The Diagnosis And Pathogenesis Of Systemic Lupus Erythematosus Complicated With Thrombotic Microangiopathy

Background:Thrombotic microangiopathy(TMA)is a life-threatening complication of systemic lupus erythematosus(SLE),which has poor prognosis.There are many etiologies behind SLE-TMA,such as antiphospholipid antibodies,ADAMTS13 inhibitors and infection.However,the etiology of a considerable number of patients is still unclear and the best treatment is unknown.Sporadic reports suggest that the activation of complement pathway may play a role in the pathogenesis of SLE-TMA,which is not fully demonstrated.Objective:1.To explore the clinical manifestations and prognosis of different types of SLE-TMA;2.To investigate the role of serological detection in the diagnosis and differential diagnosis of SLE-TMA;3.To explore the role of genetic variation in SLE-TMA.Methods:In this study,we prospectively enrolled 40 SLE-TMA patients in Peking Union Medical College Hospital,14 patients with lupus nephritis(LN)and 38 patients with other types of TMA.The clinical data and follow-up data were collected and compared between SLE-TMA patients with different etiologies.Peripheral blood concentrations of CFH,complement factor B,soluble C5b-9,relative activity of complement pathway,intercellular cell adhesion molecule-1(ICAM1),vascular cell adhesion molecule 1(VCAM1)and E-Selectin were measured by ELISA in SLE-TMA patients and control groups.At the same time,genomic DNA was extracted from peripheral blood cells and whole exome sequencing(WES)was performed to analyze the genetic variats that may be related to TMA.Results:1.The cause of 47.5%of SLE-TMA patients included in the study is unclear.SLE-TMA patients was divided into different subgroups.It was found that SLE-TMA mediated by AD AMTS 13 inhibitors had severe nervous system involvement,but less kidney involvement and good response to plasma exchange.Among SLE-TMA with unknown etiology,patients with renal-only TMA had lighter hematological manifestations and lower serum creatinine level than SLE-aHUS(p=0.005).The common point is that the main organ involved is kidney,and the effect of plasma exchange is relatively poor.2.Compared with SLE-aHUS,the concentration of CFH in renal-only SLE-TMA was higher(p=0.026).The level of E-selectin in patients with renal-only SLE-TMA was significantly lower than that in SLE-aHUS patients with MAHA(p=0.016).3.There was no significant difference in genetic susceptibility among SLE-aHUS,renal-only SLE-TMA and SLE-TMA with other causes.In SLE-TMA patients,thrombophilia variants are more than complement variants.The severity of TMA related clinical manifestations may be higher in patients with variants,and the treatment response of these patients is worse than that of SLE-TMA patients without variants,although they have received more intensive plasma exchange treatment.In serological test,VC AMI level in SLE-TMA patients with complement related genetic variants was significantly higher than that in SLE-TMA patients without variants(p=0.001).Patients with compound complement variants are more likely to detect abnormal level of complement factors.Conclusion:SLE-TMA with unknown etiology can be divided into two subgroups with different severity according to the presence or absence of MAHA.The main organs involved in these patients are kidneys.The detection of complement factor and E-selectin may play a role in differentiating the two subgroups of SLE-TMA;SLE activity leads to the heterogeneity of complement factors,which may "cover up" the difference between SLE-TMA and LN.SLE-TMA patients with TMA related genetic variats have poor response to plasmapheresis and other treatments may be needed.The complement pathway is highly activated in patients with compound complement mutations,resulting in increased complement factors consumption.Complement variants may play a role in the pathogenesis of SLE-TMA by aggravating endothelial cell damage.