杨念生;
YANG Nian-sheng;Department of Rheumatology,the First Affiliated Hospital,Sun Yat-sen University;

• 1:中山大学附属第一医院风湿免疫科

摘要(Abstract)：

随着对系统性红斑狼疮(systemic lupus erythematosus,SLE)发病机制研究的深入,SLE治疗进步显著。糖皮质激素等传统药物长期应用可能引起诸多不良反用,而新药的治疗靶点越来越特异,同时毒副作应也相应减少。新批准或正在进行临床试验的药物,如利妥昔单克隆抗体、贝利木单克隆抗体、anifrolumab和巴瑞替尼等,主要靶点为淋巴细胞、细胞因子及其细胞内信号通路。联合用药可同时阻断多个靶点,提高疗效。简言之,SLE药物发展是从化学药物到生物制剂再到小分子化学抑制剂的过程,治疗方式是从非特异性抗炎到特异性免疫抑制以及多靶点治疗的螺旋式上升过程。
There have been exciting advances in the treatment for systemic lupus erythematosus(SLE) with a better understanding of the pathogenesis. Since the long term use of traditional medicines such as glucocorticoids may have negative impacts on the outcome, novel treatments have increasingly specific targets that result in fewer adverse side effects. Medicines newly approved or undergoing clinical trials, such as rituximab, belimumab, anifrolumab, and baricitinib, mainly target at lymphocytes, cytokines, or their intracellular signaling pathways. A combinatory treatment that simultaneously blocks multiple targets may bring better efficacy. Development of the pharmacological treatment is a process evolving from chemical agents to biologics and back to small molecule chemical inhibitors. The modality of treatment is involved in a spiral manner from non-specific to specific and then to the combination of multi-target therapy.

关键词(KeyWords)： 系统性红斑狼疮;治疗;发病机制
systemic lupus erythematosus;treatment;pathogenesis

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金(81971519、81671593、81471598)

作者(Authors): 杨念生;
YANG Nian-sheng;Department of Rheumatology,the First Affiliated Hospital,Sun Yat-sen University;

