Study On The Efficacy And Safety Of High Dose Glucocorticoid In Treating Thyroid Associated Ophthalmopathy

Background:Thyroid-associated ophthalmopathy（Thyroid-associated ophthalmopathy,TAO）is a thyroid-related organ autoimmune disease,with eyelid contracture,intraocular ball adipose tissue hyperplasia,extraocular muscle thickening,optic nerve compression as a characteristic manifestation.TAO patients with local orbital symptoms seriously affect the lives of patients,but also lead to the risk of blindness.According to the 2016 EUGOGO guidelines,intravenous methylprednisolone（IVMP）is recommended as a first-line treatment for moderate to severe TAO patients.A large number of clinical practice confirmed that IVMP treatment has a good effect,but in clinical work for glucocorticoid（Glucocorticoids,GCs）cumulative dose of the existence of many controversies,treatment of TAO patients with the best cumulative dose of GCs is uncertain;In addition,GCs induced adverse reactions are of concern,IVMP treatment of liver damage,glucose metabolism disorders,electrolyte loss is often reported;On the IVMP treatment of TAO patients caused by glucose metabolism disorders,previous reports did not involve the mechanism of increased blood sugar,GCs caused by elevated blood glucose risk factors are also rarely reported.In this study,we would study with moderate to severe TAO who treatmented with IVMP in different accumulative doses of GCs.The efficacy and adverse reactions by IVMP treatment would be discussed.We had explored the changes of blood glucose in patients with TAO under different cumulative doses of GCs,and the possible mechanism and related risk factors of elevated blood glucose were explored in TAO patients after IVMP treatment.Methods:According to the cumulative dose of GCs,The patoents was divided into three groups:A group,middle dose group and high dose group（GCs cumulative dose>7.5g,average 10.7±2.0g）,and the accumulation of different GCs Dose of IVMP treatment and observe the incidence of adverse reactions;Screening cases of OGTT trials,To study the changes of glucose metabolism in patients with TAO after IVMP treatment,according to OGTT test results were divided into normal blood glucose group and hyperglycemia group,calculate the TAO patients after the use of IVMP treatment of pancreaticβ-cell function evaluation indicators,insulin resistance evaluation indicators,after IVMP treatment The possible mechanism of elevated blood glucose;the final analysis of the risk factors associated with elevated blood glucose.Patients with moderate to severe TAO treated with IVMP were divided into three groups according to the cumulative dose of GCs:56 patients（GCs cumulative dose≦4.5 g）in group A、47 patients in group B（4.5 g<GCs cumulative dose≦7.5）,68 patients in group C（GCs cumulative dose>7.5）;According to the cumulative dose of GCs,C group was divided into three groups:low dose group（GCs cumulative dose≦4.5g,n=68）,middle dose group（4.5g）<GCs cumulative dose≦7.5g,n=68),high dose group（GCs cumulative dose>7.5g,n=68）.To study the efficacy of IVMP in the accumulation of different GCs and to observe the incidence of adverse reactions.According to the 22 cases of OGTT test,the changes of glucose metabolism in TAO patients with different concentrations of GCs were analyzed.The evaluation indexes of insulinβ-cell function and insulin resistance were calculated.The possible mechanism of blood glucose elevation after IVMP treatment was studied.Finally,the risk factors associated with elevated blood glucose were analyzed.Results:（1）Before IVMP treatment There were not significant differences in age,sex,FT3,FT4,TSH,NOSPECS,number of photoreceptors,number of cases of diplopia,number of cases of foreign body,TSHR-Ab,TG-Ab,TPO-Ab in group A,B and C（P>0.05）.The CAS scores were 2.3±1.0,2.7±1.2,2.8±1.0 in the there group respectively.There were significant differences（P<0.05）.（2）With the cumulative dose of GCs increased,A,B,C group TAO patients with CAS grade decreased gradually（0.2±0.7,1.0±0.8,1.3±0.8）,the three groups were statistically significant（P<0.05）.The proportion of patients with A,B and C group was 19.6%,76.6%and 86.8%,respectively.There was significant difference between the three groups（P<0.05）.The scores of CAS score in the low,middle and high dose groups were 0.3±0.6,0.7±0.8and 1.3±0.8,respectively.There was significant difference between the two groups（P<0.05）The proportion of patients was 23.5%,57.4%and 86.8%respectively.There was significant difference between the two groups（P<0.05）（3）With the increase of the cumulative dose of GCs,the proportion of cases of photoreceptor,foreign body sensation and diplopia remission in group A,B and C increased gradually,and there was significant difference between the three groups（P<0.05）.The proportion of cases of photoreceptor,foreign body sensation and diplopia remission in group low,medium and high dose increased gradually.High group was significantly higher than that of the low dose group（63.2%Vs 82.3%,P<0.05）.