Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology - Nature
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M E C H A N I S M S O F N O N - B I O LO G I C A N T I R H E U M AT I C D R U G S
Mechanisms of action of
hydroxychloroquine and chloroquine:
implications for rheumatology
Eva Schrezenmeier1 and Thomas Dörner 2,3 ✉
Abstract | Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and
chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE)
and other inflammatory rheumatic diseases, insights into the mechanism of action of these
drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a
characteristic ‘deep’ volume of distribution and a half-life of around 50 days. These drugs
interfere with lysosomal activity and autophagy , interact with membrane stability and alter
signalling pathways and transcriptional activity , which can result in inhibition of cytokine
production and modulation of certain co-stimulatory molecules. These modes of action,
together with the drug’s chemical properties, might explain the clinical efficacy and well-known
adverse effects (such as retinopathy) of these drugs. The unknown dose–response relationships
of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and
what doses are toxic pose challenges to clinical practice. Further challenges include patient
non-adherence and possible context-dependent variations in blood drug levels. Available
mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine
and provide the rationale to search for more potent and/or selective inhibitors.
The antimalarial drugs hydroxychloroquine and chloro In addition to having direct immunomodulatory
quine are DMARDs introduced serendipitously and effects, chloroquine and hydrochloroquine can reduce
empirically for the treatment of various rheumatic dis rates of atherosclerosis, improve hyperglycaemia and
eases (Fig. 1). Neither chloroquine nor hydroxychloro hyperlipidaemia and protect against infections in patients
quine underwent conventional drug development, but with inflammatory rheumatic diseases15,16. The underly
their use has become a part of current treatment guide ing mechanisms of these clinical consequences, however,
lines for rheumatoid arthritis (RA)1, systemic lupus remain largely unknown. An important question is if
erythematosus (SLE)2–4, antiphospholipid syndrome these observed effects share a common mode of action
(APS)5 and primary Sjögren syndrome6,7. or result from a variety of distinct processes. The mecha
Systematic reviews8,9 of randomized controlled and nisms of action of hydroxychloroquine and chloroquine
observational studies of antimalarial drugs in SLE, remain under continuous study in modern molecular
with particular emphasis on hydroxychloroquine, have medicine17,18 using advanced tools in computational biol
1
Department of Nephrology
found strong evidence that this molecule has an immuno ogy19, synthetic biology20–22, immunology23,24, structural
and Intensive Medical Care,
Charité-Universitätsmedizin
modulatory capacity, including the ability to prevent disease biology25,26 and ‘big data’-driven public health science27,28.
Berlin, Berlin, Germany. flares and promote long-term survival in SLE and control Detailed studies on the mode of action of hydroxychloro
2
Department of Rheumatology autoimmune disease activity during pregnancies without quine are needed to better understand dose–response
and Clinical Immunology, evidence of fetotoxic or embryotoxic effects. Evidence sug relationships and safety-related aspects. Such knowledge
Charité-Universitätsmedizin gests that hydroxychloroquine can delay or prevent organ should guide the development of new therapies that
Berlin, Berlin, Germany.
damage10, including bone destruction11, in autoimmunity, modulate lysosomal activity and interfere with autophagy.
3
Deutsches and that this drug has antithrombotic effects12. Trials The main aim of this Review is to discuss the mode of
Rheumaforschungszentrum
(DRFZ), Berlin, Germany.
assessing antimalarial drugs in hand osteoarthritis, how action of hydroxychloroquine and chloroquine, includ
✉e-mail: thomas.doerner@ ever, have found that hydroxychloroquine is no more ing pharmacokinetic and pharmacodynamic properties
charite.de effective than placebo in providing pain relief13,14, implying that potentially explain the clinical efficacy and adverse
https://doi.org/10.1038/ that although antimalarial drugs are useful for a selection effects of these antimalarial drugs. For a comprehensive
s41584-020-0372-x of rheumatic diseases, they are not ‘wonder drugs’. overview of the clinical aspects of hydroxychloroquine
NaTure RevIewS | RHeuMaTology volume 16 | March 2020 | 155REVIEWS
Key points and long half-life of these drugs32. Furthermore, the
dose–response relationships and thresholds of toxicity
• The DMARDs hydroxychloroquine and chloroquine are weak bases that accumulate of hydroxychloroquine and chloroquine have yet to be
in acidic compartments such as lysosomes and inflamed (acidic) tissues. fully delineated.
• Both hydroxychloroquine and chloroquine have a large volume distribution and a Hydroxychloroquine is administered as a sulfate,
long half-life, consistent with their slow onset of action and prolonged effects after whereas chloroquine is administered as a phosphate
drug discontinuation. salt. Both drugs are usually absorbed in the upper
• At the molecular level, hydroxychloroquine and chloroquine interfere with lysosomal intestinal tract37. The lag time between oral absorption
activity and autophagy, disrupt membrane stability and alter signalling pathways of hydroxychloroquine sulfate (200 mg) and its measure
and transcriptional activity.
ment in the blood is typically 0–0.85 h (mean 0.43 h)37,
• At the cellular level, direct and indirect mechanisms of these drugs inhibit immune and both hydroxychloroquine and chloroquine have an
activation by reducing Toll-like receptor signalling and cytokine production and,
overall bioavailability of 0.7–0.8 (ref.38). Some studies have
in T cells, reducing CD154 expression.
reported marked differences in the pharmacokinetics
• An increased risk of retinopathy resulted in updated ophthalmology guidelines
of hydroxychloroquine and chloroquine in humans38,39;
that recommended a maximal daily dose of 5.0 mg/kg actual body weight for
hydroxychloroquine; however, insufficient efficacy data support this recommendation.
however, these differences can be explained by dif
ferences in either the analytical methods applied, the
• Future research should address whether specific targeting of lysosome and/or
autophagosome activity has potential for the treatment of rheumatic diseases.
sample source used (that is, plasma versus whole blood),
or renal clearance of these drugs38,40.
