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7 Ashby M, Wakefield M, Beilby J. General practitioners’ knowledge and use of living wills. BMJ 1995; 310: 230. 8 Wong RE, Weiland TJ, Jelinek GA. Emergency clinicians’ attitudes and decisions in patient scenarios involving advance directives. Emerg Med J

2011; doi:10.1136/emermed-2011200287. 9 Corke C, Milnes S, Orford N, Henry MJ, Foss C, Porter D. The influence of medical enduring power of attorney and advance directives on decisionmaking by Australian intensive care

doctors. Crit Care Resusc 2009; 11: 122–8. 10 Corke C, Mann J. Effect of a supplement clarifying patients’ intentions on doctors’ willingness to follow the wishes of an agent with medical enduring power of attorney. Crit Care Resusc 2009; 11: 215–18.

REVIEW

Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects imj_2886

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C. Tang, T. Godfrey, R. Stawell and M. Nikpour2,3 1 Faculty of Medicine, Dentistry and Health Sciences, 2Department of Medicine, University of Melbourne, 3Department of Rheumatology, St. Vincent’s Hospital Melbourne, and 4Ocular Immunology Clinic, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia

Key words lupus, hydroxychloroquine, survival, cardiovascular disease, retinopathy. Correspondence Mandana Nikpour, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, Melbourne, Vic. 3065, Australia. Email: [email protected]

Abstract Due to multiple beneficial effects, including control of disease activity, reduction in cardiovascular events and improved survival, hydroxychloroquine is now recommended long-term for all patients with systemic lupus erythematosus. However, patients must be made aware of the possible risk of retinal toxicity and have eye examinations to monitor for this complication. As hydroxychloroquine becomes more widely used in systemic lupus erythematosus, physicians must also be aware of rare but serious adverse effects, including neuromyotoxicity and cardiotoxicity.

Received 18 April 2012; accepted 10 July 2012. doi:10.1111/j.1445-5994.2012.02886.x

Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disease that affects 1 in 1000 individuals, most frequently women in their child-bearing years.1 SLE usually has a relapsing-remitting course, although a significant proportion of patients experience periods of persistent disease activity.2 SLE carries substantial morbidity and mortality in part due to the disease itself but also because of infective complications and accelerated atherosclerotic coronary artery disease.3 Corticosteroids and immunosuppressive drugs, such as azathioprine, mycophenolate and cyclophosphamide, are currently the mainstay of treatment in SLE.4 While antimalarials have been used in the treatment of SLE for over a century, it is only in recent years that the broad

Funding: The University of Melbourne and St. Vincent’s Hospital Melbourne Research Endowment Fund. Conflict of interest: None.

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spectrum of beneficial effects of these drugs in SLE has been demonstrated.5 Hydroxychloroquine has become a staple component of treatment in SLE, and most experts now recommend lifelong treatment in all SLE patients regardless of disease severity or other therapy, provided that no contraindications exist.5 In this article, we will review the evidence favouring the use of antimalarials in SLE and present an overview of indications for use, pharmacology, mechanisms of action and potential toxicity of these drugs.

Pharmacology of hydroxychloroquine and chloroquine Hydroxychloroquine is very similar to chloroquine except for the addition of a hydroxyl group to the side chain and b-hydroxylation of the N-ethyl substituent. Hydroxychloroquine is administered orally and, like chloroquine, is rapidly absorbed in the gastrointestinal tract with a large volume of distribution. An array of © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians

Hydroxychloroquine in lupus

cytochrome P450 enzymes converts hydroxychloroquine into its active metabolite, desethyl hydroxychloroquine.6 The onset of action may take up to 4–6 weeks postcommencement of therapy, and it may take 3–6 months to achieve maximal clinical efficacy. The recommended maintenance dose of hydroxychloroquine is 200–400 mg daily. Giving a larger hydroxychloroquine dose of 1200 mg/day for the first 6 weeks of treatment has been shown to accelerate clinical response in patients with rheumatoid arthritis.7 However, in this study, there was also a higher incidence of gastrointestinal side-effects. Most of the systemic clearance is by renal excretion, with a long tissue half-life of 40–50 days.8,9 The metabolism and clearance of chloroquine are similar to hydroxychloroquine, and the usual prescribed dose in SLE is 250 mg daily. In Australia, chloroquine is no longer available through the Pharmaceutical Benefits Scheme. However, this drug may be obtained at cost through selected compounding pharmacies. Caution is advised in the use of antimalarials in severe renal and hepatic impairment. While dose adjustments may be necessary in this setting, there are no specific recommendations in this regard.

