in Arthritis by drdoc on-line
therapy is considered a mild disease modifying therapy in the management
of inflammatory arthritis, in particular for Rheumatoid arthritis. The
drug is available in several forms.
Chloroquine sulphate -
Nivaquine / plasmoquine
Chloroquine phosphate - Chloroquine
Hydroxychloroquine - Plaquenil
The decision regarding
usage is based on need for treatment of the actual immune process rather
than treatment of symptoms of pain. The response is seen only at 6 weeks
- 2 months, but response may take as long as 6 months to start. The drug
may be used alone or in combination with other disease modifying drugs -
in particular methotrexate. Interesting combination with methotrexate
seems to reduce side effects of the methotrexate. There are other
diseases where antimalarials have been used with variable results.
The most common
indication other than Rheumatoid arthritis, is for Systemic Lupus
Erythematosus, where there is especially a response in skin and joint
Use in Psoriasis is controversial
as most dermatologists have concerns relating to aggravation of the skin
disease. However recent publication suggests that the skin is
statistically not worse in patients taking antimalarials with benefit.
Some early work is in
progress in therapy of osteoarthritis, especially in subtypes with
inflammatory component, including erosive osteoarthritis, and those
patients with early, aggressive onset and progression, as well as those
with a bad family history. No good publications exist regarding
efficacy, but anecdotal responses are reported, and many rheumatologists
are utilizing this in such patients and in trials.
The drug is felt to be
safe with a range of low grade toxicity including:
Sun / photo sensitivity
with tendency to burn in the sunlight more easily
Increased pigmentation is possible, including facial, over the arms,
forearms and shins.
Allergic rashes are also possible and may lead to requirement to stop
Nausea - aggravated by its bitter taste.
Buzzing ears (tinnitis) and complaints of hearing difficulty - dose
dependant and reversible
Visual impairment due to retinal toxicity is described rarely. This is
dose dependent and is only very rarely seen at currently recommended
doses. A deposit of chloroquine in the cornea may be noted. This may be
a suggestion that a dose adjustment may be required, but does NOT
represent retinal toxicity. The onset of fundal (the back of the
eyeball), change however, is suggestive of toxicity, with a reduction in
the visual fields and changes on the back of the eye may be seen, with a
"bulls eye" appearance of the macula of the retina.
The change is only very
rarely irreversible, especially if the dose is high and the problem is
missed. It is for this reason that the eyes should be checked yearly by
an ophthalmologist. Some people feel that this is not required, but it
is my personal practice to support yearly eye checks, with particular
focus on doing peripheral field testing including red light field
Recommended maximal doses depend
on the type of antimalarial
Chloroquine - 4mg/kg
Hydroxychloroquine - 6mg / kg
I ensure 12 monthly ophthalmologic
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Database Syst Rev 2000;(4)
Antimalarials for treating rheumatoid arthritis. Suarez-Almazor ME,
Belseck E, Shea B, Homik J, Wells G, Tugwell P. Health
Services Research, Veterans Affairs Medical Center, Mailbox Station 152,
2002 Holcombe Blvd, Houston,
Texas 77024, USA.
OBJECTIVES: To assess the short-term efficacy and toxicity of
treatment of rheumatoid arthritis (RA).
SEARCH STRATEGY: We searched the
Musculoskeletal Group's trials register, the Cochrane Controlled Trials
Medline and Embase up to and including August 2000. We also carried
a handsearch of the reference lists of the trials retrieved from the
search. SELECTION CRITERIA: All randomized controlled trials (RCTs)
controlled clinical trials (CCTs) comparing antimalarials against
with RA DATA COLLECTION AND ANALYSIS: Data abstraction was carried out
by two reviewers. The same two reviewers using a validated
(Jadad 1996) assessed the methodological quality of the RCTs and CCTs.
arthritis outcome measures were extracted from the publications for
6-month endpoint. The pooled analysis was performed using standardized
for joint counts, pain and global assessments. Weighted mean
were used for erythrocyte sedimentation rate (ESR). Toxicity was
with pooled odds ratios for withdrawals. A chi-square test was used to
heterogeneity among trials. Fixed effects models were used throughout.