After absorption, the half-lives of the two drugs are
and chloroquine in the treatment of certain diseases, we comparably long (40–60 days) owing to a large volume
refer the reader to the more specialized literature15,29,30. of distribution in the blood (47,257 l for hydroxychloro
quine and 65,000 l for chloroquine)39. Both drugs can
Pharmacokinetics distribute to aqueous cellular and intercellular compart
Drug structure and chemistry ments, resulting in long mean residence times (~1,300 h
Commonly used antimalarial drugs can be divided into for hydroxychloroquine and ~900 h for chloroquine)39.
Enantiomers different classes on the basis of their core structure. Renal clearance is also an important clinical consid
R and S enantiomers are mirror Hydroxychloroquine and chloroquine belong to a class of eration32, especially in patients with kidney failure, as
images of each other, but have
drugs known as 4-aminoquinolines, whereas other less decreased clearance increases the bioavailability of these
different optical activities;
enantiomers can interact frequently used antimalarial drugs belong to other groups drugs (Fig. 2c).
differently with biomolecules (such as the endoperoxidases (artemisinin) or acridines Plasma, blood and serum concentrations of hydroxy
and hence can have different (mepacrine))31. Figure 2 depicts the structure and metab chloroquine and chloroquine can vary in individual
biologic and possibly clinical olism of hydroxychloroquine and chloroquine. Both patients (particularly concentrations measured in
activities or toxicities.
drugs have a flat aromatic core structure and are weak the serum and whole blood) and between patients
Volume of distribution bases due to the presence of a basic side chain. The basic (interpatient variability)38. Little information is avail
A pharmacokinetic parameter side chain is thought to contribute to the accumulation able concerning drug concentrations in ‘deep’ organs
used to describe the of these drugs in intracellular compartments, especially (for example, in lymphoid tissue, immune cells, bone
distribution of a drug in the
lysosomal compartments, which seems to be crucial for marrow, synovial tissue and other connective tissues) and
body; the volume of distribution
is the theoretical volume their activity and the potential interaction of these drugs the pharmacological three-compartment model of drug
needed to contain the total with nucleic acids. distribution between tissues cannot be used to predict
amount of an administered Both hydroxychloroquine and chloroquine occur as the drug concentrations in these ‘deep’ organs.
drug at the same concentration enantiomers (R and S isomers). (R)-(−)-hydroxychloro As a weak base, hydroxychloroquine accumulates
as that present in the plasma.
quine (the stereochemical ‘rectus’ configuration of within acidic vesicles, such as the lysosomal compart
Bioavailability hydroxychloroquine) is present at higher concentra ment (an important site of action of this drug) 41,42.
The fraction of an administered tions in the blood than (S)-(+)-hydroxychloroquine (the Patients with RA and mild joint symptoms have been
dose of an unchanged drug stereochemical ‘sinister’ configuration of hydroxychloro reported to have higher blood concentrations of hydroxy
that reaches the circulation; by
quine)32, suggesting the existence of stereoselective pro chloroquine than patients with active seropositive
definition, the bioavailability of
an intravenously administered cesses in the deposition and/or metabolism of this drug. disease43. It is possible that drug level fluctuations could
medication is 100%. The efficacy and safety of the drug enantiomers might further be influenced by the condition of an individual,
also differ. However, the (R)-(−) and (S)-(+) isomers of such as overt or subclinical inflammation (that is, an
Three-compartment model chloroquine have similar effects in vitro33, and the embry acidic milieu) sequestering these drugs.
A model used to predict the
rate and extent of distribution
otoxicity of chloroquine enantiomers in rats is also equiv In 2018, to better understand the complexity of the
of a drug once administered; alent34. Stereoisomer-specific drug formulations have pharmacokinetics and pharmacodynamics of hydroxy
this model divides the body been developed to reduce adverse effects such as risk chloroquine, researchers used a physiologically based
into a central compartment of retinopathy, but their effects require further clinical pharmacokinetics model to describe the tissue-specific
(compartment 1) and two
investigation35,36 (see below). absorption, distribution, metabolism, excretion and
peripheral compartments
(compartments 2 and 3). The lysosome-specific sequestration of this drug44. The
central compartment consists Absorption, distribution and elimination clinical applicability of this model, which requires
of the plasma and tissues Available data on the pharmacokinetics of hydroxy measurement of plasma concentrations, still needs
where the drug is immediately chloroquine and chloroquine (Fig. 2) are largely based investigation, but could offer new and important
distributed. The peripheral
compartments consist of
on studies of healthy individuals32. The pharmacokinetic insights into the tissue distribution, dose–response
tissues and cells in which the characteristics of hydroxychloroquine and chloroquine interrelationship and in situ context-related effects of
drug is distributed more slowly. are complex owing to the large volume of distribution hydroxychloroquine.
