Exploring The Early Syndrome Characteristics And Scientific Connotations Of Different Hip Joint Diseases Based On The Theory Of "different Diseases With The Same Syndrome

Objective:1.Analyze the characteristics of Osteonecrosis of the femoral head(ONFH),Osteoarthritis of hip(HO A)and Rheumatoid arthritis of hip(HRA),explore the distribution rules and similarities of syndrome types,and enrich the theoretical connotation of orthopedics diseases.2.Analysis the similarities and differences of early clinical data of ONFH,HOA and HRA,provide objective clinical basis for the early syndrome characteristics of the three diseases.3.Analyze the scientific connotation of ONFH,HOA and HRA early syndrome from"syndrome-symptom" association network,provide objective theoretical basis for the characteristics of early syndrome of the three diseases.Methods:This study is a prospective,cross-sectional study.ONFH,HOA,and HRA patients attending the Minimally Invasive Joint Department,Trauma Joint Department,and Rheumatology Department of The Third Affiliated Hospital of Beijing University of Chinese Medicine from June 2020 to January 2022 are included.ONFH is non-traumatic,ARCO stage I-II,HOA is K-L stage 0-Ⅱ,HRA is acute or subacute stage.According to symptoms,syndrome differentiation scale and other contents,combined with the hip syndrome syndrome differentiation scale,Case Report Form is formulated,including demographic data,TCM syndrome scale,symptom and sign score,laboratory examination,Harris score.1.Explore the early syndrome characteristics of three hip joint diseases based on the same syndrome theory of different diseasesCollect TCM syndrome information of ONFH,HOA,HRA patients according to CRF(33 symptoms and signs,5 tongue signs,7 pulse signs).If the patient is bilateral,the relatively severe side of the disease is included,and if the two sides are the same,the right side will prevail.The collected TCM syndrome information is analyzed as a whole and in layers,and the syndromes with an incidence rate of less than 10%are removed.The principal component analysis method is used to extract the common factors and meaningful syndromes.Combining with the criteria for the determination of syndrome elements,the characteristics of syndrome elements are determined,and the obtained common factors are clustered by systematic clustering,and the distribution rules of the whole and their respective syndrome types are obtained by analysis.The significant syndromes extracted from the hierarchical analysis are compared between groups,and the similarities and differences in the distribution of syndromes in the early stages of the three diseases are analyzed.2.Clinical basic research on early syndrome characteristics of three hip joint diseasesOn the basis of the research on the characteristics of the syndrome,the patients whose disease position syndrome elements are tendons and bones,spleen and kidney,and disease syndrome elements are qi deficiency,blood stasis,phlegm stasis,and cold-dampness are included.The demographic data(gender,age),"blood stasis" syndrome indexes(joint pain and PLT,PT,APTT,etc.),"phlegm stasis" syndrome indexes(HDL,LDL,CHO,TG,etc.),"colddamp" syndrome index(morning stiffness time score),"liver and kidney deficiency" syndrome index(RBC,HGB),immune factor index(CRP,ESR),inflammatory factor index(WBC,NEUT,LYMPH,etc.)and joint function indicators(Harris joint function score,total score,etc.)are extracted from the CRF.The similarities and differences of ONFH,HOA and HRA in the above indicators are compared by χ2 test,χ2 segmentation,one-way ANOVA,Tukey or GamesHowell test.3.Exploring the scientific connotation of early syndrome characteristics of three hip joint diseases from "syndrome-symptom " association networkCombined with expert opinions and the results of the research on syndrome characteristics,the syndromes of the early typical syndromes of ONFH,HOA and HRA are included.The included syndromes were converted according to the " WHO International Standard Terminologies on Traditional Medicine in the Western Pacific Region" and the syndromes without corresponding genes are excluded.Use databases such as HPO and DisGeNET to collect and incorporate syndrome gene information,and integrate and deduplicate to form a syndrome gene set of the three diseases.The potential targets of ONFH disease use the differential gene set obtained by our team based on genome-wide expression profiling technology in the early stage,and the potential targets of HOA and HRA diseases are mined through databases such as OMIM,GeneCards,TTD and DRUGBANK.The three syndrome gene sets and disease differential gene sets are merged and deduplicated respectively,and the interaction information of genes is extracted