MAIN RESULTS: We found four trials, with 300 patients randomized to
and 292 to placebo. Only trials evaluating hydroxychloroquine
be pooled in the analysis. A statistically significant benefit was
when hydroxychloroquine was compared to placebo. The standardized mean
for the various outcome measures ranged from -0.33 to -0.52, and
statistically significant. Statistically significant differences were
for ESR. Overall withdrawals and withdrawals due to lack of efficacy
significantly more frequent in the placebo group. No differences were
in withdrawals due to toxicity.
appears to be efficacious for the treatment of RA. Its
effect appears to be moderate, but its low toxicity profile should be
when treating patients with RA.
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Consequences of delayed therapy with second-line agents in rheumatoid
arthritis: a 3 year
followup on the hydroxychloroquine in early rheumatoid arthritis (HERA)
Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC,
M'Seffar A, Joseph L,
Bombardier C, Esdaile JM.
Department of Medicine, McGill University, Montreal, Quebec, Canada.
OBJECTIVE: To assess the longterm effect of delaying therapy with
in patients with early rheumatoid arthritis (RA). METHODS: One hundred
patients who participated in a 9 month placebo controlled randomized
of hydroxychloroquine sulfate (HCQ) were followed prospectively for an
3 years. Those randomized to HCQ are referred to as the early
group and those randomized to placebo as the delayed treatment group.
were assessed annually for pain [Arthritis Impact Measurement
(AIMS) and Stanford Health Assessment Questionnaire (HAQ)], physical
(AIMS and HAQ), and the RA global well being scale (AIMS). Conversion
results into standard deviation (SD) units permitted defining a
as per Felson as > 0.30 SD units and a clinically indistinguishable
as < or = 0.06 SD units.
RESULTS: One hundred fifteen patients (97%)
and complete data were available on 104 (87%). Compared to the
treatment group, the delayed group remained worse for both the pain and
physical disability outcomes over the additional 3 year followup. The
in the RA global well being score became clinically indistinguishable
the early and delayed groups only after the 2 year post-trial
between-group differences were not explained by post-trial therapy with
other second-line agents, or nonsteroidal antiinflammatory
and analgesic preparations.
CONCLUSION: These findings show that a delay
instituting therapy with second-line agents, even a 9 month delay in
a moderately powerful second-line agent such as HCQ, has significant
on longterm patient outcome, and provides strong evidence in support of
therapy in RA.
Med J 2001 May;24(5):329-34
Progression of hydroxychloroquine retinopathy after discontinuation of
therapy: case report.
Wei LC, Chen SN, Ho CL, Kuo YH, Ho JD. Department of Ophthalmology,
Chang Gung Memorial Hospital, Taipei, Taiwan, R.O.C.
Chloroquine and its derivative, hydroxychloroquine sulfate, have been
used in treating malaria, dermatitides of systemic lupus erythematosus
and rheumatoid arthritis. Hydroxychloroquine retinopathy is uncommon in
Taiwan. Here we report a patient with hydroxychloroquine retinopathy
which progressed even after discontinuation of hydroxychloroquine. A
42-year-old woman had systemic lupus erythematosus for twenty years. She
had been treated with 200 to 400 mg of hydroxychloroquine per day (4 to
8 mg/kg of body weight/day) with a cumulative dose of 657 g. After
bull's-eye maculopathy was found, hydroxychloroquine was discontinued.
Her medical history revealed no chloroquine administration and no other
systemic disease. Five years after cessation of the therapy, her visual
acuity and visual fields continued to deteriorate. Ophthalmoscopic
examination revealed the hydroxychloroquine retinopathy had advanced. To
the best of our knowledge, the progression of hydroxychloroquine
retinopathy after discontinuation of medications is a rare phenomenon.