156 | March 2020 | volume 16 www.nature.com/nrrheumM E C H A N I S M S O F N O N - B I O LO G I C A N T I R H E U M AT I C D R U G S
(1980–1990s) Chloroquine
First apparent use Chemical synthesis of quinine identified as an inhibitor of
of an antimalarial and related compounds achieved autophagy in vitro
drug (quinine; in
the form of
powdered bark of Quinine first Chloroquine (1960s) Chloroquine (2011 onwards) New
a ‘miracle tree‘) to extracted and approved by FDA found to have potential antimalarial drug derivative
treat malaria isolated for medical use anti-tumour activity in clinical development
1630 1740 1820 1934 1944 1949 1950 1955 1960 1970 1980 1990 2000 2011
Miracle tree Chloroquine Hydrochloro- (1970s) Lysosomotrophic (2000 onwards) Ongoing
given the name synthesized and quine first effect of chloroquine efforts to evaluate
Cinchona named Resochin synthesized identified adherence to hydroxy-
chloroquine, appropriate
dosing strategies and
Hydroxychloroquine approved hydroxychloroquine-
by FDA for medical use associated retinopathy
Clinical insights Basic science insights
Fig. 1 | Timeline of empiric introduction of chloroquine and hydroxychloroquine. After the very early use of plant
extracts for treating malaria, antimalarial drugs were synthesized154 and subsequently approved for medical use155,156.
Since the 1940s, chloroquine and hydroxychloroquine have been used for the treatment of rheumatic diseases.
New derivatives of these compounds that target autophagosome activity are in development.
Hydroxychloroquine binds strongly to melanin of other drugs that are also metabolized by CYP2D6,
and can deposit in melanin-containing tissues such such dextromethorphan56, are not increased during
as the skin and the eyes, which might explain certain hydroxychloroquine therapy. As antimalarial drugs are
tissue-specific mechanisms (such as hydroxychloro thought to interfere with medications that influence the
quine retinopathy or the efficacy of this drug in the QT interval, patients on hydroxychloroquine therapy con
treatment of skin manifestations). Clinical observations currently taking such drugs for the treatment of cardiac
suggest that hydroxychloroquine is associated with comorbidities should also be monitored for the potential
a lower risk of retinopathy than chloroquine, which risk of cardiac arrhythmia57.
might be explained by the lower volume of distribution According to ophthalmology recommendations,
of hydroxychloroquine compared with chloroquine45. co-medication of tamoxifen (a selective oestrogen recep
tor modulatory used to treat breast cancer) with hydroxy
Drug–drug interactions chloroquine is associated with an increased risk of eye
The effect of antimalarial drugs on other drugs (and toxicity owing to synergistic inhibition of lysosomal
vice versa) is an important clinical consideration. Both enzymes in retinal epithelial cells58. Thus, combined use
chloroquine and hydroxychloroquine are substrates for of tamoxifen with hydroxychloroquine or chloroquine
cytochrome P450 (CYP) enzymes (enzymes responsi should be limited to 6 months.
ble for the metabolism of multiple drugs) and hence can Another relevant drug interaction to consider is
interfere with other drugs38,46,47. the interaction between antimalarial drugs and other
CYP enzymes catalyse the dealkylation of chloro DMARDs. Hydroxychloroquine can reduce the gastro
quine and hydroxychloroquine to pharmacologically intestinal absorption of methotrexate through local pH
active metabolites38,40,48–50 (Fig. 2b). The specific CYP changes and hence lowers the bioavailability of metho
enzymes responsible for the metabolism of various trexate38,59. This effect might explain the decreased risk
drugs have been investigated using microsomal sta of methotrexate-associated acute liver adverse effects
bility assays or recombinant enzymes48,51,52. CYP2C8, during co-administration with hydroxychloroquine60.
CYP3A4, CYP2D6 and CYP1A1 can metabolize No other interactions between hydroxychloroquine
chloroquine48–50,52,53. However, the contribution of these and methotrexate (such as interaction on the enzymatic
isoforms might vary between individuals51,53 and indeed level47,60) have been reported. Hydroxychloroquine
blood concentrations of hydroxychloroquine are can also increase levels of ciclosporin; hence, levels of
reported to vary among individuals54. ciclosporin should also be closely monitored during
In terms of other drugs, concurrent use of chloroquine combined therapy61.
increases the plasma concentration of digitoxin (a cardiac Some drugs can also interfere with the bioavailability
glycoside) fourfold55. Hence, levels of digitoxin require of hydroxychloroquine and chloroquine. For example,
close monitoring during antimalarial therapy. Hydroxy agents that increase the pH of gastric acid (for example,
chloroquine influences the levels of metoprolol through proton-pump inhibitors62) might interfere with the oral
prevention of its metabolism by competing for the same absorption and oral bioavailability of antimalarial drugs.
CYP enzyme, CYP2D656. As a result, plasma concen However, in one study of patients with SLE, the plasma
trations and the bioavailability of metoprolol increases concentrations of hydroxychloroquine between patients
with hydroxychloroquine therapy. Interestingly, levels taking proton-pump inhibitors and patients not taking
NaTure RevIewS | RHeuMaTology volume 16 | March 2020 | 157REVIEWS
a b
NH2
Chloroquine Hydroxychloroquine
N
4-Aminoquinoline: core structure
Basic side chain
Desethylchloroquine Desethylhydroxychloroquine
N
HN
Active
metabolites
Cl N
Chloroquine
Bisdesethylchloroquine
Basic side chain
OH
N
HN Transient metabolites
Cl N
CYP enzymes
Hydroxychloroquine
c Hydroxychloroquine Bioavailability 0.7–0.8 Chloroquine
Oral administration: Oral administration:
absorption in upper absorption in upper
intestinal tract intestinal tract
Metabolism in the liver:
• Desethylchloroquine 18% Metabolism in the liver:
• Desethylhydroxychloroquine 16% Desethylchloroquine 39%
Renal clearance 21% Renal clearance 51%
Volume of distribution: Volume of distribution:
• Blood 47,257 l • Blood 65,000 l
• Plasma 5,500 l • Plasma 15,000 l
• Unmetabolized excretion 62% • Unmetabolized excretion 58%
• Terminal half-life 45 ± 15 days • Terminal half-life 41 ± 11 days
Fig. 2 | Pharmacokinetic properties of hydroxychloroquine and chloroquine. a | Hydroxychloroquine and chloroquine
belong to a class of drugs known as 4-aminoquinolines. These drugs have a 4-aminoquinoline core structure and
a basic side chain. b | Cytochrome P450 (CYP) enzymes mediate dealkylation of chloroquine and hydroxychloroquine.
