Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Nature Reviews Rheumatology volume 16, pages 155–166 (2020)Cite this article

Subjects

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.

Key points

  • The DMARDs hydroxychloroquine and chloroquine are weak bases that accumulate in acidic compartments such as lysosomes and inflamed (acidic) tissues.

  • Both hydroxychloroquine and chloroquine have a large volume distribution and a long half-life, consistent with their slow onset of action and prolonged effects after drug discontinuation.

  • At the molecular level, hydroxychloroquine and chloroquine interfere with lysosomal activity and autophagy, disrupt membrane stability and alter signalling pathways and transcriptional activity.

  • At the cellular level, direct and indirect mechanisms of these drugs inhibit immune activation by reducing Toll-like receptor signalling and cytokine production and, in T cells, reducing CD154 expression.

  • An increased risk of retinopathy resulted in updated ophthalmology guidelines that recommended a maximal daily dose of 5.0 mg/kg actual body weight for hydroxychloroquine; however, insufficient efficacy data support this recommendation.

  • Future research should address whether specific targeting of lysosome and/or autophagosome activity has potential for the treatment of rheumatic diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Timeline of empiric introduction of chloroquine and hydroxychloroquine.
Fig. 2: Pharmacokinetic properties of hydroxychloroquine and chloroquine.
Fig. 3: Potential molecular mechanisms of hydroxychloroquine during autoimmunity.
Fig. 4: Potential cellular effects of hydroxychloroquine during autoimmunity.

Similar content being viewed by others

References

  1. Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann. Rheum. Dis. 73, 492–509 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Fanouriakis, A. et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann. Rheum. Dis. 78, 736–745 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Pons-Estel, B. A. et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR). Ann. Rheum. Dis. 77, 1549–1557 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Gordon, C. et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology 57, e1–e45 (2018).

    Article  PubMed  Google Scholar 

  5. Tektonidou, M. G. et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann. Rheum. Dis. 78, 1296–1304 (2019).

    Article  PubMed  Google Scholar 

  6. Brito-Zeron, P., Ramos-Casals, M. & EULAR-SS task force group. Advances in the understanding and treatment of systemic complications in Sjogren’s syndrome. Curr. Opin. Rheumatol. 26, 520–527 (2014).

    Article  PubMed  Google Scholar 

  7. Vivino, F. B. et al. New treatment guidelines for Sjogren’s disease. Rheum. Dis. Clin. North. Am. 42, 531–551 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ruiz-Irastorza, G. et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 69, 20–28 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Ostensen, M. et al. Pregnancy and reproduction in autoimmune rheumatic diseases. Rheumatology 50, 657–664 (2011).

    Article  PubMed  Google Scholar 

  10. Akhavan, P. S. et al. The early protective effect of hydroxychloroquine on the risk of cumulative damage in patients with systemic lupus erythematosus. J. Rheumatol. 40, 831–841 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Mok, C. C., Mak, A. & Ma, K. M. Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus. Lupus 14, 106–112 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Petri, M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr. Rheumatol. Rep. 13, 77–80 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Kingsbury, S. R. et al. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial. Ann. Intern. Med. 168, 385–395 (2018).

    Article  PubMed  Google Scholar 

  14. Lee, W. et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res. 70, 1320–1325 (2018).

    Article  CAS  Google Scholar 

  15. Rempenault, C. et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 77, 98–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Ruiz-Irastorza, G. et al. Predictors of major infections in systemic lupus erythematosus. Arthritis Res. Ther. 11, R109 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Flannery, E. L., Chatterjee, A. K. & Winzeler, E. A. Antimalarial drug discovery – approaches and progress towards new medicines. Nat. Rev. Microbiol. 11, 849–862 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ridley, R. G. Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 415, 686–693 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Minie, M. et al. CANDO and the infinite drug discovery frontier. Drug Discov. Today 19, 1353–1363 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paddon, C. J. et al. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496, 528–532 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Hale, V. et al. Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable antimalarial drugs. Am. J. Trop. Med. Hyg. 77, 198–202 (2007).

