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EXTENDED REPORTS
Long term eVectiveness of antimalarial drugs in
rheumatic diseases
J Antonio Aviña-Zubieta, Griselda Galindo-Rodriguez, Stephen Newman,
Maria E Suarez-Almazor, Anthony S Russell
Abstract
Objective—The purpose of this study was
to compare the long term eVectiveness
between chloroquine (CQ) and hydroxy-
chloroquine (HCQ).
Methods—Medical charts of all patients
seen by eight rheumatologists practising
in two tertiary care centres and starting
antimalarial treatment between January
1985 and December 1993 were reviewed.
Patient characteristics, disease, and treat-
ment information were collected. The
main outcome measures were the cause of
and the time to the discontinuation of
antimalarial drugs resulting from all
causes, principally toxicity or ineYcacy,
or both. Bivariate analysis including t
tests and ÷
2
tests were used to assess
diVerences between means and propor-
tions respectively. Survival curves were
evaluated using the Kaplan-Meier
method. Multivariate analysis (Cox re-
gression) was used to adjust for potential
confounders.
Results—After all medical records were
reviewed, 1042 eligible cases were identi-
fied. From these, 940 (90%) had usable
information and they represent the co-
hort. Five hundred and fifty eight had
rheumatoid arthritis, 178 had systemic
lupus erythematosus, 127 had palindro-
mic arthritis, and 77 had other diagnoses.
Fifty seven per cent of the patients
received CQ and 43% HCQ. The propor-
tion of patients with side eVects taking
HCQ and CQ was 15% and 28% respec-
tively (p=0.001). Using Cox regression
model to adjust for age at the onset of
antimalarial treatment, physician diVer-
ences, sex, disease type, disease duration
before treatment, and rank selection,
there were no diVerences in the hazard
ratio (HR) for overall discontinuations
between CQ and HCQ. While the HR for
discontinuations because of toxicity was
lower for HCQ (HR= 0.6, 95% CI 0.4, 0.9),
the HR for discontinuations because of
ineYcacy was significantly higher for
HCQ (HR= 1.4, 95% CI 1.1, 1.9).
Conclusions—After adjusting for time and
several confounders HCQ was less toxic
but less eVective than CQ. Only one case
of probable/possible retinopathy was
found. Therefore, we propose a careful
baseline ophthalmological evaluation by
an expert and then one or every two years
if proper doses are used.
(Ann Rheum Dis 1998;57:582–587)
Antimalarial drugs have become one of the
most commonly prescribed drugs in the treat-
ment of many rheumatic diseases such as rheu-
matoid arthritis (RA), systemic lupus ery-
thematosus (SLE), palindromic arthritis (PA),
and psoriatic arthritis.
1–7
This seems to be
related mainly to their low toxicity in compari-
son with the other antirheumatic agents.
7–10
Chloroquine (CQ) and hydroxychloroquine
(HCQ) are the only 4-aminoquinoline deriva-
tives that are used as antirheumatic drugs,
11
and although structural similarities between
CQ and HCQ exist, it has been suggested that
there are diVerences in eYcacy and in
toxicity.
12–16
In addition, there are considerable
diVerences in costs between these two drugs,
HCQ being seven times more expensive than
CQ, at least in Canada. DiVerences in the pre-
scription patterns for antimalarial drugs among
rheumatologists have been reported.
10 17 18
Long term eVectiveness (eYcacy and toxicity
under non-experimental conditions) should be
considered when selecting one drug over
another. However, most studies reviewing the
long term eVectiveness of antimalarial drugs
considered both drugs as a single group.