Desethylchloroquine is an immediate downstream product of CYP-mediated dealkylation of both drugs, whereas
desethylhydroxychloroquine is a metabolite of only hydroxychloroquine. Bisdesethylchloroquine is a downstream
metabolite of both drugs. c | Some of the pharmacokinetic properties of hydroxychloroquine and chloroquine differ.
The large volume of distribution and long half-life is characteristic of both drugs; however, these drugs have notably
different renal clearance rates. The data in this figure were taken from Costedoat-Chalumeau et al.143 and McChesney40.
158 | March 2020 | volume 16 www.nature.com/nrrheumM E C H A N I S M S O F N O N - B I O LO G I C A N T I R H E U M AT I C D R U G S
a Autoantigen presentation b TLR signalling
Autophagy pathway Endocytosis (phagocytosis) DNA or RNA
Anti-DNA or anti-
RNA autoantibody
FcγRIIa
Cargo (such
as proteins
and organelles)
Accumulation
Lysosome of HCQ in
HCQ endosomes
Lysosomal
enzymes HCQ HCQ
Accumulation
TLR7 cGAS
of HCQ in Clearance and
acidic lysosomes recycling of cargo or TLR9
MHC class II
Autolysosome TLR signalling cGAS–STING
signalling
Autoantigen
MHC class II- Expression of
mediated pro-inflammatory
MHC class II- autoantigen cytokines
containing endosome Autolysosome presentation Promotor
Fig. 3 | Potential molecular mechanisms of hydroxychloroquine during autoimmunity. a | Hydroxychloroquine (HCQ)
enters and accumulates in lysosomes along a pH gradient. In lysosomes, hydroxychloroquine inhibits the degradation
of cargo derived externally (via endocytosis or phagocytosis) or internally (via the autophagy pathway) in autolysosomes
by increasing the pH to prevent the activity of lysosomal enzymes. Inhibition of lysosomal activity can prevent MHC
class II-mediated autoantigen presentation. b | Hydroxychloroquine can also accumulate in endosomes and bind to
the minor groove of double-stranded DNA. This drug can inhibit Toll-like receptor (TLR) signalling by altering the pH
of endosomes (involved in TLR processing) and/or preventing TLR7 and TLR9 from binding their ligands (RNA and DNA,
respectively). Hydroxychloroquine can also inhibit the activity of the nucleic acid sensor cyclic GMP-AMP (cGAMP)
synthase (cGAS) by interfering with its binding to cytosolic DNA. By preventing TLR signalling and cGAS–stimulator
of interferon genes (STING) signalling, hydroxychloroquine can reduce the production of pro-inflammatory cytokines,
including type I interferons.
proton-pump inhibitors did not differ63. Finally, smoking events in the child75. Continued therapy after delivery
has previously been suspected to interfere with the bio even has the advantage of preventing flares in mothers69.
availability of hydroxychloroquine64; however, a study in Overall, hydroxychloroquine is considered safe to use
2017 found no correlation between hydroxychloroquine during pregnancy and breastfeeding.
plasma concentration and smoking status65.
Mechanisms of action
Pregnancy and breastfeeding Various modes of action are postulated to explain the
Although both chloroquine and hydroxychloroquine therapeutic and/or adverse effects of hydroxychloroquine
cross the placenta, and despite initial concerns relating and chloroquine, most of which have been based on
to the presence of drug-related pigmentations in fetal in vitro studies. Notably, the link between these mecha
tissue66, these drugs are not considered to have notable nisms and the clinical efficacy and safety observed in vivo
toxic effects on the fetus67. Current guidelines strongly have yet to be fully delineated. Antimalarial drugs have
recommend maintaining treatment with hydroxychloro direct molecular effects on lysosomal activity, autoph
quine during pregnancy in patients with an autoimmune agy and signalling pathways (Fig. 3). Data on the effects
disease68–70. Some data suggest that hydroxychloroquine of these drugs on plasmacytoid dendritic cells (pDCs),
during pregnancy is protective against the induction of B cells, other antigen-presenting cells and T cells are also
congenital heart block71,72, possibly owing to a reduction available (Fig. 4). As with various therapeutic interven
in expression of a type I interferon (IFN) signature73. tions of the immune system (Box 1), the mechanism of
Notably, evidence of fetal cardiotoxic effects was absent action is probably context-dependent (that is, dependent
in one case study74. Hydroxychloroquine can also be trans on the inflammatory conditions and/or affected tissues
ferred in breast milk, but is not associated with adverse or organs).
