key: cord-0845385-qfucd52a
authors: Dima, Alina; Jurcut, Ciprian; Chasset, François; Felten, Renaud; Arnaud, Laurent
title: Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge
date: 2022-02-14
journal: Ther Adv Musculoskelet Dis
DOI: 10.1177/1759720x211073001
sha: 8938cca0903edbaefef5346390720769346a68a0
doc_id: 845385
cord_uid: qfucd52a

The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ’s effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon.

Hydroxychloroquine (HCQ) is an antimalarial drug used initially for the treatment of Plasmodium parasitic infection, from where the name of the drug class came from. Beyond its initial indication as antimalarial, HCQ has been used in autoimmune and infectious diseases, as well as in metabolic or neoplastic disorders. 1 But, as recently reviewed, 2 clear benefits were reported mainly in systemic lupus erythematosus (SLE).

Thus, HCQ is now one of the most valuable therapies in SLE, showing multiple benefits over several outcomes associated with the disease itself, but also to its related comorbidities. HCQ is an inexpensive, generally available, well-tolerated immunomodulator. 3 For more than a decade, different authors emphasized that all patients with SLE should be given HCQ [4] [5] [6] [7] and the latest guidelines' recommendations also stated the HCQ importance in SLE unless there are contraindications or side effects. [8] [9] [10] [11] The history of HCQ is supposed to start circa 1600 with the Incas in Chile, from whom the cinchona bark properties were learned by the Jesuits. The main alkaloids of quinine and cinchonine were isolated in 1820 and subsequently chloroquine (CQ) was obtained much later in 1934. 12 HCQ sulfate is the hydroxylated analogue of CQ, synthesized in 1946. Due to a better safety profile, HCQ was given since 1955 as an alternative to CQ. 12, 13 For SLE, the first report of the antimalarials use dates back to 1894, regarding the improvement of cutaneous lupus lesions with quinine. 14, 15 In the United States, HCQ was approved for SLE in 1955 for symptoms like fatigue, rashes, joint pain, and mouth sores 16 and, with specific approval and license characteristics for each country, is now among the main drugs used for SLE treatment worldwide.

The knowledge about the pharmacokinetics of antimalarials is not completely understood and still debated. These pharmacokinetic characteristics are complex [17] [18] [19] due to the large volume of distribution, 19, 20 significant tissue binding, [20] [21] [22] and long terminal elimination half-life. 18, 19, 23, 24 Indeed, important differences have been observed between HCQ pharmacokinetic parameters as evidenced recently by its use in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease . 25 Historically, terminal elimination half-lives were considered very long, 40-50 days for HCQ 18, 23 and up to 60 days for CQ. 19, 24 More recent studies suggest a shorter half-life of about 5 days. 25,26 A long HCQ half-life can be attributed to extensive tissue uptake rather than to an intrinsic inability to clear the drug. The expected delay in the attainment of steady-state concentrations (3-4 months) may be in part responsible for the slow therapeutic response observed with HCQ. 27 Renal clearance is an important consideration for both drugs as reduced clearance increases the bioavailability 28 and subsequently the related side effects. 19, 20, 24 Finally, dose-response relationships and toxicity thresholds have not yet been fully defined. The main pharmacodynamic properties of antimalarials are shown in Table 1 .

Galenic and commercial presentations HCQ is commercialized as 200 mg HCQ sulfate tablets corresponding to 155 mg HCQ base for each tablet. 29 The daily dosage of HCQ varies accordingly to its indication, 29 with the American Academy of Ophthalmology (2016-AAO) recommending no more than 5 mg/kg/day of real body weight in SLE to decrease retinopathy occurrence, 30 recommendation that has been recently reinforced by agreement of four medical societies. 31 The indication is based on an ophthalmological study by Melles and Marmor 32 of nearly 2500 patients in whom daily HCQ intake below 5 mg/kg/day of regular body weight was associated with a low risk of toxicity, <2% within the first 10 years of use. However, some authors highlighted that in that study, the dose of HCQ was based on pharmacy refill information and not on prescribed dose. 33 Dose adjustments with 50% reduction of posology are needed for patients with renal impairment and lower than 30 ml/min filtration rate. 34 For patients weighting more than 80 kg, a maximum daily dose of 400 mg is recommended in SLE. Doses for CQ were established only from extrapolation of HCQ and those lower than 2.3 mg/kg/ day were considered safe. 30, 35 As the terminal elimination half time is not short, 36 dosing can be adjusted by alternate day regimens, such as 200 mg on the first day and 400 mg on the second day, yielding a mean dose equivalent to 300 mg per day. 32 Based on recent surveys, the most common daily dosage for HCQ is 400 mg daily. 37,38