6–10
Table 1 Patients characteristics
Variable AM n (%) CQ n (%) HCQ n (%) p Value*
Sex
Female 719 (77) 403 (75) 316 (79) NS
Male 221 (23) 136 (25) 85 (21) NS
Disease duration (y)† mean (SD) 4.1 (6.6) 4.0 (6.5) 4.2 (6.8) NS
Age mean (SD)† 47 (15.5) 45.3 (14.8) 49.2 (16.2) <0.0001
Drug
CQ 541 (58) — —
HCQ 399 (42) — —
Disease
RA 557 (59) 287 (53) 270 (68) <0.0001
SLE 178 (19) 113 (21) 65 (16) NS
PA 128 (14) 91 (17) 37 (9) <0.001
Other 77 (8) 50 (9) 27 (7) NS
Rank
First 676 (72) 400 (74) 276 (69) <0.05
Other 264 (28) 139 (26) 125 (31) <0.05
Combination 174 (19) 85 (16) 89 (22) <0.01
*CQ v HCQ, †at the onset of AM therapy, NS = not significant.
Ann Rheum Dis 1998;57:582–587582
Division of
Rheumatology,
Department of
Medicine, University
of Alberta, Canada
J A Aviña-Zubieta
A S Russell
Health Care Quality
Outcome and
Research Centre,
Faculty of Medicine,
University of Alberta,
Canada
G Galindo-Rodriguez
Department of Public
Health Sciences,
University of Alberta,
Canada
S Newman
M E Suarez-Almazor
Correspondence to:
Dr A Aviña-Zubieta, Clinical
Epidemiology Research Unit,
Hospital de Especialidades
7° Piso, Centro Medico La
Raza, Instituto Mexicano del
Seguro Social, Seris y
Zaachila SN, Mexico, DF
02990, Mexico.
Accepted for publication
26 June 1998
In this study we evaluated the long term
eVectiveness of antimalarial drugs in rheumatic
diseases, also considering potential diVerences
between CQ and HCQ.
Methods
STUDY POPULATION
A cohort of patients with several rheumatic
disorders who received antimalarial treatment
was retrospectively assembled. All eight rheu-
matologists practising in Edmonton between
1985 and 1993 participated in the study
permitting us to review their medical records.
All the records of patients with any rheumatic
disorder who received any antimalarial drug
were further reviewed. Patients were eligible for
the study according to the following criteria:
(a) diagnosis of any rheumatic disorder con-
firmed by a rheumatologist, (b) onset of
antimalarial treatment between January 1985
to December 1993. All medical records were
reviewed by one of us (JAAZ) and the informa-
tion about antimalarial treatment was recorded
on a structured form. Patient characteristics,
disease, and other treatments were also re-
corded. The main outcome measures were the
cause and time of discontinuation. The follow-
ing were considered as causes of discontinua-
tion according to the treating rheumatologist:
(a) ineYcacy, (b) toxicity, (c) other, and (d)
uncertain.
STATISTICAL ANALYSIS
The ÷
2
test with Yates’s corrections were used
to compare diVerences in proportions. Two
tailed Student t tests were used to compare dif-
ferences in means between two groups.
Kaplan-Meier survival analyses were per-
formed to estimate rates of discontinuation for
each drug. Cox regression models were used to
evaluate the eVects of age, sex, disease type,
disease duration, rank selection (the order in
which the diVerent antimalarial drugs were
chosen for treatment), rheumatologist, and
type of antimalarial drug. Hazard ratios (HR)
were estimated for discontinuation of use
because of: (a) all causes, (b) toxicity, and (c)
ineYcacy. Models were built using two meth-
ods: (1) Univariate: each variable was entered
separately to test whether that single variable
was a significant predictor. (2) Multivariate
(best model): this model was an investigator
driven model with the purpose of finding the
variables that explained most of the variability
of the dependent variable. This model was built
in a forward stepwise fashion using the
likelihood ratio test as method for comparison
and selection of the variables as well as the
models. All the analyses were performed using
SPSS for Windows, version 6.1.
Results
After all medical records were reviewed, 1042
eligible cases were identified. From these, 940
(90%) had the minimum required information.
Table 1 shows the patient and clinical charac-
teristics of the study group. RA accounted for
59% of the antimalarial prescriptions, followed
by SLE (19%), PA (14%), and other various
diseases (8%). CQ accounted for 58% of the
antimalarial prescriptions and was the main
antimalarial in all disease groups. Six per cent
of the patients received both antimalarial drugs
at diVerent times, however, only the first
antimalarial drug received was considered in
the analysis.