NaTure RevIewS | RHeuMaTology volume 16 | March 2020 | 159REVIEWS
Molecular effects and inhibit antigen presentation along the lysosomal
Inhibition of lysosomal activity and autophagy. An pathway (Fig. 3). Overall, the available studies suggest
important mode of action of chloroquine and hydroxy that hydroxychloroquine and chloroquine impair or
chloroquine is the interference of lysosomal activity inhibit lysosomal and autophagosome functions and
and autophagy. It is widely accepted that chloroquine and subsequently immune activation.
hydroxychloroquine accumulate in lysosomes (lyso Beyond lysosomotropism, efforts to identify exact
somotropism) and inhibit their function. In vitro, chloro molecular targets of hydroxychloroquine within the lyso
quine can destabilize lysosomal membranes and promote some are also currently underway. One study has identi
the release of lysosomal enzymes inside cells76. Although fied palmitoyl-protein thioesterase 1 (PPT1), an enzyme
evidence of this latter mechanism is scarce, the ability of involved in the catabolism of lipid-modified proteins,
these drugs to interfere with lysosomal activity has been as a potential lysosomal target of chloroquine and
repeatedly documented77–79. Interference of lysosomal chloroquine derivatives86. Hydroxychloroquine can bind
activity might inhibit the function of lymphocytes and have and inhibit PPT1 activity86, and, notably, PPT1 is over
immunomodulatory or even anti-inflammatory effects. expressed in the synovial tissue of patients with RA87.
One mechanism by which these drugs might have Although an interesting example of ongoing research,
anti-inflammatory effects is by impairing antigen pre confirmatory functional studies and the identification
sentation via the lysosomal pathway. Lysosomes contain of other molecular targets within the lysosomes are
hydrolytic enzymes and cooperate with other vesicles to nevertheless warranted.
digest cargo (such as organelles and material from inside
the cell (in a process known as autophagy) or material Inhibition of signalling pathways. Hydroxychloroquine
from outside the cell (via the endocytosis or phagocytosis and chloroquine can also interfere with Toll-like recep
pathway)). Lysosomes are involved not only in recycling tor (TLR) signalling. For example, changes in endosomal
cellular substrates80 but also in antigen processing and pH can interfere with TLR9 and TLR7 processing88, and,
MHC class II presentation, indirectly promoting immune hence, these antimalarial drugs might prevent TLR acti
activation81. Autophagy is also involved in antigen pre vation upon extracellular stimuli by mediating changes
sentation and immune activation82,83. For example, data in the local pH88. Chloroquine or hydroxychloroquine
from one study suggest that autophagy is important for can also directly bind to nucleic acids and hence might
MHC class II-mediated autoantigen presentation by block TLR9 signalling at the intracellular level by inhib
antigen-presenting cells to CD4+ T cells84. As the pH in iting TLR–ligand interactions (steric blockade) (Fig. 3).
lysosomes is optimal for lysosomal enzymes involved This latter hypothesis is supported by an analysis based
in hydrolysis, by increasing the pH of endosomal compart on surface plasmon resonance and fluorescence spec
ments85, chloroquine and hydroxychloroquine might troscopy showing that antimalarial drugs can directly
impair the maturation of lysosomes and autophagosomes inhibit CpG–TLR9 interactions89,90. In addition to TLR9
HCQ
Cellular
debris Cytokine Co-stimulatory Cytokine
production molecule production
upregulation
TLR TNF BAFF
IL-6 IL-1
IL-6 TNF
IFNγ IL-1
CD154
Antigen MHC HCQ
processing class II
TCR
Signalling
and T cell
activation activation
Antigen Antigen Antigen
presentation presentation processing
IL-1 APC
IFNα T cell B cell
Cytokine
IL-6 production
Fig. 4 | Potential cellular effects of hydroxychloroquine during autoimmunity. Hydroxychloroquine (HCQ) can
interfere with immune activation at various cellular levels by inhibiting various innate and adaptive immune processes.
During autoimmunity, cellular debris can activate Toll-like receptor 7 (TLR7) and TLR7 signalling pathways in plasmacytoid
dendritic cells (pDCs) and other immune antigen-presenting cells (APCs), including monocytes, macrophages and B cells,
resulting in the activation of multiple cell types and secretion of various pro-inflammatory cytokines. In APCs, hydroxy
chloroquine potentially interferes with TLR7 and TLR9 ligand binding and TLR signalling (through lysosomal inhibition and
reduced MyD88 signalling), which inhibits TLR-mediated cell activation and cytokine production. In APCs, such as pDCs
and B cells, this drug also inhibits antigen processing and subsequent MHC class II presentation to T cells, preventing T cell
activation, differentiation and expression of co-stimulatory molecules (such as CD154) and also reducing the production
of cytokines (such as IL-1, IL-6 and TNF) by both T cells and B cells. BAFF, B-cell activating factor.
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Box 1 | Main mechanisms of actions by hydroxychloroquine and chloroquine Furthermore, in patients with RA, long-term treatment
with hydroxychloroquine (200–400 mg/day) can reduce
Hydroxychloroquine and chloroquine can inhibit certain cellular functions and molecular circulating levels of IL-1 and IL-6 and is associated with
pathways involved in immune activation, listed below, partly by accumulating in lysosomes improvement in erythrocyte sedimentation rate103,104.
and autophagosomes of phagocytic cells and changing local pH concentrations: The anti-inflammatory effects of hydroxychloro
• Inhibition of MHC class II expression, antigen presentation and immune activation quine and chloroquine could be explained in part by the
(reducing CD154 expression by T cells) upstream interference of immune activation (including
• Inhibition of production of various pro-inflammatory cytokines, such as IL-1, IFNα inhibition of lysosomal activity). Indeed, treatment with
and TNF, which can protect against cytokine-mediated cartilage resorption hydroxychloroquine is associated with a dose-dependent
• Interference with Toll-like receptor 7 (TLR7) and TLR9 signalling pathways downregulation of the co-stimulatory molecule CD154
• Interference with cyclic GMP-AMP (cGAMP) synthase (cGAS) activity on CD4+ T cells from patients with SLE, which is accom
panied by a decrease in intracellular Ca2+ mobilization
signalling, chloroquine can also inhibit RNA-mediated and translocation of nuclear factor of activated T cells cyto
activation of TLR7 signalling91,92. Although the exact plasmic 1 (NFATc1) and NFATc2105. However, the direct
modes of action by which these drugs inhibit TLR7 effect of antimalarial drugs on cytokine production
and TLR9 requires further delineation at the molecular requires further delineation.
