NSC 4375

Hydroxychloroquine in systemic lupus erythematosus (SLE)

Ponticelli C and Moroni G



MD, Senior Consultant Nephrological Unit, Humanitas Clinical and Research Center,

Rozzano (Milano),Italy


MD, Nephrological Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,

Milan, Italy.

Author address
Claudio Ponticelli, MD,FRCP (edin)
Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milano) Phone ++39-3356499870 email. [email protected]

Gabriella Moroni, MD
Nephrological Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 15, 20122 Milano, Italy. Phone ++39-0255036374 email. [email protected]

Corresponding author
C Ponticelli
Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (Milano) Phone ++39-3356499870 email. [email protected]


Key words. Systemic lupus erythematosus , Hydroxychloroquine, Antimalarial agents, Retinopathy, Lupus flares, Cutaneous lupus, Lupus nephritis.


Hydroxychloroquine (HCQ) is an alkalinizing lysosomatropic drug that accumulates in

lysosomes where it inhibits some important functions by increasing the pH. HCQ has

proved to be effective in a number of autoimmune diseases including systemic lupus erythematosus (SLE).

Areas covered.

In this review the mechanisms of action, the efficacy, and the safety of HCQ in the

management of patients with SLE have been reviewed. HCQ may reduce the risk of flares,

allow the reduction of the dosage of steroids, reduce organ damage, and prevent the

thrombotic effects of anti-phospholipid antibodies. The drug is generally safe and may be

prescribed to pregnant women. However, some cautions are needed to prevent retinopathy, a rare but serious complication of the prolonged use of HCQ.

Expert opinion.

HCQ may offer several advantages not only in patients with mild SLE but can also exert

important beneficial effects in lupus patients with organ involvement and in pregnant

women. The drug has a low cost and few side effects. These characteristics should encourage a larger use of HCQ, also in lupus patients with organ involvement .

1. Introduction

Hydroxychloroquine sulfate (HCQ) is the hydroxylated analog of chloroquine. The drug

has been initially used as an antimalarial agent, since it may inhibit the plasmodial heme

polymerase. However, a number of experimental and clinical observations also outlined

the efficacy of HCQ in a wide array of conditions, including diabetes mellitus,

dyslipidemias, coagulopathies, infectious diseases, malignancies, as well as in a number

of autoimmune diseases, including Sjogren’s syndrome, rheumatoid arthritis, and systemic lupus erythematosus [1].

Following a systematic review of the literature on Entrez-PubMed , we have provided an

overview of the main mechanisms of action, the pharmacological and clinical data, and the safety of HCQ in the management of SLE.

2 Efficacy and safety

2.1 Mechanisms of action (Table 1).




In SLE, HCQ can interfere with the immune response at different levels (Fig.1). The drug

can interfere with the activation of the innate immunity by inhibiting TLR7 and 9

signaling. These receptors are located intracellularly on endosomal membranes, and their

ligands must be taken up into the endosome to result in activation[27]. Theoretically HCQ

might interfere with TLR7 and TLR9 by inhibiting the endosomal acidification. However, it

is more likely that HCQ directly binds to inhibitors to nucleic acids masking their TLR-

binding epitope [28]. HCQ accumulation in the lysosomes of antigen-presenting cells

(DCs, macrophages, B cells) can inhibit the presentation of the major histocompatibility

complex peptides to T cells, since acidic cytoplasmic components are needed for the

antigen to be digested and for binding to assemble to the α and β chains of the MHC type

II [29]. This effect can be enhanced by the co-administration of minocycline [30]. HCQ

can inhibit the proinflammatory cytokines IL-6, IL-1β TNF-α [31], and can block T cell

activation by disrupting the T cell receptor dependent calcium signaling [32]. Moreover,

HCQ is a powerful inhibitor of lysosome-dependent autophagy. By preventing the

acidification of lysosomal compartment HCQ can impair autophagic protein degradation,

which is a critical step for activating innate and acquired immunity. This effect is currently

investigated by oncologists, who are using combination of HCQ with anti-cancer

treatments in different types of malignancy [33]. Finally, treatment with HCQ has been

associated with reduced risk of thrombosis in antiphospholipid syndrome .By using

techniques of ellipsometry and atomic force microscopy, Rand et al demonstrated that

HCQ can inhibit the binding of antiphospholipid antibody – β2-glycoprotein I complexes to

phospholipid bilayers [34] . HCQ can also exert another mechanism of protection against


antiphospholipid syndrome. Annexin A5 is a protein that crystallizes over phospholipid

bilayers. Antiphospholipid antibodies disrupt the annexin A5 binding , so inhibiting the

activity of this potent anticoagulant protein. HCQ can reverse the effect of

antiphospholipid antibodies on annexin 5 and restore annexin A5 binding tophospholipid

bilayers, so protecting the annexin A5 anticoagulant activity from disruption by antiphospholipid antibodies[35].

2.2 Pharmacological data

HCQ sulfate is a weak base that is completely absorbed from the gastrointestinal tract.