The mechanisms of action for HCQ are complex and still not completely understood (see Table 2 and Figure 1 ). Because of its high lipophilicity, lysosomotropism, and pH, 39,40 HCQ can pass through cell membranes and accumulate into lysosomes 40 where it disrupts key important cellular functions via the inhibition of the Toll-like receptors (TLRs) 41-43 and of the Cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway. 44 The main effects include the inhibition of enzyme and cytokine release, 45-47 receptor recycling, plasma membrane repair, cell signaling, apoptosis, 48-50 autophagy, 39,51 antigen presentation, 52 T-cell polarization, [53] [54] [55] [56] inhibition of the natural killer (NK) cells, 57 Reports not referring to HCQ or CQ use in SLE, not involving human subjects, not including adult cases, and presenting other types of studies than 

In the liver, N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine 17, 18 In the liver, N-dealkylated primarily by CYP2 C8 and CYP3A4 to N-desethylchloroquine N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1 19 Not available Elimination 40-50% of HCQ is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces 19, 20 Predominantly eliminated in the urine, renal excretion: 65-70%. 24 50% of a dose is recovered in the urine as unchanged CQ, with 10% of the dose recovered in the urine as desethylchloroquine 19 Less than 11% is eliminated in the urine daily 28 65 Sjolin-Forsberg et al. 59 Wozniacka et al. 64 Wozniacka et al. 60 Bondeson and Sundler 61 el Tahir et al. 62 Segal-Eiras et al. 63 Decrease NET formation and circulating DNA 53 Zhao et al. 54 Shin et al. 55 Sailler et al. 56 Inhibition of NK cells Decrease proliferation, cytotoxicity, and cytokine production of NK cells RCTs were excluded. A total of eight RCTs were identified in the initial search with one more identified after the references and citations screen (see Supplemental Figure 1 -Flowchart Diagram, Supplemental Table 1 ). For each RCT included, the following information was extracted: study design, drug posology, time of follow-up, study's endpoints, proven efficacy, and side effects noted (as presented in Supplemental Table 2a , 2b).

To the best of our knowledge, the first RCT involving antimalarial therapy in SLE was journals.sagepub.com/home/tab 5 published in 1991 by Canadian Hydroxychloroquine Study Group 66 and reported a 2.5fold increase in the risk of mild flare after HCQ withdrawal in the placebo group. 66 In 1998, Tsakonas et al. 67 presented an extension phase in 1991 and evaluated the risk of major flare after HCQ withdrawal. 67 The endpoint considered, namely flare, subtype of flare, and hospitalization, were all improved under long-term HCQ therapy; however, the results did not reach statistical significance most probably due to the small sample size. 67 Other RCTs have also demonstrated improvement of arthralgia 14 even if without a significant impact over arthritis, 68 prevention of SLE flares and reduction of the corticosteroids dose, 14 improvement of lipid metabolism 69 with decrease in total cholesterol and triglycerides, while increase in HDL-cholesterol, 70 and a safety profile of administration during pregnancy. 71 Also, the PLUS (Plaquenil LUpus Systemic) failed to demonstrate that adjusted HCQ dosing schedules targeting [HCQ] ⩾1000 ng/ml might reduce the occurrence of SLE flares. 72 Most recently, Zanetti et al. 73 tested the efficacy of lower HCQ doses (2-3 mg/ kg/day) 30 and found similar 6-and 12-month flare rates between groups. 73 For cutaneous lupus erythematosus (CLE), the first RCT by Kraak et al. 74 in 1965 tested HCQ up to a maximum posology of 1200 mg daily. Furthermore, the efficacy of antimalarials has been tested in RCTs against placebo, 75 acitrecin, 76 or clofazimine 77 in RCTs showing proven efficacy in RCT with better safety profile than clofazimine or acitrecin. Table 3 ; Supplemental Table 3 ).

