SYSTEMIC DERMATOLOGIC THERAPY 0733-8635/01 $15.00 + .

OO

ANTIMALARIALS
Marta J. Van Beek, MD, and Warren W. Piette, MD

Antimalarial medications have become the Although chloroquine (CQ) was developed
parenteral drugs of choice for treating the in 1934, it languished until the 1950s, when
cutaneous manifestations of lupus erythema- studies showed that it was equally effective
tosus (LE). The immune-modulating activity as and better tolerated than QE.40Hydro-
of these agents has made them useful in a xychloroquine (HCQ) was introduced in 1955,
variety of other dermatoses. With prudent and its efficacy in LE was documented by
dosage and monitoring, these agents can be 1956.12,55 Amodiaquine (Camoquine) was in-
used safely and effectively in the treatment troduced in 1957 for the treatment of systemic
and management of dermatologic disease. lupus erythematosus (SLE) but was with-
drawn several years later after reports of
agranulocytosis.lofl
HISTORY

Quinine, the parent compound of contem- PHARMACOKINETlCS

porary antimalarials and a derivative of the
chinchona bark, first was used as an antipy- Chloroquine
retic by Jesuit priests in the 1650s. In 1894,
Payne first described the lupus rash, pre- CQ is a 4-aminoquinoline that is absorbed
scribed quinine to induce pallor, and noted almost completely by the gastrointestinal
subsequent Similar re- tract, even in the presence of diarrhea.37With
sponses were confirmed by Davidson and an extended half-life of 40 to 50 days, approx-
BirP in 19 of 29 patients with LE in 1938. imately 50% is excreted renally depending
The synthetic quinacrine (Atabrine, mepa- on the acidity of the urine. Such excretion is
crine, Chinacrin) was introduced in the 1930s. extremely slow and proportional to creatinine
Quinacrine (QE) established its superiority clearance, with CQ detectable in the urine,
over quinine during World War 11, with 3 red cells, and plasma for 5 years after discon-
million to 4 million American servicemen tak- tinuation of the medication. Peak plasma lev-
ing 100 mg of QE daily for 4 years.2Unaware els are reached within 4 to 8 hours after an
of previously published articles touting QE individual dose; however, equilibrium
for treatment of LE,76 Page67noted the im- plasma levels are not reached until 4 to 6
provement of cutaneous manifestations of lu- weeks of constant daily dosing.
pus and inflammatory arthritis in soldiers Largely bound by plasma proteins in the
taking Atabrine. Page67subsequently reported circulation, CQ eventually is deposited into
successful treatment of 18 quinine-resistant, metabolically active tissues. Concentrations of
cutaneous lupus patients with QE. 200 to 20,000 times plasma levels are found

From the Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa

DERMATOLOGIC CLINICS

VOLUME 19 NUMBER 1 * JANUARY 2001 147

148 VAN BEEK & PIETTE

in the liver, spleen, kidney, lung, pigmented Quinacrine

tissues, and blood elements.37Sjolin-Forsberg
et alas showed CQ in suction blister fluid in
the absence of detectable plasma levels 7 QE (Atabrine) differs from the chloroquines
months after treatment cessation, suggesting by an acridine nucleus, which contains an
skin as a possible predilection site. Eventu- extra benzene ring.lo2The drug is absorbed
ally, CQ is metabolized into three N-dealky- rapidly after oral administration, with peak
lated metabolites that are of toxologic and plasma levels at 8 to 12 hours. Steady-state
pharmacologic i m p ~ r t a n c e . The
~ ~ drug concentration is attained by the fourth week,
crosses the placenta readily and is excreted in resulting in a faster onset of action compared
small amounts in breast milk; a nursing child with the 4-aminoquinolines.
receives less than 1%of the maternal dose.4l Eighty percent to 90% is bound to plasma
proteins and metabolic tissues in therapeutic
As a result, this agent also is slowly
excreted from the body, with less than 11%
Hyd roxychloroqine eliminated in the urine daily. Highest tissue
concentrations are found in the liver (20,000
HCQ (Plaquenil) is a 4-aminoquinoline that times plasma levels) and spleen. Skin depos-
differs from CQ by a hydroxyl group. Ab- its often are visible as yellow or blue-black
sorption in the gastrointestinal tract is 75% to pigmentati~n.~~ QE also has been shown to
loo%, and 50% is bound to serum proteins.37 cross the placenta. Because there is no cross-
Excretion occurs in two stages: a rapid stage reactivity of the 4-aminoquinoline derivatives
with a half-life of 3 days and a slower stage and QE, an adverse effect from one agent
with a half-life of 40 to 50 days. Forty-five does not preclude treatment with the
percent is excreted by the kidney, 3% is ex-
creted by the skin, and 20% is excreted by the
bowel. Similar to CQ, renal excretion of HCQ
can be enhanced by acidification of the DOSAGE
urine.53
Steady-state is reached after 6 months of
therapy. Highest concentrations are in the ad- HCQ typically is started at 400 mg daily
renal and pituitary glands, pigmented tissues, (once daily or in 200-mg divided doses) or at
liver, spleen, and l e ~ k o c y t e sEpidermal
.~~ lev- 5 to 7 mg/kg/d.'03 Responses are not seen
els are 100 to 200 times the plasma concentra- until 2 to 3 months, with peak efficacy evi-
tions. Although both 4-aminoquinolines bind dent at 6 to 12 months. CQ often is started at
to corneal tissues, CQ binds more avidly than 250 to 500 mg daily (approximately 4 mg/
HCQ. With slit-lamp examination, 90% of pa- kg/d); effects are evident within 1 to 2
tients receiving the standard therapeutic dose months. QE usually is given as a 100- to 200-
of CQ have corneal deposits compared with mg daily dose with onset of action at 3 to 6
5% of patient on standard doses of HCQ." weeks. Further recommendations on dosing
Enantiomers of HCQ bind differently to are listed in Table 1. Dosage, contraindica-
specific tissues; metabolism and renal clear- tions, drug interactions, and toxicities are
ance are stereo~pecific.~~ Dosage of CQ and listed in Table 2. The most common reason
HCQ must be adjusted in patients with renal for treatment failure with antimalarials is not
failure. Dialysis is unhelpful in removing ei- allowing adequate time to judge the response.
ther drug because the agents are sequestered After 1 to 2 years of successful therapy, the
extensively. antimalarials can be tapered or discontinued.