    Article  PubMed  Google Scholar 

  22. Mitchell, W. Natural products from synthetic biology. Curr. Opin. Chem. Biol. 15, 505–515 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Conway, D. J. Paths to a malaria vaccine illuminated by parasite genomics. Trends Genet. 31, 97–107 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Karunamoorthi, K. Malaria vaccine: a future hope to curtail the global malaria burden. Int. J. Prev. Med. 5, 529–538 (2014).

    PubMed  PubMed Central  Google Scholar 

  25. de Beer, T. A. et al. Antimalarial drug discovery: in silico structural biology and rational drug design. Infect. Disord. Drug Targets 9, 304–318 (2009).

    Article  PubMed  Google Scholar 

  26. Vedadi, M. et al. Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms. Mol. Biochem. Parasitol. 151, 100–110 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Buckee, C. O. et al. Mobile phones and malaria: modeling human and parasite travel. Travel. Med. Infect. Dis. 11, 15–22 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hay, S. I. et al. Big data opportunities for global infectious disease surveillance. PLoS Med. 10, e1001413 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ponticelli, C. & Moroni, G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert. Opin. Drug Saf. 16, 411–419 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, S. Q. et al. Is hydroxychloroquine effective in treating primary Sjogren’s syndrome: a systematic review and meta-analysis. BMC Musculoskelet. Disord. 18, 186 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Manohar, S., Tripathi, M. & Rawat, D. S. 4-aminoquinoline based molecular hybrids as antimalarials: an overview. Curr. Top. Med. Chem. 14, 1706–1733 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Rainsford, K. D. et al. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 23, 231–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Witiak, D. T. et al. Synthesis and preliminary pharmacological evaluation of asymmetric chloroquine analogues. J. Med. Chem. 24, 712–717 (1981).

    Article  CAS  PubMed  Google Scholar 

  34. Tagoe, C. N. & Ofori-Adjei, D. Effects of chloroquine and its enantiomers on the development of rat embryos in vitro. Teratology 52, 137–142 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Ducharme, J. et al. Enantioselective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects. Br. J. Clin. Pharmacol. 40, 127–133 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tett, S. E. et al. Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate. Chirality 6, 355–359 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Tett, S. E. et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br. J. Clin. Pharmacol. 27, 771–779 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Furst, D. E. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 5, S11–S15 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Cutler, D. J., MacIntyre, A. C. & Tett, S. E. Pharmacokinetics and cellular uptake of 4-aminoquinoline antimalarials. Agents Actions Suppl. 24, 142–157 (1988).

    CAS  PubMed  Google Scholar 

  40. McChesney, E. W. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am. J. Med. 75, 11–18 (1983).

    Article  CAS  PubMed  Google Scholar 

  41. Fishbain, D. A. et al. Do some chronic pain patients with atypical facial pain overvalue and obsess about their pain? Psychosomatics 34, 355–359 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Tett, S. et al. Insights from pharmacokinetic and pharmacodynamic studies of hydroxychloroquine. Agents Actions Suppl. 44, 145–190 (1993).

    CAS  PubMed  Google Scholar 

  43. Tett, S. E., Day, R. O. & Cutler, D. J. Concentration-effect relationship of hydroxychloroquine in rheumatoid arthritis – a cross sectional study. J. Rheumatol. 20, 1874–1879 (1993).

    CAS  PubMed  Google Scholar 

  44. Collins, K. P., Jackson, K. M. & Gustafson, D. L. Hydroxychloroquine: a physiologically-based pharmacokinetic model in the context of cancer-related autophagy modulation. J. Pharmacol. Exp. Ther. 365, 447–459 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rynes, R. I. & Bernstein, H. N. Ophthalmologic safety profile of antimalarial drugs. Lupus 2, S17–S19 (1993).

    Article  PubMed  Google Scholar 

  46. Munster, T. et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 46, 1460–1469 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Carmichael, S. J., Charles, B. & Tett, S. E. Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis. Ther. Drug Monit. 25, 671–681 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Spaldin, V. et al. The effect of enzyme inhibition on the metabolism and activation of tacrine by human liver microsomes. Br. J. Clin. Pharmacol. 38, 15–22 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Projean, D. et al. In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab. Dispos. 31, 748–754 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gil, J. P. & Gil Berglund, E. CYP2C8 and antimalaria drug efficacy. Pharmacogenomics 8, 187–198 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Projean, D. et al. Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica 33, 841–854 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Kim, K. A. et al. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch. Pharm. Res. 26, 631–637 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Li, X. Q. et al. Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur. J. Clin. Pharmacol. 59, 429–442 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Lee, J. Y. et al. Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus. Arthritis Rheumatol. 68, 184–190 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Leden, I. Digoxin-hydroxychloroquine interaction? Acta Med. Scand. 211, 411–412 (1982).