Antimalarials: chloroquine diphosphate (CDP) or hydroxychloroquine sulfate (HCQ).The most significant HCQ effect is the control of SLE disease activity itself, which implies amelioration of active clinical involvements, decrease in serum markers, decrease in activity scores, prevention of disease flares, and sustained remission on long-term use. For neonatal lupus, one retrospective study that analyzed data of a historical cohort counting more than 200 pregnancies in SLE patients with positive anti-Ro/SS-A antibodies found HCQ benefits over recurrence and outcome of the neonatal lupus. 184 In another research, HCQ was not identified as independent protective factor for neonatal lupus after adjusting for confounders like age, race, antibodies status, corticosteroids, and prior cardiac-neonatal lupus risk, even if the neonatal lupus cases were less frequent in pregnancies treated by HCQ (14% versus 37%). 185 Despite potential benefits of HCQ during pregnancy, adherence seems to be low. A populationbased registry identified 376 pregnancies in which discontinuation of antimalarials occurred in 16 .7% of cases in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second, and 26.0% in the third. 186 Importantly, HCQ passes the placenta and has fetal serum concentrations equal to those measured in the maternal blood. However, HCQ use during pregnancy 80,119,120,123,187-189 and breastfeeding is considered safe. 5, 190 During lactation, HCQ passes in the maternal milk, but with lower concentrations than in maternal blood, estimated to be 0.2 mg/kg/day. 5 There are reports of CQ overdose in children and, by parallel, cautions are related to HCQ. Antimalarials might be toxic in children in relatively small doses and patients should be counseled to keep these drugs out of children. 5 SLE disease itself is a risk factor for thrombosis. Also, about 20% of patients with SLE have antiphospholipid syndrome (APS). 191 Antimalarials might reduce the antiphospholipid antibodies titers 124 and the risk of thrombosis, 116, [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] but not all published studies reported a protective effect over thrombosis. [192] [193] [194] HCQ has also some metabolic effects by lowering fasting glucose, 136 yielding protection against diabetes, 137 and improvement of the lipids profile in most 81,90,138-147 but not all 195, 196 studies. However, the efficacy of HCQ upon atherosclerosis is more controversial. 151, 152, 197, 198 It is to remember that smoking might inhibit HCQ effects 7,109,110,112 and determine a twofold lower response of cutaneous involvement under HCQ; 199 counseling for smoking cessation is therefore important. Possible anti-neoplastic properties of HCQ have been poorly assessed in SLE. 168 HCQ might inhibit the conversion of 25-(OH)vitamin D to 1,25-(OH)2-vitamin D. 200 However, data regarding the impact of HCQ on bone metabolism in SLE remain controversial. 86 Therefore, based on its wide spectrum of effects, HCQ should probably be considered a possible confounder in all research involving patients with SLE.

The first systematic review regarding HCQ in SLE included a total of 95 studies published between 1982 and 2007. 13 All studies which considered disease activity as the main outcome (11 articles) found positive results, with more than 50% reduction in disease activity in most reports and a decrease in corticosteroid needs in three studies; 13 however, the risk of severe SLE flare was reduced only with borderline significance. 13 Also, the HCQ benefits as adjuvant therapy for LN was also confirmed. 13 The potential benefits upon accrual damage and survival were reported in a limited number of studies. 13 This systematic review was continued by another one using a similar methodology for the 2007-2012 period. 3 The authors reported further evidence thrombosis prevention, increased survival, control of disease activity, lipid profile improvement, and prevention of damage accrual 3 (see Supplemental Table 4 ).

The protective effect of HCQ against infections was further confirmed in two systematic reviews and meta-analysis. 153, 161 Also, two meta-analyses reported improvement of the lipid profile under HCQ in SLE. 149, 150 For cutaneous involvement, Fairley et al. 114 reported in one systematic review only moderate HCQ efficacy.