Table 1. RECOMMENDED DOSAGE VERSUS DOSAGE BASED ON IDEAL BODY WEIGHT

Hydroxychloroquine Chloroquine
6.5 mglkgld 3.5 mglkgld Quinacrine
Recommended dose 400 mg/d 250 mg/d 100 mg/d
Male (70 kg) 455 mg 245 mg 100-200 mg
Female (55 kg) 357.5 mg 192.5 mg 100-200 mg
Tablet (mg) 200 mg or 400 mg 250 mg or 500 mg 100 mg

*Ideal body weight: males, 50.0 kg + 2.3 kg (each inch of height >5 ft); females, 45.5 kg + 2.3 kg (each inch of height >5 ft).
 ANTIMALARIALS 149

Table 2. CONTRAINDICATIONS AND DRUG INTERACTIONS

Hydroxychloroquine Chloroquine Quinacrine
Drug interactions Anticonvulsants Anticonvulsants Synergy with other marrow-
(antagonized) (antagonized) suppressant drugs
Digoxin (altered Ampicillin (decreased
plasma levels) bioavailability)
Cimetidine (decreases D-Penicillamine
HCQ clearance) (antagonized)
Amiodarone Cimetidine (decreases
(increased CQ clearance)
arrhythmia risk) Cyclosporine
(synergy)
Side effects in therapeutic Hemolysis in G6PD Hemolysis in G6PD Headache, dizziness
range Gastrointestinal Gastrointestinal Diarrhea
(nausea and (nausea and Nausea, vomiting
vomiting) vomiting) Aplastic anemia
Hyperpigmentation Hyperpigmentation Lichenoid drug eruption
Bleaching of hair Bleaching of hair Gastrointestinal (nausea and
Neuromuscular Neuromuscular vomiting)
symptoms symptoms
Exfoliative dermatitis Exfoliative dermatitis
Corneal deposits
Complications of exceeding Retinopathy Retinopathy Vertigo, insomnia
maximum dose Corneal deposits Psychosis Hyperirritability
Psychosis Psychosis
Aplastic anemia
Progression of symptoms Headache, drowsiness, Headache, drowsiness, Headache, hyperirritability,
from lethal overdose dyspnea, dysphagia, dyspnea, dysphagia, dyspnea, dysphagia, hoarseness
CQ '2 R hoarseness hoarseness Cardiovascular collapse
Cardiovascular Cardiovascular Convulsions
collapse collapse
Convulsions Convulsions
Respiratory and Respiratory and
cardiovascular arrest cardiovascular arrest
Absolute contraindications Existing retinal disease Existing retinal disease Known hypersensitivity
Known Known Concomitant marrow-suppressant
hypersensitivity hypersensitivity therapy
Relative contraindications Liver or renal disease Liver or renal disease Liver or renal disease
Psoriasis (?) Psoriasis (?) Psoriasis (?)
Pregnancy (?) Pregnancy (?) Pregnancy (?)

HCQ = Hydroxychloroquine; CQ = chloroquine; QE = quinacrine.

MECHANISMS OF ACTION ity.*09There has been no demonstrable effect

of these agents on the minimal erythema
Although the in vivo and in vitro effects of dose, however.
the CQs have been well studied, the exact
manner in which antimalarials exert a thera-
peutic effect is unclear. Any model of action Immunologic Effects at the Cellular
must account for the delayed onset of action, Level
the decrease in acute-phase reactants (eryth-
rocyte sedimentation rate, C-reactive protein, HCQ and CQ are weak, diprotic bases that
and serum immunoglobulin levels), and the pass through lipid cell membranes and con-
paucity of concomitant opportunistic infec- centrate in acidic cytoplasmic vesicles.43Once
tions that characterize antimalarial therapy.33 inside, the antimalarial becomes protonated
Systemically administered 4-aminoquino- and trapped within the vesicle. Additional
lines are bound in the epidermis in relatively hydrogen ions pumped into the cell by the
high concentrations and absorb UV light in adenosine triphosphatase (ATPase) pump at-
a concentration-dependent manner.83QE has tract more unprotonated HCQ and CQ into
been shown to impede photodynamic actions the vesicle; this results in a 100 times concen-
and can inhibit laser-induced photosensitiv- tration of drug within intercellular vesicles.
150 VAN BEEK & PIETTE

