Analysis Of The Factors Causing Ankylosing Spondylitis Recurring After Discontinuing The Treatment Of Etanercept And The Effects Of GuLingTang On The Relapse

BackgroudsAnkylosing spondylitis (AS) is an inflammatory arthritis and enthesitis involving the spine and peripheral joints. Inflammation of sacroiliac joints, the spine,and entheses leads to new bone formation, syndesmophytes,and ankylosis of joints Patients with AS may also have associated peripheral arthritis, enthesitis,osteoporosis, or extraarticular involvement such as uveitis and inflammatory bowel disease。Compared with the general population, patients with AS have increased rates of work disability and unemployment and a higher mortality rate. Until recently, treatment options for patients with AS have been limited to non steroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and physical therapy. A few studies have been done on treatment of patients with ankylosing spondylitis with disease-modifying antirheumatic drugs, none of which have proved clearly effective in axial disease. Tumour necrosis factor-alpha (TNF-a) is one of the most critical mediators in the pathogenesis of chronic inflammation. TNF-a plays a key proinflammatory role in AS. Using a sacroiliac biopsy technique that is guided by computed tomography, we have shown that TNF-a is expressed in inflamed sacroiliac joints of patients with ankylosing spondylitis. Therapeutic agents that target the proinflammatory cytokine TNF-a may be the most viable alternative to existing treatment options. Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kDa TNF receptor. Etanercept has been successfully used to treat patients with AS. A pivotal phase III study in AS showed that etanercept was superior to placebo, significant differences being apparent as soon as 2-weeks. But for patients in most parts of the world, the major drawback of this TNF-a blockers is that they are very expensive. Most patients cannot use this drug for long time. But after discontinuing the etanercept almost patients completed disease relapsed within short times. Which clinical or laboratory parameters would predict the duration of flare after discontinuation of etanercept therapy, how we can prevent the relapse, which drug would prolong the duration of remission, are the important question of the rheumatologist caring about.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 osteoclasia in AS. Our Group under the pathogenesis of OP in Traditional Chinese Medicine developed with Gu Ling Wan for treatment of OP. Correlated research confirmed Gu Ling Wan can regulate the level of cytokine,such as TNF-a, IL-6. And Gu Ling Wan can regulate the bone resorption and bone formation by multichanne and effective fight against osteoporosis. Osteoporosis is considered now as a common feature of AS even in early stages of the disease. Old studies suggest that anti-osteoporosis drug pamidronate represents an attractive treatment option for ankylosing spondylitis. Therefore, GuLingTang combined with etanercept maybe delay relapse after discontinuing the treatment of etanercept in AS.Objective1. To explore the clinical or laboratory parameters predictive of flare after discontinuation of etanercept therapy.2. To analyze the difference of relapsing rate of the two groups after discontinuation of etanercept treatment to further illuminate Gu Ling Tang, etanercept for Ankylosing spondylitis treating approachs.Methods1. Patients:Sixty patients from Nanfang Hospital diagnosed with AS from January 2007 to October 2009. Patients classified as having AS (according to the modified New York criteria), with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of>4 (range 0-10),and with a spinal pain assessment score of>4 on a visual analog scale (VAS; range 0-10 cm),and attained an ASAS20 response at week 12 were eligible for the study. 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 etanercept.2. Study groups and usage of the drug:60 patients were randomly divided into two groups. Treatment group 1 (30 cases) received etanercept at a dosage of 25 mg twice weekly by subcutaneous administration and Gu ling tang a day, twice daily by oral during the 12-week study. Treatment group 2 (30 cases) received etanercept at a dosage of 25 mg twice weekly by subcutaneous administration during the 12-week study. NSAID were to continue to be stable during the study. After 12 weeks, patients stopping using etanercept, were followed up until relapse or 9 month after not using etanercept. The medications such as NSAIDs, Gulingtang were left. 3. Evaluation:baseline demographics include gender, age, Clinical characteristics include course of disease, hip joint damaged and Efficacy evaluations,such as the Bath Ankylosing Spondylitis Disease Activity Index(BASDAI), the Bath Ankylosing Spondylitis Functional Index(BASFI), patient's global assessment(PGA), spinal pain, And the level of CRP and ESR were detected. The content in the follow-up period were BASDAI, spinal pain, ESR, CRP. Record the time of recurrence.4. The replase was defined as>2 increase in BASDAI compared with 12 weeks when etanercept was finished.5. Statistical analysis. All data used SPSS13.0 statistical analysis software. Measurement data are expressed as x±s. The statistical tools used were the Cox proportionate hazard model and the logrank method. Baseline measurement data were analyzed by an independent sampler t-test and enumeration data were analyzed byχ2 test in two groups. P<0.05 was considered statistically significant.Results1. Follow-up to assess time of relapse:There were 53 patients who attained an improvement of>ASAS20 at weekl2 were followed using a definition of relapse. 81.1% of these patients relapsed within 36 weeks afterwards. The percent of patients who relapsed within 4,12 and 24 weeks were 11.3%,32.1% and 71.7%respectively.2. Predictors of duration of relapse:The statistical tools used were the Cox proportionate hazard analysis to test if any of the parameters at baseline can predict a faster relapse. The variable was the duration of relapse, the concomitant variable consists of gender, age, course of disease, therapy methods, BASDAI, BASFI, Spine pain, Hip joint damaged, ESR, CRP. The predictor of the duration of relapse after discontinuing the etanercept were BASDAI, CRP, Hip joint damaged and therapy methods(P<0.05). The higher of BASDAI and CRP, the shorter of the duration of relapse. The patients with hip joint damaged had a faster relapse than that with not hip jiont damaged. A smaller risk of relapse in the treatment group 1 than in the treatment group 2.3. According to the median of BASDAI and CRP and whether hip joint damaged or not divided into two different groups. The statistical tools used were the log-rank method. Between the two groups according to the BASDAI, CRP and hip joint damaged, the rate of relapse were significantly different, the results being(χ2=9.061 P=0.003),(X2=4.479 P=0.034),(χ2=6.056 P=0.014) respectively.4. The 53 patients which were followed consist of 28 patients being in groupl,25 patients being in group2. General information,baseline characteristics and clinical characteristics at week12, Differences of gender, age, course of disease and the effect of index were no significant statistical difference among groups (P>0.05). The duration of relapse of groupl was 20 weeks, however that in the group2 was 14 weeks. Using the logrank method, the differents betwent the two groups were significantly(x 2=4.822, P=0.028).ConclusionAfter discontinuing the etanercept almost patients completed disease relapsed within short times. BASDAI,CRP and hip joint damaged could predict the duration of flare after discontinuation of etanercept therapy. Gu Ling tang with etanercept could prolong the duration of remission. It is important for the patients that cannot use this drug for long time because of the cost.