Drug interactions Antimalarials may decrease the metabolism of some betablockers, and concomitant therapy with these agents must be monitored.10 Importantly, antimalarials may increase the serum concentration of cardiac glycosides, such as digoxin, and increase the risk of toxicity.11 Therefore, drug doses may need to be modified accordingly. There is a theoretical risk of interaction with proton pump inhibitors.12 As chloroquine and hydroxychloroquine are weak bases that tend to accumulate in acidic environments, competition with proton pump inhibitors may inhibit accumulation of these antimalarials at their site of action, thus mitigating their immunomodulatory effects. The true in vivo impact of this potential drug– drug interaction is unknown.

Mechanisms of action Immunomodulatory effects Antimalarials have immunomodulatory properties in part mediated through blocking pro-inflammatory pathways. The exact mechanism through which this occurs has not been fully defined. There is some evidence that antimalarials decrease secretion of monocyte-derived pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNFa).13 In one study, serum levels of proinflammatory cytokines interleukin (IL) 6 and TNFa among SLE patients decreased significantly, following © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians

3 months of treatment with chloroquine.14 This antimalarial-mediated downregulation of TNFa levels is influenced by polymorphisms in IL-10 and TNFa promoters; this may explain the variable responses to treatment among individuals.15 Furthermore, SLE patients with a low IL-10/high TNFa genotype receiving antimalarial therapy have increased number and function of regulatory T cells and lower levels of cytokines (interferon alpha, IL-10 and IL-2) associated with SLE activity than those with the converse genotype.16 Antimalarials have also been shown to have important actions related to toll-like receptors (TLRs), which are pivotal in innate immune responses.17–19 Hydroxychloroquine has an inhibitory effect on TLR signalling, and chloroquine may block TLR-9 pathways.20 Antimalarials may also exert their effects through inhibition of activation of intracelleular TLR-3 and TLR-7.21 Another proposed mechanism of action of antimalarials is interference with normal physiological functions of subcellular compartments that rely on an acidic milieu.22 Through this ‘lysosomotropic action’, antimalarials, which are weakly basic, enter not only lysosomes but also all other acidic compartments wherein they interfere with functions dependent on an acidic milieu, such as receptor recycling and secretion of inflammatory mediators, lymphocyte proliferation, and autoantibody production.23,24

Effects on lipids In a cohort of 264 patients with SLE, Petri et al. have shown that hydroxychloroquine is associated with a significantly lower serum cholesterol.25 Studies have shown that irrespective of concomitant steroid administration, patients with SLE who are taking hydroxychloroquine have lower levels of atherogenic lipids, such as total cholesterol, low-density lipoprotein cholesterol and triglycerides, than patients who are not taking hydroxychloroquine.26,27 There are conflicting reports of the effect of antimalarials on high-density lipoprotein cholesterol levels.28 The mechanism underlying the lipid-lowering effect of antimalarials is unknown. However, it is postulated that in this regard, effects on receptor recycling may be important.

Effects on glucose metabolism Hydroxychloroquine has been shown to have a dosedependent insulin-sparing effect in diabetic rats.29 In addition, there are case reports of hypoglycaemia induced by hydroxychloroquine in non-diabetic patients with rheumatoid arthritis.30 In one study of patients with noninsulin-dependent type 2 diabetes controlled by diet 969

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alone, chloroquine at a dose of 250 mg four times daily decreased the metabolic clearance rate of insulin by 39%, increased fasting C-peptide secretion by 17% and reduced feedback inhibition of C-peptide by 9.1% and 10.6% during low- and high-dose insulin infusions respectively.31 In a more recent study of 72 women with SLE taking hydroxychloroquine, after adjustment for covariates, serum glucose was lower in hydroxychloroquine users than in non-users (85.9 vs 89.3 mg/dL, P = 0.04).32 A randomised, placebo-controlled study found that in patients who are resistant to sulfonylureas, hydroxychloroquine use for 6 months reduced glycated haemoglobin A1c by 1.02% (95% CI 0.24–1.81).33 This is supported by Petri et al. who also found hydroxychloroquine beneficial for control of diabetes mellitus in patients with SLE.34