The drug has a good bioavailability (about 0.74) and is metabolized in the liver by

cytochrome P450 enzymes to N-desethylhydroxychloroquine, desethylchloroquine, and

bisdesethylchloroquine . It is mainly excreted via the kidneys with a long half-life of elimination, approximately 40-60 days [36]. The drug is extensively sequestered in the

tissues. The slow accumulation can account for its delay in achieving steady-state

concentrations and elimination. Variable concentrations may arise after standard

administered doses because of inter-individual pharmacokinetic variability. These factors

are likely to contribute to the delayed therapeutic response and the variable response,

respectively. Pharmacokinetic interaction studies are limited. Potentially important kinetic

interactions have been documented for d-penicillamine and cimetidine but have not been found for aspirin, ranitidine or imipramine [37]. Drugs that induce cytochrome P450

enzymes (such as isoniazide or anticonvulsivant agents) may reduce the blood levels of

HCQ while inhibitors of cytochrome P450 (such as nondihydropyridinic calcium channel

blockers) may increase the blood levels. HCQ improves both beta cell function and insulin

sensitivity in non-diabetic individuals. These metabolic effects may explain why HCQ

treatment is associated with a lower risk of type 2 diabetes [38]. However, dose altering is

recommended in patients taking insulin to prevent severe hypoglycemia. In SLE patients,

the initial dosage of HCQ is 400 mg orally once or twice a day. Therapeutic effect may

appear after several weeks or months. The maintenance dose ranges between 200 and 400 mg per day. There is controversy about the best dose of this medication , with some

advocating dosing based on actual body weight , whilst others are in favor of calculating the daily dose based on ideal body weight.

HCQ concentration in the blood displays a great variability among patients under treatment and even in healthy volunteers and adherent patients [39]. Low HCQ blood levels can be

associated with development of flares in patients with inactive SLE. In unselected patients

with SLE who were receiving HCQ at a dose of 400 mg per day for at least 6 months, the

mean blood levels of HCQ were significantly lower (mean 694 ng/ml) in those with active

disease than in those with inactive disease (mean 1079 ng/ml). A multivariate logistic

regression showed that the HCQ concentration was the only predictor of exacerbation

[40]. In another study on SLE patients, it was shown that the blood levels of HCQ were

similar regardless of height and ideal body weight. There was a trend toward higher

disease activity with lower HCQ levels. The authors concluded that a dose of 6.5 mg/kg

of actual body weight (max 400 mg daily) is appropriate. Accordingly, the daily dose should be reduced below 400 mg per day for those weighing less than 61 kg [41].

2.3 Efficacy in SLE.

The first reports on the use of HCQ in SLE were published more than 50 years ago [42].

For some decades, the drug was mainly used in patients with cutaneous lupus, often in

association with other antimalarial agents. Retrospective reviews of large series reported

good results in different categories of skin lupus treated with HCQ, either alone or in

combination with other antimalarial agents, particularly when blood concentrations of HCQ

were monitored [43-45]. Today, the benefit of antimalarials in the treatment of cutaneous

SLE is well established. However, about 50% of patients with cutaneous SLE fail to

respond to HCQ. In these patients a progressive increase of HCQ doses to reach blood

concentrations greater than 750 ng/ml may obtain response in 81% of cases. Thus, it has

been suggested to increase HCQ doses to reach blood concentrations greater than 750

ng/ml before addition of other treatments in refractory skin lupus [46]. In patients who do

not respond to adequate dosage of HCQ, additional treatments can be proposed [47].

These may include synthetic drugs (such as glucocorticoids, cyclophosphamide,

azathioprine, mycophenolate ,cyclosporine, and tacrolimus) and biologic agents (such as, belimumab, and intravenous immunoglobulins)

There is growing evidence of the beneficial effects of HCQ to treat mild symptoms of systemic lupus- such as arthralgia, fatigue, fever, rash – and to prevent disease flares[48-

51]. As pointed out above, HCQ can also decrease the risk of thromboembolism in

patients with antiphospholipid antibodies [52-55]. Although HCQ passes through the

placenta, the available studies showed that it is neither teratogenic nor harmful for the

baby and can allow for the reduction of the average dose of glucocorticoids during pregnancy[56-60].

A main advantage of HCQ consists in its potential prevention of some severe

complications. Osteoporosis is frequent in patients with SLE, particularly in women

receiving prolonged steroid treatment. The use of HCQ may increase the spine bone

mineral density in women with SLE [61]. Accelerated atherosclerosis and its long-term

sequelae are a major cause of late morbidity and mortality among patients with SLE. HCQ

can interfere with some risk factors of atherogenesis, by reducing the incidence of

thrombotic events, lowering total cholesterol in patients receiving steroids and lowering


fasting blood glucose concentration[62,63]. Murine models suggested also other

cardioprotective mechanisms of HCQ. By enhancing phosphorylation of the pro-survival

kinase ERK1/2, HCQ can exert protection in a myocardial ischemia-reperfusion injury model [64]. In a model of SLE with endothelial damage caused by reactive oxygen

species, an early administration of HCQ could exert vascular protection, via an anti-oxidant effect [65] . In NZBWF1 lupus mice, chronic HCQ treatment reduced hypertension,

endothelial dysfunction, and organ damage, despite the persistent elevation of anti-double- stranded DNA[66]. Thus, although atherosclerotic complications are caused by multiple

factors, clinical and experimental studies would suggest the possibility of reducing the burden of cardiovascular diseases in lupus patients [67].

