| Part ⅠObjective:To summarize and analyze the clinical manifestations,genotypes and treatment methods of children with monogenic autoinflammatory diseases(AIDs)who was diagnosed and treated in our center.Methods:Retrospectively analyze the clinical data,genotypes and treatment methods of children with monogenic AIDs who was diagnosed and treated in our center from December 1st,2008 to December 1st,2019.Results:(1)From December 1 st,2008 to December 1 st,2019,a total of 90 children with monogenic AIDs were admitted to our center,including 18 cases diagnosed before September 1 st,2015.These patients included 13 cases of type Ⅰ interferonopathies(14.5%),36 cases of inflammasomopathies(40.0%),39 cases of non-inflammasome-related conditions(43.3%),and 2 cases of unclassified syndrome(ROSAH syndrome)(2.2%).The male to female ratio was 46/44,of which 17 patients had a positive family history,all of which were autosomal dominant genetic diseases.(2)The clinical characteristics of AD A2 deficiency are recurrent fever,accompanied by livedo in lower extremities,elevation of inflammatory biomarkers,decreased immunoglobulins,and negative or low titer of autoantibodies.The main characteristics of other type Ⅰ interferonopathies included:①Special skin rashes,including chilblain and livedo.②Intracranial calcification,which may appear as diseases progress.③Complication with subclinical hypothyroidism.④ Elevation of inflammatory biomarkers.⑤Positive in multiple autoantibodies.Inflammasomopathies and non-inflammasome-related conditions were characterized by recurrent fever,rash,arthritis,etc.,and their inflammatory biomarkers usually increased significantly.Children with type Ⅰinterferonopathies were treated with Janus kinase inhibitors,and ADA2 deficiency and most children with non-inflammasome-related diseases were treated with tumor necrosis factor-α inhibitors.Because interleukin 1 inhibitors have not yet been marketed in China’s mainland,children with inflammasomopathies have no effective treatment.(3)Two patients with newly found monogenic AIDs,namely,the ROSAH syndrome,were diagnosed and treated in our center.Their clinical manifestations were relatively homogeneous,prominently presenting with juvenile onset oculopathy and splenomegaly.Conclusions:(1)Special rashes,including chilblain and livedo,intracranial calcification,complication with subclinical hypothyroidism,and significantly elevated IgG in patients with autoimmune diseases,are important clues to identify type Ⅰ interferonopathies.(2)Targeted biological therapy can significantly improve the symptoms and laboratory indicators of children with monogenic AIDs.Part ⅡObjective,Taking the cryopyrin-associated periodic syndrome(CAPS),one of the monogenic AIDs,as an example to explore the efficacy and safety of tranilast,an anti-allergy drug,in children with CAPS.Methods:This part is a single-center,one-arm prospective cohort study.The primary endpoint is the reduction of the autoinflammatory diseases activity index(AIDAI)after 3 months of treatment.The secondary endpoints are the reduction of AIDAI after 1 month of treatment,the reduction of C-reactive protein,erythrocyte sedimentation rate,white blood cells,and platelets after 1 and 3 months of treatment,the improvement of the VAS score of disease activity by the doctors after 1 and 3 months of treatment,and the occurrence of adverse reactions during the treatment of tranilast.The effects and safety of tranilast were evaluated by comparing the above index among the baseline,1 month and 3 months later.Results:(1)Five children with CAPS were enrolled and completed the follow-up from April 20th,2019 to January 20th,2020.Before starting therapy of tranilast,one patient had been treated with recombinant human type Ⅱ tumor necrosis factor receptor antibody fusion protein for 1.5 months,and two patients had been treated with low-dose glucocorticoids and thalidomide for several years.With their previous treatment unchanged,the three children started with tranilast.