Clinical Significance Of Serum Detection Of VEGF,HA,bFGF,sICAM-1 And Immunotherapy Of Graves' Ophthalmopathy.

Background:Graves' ophthalmopathy (GO) is a chronic autoimmune disease, which is characteristic of inflammatory reaction and hydrophilia glycosaminoglycan accumulation in orbital connective tissue, with or without hyperplasia of orbital adipose tissue and extraocular muscles. As a result, the increased volume in the bony orbital leads to various clinical manifestations, such as ophthalmalgia, proptosis, periorbital edema, extraocular muscles motor disorder, inflammation and vision damage. Up to now,20～25% patients with Graves' disease have got Graves' ophthalmopathy in the world. The pathogenesis of GO is still unclear, and it also remains a therapeutic dilemma.In the early active phase of GO, lymphocytes and some other autoimmune cells infiltrate into the local site, accompanied by hydrophilia glycosaminoglycan cumulation in orbital connective tissue. While in the advanced stable phase, the fibrosis of retroorbital tissue is apparent. As special treatment for each GO patient in active or inactive phase, the outcomes may be different. Therefore evaluation of the condition of patients correct and efficient is of great importance for the prognosis and treatment of this disease. Increased evidence shows that the serum levels of HA and sICAM-1 can be used as the important indicators of the activity and severity of GO. Numerous reports showed that, VEGF and bFGF high expression in the orbital fibrous and adipose tissue biopsy in active GO patients. It was believed that VEGF and bFGF may play a pivotal role in the pathogenesis of GO, and be related to the activity and severity of GO.Until now,the most common immunotherapy medicine of GO is glucocorticoid. Culminating evidences indicated that glucocorticoid treatment was effective for moderate-to-severe GO. In addition, the reported response rate to intravenous glucocorticoid pulse therapy in moderate-to-severe and active GO patients was about 77%. Recently, researchers verified that mycophenolate mofetil, ciclosporin and tripterygium wilfordii were effective immunosuppressive drugs for GO. Lots of evidence-based medicine investigations manifested that tripterygium wilfordii was effective for GO, which suppressed the cell and humoral immunity, inhibited the autoantibody's formation of retroorbital tissue, and finally relieved the sufferings of patients. In our previous studies, treatment with mycophenolate mofetil in patients with GO has been found to be more effective with fewer side effects than ciclosporin, which may be bring new hope to patients in the future.Objective:In order to evaluate the activity and severity of GO, we detected the serum levels of VEGF,HA,bFGF and sICAM-1 in patients with GO and correlated their levels with clinical activity scores. We also observed the effects of immunosuppressive drugs on the serum levels of the four parameters in patients with GO such as mycophenolate mofetil, glucocorticoid and tripterygium wilfordii.Methods:1.The serum levels of VEGF, bFGF, HA, and sICAM-1 were determined in fifty patients with GO and thirty-one patients with Graves' disease by enzyme linked immunosorbent assay (ELISA). The relationships between the variables were evaluated by Spearman's test. According to CAS, GO patients were divided into active and inactive groups. And the serum levels of the four markers were detected and analyzed between the two groups.2.Twelve patients with GO were divided into three groups:mycophenolate mofetil(MMF) group(n=4)(0.5g,po,bid,12weeks), glucocorticoidgroup(n=4)(40mg/d× 4w,20mg/d×4w,10mg/d×4w),tripterygium wilfordii (TII)gourp(n=4) (20mg,po,tid,12 weeks). The serum levels of the four parameters and clinical activity scores were detected and analyzed before and after treatment.3.All data were performed using SPSS16.0, measurement data were expressed by mean±standard deviation (x±s), and the normality and homogeneity of variance were analyzed. The variables of two groups were analyzed using two independent samples t test. Paired-samples t test was used to analyze the variables of GO patients before and after treatment groups. The relationships between the variables were evaluated by Spearman's test. P<0.05 was considered statistically significance.Results:1) Compared with Graves'disease group, the serum levels of VEGF, HA, bFGF, sICAM-1 were significantly higher in GO group (P<0.05). In GO group, the serum levels of the four parameters were positively correlated to clinical activity scores (P<0.05), but the association of four parameters with age or duration was not found (P>0.05).2)Compared with inactive GO group, the serum level of sICAM-1 were significantly higher in active GO group (P<0.05). But the serum HA, VEGF and bFGF levels showed no on significance between the two groups(P>0.05).3) The serum VEGF, bFGF and HA levels were positively correlated to each other (P<0.05). But the serum sICAM-1level was found no obvious correlation with serum HA, VEGF and bFGF levels(P>0.05).4) After 12 weeks treatment, all patients with GO got improvement of their objective and subjective symptoms. Compared with pretherapy group, clinical activity scores and the serum levels of VEGF, HA, bFGF, sICAM-1 were significantly decreased in GO patients after treated with immunosuppressive drugs (P<0.05). Treatment with MMF or TII in patients with GO had less side effects than prednisone.Conclusion:1) Our results suggested that HA,sICAM-1,VEGF and bFGF may play an important role in the pathogenesis of GO and could be considered as good markers of active processes in GO.2) According to the results that the serum levels of VEGF, HA, bFGF, sICAM-1 were decreased in patients with GO after treated with immunosuppressive drugs, the evaluation of these markers could be considered as a useful tool in monitoring Graves' patients and in modulating the treatment of GO.