To assess whether HCQ influenced survival in SLE patients, a multiethnic case-control

study, called Lumina, was performed. In Lumina study, 61 deceased patients (cases)

were matched for disease duration (within 6 months) with 547 living patients (controls) in

a proportion of 3:1. Propensity scores were derived by logistic regression to adjust for

confounding by indication as patients with SLE with milder disease manifestations are

more likely to be prescribed HCQ. Hydroxychloroquine was well tolerated and

demonstrated a protective effect on survival which was evident even after taking into consideration the factors associated with treatment decisions [68] . In another study, the

group of Toronto evaluated whether HCQ may prevent organ damage in SLE. The

Authors conducted a nested case-control study embedded in an inception cohort of

patients with lupus. Patients with Systemic Lupus International Collaborating Clinics

Damage Index (SDI) > 0 at 3 years were considered cases and patients with SDI = 0 were

controls. Among 481 patients who had 3 or more years of follow-up 151 cases were matched with 151 controls. Univariate analysis identified age, the use of any


immunosuppressive drugs, HCQ, and cumulative dose of steroids as significant covariates

associated with damage accrual. In multivariate analysis, the use of HCQ remained

significantly associated with less damage (OR 0.34 ) while age (OR 1.05) and a variable

combining SLE activity and steroid dose (OR 1.73) were associated with damage at 3

years. The investigators acknowledged that there were limitations to their analysis but

concluded that HCQ use was associated with less damage at 3 years after diagnosis of

SLE when attention was given and adjustment done for disease activity and steroid dose, duration of disease, and calendar year of diagnosis [69] . A systematic review of the

English literature between 1982 and 2007 reported that there was a high level of evidence

that chloroquine and HCQ can prevent lupus flares and increase long-term survival of

patients with SLE; there was moderate evidence of protection against irreversible organ

damage, thrombosis and bone mass loss. Toxicity of these drugs was infrequent, mild and

usually reversible, with HCQ having a safer profile. By contrast, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak [70].

In summary, there is evidence that HCQ may exert a number of potential benefits not only

in patients with mild forms of SLE but also in patients with organ involvement. In

prescribing the dose the physician should take into account that HCQ is a slow-acting

drug, its benefit may often manifest after 6 months. Therefore in acute phases of SLE

should be used in combination with other therapeutic agents which could later be reduced when the antimalarial effect becomes manifest

When using HCQ in patients with lupus nephritis is preferable not to check proteinuria by

dipstick. In fact, the analytical interference of HCQ with standard dipstick test may lead to

a high rate of false positive results [71]. Although many authorities believe that HCQ should be given to most patients with SLE during the whole course of the disease,


irrespective of its severity, the percentage of lupus patients taking HCQ remains lower than expected [72] .

2.4 Safety evaluation

HCQ is considered to be a safe drug. However, as any other medicament HCQ can be

responsible of a number of adverse events. HCQ side effects are usually dose-dependent

and many adverse events reflect intentional or unintentional over-dosage. Patients with

allergy, psoriasis, porphyria, alcoholism, are more susceptible to cutaneous side effects.

Children are particularly vulnerable to side effects for even small over-dosage of

chloroquine. There is limited data on pediatric HCQ overdoses and no reports of toxicity

from 1-2 pills, but given its similarity to chloroquine, also HCQ should be considered

potentially toxic at small doses in the pediatric population [73] . As a general rule,

monitoring side effects should be continued throughout the time patients are taking HCQ long-term.

We report here the most serious side effects of HCQ, taking into account that not all the reported complications occurred in patients without SLE.

Ocular complications . About 10% of patients receiving HCQ may develop corneal

deposits. These changes are dose-dependent, transient and reversible [74] . The most

worrying ocular complication is retinopathy. It is characterized by edema, atrophy, loss of

foveal reflex, increased macular recovery time following exposure to a bright light, and

elevated retinal threshold to red light in macular, paramacular, and peripheral retinal areas.

Visual field defects have included pericentral or paracentral scotoma, central scotoma with

decreased visual acuity, rarely field constriction, and abnormal color vision. The most

common visual symptoms attributed to retinopathy are reading and vision difficulties

(words, letters, or parts of objects missing), photophobia, blurred distance vision, missing


or blacked out areas in the central or peripheral visual field, and light flashes and streaks.

High dose and long duration of use are the most significant risks of developing retinopathy.

The risk dramatically increases with cumulative doses higher than 1,000 grams of HCQ [75] . At recommended doses of 6.5 mg/kg, the risk of retinal toxicity up to 5 years is

under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years .

However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year [76]. In most cases retinopathy is not reversible, and there is no

present therapy. Recognition at an early stage is important to prevent central visual loss.

The American Academy of Opthalmology recommends that patients and prescribing

physicians should be informed about risk of toxicity, and the importance of regular annual

screening. A maximal daily HCQ use ≤ 5mg/kg real body weight is recommended . The

primary screening tests are automated visual fields plus spectral-domain optical coherence

tomography . These should look beyond the central macula in Asian patients. The

multifocal electroretinogram can provide objective corroboration for visual fields, and

fundus autofluorescence can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus [ 76].