Such an effect may be more pronounced in dent of the effect of high lysosomal concentra-
cells with an increased number of acidic tion~?~
vesicles-such as phagocytizing cells and CQ blocks prostaglandin effects by inhib-
macro phage^.^^ iting phospholipases A, and C.33QE also is a
Increasing 4-aminoquinoline concentration powerful inhibitor of phospholipase A, re-
in lysosomes results in the accumulation of sulting in decreased leukotriene, prostaglan-
inclusion bodies (myelin bodies) containing din, bradykinin, and histamine levels. For the
plasma membrane phospholipid. This accu- same reason, it can impede IL-2 receptor ac-
mulation results in decreased phagocytosis, tivity. This inhibition results in the suppres-
chemotaxis, and overall cell functioning. CQ sion of the mitogenic response of T cells to
and its derivatives also delay the recycling of allogeneic antigens.
proteins, such as enzymes and surface recep- QE also is a nonselective antilipolytic agent,
tors from lysosomes to the cell surface. This decreasing prostaglandin E2 production in a
depletion of cell surface receptors alters the dose-dependent fashion. Thromboxanes B,
cell's responsiveness to mitogenic ~timuli.4~ and A, specifically are suppressed. QE stabi-
The increase in lysosomal pH is thought to lizes cell membranes through inhibition of
disrupt the normal assimilation of peptides Na-K ATPase activity. Strongly concentrated
with class I1 major histocompatibility com- in leukocytes and lysosomes, QE inhibits
plex (MHC) molecules. Because cryptic self- phagocytosis, chemotaxis, RNA synthesis,
peptides that escape thymic tolerance are and hexose monophosphate shunt burst ac-
characterized by their low affinity for self- tivity? QE inhibits natural killer cell cytotox-
MHC,38elevation of the pH within the vesicle icity and blocks the primary (not the second-
may decrease selectively the loading of au- ary) proliferative response of cytotoxic T cells
toantigen self-peptides. This action can be ac- to allogeneic non-T-cell antigen^?^
complished while leaving the response to ex-
ogenous peptides intact. Without subsequent
interaction between antigen-presenting cells Direct Effects on Cellular DNA
and T cells, there is a decrease in release of
cytokines, such as interleukin (1L)-1, IL-6, and Antimalarial agents bind to DNA by inter-
tumor necrosis factor. The decrease or ab- calation between adjacent base pairs.19 This
sence of these circulating factors decreases bond stabilizes DNA, inhibiting heat denatur-
activation of specific promoters within the ation, enzymatic depolymerization, RNA
liver, lowering acute-phase reactants.33 transcription, and translation. Dubois20docu-
In vitro the CQs can inhibit natural killer mented that the binding of QE to nucleopro-
cell activity and IL-2 production by human teins can block the LE cell factor.
lymphocytes. This activation might result
from the stabilization of lysosomal mem-
branes or from the action of complement on
autologous cells. In a dose-dependent fash- Anesthetic Effects
ion, CQ may inhibit or enhance the formation
of antigen-antibody complexes. Clinically, it Antimalarials stabilize membranes, includ-
has been shown to decrease circulating im- ing the outer cellular membrane, sarcoplas-
mune complex levels in patients with rheu- mic reticulum, and mitochondria1 mem-
matoid arthriti~.'~ branes, by competing with calcium ions for
Studies have shown that CQ and its struc- binding This competitive inhibition
tural analog (including QE) inhibit the immu- prolongs the duration and reduces the ampli-
nostimulatory effect of cytosine-phosphorothi- tude of membrane action potential, producing
olated guanine (CpG)-oligodeoxynucleotides a local anesthetic effect.
at low concentration^.^^, 90 Specifically, they in-
hibit CpG-oligodeoxynucleotides-induced IL-
6 production by unfractionated human periph- Antioxidant Effects
eral mononuclear blood cells. These nanomo-
lar concentrations are much lower than those In high doses, CQ can mhibit polymorpho-
needed for other documented anti-inflamma- nuclear oxidative CQ, HCQ, and QE
tory effects of antimalarials. Consequently, an- block superoxide release by actions at multi-
timalarials may inhibit a major immunostimu- ple sites in the metabolic pathway but only
latory effect by a specific mechanism indepen- at doses greater than those used clinically.
 ANTIMALARIALS 151

Antihyperlipidemic Effects therapy. Wallacelo’noted that patients taking

HCQ had significantly fewer thromboembolic
The lysosomotropic properties of the CQs events compared with those not given the
result in proteolysis of many plasma mem- drug. Among 96 anticardiolipin antibody-
brane re~eptors.4~CQ can increase the number positive patients, only 11%of 54 on HCQ had
of low-density lipoprotein (LDL) receptors, thromboembolic events compared with 20%
however, while inhibiting the proteolysis of of the 35 not taking the medication. As a
internalized cholesterol esters3;this results in result, Wallacelo’ recommended that all pa-
increased LDL receptor levels. CQ inhibits tients with IgG anticardiolipin antibodies of
cholesterol synthesis by its effect on 2,3-oxi- greater than 50 GPL units be prophylaxed
dosqualene-lanosterol cyclase and can in- with HCQ or another antiplatelet medication.
crease the activity hydroxymethylglutaryl- Petri et al7I reported prospectively ascer-
coenzyme A reductase in cultured fibroblasts. tained thrombotic events (venous and arte-
Wallace et allo4noted the antilipidemic ac- rial) in the Baltimore Lupus Cohort. HCQ use
tion in 155 patients with lupus or rheumatoid was found to be protective against thrombosis
arthritis taking HCQ. Patients on HCQ had in such patients. The mechanism of such an
significantly lower LDL levels, serum triglyc- effect in SLE patients may be a combination
erides, and cholesterol levels than patients on of reducing multiple atherosclerotic risk fac-
placebo. Three separate studies have con- tors (cholesterol and glucose), in addition to
firmed the significant lipid-lowering effect of a reduction of immunoglobulin levels and
antimalarials in lupus patients on prednisone overall disease activity that produce a proco-
therapy.70,72* 8o agulant state.’O