A 2018 meta-analysis of observational data failed to identify any significant beneficial effect of HCQ over fetal growth restriction and prematurity. However, the authors mentioned that these results should be regarded with caution due to lack of RCTs, high heterogeneity among reported data, and of numerous missing data like those on the antiphospholipid antibodies status. 205 Overview of guidelines We reviewed here systematically the European League against Rheumatism (EULAR) recommendations referring to the use of HCQ. We identified all EULAR guidelines (www.eular.org) for the last 5 years and searched for HCQ-related paragraphs using the terms 'Hydroxychloroquine' and the respective abbreviation 'HCQ'. All paragraphs found were extracted (see Supplemental  Table 5 ) and data were further analyzed and summarized (see Supplemental Figure 2 ).

From the total 30 EULAR management guidelines published since 2016, 10 referring to HCQ were identified, and main indications were noted (see Supplemental Table 6 ). Recommendations addressing specifically to HCQ were found in seven guidelines 8, 34, [206] [207] [208] [209] [210] while in others, HCQ was included as part of Disease Modifying AntiRheumatic Drugs (DMARDs). [211] [212] [213] The EULAR Guidelines recommendations referring mainly to SLE and related conditions are summarized in Figure 2 .

Tunnincliffe et al. 214 Table 4 .

Reviewing the antimalarials' safety profile in SLE, Ruiz-Irastorza et al. 13 noted low prevalence of antimalarials' toxicity, mainly mild gastrointestinal and cutaneous side effects. These were significantly more frequent under CQ when compared with HCQ, results parallel by higher discontinuation rates for CQ. Overall, the HCQ global safety was rated as high. 13 Eljaaly et al. 236 Thus, for long-term HCQ use, medium uptake duration of 32 months, 35 the skin hyperpigmentation is not rarely reported and might be favored On short-term use, the digestive intolerance is the most frequently encountered side effect, with occurrence possible since first HCQ administration. 237, 238 A wide range of mild neuropsychiatric manifestations, but also psychosis, was reported in relation to HCQ use, especially in elderly. However, this relation remains controversial as other concomitant Retinopathy occurrence remains the most discussed and studied HCQ's side effect in SLE.

The main risk factors for HCQ-related retinopathy are the treatment duration, daily and cumulative dose, chronic kidney disease, as well as pre-existent retinal disease. 34 Ophthalmologic screening is mandatory, yearly from baseline if there are known risk factors or at baseline, after 5 years on HCQ, and yearly therefore in patients without retinopathy risk factors. 8, 30, 31, 34 The current 2020 Joint Statement on HCQ 31 reinforced the old recommendations 8, 30, 34, 32 of the need of sensitive testing modalities such as optical coherence tomography (OCT) and automated visual fields that could detect early toxicity. 31 When available, quinacrine (mepacrine) might be considered as an alternative in SLE patients with HCQ-related ocular or cutaneous side effects.