Regular ophthalmologic examinations should be performed for patients on
hydroxychloroquine regimens because there is no satisfactory treatment
for hydroxychloroquine retinal toxicity. Ophthalmologists,
dermatologists and rheumatologists should monitor for ocular toxicity of
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Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis.
report a case of reversible sensorineural hearing loss due to
(HQ) treatment. The patient was a 34-year-old woman with 1
of rheumatoid arthritis (RA). She developed reversible hearing loss
of HQ treatment. Sensorineural deafness has previously been reported
treatment, but this is the first report of ototoxicity associated
HQ in RA.
Seckin U, Ozoran K, Ikinciogullari A, Borman P, Bostan EE.
Department of Physical Medicine and Rehabilitation, Ankara Numune
Education and Research
Hospital, Turkey. firstname.lastname@example.org
toxicity in long term hydroxychloroquine treatment.
Annals of the Rheumatic Diseases. 55(3):187-9, 1996 Mar.
To report clinical experience from patients with rheumatoid arthritis
(RA) and systemic lupus erythematosus (SLE) who were receiving
recommended doses of hydroxychloroquine for more than six years, and
were monitored for evidence of hydroxychloroquine related retinopathy
every six months. METHODS: A prospective (and continuing) evaluation was
made of the potential retinal toxicity of hydroxychloroquine in a cohort
of 360 Greek patients followed for RA and SLE, 58 of whom have received
long term treatment ( > six years). Fundoscopy, colour vision tests,
dark adaptation tests, visual field testing, automated perimetry, and
electroretinogram were performed every six months.
RESULTS: Among 58 patients receiving hydroxychloroquine for more than
six years, two relatively young women (3.5%), one treated for RA and the
other treated for SLE, developed characteristic hydroxychloroquine
related toxic retinal lesions after cumulative doses of 700 g (6.5
years) and 730 g (8 years) of hydroxychloroquine, respectively.
Bilateral visual acuity was 6/6 and 6/7.5, respectively; both patients
had normal colour perception. Despite an early diagnosis and cessation
of treatment, permanent visual field paracentral scotomata in both
patients, and persisting lesions in fluorescein angiography in the
patient with SLE, were observed at 4.5 and 3 years of follow up,
respectively. No other specific cases of hydroxychloroquine related
retinopathy have to date been identified in the remaining 302
CONCLUSION: Cases of irreversible, hydroxychloroquine related
retinopathy in patients who did not receive overdoses have not been
reported previously. The present observations in two relatively young
patients should raise our concern regarding the long term usage of an
increasingly popular medication in rheumatology practice
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retinopathy: is screening necessary?
Blyth C, Lane C.
BMJ 1998;316:717-8. (7 March.)
Intensive screening is not necessary at normal doses
The 4-aminoquinolines (chloroquine and hydroxychloroquine) are used as
second line agents for their disease modifying effect in rheumatoid
arthritis and systemic lupus erythematosus. The association between
chloroquine therapy and pigmentary maculopathy has been known since
1959.1 The manufacturer's datasheet suggests that all patients receiving
hydroxychloroquine should undergo an ophthalmic examination, including a
central visual field test, at least twice a year. If implemented this
recommendation would have a noticeable impact on the ophthalmic service.
Is it necessary?The earliest sign of chloroquine retinopathy is a
paracentral scotoma. This so called premaculopathy can be detected with
an Amsler chart.2 Later, subtle pigmentary mottling develops at the
macula, and this may progress to the characteristic bull's eye
maculopathy and widespread retinal pigment epithelial atrophy. In its
early stages chloroquine retinopathy is reversible by stopping the
drug.3 Hydroxychloroquine given at currently prescribed doses is thought
to be less toxic than chloroquine.
