Clinical Investigations Of Sjogren's Syndrome

干燥综合征的临床研究

• 批准号: 6814551
• 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/6814551
• 关键词: Sjogren's syndrome; autoantigens; clinical trials; cytokine receptors; gene rearrangement; human subject; human therapy evaluation; immunoglobulin G; immunomodulators; immunopathology chemotherapy; inflammation; information systems; medical complication; pathologic process; patient oriented research; salivary glands; Sjogren's syndrome; autoantigens; clinical trials; cytokine receptors; gene rearrangement; human subject; human therapy evaluation; immunoglobulin G; immunomodulators; immunopathology chemotherapy; inflammation; information systems; medical complication; pathologic process; 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 SS Clinic conducts clinical investigation and clinical trials, and collaborates with laboratory investigators in GTTB and Johns Hopkins in order to elucidate pathogenic mechanisms operative in this disease. A major achievement during this FY is the near completion of a secure, integrated, relational database incorporating research records since the inception of the SS Clinic in 1985. The entry of clinical data on 1800 subjects, who have participated in studies of SS and salivary dysfunction, is almost finished. The database includes information on hundreds of variables from: questionnaires completed by patients on history and symptoms; data forms completed by clinicians, such as physical findings and salivary flow rates; and information imported from the NIH Clinical Center?s Medical Information System. The importation of laboratory and pathology data relies on specific computer programs that automatically detect inconsistencies and duplicates. In addition, sophisticated algorithms have been developed within statistical computer programs to allow for the automated classification of cases to determine whether or not they meet accepted criteria of SS, and whether the cases are primary or secondary SS. When fully completed, this data-base will be a rich resource and allow rapid and convenient access to important research information. SS also can involve the skin, lungs, kidneys, and peripheral nerves, and the risk of developing lymphoma is much higher in patients with SS than in the general population. Polyclonal activation of B cells tends to evolve toward the development of monoclonality and ultimately lymphoma. We hypothesized that increased inflammation in salivary tissue, manifesting as higher focus scores, as well as increased serological activity and higher immunoglobulin levels, may be risk factors in SS patients for monoclonal expansion of B cells. We are examining gene rearrangements in minor salivary gland B cells from SS patients to address this issue. Also, in collaboration with colleagues at Johns Hopkins, the hypothesis that subsets of SS are associated with antibodies specific for distinct autoantigens has been affirmed. Primary SS and limited scleroderma patients were found to differ markedly in their pattern of centromere protein (CENP) recognition. Antibodies to CENPs were found in 26% of SS patients. While CENP-positive SS patients recognize predominantly CENP-C in isolation, this pattern was very uncommon in CENP-positive patients with scleroderma. SS patients with antibodies recognizing CENP-C were uniformly associated with the presence of antibodies to Ro and La. Dual recognition of both CENP-B and CENP-C occurred much more frequently in patients with scleroderma. Both CENP-C recognition alone and dual CENP-B and CENP-C recognition are patterns that correctly identified the phenotype in the vast majority (positive predictive value 88%) of these anti-CENP positive patients with primary SS and limited scleroderma. In clinical investigations at the SS Clinic, we have hypothesized that immunomodulatory treatments may favorably alter the course of this disease. Accordingly, we conducted a placebo-controlled, randomized clinical trial (RCT) of a new biologic agent, etanercept. Etanercept is an inhibitor of (soluble receptor for) tumor necrosis factor a, a cytokine found in increased amounts in salivary and lacrimal glands of SS patients. This RCT has recently been completed. Our results show that the drug is safe to use in SS patients, but we found no evidence for efficacy of etanercept in treatment of the exocrine component of SS. Finally, with the collaboration and support of an international group of SS investigators, the National Eye Institute, the Office of Women's Health, the Sjogren's Syndrome Foundation, and industry, the SS Clinic led a workshop to develop an international consensus on outcome measures for clinical trials in SS. From this endeavor, a framework has been established for the validation of a core set of outcome measures, as well as for the evaluation of newer potential outcome measures for which there are currently insufficient data.

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，SS诊所进行临床研究和临床试验，并与GTTB和Johns Hopkins的实验室研究人员合作，以阐明该疾病中的致病机制。在此FY期间的一项重大成就是，自1985年SS诊所成立以来，结合了研究记录的安全，综合的关系数据库即将完成。几乎完成了SS和唾液功能障碍研究的1800名受试者的临床数据。该数据库包括有关数百个变量的信息，来自：患者有关病史和症状的问卷；临床医生完成的数据表格，例如身体发现和唾液流量；以及从NIH临床中心的医疗信息系统进口的信息。实验室和病理数据的进口依赖于自动检测不一致和重复的特定计算机程序。此外，在统计计算机程序中已经开发了复杂的算法，以允许对案例进行自动分类，以确定它们是否符合SS的接受标准，以及这些案例是主要的还是次要的SS。完全完成后，该数据库将是一种丰富的资源，并可以快速方便地访问重要的研究信息。 SS还可能涉及皮肤，肺部，肾脏和周围神经，而SS患者的淋巴瘤的风险要高于一般人群。 B细胞的多克隆激活倾向于发展为单克隆性的发展和最终的淋巴瘤。我们假设唾液组织中的炎症增加，表现为较高的焦点评分，血清学活性和更高的免疫球蛋白水平增加可能是SS患者的危险因素，用于B细胞的单克隆膨胀。我们正在研究来自SS患者的次要唾液腺B细胞中的基因重排以解决此问题。同样，与约翰·霍普金斯（Johns Hopkins）的同事合作，已经确认了SS子集与针对不同自动抗原特定的抗体相关的假设。原发性SS和有限的硬皮病患者的丝粒蛋白质（CENP）识别模式明显不同。在26％的SS患者中发现了与CENP的抗体。虽然CENP阳性SS患者主要隔离CENP-C，但这种模式在CENP阳性患者的硬皮病患者中并不常见。识别CENP-C的抗体患者的SS患者与CENP-B和CENP-C双重识别的抗体均匀相关。 CENP-C识别和双CENP-B和CENP-C识别都是这些模式的模式，这些模式在这些抗CENP阳性患者中正确识别了绝大多数（正预测值88％）中的表型，而原代SS和有限的硬皮病患者。 在SS诊所的临床研究中，我们假设免疫调节治疗可能会有利地改变这种疾病的病程。因此，我们进行了一项新生物学剂Etanercept的安慰剂对照，随机临床试验（RCT）。 Etanercept是肿瘤坏死因子A（可溶性受体）的抑制剂，这是SS患者唾液和泪腺中含量增加的细胞因子。该RCT最近已完成。我们的结果表明，该药物可安全地用于SS患者，但我们没有发现依那耐酸治疗SS外分泌成分有效性的证据。最后，在国际SS调查人员，国家眼科研究所，妇女健康办公室，Sjogren综合征基金会和行业的合作和支持下，SS诊所领导了一个研讨会，为SS的临床试验成果制定了国际共识。从这项工作中，已经建立了一个框架，以验证一组核心结果指标，以及评估当前数据不足的较新的潜在结果指标。