The role of antimalarial agents in the treatment of SLE and lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE. Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however, their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall, antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a good safety profile.

Key Points

  • Antimalarial therapy for patients with systemic lupus erythematosus (SLE) is associated with improved survival and reduced disease activity, as well as cardioprotective and anticancer effects

  • In lupus nephritis, antimalarial therapy is associated with reduced corticosteroid use, reduced disease activity, extended time to end-stage renal disease, and, with adjunctive immunomodulatory treatment, improved duration of renal remission

  • Treatment with antimalarial agents should be continued in pregnant women with SLE; the beneficial effects may include a reduction in the risk of cardiac manifestations of neonatal SLE

  • Antimalarial drugs have a good safety profile; gastrointestinal symptoms are the most common adverse effect

  • Baseline monitoring for retinopathy is required, but regular monitoring is recommended by the American Academy of Ophthalmology guidelines only for patients who have taken antimalarial agents for >5 years

  • In patients with impaired renal function, caution with dosing of antimalarial agents is recommended and careful monitoring for adverse events should be undertaken

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Schmajuk, G., Yazdany, J., Trupin, L. & Yelin, E. Hydroxychloroquine treatment in a community-based cohort of patients with systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 62, 386–392 (2010).

    Article  Google Scholar 

  2. 2

    Ruiz-Irastorza, G., Ramos-Casals, M., Brito-Zeron, P. & Khamashta, M. A. 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 

  3. 3

    Wallace, D. J. The history of antimalarials. Lupus 5 (Suppl. 1), S2–S3 (1996).

    Article  PubMed  Google Scholar 

  4. 4

    Tett, S. E., Cutler, D. J., Day, R. O. & Brown, K. F. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br. J. Clin. Pharmacol. 27, 771–779 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Furst, D. E. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 5 (Suppl. 1), S11–S15 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Kalia, S. & Dutz, J. P. New concepts in antimalarial use and mode of action in dermatology. Dermatol. Ther. 20, 160–174 (2007).

    Article  PubMed  Google Scholar 

  7. 7

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

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Leecharoen, S., Wangkaew, S. & Louthrenoo, W. Ocular side effects of chloroquine in patients with rheumatoid arthritis, systemic lupus erythematosus and scleroderma. J. Med. Assoc. Thai. 90, 52–58 (2007).

    PubMed  Google Scholar 

  9. 9

    Barré, P. E., Gascon-Barré, M., Meakins, J. L. & Goltzman, D. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. Am. J. Med. 82, 1259–1262 (1987).

    Article  PubMed  Google Scholar 

  10. 10

    Fox, R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus 5 (Suppl. 1), S4–S10 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Ermann, J. & Bermas, B. L. The biology behind the new therapies for SLE. Int. J. Clin. Pract. 61, 2113–2119 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    van den Borne, B. E., Dijkmans, B. A., de Rooij, H. H., le Cessie, S. & Verweij, C. L. 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).

    CAS  PubMed  Google Scholar 

  13. 13

    Karres, I. et al. Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am. J. Physiol. 274, R1058–R1064 (1998).

    CAS  PubMed  Google Scholar 

  14. 14

    Wozniacka, A., Lesiak, A., Narbutt, J., McCauliffe, D. P. & Sysa-Jedrzejowska, A. Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 15, 268–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Jang, C. H., Choi, J. H., Byun, M. S. & Jue, D. M. Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford) 45, 703–710 (2006).

    Article  CAS  Google Scholar 

  16. 16

    Jeong, J. Y. & Jue, D. M. Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages. J. Immunol. 158, 4901–4907 (1997).

    CAS  PubMed  Google Scholar 

  17. 17

    Sperber, K. et al. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J. Rheumatol. 20, 803–808 (1993).

    CAS  PubMed  Google Scholar 

  18. 18

    Weber, S. M., Chen, J. M. & Levitz, S. M. Inhibition of mitogen-activated protein kinase signaling by chloroquine. J. Immunol. 168, 5303–5309 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Löffler, B. M., Bohn, E., Hesse, B. & Kunze, H. Effects of antimalarial drugs on phospholipase A and lysophospholipase activities in plasma membrane, mitochondrial, microsomal and cytosolic subcellular fractions of rat liver. Biochim. Biophys. Acta 835, 448–455 (1985).