Antithrombotic and endothelial effects Hydroxychloroquine has antithrombotic potential through multiple mechanisms, including inhibition of platelet aggregation and adhesion, cholesterol lowering mechanisms, and inhibition of antiphospholipid antibody production.35,36 Antimalarials have been found to increase endothelium-dependent vasodilatation.37 One study has shown a significantly lower prevalence of vascular stiffness in premenopausal women with SLE treated with hydroxychloroquine.38 A small study found that hydroxychloroquine increased large artery elasticity and lowered systemic vascular resistance in lupus patients compared with those receiving no treatment or on corticosteroids alone.39

Other effects Antimalarials block ultraviolet light absorption, and this may protect against lupus skin lesions. Indeed hydroxychloroquine has been shown to reduce the severity of rash and skin symptoms among non-SLE patients who are susceptible to polymorphic light eruptions.40 Hydroxychloroquine may have antineoplastic effects, with one prospective study showing a lower adjusted hazard ratio for cancer among SLE patients who were antimalarial drug users compared with non-users (hazard ratio 0.15, 95% CI 0.02–0.99).41

Indications for use of antimalarials in SLE Control of active disease and reduction in frequency and severity of flares In the 1960s, Kraak et al. demonstrated the efficacy of hydroxychloroquine in treating discoid lupus erythema970

tosus in a double-blinded study.42 An observational study has shown that hydroxychloroquine has a beneficial effect in inducing renal remission in membranous lupus nephritis in combination with mycophenolate as the initial therapy.43 A Canadian randomised, double-blinded, placebocontrolled trial evaluated the effects of withdrawing hydroxychloroquine in 47 patients with clinically stable SLE.44 The investigators found that flares were more frequent after discontinuing hydroxychloroquine. In the 6 months following treatment cessation, the risk of flares was increased 2.5-fold (95% CI 1.08–5.58).44 This benefit of hydroxychloroquine in reducing SLE disease activity has been supported by many studies. Antimalarials not only decrease disease activity but may also reduce the severity of the flares. The aforementioned Canadian study also showed that the placebo group had a higher relative risk of severe exacerbations, 6.1 times (95% CI 0.72–52.44) greater than those receiving hydroxychloroquine.44 A systematic review of the clinical efficacy and sideeffects of antimalarials in SLE found high-level evidence of antimalarials preventing lupus flares.45 Further, antimalarials were reported to decrease SLE activity and in most studies by over 50%.45 In pregnant women, high levels of evidence were found that hydroxychloroquine decreases disease activity without causing harm to the baby. In contrast, in the same systematic review, evidence supporting an effect on severe lupus activity was weak.

Cardioprotection and reduction in organ damage and mortality Antimalarials may significantly reduce the risk of thrombovascular events in lupus patients. In a study by Jung et al., 54 SLE patients with thrombovascular events were matched to controls based on the calendar year of their first visit, duration of follow up and highest disease activity measured by SLE Disease Activity Index 2000 (SLEDAI-2K) during the 2-year observation period. They found that antimalarials reduced the risk of all thrombovascular events by 68%.46 Other reports from the Toronto cohort have also shown a reduction in risk of cardiovascular events with antimalarial therapy.47 In the systematic review by Ruiz-Irastorza et al., there was overall moderate evidence of protection against thrombosis and irreversible organ damage.45 Further investigations are required to determine whether this protective effect of antimalarials against thrombosis is arterial, venous or both.45 Analysis of data from a multiethnic US cohort (Systemic Lupus Erythematosus in a Multiethnic US Cohort; LUMINA) has shown that patients who have © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians


hydroxychloroquine have a lower frequency of World Health Organization class IV glomerulonephritis and lower disease activity overall.48 Further, in this study, among patients with lupus nephritis, after adjusting for possible confounders, hydroxychloroquine had a protective effect in retarding the occurrence of renal damage. Another study from the LUMINA cohort has revealed a significant survival benefit with hydroxychloroquine, with an odds ratio after propensity score adjustment of 0.32 (95% CI 0.12–0.86).49 Another prospective study demonstrated a 50% decrease in death in SLE patients treated with hydroxychloroquine compared with SLE patients who were not.50 Shinjo et al. showed that antimalarials reduce mortality in SLE by 38% (hazard ratio 0.62, 95% CI 0.39–0.99).51 An important aspect of this study was that this protective effect appeared to be dependent on the length of treatment with antimalarials. The mortality rate (per 1000 person-months of follow up) was 3.85 (95% CI 1.41–8.37) in patients receiving antimalarials for 6–11 months compared with 0.54 (95% CI 0.37–0.77) for patients treated with antimalarials for at least 2 years.51

Delayed onset of clinical disease There is some evidence that early institution of therapy with hydroxychloroquine delays the onset of first clinical symptoms of SLE in susceptible individuals, lowers the rate of autoantibody accumulation, and decreases the number of autoantibody specificities at and after diagnosis.52 However, a prospective intervention study is required to confirm these findings.

Use of hydroxychloroquine in paediatric SLE Hydroxychloroquine is routinely used at a dose of 5 mg/ kg/day (maximum of 400 mg daily) for the treatment of paediatric SLE.53 Monitoring for ocular toxicity is recommended as outlined later. There is little evidence to inform the duration of therapy in the paediatric population.

Adverse effects Adverse effects of antimalarials are generally infrequent and mild.45 Rare but serious adverse events include neuropmyopathy, cardiomyopathy and arrhythmias, which may not resolve completely following cessation of therapy. Retinopathy is a rare and irreversible adverse effect of antimalarials that we will discuss in more detail below. © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians

Gastrointestinal The most common adverse effect is gastrointestinal upset, which may be severe enough to cause a loss of appetite. It is more prevalent with chloroquine (20%) than hydroxychloroquine (10%).54 Vomiting and diarrhoea may also occur. Other symptoms have been reported and usually resolve with time or by decreasing the administered dose.55 Hepatotoxicity related to antimalarial use is rare, and in general, routine blood monitoring is not required.

Cutaneous Ten to twenty percent of patients on long-term antimalarial therapy develop blue-grey skin pigmentation, typically on the face, hard palate, forearms and shins.55–58 This abnormal pigmentation is not always reversible with cessation of therapy. Bleaching of the hair and transverse bands on the nail beds may also occur.59,60 Some patients may have an allergic reaction to antimalarials wherein pruritus and skin eruptions develop. The lesions vary extensively and include erythroderma, urticaria, alopecia and eczema.54,61 Depending on clinical indications, desensitisation to antimalarials may be attempted. Mates et al. have described successful slow oral desensitisation to hydroxychloroquine in four patients with rheumatological conditions.62

Central nervous system The most common central nervous system side-effects are nightmares, headaches, light-headedness and tinnitus.55,63 These effects may spontaneously resolve after several weeks of therapy, although temporary dose adjustment may be required. Other reported side-effects are irritability, hyperexcitability, increased nervousness, psychosis and convulsions.22

Ocular Transient diplopia may occur on initation of therapy. Deposition of antimalarials in the cornea may result in altered vision, such as halos or photosensitivity, but there is usually no change in visual acuity.64 This side-effect is rare with hydroxychloroquine at a dose of 400 mg/day and a little more common with chloroquine. Corneal deposits are not a contraindication to continued treatment65 and usually resolve 1.5–2 months after treatment is stopped.55 Retinopathy is an irreversible and serious side-effect of antimalarials (Fig. 1). Retinopathy is an absolute contraindication for ongoing therapy.55 Fortunately, with 971

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Figure 1 Fundal photograph (top) showing retinal pigment epithelial changes in the macula (bull’s eye maculopathy) because of chloroquine toxicity. Perimetry (below) using Humphrey automated visual fields in the same patient showing reduced retinal sensitivity at six paracentral locations. Photographs courtesy of Dr Daniel Polya and Dr Richard Stawell.

