Le renouveau.
Rev Méd Interne 2008;29:735–737.
2. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA.
Clinical efficacy and side effects of antimalarials in systemic lupus
erythematosus: a systematic review. Ann Rheum Dis 2010;69:
For personal use only.
20–28.
3. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y.
Hydroxychloroquine: from malaria to autoimmunity. Clin Rev
Allergy Immunol 2012;42:145–153.
4. Lee SJ, Silverman E, Bargman M. The role of antimalarial agents
in the treatment of SLE and lupus nephritis. Nat Rev Nephrol 2011;
7:718–729.
5. Nelson AA, Fitzhugh OG. Chloroquine (SN-7618): pathologic
changes observed in rats which for two years had been fed various
proportions. Arch Pathol 1948;45:454–462.
6. Alving AS, Eichelberger L, Craige Jr B, et al. Studies on the
chronic toxicity of chloroquine. J Clin Invest 1948;27:60–65.
7. Cambiaggi A. Unusual ocular lesions in a case of systemic lupus
erythematosus. Arch Ophthalmol 1957;57:451–453.
8. Loftus LR. Peripheral neuropathy following chloroquine therapy.
Can Med Assoc J 1963;89:917–920.
9. Whisnant JP, Espinosa RE, Kierland RR, Lambert EH. Chloroquine
neuromyopathy. Proc Staff Meet Mayo Clin 1963;38:501–513.
10. Hughes JT, Esiri M, Oxbury JM, Whitty CW. Chloroquine
myopathy. Q J Med 1971;40:85–93.
11. Edwards AC, Meredith TJ, Sowton E. Complete heart block due to
chronic chloroquine toxicity managed with permanent pacemaker.
Br Med J 1978;1:1109–1110.
12. Tett SE. Clinical pharmacokinetics of slow-acting antirheumatic
drugs. Clin Pharmacokinet 1993;25:392–407.
13. Ducharme J, Farinotti R. Clinical pharmacokinetics and metabol-
ism of chloroquine – focus on recent advancements. Clin
Pharmacokinet 1996;31:257–274.
14. Rubin M, Zvaifler N, Bernstein H, Mansour A. Chloroquine
toxicity. Proc. 2nd Int. Pharm. Meeting, Prague, 1963. Vol. 4: Drugs
and enzymes, pp. 467–487. Oxford/Prague, 1965.
15. Halliwell WH. Cationic amphiphilic drug-induced
phospholipidosis. Toxicol Pathol 1997;25:53–60.
16. MacDonald RD, Engel AG. Experimental chloroquine myopathy.
J Neuropathol Exp Neurol 1970;29:479–499.
17. Klinghardt GW. Experimentelle Schädigungen von Nervensystem
und Muskulatur durch Chlorochin: Modelle verschiedenartiger
Speicherdystrophien. Acta Neuropathol 1974;28:117–141.
18. Gérard JM, Stoupel N, Collier A, Flament-Durand J. Morphologic
study of a neuromyopathy caused by prolonged chloroquine
treatment. Eur Neurol 1973;9:363–379.
Immunopharmacol Immunotoxicol, 2013; 35(3): 434–442
19. Rewcastle NB, Humphrey JG. Vacuolar myopathy: clinical,
histochemical, and microscopic study. Arch Neurol 1965;12:
570–582.
20. Marmor MF, Carr RE, Easterbrook M, et al. Recommendations
on screening for chloroquine and hydroxychloroquine retinopathy
(A Report by the American Academy of Ophthalmology).
Ophthalmology 2002;109:1377–1382.
21. Tegnér R, Tomé FMS, Godeau P, et al. Morphological study of
peripheral nerve changes induced by chloroquine treatment.
Acta Neuropathol 1988;75:253–260.
22. Wang C, Fortin PR, Li Y, et al. Discontinuation of antimalarial
drugs in systemic lupus erythematosus. J Rheumatol 1999;26:
808–815.
23. Casado E, Gratacós J, Tolosa C, et al. Antimalarial myopathy: an
underdiagnosed complication? Prospective longitudinal study of
119 patients. Ann Rheum Dis 2006;65:385–390.