Cardiovascular side effects.

Cardiotoxicity is a rare but serious complication of HCQ. Cardiotoxicity commonly

manifests clinically as a restrictive or dilated cardiomyopathy or with conduction system

abnormalities including atrioventricular block and bundle branch block. However, non-

specific chest discomfort may be a presenting feature [77]. Risk factors for the

development of HCQ-induced cardiotoxicity include older age, female gender, longer

duration of therapy (>10 years), elevated per-kilogram daily dose, pre-existing cardiac

disease, and renal insufficiency [78,79]. The pathogenetic role of HCQ has been

questioned , but it is possible that the lysosomal dysfunction caused by HCQ can lead to

endomyocardial accumulation of pathologic metabolic products [80]. The diagnosis may be

difficult and often requires endomyocardial biopsy that may reveal myocyte vacuolization

at optic microscopy and pathognomonic sarcoplasmic myelinoid and curvilinear bodies on

electron microscopy [81]. Prognosis in HCQ cardiotoxicity can vary from death to cardiac transplantation to partial or complete improvement [77,82].

Cutaneous complications

Dermatologic adverse events have included nonlight-sensitive psoriasis, bleaching of hair,

alopecia, pruritus, skin and mucosal pigmentation, photosensitivity, and skin eruptions.

These side effects are often caused by allergic reactions [83]. Exceptional cases of life-

threatening epidermal necrolysis [84-86] have been reported. HCQ in the skin can be

detected in some patients with mucocutaneous hyperpigmentation. It may be attributed to

the strong binding of HCQ to melanin HCQ in the skin can be detected in some patients with mucocutaneous hyperpigmentation [87].

Neurologic and psychiatric complications

Nervous system side effects include headache, dizziness, vertigo, tinnitus. and difficulty in

seeing to read . Rare cases of convulsions have been reported [88]. Peripheral

neuropathy may be associated with a bilateral progressive proximal weakness of the

lower extremities with variable polyneuropathy, especially in patients with worsening renal

function [89]. HCQ may also cause myopathy that may be so severe to cause respiratory

failure [90]. HCQ-related neuromyopathy may be underdiagnosed because its signs,

symptoms, and laboratory results are similar to other chronic diseases [91]. Therapeutic

doses of HCQ sometimes cause psychosis, delirium, personality change, and depression [92].


Liver complications

Hepatic side effects include isolated cases of abnormal liver function and fulminant hepatic failure [93-95].

Gastrointestinal complications.

Diarrhea , loss of appetite, nausea or vomiting and stomach cramps may occur in these

patients. These troubles may be caused by microbiota modifications induced by HCQ

[96]. To prevent gastric discomfort a tablet of HCQ may be taken once or twice a day with

a glass of milk or a meal to decrease nausea. Antiacids should not be prescribed as they

can impair gastrointestinal absorption. Gastrointestinal side effects may be reversed by adjusting the dose or by withdrawing the drug for a short period.


The available data show that the use of HCQ in patients with SLE is effective and safe.

HCQ can be used for treatment of constitutional symptoms of lupus, such as joint pain

and swelling, rashes, and fatigue. However, the drug may also be given along with

steroids and immunosuppressive drugs to improve the life expectancy of patients with

SLE and in reducing lupus flares and organ damage accrual. Of great importance, HCQ

may prevent the thrombotic complications in patients with antiphospholipid syndrome and

may be used safely during pregnancy. Further benefits may include protection against osteoporosis and atherosclerosis.

HCQ is generally considered to be a safe drug. However, its long-term use may be rarely

complicated by some serious side effects, particularly retinopathy. To minimize the risk of

ocular complications some precautions are needed. These include a fundus oculi

evaluation before prescribing the drug and an annual ophthalmologic control thereafter.

Retinopathy and other side effects are usually related to the cumulative dosage of HCQ.


In adults the daily dose should not exceed 400 mg. Overdose is particularly dangerous in children.

4. Expert opinion

SLE is a chronic autoimmune disease that mainly affects women in childbearing age and

certain racial groups. The disease has protean manifestations and follows a relapsing and

remitting course. Many organs and tissues are involved in SLE, such as the kidneys, the

heart, and the brain as well as the skin, the joints, the pleura and the pericardium. The

prognosis of SLE was ominous until few years ago, particularly for patients with organ

involvement and frequent flares. Today, the life expectancy is considerably improved [97]

. Even in lupus nephritis, the most severe form of SLE, the patient survival at 20 years

ranges around 95% [98]. A better understanding of the disease, an earlier diagnosis and a

more refined treatment in comparison with the recent past accounted for these improved

results. Yet, SLE is still a challenge for physicians. Most patients with lupus need a

continuous treatment with glucocorticoids and /or immunosuppressive agents which have

significant side effects. This iatrogenic morbidity can impair the quality of life and the long-

term prognosis. Biological agents may allow to reduce the dosage of synthetic drugs but

the long-term safety and efficacy of the available monoclonal antibodies are still poorly

defined [99,100] while their high cost is a main limitation to their extensive use in lupus patients, particularly in those with poor socio-economic status.

