Changes Of Bone Metabolism, Radiology And OPG/RANKL Serum Levels In Patients With Ankylosing Spondylitis During Gu Ling Tang And Rh TNFR:Fc Therapy

Backgrounds:Ankylosing spondylitis(AS) is a seronegative spondyloanthropathy characterized by chronic inflammation in the sacroiliac joint and insertion of tendons or ligaments involving the sacroiliac joint,spine and hip joints.It has been established that bone loss occurs in the early phase of the disease,and many patients with AS have osteoporosis and bone destruction.Spinal and peripheral joint stiffness, deformity occurs resulting in serious damage in the advanced stage of the disease. Inflammatory bone destruction is the dynamic link of the joint deformity.It is the key to interrupt the development of AS and to protec joint function and prevent disability that preventing inflammation and bone destruction to against osteoporosis effectively.Previous study found that,osteoclasia in AS involves the relationship between skeletal system and the immune system.T cells and receptor activator of nuclear factor-κB ligand(RANKL) were the most important two factors associating bone system and immune system.The major cause of ossa articularia's corrosion and regional/systematic osteopenia due to AS,is that the absolute/relative rise of bone resorption,which is caused by the post-maturity and activation of Osteoclast, disturbed the balance of bone metabolism;while the ultimate regulatory factor which is involved in OC differentiation and function maintenance——osteoprotegerin(OG), induced the basic process of AS'osteoclasia,along with RANKL.TNF-αis the main proinflammatory cytokine that causes AS.It can promote proliferation of fibroblasts, increase the permeability of vascular endothelial cells,and worsen the inflammatory edema and infiltration of inflammatory cells in local tissue.In addition to TNFαis a strong factor that it can stimulate osteoblasts to secrete RANKL,and facilitate the osteolysis of osteoclasts,and advance chondrocyte to synthetic and secrete metalloproteases,therefore TNF-αcan lead to the destroy of the cartilage. According to this basic pathology,TNF antagon has now been used as a treatment to the patients who has AS.The previous research showed that rh TNFR:Fc could made the symptom efficiently controlled,stopped the exacerbation of clinical and radiology test,and anesis bone loss of inflammatory area near the end of tendon.But at present domestic hasn't the research about AS how to evoke the bony erosion.Ankylosing spondylitis is the definition of Traditional Chinese Medicine"arthralgia syndrome".Its pathogenesis is mainly due to osteoclasia,tendon contraction and spine rigidity caused by deficiency of kidney-QI or cold dampness and hot exogenous evil,incoordination of YIN and YANG.The bone strong or weak is an important symbol of the pneuma of kidney.The clinical trials and research had confirmed that Traditional Chinese Medicine has its own ascendancy on preventing and curing OP in AS.Our Group under the pathogenesis of OP in Traditional Chinese Medicine developed with Gu Ling Wan for treatment of OE Correlated research confirmed Gu Ling Wan can regulate bone resorption and bone formation by multichanne and effective fight against osteoporosis.Therefore,the use of Gu Ling Tang joint rh TNFR:Fc treatment of AS may further confrontation in the bone erosion and inflammation associated with osteoporosis.Objective1.To explore better treatment programmes to improve the treatment to bone destruction in AS by observing the bone metabolism,imaging and RANKL/ OPG expression of treatment group 1(Gu ling tang and rh TNFR:Fc) and the treatment group2(rh TNFR:Fc) before and after treatment.2.To analyze the difference of each index of Two groups after treatment to further illuminate GU Ling Tang,rh TNFR:Fc for bone erosion mechanism.Methods1.Patients:Fifty-two patients from Nanfang Hospital diagnosed with AS from August 2006 to October 2007.Patients were excluded from the study if they had Spinal ankylosis or sacroiliac joint,hip ankylosis;other rheumatic diseases,severe infections,tuberculosis,cancer and important organ failure.Patients were excluded from the study if they had previously received TNF inhibitors,including rh TNFR:Fc. Patients were excluded if they had taken estrogen,glucocorticoids,vitamin D,or calcium supplement.2.Study groups and usage of the drug:52 patients were randomly divided into two groups.Treatment group 1(26 cases) received rh TNFR:Fc at a dosage of 25 mg twice weekly by subcutaneous administration and Gu ling tang a day,twice daily by oral during the 24-week study.Treatment group 2(26 cases) received rh TNFR:Fc at a dosage of 25 mg twice weekly by subcutaneous administration during the 24-week study.3.Evaluation of disease activity:Measured C-reactive protein(CRP) and erythrocyte sedimentation rate(ESR) before and after treatment.Recorded Bath AS disease activity index(BASDAI).4.Bone metabolism markers and RANKL and OPG:Serum was collected before and after 24 weeks of treatment at-20℃or lower until analyses.Measure OC,CTX according to brochures of kit.Measure OPG and RANKL levels by enzyme-linked immunosorbent assay(ELISA).5.Radiological assessment:Let Fifty-two AS patients undertanke the pelvic plain film before and after treatment.ALL inmages of the joints were evaluated twice in blinded manet by two doctors.The sacroiliac joints and hip joints wer separately evaluated by Bath AS radiology using standard score(BASRI).6.Observation of Safety:Check regular inspections of blood,liver and renal function,autoantibody,TBantibody and hepatitis B virus 5 items.Record the occurrence of adverse events to observe the safety of medication.7.Statistical Analysis:All data used SPSS 11.5 statistical analysis software. Measurement data are expressed as(?)±S.Baseline measurement data were analyzed by an independent sampler t-test and enumeration data were analyzed by X~2 test in two groups.Differences in the same group before and after treatment were analyzed by paired t test.Differences among groups were analyzed by covariance analysis.P＜0.05 was considered statistically significant.Results1.General information and baseline characteristics:Differences of gender,age, course of disease and the effect of index before treatment were no significant statistical difference among groups(P＞0.05).2.The clinical efficacy indexes:After 24weeks of treatment,BASDAI,CRP and ESR were significantly improved in patients of both groups(P＜0.05),and no significant difference was found in the indexes between the two groups at the same time. 3.Bone metabolism:Serum levels of OC were significantly increased(P＜0.05), while serum levels of CTX were significantly decreased(P＜0.05) in the two groups after 24 weeks.Between two groups,Serum levels of OC were significantly increased, while serum levels of CTX were significantly decreased(P＜0.05) after24 weeks of treatment.4.BASRI:Changes of BASRI-SIJ and BASRI-h were not significant after 24 weeks in two grops and between two groups(P＞0.05).5.Serum levels of OPG and RANKL:Serum levels of OPG were significantly elevated(P＜0.05),serum levels of RANKL and OPG/RANKL were significantly decreased after treatment at week 24(P＜0.05),in two groups.Between two groups, serum levels OPG were significantly elevated(P＜0.05),serum levels of RANKL and OPG/RANKL were significantly decreased after treatment at week 24(P＜0.05).6.Safety:Each groups of patients had one case of respiratory infection.There were no serious adverse reactions during the observation.ConclusionGu Ling tang with rh TNFR:Fc may be effective for reducing disease activity and improving bone metabolism.It is indicated that Gu Ling tang may interrupt the osteoclasia and radiological improvement through adjusting OPG system in patients with AS.