Overall, antimalarial drugs were the first
choice for second line treatment in 72% of the
patients. Six per cent of the patients received
more than one course of antimalarial treat-
ment. However, for the purposes of this study
only the first cycle was included in the analysis.
DISCONTINUATION OF TREATMENT
At the time of data collection 50% of the
patients were still receiving the drug (table 2).
Fifteen per cent and 19% of the cases
discontinued the drug because of toxicity and
ineYcacy respectively. Other various reasons
accounted for 16% of discontinuations. Toxic-
ity was the main cause of discontinuation for
CQ while ineYcacy was for HCQ.
Survival analysis was conducted using the
Kaplan-Meier product limit method to calcu-
late the proportion of patients still receiving
antimalarial drugs at diVerent points in time.
Survival was calculated for each drug for all
causes of discontinuations, toxicity, and ineY-
cacy (figs 1 to 3). Overall, around 30% of the
patients were still receiving treatment at 120
months with no diVerences between CQ and
HCQ (fig 1). This similarity is seen across all
Table 2 Reason for discontinuation of AM in total (and
by drug)
AMn(%) CQn(%)
HCQ n
(%)
Total receiving therapy 940 541 (58) 399 (42)
Total discontinued 472 (50) 290 (54) 182 (46)
Toxicity 145 (15) 97 (18) 48 (12)
IneYcacy 175 (19) 93 (17) 82 (21)
Other causes 152 (16) 100 (18) 52 (13)
no longer needed 27 (3) 17 (3) 10 (3)
by patient 63 (7) 44 (8) 19 (5)
pregnancy 14 (2) 12 (2) 2 (0.5)
concomitant disease 19 (2) 12 (2) 7 (2)
other 6 (0.6) 2 (0.4) 4 (1)
unknown 23 (2) 13 (2) 10 (3)
Figure 1 Kaplan-Meier curves for any cause of discontinuation of treatment.
1.0
0.8
0.4
0.6
0.2
0.0
806040 100 140
Time (months)
Cumulative survival
200 120
HCQ
CQ
p = 0.57
Antimalarial drugs and rheumatic diseases 583
diVerent points in time. However, when
survival curves were estimated for discontinua-
tions resulting from toxicity alone (all other
causes of discontinuation and no discontinua-
tions were considered as censored) a trend for
more discontinuations in patients who received
CQ than those who received HCQ was seen.
However, this diVerence was not statistically
significant using the log rank test (fig 2). IneY-
cacy discontinuations between CQ and HCQ
were statistically significant (log rank test p=
0.009) (fig 3). Patients who received CQ
discontinued less often as a consequence of
ineYcacy than patients who received HCQ.
This diVerence starts to be noticeable at about
one year and continues until 70 months when a
plateau is reached in both drugs.
Multivariate analysis was used (Cox regres-
sion) to examine the associations of diVerent
variables with the outcome of antimalarial
treatment (for example, overall, toxicity, and
ineYcacy discontinuations). Initially all the
variables were modelled individually (univari-
ate) and results are shown in table 3. Type of
antimalarial drug was a significant predictor
only for discontinuations resulting from ineY-
cacy. Thus HCQ had a higher chance of
discontinuation because of ineYcacy than CQ
(HR= 1.4; 95%CI 1.09, 1.99). A second model
was built (multivariate), this was an investiga-
tor driven model with the purpose of finding
the best predictor variables. For all causes of
discontinuation, disease type and physician
were the best predictor variables (table 4).
Thus, patients with SLE and PA had less
chance of discontinuation than patients with
RA. Type of antimalarial drug was not a
significant predictor in this model. When the
same variables were evaluated to find the best
predictors for discontinuation because of
toxicity, type of antimalarial drug was a statisti-
cally significant predictor. Thus, patients who
received HCQ had less chance of discontinua-
tion resulting from toxicity than patients who
received CQ (HR= 0.62; 95% CI 0.40, 0.96)
(table 4). For discontinuation resulting from
ineYcacy type of antimalarial drug was a
significant predictor among others with pa-
tients receiving HCQ at higher risk for discon-
tinuation (HR = 1.4; 95% CI 1.06, 1.96).