based on the STRING database.Cytoscape v3.8.0 is used to optimize the interaction network between genes.The core gene sets are screened by the median of the three network topological eigenvalues of degree,betweenness centrality and closeness centrality as the card value.The core gene sets of the three are compared between groups to obtain the intersection and specific core genes.The David database was used to analyze the biological functions involved in the intersection of the three core gene sets and specific core genes.Results:1.Explore the early syndrome characteristics of three hip joint diseases based on the same syndrome theory of different diseasesA total of 410 patients(150,160,and 100 ONFH,HOA,and HRA patients,respectively)were included,including 158 males and 252 females,with an age of 48.28±11.33 years.There were 36 and 114 hips in ARCO I and II stages in ONFH,48 and 112 hips in K-L I and II in HOA,and 33 and 67 hips in HRA in acute and subacute stages.The overall results showed that the KMO statistic for the three diseases is 0.902,and the Bartlett’s test P<0.001;the extracted eight common factors explained 66.27%of the data variation,and 45 significant symptoms are extracted.The syndrome elements of disease location involve muscles and bones,spleen,kidney,and liver,and the syndrome elements of disease nature include blood stasis,qi deficiency,phlegm(dampness),cold(dampness),yang deficiency,essence deficiency,yin deficiency,and blood deficiency.The clustering results showed that the early syndromes of the three are preliminarily divided into five categories:spleen deficiency and phlegm stasis syndrome,tendon-bone blood stasis syndrome,qi deficiency and cold-dampness syndrome,liver and kidney deficiency syndrome,and spleen and kidney deficiency syndrome.The frequencies are 33.17%,31.95%,21.46%,7.32%,and 6.10%,respectively.The hierarchical results show that the KMO statistics of ONFH,HOA and HRA are 0.808,0.668,and 0.694,respectively,and Bartlett’s test P<0.001;7,7,and 5 common factors are extracted,and the cumulative explanations are 60.87%,55.93%,and 54.01%.There are 32,37,and 33 meaningful symptoms extracted from the data variation,and the symptoms of the three disease locations all involve muscles and bones,spleen,kidney,and liver.The symptoms of ONFH disease include blood stasis,qi deficiency,phlegm(dampness),Yang deficiency,Jing deficiency;TCM syndrome types are initially divided into four categories:muscle-bone blood stasis syndrome,phlegm stasis syndrome,liver-kidney deficiency syndrome,and kidneyessence deficiency syndrome,with frequencies of 43.33%,38.00%,12.00%,6.67%;HOA disease syndrome elements include blood stasis,qi deficiency,phlegm(dampness),yang deficiency,and essence deficiency;TCM syndromes are preliminarily divided into spleenkidney yang deficiency syndrome,muscle-bone blood stasis syndrome,spleen deficiency phlegm stasis syndrome,spleen deficiency syndrome,liver and kidney deficiency syndrome 5 categories,the frequencies are 37.50%,26.87%,18.75%,9.38%,7.50%;HRA disease syndrome elements include blood stasis,qi deficiency,phlegm(dampness),yin and yang deficiency,cold(dampness),essence deficiency;TCM syndrome types are initially divided into 4 types:spleen deficiency and phlegm stasis syndrome,spleen and kidney deficiency syndrome,muscle-bone blood stasis syndrome,liver and kidney deficiency syndrome,and the frequencies are 34.00%,28.00%,23.00%,and 15.00%respectively.There are 21 similar syndromes in the early stage of the three,mainly syndromes of blood stasis and spleen deficiency,such as hip joint pain,tingling,fatigue,fat and tender tongue,dark tongue,white and greasy coating,etc.There are 11,16,and 12 separate syndromes for ONFH,HOA,and HRA,respectively.ONFH is mainly based on the syndrome of phlegm and blood stasis,such as obesity,chest and flank distention,slippery pulse,etc.HOA is mainly based on the syndrome of kidney deficiency and cold-dampness,such as backache,dizziness,cold joints,morning stiffness,pale tongue,etc.HRA is mainly based on the symptoms of liver and kidney deficiency and phlegm stasis,such as morning stiffness,lower extremity stiffness,dizziness,chest and flank fullness,pale tongue,slippery pulse,etc.2.Clinical basic research on early syndrome characteristics of three hip joint diseasesA total of 355 patients are included(122,148,and 85 in ONFH,HOA,and HRA,respectively),including 135 males and 220 females;with an age of 51.02± 9.49 years.In terms of "blood stasis" syndrome indicators,joint tenderness score(F=2.517,P=0.082),Harris joint range of motion score(F=1.812,P=0.165),PT(F=2.296,P=0.102),APTT(F=2.437,P=0.089)and TT(F=2.064,P=0.128)have no significant difference.Joint pain score(F=8.313,P<0.001),Harris pain