Hypoglycemic Effects

Smith et als6 and Quatraro et a178 docu- Dubois19documented case histories of par-
mented a significant decrease in glucose pro- tial responses to single antimalarial agents
files, such as glycated hemoglobin Alc, in with subsequent superior responses to combi-
patients treated with CQ or HCQ compared nation therapies. As a result, Triquin (a com-
with patients on placebo. The hypoglycemic bination of CQ, 65 mg; HCQ, 50 mg; and QE,
effect of CQ has been attributed to insulin 25 mg) was developed. Despite impressive
degradation because C-peptide levels are not results (44 of 45 recalcitrant LE patients re-
increased.86In a cross-sectional study of 128 sponding) published in 1959,96Triquin was
SLE patients, Petri and YOO” found that HCQ taken off the market in the early 1970s during
treatment was protective against an abnormal the campaign against polypharmacy.
glucose tolerance test; this was true even after Feldman30studied 14 chronic cutaneous LE
adjusting for age, prednisone use, and family patients who had failed monotherapy. Ten
history of diabetes mellitus. (71%) had significant improvement with a
combination of CQ and QE. Lipsker et a156
reported that 12 of 15 patients improved
Antiplatelet Effects markedly on QE and CQ after previous treat-
ment failures with monotherapy.
HCQ and CQ can inhibit platelet aggrega-
tion and adhesionA6 Several trials have pro-
vided conflicting assessments of clinical ef- Combination Therapy
fect, however.”, 5 8 , 74 QE inhibits loss of
arachidonic acid from platelet phospholip- The aim of combination therapy is to in-
i d ~ . It
’ ~also
~ inhibits the association of fi- crease disease suppression through additive
brinogen with its platelet receptor, inhibiting or synergistic benefit. Ideally the medications
platelet aggregation induced by adenosine di- used should have a different site or mecha-
phosphate or collagen. The antiphospholipase nism of action to confer a pharmacokinetic
action of QE suppresses thrombin-induced advantage. Studies of combination therapy
platelet responses. are difficult because large patient numbers
Such reports prompted Wallacelo’to evalu- are required to show a difference between
ate retrospectively this lupus population in combined drug therapy and a single agent.
relation to thrombotic events and antimalarial Also, in the case of a presumed drug reaction,
152 VAN BEEK & PIElTE

it may be impossible to decide which drug is SLE patients on QE and 7 of 28 patients on

responsible. CQ were able to discontinue steroid therapy
No advantage has been shown in combin- during an uncontrolled trial.21
ing antimalarials with gold, penicillamine, or found HCQ to be particularly useful for anti-
sulfasalazine compared with monotherapeu- Ro/SSA-positive disease, confirmed its ste-
tic regimens.= There is some evidence to sug- roid-sparing properties, and advocated com-
gest a beneficial combination of antimalarials bined antimalarial therapy for resistant cases.
with methotrexate. In a review of nearly 2600 In 1991, the Canadian Hydroxychloroquine
patients with rheumatoid arthritis, the per- Study Group reported a 6-month multicenter,
centage of patients with elevated serum trans- placebo-controlled, double-blind, randomized
aminase levels was significantly lower in pa- study of the effect of withdrawing HCQ in
tients receiving methotrexate combined with stable SLE patients.93Patients randomized to
HCQ than in patients receiving methotrexate placebo were 2.5 times more likely to have a
49 There is a reduction in the area mild clinical flare than those who remained
under the plasma methotrexate concentration on HCQ. These patients also averaged a
versus time curve observed in patients with larger increase in daily prednisone (2.7 mg/
coadministration of HCQ. A survey of 200 d) compared with patients receiving HCQ
American rheumatologists revealed that 93% (0.4 mg/d).
use combination therapy.66The most com- In a series of 156 SLE patients treated with
monly used combination was methotrexate antimalarials (97% on HCQ), the most com-
and HCQ. mon reason for stopping medication was clin-
ical remission (42%).'05Of patients, 29% dis-
continued the first course secondary to side
Smoking and Antimalarial Therapy effects, most commonly gastrointestinal. In re-
viewing the 20 clinical trials published on
Smoking potentially can alter the pharma- the use of QE in LE patients (1939-1961),
cokinetics of a drug by decreasing absorption, Wallace102noted an overall 73% response rate
increasing plasma clearance, or inducing the among 771 patients studied.
cytochrome P-450 enzyme system.84As stated The cutaneous manifestations of LE are
previously, approximately 30% to 50% of CQ particularly responsive to QE with healing of
is metabolized by the various hepatic iso- discoid lesions and mouth ulcerations ob-
forms of cytochrome P-450.37Polycyclic aro- served within 2 to 3 weeks.'02 QE is a report-
matic hydrocarbons, present in cigarette edly greater cerebral cortical stimulant than
smoke, are potent inducers of cytochrome P- the CQs and may be the most effective non-
450 enzymesw Cigarette smoke may induce steroid drug in the management of lupus-
other cytochromes, which metabolize chlo- associated fatigue.27
roquine through an alternative pathway that
does not lead to active metabolites. Conse-
quently, smoking appears to decrease the ef- Porphyria Cutanea Tarda
ficacy of antimalarial therapy in cutaneous
lupus. Rahman et a179reported complete reso- In addition to inhibiting porphyrin synthe-
lution of the cutaneous eruption in 3 of 17 sis, CQs can mobilize lysosomal stores by
smokers versus 9 of 17 nonsmokers after 6 forming water-soluble complexes that are ex-
months of antimalarial therapy. creted in the urine.1° CQ also may chelate iron
in the hepatocyte.92 In 1957, London57 first
reported the benefit of CQ in treating por-
CLINICAL STUDIES phyria cutanea tarda in one patient receivhg
500 mg daily; fear of severe hepatotoxicity
Cutaneous Lupus Erythematosus limited its use, however.15 Subsequently, low-
dose CQ has been shown to be a successful
Since the 1930s, antimalarials have proved addition or alternative to phlebotomy.42Valls
effective for cutaneous manifestations, poly- et a197followed 53 patients with active por-
arthralgias, pleuritis, and low-grade pericar- phyria cutanea tarda without severe iron
dial inflammation associated with SLE.16,64, 76 overload (serum ferritin <400 pg/L). Patients
D ~ b o i s 'claimed
~ that 90% to 95% of LE pa- were given 125 mg CQ twice weekly for the
tients improved with HCQ compared with a first 2 weeks followed by 250 mg twice
10% spontaneous remission rate. Nine of 34 weekly thereafter. Of patients (%YO), 50
 ANTIMALARIALS 153