level93, inhibition of TLR processing and inhibition of
TLR binding are likely central mechanisms of action. Cardiovascular effects
Another potential mode of action of hydroxychloro Although hydroxychloroquine is not an anticoagulant,
quine and chloroquine is interference with cyclic GMP- this drug is widely believed to have vascular protective
AMP (cGAMP) synthase (cGAS) activity by inhibiting effects and prevent the development of thrombotic
ligand binding94. The cGAS–stimulator of IFN genes complications. This protective effect seems to be most
(STING) pathway is a major source of the type I IFN relevant for patients with a secondary coagulopathy
response. Cytosolic DNA binds to cGAS and the sec owing to systemic inflammation106 and in patients with
ond messenger cGAMP to mediate STING-dependent primary APS107.
transcription of type I IFNs through the transcription Patients with inflammatory rheumatic diseases are
factor IFN regulatory factor 3 (IRF3)95,96. Notably, cGAS at an increased risk of developing cardiovascular com
inhibitors are currently in development for the treatment plications compared with the general population108–111.
of inflammatory rheumatic diseases97. This increased risk is caused by the underlying disease,
drugs used to treat the disease (such as NSAIDs, includ
Cellular effects ing COX-2 inhibitors112 and high-dose glucocorticoids)
Cytokine production and immune activation. Hydroxy and the presence of comorbidities, such as arterial hyper
chloroquine and chloroquine can indirectly reduce the tension, hyperlipidaemia, chronic kidney failure and
production of anti-inflammatory cytokines by various diabetes mellitus. By contrast, treatment with hydroxy
cell types. In vitro, hydroxychloroquine and chloroquine chloroquine seems to counter these effects and provide
inhibit the production of IL-1, IL-6, TNF and IFNγ by long-term benefits by reducing the risk of cardiovascular
mononuclear cells98 (Fig. 4). Furthermore, treatment events, lowering fasting glucose levels113 and reducing
with hydroxychloroquine inhibits the production of hyperlipidaemia15,114. For example, in a study of patients
TNF, IFNα, IL-6 and CCL4 (also known as MIP1β) in with SLE, combined use of low-dose aspirin and hydroxy
pDC and natural killer cell co-cultures stimulated with chloroquine was superior to treatment with aspirin or
RNA-containing immune complexes99,100. hydroxychloroquine alone in terms of preventing cardio
TLR signals stimulate the production of cytokines, vascular complications115. However, sufficiently large and
and hence hydroxychloroquine and chloroquine might controlled studies are needed to quantify the benefit-to-
inhibit cytokine production by inhibiting TLR pathways. risk profile of hydroxychloroquine in the prevention of
Notably, a small molecule inhibitor of IL-1 receptor- cardiovascular complications in patients with rheumatic
associated kinase 4 (IRAK4; a component of the TLR7 diseases and other non-rheumatological cohorts116.
and TLR9 signalling pathways) could reduce produc Potential mechanisms by which hydroxychloroquine
tion of cytokines by peripheral blood mononuclear and chloroquine reduce the procoagulatory state in
cells (PBMCs) more strikingly than hydroxychloro autoinflammatory diseases include inhibition of anti
quine101. Upon stimulation, IRAK4 inhibition altered phospholipid antibody binding117 or inhibition of plate
the expression of a larger number of RNA-induced and let aggregation118–120. Notably, in a mouse model of APS,
immune-complex-induced genes than hydroxychloro hydroxychloroquine treatment was associated with
quine (492 versus 65 genes). This finding suggests that improvement in endothelial function121,122. The exact
hydroxychloroquine is less effective at inhibiting the molecular mechanisms by which these drugs mediate
production of a wide range of cytokines than the IRAK4 their antithrombotic effects remain largely unknown.
inhibitor. Nevertheless, this study also convincingly
shows that hydroxychloroquine has a notable effect on Therapeutic implications
cytokine production and gene expression, including an Adverse effects: drug toxicity
inhibitory effect on TNF production by PBMCs from Hydroxychloroquine and chloroquine have a known and
patients with SLE101. Indeed, in other studies, treatment good safety profile and are considered to function as
with hydroxychloroquine was associated with a reduc immunomodulatory rather than immunosuppressant
tion in serum levels of IFNα in patients with SLE102. drugs. The various immune pathways targeted by these
NaTure RevIewS | RHeuMaTology volume 16 | March 2020 | 161REVIEWS
drugs (such as TLR7 and TLR9 signalling, T cell receptor tomography133. However, the dose–response relation
(TCR) and B cell receptor (BCR) activation and others ships for hydroxychloroquine and chloroquine are still
discussed above) remain largely preserved (that is, not unknown due to their complex pharmacokinetics. Both
fully inhibited) during treatment. hydroxychloroquine and chloroquine have a gradual
Unlike treatment with immunosuppressant drugs onset of action41,42,136 that might take weeks to reach max
such as methotrexate and leflunomide, treatment with imal activity; furthermore, both drugs have a prolonged
hydroxychloroquine or chloroquine is not associated efficacy that is evident even after drug discontinuation.