    Article  CAS  PubMed  Google Scholar 

  56. Somer, M. et al. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br. J. Clin. Pharmacol. 49, 549–554 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kormelink, T. G. et al. Decrease in immunoglobulin free light chains in patients with rheumatoid arthritis upon rituximab (anti-CD20) treatment correlates with decrease in disease activity. Ann. Rheum. Dis. 69, 2137–2144 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Toimela, T., Tahti, H. & Salminen, L. Retinal pigment epithelium cell culture as a model for evaluation of the toxicity of tamoxifen and chloroquine. Ophthalmic Res. 27, 150–153 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Bannwarth, B. et al. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin. Pharmacokinet. 30, 194–210 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Carmichael, S. J. et al. Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J. Rheumatol. 29, 2077–2083 (2002).

    CAS  PubMed  Google Scholar 

  61. van den Borne, B. E. et al. Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine. J. Rheumatol. 25, 1493–1498 (1998).

    PubMed  Google Scholar 

  62. Namazi, M. R. The potential negative impact of proton pump inhibitors on the immunopharmacologic effects of chloroquine and hydroxychloroquine. Lupus 18, 104–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Jallouli, M. et al. Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus. Arthritis Rheumatol. 67, 2176–2184 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Ezra, N. & Jorizzo, J. Hydroxychloroquine and smoking in patients with cutaneous lupus erythematosus. Clin. Exp. Dermatol. 37, 327–334 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Yeon Lee, J. et al. Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus. Arthritis Care Res. 69, 536–542 (2017).

    Article  CAS  Google Scholar 

  66. Borden, M. B. & Parke, A. L. Antimalarial drugs in systemic lupus erythematosus: use in pregnancy. Drug Saf. 24, 1055–1063 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Costedoat-Chalumeau, N. et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature. Autoimmun. Rev. 4, 111–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Teng, Y. K. O. et al. An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus erythematosus. Rheumatology 57, 1707–1720 (2017).

    Article  CAS  Google Scholar 

  69. Andreoli, L. et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann. Rheum. Dis. 76, 476–485 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Gotestam Skorpen, C. et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann. Rheum. Dis. 75, 795–810 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Izmirly, P. M. et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 126, 76–82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Saxena, A. et al. Prevention and treatment in utero of autoimmune-associated congenital heart block. Cardiol. Rev. 22, 263–267 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lisney, A. R. et al. High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block. Ann. Rheum. Dis. 76, 1476–1480 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Friedman, D. et al. No histologic evidence of foetal cardiotoxicity following exposure to maternal hydroxychloroquine. Clin. Exp. Rheumatol. 35, 857–859 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. Sammaritano, L. R. & Bermas, B. L. Rheumatoid arthritis medications and lactation. Curr. Opin. Rheumatol. 26, 354–360 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Circu, M. et al. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells. PLoS One 12, e0184922 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 14, 1435–1455 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Frustaci, A. et al. Inhibition of cardiomyocyte lysosomal activity in hydroxychloroquine cardiomyopathy. Int. J. Cardiol. 157, 117–119 (2012).

    Article  PubMed  Google Scholar 

  79. Sundelin, S. P. & Terman, A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS 110, 481–489 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Ballabio, A. & Bonifacino J. S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2019).

    Article  PubMed  Google Scholar 

  81. Lotteau, V. et al. Intracellular transport of class II MHC molecules directed by invariant chain. Nature 348, 600–605 (1990).

    Article  CAS  PubMed  Google Scholar 

  82. Ghislat, G. & Lawrence, T. Autophagy in dendritic cells. Cell Mol. Immunol. 15, 944–952 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Munz, C. Autophagy beyond intracellular MHC class II antigen presentation. Trends Immunol. 37, 755–763 (2016).

