Phenotypes And Genotypes Of Chinese Adult Patients With Autoinflammatory Diseases And The Potential Role Of Autophagy In Pathogenesis

Background:Autoinflammatory diseases(AUIDs)are disorders with systemic inflam-mation responses caused by dysregulation of innate immune system,including mono-genic AUIDs and polygenic AUIDs.Differences of disease spectrums,phenotypes and genotypes probably exist between Chinese and other populations,and between adult and child AUIDs.However,both basic and clinical studies of AUIDs are insufficient in China.Objectives:Establish the prospective cohort of Chinese adult AUIDs,and compare disease spectrums,phenotypes and genotypes with other populations and with child AUIDs.Reg-ular follow-up visits are required for these patients once diagnosed as monogenic or poly-genic AUIDs.Establish a model to evaluate the severity of diseases with objective indica-tors,and observe the changes of disease severity before and after treatments.Identify in-dependent predictors of conventional non-biological immunosuppressive agents resistancy,and identify new serum biomarkers for evaluating disease severity.Establish approaches for evaluating cell autophagy functions in AUIDs patients,and explore the possible role of autophagy in pathogenesis of AUIDs.Methods:Patients(age ≥ 16)suspected of AUIDs were enrolled in the prospective cohort,according to Kastner’s criteria in 2010.Demographic and clinical data were collected for describing clinical features of different diseases,and for translational researches as well.AUIDs disease spectrums,phenotypes and genotypes in Chinese populations were com-pared with other adult populations and with child AUIDs.Mann Whitney test was used to identify differences among groups with different disease activities.Multiple linear regres-sion was used to evaluate disease severities whilst clinical manifestations,inflammation biomarkers and SF-36 scores were included in this model.AUIDs treatment effects were evaluated with the new model and Logistic regression analysis was used to identify the independent indicators of resistancy to conventional non-biological immunosuppressive agents.BD Cytometric Bead Array was used to quantify serum cytokines concentration.Autophagy functions were evaluated with western blotting in peripheral blood mononu-clear cell(PBMCs)or white blood cells in AUIDs patients.Results:From April 2015 through April 2017,a total of 103 patients were enrolled in the prospective cohort at the adult AUIDs center,Department of Rheumatology,Peking Union Medical College Hospital.26 cases(25.2%)were diagnosed with monogenic AUIDs,and 61 cases(59.2%)with polygenic AUIDs.Among adult monogenic AUIDs in Chinese pop-ulations,the proportions of NLRP12 autoinflammatory disease(NLRP12-AD)and Blau syndrome(BS)were higher and that of tumor necrosis factor receptor-associated periodic syndrome(TRAPS)was lower,compared with other populations.The proportions of fa-milial Mediterranean fever(FMF)and hyperimmunoglobulinaemia D and periodic fever syndrome(HIDS)were lower than child AUIDs,while NLRP12-AD was not found in children.FMF genotypes in Chinese populations were different from other populations but more similar to Japanese.Adult patients with FMF had higher rates of fatigue and con-junctivitis,a lower rate of arthralgia/arthritis compared with child FMF,and no rashes were found.Compared with children,adult patients with cryopyrin-associated periodic syn-drome(CAPS)had lower rates of cutaneous manifestations;adult patients with periodic fever,aphthous stomatitis,pharyngitis and adenitis(PFAPA)had higher rates of fatigue and myalgia,and lower rates of odynophagia and abdominal pain.Among 87 cases of monogenic and polygenic AUIDs,the majority were treated with tra-ditional non-biological immunosuppressive agents and a few were treated with biological agents.To evaluate disease severities more precisely and reliably,we introduced disease severity index(DSI)which is calculated with the number of clinical manifestations,CRP level and SF-36 score instead of disease activity index,which were subjecti-vely proposed by doctors and patients.Evaluating with DSI,FMF patients received a good remission after colchicine and glucocorticoid treatment,and a majority of patients with adult onset Still disease(AOSD)responded well to traditional immunosuppressive agents.Risk factors of resistantcy to conventional non-biological immunosuppressive agents included male gen-der,high level of Hgb or RBC counts,while protective factors included female gender,arthralgia/arthritis,cutaneous manifestations and lymphadenopathy.Logistic regression analysis revealed that high RBC level was the independent indicator for poor response to traditional immunosuppressive agents in AOSD patients.Serum cytokines quantitative analysis revealed a linear correlation between CD54 and DSI.We established a method for testing autophagy functions in cells of AUIDs patients.We found that MDP-induced autophagy was less activated in PBMCs from AOSD patients with high disease activities than in those with low disease activities and in healthy controls,although there were no significant differences.WBC extracted from gout patients blood samples might be used for testing autophagy functions.Conclusions:This study established the prospective cohort of Chinese adult AUIDs and collected Demographic,clinical data and blood samples.Differences of disease spectrums,phenotypes and genotypes were found between Chinese and other populations,and be-tween adult and child AUIDs.This study established a model for evaluating disease sever-ity taking into account clinical manifestations,inflammation biomarkers and SF-36 scores.Evaluating with the new model,AUIDs patients received a good remission after treatments.High RBC level was found to be the independent indicator for poor response to traditional immunosuppressive agents in AOSD.CD54 might be the new biomarker for evaluating disease severity.A method for testing cell autophagy functions of AUIDs patients was established.