with an increased risk of infectious complications16 or The complex pharmacokinetics of these drugs could
cancer123. The most common adverse effect of these be explained by the long plasma elimination half-lives
antimalarial drugs are gastrointestinal effects, including of hydroxychloroquine, chloroquine and their dealky
nausea, vomiting, diarrhoea and abdominal discom lated metabolites, as well as their extensive volume of
fort124. In addition, several studies have reported the distribution.
occurrence of hydroxychloroquine-associated myop Therapeutic drug measurements of hydroxychloro
athy125–128 and hydroxychloroquine-mediated and/or quine in patients with rheumatic diseases have provided
chloroquine-mediated cardiotoxic effects, including a number of important insights. First, low blood con
rhythm disorders (such as a prolonged QT interval) centrations of hydroxychloroquine are predictive of
and the development of cardiomyopathy in patients with subsequent flares in patients with SLE during hydroxy
rheumatic diseases129–132. However, conclusive evidence chloroquine treatment137. Second, non-adherence to
of cardiotoxicity caused by these drugs is lacking and hydroxychloroquine is a major cause of flares in patients
further pharmacovigilance is required. Impaired renal with SLE138. Among 305 patients with SLE who were
function can increase the bioavailability of antimalarial enrolled in a prospective study, 18.4% were non-adherent
drugs and increase the risk of adverse effects. to hydroxychloroquine therapy, defined as having
The most severe complication attributed to anti hydroxychloroquine concentrations below 200 ng/ml
malarial treatment is the development of retinopathy. or undetectable concentrations of desethylchloroquine,
These drugs are thought to cause retinal damage by dis whereas 23.4% of patients were non-adherent accord
rupting lysosomal degradation of photoreceptor outer ing to self-administered questionnaires138. Risk factors
segments in the retinal pigment epithelium (an impor of non-adherence in this population were younger
tant step in the visual cycle). Mechanistically, this inter age, absence of steroid co-medication, higher body
ference is thought to lead to an increase in lipofuscin in mass index and unemployment. Thus, non-adherence
retinal pigment epithelial cells and photoreceptor deg is an issue and therapeutic drug monitoring might
radation133. Retinopathy is more commonly associated be useful.
with chloroquine than with hydroxychloroquine and In chronic kidney disease, despite the fact that dec
can result in patients developing circular defects (known reased drug clearance can result in increased (and poten
as bull’s eye maculopathy) and diametric defects of the tially toxic) concentrations of hydroxychloroquine,
retina. Details on the pathophysiology, epidemiology and current guidelines do not include the recommendation
treatment of hydroxychloroquine retinopathy have been to reduce the dosage of hydroxychloroquine in patients
reviewed extensively elsewhere133. Notably, advances in with chronic kidney diseases. In a real-world cohort of
diagnostic procedures in the past few years, and the patients with SLE and end-stage renal disease, 20%
resulting realization that hydroxychloroquine-related of the patients were still taking hydroxychloroquine139.
retinopathy is more common that previously realized, The adverse effects of hydroxychloroquine in the kidney
have led to the development of new ophthalmology can mimic Fabry’s disease140. In patients with RA, reduced
guidelines134,135. Various factors are thought to increase concentrations of hydroxychloroquine and desethyl
the risk of developing retinopathy during treatment hydroxychloroquine in the blood are associated with
with hydrochloroquine: a drug dose of >5 mg/kg increased morning stiffness, pain intensity and positivity
actual body weight per day, prolonged use of the drug for rheumatoid factor43,46. Hence, studies that investigate
(10–25 years), a high cumulative dose (above 600–1,000 g), levels of these drugs and clinical response of patients
stage 3–5 chronic kidney disease and comedication with could help to overcome limited knowledge on the dose–
tamoxifen (>6 months)133. The most important predic response characteristics within different diseases as well
tors of hydroxychloroquine retinopathy are thought as during active versus quiescent periods.
to be high-dose and long-term (>5 years) use, but cur The latest guidelines from the American Academy
rent evidence is limited to retrospective studies, most of Ophthalmology, the Royal College of Ophthalmology
of which are based on health care records and have and EULAR2,134,141 recommend the use of a lower dose
substantial limitations (such as limited data on renal of hydroxychloroquine (maximum of 5.0 mg/kg actual
impairments)133. body weight per day) than previously used for many
patients. This maximum dosage is controversial and is
Dosing considerations largely based on an ophthalmological study by Melles
According to ophthalmology guidelines, the occurrence and Marmor142. As this study used pharmacy refill infor
of ocular adverse reactions during hydroxychloroquine mation, the dosing estimates represent actual hydroxy
or chloroquine therapy can be minimized by using the chloroquine intake rather than prescribed dosages.
appropriate drug dosage (that is, taking into consider Thus, the cut-off of 5 mg/kg in this study probably cor
ation the actual body weight of the patient) and by using responds to a prescribed dose of 6 mg/kg actual body
advanced screening modalities such as optical coherence weight (as discussed elsewhere143).