24. Estes ML, Ewing-Wilson D, Chou SM, et al. Chloroquine
neuromyotoxicity – clinical and pathologic perspective. Am J
Med 1987;82:447–455.
25. Avina-Zubieta JA, Johnson ES, Suarez-Almazor ME, Russell AS.
Incidence of myopathy in patients treated with antimalarials.
A report of three cases and a review of the literature. Br J
Rheumatol 1995;34:166–170.
26. Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity.
J Rheumatol 2000;27:2927–2931.
27. Stevens MA, Yeaney GA, Lacomis D. 42-year-old man with
discoid lupus and progressive weakness. Brain Pathol 2009;19:
153–156.
28. Magnussen I, De Fine Olivarius B. Cardiomyopathy after chloro-
quine treatment. Acta Med Scand 1977;202:429–431.
29. Cervera A, Espinosa G, Cervera R, et al. Cardiac toxicity secondary
to long term treatment with chloroquine (letter to the editor).
Ann Rheum Dis 2001;60:301.
30. Motan J, Topinka I, Dura J, Kvapilova H. Chlorochinova
kardiodystrofie. Vnitr Lek 1978;24:1122–1128.
31. Godeau P, Guillevin L, Fechner J, et al. Les troubles de
conduction au cours du lupus érythémateux: fréquence et incidence
dans une population de 112 patients. Ann Méd Interne 1981;132:
234–240.
32. Ratliff NB, Estes ML, Myles JL, et al. Diagnosis of chloroquine
cardiomyopathy by endomyocardial biopsy. N Engl J Med 1987;
316:191–193.
33. McAllister Jr HA, Ferrans VJ, Hall RJ, et al. Chloroquine-induced
cardiomyopathy. Arch Pathol Lab Med 1987;111:953–956.
34. Verny C, de Gennes C, Sébastien P, et al. Troubles de la
conduction cardiaque au cours d’un traitement prolongé par
chloroquine – deux nouvelles observations. Presse Méd 1992;
21:800–804.
35. Iglesias Cubero G, Rodriguez Reguero JJ, Rojo Ortega JM.
Restrictive cardiomyopathy caused by chloroquine. Br Heart J
1993;69:451–452.
36. August C, Holzhausen HJ, Schmoldt A, et al. Histological and
ultrastructural findings in chloroquine-induced cardiomyopathy.
J Mol Med 1995;73:73–77.
37. Veinot JP, Mai KT, Zarychanski R. Chloroquine related cardiac
toxicity. J Rheumatol 1998;25:1221–1225.
38. Baguet JP, Tremel F, Fabre M. Chloroquine cardiomyopathy with
conduction disorders. Heart 1999;81:221–223.
39. Teixeira RA, Martinelli Filho M, Benvenuti LA, et al. Cardiac
damage from chronic use of chloroquine: a case report and review
of the literature. Arq Bras Cardiol 2002;79:85–88.
40. Roos JM, Aubry MC, Edwards WD. Chloroquine cardiotoxicity:
clinicopathologic features in three patients and comparison with
three patients with Fabry disease. Cardiovasc Pathol 2002;11:
277–283.
41. Charlier P, Cochand-Priollet B, Polivka M, et al. Cardiomyopathie
à la chloroquine révélée par un bloc auriculo-ventriculaire complet.
Arch Mal Cœur Vaiss 2002;95:833–837.
42. Freihage JH, Patel NC, Jacobs WR, et al. Heart transplantation in a
patient with chloroquine-induced cardiomyopathy. J Heart Lung
Transplant 2004;23:252–255.
43. Nord JE, Shah PK, Rinaldi RZ, Weisman MH. Hydroxychloroquine
cardiotoxicity in systemic lupus erythematosus: a report of 2 cases
and review of the literature. Semin Arthritis Rheum 2004;33:
336–351.
 DOI: 10.3109/08923973.2013.780078
44. Naqvi TZ, Luthringer D, Marchevsky A, et al. Chloroquine-induced
cardiomyopathy – echocardiographic features. J Am Soc
Echocardiogr 2005;18:384–388.