In this complicated setting, the use of HCQ may offer several advantages. It may control

constitutional symptoms, spare the use of glucocorticoids, decrease the risk of flares and

organ damage , and increase the life expectancy of SLE patients . HCQ can also reduce

the risk of antiphospholipid syndrome complications and can be used safely in pregnant women. Importantly, HCQ has a low cost and few side effects. These characteristics


should encourage a larger use of HCQ not only in patients with mild SLE but also in those with organ involvement.


This paper is not funded

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with the

subject matter or materials discussed in the manuscript. This includes

employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.


Papers of special note have been highlighted as:

* of interest


4) Kaufmann AM, Krise JP . Lysosomal Sequestration of Amine-containing Drugs: Analysis and Therapeutic Implications. J Pharm Sci. 2007; 96 (4): 729–46


5) Settembre C, Di Malta, Polito VA et al. TFEB links autophagy to lysosomal

biogenesis. Science. 2011;332:1429–33**The identification of a master gene, transcription factor EB that regulates lysosomal biogenesis and autophagy

6) Ghodke-Puranik Y, Niewold TB. Immunogenetics of systemic lupus erythematosus: a comprehensive review. J Autoimmun. 2015; 64: 125–36 * An excellent review of genetic and epigenetic polymorphisms involved in SLE pathogenesis.
6) Bijl M., Kallenberg C.G. Ultraviolet light and cutaneous lupus. Lupus. 2006;15:724– 7.

7) Draborg A.H., Duus K., Houen G. Epstein-Barr virus and systemic lupus erythematosus. Clin. Dev. Immunol. 2012;2012:370516.

8) Simard J.F., Costenbader K.H., Liang M.H., Karlson E.W., Mittleman M.A.

Exposure to maternal smoking and incident SLE in a prospective cohort study. Lupus. 2009;18:431–5

10) Fadeel B, Xue D, Kagan V. Programmed cell clearance: molecular regulation of

the elimination of apoptotic cell corpses and its role in the resolution of inflammation Biochem Biophys Res Commun. 2010 ; 396(1): 7–10

11) Fenton K. The effect of cell death in the initiation of lupus nephritis. Clin Exp Immunol 2015; 179(1):11-6

11)Niewold TB, Clark DN, Salloum R, Poole BD. Interferon alpha in systemic lupus erythematosus. J Biomed Biotechnol. 2010;2010:948364.

12)Choi J, Kim ST, Craft J. The pathogenesis of Systemic Lupus Erythematosus -An update. Curr Opin Immunol. 2012; 24(6), 651-7

13)Moody KL, Uccellini MB, Avalos AM, Marshak-Rothstein A, Viglianti GA. Toll-Like

Receptor-Dependent Immune Complex Activation of B Cells and Dendritic Cells. Methods Mol Biol. 2016;1390:249-72.


15)Niewold TB. Interferon alpha as a primary pathogenic factor in human lupus. J Interferon Cytokine Res. 2011;31:887–92

16)Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell

differentiation by IFN-alpha in systemic lupus erythematosus. Science.

2001;294:1540–3. ** The capacity of SLE patients’ serum to induce dendritic cell differentiation depends on the actions of interferon-alpha

17) Lamphier M, Zheng W, Latz E, et al. Novel small molecule inhibitors of TLR7 and

TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2014 ;85(3):429- 40.

18) Crispin JC, Kyttaris VC, Terhorst C, Tsokos GC. T cells as therapeutic targets in

SLE. Nat Rev Rheumatol. 2010;6:317–325.* Therapeutic approaches that limit

the cognate interaction between T cells and B cells prevent inappropriate tissue homing and restore Treg cell function

19)Jenks SA, Sanz I. Altered B cell receptor signaling in human systemic lupus erythematosus Autoimmun Rev. 2009; 8 (3):209-13

20)Liu Z, Davidson A. BAFF and selection of autoreactive B cells. Trends Immunol. 2011 A; 32(8):388-94

21)Codogno P, Mehrpour M, Proikas-Cezanne T. Canonical and non-canonical

autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol. 2011; 13, 7-12

22) Levine B,Deretic V. Unveiling the roles of autophagy in innate and adaptive

immunity. Nat Rev Immunol. 2007 ;7(10):767-77. * An important review showing the impact of autophagic processes on activation of innate and adaptive immunity

23) Wang L, Law HK. The Role of Autophagy in Lupus Nephritis. Int J Mol Sci. 2015 ;16(10):25154-67.


24)Gros F, Arnold J, Page N, et al. Macroautophagy is deregulated in murine and human lupus T lymphocytes. Autophagy. 2012 ;8(7):1113-23.

25)Clarke AJ, Ellinghaus U, Cortini A, et al. Autophagy is activated in systemic lupus

erythematosus and required for plasmablast development. Ann Rheum Dis. 2015;74(5):912-20.

28)Kuznik A, Bencina M, Svajger U, et al. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol. 2011 ;186(8):4794-804.

29)Fox R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus. 1996 ;5 Suppl 1:S4-10

30)Kalish RS, Koujak S. Minocycline inhibits antigen processing for presentation to

human T cells: additive inhibition with chloroquine at therapeutic concentrations. Clin Immunol. 2004 ;113(3):270-7.