SIDE EFFECTS
Overall, there were 212 (23%) cases who expe-
rienced side eVects. Of these only 146 (69%)
required discontinuation of the drug perma-
nently, 11 (5%) discontinued the drug tempo-
rarily, 12 (6%) required only a decrease in
dose, 27 (13%) switched to the other antima-
larial drug, and 45 (21%) did not require any
action. Fifty nine (15%) of those who received
HCQ had side eVects in comparison with 153
(28%) of those with CQ (p<0.00001): of these,
48 (81%) and 97 (64%) respectively discontin-
Figure 2 Kaplan-Meier curves for discontinuation of treament because of toxicity.
1.0
0.8
0.4
0.6
0.2
0.0
806040 100 140
Time (months)
Cumulative survival
200 120
HCQ
CQ
p = 0.18
Figure 3 Kaplan-Meier curves for discontinuation of treatment because of ineYcacy.
1.0
0.8
0.4
0.6
0.2
806040 100 140
Time (months)
Cumulative survival
200 120
HCQ
CQ
p = 0.009
Table 3 Cox regression for discontinuation of treatment (univariate)
Predictor (reference
category)
All causes Toxicity IneYcacy
HR 95% CI p Value HR 95% CI p Value HR 95% CI p Value
Type of AM (CQ) 1.05 0.9, 1.3 NS 0.8 0.5, 1.1 NS 1.4 1.09, 1.9 0.01
Sex (male) NS NS 0.7 0.5, 0.9 0.02
Age (<46) 1.009 1.002, 1.01 0.005 1.9 1.4, 2.7 0.0001 NS
Disease duration (<2 y) NS NS 1.3 1.02, 1.9 NS
Physician (Rh 1) NS NS NS
Disease (RA) NS NS — — 0.0001
SLE 0.3 0.1, 0.4 0.0001
PA 0.6 0.4, 1.0 0.05
Other 0.7 0.4, 1.2 NS
Rank (first) 1.1 1.0, 1.2 0.002 0.6 0.4, 0.9 0.0003 0.6 0.4, 0.8 0.0001
HR = hazard ratio.
584 Aviña-Zubieta, Galindo-Rodriguez, Newman, et al
ued the drug permanently (p<0.01). Further-
more, there were significant diVerences in the
type of side eVects (table 5), all of them in
favour of HCQ. Certain rare side eVects such
as hair bleaching (two cases), nightmares (four
cases), and neuromyopathy (six cases) oc-
curred only in patients with CQ. With respect
to retinal toxicity three possible cases were
identified (two with CQ and one with HCQ)
and that was the reason of discontinuation.
However, when these patients were re-
evaluated by a retinologist with experience in
senile and antimalarial maculopathy, only one
case could be retained as retinal changes
“probably” related to CQ . These changes dis-
appeared after CQ was discontinued.
Discussion
Although CQ and HCQ have been used for the
treatment of rheumatic diseases for more than
40 years, they have been considered as a single
drug in the few studies that have evaluated long
term eVectiveness.
7–10
Therefore, to our knowl-
edge this report is the first comparing the long
term eVectiveness of CQ and HCQ.
In general, the characteristics of this cohort
are similar to those reported elsewhere for
patients receiving antimalarial treatment.
1 5 7–10 19
The female-male ratio was 3 to 1 (table 1) in
accordance with the demographic distribution
of rheumatic diseases. More discontinuations
because of toxicity were seen in patients receiv-
ing CQ (table 2). This trend was also seen in
the Kaplan-Meier curves although with this
type of analysis it did not reach a statistically
significant diVerence (fig 2). Furthermore, in
the multivariate analysis the HR for discon-
tinuation because of toxicity was lower for
HCQ (HR= 0.62; 95% CI 0.40, 0.96). In other
words, after adjusting for time and several con-
founders patients taking CQ were 40% more
likely to discontinue because of toxicity than
patients who received HCQ. On the other
hand—again after adjustment for time and
confounders—patients taking HCQ had a 40%
larger chance of discontinuing the drug be-
cause of ineYcacy.