45. Keating RJ, Bhatia S, Amin S, et al. Hydroxychloroquine-induced
cardiotoxicity in a 39-year-old woman with systemic lupus
erythematosus and systolic dysfunction. J Am Soc Echocardiogr
2005;18:981.e1–5.
46. Reffelmann T, Naami A, Spuentrup E, Kühl HP. Contrast-enhanced
magnetic resonance imaging of a patient with chloroquine-induced
cardiomyopathy confirmed by endomyocardial biopsy. Circulation
2006;114:357–358.
47. Costedoat-Chalumeau N, Hulot JS, Amoura Z, et al.
Cardiomyopathy related to antimalarial therapy with illustrative
case report. Cardiology 2007;107:73–80.
48. Cotroneo J, Sleik KM, Rene Rodriguez E, Klein AL.
Hydroxychloroquine-induced restrictive cardiomyopathy. Eur J
Immunopharmacology and Immunotoxicology Downloaded from informahealthcare.com by York University Libraries on 10/18/13
Echocardiogr 2007;8:247–251.
49. Hernández Jiménez V, Saavedra Falero J, Navas R. Miocardiopatia
restrictiva reversible secundaria a cloroquina (Cartas al editor).
Med Clin (Barc) 2007;129:157.
50. Soong TR, Barouch LA, Champion HC, et al. New clinical and
ultrastructural findings in hydroxychloroquine-induced cardiomy-
opathy – a report of 2 cases. Hum Pathol 2007;38:1858–1863.
51. Manohar VA, Moder KG, Edwards WD, Klarich KW.
Restrictive cardiomyopathy secondary to hydroxychloroquine
therapy. J Rheumatol 2009;36:440–441.
52. Saussine A, Loriot M-A, Picard C, et al. Cardiotoxicité après un
traitement au long cours par chloroquine chez deux patientes
lupiques. Ann Dermatol Venereol 2009;136:530–535.
53. Fragasso G, Sanvito F, Baratto F, et al. Cardiotoxicity after
low-dose chloroquine antimalarial therapy. Heart Vessels 2009;24:
385–387.
54. Lee JH, Chung WB, Kang JH, et al. A case of chloroquine-induced
cardiomyopathy that presented as sick sinus syndrome. Korean Circ
For personal use only.
J 2010;40:604–608.
55. Pieroni M, Smaldone C, Camporeale A, et al. Chloroquine-induced
transition from dilated to restrictive cardiomyopathy (Images in
Cardiology). J Am Coll Cardiol 2011;57:515.
56. Muthukrishnan P, Roukoz H, Grafton G, et al.
Hydroxychloroquine-induced cardiomyopathy: a case report.
Circ Heart Fail 2011;4:e7–e8.
57. Newton-Cheh C, Lin AE, Baggish AL, Wang H. A 47-year-old
man with systemic lupus erythematosus and heart failure (Case
11–2011). N Engl J Med 2011;364:1450–1460.
58. Hartmann M, Meek IL, van Houwelingen GK, et al. Acute left
ventricular failure in a patient with hydroxychloroquine-induced
cardiomyopathy. Neth Heart J 2011;19:482–485.
59. Tönnesmann E, Stroehmann I, Kandolf R, et al. Cardiomyopathy
caused by longterm treatment with Chloroquine: a rare disease, or a
rare diagnosis? (letter to the editor). J Rheumatol 2012;39:
1099–1104.
60. Frustaci A, Morgante E, Antuzzi D, et al. Inhibition of
cardiomyocyte lysosomal activity in hydroxychloroquine cardio-
myopathy. Int J Cardiol 2012;157:117–119.
61. Abbasi S, Tarter L, Farzaneh-Far R, Farzaneh-Far A.
Hydroxychloroquine: a treatable cause of cardiomyopthy (Images
in Cardiology). J Am Coll Cardiol 2012;60:786.