31) Wozniacka A, Lesiak A, Boncela J, et al. The influence of antimalarial treatment on

IL-1beta, IL-6 and TNF-alpha mRNA expression on UVB-irradiated skin in systemic lupus erythematosus. Br J Dermatol. 2008;159(5):1124–30

32) Goldman FD, Gilman AL, Hollenback C, et al Hydroxychloroquine inhibits calcium

signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood. 2000 ;95(11):3460-6.

33) Lotze MT, Maranchie J, Appleman L. Inhibiting autophagy: a novel approach for the treatment of renal cell carcinoma. Cancer J. 2013 ;19(4):341-7

34) Rand JH, Wu XX, Quinn AS,et al. Hydroxychloroquine directly reduces the binding

of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid

bilayers. Blood. 2008 ;112(5):1687-95* The demonstration that the antithrombotic

effects of hydroxychloroquine are related to its binding to aPL-beta2GPI complexes

35) Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the annexin A5

anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood. 2010 ;115(11):2292-9.

36) Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and

pharmacological properties of hydroxychloroquine and chloroquine in treatment of

systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015 ;23(5):231-69

37)Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus. 1996 ;5 Suppl 1:S11-5.

38)Wasko MC, McClure CK, Kelsey SF, et al. Antidiabetogenic effects of

hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial.Diabetologia. 2015 ;58(10):2336-43.

39) Tett SE, Cutler DJ, Beck C, Day RO. Concentration-effect relationship of

hydroxychloroquine in patients with rheumatoid arthritis–a prospective, dose ranging study, J. Rheumatol. 2000; 27:1656–60.

40) Costedoat-Chalumeau N, Amoura Z, Hulot JS, et al. Low blood concentration of

hydroxychloroquine is a marker for and predictor of disease exacerbations in

patients with systemic lupus erythematosus, Arthritis Rheum.2006; 54 :3284–90.

41) Durcan L, Clarke WA, Magder LS, Petri M Hydroxychloroquine Blood Levels in

Systemic Lupus Erythematosus: Clarifying Dosing Controversies and Improving


Adherence. J Rheumatol. 2015;42(11):2092-7.* Useful guidelines for the use of HCQ in SLE.

42) Tye MJ, White H, Appel B, Ansell HB. Lupus erythematosus treated with a

combination of quinacrine, hydroxychloroquine and chloroquine. N Engl J Med. 1959 ;260(2):63-6.

43) Jessop S, Whitelaw DA, Delamere FM. Drugs for discoid lupus erythematosus. Cochrane Database Syst Rev. 2009 ;(4):CD002954.

43)Yokogawa N, Tanikawa A, Amagai M, et al. Response to hydroxychloroquine in

Japanese patients with lupus-related skin disease using the cutaneous lupus

erythematosus disease area and severity index (CLASI). Mod Rheumatol. 2013;23(2):318-22.

45) Francès C, Cosnes A, Duhaut P, et al. Low blood concentration of

hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. Arch Dermatol. 2012 ;148(4):479-84

46) Chasset F, Arnaud L, Costedoat-Chalumeau N,et al. The effect of increasing the

dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus

erythematosus (CLE): An open-label prospective pilot study. J Am Acad Dermatol. 2016; 74(4):693-9

47)Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: issues in diagnosis and treatment. Am J Clin Dermatol. 2009;10(6):365-81.

48)Ben-Zvi I., Kivity S., Langevitz P., Shoenfeld Y. Hydroxychloroquine: From malaria to autoimmunity. Clin. Rev. Allergy Immunol. 2012;42:145–53

49)Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus. 1996;5 Suppl 1:S16-22


50) Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ. The relevance of antimalarial

therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE.

Lupus. 1993 ;2 Suppl 1:S13-5. *One of the first papers showing benefits of HCQ on thrombosis, hyperlipidaemia and immune response

51) Mok CC, Penn HJ, Chan KL, et al. Hydroxychloroquine Serum Concentrations and

Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis. Arthritis Care Res (Hoboken). 2016 ; 68(9):1295-302.

52) Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus

erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep. 2011 ;13(1):77-80

53) Broder A, Putterman C. Hydroxychloroquine use is associated with lower odds of

persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol. 2013;40(1):30-3.

54)Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015 ;14(4):358-62.

55)Gerosa M, Meroni PL, Erkan D. Recognition and management of antiphospholipid syndrome. Curr Opin Rheumatol. 2016 ;28(1):51-9

56)Khamashta MA, Buchanan NM, Hughes GR. The use of hydroxychloroquine in lupus pregnancy: the British experience. Lupus. 1996 ;5 Suppl 1:S65-6.

57)Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 2006 ;54(11):3640-7.

58)Diav-Citrin O, Blyakhman S, Shechtman S, Ornoy A. Pregnancy outcome following

in utero exposure to hydroxychloroquine: a prospective comparative observational study. Reprod Toxicol. 2013 ;39:58-62

59) Ponticelli C, Moroni G. Immunosuppression in pregnant women with systemic lupus erythematosus. Expert Rev Clin Immunol. 2015 ;11(5):549-52

60)Moroni G, Ponticelli C. Pregnancy in women with systemic lupus erythematosus (SLE). Eur J Intern Med. 2016 ;32:7-12

61)Mok CC, Mak A, Ma KM. Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus. Lupus. 2005;14(2):106-12.