doses used to treat SLE, retinal toxicity is rare. Large cohort studies inclusive of thousands of patient-years of treatment have reported the risk of retinopathy in the first 5 and 7 years of therapy as 0.29% and 0.33%, respectively, whereas the risk at 10, 15 and 20 years was 1.0%, 2.1% and 3.1% respectively.66 Ten-percent incidence of retinopathy has been reported with long-term chloroquine use.67,68 The earliest stage of antimalarial-induced retinopathy will be manifest as small paracentral scotomas around central fixation and will not be visible clinically. The clinical signs of early toxicity may be very subtle changes in the retinal pigment epithelium around the fovea. At this stage, if the drug is ceased, there may be some recovery of vision. The classic sign of ‘bull’s eye’ maculopathy with a ring of perifoveal retinal pigment layer atrophy is 972

a late sign (Fig. 1). By this stage, symptoms may include photophobia, photopsia, significant visual field defects around central fixation and ultimately visual loss.69,70 These more advanced changes are irreversible and may even progress for a period of time following cessation of treatment. The older literature related antimalarial retinal toxicity to the daily drug dose.71 It recommended using less than 4 mg/kg/day of chloroquine and less than 6.5 mg/kg/day of hydroxychloroquine in order to avoid ocular toxicity. The case series reported by Levy et al. and Wolfe et al. demonstrated that the risk of toxicity relates not to the daily dose but the cumulative exposure.68,72 In a recent case series of 16 patients with hydroxychloroquine retinal toxicity, most patients had taken greater than 6.5 mg/kg/day for an extended period, when dose was © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians


calculated based on lean (rather than actual) bodyweight. Sustained improvement following cessation of drug therapy was not observed in any patients. This study also highlighted that there may be substantial abnormalities detected with visual field and multifocal electroretinography testing even in the presence of a normal macular appearance.73 The most recent American Academy of Ophthalmology (AAO) recommendations of screening for hydroxychloroquine retinopathy, published in 2011, are based on new knowledge about the prevalence of toxicity and improved screening tools.74 These recommendations highlight the rise in retinal toxicity towards 1% after 5–7 years of use of hydroxychloroquine or a cumulative dose of 1000 g, with further increase in risk with continued use. The AAO suggested that daily doses be limited to 400 mg of hydroxychloroquine and that lower doses (in the range of 6.5 mg/kg be calculated on the basis of ideal bodyweight) be used for individuals who are of short stature.67,75–77 The AAO recommends a baseline eye examination for patients starting hydroxychloroquine to serve as a point of reference and to rule out pre-existing macular disease. Such disease will make it difficult to detect subtle early signs of toxicity and hence is a relative contraindication to antimalarial therapy. Annual screening may then begin after 5 years or sooner in older patients, those at risk of macular disease and those with pre-existing renal or liver disease. These baseline and annual screening tests should include biomicroscopy and an automated threshold 10-2 protocol field test, along with one objective test if available.78 These newer objective tests include multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) that can be more sensitive than visual fields in detecting the earliest changes of hydroxychloroquine retinopathy.79–82 These modalities are now becoming more widely available in Australia but are not currently subsidised through Medicare. It is now recommended that along with automated 10-2 visual fields, at least one of the newer tests be used for routine long-term screening, where available. The Amsler grid and colour vision testing are only adjunct tests and not sufficiently sensitive for detection of early hydroxychloroquine retinopathy. Fundus examinations are still advised for documentation, but visible maculopathy is a late and irreversible change and should not be relied on for screening.

Neuromuscular toxicity There are several case reports of hydroxychloroquineinduced myopathy, presenting as diffuse skeletal muscle © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians

weakness. Some of these cases are associated with cardiac myotoxicity, manifesting as chest pain, cardiac failure and elevated cardiac enzymes. Other cases may be associated with a peripheral neuropathy. Muscle biopsy consistently reveals myeloid and curvilinear bodies (on electron microscopy), and muscle fibre atrophy with vacuolar changes in absence of changes of myositis or myocarditis. In most cases, there is an improvement in signs and symptoms following discontinuation of hydroxychloroquine, although this may take up to 18 months. In some cases, resolution may be incomplete.83,84