62. Azimian M, Gultekin SH, Hata JL, et al. Fatal antimalarial-induced
cardiomyopathy – report of 2 cases. J Clin Rheumatol 2012;18:
363–366.
63. Oli JM, Ihenacho HN, Talwar RS. Chronic chloroquine toxicity and
heart block: a report of two cases. East Afr Med J 1980;57:
505–507.
64. Ladipo GO, Essien EE, Andy JJ. Complete heart block in chronic
chloroquine poisoning. Int J Cardiol 1983;4:198–200.
65. Ihenacho HN, Magulike E. Chloroquine abuse and heart block in
Africans. Aust NZ J Med 1989;19:17–21.
66. Ogola ES, Muita AK, Adala H. Chloroquine related complete heart
block with blindness: case report. East Afr Med J 1992;69:50–52.
67. Fellahi JL, Dumazer P, Delayance S, et al. Cardiomyopathie sous
traitement par hydroxychloroquine révélée par un bloc auriculo-
ventriculaire complet. Rev Méd Interne 1993;14:275–276.
68. Guedira N, Hajjaj-Hassouni N, Srairi JE, et al. Third-degree
atrioventricular block in a patient under chloroquine therapy.
Rev Rhum (Engl. Ed.) 1998;65:58–62.
Chloroquine cardiomyopathy 441
69. Reuss-Borst M, Berner B, Wulf G, Müller GA. Complete heart
block as a rare complication of treatment with chloroquine.
J Rheumatol 1999;26:1394–1395.
70. Duvic C, Pats B, Rouvier B. Bloc auriculoventriculaire complet
après prise chronique de chloroquine (Lettres à la rédaction).
Rev Méd Interne 2000;21:462–463.
71. El aichaoui S, Amine B, Saoud B, et al. Bloc auriculoventriculaire
complet au cours d’un traitement par chloroquine. Rev Méd Interne
2007;28:134–136.
72. Puymirat E, Douard H, Roudaut R. Bloc auriculo-ventriculaire
complet après prise de chloroquine au long cours. Rev Méd Interne
2008;29:741–743.
73. Queyriaux B, Carlioz R, Perrier E, et al. Les effets cardiovascu-
laires liés à l’utilisation de la chloroquine. Ann Cardiol Angeiol
2001;50:285–292.
74. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use
associated with QT prolongation and refractory ventricular arrhyth-
mia (case report). Clin Toxicol (Phila.) 2006;44:173–175.
75. Stas P, Faes D, Noyens P. Conduction disorder and QT prolongation
secondary to long-term treatment with chloroquine (letter to the
editor). Int J Cardiol 2008;127:e80–e82.
76. Sanghvi LM, Mathur BB. Electrocardiogram after chloroquine and
emetine. Circulation 1965;32:281–289.
77. Seferovic PM, Ristic AD, Maksimovic R, et al. Cardiac arrhythmias
and conduction disturbances in autoimmune rheumatic diseases.
Rheumatology 2006;45:iv, 39–42.
78. Smith B, O’Grady F. Experimental chloroquine myopathy. J Neurol
Neurosurg Psychiatry 1966;29:255–258.
79. Jain D, Halushka MK. Cardiac pathology of systemic lupus
erythematosus. J Clin Pathol 2009;62:584–592.
80. Voskuyl AE. The heart and cardiovascular manifestations in
rheumatoid arthritis. Rheumatology 2006;45:iv, 4–7.
81. Costedoat-Chalumeau N, Amoura Z, Hulot JS, et al. Low blood
concentration of hydroxychloroquine is a marker for and predictor
of disease exacerbations in patients with systemic lupus erythema-
tosus. Arthritis Rheum 2006;54:3284–3290.
82. Baccouche H, Mahrholdt H, Meinhardt G, et al. Diagnostic synergy
of non-invasive cardiovascular magnetic resonance and invasive
endomyocardial biopsy in troponin-positive patients without cor-
onary artery disease. Eur Heart J 2009;30:2869–2879.
83. Yilmaz A, Kindermann I, Kindermann M, et al. Comparative
evaluation of left and right ventricular endomyocardial biopsy –
differences in complication rate and diagnostic performance.