参考文献(References)：

• [1] Andrade RM,Alarcón GS,Fernández M,et al.Accelerated damage accrual among men with systemic lupus erythematosus:XLIV.Results from a multiethnic US cohort[J].Arthritis Rheum,2007,56:622- 630.
• [2] Thamer M,Hernan MA,Zhang Y,et al.Prednisone,lupus activity,and permanent organ damage[J].J Rheumatol,2009,36:560- 564.
• [3] Appel GB,Contreras G,Dooley MA,et al.Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis[J].J Am Soc Nephrol,2009,20:1103- 1112.
• [4] Ginzler EM,Dooley MA,Aranow C,et al.Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis[J].N Engl J Med,2005,353:2219- 2228.
• [5] Mok CC,Ying KY,Yim CW,et al.Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis:a randomised controlled trial and long-term follow-up[J].Ann Rheum Dis,2016,75:30- 36.
• [6] Liu Z,Zhang H,Liu Z,et al.Multitarget therapy for induction treatment of lupus nephritis:a randomized trial[J].Ann Intern Med,2015,162:18- 26.
• [7] Fanouriakis A,Kostopoulou M,Alunno A,et al.2019 update of the EULAR recommendations for the management of systemic lupus erythematosus[J].Ann Rheum Dis,2019,78:736- 745.
• [8] Merrill JT,Neuwelt CM,Wallace DJ,et al.Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus:the randomized,double-blind,phase Ⅱ/Ⅲ systemic lupus erythematosus evaluation of rituximab trial[J].Arthritis Rheum,2010,62:222- 233.
• [9] Rovin BH,Furie R,Latinis K,et al.Efficacy and safety of rituximab in patients with active proliferative lupus nephritis:the Lupus Nephritis Assessment with Rituximab study[J].Arthritis Rheum,2012,64:1215- 1226.
• [10] Murray E,Perry M.Off-label use of rituximab in systemic lupus erythematosus:a systematic review[J].Clin Rheumatol,2010,29:707- 716.
• [11] Navarra SV,Guzman RM,Gallacher AE,et al.Efficacy and safety of belimumab in patients with active systemic lupus erythematosus:a randomised,placebo-controlled,phase 3 trial[J].Lancet,2011,377:721- 731.
• [12] Furie R,Petri M,Zamani O,et al.A phase Ⅲ,randomized,placebo-controlled study of belimumab,a monoclonal antibody that inhibits B lymphocyte stimulator,in patients with systemic lupus erythematosus[J].Arthritis Rheum,2011,63:3918- 3930.
• [13] Merrill JT,Wallace DJ,Wax S,et al.Efficacy and Safety of Atacicept in Patients With Systemic Lupus Erythematosus:Results of a Twenty-Four-Week,Multicenter,Randomized,Double-Blind,Placebo-Controlled,Parallel-Arm,Phase Ⅱb Study[J].Arthritis Rheumatol,2018,70:266- 276.
• [14] Isenberg D,Gordon C,Licu D,et al.Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE):52-week data (APRIL-SLE randomised trial)[J].Ann Rheum Dis,2015,74:2006- 2015.
• [15] Alexander T,Sarfert R,Klotsche J,et al.The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus[J].Ann Rheum Dis,2015,74:1474- 1478.
• [16] Merrill JT,Shanahan WR,Scheinberg M,et al.Phase Ⅲ trial results with blisibimod,a selective inhibitor of B-cell activating factor,in subjects with systemic lupus erythematosus (SLE):results from a randomised,double-blind,placebo-controlled trial[J].Ann Rheum Dis,2018,77:883- 889.
• [17] Onuora S.Positive results for anifrolumab in phase Ⅲ SLE trial[J].Nat Rev Rheumatol,2020,16:125.
• [18] Khamashta M,Merrill JT,Werth VP,et al.Sifalimumab,an anti-interferon-α monoclonal antibody,in moderate to severe systemic lupus erythematosus:a randomised,double-blind,placebo-controlled study[J].Ann Rheum Dis,2016,75:1909- 1916.
• [19] Zhao J,Wang H,Dai C,et al.P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway[J].Arthritis Rheum,2013,65:3176- 3185.
• [20] Zhao J,Zhang H,Huang Y,et al.Bay11- 7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation[J].Int Immunopharmacol,2013,17:116- 122.
• [21] van Vollenhoven RF,Hahn BH,Tsokos GC,et al.Efficacy and safety of ustekinumab,an IL- 12 and IL- 23 inhibitor,in patients with active systemic lupus erythematosus:results of a multicentre,double-blind,phase 2,randomised,controlled study[J].Lancet,2018,392:1330- 1339.
• [22] He J,Zhang R,Shao M,et al.Efficacy and safety of low-dose IL- 2 in the treatment of systemic lupus erythematosus:a randomised,double-blind,placebo-controlled trial[J].Ann Rheum Dis,2020,79:141- 149.
• [23] Wang S,Yang N,Zhang L,et al.Jak/STAT signaling is involved in the inflammatory infiltration of the kidneys in MRL/lpr mice[J].Lupus,2010,19:1171- 1180.
• [24] Zhou M,Guo C,Li X,et al.JAK/STAT signaling controls the fate of CD8(+)CD103(+) tissue-resident memory T cell in lupus nephritis[J].J Autoimmun,2020,102424.
• [25] You H,Zhang G,Wang Q,et al.Successful treatment of arthritis and rash with tofacitinib in systemic lupus erythematosus:the experience from a single centre[J].Ann Rheum Dis,2019,78:1441- 1443.
• [26] Deng GM,Liu L,Bahjat FR,et al.Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice[J].Arthritis Rheum,2010,62:2086- 2092.
• [27] Zhao J,Wang H,Huang Y,et al.Lupus nephritis:glycogen synthase kinase 3beta promotion of renal damage through activation of the NLRP3 inflammasome in lupus-prone mice[J].Arthritis Rheumatol,2015,67:1036- 1044.
• [28] Djabarouti S,Breilh D,Duffau P,et al.Steady-state mycophenolate mofetil pharmacokinetic parameters enable prediction of systemic lupus erythematosus clinical flares:an observational cohort study[J].Arthritis Res Ther,2010,12:R217.