As the eye side effects are dose-related, not only the duration of use but also the blood levels are predictors of retinopathy development with a statistical association in patients with [HCQ] blood levels >1200 ng/ml. 226, 227 However, association between HCQ blood concentration and retinopathy has not been confirmed in another study. 240 For non-rheumatic diseases, doses of up to 1000 mg daily (up to 20 mg/kg daily) showed eye toxicity within 2 years in 25-40% of the patients exposed, 30 while for the doses up to 5 mg/kg of real body weight, the risk of retinopathy within 10 years was 2%. 32 For lifetime HCQ users, definite or probable toxicity was documented in only 0.65% even if 6.5% patients discontinued therapy because of eye-related side effects. 228 One longitudinal study showed ophthalmological alterations confirmed by ophthalmological examination in 5.5% of cases. 241 When compared with HCQ, the risk of retinopathy related to CQ seems to be much higher, hence CQ is not recommended as the first-line antimalarial for the SLE treatment. One systematic review including four studies for CQ versus six studies for HCQ found definite retinal toxicity in 2.5% versus 0.1% and probable retinopathy in 2.6% versus 0.3% patients. 13 A recent report from the Hopkins cohort showed a higher overall frequency of retinopathy of 4.3%, but the risk increased significantly after 15 years of HCQ use, 226 namely 1% in the first 5 years, 1.8% for 6-10 years, 3.3% for 11-15 years, and 11.5% for 16-20 years. 226 For antimalarials cardiac toxicity, the results of 86 articles were systematically reviewed and a total of 127 patients (65.4% female) were identified, of which about 60% had taken CQ, while the rest HCQ. 218 The most frequent cardiac side effects reported were conduction disorders (85%), followed by cardiac hypertrophy (22%), hypokinesia (9.4%), cardiac failure (26.8%), pulmonary arterial hypertension (3.9%), and valvular dysfunction (7.1%). Less than half of the patients (44.9%) recovered normal heart function after the antimalarial drug withdrawal. 218 Disparate cases of HCQ-related neuromyopathy, particularly manifested as insidious onset of proximal myopathy that may be later associated with peripheral neuropathy and cardiac myotoxicity, are reported. The frequency of HCQ-related myopathies is not known, but is probably extremely rare. 35 Early recognition is important as the recovery after the drug withdrawal might be incomplete. 223 Different case reports presented rare and very rare sides effects attributable to HCQ in the absence of other identifiable causes, like early fulminant hepatic failure, 229 toxic myopathy with respiratory failure, 224 and rare cutaneous lesi ons. [230] [231] [232] [233] [234] [235] 239 Hydroxychloroquine blood level monitoring and withdrawal Even if the HCQ role in SLE is acknowledged, less than half of the patients are taking HCQ as prescribed. 242 Measurement of HCQ in whole blood was proposed to monitor both response and adherence to treatment, but an appropriate cut-off for defining efficient HCQ's blood levels remains under debate. For CLE, one prospective multicenter study found significantly higher median blood [HCQ] levels in patients with complete remission (910 ng/ml in remission versus 692 ng/ ml when partial remission and 569 ng/ml in treatment failure, p = 0.007). 107 In a prospective study, improvement of cutaneous lesions was observed when [HCQ] blood levels higher than 750 ng/ml were reached. 113 Also, one study defined subtherapeutic [HCQ] levels, associated with trend of more disease flares, as less than 500 ng/ml. 243 A recent report showed that low [HCQ] blood levels are associated with thrombotic events (720 ng/ml versus 935 ng/ml; p = 0.025). 135

On one hand, a decrease in the flare rate was not observed when [HCQ] level was maintained over 1000 ng/ml. 72 On the other hand, decrease to 2-3 mg/kg/day did not modify serum [HCQ] levels significantly at 3 and 6 months, but only at 12 months. 73 One of the main reasons for using [HCQ] blood levels in daily practice is the great interindividual variability, of which determinants are not completely characterized. 5 [HCQ] levels were found to be related to its major metabolite, N-desethylhydroxychloroquine (DHCQ), to HCQ weight-adjusted oral dose and also to the time since last dose taken. 243, 244 Analyzing a longitudinal cohort, Mok et al. 243 found that the majority of SLE patients screened had mainly [HCQ] subtherapeutic levels: <10 ng/ ml (defined as total non-adherence) in 11%, 10-500 ng/ml (subtherapeutic levels) in 77%, and >500 ng/ml (therapeutic levels) in only 12% patients. Levels correlated with the dose prescribed 243 and, importantly, higher [HCQ] levels were associated with less SLE flare occurrence over time. 243 Monitoring HCQ levels might allow identification of early nonadherence 243 and improve nonadherence. 72 HCQ levels measurement might help in counseling before the treatment change in regard to lack of adherence versus lack of treatment efficacy. 5 Finally, considering the HCQ's side effects related to long-term use, one important question is how to identify the appropriate moment for stopping the treatment. The first RCT designed for HCQ 66, 67 showed efficacy of long-term HCQ use in sustaining remission. In this RCT, the average HCQ total treatment duration before withdrawal was about 3 years. 66 

Multifaceted effects of hydroxychloroquine in human disease

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Atherosclerosis in systemic lupus erythematosus

2019 update of the EULAR recommendations for the management of systemic lupus erythematosus

American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis

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First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR)

The history of lupus throughout the ages

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Hydroxychloroquine effects on lipoprotein profiles (the HELP trial): a double-blind, randomized, placebo-controlled, pilot study in patients with systemic lupus erythematosus

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Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study)