Circulation 2010;122:900–909.
84. Boldrini R, Biselli R, Santorelli FM, Bosmann C. Neuronal ceroid
lipofuscinosis: an ultrastructural, genetic, and clinical study report.
Ultrastruct Pathol 2001;25:51–58.
85. Dolman CL, Chang E. Visceral lesions in amaurotic familial idiocy
with curvilinear bodies. Arch Pathol Lab Med 1972;94:425–430.
86. Neville HE, Maunder-Sewry CA, McDougall J, et al. Chloroquine-
induced cytosomes with curvilinear profiles in muscle. Muscle
Nerve 1979;2:376–381.
87. Ramsey MS, Fine BS. Chloroquine toxicity in the human eye:
histopathologic observations by electron microscopy. Am J
Ophthalmol 1972;73:229–235.
88. Lee HS, Daniels BH, Salas E, et al. Clinical utility of LC3 and p62
immunohistochemistry in diagnosis of drug-induced autophagic
vacuolar myopathies: a case-control study. PLoS One 2012;7:
e36221.
89. Marmor MF, Kellner U, Lai TYY, et al. Revised recommendations
on screening for chloroquine and hydroxychloroquine retinopathy.
Ophthalmology 2011;118:415–422.
90. Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine
retinal toxicity in patients with rheumatoid arthritis and systemic
lupus erythematosus. Arthritis Care Res 2010;62:775–784.
91. Wozniacka A, Cygankiewicz I, Chudzik M, et al. The cardiac safety
of chloroquine phosphate treatment in patients with systemic lupus
erythematosus: the influence on arrhythmia, heart rate variability
and repolarization parameters. Lupus 2006;15:521–525.
92. Costedoat-Chalumeau N, Hulot JS, Amoura Z, et al. Heart
conduction disorders related to antimalarials toxicity: an analysis
of electrocardiograms in 85 patients treated with hydroxychlor-
oquine for connective tissue diseases. Rheumatology 2007;46:
808–810.
 442 E. Tönnesmann et al.
93. Morand EF, McCloud PI, Littlejohn GO. Continuation of long
term treatment with hydroxychloroquine in systemic lupus
erythematosus and rheumatoid arthritis. Ann Rheum Dis 1992;
51:1318–1321.
94. Avina-Zubieta JA, Galindo-Rodriguez G, Newman S, et al. Long
term effectiveness of antimalarial drugs in rheumatic diseases.
Ann Rheum Dis 1998;57:582–587.
95. Jover JA, Leon L, Pato E, et al. Long-term use of antimalar-
ial drugs in rheumatic diseases. Clin Exp Immunol 2012;30:
380–387.
96. Mastaglia FL, Papadimitriou JM, Dawkins RL, Beveridge B.
Vacuolar myopathy associated with chloroquine, lupus erythema-
tosus and thymoma. J Neurol Sci 1977;34:315–328.
Immunopharmacology and Immunotoxicology Downloaded from informahealthcare.com by York University Libraries on 10/18/13
For personal use only.
Immunopharmacol Immunotoxicol, 2013; 35(3): 434–442
97. Abdel-Hamid H, Oddis CV, Lacomis D. Severe hydroxychlor-
oquine myopathy. Muscle Nerve 2008;38:1206–1210.
98. Shinjo SK, Maia Júnior OO, Tizziani VAP, et al. Chloroquine-
induced bull’s eye maculopathy in rheumatoid arthritis: related to
disease duration? Clin Rheumatol 2007;26:1248–1253.
99. Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal
toxicity associated with hydroxychloroquine and chloroquine.
Arch Ophthalmol 2011;129:30–39.
100. Tang C, Godfrey T, Stawell R, Nikpour M. Hydroxychloroquine in
lupus: emerging evidence supportive multiple beneficial effects.
Intern Med J 2012;42:968–978.
101. Mackenzie AH. Dose refinements in long-term therapy of
rheumatoid arthritis with antimalarials. Am J Med 1983;75:40–45.