    Article  CAS  PubMed  Google Scholar 

  84. Ireland, J. M. & Unanue, E. R. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med. 208, 2625–2632 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ohkuma, S. & Poole, B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc. Natl Acad. Sci. USA 75, 3327–3331 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rebecca, V. W. et al. PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov. 9, 220–229 (2019).

    Article  PubMed  Google Scholar 

  87. Ma, C. et al. Identifying key genes in rheumatoid arthritis by weighted gene co-expression network analysis. Int. J. Rheum. Dis. 20, 971–979 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Ewald, S. E. et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456, 658–662 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kuznik, A. et al. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J. Immunol. 186, 4794–4804 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Hacker, H. et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 17, 6230–6240 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vollmer, J. et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202, 1575–1585 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. An, J. et al. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu. Rev. Med. 68, 317–330 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Zhang, X. et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 6, 421–430 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang, X. et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Shu, C., Li, X. & Li, P. The mechanism of double-stranded DNA sensing through the cGAS-STING pathway. Cytokine Growth Factor Rev. 25, 641–648 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. An, J. et al. Cutting edge: antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction. J. Immunol. 194, 4089–4093 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. van den Borne, B. E. et al. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J. Rheumatol. 24, 55–60 (1997).

    PubMed  Google Scholar 

  99. Wallace, D. J. et al. The effect of hydroxychloroquine therapy on serum levels of immunoregulatory molecules in patients with systemic lupus erythematosus. J. Rheumatol. 21, 375–376 (1994).

    CAS  PubMed  Google Scholar 

  100. Wallace, D. J. et al. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 2, S13–S15 (1993).

    Article  PubMed  Google Scholar 

  101. Hjorton, K. et al. Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis Res. Ther. 20, 238 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Willis, R. et al. Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus 21, 830–835 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Klinefelter, H. F. & Achurra, A. Effect of gold salts and antimalarials on the rheumatoid factor in rheumatoid arthritis. Scand. J. Rheumatol. 2, 177–182 (1973).

    Article  CAS  PubMed  Google Scholar 

  104. Dixon, J. S. et al. Biochemical indices of response to hydroxychloroquine and sodium aurothiomalate in rheumatoid arthritis. Ann. Rheum. Dis. 40, 480–488 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wu, S. F. et al. Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res. Ther. 19, 183 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Qushmaq, N. A. & Al-Emadi, S. A. Review on effectiveness of primary prophylaxis in aPLs with and without risk factors for thrombosis: efficacy and safety. ISRN Rheumatol. 2014, 348726 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Nuri, E. et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol. Res. 65, 17–24 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Dadoun, S. et al. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine 80, 29–33 (2013).

    Article  PubMed  Google Scholar 

  109. van den Hoek, J. et al. Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. Rheumatol. Int. 37, 487–493 (2017).

    Article  PubMed  Google Scholar 

  110. Avina-Zubieta, J. A. et al. Risk of myocardial infarction and stroke in newly diagnosed systemic lupus erythematosus: a general population-based study. Arthritis Care Res. 69, 849–856. (2017).

    Article  Google Scholar 

  111. Tselios, K., Gladman, D. D., Su, J., Ace, O. & Urowitz, M. B. Evolution of risk factors for atherosclerotic cardiovascular events in systemic lupus erythematosus: a longterm prospective study. J. Rheumatol. 44 1841–1849 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Padol, I. T. & Hunt, R. H. Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: an evidence-based interpretation. Rheumatology 49, 837–843 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Hage, M. P., Al-Badri, M. R. & Azar, S. T. A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti-inflammatory role. Ther. Adv. Endocrinol. Metab. 5, 77–85 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cansu, D. U. & Korkmaz, C. Hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient treated for RA. Rheumatology 47, 378–379 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Fasano, S. et al. Longterm hydroxychloroquine therapy and low-dose aspirin may have an additive effectiveness in the primary prevention of cardiovascular events in patients with systemic lupus erythematosus. J. Rheumatol. 44, 1032–1038 (2017).

