Summary of dihydroartemisinin and its application for the treatment of lupus erythematosus

Abstract

Dihydroartemisinin (DHA) is the first generation of artemisinin derivatives with the antimalarial activity 10 times higher than artemisinin and recurrence rate as low as 1.95%. Since DHA was developed and marketed as a new antimalarial drug in 1992, Tu Youyou’s group has been paying attention to explore new clinical indications of DHA. The project of DHA for the treatment of lupus has made a great progress, which preclinical studies have been completed and the application for its clinical trials was approved by SFDA in 2016. Lupus erythematosus (LE) is a chronic autoimmune disease in which the human immune system becomes hyperactive and attacks healthy tissues including joints, skin, kidneys, blood cells, heart, and lungs. Systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) are two common forms of LE. Lupus nephritis is the most common severe systemic manifestation of SLE affecting up to 50% of adult patients during the course of their disease. Antimalarials, nonsteroidal anti-inflammatory drugs and local agents are widely used for the treatment of mild manifestations of lupus. For patients with moderate or severe disease, glucocorticoids are the mainstay of therapy in the acute phase. For disease modification in the induction and maintenance phase, various immunosuppressive or immunomodulatory drugs alone or in combination are used. Biologic therapies have been used to treat moderate-to-severe SLE. In 2011, Belimumab gained regulatory approval as the first biologic therapy for SLE treatment. In a word, standard treatment regimens that are commonly used, target inflammation non-specifically and cause immune suppression giving rise to increased risks of debilitating side effects. So more effective and less toxic treatments are needed. DHA has better efficiency and lower toxicity in antimalarial compared with hydroxychloroquine which is also used as LE treatment. The efficacy and mechanism of DHA for treating lupus was tested on BXSB mice and lupus-prone MRL/lpr mice, the two commonly used animal models of SLE. In BXSB mice, DHA could promote the proliferation of CD4 and CD8 T cells through inhibiting proliferation and decreasing the level of secretory autoantibody of B cells, resulting in the treating effect on lupus; DHA may relieve damage in lupus nephritis and inhibit the expression of NF- κ B p65 in lupus nephritis; DHA could inhibit the production of anti-dsDNA antibody and secretion of TNF α and improve the pathologic lesion of lupus nephritis; inhibitory effects of DHA on TNF α production may result from the block in the NF- κ B signaling pathway upstream of 1 κ B degradation. In lupus-prone MRL/lpr mice, DHA could inhibit development of mouse lupus nephritis through increasing SIGIRR expression which inhibited TLR4/NF- κ B signal pathway; DHA inhibited CCL2 secretion of HK-2 cells which were irritated by LPS, and it may be associated with increased expression of SIGIRR; DHA inhibits LPS-induced cell activation possibly by suppressing the TLR4/IRF/IFN pathway in spleen cells. All the results suggest that DHA has the potential therapeutic utility for the treatment of SLE. Furthermore, a preliminary clinical trial observation for curing LE with DHA was carried out. Seventy-three patients, including 36 cases of SLE and 37 cases of DLE, received DHA oral tablets, 60 or 80 mg d -1 for a median of 9.1 weeks. The effective rate of SLE and DLE were 86.1% (31/36) and 97.3% (36/37), respectively and no serious adverse effects were observed. So DHA is potential to become a new efficacy and safety drug in the treatment of LE.