Five per cent of the patients had more than
one cycle of antimalarial treatment and we
decided to analyse only the first cycle to
simplify the analysis. Thus, we were interested
in the outcome of the antimalarial drug
received for the first time. Moreover, including
several outcomes in the same patient receiving
the same drug at diVerent times may produce
bias, as patients could discontinue the drug
early or later based on their previous experi-
ence with the drug. In addition, for those
patients who received both drugs only the first
antimalarial drug was included in the analysis.
This was to avoid bias because the second anti-
malarial drug would depend on which was the
first antimalarial drug. Furthermore, toxicity
would be the only reason to choose another
drug as discontinuation because of ineYcacy
would hardly be associated with a second
attempt with the other antimalarial drug.
A limiting factor of this study was that we did
not have baseline characteristics of disease to
adjust for. However, there is no evidence to
suggest that disease severity influenced the
rheumatologist to prescribe one of the antima-
larial drugs in preference to the other. This is
more related to patterns of practice, which we
had previously reported for the rheumatolo-
gists who participated in the study.
17 18
We did
not evaluate factors associated with patterns of
prescriptions for the two antimalarial drugs.
However, all but two rheumatologists have
been using the same antimalarial drug while
practising. In addition, we observed differences
in the rates as well the causes of discontinua-
tion among rheumatologists, and we adjusted
for these diVerences in the multivariate analy-
sis. Concomitant use of corticosteroids was not
registered in the study and this could have
contributed to the eVectiveness. If this were the
case then the eVect of this would probably not
be important because the use of corticosteroids
by the specific rheumatologists participating in
the study has already been reported to be low
10
Table 4 Cox regression for discontinuation of treatment (multivariate)
Predictor (reference
category)
All causes Toxicity IneYcacy
HR 95% CI p Value HR 95% CI p Value HR 95% CI p Value
Type of AM (CQ) NS 0.6 0.4, 0.9 0.03 1.4 1.06, 1.9 0.01
Sex (male) NS NS 0.7 0.5, 0.9 0.03
Age (<46) NS 1.8 1.3, 2.6 0.0001 NS
Disease duration (<2 y) NS NS NS
Physician (Rh 1) — — 0.01 NS NS
Disease (RA) — — 0.02 NS — — 0.0001
SLE 0.6 0.4, 0.8 0.001 0.3 0.1, 0.4 0.0001
PA 0.7 0.6, 0.9 0.04 0.7 0.4, 1.1 NS
Other 0.7 0.6, 1.1 NS 0.7 0.4, 1.2 NS
Rank (first) NS 0.7 0.5, 1.0 0.05 0.6 0.4, 0.8 0.0001
HR = hazard ratio.
Table 5 Side eVects between AM
Side eVect AM n (%) CQ n (%) HCQ n (%) p Value
Total number of patients 940 541 399
Mucocutaneous 33 (3.5) 25 (4.6) 8 (2) NS
Rash 31 (2.4) 23 (4.3) 8 (2) <0.05
Hair bleaching 2 (0.2) 2 (0.4) 0 (0) NS
Ocular 70 (7.4) 63 (11.7) 9 (2.2) <0.0001
Corneal deposits 41 (4.4) 38 (7) 3 (0.8) <0.00001
Blurred vision 26 (2.8) 21 (3.9) 5 (1.3) <0.01
Retinal changes* 3 (0.3) 2 (0.3) 1 (0.2) NS
Gastrointestinal 67 (7.1) 34 (6.3) 33 (8.2) NS
Nausea/vomiting 46 (4.9) 26 (4.8) 20 (5) NS
Diarrhoea 14 (1.5) 5 (0.9) 9 (2.3) NS
Abdominal pain 7 (0.7) 3 (0.6) 4 (1) NS
Neuromuscular 19 (2) 17 (3.2) 2 (0.5) NS
Headache 9 (1) 7 (1.3) 2 (0.5) NS
Nightmares 4 (0.4) 4 (0.7) 0 (0.0) NS
Myopathy 6 (0.6) 6 (1.1) 0 (0) 0<0.03
Unknown 23 (2.4) 16 (2.9) 7 (1.7) NS
Total 212 (22.6) 153 (28.4) 59 (14.7) <0.00001
*Only one patient was confirmed to have a true retinopathy (see text).