    Article  PubMed  Google Scholar 

  20. 20

    Kim, W. U. et al. Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes. Clin. Exp. Immunol. 144, 503–511 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Potvin, F., Petitclerc, E., Marceau, F. & Poubelle, P. E. Mechanisms of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells. J. Immunol. 158, 1872–1879 (1997).

    CAS  PubMed  Google Scholar 

  22. 22

    Wozniacka, A. 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. 159, 1124–1130 (2008).

    CAS  PubMed  Google Scholar 

  23. 23

    Hurst, N. P., French, J. K., Gorjatschko, L. & Betts, W. H. Studies on the mechanism of inhibition of chemotactic tripeptide stimulated human neutrophil polymorphonuclear leucocyte superoxide production by chloroquine and hydroxychloroquine. Ann. Rheum. Dis. 46, 750–756 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Nguyen, T. Q., Capra, J. D. & Sontheimer, R. D. 4-Aminoquinoline antimalarials enhance UV-B induced c-jun transcriptional activation. Lupus 7, 148–153 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Lesiak, A. et al. Effect of chloroquine phosphate treatment on serum MMP-9 and TIMP-1 levels in patients with systemic lupus erythematosus. Lupus 19, 683–688 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Lim, E. J. et al. Toll-like receptor 9 dependent activation of MAPK and NF-kB is required for the CpG ODN-induced matrix metalloproteinase-9 expression. Exp. Mol. Med. 39, 239–245 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Wallace, D. J., Linker-Israeli, M., Metzger, A. L. & Stecher, V. J. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 2 (Suppl. 1), S13–S15 (1993).

    Article  PubMed  Google Scholar 

  28. 28

    Toubi, E. et al. The reduction of serum B-lymphocyte activating factor levels following quinacrine add-on therapy in systemic lupus erythematosus. Scand. J. Immunol. 63, 299–303 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Dubois, E. L. Antimalarials in the management of discoid and systemic lupus erythematosus. Semin. Arthritis Rheum. 8, 33–51 (1978).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Dubois, E. L. Quinacrine (atabrine) in treatment of systemic and discoid lupus erythematosus. AMA Arch. Intern. Med. 94, 131–141 (1954).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Rudnicki, R. D., Gresham, G. E. & Rothfield, N. F. The efficacy of antimalarials in systemic lupus erythematosus. J. Rheumatol. 2, 323–330 (1975).

    CAS  PubMed  Google Scholar 

  32. 32

    [No authors listed] A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N. Engl. J. Med. 324, 150–154 (1991).

  33. 33

    Meinão, I. M., Sato, E. I., Andrade, L. E., Ferraz, M. B. & Atra, E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus 5, 237–241 (1996).

    Article  PubMed  Google Scholar 

  34. 34

    Alarcón, G. S. et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann. Rheum. Dis. 66, 1168–1172 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Fessler, B. J. et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 52, 1473–1480 (2005).

    Article  PubMed  Google Scholar 

  36. 36

    Molad, Y. et al. Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort. Lupus 11, 356–361 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Shinjo, S. K. et al. Antimalarial treatment may have a time-dependent effect on lupus survival: data from a multinational Latin American inception cohort. Arthritis Rheum. 62, 855–862 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Westlake, S. L. & Edwards C. J. Anti-malarials and lupus in West Africa use and lupus in Africans. Lupus 18, 193–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Hodis, H. N., Quismorio, F. P. Jr, Wickham, E. & Blankenhorn, D. H. The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J. Rheumatol. 20, 661–665 (1993).

    CAS  PubMed  Google Scholar 

  40. 40

    Petri, M., Lakatta, C., Magder, L. & Goldman, D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am. J. Med. 96, 254–259 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Tam, L. S., Gladman, D. D., Hallett, D. C., Rahman, P. & Urowitz, M. B. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J. Rheumatol. 27, 2142–2145 (2000).

    CAS  PubMed  Google Scholar 

  42. 42

    Borba, E. F. & Bonfá, E. Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J. Rheumatol. 28, 780–785 (2001).

    CAS  PubMed  Google Scholar 

  43. 43

    Sachet, J. C. et al. Chloroquine increases low-density lipoprotein removal from plasma in systemic lupus patients. Lupus 16, 273–278 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Cardoso, C. R., Signorelli, F. V., Papi, J. A. & Salles, G. F. Prevalence and factors associated with dyslipoproteinemias in Brazilian systemic lupus erythematosus patients. Rheumatol. Int. 28, 323–327 (2008).