62)Stoyan G, Petri M: Atherosclerosis in systemic lupus erythematosus . J Cardiovasc Pharmacol 2013;62 (3):255-62

63)Chen YM, Lin CH, Lan TH, et al. Hydroxychloroquine reduces risk of incident

diabetes mellitus in lupus patients in a dose-dependent manner: a population-based cohort study. Rheumatology (Oxford). 2015 ;54(7):1244-9

64) Bourke L, McCormick J, Taylor V, et al. Hydroxychloroquine Protects against

Cardiac Ischaemia/Reperfusion Injury In Vivo via Enhancement of ERK1/2 Phosphorylation. PLoS One. 2015;10(12):e0143771.

65) Virdis A, Tani C, Duranti E. et al. Early treatment with hydroxychloroquine prevents

the development of endothelial dysfunction in a murine model of systemic lupus erythematosus. Arthritis Res Ther. 2015 ;17:277

66) Gómez-Guzmán M, Jiménez R, Romero M,et al. Chronic hydroxychloroquine

improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. Hypertension. 2014;64(2):330-7.

67)Sun L, Liu M, Li R, et al . Hydroxychloroquine, a promising choice for coronary artery disease? Med Hypotheses. 2016 ;93:5-7.

68)Alarcón GS, McGwin G, Bertoli AM, et al . Effect of hydroxychloroquine on the

survival of patients with systemic lupus erythematosus: data from LUMINA, a

multiethnic US cohort (LUMINAL). Ann Rheum Dis. 2007 ;66(9):1168-72.** A large

multiethnic study showing that the use of HCQ in lupus patients had a protective effect on survival.


69) Akhavan PS, Su J, Lou W, et al. The early protective effect of hydroxychloroquine

on the risk of cumulative damage in patients with systemic lupus erythematosus. J

Rheumatol. 2013 ;40(6):831-41 *A retrospective analysis showing that HCQ use was associated with less organ damage at 3 years after diagnosis of SLE

70) Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy

and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010 ;69(1):2

71) Wang JM, Li JY, Huang WC, et al. Confirmed False Positive Proteinuria in Patients

with Systemic Lupus Erythematosus Taking Hydroxychloroquine: a Spot Sample Measurement. Clin Lab. 2015;61(5-6):581-6.

72) Costedoat-Chalumeau N, Dunogué B, Morel N, Le Guern V, Guettrot-Imbert G.

Hydroxychloroquine: a multifaceted treatment in lupus. Presse Med. 2014 ;43:e167- 80.

73) Smith ER, Klein-Schwartz W. Are 1-2 dangerous? Chloroquine and

hydroxychloroquine exposure in toddlers. J Emerg Med. 2005 ;28(4):437-43.

74)Easterbrook M. Is corneal deposition of antimalarial any indication of retinal toxicity? Can J Ophthalmol. 1990 ;25(5):249-51.

75)Brandao LM, Palmowski-Wolfe AM. A possible early sign of hydroxychloroquine macular toxicity. Doc Ophthalmol. 2016 ;132(1):75-81

76) Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF.

American Academy of

Ophthalmology. Recommendations on Screening for Chloroquine and

Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016

;123(6):1386-94.** The updated recommendations of the American Academy of Ophthalmology on screening for hydroxychloroquine retinopathy.


77) Joyce E, Aurelie Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting

as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care. 2013; 2(1): 77–83.

78)Baguet JP, Tremel F, Fabre M. Chloroquine cardiomyopathy with conduction disorders. Heart 1999; 81: 221–3

79)Nord JE, Shah PK, Rinaldi RZ, et al. Hydroxychloroquine cardiotoxicity in systemic

lupus erythematosus: a report of 2 cases and review of the literature. Semin Arthritis Rheum 2004; 33: 336–51

80)Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy – a review of the literature. Immunopharmacol Immunotoxicol. 2013 ;35(3):434-42.

81)Roos JM, Aubry MC, Edwards WD. Chloroquine cardiotoxicity: clinicopathologic

features in three patients and comparison with three patients with Fabry disease. Cardiovasc Pathol. 2002 ;11(5):277-83.

82)Costedoat-Chalumeau N, Hulot JS, Amoura Z, et al. Cardiomyopathy related to antimalarial therapy with illustrative case report. Cardiology 2007; 107: 73–80

83)Soria A, Barbaud A, Assier H, et al .Cutaneous Adverse Drug Reactions with Antimalarials and Allergological Skin Tests. Dermatology. 2015;231(4):353-9

84)Callaly EL, FitzGerald O, Rogers S. Hydroxychloroquine-associated, photo-induced toxic epidermal necrolysis. Clin Exp Dermatol. 2008 ;33(5):572-4.

85)Murphy M, Carmichael AJ. Fatal toxic epidermal necrolysis associated with hydroxychloroquine. Clin Exp Dermatol. 2001; 26(5):457-8

86)Cameron MC, Word AP, Dominguez A. Hydroxychloroquine-induced fatal toxic

epidermal necrolysis complicated by angioinvasive rhizopus. Dermatol Online J. 2014 ;20(11).