Cardiotoxicity and arrhythmias In a study of electrocardiograms (ECGs) in 85 unselected patients with connective tissue disease treated with hydroxychloroquine, mean PR interval, QTc interval and heart rate were not different from normal values. The frequency of heart conduction disorders was similar to what is expected in the general population, offering some reassurance regarding the cardiac safety of hydroxychloroquine.85 This contrasts numerous reports of heart conduction disorders, including bundle branch block, and incomplete or complete atrioventricular block with chloroquine.86 There are case reports of QT prolongation and associated torsade de pointes with hydroxychloroquine.87 Cardiotoxicity with antimalarials may manifest as conduction defects or heart failure, or both. Antimalarial induced toxic cardiomyopathy may be reversible if detected at an early stage, but more severe advanced cases may be refractory to cessation of antimalarial therapy. This highlights the importance of timely diagnosis.88

Haematological There are rare reports of cytopenias and haemolysis in patients with glucose-6-phosphate deficiency receiving antimalarials.89

Safety in pregnancy Although hydroxychloroquine crosses the placenta, fetal toxicity does not seem to occur at the doses used for connective tissue disorders.90 In a retrospective study of 257 pregnancies from the Johns Hopkins Lupus Cohort, there was no difference in the occurrence of adverse pregnancy outcomes among patients who were not exposed to hydroxychloroquine, those in whom treatment was ceased during first trimester or those who continued treatment with hydroxychloroquine.91 Mothers who discontinued hydroxychloroquine during 973

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pregnancy had more frequent SLE flares and required higher mean doses of prednisone. Buchanan et al. found that 36 women with SLE who were exposed to hydroxychloroquine during their pregnancy had a similar rate of successful pregnancies to a group of 53 controls.92 In a study of 133 women receiving either 200 (11 pregnancies) or 400 mg (122 pregnancies) hydroxychloroquine daily during gestation, 88% of pregnancies were successful compared with 84% in a comparable control group not receiving hydroxychloroquine. The children born from these pregnancies were also followed for up to 108 months. None of these children had any visual, hearing, growth or developmental complications.93 In a recent review of the literature, there was no evidence to suggest fetal ocular toxicity of antimalarial medications during pregnancy.94 Although a small number of infants had early (age 3–7 months) evidence of electroretinogram anomalies, all of these children had normal fundoscopy before 4 years of age. Levy et al. found that children born from mothers with lupus treated with hydroxychloroquine had higher delivery age and Apgar scores than those of mothers receiving placebo.95 In a recent study, maternal use of hydroxychloroquine was shown to reduce the risk of recurrent anti-Ro antibody-associated cardiac manifestations of neonatal lupus.96 Collectively, these studies suggest that hydroxychloroquine is not only safe during pregnancy but also may improve pregnancy outcome by reducing disease activity and corticosteroid use.95,97,98 The Australian Therapeutic Goods Administration has a Category D listing for hydroxychloroquine (http://www.tga.gov.au/hp/medicines-pregnancy.htm), implying a possible increased risk of fetal malformations. Substantial evidence to the contrary, as we have presented earlier, calls for a revision of this categorisation so that it is in line with the latest evidence. There is emerging evidence that hydroxychloroquine use is relatively safe during breast-feeding. Hydroxychloroquine does cross into human breast milk but results in an exposure of less than 2% of the maternal dose in breast-fed children.99,100 Among 13 children who were breast-fed while their mothers were on hydroxychloroquine, none suffered visual or neuropsychological abnormalities.101 Therefore, it is generally recommended to continue hydroxychloroquine treatment during pregnancy and lactation.100–104

Summary and recommendations Based on current evidence of multiple beneficial effects of hydroxychloroquine in SLE, including improved control of disease activity, reduction in frequency and severity of flares, reduced risk of cardiovascular events, and reduced overall mortality, we recommend the long974