Antimalarial drugs and rheumatic diseases 585
(at least in RA, which was the main disease
group).
Overall, the prevalence of side eVects was
higher in patients who received CQ. Of
interest, rare side eVects like retinopathy or
pre-maculopathy (one possible case), hair
bleaching (two cases), and neuromyopathy (six
cases) occurred only in patients treated with
CQ, which confirm previous reports that clini-
cally significant side eVects are more likely to
occur with CQ.
15 21
Three patients were re-
ported to have retinal changes that were
suggestive of retinopathy (two had RA and one
had SLE). All of them received the antimalar-
ial drug at conventional doses (250 mg/day for
CQ and 400 mg/day for HCQ). However,
when they were sent to a retinologist with
experience in retinopathy resulting from anti-
malarial treatment, only one case was defined
as retinal changes possibly/probably related to
CQ. This patient had SLE and had received
CQ for 59 months at a dose of 4.5 mg/kg/day
with a cumulative dose of 447.4 g. The patient
was followed up and retinal changes disap-
peared. Nineteen months after CQ was discon-
tinued she received HCQ, with no recurrence
of the retinal changes at her most recent
ophthalmological evaluation. Our results con-
firm previous and recent findings (particularly
focused on HCQ 25–27) that retinopathy is a
very rare complication when conventional
doses are used, and that daily dose based on
ideal body weight (<4 mg/kg/day for CQ and
<6 mg/kg/day) may be more important than
cumulative doses in the development of this
major complication.
15 22–29
Furthermore, there
have been other patients within and outside
this study where a confident diagnosis of anti-
malarial retinopathy made by a local ophthal-
mologist was not supported when this patient
was reviewed by an expert. Monitoring ocular
toxicity twice a year or three times a year as
recommended by manufacturers seems exces-
sive and may not be cost eVective as recently
reviewed by MacLean et al for HCQ.
30
Hence,
we suggest that patients who receive antimalar-
ial treatment should have a careful “baseline”
ophthalmological evaluation by an expert (that
is, within the first few months of use) and then
every one or two years. The physician responsi-
ble for the ongoing patient’s care could
monitor ocular toxicity using less expensive
and less time consuming methods such as
Amsler’s grid on each patient visit.
In summary, in this study crude rates of dis-
continuations were diVerent for each drug. The
main cause of discontinuation for antimalarial
treatment in general and for HCQ was
ineYcacy with 19% and 21% respectively. In
contrast, the main cause of discontinuation for
CQ was toxicity (18%). The multivariate
analysis showed that HR for discontinuations
because of toxicity are lower for
HCQ(HR=0.62,95%CI0.60, 0.96), and HR
for discontinuations because of ineYcacy are
higher for HCQ (HR=1.4, 95% CI 1.06,
1.96). No significant diVerences were observed
between CQ and HCQ in terms of HR for
overall discontinuations. Therefore, if we use
rates of discontinuation as a measure of
eVectiveness the long term eVectiveness be-
tween CQ and HCQis similar. Nevertheless
given the apparent diVerences in eYcacy and
toxicity between the two drugs (as well as eco-
nomic diVerences) potential trade oVs between
increased eYcacy and increased toxicity, and
vice versa, should be carefully considered by
the patient and physician when selecting
antimalarial treatment. Ocular and neuromus-
cular side eVects occurred more often in
patients who received CQ. No cases of definite
retinopathy were found. Monitoring each six
months for ocular toxicity seems to be
excessive if conventional doses are used.
The authors wish to thank the rheumatologists in Edmonton.
This study would not have been possible without the
cooperation of Dr Stephen Aaron, Dr Paul Davis, Dr Avril Fit-
zgerald, Dr Sharon LeClercq, Dr Walter P Maksymowych, Dr
John Percy, and Dr Keneth Skeith.
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