| Haemophilia is a kind of hereditary coagulation factor deficiency disease,joint bleeding is the most common clinical manifestation.Frequent joint bleeding will stimulate synovial hyperplasia and inflammatory cell infiltration,causes hemophilic chronic synovitis.Removal of hyperplastic synovium will relievie the destruction of cartilage and bone,maintain and improve the joint motion function.It has been reported that intraarticular injection of lauromacrogol can cause necrosis of hyperplastic synovium.However,there are no basic and clinical studies on the treatment of hemophilic chronic synovitis with lauromacrogol.This study was to investigate the safety and efficacy of ultrasound-guided intra-articular injection of lauromacrogol for treatment of chronic synovitis in hemophilic arthritis animal model and haemophiliacs.This study consists of three parts:Part one:Establishment and ultrasonographic evaluation of hemophilic arthritis in animal modelsObjective:Establishing the animal model of hemophilic arthritis by injecting blood and iron dextran into knees of rabbits,the changes of joint structural and effect of different modeling methods were evaluated by ultrasound.Method:25 New Zealand white rabbits were randomly divided into three groups:group A and B have 5 rabbits respectively,group C have 15 rabbits.Rabbits in Group A and group B were injected with 1mL blood in the knee.Group A was injected 3 times a week for a total of 36 times,and group B was injected twice a week for a total of 24 times.In group C,the knee was injected with 1 mL of iron dextran,then the rabbits was averagely divided into 1 month group(C1 group),2 months group(C2 group)and 3 months group(C3 group)at random.Ultrasound was used to monitor changes in the synovium and cartilage.At the end of modeling,specimens of knee were harvested,the pathological changes of articular cartilage and synovium were observed under light microscope.Result:At the end of the modeling period,The thickness of synovium in group A(4.5±0.5mm)and C(4.1±0.4mm)measured by ultrasound was thicker than that in groups B(2.4±0.4mm),the difference was significant(P<0.05).Synovial membranes of group A and group B gradually increased in thickness and grade of Color Doppler Flow Imaging during modeling.In group C,the thickness and blood flow signal of synovial membrane increased gradually in the early stage(first 4 weeks)of modeling.With the prolongation of the modeling time,the synovial membrane thickness slightly thinned and the blood flow signal gradually weakened.At the end of modeling,the damage of articular cartilage in groups A and C can be detected by ultrasound.Synovial hyperplasia,infiltration of inflammatory cells,and destruction of cartilage were observed in each group under light microscope,which are similar to hemophilic arthritis.the pathological changes in groups A and C1 were more significant.Conclusion:The animal model of hemophilia arthritis can be established by injecting blood or iron dextroside into rabbit joint.Its symptoms,ultrasound and pathological feature can reflect the characteristic manifestations of hemophilic arthritis.Intraarticular injection of iron dextran is an effective method to establish animal mode of hemophilic arthritis,changes of synovitis and cartilage in this model can be monitored sensitively by ultrasound.Part two:Effects of intra-articular injection of lauromacrogol on joint structure and motor function in hemophilic arthritis animal model.Objective:To investigate the effects of single and multiple intra-articular injection different concentrations of lauromacrogol in hemophilic arthritis animal models.Method:30 New Zealand rabbits were randomly divided into control group,group1%,group2%,group3%,group1%*2,group1%*3,each group have five rabbits.The animal model of hemophilic arthritis was inducered by iron dextroside.The dosage and times of intra-articular injection were as follows:The control group was injected with 1 mL of saline in the joint.In group1%,group2%and group3%,1 mL 1%,2%,3%concentration lauromacrogol was intra-articular injected respectively.Group1%*2 and group1%*3 was intra-articular injeced with 1 mL of 1%concentration lauromacrogol two and three times respectively,24 hours between each injection.Changes in synovial,cartilage,and joint motor function after intervention were assessed with Lequesne MG score,ultrasound and magnetic resonance.Experimental animals were sacrificed after one month of intervention,pathological changes of cartilage and synovial tissue were evaluated under light microscopy.Result:After one month of intervention,the average synovial area index of each group was 87.8%(Control),24.2%(Group1%),19.8%(Group2%),15.6%(Group3%),19.0%(Group 1%*2),14.6%(Group1%*3).After the intervention,local adverse reactions such as skin necrosis and blisters occurred in 2%and 3%group.The Lequsene MG score,cartilage MR score and pathological score of the experimental groups were lower than those of the control group after one month of intervention.The CDFI grade,MR score,CEUS peak intensity and CEUS semi-quantitative score of synovitis were highly correlated with the synovial pathological score.The synovitis Mankin's pathological score(r=0.725,P<0.01)and the synovial area index(r=0.716,P<0.01)has the hightest correlation with CEUS semi-quantitative score of synovitis.Conclusion:Injection of 1%,2%and 3%concentration lauromacrogol into the articular of hemophilia arthritis animal model can cause synovial necrosis.There was no significant adverse effect of lauromacrogol on cartilage and joint motor function.Ultrasound color doppler flow imaging,contrast-enhanced ultrasound and enhanced magnetic resonance imaging can be used to monitor the efficacy of lauromacrogol on synovitis in animal models.Contrast-enhanced ultrasound can accurately and intuitively reflect the degree of necrosis of the synovium.Part three:Prospective study of ultrasound-guided intra-articular injection of lauromacrogol in hemophilic chronic synovitis.Objective:Lauromacrogol was injected into the joint of haemophiliacs under ultrasound guidance,preliminary explored the efficacy and safety of lauromacrogol in the treatment of hemophilic chronic synovitis.Method:Screening subjects based on inclusion and exclusion criteria,1%concentration lauromacrogol was injected into the 8 joint of 6 subjects under ultrasound guidance.After 1 week and 6 months of treatment,Changes in joint structure and motion function were assessed by ultrasound and HJHS scale.The subjects were divided into success group and failure group according to the treatment effect,compare the differences in ultrasound scores and clinical data between the two groups.Result:The frequency of joint bleeding after treatment in each subject was significantly lower than before(2.8±2.3/19.9±4.1,P<0.05).There were no significant changes in HJHS score,cartilage and bone score before and after treatment.One week and six months after treatment,the scores of ultrasound in Synovial hyperplasia,joint effusion and CEUS semi-quantitative of synovitis decreased gradually,but there was no significant difference between before and after treatment.The AUC and PI of CEUS time-intensity curve decreased significantly in all subjects except No.5 subject.No severe adverse reaction occurred in each subject after treatment.There were significant differences in the BMI,joints tested,and joint effusion volume between the successful and failed groups.Conclusion:Ultrasound-guided intra-articular injection of 1%concentration lauromacrogol can significantly reduce the frequency of joint bleeding.haemophiliacs with chronic synovitis of ankle,low body mass index and no joint effusion may have ideal therapeutic effect. |
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