Artemisinins—a Promising New Treatment for Systemic Lupus Erythematosus: a Descriptive Review
- 193 Downloads
Purpose of Review
Systemic lupus erythematosus (SLE) is a complex, potentially fatal autoimmune disease with no complete cure. Current treatments for SLE are limited by suboptimal efficacy and increased risk of infections and malignancies, and cannot meet the clinical demands of patients with SLE. Artemisinin and its derivatives (artemisinins), a new class of anti-malarial drugs, have recently been reported to have an immunosuppressive effect on lupus patients. In this review, we evaluate the therapeutic properties and potential mechanisms of artemisinins for the treatment of SLE.
Both clinical and animal studies suggest that artemisinins have potential beneficial effects for SLE. The beneficial effects associated with artemisinin treatment include improving symptoms, reducing level of antibodies and proteinuria, ameliorating renal damage, and diminishing the dosage of prednisone use. Animal studies suggest that mechanisms of action of artemisinins may include regulating T cell subsets, inhibiting activation of B cells and production of inflammatory cytokines, as well as blocking the NF-κB signal transduction pathway, thus playing a role in anti-inflammation and immunomodulation.
Artemisinin family drugs are a promising potential new medication that may challenge the current treatment paradigms available for SLE.
KeywordsSystemic lupus erythematosus Lupus nephritis Anti-malarial drug Artemisinin Treatment Artemisinin derivatives (Artemisinins)
Dr. Wang is supported by the National Center for Complementary and Integrative Health (K24 AT007323).
Dr. Wang is supported by the National Center for Complementary and Integrative Health of the National Institutes of Health (NIH, R01AT006367, R01AT005521 and K24AT007323). “The organizations above did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The investigators are solely responsible for the content of the manuscript and the decision to submit for publication.”
Dr. Mu is supported by the China Academy of Chinese Medical Sciences, Guang’anmen Hospital, Beijing.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 7.Lu YQ. The discovery and research progress of artemisinin. Life Science Research. 2012;16:260–5.Google Scholar
- 8.•• An J, Minie M, Sasaki T, Woodward JJ, Elkon KB. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu Rev Med. 2017;68:317–30. This comprehensive review summarizes and updates the chemistry of artemisinin drugs and their mechanisms of action. The authors emphasize how artemisinin drugs may impact multiple pathways of innate immunity and their current and future impact on systemic lupus erythematosus. CrossRefPubMedGoogle Scholar
- 13.Jiang W, Li B, Zheng X, Liu X, Cen Y, Li J, et al. Artesunate in combination with oxacillin protect sepsis model mice challenged with lethal live methicillin-resistant Staphylococcus aureus (MRSA) via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin. Int Immunopharmacol. 2011;11(8):1065–73.CrossRefPubMedGoogle Scholar
- 15.Xu LG, Chen P, Liang JS, Yi M, Wang Q, Ouyang D, et al. Therapeutic effect and mechanism of artesunate on experimental pulmonary fibrosis in rats. Clinical Medical Engineering. 2009;16(9):6–8.Google Scholar
- 19.• Lin ZM, Yang XQ, Zhu FH, He SJ, Tang W, Zuo JP. Artemisinin analogue SM934 attenuate collagen-induced arthritis by suppressing T follicular helper cells and T helper 17 cells. Sci Rep. 2016;29(6):38115. This study demonstrates the immunosuppressive effects of artemisinin analogue SM934 on collagen-induced arthritis both in vitro and in vivo. CrossRefGoogle Scholar
- 21.Cui XJ, Wang YY, Hou XQ, Pan L, Fu JX. Clinical observation of artesunate in the treatment of rheumatoid arthritis. Chin J Hosp Pharm. 2007;27(5):645–6.Google Scholar
- 22.Wei S, Xu GG. Clinical observation of artesunate in the treatment of rheumatoid arthritis. Shanxi Journal of Medicine. 2008;37(5):457–8.Google Scholar
- 23.Yu QB, Jin HL. Artesunate treatment on dermatosis: a clinical analysis of 90 cases. Journal of Bengbu Medical College. 1997;22(5):309–10.Google Scholar
- 24.Zhou Q, Gao YX, Jin HL. Effects of artesunate on experimental immunological myositis in animal model (in Chinese). Chinese Journal of Dermatology. 1998;31(4):241–3.Google Scholar
- 25.Ma J, Chen LH, Liao R, Xu SG, Li M, Xu DH, et al. Effect of artemether and dihydroartemisinin on scleroderma in mice. Chin J Chin Mat Med. 2009;34(2):204–7.Google Scholar
- 27.Zhong JX, Peng SQ, Zhang JY, Liang LQ. 25 cases of SLE treated with combination of traditional Chinese and western medicine. Chinese Journal of Integrated Traditional and Western Medicine. 1999;19(1):47–8.Google Scholar
- 28.Zhang JY, Zhong JX, Shi ZY, Dai XY. Effect of artesunate and Lingdan tablet on T cell subsets in SLE patients. Chinese Journal of Integrated Traditional and Western Medicine. 2002;22(7):489.Google Scholar
- 29.Zhang JY, Zhong JX, Peng SQ, Zhang FX. Study on the effect of artesunate and Lingdan tablet on IL-2 and sIL-2R in patients with SLE. Journal of Henan University of Chinese Medicine. 2003;18(2):38–9.Google Scholar
- 31.Huang XX. Clinical study of artesunate on immune function in patients with SLE. Lishizhen Medicine and Materia Medica Research. 2011;22(7):1673–4.Google Scholar