achieved metabolic remission within a me- not as effective as corticosteroids in the treat-
dian time of 8 months. Seventy percent ment of pulmonary sarcoid lesions.
showed complete normalization of porphyrin
excretion. Cumulative probability of relapse 1
year after therapy was 12%. Only one patient Sjogren’s Syndrome
suffered side effects (severe pruritus) that re-
quired drug discontinuation. Ophthalmologic In an open-label retrospective study of pa-
examinations were within normal limits, and tients with Sjogren’s syndrome, Fox et a135
none of the patients showed worsening of found a sustained improvement of local
liver function tests. symptoms (painful eyes and mouth), arthral-
Cainelli et als compared 200 mg of HCQ gias, myalgias, erythrocyte sedimentation rate
twice weekly with twice-monthly 400-mL and quantitative IgG levels after treatment
phlebotomies in 61 patients. HCQ was more with 6 to 7 mg/kg/d during a 3-year follow-
effective in decreasing porphyrin production, up. Subsequent studies showed that HCQ im-
although liver disease progressed in both proved features of immunologic hyperreac-
groups. Swanbeck and Wennerstengl suggest tivity, such as hypergammaglobulinemia and
that the combination of phlebotomy and low- autoantibody levels.35,
dose CQ treatment may reduce the severity of
the CQ hepatotoxic response, while inducing
disease remission. Most authors suggest a Polymorphous Light Eruption and
125- to 250-mg test dose of CQ with subse- Solar Urticaria
quent liver function tests before initiating CQ
therapy in porphyria cutanea tarda.97 The clinical action of CQ on photodermato-
Petersen and T h o m ~ e nadvocated
~~ short ses may be explained by their effect on immu-
courses of high-dose, daily HCQ treatment nologic reactions. Studies suggest that IL-6,
in a 1992 study of 93 episodes of porphyria IL-8, and possibly IL-1 may be involved in
cutanea tarda. Although the authors consid- the induction of inflammatory infiltrates asso-
ered high-dose HCQ therapy safe, they re- ciated with polymorphous light eruption and
ported marked increases in liver transaminase chronic actinic d e r m a t i t i ~ .Murphy
~~ et aP3
levels and required all subjects to be hospital- conducted a double-blind, placebo-controlled
ized during initiation of the therapy. The trial in 28 polymorphous light eruption pa-
overall relapse rate was reported to be 35%. tients. Solar UV radiation exposure was mea-
sured by film label badges. Patients who re-
ceived 400 mg of HCQ daily for 1 month
Sarcoidosis followed by 200 mg of HCQ daily thereafter
had substantial clearing of their eruption.
Antimalarial treatment of cutaneous sar- Similarly, solar urticaria may respond to anti-
coidosis was reported first by Shaffer in 1953. malarials. Woodburne et allo9and Sams et als3
In reviewing more than 200 patients from have shown that QE and CQ result in in-
controlled trials published 1961 to 1996, Wal- creased sunlight tolerance with improvement
lace101noted regression in 70% to 100% of in symptoms such as ”itching and burning.”
cutaneous sarcoid lesions treated with anti-
malarials. Since 1960, there have been only
two studies of HCQ treatment for sarcoid. Psoriasis
Brodthagen and Gilg6 reported a poor re-
sponse to HCQ sulfate in 15 patients with The CQs have been associated with cutane-
cutaneous manifestations. Jones and Callen48 ous psoriatic flares. In vitro studies by Wolf
noted improvement in sarcoidal skin lesions et allo8showed enhanced and irregular kerati-
in 12 of 17 patients treated with 2 to 3 mg/ nization of skin explants cultured with HCQ.
kg/d of HCQ, with the earliest onset of action These investigators speculated that the HCQ
at 4 weeks and maximal improvement by 3 inhibition of transglutaminase compromises
months of therapy. After reviewing published the epidermal barrier function, resulting in
reports, Zic et all1’ concluded that antimalari- the epidermal hyperplasia associated with
als are valuable in treating cutaneous sarcoid- psoriatic flares. Abel et all quoted a 1969
osis and effective in reducing serum calcium study in Vietnam, where 41.7% of subjects
levels associated with systemic sarcoidosis treated with prophylactic doses had a flare in
but are suppressive rather than curative and their cutaneous psoriasis.
154 VAN BEEK & PIETTE