    Article  CAS  PubMed  Google Scholar 

  116. Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Rand, J. H. et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-β2-glycoprotein I complexes to phospholipid bilayers. Blood 112, 1687–1695 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jancinova, V., Nosal, R. & Petrikova, M. On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb. Res. 74, 495–504 (1994).

    Article  CAS  PubMed  Google Scholar 

  119. Bertrand, E. et al. Antiaggregation action of chloroquine. Med. Trop. 50, 143–146 (1990).

    CAS  Google Scholar 

  120. Nosal, R., Jancinova, V. & Petrikova, M. Chloroquine inhibits stimulated platelets at the arachidonic acid pathway. Thromb. Res. 77, 531–542 (1995).

    Article  CAS  PubMed  Google Scholar 

  121. Miranda, S. et al. Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: role of reduced inflammation and endothelial dysfunction. PLoS One 14, e0212614 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Edwards, M. H. et al. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 96, 4380–4384 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Lazarus, M. N. et al. Incidence of cancer in a cohort of patients with primary Sjogren’s syndrome. Rheumatology 45, 1012–1015 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Srinivasa, A., Tosounidou, S. & Gordon, C. Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: a brand-related issue? J. Rheumatol. 44, 398 (2017).

    Article  PubMed  Google Scholar 

  125. Abdel-Hamid, H., Oddis, C. V. & Lacomis, D. Severe hydroxychloroquine myopathy. Muscle Nerve 38, 1206–1210 (2008).

    Article  PubMed  Google Scholar 

  126. Jafri, K. et al. Antimalarial myopathy in a systemic lupus erythematosus patient with quadriparesis and seizures: a case-based review. Clin. Rheumatol. 36, 1437–1444 (2017).

    Article  PubMed  Google Scholar 

  127. Khosa, S. et al. Hydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities. Neuropathology 38, 646–652 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Stein, M., Bell, M. J. & Ang, L. C. Hydroxychloroquine neuromyotoxicity. J. Rheumatol. 27, 2927–2931 (2000).

    CAS  PubMed  Google Scholar 

  129. Dogar, M. U. et al. Hydroxychloroquine-induced restrictive cardiomyopathy: a case report. Postgrad. Med. J. 94, 185–186 (2018).

    Article  PubMed  Google Scholar 

  130. Chang, I. C. Y. et al. Hydroxychloroquine-mediated cardiotoxicity with a false-positive 99mTechnetium-labeled pyrophosphate scan for transthyretin-related cardiac amyloidosis. Circ. Cardiovasc. Imaging 11, e007059 (2018).

    Article  PubMed  Google Scholar 

  131. Chatre, C. et al. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 41, 919–931 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Costedoat-Chalumeau, N. et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology 46, 808–810 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Jorge, A. et al. Hydroxychloroquine retinopathy – implications of research advances for rheumatology care. Nat. Rev. Rheumatol. 14, 693–703 (2018).

    Article  PubMed  Google Scholar 

  134. Marmor, M. F. et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology 123, 1386–1394 (2016).

    Article  PubMed  Google Scholar 

  135. Yusuf, I. H. et al. The Royal College of Ophthalmologists recommendations on screening for hydroxychloroquine and chloroquine users in the United Kingdom: executive summary. Eye 32, 1168–1173 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  136. MacIntyre, A. C. & Cutler, D. J. Kinetics of chloroquine uptake into isolated rat hepatocytes. J. Pharm. Sci. 82, 592–600 (1993).

    Article  CAS  PubMed  Google Scholar 

  137. Costedoat-Chalumeau, N. et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 3284–3290 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Costedoat-Chalumeau, N. et al. A prospective international study on adherence to treatment in 305 patients with flaring SLE: assessment by drug levels and self-administered questionnaires. Clin. Pharmacol. Ther. 103, 1074–1082 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Bethel, M. et al. Hydroxychloroquine in patients with systemic lupus erythematosus with end-stage renal disease. J. Investig. Med. 64, 908–910 (2016).

    Article  PubMed  Google Scholar 

  140. Sperati, C. J. & Rosenberg, A. Z. Hydroxychloroquine-induced mimic of renal Fabry disease. Kidney Int. 94, 634 (2018).