    Article  PubMed  Google Scholar 

  45. 45

    Bevan, A. P., Christensen, J. R., Tikerpae, J. & Smith, G. D. Chloroquine augments the binding of insulin to its receptor. Biochem. J. 311, 787–795 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Petri, M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 5 (Suppl. 1), S16–S22 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Rekedal, L. R. et al. Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. Arthritis Rheum. 62, 3569–3573 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Penn, S. K. et al. Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J. Rheumatol. 37, 1136–1142 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Gerstein, H. C., Thorpe, K. E., Taylor, D. W. & Haynes, R. B. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas—a randomzed trial. Diabetes Res. Clin. Pract. 55, 209–219 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Bellomio, V. et al. Metabolic syndrome in Argentinean patients with systemic lupus erythematosus. Lupus 18, 1019–1025 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Razani, B., Feng, C. & Semenkovich, C. F. p53 is required for chloroquine-induced atheroprotection but not insulin sensitization. J. Lipid Res. 51, 1738–1746 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Roman, M. J. et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N. Engl. J. Med. 349, 2399–2406 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Zhang, C. Y. et al. Evaluation of risk factors that contribute to high prevalence of premature atherosclerosis in Chinese premenopausal systemic lupus erythematosus patients. J. Clin. Rheumatol. 15, 111–116 (2009).

    Article  PubMed  Google Scholar 

  54. 54

    Souza, A. W., Hatta, F. S., Miranda, F. Jr & Sato, E. I. Atherosclerotic plaque in carotid arteries in systemic lupus erythematosus: frequency and associated risk factors. Sao Paulo Med. J. 123, 137–142 (2005).

    Article  PubMed  Google Scholar 

  55. 55

    Von Feldt, J. M. et al. Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2220–2227 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Selzer, F. et al. Comparison of risk factors for vascular disease in the carotid artery and aorta in women with systemic lupus erythematosus. Arthritis Rheum. 50, 151–159 (2004).

    Article  PubMed  Google Scholar 

  57. 57

    Selzer, F. et al. Vascular stiffness in women with systemic lupus erythematosus. Hypertension 37, 1075–1082 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Tanay, A. et al. Vascular elasticity of systemic lupus erythematosus patients is associated with steroids and hydroxychloroquine treatment. Ann. NY Acad. Sci. 1108, 24–34 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Bessant, R. et al. Prevalence of conventional and lupus-specific risk factors for cardiovascular disease in patients with systemic lupus erythematosus: a case-control study. Arthritis Rheum. 55, 892–899 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Urowitz, M. B. et al. Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 62, 881–887 (2010).

    Article  CAS  Google Scholar 

  61. 61

    Ruiz-Irastorza, G. et al. Antimalarials may influence the risk of malignancy in systemic lupus erythematosus. Ann. Rheum. Dis. 66, 815–817 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Sisó, A. et al. Previous antimalarial therapy in patients diagnosed with lupus nephritis: Influence on outcomes and survival. Lupus 17, 281–288 (2008).

    Article  PubMed  Google Scholar 

  63. 63

    Ruiz-Irastorza, G. et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 15, 577–583 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Jung, H. et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. 62, 863–868 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Tsakonas, E. et al. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus 7, 80–85 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Pons-Estel, G. J. et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 61, 830–839 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Vlad, S. C. Protective effect of hydroxychloroquine on renal damage may be biased: comment on the article by Pons-Estel et al. Arthritis Rheum. 61, 1614 (2009).

    Article  PubMed  Google Scholar 

  68. 68

    Vinet, E., Bernatsky, S. & Suissa, S. Have some beneficial effects of hydroxychloroquine been overestimated? Potential biases in observational studies of drug effects: comment on the article by Pons-Estel et al. Arthritis Rheum. 61, 1614–1615 (2009).

    Article  PubMed  Google Scholar 

  69. 69

    Kasitanon, N., Fine, D. M., Haas, M., Magder, L. S. & Petri, M. Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus 15, 366–370 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Parke, A. Antimalarial drugs and pregnancy. Am. J. Med. 85, 30–3 (1988).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Parke, A. & West, B. Hydroxychloroquine in pregnant patients with systemic lupus erythematosus. J. Rheumatol. 23, 1715–1718 (1996).