Rheumatologists have used the CQs in drug cessation at the first detection of preg-
combination therapy for psoriatic arthritis. nancy.
Gladman et a139evaluated 32 psoriatic arthri- Khamashta et a151reviewed the British ex-
tis patients on 250 mg daily CQ. Despite a perience of lupus patients treated with anti-
significant reduction in the number of ac- malarials during pregnancy. Despite pro-
tively inflamed joints, there was no significant longed fetal exposure to antimalarials (28.4 ?
difference in the number of cutaneous psori- 10.8 weeks), no difference was noted in fetal
atic flares between the control and treatment death, intrauterine growth rate, fetal distress,
groups. Katugampola and K a t u g a m p ~ l aob-
~~ or infant visual impairment compared with
served 50 psoriatic patients taking CQ for controls. Lupus flares (associated with cessa-
prophylaxis or for active malarial fever; 88% tion of antimalarial therapy) are associated
reported no change in psoriatic disease pat- with prematurity, fetal growth retardation,
tern with CQ therapy. and pregnancy loss. Khamashta et a151advo-
cate antimalarial therapy throughout preg-
nancy and breast-feeding. In a similar review
Pediatric Dermatoses of the North American experience, there are
additional reports of patients treated with an-
Although documented in reports of small timalarials throughout pregnancy who subse-
patient numbers, HCQ and CQ have been quently deliver full-term, healthy infants.@
used with success in treating dermatomyo-
sitis, lupus p r o f ~ n d u s ,pseudopelade
~~ of
Brocq; morphea,lloporphyria cutanea tarda,ls ADVERSE REACTIONS
and Weber-Christian panniculitisE8in pediat-
ric patients. The published data of antimalar- Generalized and Gastrointestinal
ial use in children emphasize nausea and Reactions
vomiting as the most common side effects.
Although fatal toxicity resulting in depressed Ten percent of patients receiving HCQ and
cardiac excitability and conductivity and oph- 20% receiving given CQ complain of an-
thalomologic toxicity has been reported, it is orexia, abdominal distention and cramps,
generally agreed that on a milligram-per-kilo- heartburn, nausea, vomiting, diarrhea, and
gram basis, the safety profile of antimalarials weight loss (see Table 2).99Such symptoms
is equivalent in adults and children.l12 are transient and improve or disappear with
decreasing dosages. QE may cause these
symptoms in 30% of patients, with diarrhea
as the most commonly reported complaint.
Other Dermatologic Conditions Low-dose bismuth suspensions can alleviate
this symptom.
Scattered reports and several studies advo-
cate the efficacy of 4-aminoquinolines in the
treatment of atopic dermatitis,s7 lichen pla- Musculoskeletal Symptoms and
nus,26and granuloma a n n ~ l a r e . ~ Myopathy

Initially, CQs can cause musculoskeletal

Pregnancy flulike symptoms, such as aching and fatigue.
These symptoms typically resolve in 1 to 2
It is well known that 4-aminoquinolines weeks despite continuation of therapy.53CQ
readily cross the placenta and accumulate in neuromyopathy (consisting of muscle weak-
melanin-rich fetal tissues and ocular struc- ness, numbness, tingling, and occasional my-
t u r e ~ The
. ~ ~literature has suggested discon- asthenic symptoms) has been reported in ap-
tinuing antimalarial therapy during preg- proximately 12 patients receiving CQ. A
nancy when treating dermatologic and myasthenia gravis-like picture with ptosis
rheumatologic diseases. Because of the ex- has been reported with resolution on drug
tended half-life and the extensive accumula- discontinuation. Muscle enzyme levels are el-
tion and concentration in tissues, however, evated only occasionally, and electromyogra-
these medications are detectable in plasma phy may reveal a variety of abnormalities.
and urine long after cessation. The fetus often Wang et allo5described 2 of 156 SLE pa-
is exposed to significant plasma levels despite tients who experienced proximal myopathy
 ANTIMALARIALS 155