degree and joint deformity score(F=5.985,P=0.003;F=8.059,P<0.001),PLT(F=83.414,P<0.001),FIB(F=262.081,P<0.001)the difference is statistically significant.In terms of "phlegm and blood stasis" syndrome indicators,there are significant differences in CHO and TG(F=13.195,P<0.001;F=478.692,P<0.001),but there is no statistical difference in HDL,LDL,ApoA1,ApoB,and ApoB/ApoA1(F=2.343,P=0.097;F=2.475,P=0.085;F=2.396,P=0.092;F=1.789,P=0.168;F=0.026,P=0.975).In terms of "cold-damp"syndrome index,the difference in morning stiffness time score is statistically significant(F=357.278,P<0.001).In terms of "liver-kidney deficiency"syndrome indicators,the differences in RBC and HGB are statistically significant(F=80.537,P<0.001;F=282.389,P<0.001).In terms of immune-related factors,the differences in CRP and ESR are statistically significant(F=1394.636,P<0.001;F=1209.330,P<0.001).In terms of inflammatory factors,NEUT%(F=13.704,P<0.001),LYMPH(F=41.572,P<0.001),and LYMPH%(F=45.407,P<0.001)are significantly different.There is no significant difference in WBC and NEUT(F=2.224,P=0.109;F=2.455,P=0.087).In terms of joint function indicators,the total Harris score is significantly different(F=10.063,P<0.001),but there is no significant difference in joint function score and Harris joint function score(F=0.772,P=0.463;F=2.709,P=0.068).3.Exploring the scientific connotation of early syndrome characteristics of three hip joint diseases from "syndrome-symptom" association networkONFH includes the syndrome of tendon-bone blood stasis syndrome and phlegm stasis blocking collaterals syndrome,HOA includes the syndrome of spleen-kidney deficiency syndrome and syndrome of tendon-bone blood stasis syndrome,HRA includes the syndrome of spleen deficiency phlegm stasis syndrome,spleen-kidney deficiency syndrome and musclebone blood stasis syndrome Syndromes.After conversion,13,8,and 14 syndromes are finally included in the three,and the syndrome gene sets are 909,254,and 1597 respectively;the differential gene sets are 101,286,and 191 respectively;the core gene sets obtained are 245,114,and 139,respectively.By comparison,it us found that there are 19 intersections of the core gene sets,and 170,48,and 75 specific core genes without overlap.The results of molecular network analysis showed that the enriched pathways of the core gene set included Osteoclast differentiation,NF-kappa B signaling pathway,FoxO signaling pathway,etc.,covering the body’s muscle,bone metabolism,immune-inflammatory balance and blood circulation.The pathways enriched by ONFH-specific core genes also include Regulation of lipolysis in adipocytes,mTOR signaling pathway,etc.,which are involved in the regulation of lipid metabolism.The pathways enriched by HOA-specific core genes also include Linoleic acid metabolism,Arachidonic acid metabolism,etc.,which are involved in the regulation of bone metabolism.The enriched pathways of HRA-specific core genes also include HIF-1 signaling pathway,cAMP signaling pathway,Estrogen signaling pathway,etc.,which are related to synovial pannus formation,substance and energy metabolism,liver and kidney development and metabolic response.Conclusion:1.The early syndrome characteristics of ONFH,HOA and HRA have their own emphasis.ONFH is mainly characterized by spleen deficiency,phlegm stasis,and blood stasis.HOA is mainly characterized by deficiency of the spleen and kidney,cold-dampness,and blood stasis.HRA is mainly characterized by spleen and kidney deficiency,liver and kidney deficiency,phlegm stasis and blood stasis.Spleen deficiency and blood stasis are the common syndrome characteristics of the three diseases in the early stage.2.In the early stage of the three diseases,there is consistency in joint tenderness,PT,APTT,TT and other indicators,which are consistent with the common syndrome characteristics of blood stasis,the CHO and TG of ONFH are consistent with the characteristics of phlegm and blood stasis syndrome,the morning stiffness of HOA is consistent with the characteristics of colddamp syndrome,the RBC and HGB of HRA are consistent with the characteristics of liverkidney deficiency syndrome.3.The pathways involved in the intersection of the core gene sets of the three diseases are consistent with the common syndrome characteristics of spleen deficiency and blood stasis.The pathways involved in ONFH core genes are consistent with the characteristics of phlegm-stasis syndrome and the pathogenesis of lipid metabolism disorders.The pathways involved in HOA core genes are consistent with the pathogenesis of abnormal cartilage metabolism.The pathways involved in HRA core genes are consistent with the characteristics of liver-kidney deficiency syndrome and the pathogenesis of synovial hyperemia and edema.