term use of hydroxychloroquine in patients with SLE, continued during pregnancy provided that no contraindications exist. The dose of hydroxychloroquine should be titrated based on the individual’s bodyweight, aiming for an average dose of ⱕ6.5 mg/kg per day or a dose of 400 mg daily in most patients. Patients should be counselled regarding the risk of retinal toxicity. As ocular toxicity increases after 5 years of hydroxychloroquine use, patients must have eye examinations, including fundoscopy and visual field testing at baseline and annually after 5 years. Some experts prefer annual or biannual eye examinations even in the first 5 years of follow up; however, ocular toxicity with less than 5 years duration of hydroxychloroquine use in therapeutic doses in absence of renal or liver disease is rare. Patients at high risk of retinopathy, such as those with pre-existing renal or liver disease, must have annual eye examinations from the outset. We acknowledge that the newer, more sensitive methods (mfERG, SD-OCT or FAF) of screening for ocular toxicity are not widely available in Australia. Physicians should be aware of other rare toxic side-effects of antimalarials, including neuromyopathy, cardiomyopathy and conduction defects as cessation of the drug may lead to improvement or even resolution. At present, we do not advocate routine screening blood tests or ECGs for these rare adverse events, as in absence of symptoms indicative of toxicity, the yield will be very low. Among SLE patients who have persistent cutaneous disease activity despite treatment with hydroxychloroquine and other immunosuppressives, where available, a short period (less than 6 months) of treatment with chloroquine may be a therapeutic option, subject to drug availability. However, we do not advocate the long-term use of chloroquine because of ocular toxicity. Finally, there is some evidence that in patients who are at risk but have no history of clinical SLE, use of antimalarials may delay the onset of symptomatic SLE. At present, there is insufficient evidence to recommend hydroxychloroquine in all of these patients, and we suggest that this decision be made on an individual case basis.

Acknowledgements We thank Dr Richard Stawell and Dr Daniel Polya for providing Figure 1. We also thank Dr Andrea Bendrups, Dr Rachael Knight and Dr Lyndell Lim for help with preparation of the manuscript. We acknowledge the support of St Vincent’s Hospital Melbourne Research Endowment Fund, UCB Australia and GSK Australia, who provide financial support for lupus research at St Vincent’s Hospital Melbourne. © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians


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O R I G I N A L A RT I C L E S

Rheumatic heart disease in pregnancy: cardiac and obstetric outcomes imj_2725

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J. B. Sartain,1 N. L. Anderson,4 J. J. Barry,1 P. T. Boyd2 and P. W. Howat3 Departments of 1Anaesthesia, Intensive Care and Perioperative Medicine, 2Medicine and 3Women’s Health, Cairns Base Hospital, Cairns and 4 Department of Anaesthetics, Mater Children’s Hospital, Brisbane. Queensland, Australia

Key words rheumatic heart disease, mitral valve stenosis, cardiovascular, pregnancy complication, interdisciplinary communication, obstetrical, anaesthesia. Correspondence James B Sartain, Department of Anaesthesia, Intensive Care and Perioperative Medicine, Cairns Base Hospital, PO Box 902, Cairns, Qld 4870, Australia. Email: [email protected] Received 4 October 2011; accepted 4 January 2012. doi:10.1111/j.1445-5994.2012.02725.x

Abstract Background: Rheumatic heart disease (RHD) remains an important health issue for indigenous women of child-bearing age in northern Australia. However, the influence of RHD on maternal outcomes with current clinical practice is unclear. Aims: To determine maternal cardiac complications and obstetric outcomes in patients with RHD. Methods: Retrospective case note analysis of women with RHD who received obstetric care between July 1999 and May 2010 at Cairns Base Hospital in north Queensland. Outcome measures were obstetric interventions and outcomes, cardiac interventions and complications, stratified according to a cardiac risk score (CRS). Results: Ninety-five confinements occurred in 54 patients, of whom 52 were Indigenous Australians. There were no maternal or neonatal deaths. With a CRS of 0, cardiac complications occurred in 0 of 70 confinements; with a CRS of 1, complications occurred in 5 of 17 confinements (29%); with a CRS of >1, complications occurred in 2 of 4 confinements (50%). Another four patients were first diagnosed with RHD after developing acute pulmonary oedema during the peripartum period. Conclusions: RHD has a major impact on maternal cardiac outcomes. However, with current management practices, maternal and fetal mortality are low, and the incidence of complications is predictable based on known risk factors.

Introduction Funding: None. Conflict of interest: None.

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Although acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are now rare in affluent populations, they remain major health issues among Indigenous © 2012 The Authors Internal Medicine Journal © 2012 Royal Australasian College of Physicians