    CAS  PubMed  Google Scholar 

  72. 72

    Costedoat-Chalumeau, N., Amoura, Z., Huong, D. L., Lechat, P. & Piette, J. C. 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 

  73. 73

    Germain, S. & Nelson-Piercy, C. Lupus nephritis and renal disease in pregnancy. Lupus 15, 148–155 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Clowse, M. E., Magder, L., Witter, F. & Petri, M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 54, 3640–3647 (2006).

    Article  PubMed  Google Scholar 

  75. 75

    Levy, R. A. et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 10, 401–404 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Izmirly, P. M. et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann. Rheum. Dis. 69, 1827–1830 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Wang, C. et al. Discontinuation of antimalarial drugs in systemic lupus erythematosus. J. Rheumatol. 26, 808–815 (1999).

    CAS  PubMed  Google Scholar 

  78. 78

    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 

  79. 79

    Marmor, M. F., Kellner, U., Lai, T. Y., Lyons, J. S. & Meiler, W. F. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 118, 415–422 (2011).

    Article  PubMed  Google Scholar 

  80. 80

    Rynes, R. I. Ophthalmologic considerations in using antimalarials in the United States. Lupus 5 (Suppl. 1), S73–S74 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Spalton, D. J. Retinopathy and antimalarial drugs—the British experience. Lupus 5 (Suppl. 1), S70–S72 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Marmor, M. F., Carr, R. E., Easterbrook, M., Farjo, A. A. & Mieler, W. F. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 109, 1377–1382 (2002).

    Article  PubMed  Google Scholar 

  83. 83

    Mavrikakis, I. et al. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal. Ophthalmology 110, 1321–1326 (2003).

    Article  PubMed  Google Scholar 

  84. 84

    Lyons, J. S. & Severns, M. L. Using multifocal ERG ring ratios to detect and follow Plaquenil retinal toxicity: a review: review of mfERG ring ratios in Plaqunil toxicity. Doc. Ophthal. 118, 29–36 (2008).

    Article  Google Scholar 

  85. 85

    Wolfe, F. & Marmor, M. F. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 62, 775–784 (2010).

    Article  CAS  Google Scholar 

  86. 86

    Levy, G. D. et al. Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. 40, 1482–1486 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    The Royal College of Ophthalmologists. Hydroxychloroquine and Ocular Toxicity Recommendations on Screening [online], (2009).

  88. 88

    Nord, J. E., Shah, P. K., Rinaldi, R. Z. & Weisman, M. H. Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature. Semin. Arthritis Rheum. 33, 336–351 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Puri, P. K., Lountzis, N. I., Tyler, W. & Ferringer, T. Hydroxychloroquine-induced hyperpigmentation: the staining pattern. J. Cutan. Pathol. 35, 1134–1137 (2008).

    Article  PubMed  Google Scholar 

  90. 90

    Herman, S. M., Shin, M. H., Holbrook, A. & Rosenthal, D. The role of antimalarials in the exacerbation of psoriasis: a systematic review. Am. J. Clin. Dermatol. 7, 249–257 (2006).

    Article  PubMed  Google Scholar 

  91. 91

    Bracamonte, E. R., Kowalewska, J., Starr, J., Gitomer, J. & Alpers, C. E. Iatrogenic phospholipidosis mimicking Fabry disease. Am. J. Kidney Dis. 48, 844–850 (2006).

    Article  PubMed  Google Scholar 

  92. 92

    Costedoat-Chalumeau, N. et al. Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus. Ann. Rheum. Dis. 66, 821–824 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    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 

  94. 94

    Calvo-Alén, J. et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIV. Cytotoxic treatment is an additional risk factor for the development of symptomatic osteonecrosis in lupus patients: results of a nested matched case-control study. Ann. Rheum. Dis. 65, 785–790 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    James, J. A. et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus 16, 401–409 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    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 

  97. 97

    Shinjo, S. K. Systemic lupus erythematosus in the elderly: antimalarials in disease remission. Rheumatol. Int. 29, 1087–1090 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Pons-Estel, G. J. et al. Possible protective effect of hydroxychloroquine on delaying the occurrence of integument damage in lupus: LXXI, data from a multiethnic cohort. Arthritis Care Res. (Hoboken) 62, 393–400 (2010).