The recommended dose for hydroxychloroquine is 6.5 mg/kg lean body
weight per day.4 In their prospective study of 73 patients treated
with hydroxychloroquine for at least 18 months, Morsman et al
reported one case of possible toxic retinopathy and this patient had
received twice the recommended daily dose.5 In a retrospective study of
82 patients taking hydroxychloroquine for over a year (mean
38.6 months) Spalton et al found no cases of retinopathy.6 No
correlation was present between the computerised visual field indices
and any measure of increasing drug exposure. The authors concluded that
visual field testing was unnecessary in these patients.6 Bernstein
analysed all published cases and Food and Drug Administration reports of
hydroxychloroquine retinopathy. He found no evidence of permanent visual
loss among more than 1500 patients who did not exceed the
recommended daily dosage for up to 10 years.7 More recently,
however, two well documented cases of hydroxychloroquine retinopathy
have been reported in patients treated for 6.5 and 8 years
without exceeding the recommended maximum daily dose.8The Royal College
of Ophthalmologists' guidelines for managing patients receiving
hydroxychloroquine recommend a baseline ophthalmic examination at the
start of treatment, including best corrected visual acuity, fundoscopy,
and a central visual field test.9 Thereafter the prescribing medical
practitioner should be responsible for any screening considered
necessary. Patients should be warned to report any visual disturbance
and may be given an Amsler chart to use on a monthly basis. No further
ophthalmic examination is necessary unless the patient becomes
Current evidence suggests that hydroxychloroquine retinopathy is
extremely rare if the recommended dose is not exceeded. In most cases a
baseline ophthalmic assessment and issue of an Amsler chart with
instructions on its use will suffice. The small number of patients who
have received hydroxychloroquine for longer than six years should be
kept under ophthalmic review until more information is available about
the safety of long term treatment.
Chris Blyth, Senior registrar in ophthalmology.
Carol Lane, Consultant ophthalmologist.Cardiff Eye Unit, University
Hospital of Wales Healthcare NHS Trust, Cardiff CF4 4XW
1. Hobbs HE, Sorsby A,
Freedman A. Retinopathy following chloroquine therapy. Lancet 1959; ii:
2. Easterbrook M. The sensitivity of Amsler grid testing in early
chloroquine retinopathy. Trans Ophthalmol Soc UK 1985; 104: 204-207.
3. Crews SJ. Chloroquine retinopathy with recovery in early stages.
Lancet 1964; ii: 436-438.
4. Mackenzie AH. Dose refinements in long-term therapy of rheumatoid
arthritis with antimalarials. Am J Med 1983; 75(suppl): 40-45.
5. Morsman CDG, Livesey SJ, Richards IM, Jessop JD, Mills PV. Screening
for hydroxychloroquine retinal toxicity: is it necessary? Eye 1990; 4:
6. Spalton DJ, Roe GMV, Hughes GRV. Hydroxychloroquine, dosage
parameters and retinopathy. Lupus 1993; 2: 355-358
7. Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol
1991; 23: 292-296[
8. Mavrikakis M, Papazoglou S, Sfikakis PP, Vaiopoulos G, Rougas K.
Retinal toxicity in long term hydroxychloroquine treatment. Ann Rheum
Dis 1996; 55: 187-189
9. Royal College of Ophthalmologists. Chloroquine, hydroxychloroquine
and the eye. London: RCO , 1993
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J Rheumatol 1997
Safety and efficacy of hydroxychloroquine as maintenance therapy for
rheumatoid arthritis after combination therapy with methotrexate and
Clegg DO, Dietz F, Duffy J, Willkens RF, Hurd E, Germain BF, Wall B,
Wallace DJ, Bell CL, Sleckman J. Department of Medicine, University of
Utah School of Medicine, Salt Lake City, Utah, USA.
OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ)
to extend the response to combination therapy with HCQ and methotrexate
(MTX) and the safety of longterm HCQ maintenance therapy in patients
with active rheumatoid arthritis (RA).
METHODS: Two-part study consisting of an open label segment evaluating
combination HCQ/MTX therapy followed by a double blind segment
evaluating maintenance therapy for a total of 60 weeks. First, all
patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for
24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with
MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41),
or (3) placebo with MTX as needed for disease flare (n = 40), each for
RESULTS: Clinical disease and laboratory variables improved
significantly during initial combination therapy with HCQ and MTX. After
MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of
disease flare (p = 0.023). There were no unexpected adverse events at
any time or between-group differences in the distribution of adverse
events during the double blind segment.
CONCLUSION: Combination of HCQ and MTX appeared to be effective and well
tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the
response seen with combination therapy and was well tolerated for 36
weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ,
may be a useful alternative for the treatment of RA.
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