(2)After comparing the above endpoints at baseline,1 month and 3month treatment of tranilast,we found CAPS children’s symptoms and laboratory indexes did not significantly improve,and no adverse reactions occurred after the treatment with tranilast as well.Conclusions:Tranilast is safe for CAPS children and its efficacy need to be validated in further study.Part ⅢObjective:To study the genetic background and pathogenesis of systemic juvenile idiopathic arthritis(sJIA),one of the polygenic AIDs.Methods:(1)Second-generation sequencing was performed in children with sJIA and then variation of the genes encoding pattern recognition molecules of the inflammasomes were analyzed.Odd ratio with 95%confidence interval based on allelic frequency of mutations or variants was used to evaluate the difference between sJIA and healthy children.(2)Based on the differences of TREM1 variants between sJIA and healthy children found in genetic analysis,enzyme-linked immunosorbent assay and flow cytometry were used to detect the plasma soluble triggering receptor expressed on myeloid cells 1(sTREMl)and TREM1 on the surface of peripheral blood mononuclear cells,respectively.Then we compared the differences in TREM1 expression between sJIA and healthy children,adult-onset Still’s disease and healthy adults.(3)Spearman analysis was used to study the correlation between sTREMl and serum white blood cell count,neutrophil percentage,platelet count,erythrocyte sedimentation rate,c-reactive protein,ferritin,prealbumin,interleukin-1,interleukin-18 and interleukin-18 binding proteins in the same batch of specimens.Results:(1)A total of 59 sJIA children completed the second-generation sequencing.Many low-frequency variants of genes encoding pattern recognition molecules of inflammasomes were found different between sJIA and healthy children,including1,NLRP3,NLRC4,NLRP7,NLRP12,DDX58 and PLCG2.(2)The frequency of rs2234246 in TREM1 gene was significantly lower than that of healthy controls,and the odds ratio was 0.55(0.33-0.91).In this section,58 plasma samples were collected from sJIA patients and healthy children respectively,including 28 active and 30 inactive sJIA samples.Compared with healthy children,plasma sTREM1 levels in children with sJIA were significantly elevated(256.66 ± 162.75 vs 99.74 ± 37.33,t＝-8.397,P<0.001).Compared with children with inactive sJIA,there was no significant difference in plasma sTREMl levels in active sJIA children(259.90 ± 141.85 vs 247.93 ±228.17,t=0.646,P=0.521).Compared with healthy children,the plasma sTREMl levels of children with inactive sJIA markedly increased(247.93±228.17 vs 109.31 ±40.47,t=-5.451,P<0.001).Compared with healthy children,the plasma sTREMl levels of children with active sJIA significantly increased(259.90 ±141.85 vs 94.16 ± 38.64,t=6.785,P<0.001).In this section,10 plasmas were collected from adult-onset Still’s disease patients and adult healthy controls.Compared with healthy controls,plasma sTREMl levels in adult-onset Still’s disease patients were elevated(570.35 ± 456.21 vs 176.95±74.88,t=-2.748,P=0.023).The expression of TREM1 on the surface of monocytes in children with sJIA was higher than that in healthy children.The difference was statistically significant(14.30 ±4.60 vs 11.68 ± 4.48,t=-2.598,P=0.020).Compared with children in the inactive phase,there was no difference in the expression of TREM1 on the surface of monocytes in children with active sJIA(16.64 ± 3.78 vs 13.23±4.69,t=-1.419,P=0.178).Results of Spearman correlation analysis revealed that sTREM1 was correlated with blood white blood cell count,neutrophil percentage,serum prealbumin and interleukin 18(correlation coefficients were r=0.540,P<0.001;r=0.500,P<0.001;r=0.380,P=0.005;r=0.484,P=0.005),but not correlated with platelet count,ESR,CRP,ferritin,interleukin 18 binding protein,and interleukin 1β(correlation coefficients are r=0.050,P=0.70;r=0.130,P=0.30;r=0.170,P=0.19;r=0.330,P=0.06;r=0.204,P=0.263;r=0.105,P=0.580,respectively).Conclusions:(1)Low-frequency variations of genes encoding pattern recognition molecules of inflammasomes are risk factors for the incidence of sJIA.(2)TREM1 was involved in the occurrence and development of sJIA,and the specific mechanism remains to be further studied. |