    Article  Google Scholar 

  99. 99

    de Leeuw, K. et al. Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. Lupus 15, 675–682 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Choojitarom, K. et al. Lupus nephritis and Raynaud's phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies. Clin. Rheumatol. 27, 345–351 (2008).

    Article  PubMed  Google Scholar 

  101. 101

    Kaiser, R., Cleveland, C. M. & Criswell, L. A. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann. Rheum. Dis. 68, 238–241 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Tektonidou, M. G., Laskari, K., Panagiotakos, D. B. & Moutsopoulos, H. M. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum. 61, 29–36 (2009).

    Article  Google Scholar 

  103. 103

    Barber, C. E., Geldenhuys, L. & Hanly, J. G. Sustained remission of lupus nephritis. Lupus 15, 94–101 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Buchanan, N. M. et al. Hydroxychloroquine and lupus pregnancy: review of a series of 36 cases. Ann. Rheum. Dis. 55, 486–488 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Costedoat-Chalumeau, N. et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. 48, 3207–3211 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Carvalheiras, G. et al. Pregnancy and systemic lupus erythematosus: review of clinical features and outcome of 51 pregnancies at a single institution. Clin. Rev. Allergy Immunol. 38, 302–306 (2010).

    Article  PubMed  Google Scholar 

  107. 107

    Aviña-Zubieta, J. A., Galindo-Rodriguez, G., Newman, S., Suarez-Almazor, M. E. & Russell, A. S. Long-term effectiveness of antimalarial drugs in rheumatic diseases. Ann. Rheum. Dis. 57, 582–587 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Finbloom, D. S., Silver, K., Newsome, D. A. & Gunkel, R. Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity. J. Rheumatol. 12, 692–694 (1985).

    CAS  PubMed  Google Scholar 

  109. 109

    Spalton, D. J., Verdon Roe, G. M. & Hughes, G. R. Hydroxychloroquine, dosage parameters and retinopathy. Lupus 2, 355–358 (1993).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Morand, E. F., McCloud, P. I. & Littlejohn, G. O. Continuation of long term treatment with hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis. Ann. Rheum. Dis. 51, 1318–1321 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Costedoat-Chalumeau, N. et al. Cardiomyopathy related to antimalarial therapy with illustrative case report. Cardiology 107, 73–80 (2007).

    Article  PubMed  Google Scholar 

  112. 112

    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 (Oxford) 46, 808–810 (2007).

    Article  CAS  Google Scholar 

  113. 113

    Wozniacka, A., Cygankiewicz, I., Chudzik, M., Sysa-Jedrzejowska, A. & Wranicz, J. K. The cardiac safety of chloroquine phosphate treatment in patients with systemic lupus erythematosus: the influence on arrhythmia, heart rate variability and repolarization parameters. Lupus 15, 521–525 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Cervera, A., Espinosa, G., Font, J. & Ingelmo, M. Cardiac toxicity secondary to long term treatment with chloroquine. Ann. Rheum. Dis. 60, 301 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Di Giacomo, T. B., Valente, N. Y. & Nico, M. M. Chloroquine -induced hair depigmentation. Lupus 18, 264–266 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Bezerra, E. L., Vilar, M. J., da Trindade Neto, P. B. & Sato, E. L. Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus. Arthritis Rheum. 52, 3073–3078 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Van Beek, M. J. & Piette, W. W. Antimalarials. Dermatol. Clin. 19, 147–160 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Casado, E. et al. Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann. Rheum. Dis. 65, 385–390 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Collins, G. B. & McAllister, M. S. Chloroquine psychosis masquerading as PCP: a case report. J. Psychoactive Drugs 40, 211–214 (2008).

    Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

S-J. Lee and E. Silverman researched the data for the article. S-J. Lee and J. M. Bargman were the principal contributors to writing the article and discussing its content, although E. Silverman was also involved in these aspects of the manuscript. J. M. Bargman, and to a lesser extent S-J. Lee, participated in the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Joanne M. Bargman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, SJ., Silverman, E. & Bargman, J. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol 7, 718–729 (2011). https://doi.org/10.1038/nrneph.2011.150

Download citation

Further reading

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