with positive electromyography while on in 2000 soldiers taking 100 mg daily devel-
HCQ. One patient had a muscle biopsy show- oping a lichenoid dermatitis compared with
ing vacuolar changes consistent with antima- 1 in 500 soldiers taking 200 mg daily. Anhi-
larial myopathy. Both patients regained clini- drosis, cutaneous atrophy, alopecia, and vari-
cally normal muscle strength within 2 to 3 ous nail changes often were associated with
months after discontinuation of HCQ. Aver- the eruption. Oral lichenoid lesions were
age daily doses for both patients were 4.8 manifested by mucosal erosions or leukopla-
mg/kg and 6.90 mg/kg. kia of the tongue. Although most such erup-
tions were transient, resolving within months
of drug cessation, squamous cell carcinomas
Cutaneous and Pigmentary Changes were documented at the sites of persistent
lichenoid lesions. In these patients, however,
Electrostatic forces generate the heightened the medications were continued for months
affinity of the CQs for melanin.95The at- to years after the onset of the eruption.
traction of positively charged drug molecules
to negatively charged drug molecules to neg-
atively charged melanin polymers may result Central Nervous System
in the blue-black discoloration of the skin,
hair, or nail beds. Consequently, 10% to 25% QE and, to a much lesser extent, CQ are
of patients receiving long-term therapy with cerebral cortical stimulants and may amelio-
CQ or HCQ develop blue-gray pigmentation rate symptoms of fatigue and mental cloud-
of the face, hard palate, neck, lower extremit- ingZ7Excessive dosing can result in psycho-
ies, or forearms.89The roots of scalp hair, eye- sis, seizures, and hyperexcitability, however.
lashes, or eyebrows may turn white to gray A low incidence (0.4%) of reversible toxic psy-
in color with subsequent streaking during chosis was reported among 7604 American
prolonged courses. This effect is less common soldiers taking 100 mg of QE daily during
with lower doses of these medications, how- World War II?9 Ward et allo6reported a case
ever. Nail beds may develop transverse bands of toxic psychosis in a discoid lupus erythe-
or become diffusely pigmented. Skin pigmen- matosus (DLE) patient treated with an acci-
tation may darken with UV exposure or with dental overdose of HCQ (800 mg daily for 10
prolonged treatment regimens. On skin bi- days). Evans et alZ9summarized the reported
opsy, melanin granules and hemosiderin de- cases of CQ and QE psychosis in the litera-
posits are seen within the dermis. Although ture. Most cases began within days to weeks
it often takes several months, such pigmenta- after initiation of therapy. All reports noted
tion typically resolves after drug cessation.95 transient episodes; no correlation could be
QE binds to melanin, producing asymp- made with cumulative dosage.
tomatic black-and-blue discoloration on the
shins, nailbeds, and hard palate.94QE can in-
duce a dose-related diffuse yellow stain, Hematologic Toxicity
which typically resolves with cessation of
therapy. Such yellowing can affect the sclerae CQ has been implicated in glucosed-phos-
and bodily secretions, mimicking jaundice. phatase deficiency hemolysis and agranulocy-
Both types of discoloration consist of mem- tosi~.~O~Toxic granulation has been observed
brane-bound intracellular granules of QE that in the leukocytes of patients on long-term CQ
contain large amounts of iron and sulfur.61,94 therapy. This granulation likely represents the
Approximately 3% of patients have to dis- large membrane-bound (CQ-driven) myelin
continue antimalarials secondary to various bodies in the mature neutrophils and lym-
cutaneous reactions. Although pruritus is the phocyte~.~* Only one case of agranulocytosis
most commonly reported cutaneous symp- has been reported with HCQ.77This case was
tom, exfoliative dermatitis, alopecia, photo- in a patient given 1200 mg daily-3 to 6 times
sensitivity, erythroderma, and lichenoid erup- the current recommended dose. Almost all
tions have been d o c ~ m e n t e d Perhaps
.~~ the antimalarials are capable of inducing a severe
most well-recognized cutaneous reaction is le~kopenia.~~
the lichenoid drug eruption ascribed to QE. Aplastic anemia among American soldiers
Of the drug eruptions attributed to QE during during World War I1 increased from 0.66 to
World War 11, 20% were lichenoid.z Such 2.84 per 100,000 after the introduction of QE.2
eruptions appeared to be dose related, with 1 Of the 58 patients reported to have had aplas-
156 VAN BEEK & PIETTE

tic anemia during World War 11, 48 received ferent visual-field Reports of such
QE. Sixteen of these subjects received higher maculopathy manifested by progressive vi-
than recommended dosages, and two re- sion loss originated in the late 1950s. Multiple
ceived concomitant marrow-suppressant subsequent reports of such vision loss in the
drugs. Twenty-five subjects with QE-associ- 1960s and 1970s may reflect the high standard
ated aplastic anemia had a preceding lichen dosages at the time.
planus and lichenoid drug eruption. Such Easterbrook's studies as suggest that reti-
eruptions are thought to be reversible with nopathy does not progress in patients with
cessation of therapy. asymptomatic, normal vision and shallow,
paracentral scotomas if the drug is discon-
tinued. Two thirds of patients with symptoms
Ocular Toxicity (<20/20 vision, abnormal color vision, or
positive fundus changes), however, continue
As a melanotropic compound, CQ has af- to lose central or other field vision after the
finity for the retinal pigment epithelium and drug is discontinued.
may be stored in the retina for years after Although most documented cases of reti-
drug cessation. Reversible deposition of CQ nopathy have been in patients treated with
salts in the cornea is common; however, the long-term, high-dose regimens, much debate
most devastating ocular effect is irreversible has centered on daily dosage versus cumula-
retinopathy characterized by a "bull's-eye" tive dosage as a marker for increased retinal
maculopathy with paracentral or central vi- toxicity risk. Historically, toxic doses have
sual-field scotomata. been based on cumulative measurements. In
Initially, CQ therapy may result in ocular an effort to find a safe maximum, cumulative
symptoms independent of retinal toxicity. For dosage, Mackenzie60followed more than 900
example, patients may complain of blurring rheumatoid arthritis patients for an average
of vision or diplopia during initial therapy. of 7 years documenting eye examinations, se-
Such symptoms are secondary to the depres- rum drug levels, and cumulative and daily
sant effect on the ocular muscles and improve dosage regimens. Mackenzie60 identified 84
with time or a decrease in dosage. subjects who had consumed greater than 1.0
Corneal deposition of the CQs typically is kg of CQ or HCQ and had not developed
an asymptomatic effect of therapy. Easter- retinopathy. The mean daily dosage for these
brook23estimates that 90% of patients on 250 patients was 3.65 mg/kg/d of CQ and 6.49
mg daily of CQ develop corneal deposits mg/kg/d of HCQ. Patients who developed
(1 -t keratopathy), whereas almost none of retinopathy received an average daily dose of
the patients on 400 mg daily of HCQ express 5.11 mg/kg/d of CQ and 7.77 mg/kg/d of
such changes unless overdosed. Symptoms HCQ. After calculating toxic-to-therapeutic
of corneal deposition include blurred vision, ratios, Mackenzie'jO recommended a safe dos-
colored halos around lights (particularly at age zone of less than 4.0 mg/kg/d of CQ and
night), and photophobia. These deposits are less than 6.5 mg/kg/d of HCQ in preventing
dose-related, are reversible, and are not a con- associated retinopathy. Mackenzie60 also
traindication to continued therapy because noted that daily doses much higher than
deposits typically appear within 4 to 6 weeks those recommended resulted in more rapid
of treatment and resolve 6 to 8 weeks after manifestations of retinopathy than doses min-
cessation. imally above the recommended dose.
Retinal toxicity is an absolute contraindica- Johnson and Vine47studied nine patients
tion to ongoing therapy. In its early stages who had received less than 6.5 mg/kg/d of
(premaculopathy), the fine macular pigmen- HCQ with a total cumulative dose in excess
tary stippling and asymptomatic paracentral of 1000 g (1054-3923 g). These patients toler-
scotomata are reversible on discontinuation ated the massive cumulative doses without
of the medication. With progression, the pig- functionally significant retinal toxicity. Levy
mented area in the macula is surrounded by et a154presented the largest retrospective
a zone of depigmentation encircled by an area study of potential HCQ retinal toxicity. None
of pigment, giving a bull's-eye appearance of the 1207 patients treated with HCQ, less
associated with irreversible loss of vision. than 6.5 mg/kg/d, from 1991 through 1993
Clinically, antimalarial retinopathy is de- developed retinal toxicity.
fined as bilateral, reproducible, permanent vi- In support of these findings, retinopathy
sual-field abnormalities confirmed by two dif- rarely is reported at a dose less than 4 mg/
 ANTIMALARIALS 157