（4）With the increase of the cumulative dose of GCs,the proportion of total diameter of extracorporeal muscle in group A,B and C decreased,and the proportion of patients with reduced total diameter of extracorporeal muscle increased gradually,but there was no significant difference between the three groups（P<0.05）.The degree of total diameter of the extracorporeal muscle in the low,middle and high dose groups was-0.1±5.0,0.6±4.5and 0.5±5.1,respectively.There was no significant difference between the three groups（P>0.05）.The proportion of patients with reduced total diameter of extra-curvature was increased with the cumulative dose of GCs,and there was no significant difference between the three groups（P>0.05）.（5）With the increase of cumulative dose of GCs,the decrease of NOSPECS grade in group A,B and C,and the number of patients with NOSPECS decreased gradually,but there was significant difference between the three groups（P<0.05）.The levels of NOSPECS in the low,middle and high dose groups were 0.2±5.0,0.3±0.6 and 0.4±0.6,respectively.There was no significant difference between the two groups（P>0.05）.The proportion of NOSPECS decreased in the low,middle and high dose groups with the cumulative dose of GCs increased gradually（23.5%,29.4%,32.4%）,but there was no significant difference between the two groups（P>0.05）.（6）With the increase of the cumulative dose of GCs,the proportion of thyroid-associated antibodies（TPO-Ab,TG-Ab,TSHR-Ab）in group A,B and C changed from normal to normal.The proportion of TSHR-Ab that changed from abnormal to normal was7.3%,12.8%and 33.8%,respectively.With the increase of cumulative dose of GCs,the proportion of thyroid-associated antibodies（TPO-Ab,TG-Ab,TSHR-Ab）in the low,middle and high groups increased from abnormal to normal,the proportion of TSHR-Ab that changed from abnormal to normal was 4.4%,19.1%,33.8%.（7）Before IVMP treatment,the total diameter of the extracranial muscles was significantly correlated with the CAS score（r=0.330,p<0.05）;The total diameter of the extracorporeal muscle was significantly correlated with NOSPECS rating（r=0.229,p<0.05）.There was no significant correlation between total diameter of extracorporeal muscle and TSHR-Ab（r=0.184,p>0.05）.After IVMP treatment,the decrease in the total diameter of extracorporeal muscle in group C was significantly correlated with the CAS score（r=0.335,p<0.05）.（8）The levels of AST and ALT in group A,B and C were<100U/L,and the proportion of liver damage was 3.6%,8.4%and 7.4%respectively.The percentage of liver damage in low,middle and high dose groups was 4.4%,5.9%and 7.4%,respectively.（9）After IVMP treatment,the proportion of cases of hypocalcemia in group A,B and C was 16.1%,40.4%and 30.9%respectively.The proportion of patients with hypokalemia in group B and group A was significantly higher than that in group A（40.4%Vs 16.1%,P<0.05）.The incidence of hypokalemia was 3.6%,10.6%and 7.4%in the three groups,respectively.There was no significant difference between the two groups（P>0.05）.The percentage of cases of hypocalcemia in low,middle and high dose groups was 29.4%,25.0%and 30.9%respectively.There was no significant difference between the two groups（P>0.05）.The low,middle and high dose groups had hypokalemia The proportion of cases was11.8%,17.6%and 7.4%respectively.There was no significant difference between the two groups（P>0.05）.（10）After IVMP treatment,the incidence of renal insufficiency in group A,B and C was 14.5%,6.4%and 2.9%respectively.The incidence of renal insufficiency was significantly decreased in group C and group A（2.9%vs 14.5%,P<0.05）.The incidence of renal insufficiency in the low,medium and high dose groups was 1.5%,2.9%and 2.9%,respectively.（11）After IVMP treatment,the proportion of patients with weight greater than or equal to 5Kg was 10.7%,8.7%and 11.8%respectively.The low,middle and high dose groups were 4.4%,4.4%and 7.4%respectively.（12）After IVMP treatment,the proportion of hypertensive patients in group A,B and C was 8.9%,4.3%and 8.8%respectively.The proportion of hypertension cases in low,middle and high dose groups was 4.4%7.4%,8.8%respectively.（13）After treatment with IVMP,the incidence of abnormal glucose metabolism was5.4%,13.1%and 2.9%in group A,B and C,respectively.The incidence of abnormal glucose metabolism was 5.9%,7.3%,2.9%respectively.（14）Of the 22 patients undergoing OGTT trial,27.27%TAO patients（6 patients）had impaired glucose regulation after IVMP treatment,The incidence of impaired glucose regulation was not associated with GCs cumulative dose（r=-0.296,P=0.181）.（15）There were obvious decreases in CISI and OGSI of the HBG group（compared with NBG group,P<0.05）.There was no significant difference in HOMA-IR,QUICKI,HOMR-β,IGI,DI,AUC_C-P/AUC_G between HBG group and NBG group（P>0.05）;HBG group compared with NBG group DI₀,DI₁₂₀,DI₁₈₀ were significantly reduced（P<0.05）.Conclusion:（1）IVMP treatment of moderate to severe TAO patients,medium and high doses of GCs（GCs cumulative dose>4.5g）are more effective than low doses（GCs cumulative dose≤4.5g）,but medium and high doses will increase the risk of adverse reactions.（2）High dose GCs（GCs cumulative dose>7.5g）compared with the middle dose GCs（4.5g<GCs cumulative dose≤7.5g）,the incidence of adverse reactions did not increase significantly,which suggest that high dose GCs therapy can be selected in patients with moderate to severe TAO who are difficult to control in the middle dose of GCs in close monitoring of adverse reactions.（3）IVMP treatment in TAO patients can cause elevated blood glucose,but has nothing to do with the cumulative dose of GCs.The mechanism of elevated blood glucose may be mainly for pancreaticβ-cell reserve dysfunction.