162 | March 2020 | volume 16 www.nature.com/nrrheumM E C H A N I S M S O F N O N - B I O LO G I C A N T I R H E U M AT I C D R U G S
In cancer studies, the prescribed doses of hydroxy possibly occur, at least in part, through drug-mediated
chloroquine can reach up to 1,200 mg daily. Despite changes in the pH of autophagosomes and/or lysosomes,
such high doses, no relevant toxic adverse effects (beside which indirectly influence immune activation; however,
cytopenia) were reported in these studies, even when such a mode of action requires additional validation to
hydroxychloroquine was combined with other oculo aid with future drug development.
toxic agents144–148. However, the treatment periods for An important feature of hydroxychloroquine and
oncological conditions are generally much shorter than chloroquine (and other DMARDs) seems to be their
for rheumatic diseases, and therefore the cumulative ability to inhibit both innate and adaptive immunity149.
dose is usually lower in patients with cancer than in However, hydroxychloroquine and chloroquine are less
patients with rheumatic diseases. effective at inhibiting the production of cytokines than
A relevant problem with the current ophthalmology glucocorticoids, Janus kinase (JAK) inhibitors and biolog
guidelines is that the efficacy of the recently recom ical drugs, and have a delayed onset of action. However,
mended maximum dose (5 mg/kg actual body weight apart from the risk of retinopathy, these antimalar
per day) has not been evaluated for patients with inflam ial drugs have a good safety profile, probably because
matory rheumatic disease. The clinical consequences of they do not notably interfere with important pathways
following this dosing strategy might be manifold. Many involved in protection against infection such as BCR or
past studies evaluating the efficacy of hydroxychloro TCR signalling, JAK–STAT-dependent cytokine signal
quine investigated a dosage of at least 6.5 mg/kg ideal ling, TLR4 signalling and certain chemokine signalling
body weight per day. As a result, the effective dose during pathways. Importantly, interference of TLR7 and TLR9
flares might be higher than the recommended maximum signalling and MHC class II presentation by antimalarial
dose. Moreover, patients with different diseases might drugs does not result in an increased risk of infection.
require different dosages of antimalarial drugs. There is a great deal of interest in developing spe
cific inhibitors of autophagy150 for the treatment of can
Current and future directions cers, which might have clinical value for rheumatology.
It is of utmost importance to further delineate the mode Inhibitors of IRAK4 are also under investigation for
of action of hydroxychloroquine and chloroquine, the treatment of autoimmune diseases151 as well as for the
together with the safety and efficacy of these drugs at treatment of cancer152. This strategy does not interfere
the current recommended doses. The identification with MHC class II presentation, but might have more
of molecular targets of these drugs, as exemplified by potent anticytokine effects than antimalarial drugs.
PPT1, should permit the development of new treatment Finally, oral administration of a non-degradable poly
modalities. Additional knowledge gaps and research meric form of chloroquine is under investigation for the
topics are listed in Box 2. One current line of investiga treatment of inflammatory bowel diseases. Clinical data
tion is whether these drugs can sufficiently prevent the suggest that this formulation can suppress the production
production of IFNα by blocking TLR7 and TLR9 engage of IL-6 and IL-1β and upregulate the production of IL-2
ment, as these are important pathways in connective in the intestine153 as a result of altered mucosal immune
tissue diseases. How these drugs interfere with signalling homeostasis.
downstream of nucleic acid sensors, including sensors
of double-stranded DNA and RNA (such as TLR9 and Conclusion
TLR7), and the selectivity and size of these effects, Although hydroxychloroquine and chloroquine are
also requires further study. Another unique feature of well-known DMARDs that have been used for the treat
these drugs is their ability to inhibit lysosomal activity ment of patients with rheumatic diseases for many years,
and block MHC class II presentation. These processes their exact mechanisms of action are only beginning
to be understood. Important to the pharmacokinetic,
Box 2 | Hydroxychloroquine: knowledge gaps and research agenda pharmacodynamics and toxic properties of these drugs
is their ability to accumulate in acidic compartments
• Dose–response assessment of the efficacy and safety profile (such as the effects of such as lysosomes, as well as inflamed (acidic) tissues.
long-term exposure) of hydroxychloroquine, including the effect on damage accrual
The large volume distribution and long half-lives of these
and mortality of the recommended dosage of up to 5 mg/kg
drugs can explain some of their clinical characteristics,
• Lowest dose required for the treatment of various inflammatory conditions and the
such as their slow onset of action and prolonged effects
effect of disease activity on blood drug concentrations (that is, whether the dose
requires adjustments during flares versus stable disease)
after drug discontinuation. At the cellular level, several
direct and indirect mechanisms have been described that
• Establishing whether dose adjustments are required for patients with kidney failure
account for the immunomodulatory effects of hydroxy
• Identification of relevant co-medications that interfere with cytochrome P450 (CYP)
chloroquine and chloroquine. In particular, inhibition
enzyme activity and hydroxychloroquine bioavailability
of autophagy prevents immune activation of different
• Quantification of the effects of hydroxychloroquine on cardiovascular events,
cell types, which inhibits cytokine production and
thromboembolic events and mortality
modulates CD154 expression on T cells. Renal failure
• Ascertainment of the risk-to-benefit profile of R and S enantiomers of and certain drug interactions (such as interactions with
hydroxychloroquine
tamoxifen, glycosides, methotrexate and ciclosporin)
• Prospective assessment and quantification of the effect and risk profile of can influence the pharmacokinetics of hydroxychloro
hydroxychloroquine in the treatment of various organ manifestations
quine and chloroquine and hence require consideration.
• Validation of risk factors associated with the occurrence and progression of Although hydroxychloroquine and chloroquine are
hydroxychloroquine retinopathy
considered safe to use, these drugs are associated with
NaTure RevIewS | RHeuMaTology volume 16 | March 2020 | 163REVIEWS
an increased risk of retinopathy. This increased risk has dosing strategy. Preclinical studies of compounds target
resulted in ophthalmology guidelines recommending ing lysosome and autophagosome activity are underway
a maximal daily dose of 5.0 mg/kg actual body weight and should reveal whether such strategies have value in
for hydroxychloroquine, which is debated among rheu the treatment of systemic autoimmune diseases.
matologists. Ultimately, drug level monitoring studies
are needed to reassess the risk to benefit profile of this Published online 7 February 2020
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