Clinical Investigations Of Sjogren s Syndrome

干燥综合征的临床研究

• 批准号: 6966520
• 负责人: BRUCE J BAUM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6966520
• 关键词: Sjogren' s syndrome; autoimmunity; clinical trials; connective tissue disorder chemotherapy; human subject; human therapy evaluation; patient oriented research; salivary glands

Sjogren's Syndrome (SS) is an autoimmune disease, characterized as a widespread epitheliitis, which results in dryness of the lining surfaces of the body, producing, most notably, dry mouth and dry eyes. Under this project, the GTTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in GTTB, at the Academic Medical Center (University of Amsterdam) and at Johns Hopkins University in order to understand pathogenic mechanisms operative in this disease. Few rigorous clinical trials have been undertaken to develop treatments for SS patients, and agreed-upon outcome measures for such trials have only recently been defined. Our general approach has been to screen agents that have been used effectively in the treatment of other autoimmune diseases for their potential efficacy in SS. In addition to providing possible therapies for SS patients, these agents can also serve as probes of pathogenic mechanisms operative in this disease. We have generally hypothesized that immunomodulatory treatments may favorably alter the course of SS. As reported last year, we completed a placebo-controlled, randomized clinical trial of a new biologic agent, Etanercept, which is useful in treating rheumatoid arthritis, and during this reporting period finished all data analysis. Etanercept is an inhibitor of (and soluble receptor for) tumor necrosis factor (TNF)-alpha, a cytokine found in increased amounts in salivary and lacrimal glands of SS patients. This study was a 12-week double blind trial and patients meeting American-European Consensus Group criteria for SS received either 25 mg of Etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Five Etanercept-treated patients and three placebo-treated patients showed improvement from baseline in a primary outcome variable at 12 weeks, but this difference was not statistically significant. Additionally, there were no significant differences between the test groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), IgG levels, Schirmer I test results, van Bijsterveld scores, or salivary flow rates. However, at 12 weeks, erythrocyte sedimentation rates had decreased in the Etanercept group compared with baseline (P = 0.004). Our findings show that while this drug is safe to use in SS patients, there was no evidence for any efficacy of Etanercept in treating the exocrine component of SS. Furthermore, the results suggest that either therapeutic concentrations of Etanercept were unable to reach salivary tissue after systemic administration, or that the role of TNF-alpha in the pathogenesis of SS is less important than previously thought, or that a role for this cytokine is critical at an earlier time in the pathogenic mechanism. This reporting period also was marked by considerable change in the organization of the SS Clinic. After many years at NIH, the Head of the Clinic left to join a major biotech company, and the oral medicine research fellow left to assume a university faculty position. Nonetheless, SS Clinic activities were maintained at a high level thanks to our nursing and consultant oral medicine staff. We also were successful, after a national search, in recruiting an outstanding rheumatologist/clinical investigator to become the new Head of the SS Clinic.

Sjogren综合征（SS）是一种自身免疫性疾病，其特征是一种广泛的上皮炎，可导致人体衬里表面干燥，最著名的是，尤其是眼睛干燥的眼睛干燥。在该项目下，GTTBSS诊所进行临床研究和临床试验，并与GTTB，学术医学中心（阿姆斯特丹大学）和约翰·霍普金斯大学的实验室研究人员合作，以了解这种疾病中的致病机制。 很少有严格的临床试验用于开发SS患者的治疗方法，并且直到最近才定义了此类试验的成果指标。我们的一般方法是用于筛查在其他自身免疫性疾病治疗SS中的潜在疗效的筛查药物。除了为SS患者提供可能的疗法外，这些药物还可以作为该疾病中致病机制的探针。我们通常认为免疫调节治疗可能会有利地改变SS的过程。 如去年所报道的那样，我们完成了一项新生物学剂Etanercept的安慰剂对照，随机临床试验，该试验可用于治疗类风湿关节炎，在此报告期间完成了所有数据分析。 Etanercept是肿瘤坏死因子（TNF）-Alpha的抑制剂，这是SS患者唾液和泪腺含量增加的细胞因子。这项研究是一项为期12周的双盲试验，符合SS的美国 - 欧洲共识组标准的患者接受了25 mg的Etanercept或安慰剂（车辆），每周两次皮下注射。在12周的主要结局变量中，五名经依那感治疗的患者和三名安慰剂治疗的患者在基线上表现出改善，但这种差异在统计学上并不显着。此外，测试组之间没有明显的差异，以改变口服或眼部症状（通过视觉模拟量表），IgG水平，Schirmer I测试结果，van Bijsterveld评分或唾液流量的变化。然而，在12周时，与基线相比，Etanercept组的红细胞沉降率降低了（p = 0.004）。 我们的发现表明，尽管该药物可以安全地用于SS患者，但没有证据表明Etanercept在治疗SS的外分泌成分方面有任何功效。此外，结果表明，在全身给药后，依那耐等治疗浓度无法达到唾液组织，或者TNF-α在SS发病机理中的作用不如先前想到的重要，或者该细胞因子的作用在病原机制中至关重要。 SS诊所的组织也发生了很大变化，这一报告期也有很大的变化。在NIH工作了多年后，诊所负责人加入了一家大型生物技术公司，口腔医学研究员离开了大学教职员工职位。尽管如此，由于我们的护理和顾问口腔医学人员，SS诊所活动仍处于高水平。在全国搜索之后，我们也成功地招募了一名出色的风湿病学家/临床研究者成为SS诊所的新负责人。