Antimalarials in Arthritis by drdoc on-line

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Antimalarial 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 involvement.

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.

Side effects

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 the drug.
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 testing.


Recommended maximal doses depend on the type of antimalarial

Chloroquine - 4mg/kg chloroquine base
Hydroxychloroquine - 6mg / kg


I ensure 12 monthly ophthalmologic assessments


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Efficacy and safety


Cochrane 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 antimalarials for
the treatment of rheumatoid arthritis (RA). 
SEARCH STRATEGY: We searched the
Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, Medline and Embase up to and including August 2000. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. SELECTION CRITERIA: All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing antimalarials against placebo in patients with RA DATA COLLECTION AND ANALYSIS: Data abstraction was carried out independently by two reviewers. The same two reviewers using a validated checklist (Jadad 1996) assessed the methodological quality of the RCTs and CCTs. Rheumatoid arthritis outcome measures were extracted from the publications for the 6-month endpoint. The pooled analysis was performed using standardized mean differences for joint counts, pain and global assessments. Weighted mean differences were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout. 
MAIN RESULTS: We found four trials, with 300 patients randomized to
hydrochloroquine and 292 to placebo. Only trials evaluating hydroxychloroquine could be pooled in the analysis. A statistically significant benefit was observed when hydroxychloroquine was compared to placebo. The standardized mean differences for the various outcome measures ranged from -0.33 to -0.52, and were statistically significant. Statistically significant differences were also observed for ESR. Overall withdrawals and withdrawals due to lack of efficacy were significantly more frequent in the placebo group. No differences were observed in withdrawals due to toxicity. 
Hydroxychloroquine appears to be efficacious for the treatment of RA. Its overall effect appears to be moderate, but its low toxicity profile should be considered when treating patients with RA.

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J Rheumatol 2000 Mar;27(3):623-9
Consequences of delayed therapy with second-line agents in rheumatoid arthritis:
a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study.
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 second-line
agents in patients with early rheumatoid arthritis (RA). METHODS: One hundred nineteen patients who participated in a 9 month placebo controlled randomized trial of hydroxychloroquine sulfate (HCQ) were followed prospectively for an additional 3 years. Those randomized to HCQ are referred to as the early treatment group and those randomized to placebo as the delayed treatment group. Participants were assessed annually for pain [Arthritis Impact Measurement Scales (AIMS) and Stanford Health Assessment Questionnaire (HAQ)], physical disability (AIMS and HAQ), and the RA global well being scale (AIMS). Conversion of results into standard deviation (SD) units permitted defining a substantial difference as per Felson as > 0.30 SD units and a clinically indistinguishable difference as < or = 0.06 SD units. 
RESULTS: One hundred fifteen patients (97%)
participated and complete data were available on 104 (87%). Compared to the early treatment group, the delayed group remained worse for both the pain and the physical disability outcomes over the additional 3 year followup. The difference in the RA global well being score became clinically indistinguishable for the early and delayed groups only after the 2 year post-trial assessment. The between-group differences were not explained by post-trial therapy with corticosteroids, other second-line agents, or nonsteroidal antiinflammatory drugs and analgesic preparations. 
CONCLUSION: These findings show that a delay
in instituting therapy with second-line agents, even a 9 month delay in instituting a moderately powerful second-line agent such as HCQ, has significant effects on longterm patient outcome, and provides strong evidence in support of early therapy in RA.



Chang Gung 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 hydroxychloroquine carefully.

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Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis.
Rheumatol Int
Seckin U, Ozoran K, Ikinciogullari A, Borman P, Bostan EE.
Department of Physical Medicine and Rehabilitation, Ankara Numune Education and
Research Hospital, Turkey.

We report a case of reversible sensorineural hearing loss due to hydroxychloroquine (HQ) treatment. The patient was a 34-year-old woman with 1 year of rheumatoid arthritis (RA). She developed reversible hearing loss after 5 months of HQ treatment. Sensorineural deafness has previously been reported with chloroquine treatment, but this is the first report of ototoxicity associated with HQ in RA.


Retinal toxicity in long term hydroxychloroquine treatment.
Annals of the Rheumatic Diseases. 55(3):187-9, 1996 Mar.

OBJECTIVE: 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 patients. 
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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Hydroxychloroquine retinopathy: is screening necessary?
Blyth C, Lane C. 
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 symptomatic.
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: 478-480.
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: 572-576
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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Combination therapy

J Rheumatol 1997 Oct;24(10):1896-902 
Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine. 
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 36 weeks. 
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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