Genetic Susceptibility Of Children 's Still' S Disease And The Administration Of Pearl Monoclonal Antibody

Part 1 The study of genetic predisposition of pediatric Still’s diseaseBackground:Pediatric Still’s disease, also called systemic-onset juvenile idiopathic arthritis (SoJIA), is a multi-gene autoinflammatory disease (AID).Objective:This study is to look for the gene mutations and polymorphisms involved in pathogenesis of SoJIA.Methods:We chose 22 SoJIA patients (the onset age of 2-12 years and the disease duration of more than 2 years) and their birth parents as study objects, and performed whole-exome sequencing. We analyzed the data according to monogenic diseases, and the genes that accorded with autosomal dominant inheritance (de novo mutations) and recessive inheritance (homozygous or compound heterozygous mutations) were chosen. The accumulated allele frequency of genes was calculated, and compared between SoJIA patients and 1000 genomes (Chinese) using Fisher’s exact test. We analyzed the 19 genes responsible for monogenic AIDs and compared the allele frequency between SoJIA and controls, and sanger sequencing was performed when needed.Results:The genes significantly different between SoJIA patients and controls were TTN, DNAH12, IGSF10, and COL6A6, which accorded with compound heterozygous mutations. One patient had the homozygous mutations of TNIP2, which was reported in diffuse large B-cell lymphoma. The diagnosis of lymphoma could not be excluded for that patient. We detected mutations of genes for monogenic AIDs:MEFV, SLC29A3, IL-36RN, NLRP12, NOD2, PLCG2, ILIORA, and PSTPIP1. However, only the accumulated allele frequency of NLRP12 was significantly higher in SoJIA patients (p=0.013). Two patients had compound heterozygous mutations of MEFV, and could be diagnosed as familial Mediterranean fever (FMF); one patient had de novo mutation of NLRP3, and could be diagnosed as Muckle-Wells syndrome.Conclusion:The mutation frequency of TTN, DNAH12, IGSF10, COL6A6, and NLRP12 in SoJIA patients was significantly higher than that in normal controls, however, the clinical values require further investigation. The patients clinically diagnosed as SoJIA and having poor therapeutic effects should be considered the possibility of FMF, Muckle-Wells syndrome, and lymphoma.Part 2 The investigation of the dosage of tocilizumab in pediatric Still’s disease in ChinaBackground:Tocilizumab, an anti-IL-6 receptor antibody, was shown efficacious and safe in persistent SoJIA when infused every 2 weeks (8-12mg/kg), which generated financial burdens in our country though.Objective:This study is to evaluate the curative effects of tocilizumab every 4 weeks (8mg/kg) in refractory SoJIA.Methods:This prospective intervention study used self-control method. The refractory SoJIA patients were treated with tocilizumab. We defined 0 week when the first tocilizumab was given, and evaluated the effects at 12 week:the patients who reached the Wallace criteria continued treatment and could prolong the interval after 6 doses, but those who did not should shorten the interval. We assessed the effects of tocilizumab on clinical symptoms, inflammatory indicators, blood cells count, number of patients achieving the Wallace criteria for inactive disease, and the corticosteroids dosage before each infusion. Adverse events were reported throughout the treatment process. Continuous variables were compared using the Mann-Whitney U test. The indicators above were compared between 12 week/20 week and 0 week for the patients who completed 6 tocilizumab infusions.Results:Twelve SoJIA patients were evaluated, and 7 (58.3%) of them completed 6 doses of tocilizumab. All clinical symptoms of 12 patients disappeared except fevers in 2 patients at 12 week, who discontinued cyclosporine immediately after the first tocilizumab. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, white blood cell (WBC), and platelet all declined gradually to normal levels. Hemoglobin (HGB) increased gradually, and prednisone dosage reduced step by step. All changes were significant at 20 week. Percentage of patients meeting the Wallace criteria increased from 0 at baseline to 100% at 16 week. No serious adverse event was reported.Conclusion:Tocilizumab every 4 weeks (8mg/kg) was a suitable dosage in refractory SoJIA in our country, based on effectiveness, safety, and financial factors. Simultaneously administered disease modifying anti-rheumatic drugs (DMARDs) should be reduced gradually based on the dose-dependent half-life of tocilizumab.