Clinical And Basic Research Of Juvenile Systemic Sclerosis

Part Ⅰ Clinical Research of Juvenile Systemic SclerosisObjective:To summarize the clinical characteristics of patients with juvenile systemic sclerosis(JSSc)in Peking Union Medical College Hospital(PUMCH),analyze the time of organ involvement,characteristics and related risk factors.Methods:The clinical data of patients with JSSc in PUMCH from January 2012 to December 2022 were retrospectively collected to explore the characteristics of different subtype of JSSc,to analyze the use of skin ultrasound and periungual microcirculation examination in JSSc and evaluate the characteristics of organ or system involvement,and search for risk factors for each organ or system involvement.Results:A total of 57 patients(male:female=17:40)were enrolled,including 17(29.82%)patients with limited cutaneous systemic sclerosis(lcSSc),31(54.39%)patients with diffuse cutaneous systemic sclerosis(dcSSc)and 9(15.79%)patients with overlap syndromes(OS).The disease tends to occur in adolescent female patients.The median age of onset was 11.75 years old,and the median time from onset to diagnosis was 1.00 year.Raynaud’s phenomenon(64.91%,37/57)and skin sclerosis(47.37%,27/57)were the initial clinical presentation in most patients.All patients had skin abnormalities,with 77.19%(44/57)of patients had raynaud’s phenomenon during the disease course,combined respiratory(39/57,68.42%),joints(31/57,54.39%),digestive(20/57,35.09%)and hematological(17/56,30.36%)systems involvement.Elevated liver enzymes is an independent risk factor for joint involvement(P=0.017,OR=9.19595%CI:1.456,115.138).Muscle system involvement is more common in males(P=0.029,OR=0.166 95%CI:0.026,0.834).Seven patients completed skin elastic ultrasound examination,and 13 patients underwent nailfold capillaroscopy.Elevated CRP was observed in 33.33%(15/45)at the beginning of the disease.Elevated erythrocyte sedimentation rate(ESR)was observed in 26.92%(14/52).The majority of patients(54/57,94.74%)with multiple positive autoantibodies.During the follow-up period,glucocorticoids were added to 75.44%patients,and 42.11%patients were treated with methotrexate(MTX),and 7.02%patients were treated with biologics.After 6.00(3.54,9.88)years of follow-up period,among the 57 patients,one case with dcSSc,two cases with OS died due to severe infections.Conclusion:JSSc is mainly characterized by skin abnormalities and Raynaud’s phenomenon.Some patients have abnormalities in the respiratory,joint,and digestive system,but the initial clinical manifestations may be atypical and often with delayed diagnosis.Skin ultrasound and nailfold capillaroscopy can be used to evaluate the occurrence and changes of JSSc.Most patients have positive autoantibodies,and some patients have elevated inflammatory markers for CRP and/or ESR.Infection was the leading cause of death in JSSc patients in this study,and it is recommended to pay attention to the prevention of infection during the treatment of JSSc patients.Part Ⅱ J4S and SCTC-DI in Chinese Patients with Juvenile Systemic SclerosisObjective:To validate the role of the Juvenile Systemic Sclerosis Severity Score(J4S)and the Scleroderma Clinical Trials Consortium Damage Index(SCTC-DI)in JSSc,and explore the prediction factors for disease severity,organ damage,and progression of organ damage.Methods:Based on the SCTC-DI and J4S,the disease was divided into high and low organ damage groups,high and low disease severity groups.Recording SCTC-DI with an interval of more than 0.5 years.An increase of SCTC-DI≥1 in difference from baseline SCTC-DI was considered as progression of organ damage.The items of SCTC-DI in this study was compared with adult patients from Peking University Third Hospital and Peking University People’s Hospital cohort,Australian Scleroderma Cohort Study,and Canadian Scleroderma Research Group.The characteristics of SCTC-DI in Chinese patients were analyzed.Results:Small joint contractures,fingertip ulcers,and pulmonary interstitial lesions were common findings in this cohort of patients with JSSc.Compared with adults,the proportion of JSSc patients with xerostomia,refractory gastroesophageal reflux disease,and low body mass index was significantly reduced(P<0.001).None of the patients with JSSc had esophageal strictures,dilated antral vessels,and urinary system involvement.J4S at baseline and follow-up were correlated with SCTC-DI(P<0.001).There was a correlation between J4S and SCTC-DI(R=0.796,P<0.001).The higher SCTC-DI at baseline,the more total organs involved in the course of disease(P<0.001).There was no significant difference in the area under the curve between SCTC-DI and J4s at baseline and between SCTC-DI and J4s at follow-up(P=0.532,P=0.154).Conclusion:The progression of organ damage in patients with JSSc is mainly manifested in abnormalities in the joints,respiratory,and circulatory systems.There were differences in clinical presentation between adult SSc and JSSc patients.The digestive and urinary system involvement in patients with JSSc is less than that in adults.SCTC-DI is simpler to implement than J4S,and is less subject to the subjective influence of the operator.There was a correlation between J4s and SCTC-DI.The number of organs involved increased in patients with elevated SCTC-DI at baseline.SCTC-DI can be used for children with JSSc in China,but some items need to be adjusted.Part Ⅲ Interferon Stimulated Gene Testing and Single-cell Sequencing Analysis in Patients with SclerodermaObjective:To explore the relationship the levels of interferon stimulated genes(ISGs)in patients with JSSc and calculated an interferon score(IS)to analyze the relationship between the type Ⅰ interferon(Ⅰ-IFN)pathway and JSSc.Using single-cell sequencing,we further explore the pathogenesis of scleroderm.Methods:A total of 14 patients diagnosed with JSSc in the department from May 2020 to March 2023 were selected as the research objects.The levels of ISGs and IS in patients with JSSc were determined,and their relationships with J4S and SCTC-DI were analyzed.Seven patients with scleroderma diagnosed in our department from May 2020 to March 2023 were selected as the research objects,and three healthy controls(HC)were selected from the previously published database of healthy children in China.Single-cell sequencing was used to analyze the changes in cells and signaling pathways in children with scleroderma,and to preliminarily explore the pathogenesis of scleroderma.Results:A total of 25 peripheral blood samples were tested,and 48.00%of these samples had elevated IS levels,and there was no correlation between ISGs,IS levels and disease severity,high organ damage(P>0.050).Single-cell sequencing was performed in 7 scleroderma patients(4 JSSc,3 localized scleroderma)and 3 HC.Compared with HC,the proportions of T cells and B cells in patients with scleroderma were significantly reduced,while the proportions of monocytes and dendritic cells were increased.The T cell communication intensity was the stronge in the three groups,and the monocyte communication intensity was stronger in the JSSc and JLS than in the HC.Compared with HC,the differences of intercellular communication between JLS and JSSc were mainly on B cells and monocytes,the differentially expressed genes were mainly distributed in cytokine production,bacterial response and adaptive immune response related pathway.HLA-mediated cell communication was found between the three types of cells.Conclusion:Some patients with JSSc had elevated IS,but the correlation between ISGs,IS levels and disease severity,high organ damage has not been validated.B cells and monocytes play an important role in the occurrence of scleroderma.HLA,mediated cell communication may be related to the pathogenesis of scleroderma.