87) Jallouli M, Francès C, Piette JC, et al Hydroxychloroquine-induced pigmentation in

patients with systemic lupus erythematosus: a case-control study. JAMA Dermatol. 2013;149 (8):935-40.

88) Malcangi G, Fraticelli P, Palmieri C, Cappelli M, Danieli MG Hydroxychloroquine-

induced seizure in a patient with systemic lupus erythematosus. 2000 ;20(1):31-3.

89)Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000;27(12):2927-31.

90)Siddiqui AK, Huberfeld SI, Weidenheim KM, Einberg KR, Efferen LS.

Hydroxychloroquine-induced toxic myopathy causing respiratory failure. Chest. 2007;131(2):588-90.

91) Kwon JB, Kleiner A, Ishida K, et al .Hydroxychloroquine-induced myopathy. J Clin Rheumatol. 2010 ;16(1):28-31.

91)Good MI, Shader RI. Behavioral toxicity and equivocal suicide associated with chloroquine and its derivatives Am J Psychiatry. 1977 ;134(7):798-601.

92)Makin AJ, Wendon J, Fitt S, Portmann BC, Williams R. Fulminant hepatic failure secondary to hydroxychloroquine. Gut. 1994;35(4):569-70.

93)Giner Galvañ V, Oltra MR, Rueda D, Esteban MJ, Redón J. Severe acute hepatitis

related to hydroxychloroquine in a woman with mixed connective tissue disease. Clin Rheumatol. 2007 ;26(6):971-2

95)Abdel Galil SM. Hydroxychloroquine-induced toxic hepatitis in a patient with systemic lupus erythematosus: a case report. Lupus. 2015 ;24(6):638-40

96)Angelakis E, Million M, Kankoe S, et al. Abnormal weight gain and gut microbiota

modifications are side effects of long-term doxycycline and hydroxychloroquine treatment. Antimicrob Agents Chemother. 2014;58(6):3342-7.

97) Kaul A, Gordon C, Crow MK, et al . Systemic lupus erythematosus. Nat Rev Dis Primers. 2016 ;2:16039.

98) Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli C. Progressive

improvement of patient and renal survival and reduction of morbidity over time in

patients with lupus nephritis (LN) followed for 20 years. Lupus. 2013 ;22(8):810-8

* The long-term outcome of patients with lupus nephritis improved over the time.

99) Harvey PR, Gordon C. B-cell targeted therapies in systemic lupus erythematosus: 100) successes and challenges. BioDrugs. 2013 ;27(2): 85-95.

101) Mok CC. Current role of rituximab in systemic lupus erythematosus. Int J Rheum Dis. 2015;18(2):154-63

Drug name (generic) Plaquenil
Phase (for indication
under discussion) Approved by FDA to treat lupus
Indication (specific to
discussion) Systemic Lupus Erythematosus
of action Hydroxychloroquine is an alkalinizing lysosomotropic drug that can

accumulate in lysosomes where it increases the pH from the normal levels

of 4.7-4.8 to 6.0. The alkalinization results in expansion and vacuolization

of lysosomes and inhibition of their functions, including enzyme release,

receptor recycling, plasma membrane repair, cell signaling and energy

metabolism . Hydroxychloroquine can contribute with other drugs in downregulating the immune response against auto-antigenic peptides.
Route of administration By mouth
Chemical structure Hydroxycloroquine sulfate
Pivotal trial(s) [50], [68], [69]

Crug summary box.


Captions for Fig. 1

A very short outline of pathogenesis of SLE (left) and possible pathways of interference of hydroxychloroquine (right) . SLE is initiated by a defective clearance of dying cells. This leads to accumulation in the blood of endogenous debris and nucleic proteins. These molecular patterns are recognized as antigens by toll like receptors (TLRs) 7 and 9 . Adapter molecules recruited by TLRs activate kinases that transmit the amplified signal to nuclear factors that encode the genes regulating the inflammatory response. In the inflammatory milieu, dendritic cells (DCs) capture the antigen become mature and migrate to the lymphatic system where they present the antigen to quiescent T cells. Activated T cells can cooperate with B cells favoring their production of plasmacytes and antibodies. In SLE, deregulated autophagic pathways play a key role in antigen processing presentation and in lymphocyte development, survival, and proliferation. Hydroxychloroquine (HCQ) can interfere with different steps of these mechanisms . It can inhibit the TLR signaling, can inhibit the accumulations of nucleic fragments in the lysosomes, can inhibit the autophagic protein degradation by rising lysosomal pH, and can prevent the production of antiphospholipid antibodies by inhibiting the binding of β2-glycoprotein I to phospholipids.


Table1. Main mechanisms of action of hydroxychloroquine (HCQ)

HCQ can easily pass through the cell membrane

It accumulates in the acidic lysosomes

The high concentration of alkalin HCQ increases the pH in lysosomes

The increased pH inhibits lysosomes functions interfering with metabolic and immune pathways
NSC 4375

Leave a Reply

Your email address will not be published. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>