Hydroxychloroquine blood levels in stable lupus nephritis under low dose (2-3 mg/kg/day): 12-month prospective randomized controlled trial

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Effects of hydroxychloroquine in patients with cutaneous lupus erythematosus: a multicenter, doubleblind, randomized, parallel-group trial

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Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis

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Anti-malarials exert a protective effect while mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort

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Efficacy analysis of hydroxychloroquine therapy in systemic lupus erythematosus: a study on disease activity and immunological biomarkers

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Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study

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Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus: analysis of 1002 patients from the EUSCLE database

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The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): an open-label prospective pilot study

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Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia

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Use of antimalarial drugs is associated with a lower risk of preeclampsia in lupus pregnancy: a prospective cohort study

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Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies

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Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort

The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus

Hydroxychloroquine reduces risk of incident diabetes mellitus in lupus patients in a dosedependent manner: a population-based cohort study

Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids

The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus

The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs

Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus

Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy

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Chloroquine increases low-density lipoprotein removal from plasma in systemic lupus patients

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Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect

Clinical significance of lipid profile in systemic lupus erythematosus patients: relation to disease activity and therapeutic potential of drugs

Impact of antimalarial (AM) on serum lipids in systemic lupus erythematosus (SLE) patients: a systematic review and meta-analysis

Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: a systematic review and metaanalysis

Vascular stiffness in women with systemic lupus erythematosus

Vascular elasticity of systemic lupus erythematosus patients is associated with steroids and hydroxychloroquine treatment

The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis

Open Access Predictors of major infections in systemic lupus erythematosus

Risk of serious infection for patients with systemic lupus erythematosus starting glucocorticoids with or without antimalarials

Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus

Risk factors for herpes zoster infection among Filipinos with systemic lupus erythematosus

Infections in newly diagnosed Spanish patients with systemic lupus erythematosus: journals.sagepub.com/home/tab data from the RELES cohort

Causes and factors related to hospitalizations in patients with systemic lupus erythematosus: analysis of a 20-year period (1995-2015) from a single referral centre in Catalonia

Hydroxychloroquine may reduce risk of pneumocystis pneumonia in lupus patients: a nationwide, population-based case-control study

Clinical characteristics and risk factors of infection in patients with systemic lupus erythematosus: a systematic review and meta-analysis of observational studies

Factors associated with low bone mineral density in female patients with Systemic Lupus Erythematosus

Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus

Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective longterm study of an Israeli cohort

Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort

From childhood to adulthood: the trajectory of damage in patients with juvenile-onset Systemic Lupus Erythematosus

Risk factors of damage in early diagnosed systemic lupus erythematosus: results of the Italian multicentre Early Lupus Project inception cohort

Antimalarials may influence the risk of malignancy in systemic lupus erythematosus

Causes and factors associated with frequent hospitalization in Chinese patients with systemic lupus erythematosus: an ambispective cohort study

Patterns and predictors of recurrent acute care use among Medicaid beneficiaries with systemic lupus erythematosus

Risk factors associated with mortality in systemic lupus erythematosus

Prognostic indicators of hospitalized patients with systemic lupus erythematosus: a large retrospective multicenter study in China

Outcome of patients with membranous lupus nephritis in Cape Town South Africa

Predictors of survival in Chinese patients with lupus nephritis

Effect of immunosuppressive therapies on survival of systemic lupus erythematosus: a propensity score analysis of a longitudinal cohort

Sustained complete renal remission is a predictor of reduced mortality, chronic kidney disease and end-stage renal disease in lupus nephritis

Trend of survival of a cohort of Chinese patients with Systemic Lupus Erythematosus over 25 years

Hydroxychloroquine and mortality among patients with Systemic Lupus Erythematosus in the general population

Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus

Cytokine polymorphisms influence treatment outcomes in SLE patients treated with antimalarial drugs

Clinical significance of serum and urinary interleukin-6 in systemic lupus erythematosus patients

Hydroxychloroquine suppresses interferoninducible genes and B cell activating factor in patients with incomplete and new-onset Systemic Lupus Erythematosus

Changing paradigms in the treatment of systemic lupus erythematosus

Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro associated cardiac manifestations of neonatal lupus

Evaluation of the risk of anti-SSA/Ro-SSB/La antibodyassociated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine

Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study

A systematic review and meta-analysis of pregnancy outcomes in patients with Systemic Lupus Erythematosus and Lupus Nephritis

Hydroxychloroquine and lupus pregnancy: review of a series of 36 cases

Safety of hydroxychloroquine in pregnant patients with connective tissue diseases a study of one hundred thirty-three cases compared with a control group

American College of Rheumatology Guideline for the management of reproductive health in rheumatic and musculoskeletal diseases

Risk and predictors of arterial thrombosis in lupus and non-lupus primary glomerulonephritis

Systemic Lupus Erythematosus in a multiethnic US Cohort (LUMINA) XXIII. Baseline predictors of vascular events

Incidence and risk factors of thromboembolism in Systemic Lupus Erythematosus a comparison of three ethnic groups

Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events

Hydroxychloroquine has no significant effect on lipids and apolipoproteins in Chinese systemic lupus erythematosus patients with mild or inactive disease

Antimalarials cholesterol profile of patients with systemic lupus erythematosus

Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus

Prevalence and correlates of accelerated atherosclerosis in Systemic Lupus Erythematosus

Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature

Vitamin D levels in women with Systemic Lupus Erythematosus and fibromyalgia

Six-year follow-up study of bone mineral density in patients with systemic lupus erythematosus

The role of non-corticosteroid related factors in osteonecrosis (ON) in systemic lupus erythematosus: a nested case-control study of inception patients

Why targeted therapies are necessary for systemic lupus erythematosus

Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort

Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: a systematic review and metaanalysis

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/ or antiphospholipid syndrome

EULAR recommendations for the management of antiphospholipid syndrome in adults

EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies

EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors

2018 update of the EULAR recommendations for the management of hand osteoarthritis

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update

2016 update of the EULAR recommendations for the management of early arthritis

Diagnosis, monitoring, and treatment of systemic lupus erythematosus: a systematic review of clinical practice guidelines

Systemic lupus erythematosus: state of the art on clinical practice guidelines

Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose

QTc interval prolongation in patients with systemic lupus erythematosus treated with hydroxychloroquine

Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature

Hydroxychloroquine-induced cardiomyopathy and heart failure in twins

Hydroxychloroquine-induced agranulocytosis in a patient with long-term rheumatoid arthritis

Hydroxychloroquine-induced hypoglycaemia in non-diabetic renal patient on peritoneal dialysis

Hypoglycaemia induced by hydroxychloroquine in a nondiabetic patient treated for RA

Hydroxychloroquine-induced toxic myopathy causing respiratory failure

Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article

Hydroxychloroquine blood levels predict

Additional analyses to confirm relationship of hydroxychloroquine blood levels to retinopathy: comment on the article by Petri et al

Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus

Fulminant hepatic failure secondary to hydroxychloroquine

Hydroxychloroquine-induced erythema multiforme

Hydroxychloroquine-induced dark butterfly rash in a rheumatoid arthritis patient

Woman in grey: hydroxychloroquine-induced hyperpigmentation

Hydroxychloroquine-induced podocytopathy mimicking Fabry disease

Hydroxychloroquine-induced renal phospholipidosis resembling fabry disease in undifferentiated connective tissue disease: a case report

Hydroxychloroquine safety: a meta-analysis of randomized controlled trials

Hydroxychloroquine-induced hyperpigmentation in systemic diseases: prevalence, clinical features and risk factors: a cross-sectional study of 41 cases

Hydroxychloroquine-induced pigmentation in patients with systemic lupus erythematosus a case-control study

Hydroxychloroquine-induced erythema multiforme

Risk factors for hydroxychloroquine retinopathy in systemic lupus erythematosus: a case-control study with hydroxychloroquine blood-level analysis

Treating lupus patients with antimalarials: analysis of safety profile in a single-center cohort

The clinical significance of monitoring hydroxychloroquine levels in patients with systemic lupus erythematosus: a systematic review and meta-analysis

Hydroxychloroquine serum concentrations and flares of systemic lupus erythematosus: a longitudinal cohort analysis

Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus

Discontinuation of hydroxychloroquine in older patients with systemic lupus erythematosus: a multicenter retrospective study