kg/d of CQ or 6.5 mg/kg/d of HCQ (based and can screen for shallow relative paracen-
on lean body mass) in patients with normal tral scotomas.
renal f~nction.~, l4 Although formal compari- There are 14 reported cases of ocular toxic-
son studies are lacking, review of the litera- ity reported with HCQ at doses of 6.5 mg/
ture suggests that CQ, 250 mg/d, is more kg/d or less.23These doses appear to be based
oculotoxic than HCQ, 400 mg/d.5,23After fol- on actual versus ideal body weight. Because
lowing 2000 patients treated with either CQ adipose tissue takes up less drug than highly
or HCQ, Ea~terbrook~~, 24 identified 130 pa- cellular, metabolically active tissues, some ad-
tients with antimalarial toxicity. Of these, 126 vocate that dosage should be based on ideal
cases were associated with CQ therapy in body weighPo (see Table 1).
varying dosages based on actual body Ea~terbrook~~ recommends an initial eye ex-
weight. Of these were on 3 to 4 amination within the first year of treatment
mg/kg/d, whereas 5 patients were on less because there have been no reports of macu-
than 3 mg/kg/d. Only four patients with an- lopathy in those taking the recommended
timalarial retinopathy were treated with dose for less than 2 years of treatment. Subse-
HCQ. All of these patients were dosed at quently, patients taking less than 6.5 mg/kg
higher than current recommendations (>6.5 (ideal body weight) /d need ophthalmologic
mg/kg/ d). examinations no more than every 12 to 18
In a review of the world literature in 1992, months if they have normal kidney and liver
Bernstein4 noted that no cases of HCQ reti- function. With CQ therapy, there appears to
nopathy had been reported when the dose be a higher risk of ocular toxicity in patients
did not exceed 6.5 mg/kg/d with therapy who are obese or with small body
that did not extend longer than 10 years. Ac- habitus-likely because they are not dosed by
cording to the HCQ package insert (January ideal body weight. These patients should be
2000), the manufacturer (Sanofi Pharmaceuti- seen every 6 months by an ophthalmologist.@
cals, NY, NY) recommends baseline screening One of the major advantages of QE over
and follow-up eye examinations every 3 the CQs is the lack of retinal toxicity. In 1981,
months, including visual acuity, slit-lamp, Zuelhke et a1113 described 26 patients who
received QE over a 30-year period without
funduscopic, and visual-field tests. Conse-
evidence of retinopathy. The irreversible na-
quently, Bernstein4 concluded that screening ture of late retinal toxicity has discouraged
at such intervals was unlikely to be cost-effec- many physicians from prescribing these med-
tive at the recommended dosage when a pa- ications for their patients. The dermatologist
tient has had less than 10 years of therapy. must realize that the reports of retinal toxicity
Because macular degeneration is a common in the 1960s and 1970s likely reflect much
feature of the normal aging process, some higher doses than currently recommended,
argue that it is not always possible to impli- however. With proper dosing and monitoring,
cate antimalarials as the cause of retinal dys- these medications can be beneficial in the
function. Many have questioned the need for treatment of a variety of dermatologic dis-
frequent ocular screening in patients treated eases.
with HCQ.2%54,81,82
S p a l t ~ nsuggested
~~ screening after 3 to 5
years, whereas others advocate ocular exami- References
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Marta J. Van Beek, MD
University of Iowa Hospitals and Clinics
Department of Dermatology, 2-BT
200 Hawkins Drive
Iowa City, IA 52242-1090