- 32.Yu QB, Gao YX. Clinical observation of artesunate in the treatment of 56 cases of lupus. Chinese Journal of Dermatology. 1997;30(1):51–2.Google Scholar
- 33.Yu QB, Jin HL. Clinical observation of artesunate in the treatment of 30 cases of SLE. Journal of Bengbu Medical College. 1996;21(3):173–4.Google Scholar
- 34.Chinese society of integrated Chinese and western medicine on dermatology. Five kinds of dermatological diseases: diagnosis and evaluation criteria of integrated traditional Chinese and western medicine. Chinese Journal of Integrated Traditional and Western Medicine. 1992;12(1):56–8.Google Scholar
- 36.Wu XL, Sun WS, Shi XM, Wang Z, An P, Qiao CL. Effect of artemisinin on the expressions of GRαmRNA, GRβmRNA and P300/CBP protein in lupus nephritis mice. Journal of Chinese Medical Materials. 2012;35:608–12.Google Scholar
- 37.•• Liang N, Zhong YC, Zhou J, Liu BH, Lu RR, Guan YZ, et al. Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor-κB signaling pathway in lupus nephritis mice. Exp Ther Med. 2018;15:2436–42. This study demonstrates the immunosuppressive effect of artemisinin and hydroxychloroquine combination therapy, which may provide a novel method for the treatment of lupus nephritis. The underlying mechanisms of the combined treatment may be through regulation of the expression levels of cytokines, KLF15 and NF-kB. Google Scholar
- 38.Xu LM, Chen XR, Tu YY. Effect of dihydroartemisinin on BXSB lupus mice. Chinese Journal of Dermatovenereology of Integrated Traditional and Western Medicine. 2002;1:19–20.Google Scholar
- 40.Dong YJ, Li WD, Tu YY, Zhang HN, Zou WZ, Yang LL, et al. Effect and mechanism of dihydroartemisinin on BXSB lupus mice. Chinese Pharmacological Bulletin. 2003;19:1125–8.Google Scholar
- 43.You YW, Liao PH, Yang FF, Lin X. Regulating effect of dihydroartemisinin on expression of fractalkine in renal cortex of lupus-prone MRL/lpr mice. Immunological Journal. 2014;30(7):617–22.Google Scholar
- 44.• Huang M, Jin XK, Cai QC, Li M, Lin ZB, Li WD. Effect of dihydroartemisinin on lupus mice and its relationship with SIGIRR induced immune negative regulation. Chinese Journal of Immunology. 2015;31:1637–41. 1647. The authors observe the relationship between the therapeutic effect of dihydroartemisinin and its molecular mechanism and signal pathway in lupus mouse model. Google Scholar
- 45.Zhu WX, Gu J. Effects of artesunate on interleukin-6 and transforming growth factor β in renal tissue of lupus-like mice. Chinese Journal of Dermatovenereology of Integrated Traditional and Western Medicine. 2003;2:25–7.Google Scholar
- 46.Zhu WX, Gu J. Effects of artesunate on serum level of interleukin-6 and transforming growth factor β in lupus-like mice. Chinese Journal of leprosy and skin diseases. 2004;20:318–9.Google Scholar
- 47.Jin OY, Zhang HY, Xu T, Zhao SN, Zhou KX, Sun LY. Pathological change and mechanism of artesunate treatment for lupus nephritis in MRL/lpr mice. Journal of Clinical Medicine in Practice. 2007;11(4):5–9.Google Scholar
- 48.Lin XD, Zhong JX, Qi SJ, Zhang FX. Effects of artesunate on the expression of CD4, CD8 and CD54 on peripheral blood lymphocytes in lupus like mice. Shandong J Tradit Chin Med. 2008;27:615–7.Google Scholar
- 50.Wang H, Jiang B, Zhang HY, Liu BJ, Sun LY. Artesunate relieves lupus nephritis by inhibiting the expression of ICAM-1. Journal of Clinical Medicine in Practice. 2010;14(7):1–3.Google Scholar
- 53.•• Wu YW, He SJ, Bai BX, Zhang LY, Xue L, Lin ZM, et al. Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation. Cell Mol Immunol. 2016;13:379–90. This study investigates the therapeutic effects of a modified dosage regimen of artemisinin analogue SM934 on lupus-prone MRL/lpr mice and explores its effects on B cell responses in SLE. The authors conclude that a twice daily dosing regimen of SM 934 has therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation. Google Scholar
- 56.•• Feng X, Chen W, Xiao L, Gu F, Huang J, Tsao BP, et al. Artesunate inhibits type I interferon-induced production of macrophage migration inhibitory factor in patients with systemic lupus erythematosus. Lupus. 2017;26(1):62–72. These authors report the effects and potential immune mechanisms of artesunate and find that artesunate inhibits macrophage migration inhibitory factor, and thus may have therapeutic potential for SLE-associated atherosclerosis. CrossRefPubMedGoogle Scholar
- 57.Zani B, Gathu M, Donegan S, Olliaro PL, Sinclair D. Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2014;20(1):1–160.Google Scholar
- 58.• Kovacs SD, van Eijk AM, Sevene E, Dellicour S, Weiss NS, Emerson S, et al. The safety of artemisinin derivatives for the treatment of malaria in the 2nd or 3rd trimester of pregnancy: a systematic review and meta-analysis. PLoS One. 2016;11(11):e0164963. This study provides a comprehensive review of the safety of artemisinin derivatives for the treatment of malaria during pregnancy. CrossRefPubMedPubMedCentralGoogle Scholar
- 64.• von Hagens C, Walter-Sack I, Goeckenjan M, Osburg J, Storch-Hagenlocher B, Sertel S, et al. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat. 2017;164(2):359–69. This study describes safety of use oral artesunate and emphasizes that safety monitoring should include reticulocytes, audiological and neurological exploration for cancer patients. CrossRefGoogle Scholar