Gene Screening Of Primary Immunodeficiency Diseases In Patients With Pediatric Systemic Lupus Erythematosus

Background:Systemic lupus erythematosus(SLE)is one of the most common autoimmune diseases in childhood.Pediatric SLE(pSLE)accounts for about 10%-20%of all SLE patients.Compared with adults,JSLE patients present more severe symptoms and obvious organ damage,suggesting an existence of different pathogenesis.Some children patients have a very early onset,continued reduction in complement,or show no obvious improvement after receiving standard treatment.It suggests that children with SLE may have a genetic background related to immunodeficiency.Recently,"monogenic lupus" has attracted more and more attention.It refers to a class of diseases in which the body has a lupus-like phenotype due to homozygous or heterozygous mutations of a single gene,including complement defects,type Ⅰ interferon pathway defects,and so on.This study aimed to investigate whether there are genetic mutations related to primary immunodeficiency in children with SLE,and to provide data support for the concomitant conditions of the two diseases.Methods:This was a retrospective case series of SLE children who referred to the Peking Union Medical College Hospital between 01/2016 and 09/2019.Genetic tests were performed in patients who met the inclusion criteria.We then collected demographic,clinical,and treatment information of all involved patients.Descriptive statistics were used.Inclusion criteria were as below:1)The age of onset was 5 years old or less;2)Repeated infection history of CMV or EBV;3)Persistent low complement;4)CT abnormality of basal ganglia calcification;5)Special type of rash,such as chilblain-like rash,reticulated Green spots;6)Obvious hepatosplenomegaly(moderate to severe enlargement),no improvement during treatment;7)combined with type Ⅰ diabetes;8)ESR continues to increase during treatment.Patients with a diagnosis of SLE will be recruited into the study group without additional intervention if any of the above 8 criteria are met.Exclusion criteria were as below:1)refusal of genetic testing or failure to obtain peripheral blood samples from parents;2)loss of follow-up or missing clinical data.Collect peripheral blood samples of the enrolled children and their parents and perform gene screening of PID panel.Children with genetic variation detected by second-generation sequencing and their parents then receive the first-generation sequencing verification to determine whether those variations were pathogenic mutations.Clinical data were analyzed in detail.This study was approved by the Ethics Committee of Peking Union Medical College Hospital,Chinese Academy of Medical Sciences.All parents of the enrolled children signed informed consent.Results:1.A total of 182 patients(33 males and 149 females)with a diagnosis of SLE in Peking Union Medcial College Hospital between January 2016 and September 2019 were involved.The onset age ranged from 3 to 15 years and 9 months.Most of the children went to hospital for rash(55.49%),and the other common initial symptoms were shown as below:fever(45.60%)and joint disease(31.87%).During the course of disease,the blood system was the most possible to be involved(79.12%),followed by the skin and mucous membrane(72.53%),respiratory system(60.99%)and kidney(48.35%).There was no significant difference between male and female patients.The autoimmune antibody spectrum is helpful in the diagnosis of SLE,but of limited significance in the indication of symptoms.Standardized application of glucocorticoids and immunosuppressants can effectively control SLE condition and improve prognosis.2.Seventy-one patients were finally included(eighteen boys and fifty-three girls)and received gene screening for PID,ten of which showed positive results.The most effective criterion was obvious hepatosplenomegaly(100%),intracranial basal ganglia calcification(66.67%),special type of rash(50%),and an onset age earlier than 5 years old(40%).SLE-related symptoms and immunological indicators could not significantly distinguish the positive and negative PID screening groups.3.Gene sequencing results showed that about ten patients combine with primary immunodeficiency disease,including Aicardi-Goutieres Syndrome(AGS)(n=4),Spondyloenchondro-dysplasia with immune dysregulation(SPENCDI)(n=1),STING-associated vasculopathy with onset in infancy(SAVI)(n=1),lysinuric protein intolerance(LPI)(n=1),Ras-associated autoimmune leukoproliferative disorder(RALD)(n=2),suspicious chronic granulomatosis(n=1).Conclusion:SLE patients who present atypical or refractory manifestations should attach importance to the existence of primary immunodeficiency disease.Genetic tests are recommended as soon as necessary for those with early-onset symptoms or persistent infection since childhood,especially those with obvious hepatosplenomegaly,basal ganglia calcifications and frostbite-like rashes.