    Article  PubMed  Google Scholar 

  141. Yusuf, I. H., Lotery, A. J. & Ardern-Jones, M. R. Joint recommendations for retinal screening in long-term users of hydroxychloroquine and chloroquine in the United Kingdom, 2018. Br. J. Dermatol. 179, 995–996 (2018).

    Article  CAS  PubMed  Google Scholar 

  142. Melles, R. B. & Marmor, M. F. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 132, 1453–1460 (2014).

    Article  PubMed  Google Scholar 

  143. Costedoat-Chalumeau, N., Isenberg, D. & Petri, M. Letter in response to the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis et al. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2019-215573 (2019).

  144. Karasic, T. B. et al. Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol. 5, 993–998 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Rosenfeld, M. R. et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 10, 1359–1368 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rangwala, R. et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 10, 1369–1379 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rangwala, R. et al. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10, 1391–1402 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nti, A. A. et al. Frequent subclinical macular changes in combined BRAF/MEK inhibition with high-dose hydroxychloroquine as treatment for advanced metastatic braf mutant melanoma: preliminary results from a phase I/II clinical treatment trial. Retina 39, 502–513 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Dorner, T. Crossroads of B cell activation in autoimmunity: rationale of targeting B cells. J. Rheumatol. Suppl. 77, 3–11 (2006).

    PubMed  Google Scholar 

  150. Liang, N. et al. Multifaceted roles of ATM in autophagy: from nonselective autophagy to selective autophagy. Cell Biochem. Funct. 37, 177–184 (2019).

    Article  CAS  PubMed  Google Scholar 

  151. Bahia, M. S. et al. Interleukin-1 receptor associated kinase inhibitors: potential therapeutic agents for inflammatory- and immune-related disorders. Cell Signal. 27, 1039–1055 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Khanfar, M. A. & Alqtaishat, S. Discovery of potent IRAK-4 inhibitors as potential anti-inflammatory and anticancer agents using structure-based exploration of IRAK-4 pharmacophoric space coupled with QSAR analyses. Comput. Biol. Chem. 79, 147–154 (2019).

    Article  CAS  PubMed  Google Scholar 

  153. Kanvinde, S. et al. Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease. Acta Biomater. 82, 158–170 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Messai, A. in Emerging Research on Bioinspired Materials Engineering (ed. Bououdina, M.) 160–196 (IGI Global, 2016).

  155. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs Accessdata.fda.gov https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=006002 (2014).

  156. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs Accessdata.fda.gov https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=009768 (2014).

Download references

Acknowledgements

The authors would like to thank the Clinical Scientist Program of the Berlin Institutes of Health who provided grant support to E.V.S. and the Deutsche Forschungsgemeinschaft who provided grant support to T.D. (projects Do491/7-4 and Do491/10-1). Deutsches Rheumaforschungszentrum (DRFZ) Berlin is funded by the Leibniz society.

Author information

Authors and Affiliations

  1. Department of Nephrology and Intensive Medical Care, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Eva Schrezenmeier

  2. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Thomas Dörner

  3. Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany

    Thomas Dörner

Authors
  1. Eva Schrezenmeier
    View author publications

    Search author on:PubMed Google Scholar

  2. Thomas Dörner
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Thomas Dörner.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Rheumatology thanks K. Elkon and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Enantiomers

R and S enantiomers are mirror images of each other, but have different optical activities; enantiomers can interact differently with biomolecules and hence can have different biologic and possibly clinical activities or toxicities.

Volume of distribution

A pharmacokinetic parameter used to describe the distribution of a drug in the body; the volume of distribution is the theoretical volume needed to contain the total amount of an administered drug at the same concentration as that present in the plasma.

Bioavailability

The fraction of an administered dose of an unchanged drug that reaches the circulation; by definition, the bioavailability of an intravenously administered medication is 100%.

Three-compartment model

A model used to predict the rate and extent of distribution of a drug once administered; this model divides the body into a central compartment (compartment 1) and two peripheral compartments (compartments 2 and 3). The central compartment consists of the plasma and tissues where the drug is immediately distributed. The peripheral compartments consist of tissues and cells in which the drug is distributed more slowly.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schrezenmeier, E., Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16, 155–166 (2020). https://doi.org/10.1038/s41584-020-0372-x

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41584-020-0372-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing