Clinical Investigations Of Sjogren s Syndrome

干燥综合征的临床研究

• 批准号: 7318841
• 负责人: Gabor Illei
• 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/7318841
• 关键词: Clinical; Investigations; Sjogren; Syndrome

Summary: Sjogren's Syndrome (SS) is an autoimmune disease, characterized by widespread inflammation in the exocrine glands and other organs resulting in dryness of the lining surfaces of the body, most notably, dry mouth and dry eyes. In addition, it can involve numerous other organs such as the joints, skin and nervous system. Under this project, the GTTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in GTTB, other NIH laboratories and Institutions outside the NIH in order to understand the mechanisms underlying this disease. The ultimate goal of our research is to find treatments for Sjogren?s Syndrome (SS) that are safe, effective and target specific steps in the pathogenesis of SS. To achieve this goal, we focus our research in two broad categories. Natural history studies include observational and retrospective studies with the goal to expand our knowledge about the pathogenesis of SS, to improve our diagnostic and prognostic tools and to identify targets for new therapies. The other major area involves the evaluation of novel treatments in patients with Sjogren?s Syndrome. Natural history of Sjogren?s Syndrome protocol (85%) Clinical activities (direct patient contact) This protocol focuses on the long-term evaluation of patients with SS and related diseases. We have enrolled 76 new patients. We initiated a pilot study to evaluate the feasibility of ultrasound guided needle biopsy of the parotid glands. This is a less invasive procedure than minor salivary gland biopsy and, if feasible, we plan to use it for repeat biopsies in clinical studies. Feasibility of MRI to image salivary glands Salivary gland involvement in Sjogren's syndrome (SS) results in reduction of saliva secretion at baseline and after stimulation. We have started a pilot study to test magnetic resonance imaging (MRI) as a non-invasive way to monitor salivary gland function with the ultimate goal to assess response to therapy, particularly in clinical trials. We have imaged 8 SS patients and 7 healthy volunteers and found that the mean parotid T2 values were higher in patients than controls. We plan to include this measurement in upcoming treatment studies. Gender differences in the clinical manifestations of SS (collaboration with Janine Smith, NEI) (patient data, human samples) SS predominantly affects females; in fact, 90% of patients are females. The reason for this gender difference has not been established yet and the literature is also controversial about any difference in clinical presentation and course of males and females. We started a project addressing this question in our large cohort by combining the data from NIDCR and NEI. 28 men and 294 women with SS were included. Women were matched to men by age and race. The comparison showed no difference between the two genders in clinical manifestations and objective severity in oral and ocular finding but women reported significantly more subjective discomfort. Treatment study using an anti-LFA1 monoclonal antibody in primary Sjogren?s Syndrome Our ultimate aim is to develop safe and effective treatments that target specific steps in the pathogenesis of SS. Our general approach is to start with early stage clinical studies (Phase I/II) to establish the safety of an intervention, and at the same time, collect data about its possible efficacy. Our goal is to understand why a particular drug targeting specific components of the immune system may or may not work. Therefore, we combine clinical trials with thorough basic science evaluations to learn more about the pathogenesis of SS and the biologic effects of the intervention. This protocol is using Raptiva (efalizumab, Genentech), an anti-LFA1 monoclonal antibody, which is targeting the LFA1-ICAM pathway that has several functions in Sjogren?s Syndrome, including lymphocyte trafficking and antigen presentation. Raptiva is approved for psoriasis but has no been tried in SS yet. The protocol proposes to use repeat salivary gland biopsies as part of our response criteria to address the effect of the treatment on the local inflammatory process. The protocol has been approved by the IRB and patient enrollment has started in September. Laboratory projects directly supporting clinical studies (15%) In the laboratory we have focused our efforts on various aspects of acetylcholine (Ach) and its receptors (AChR) since SS patients demonstrate multiple abnormalities of this pathway, which is crucial for the production of saliva. Sjogren?s patients are thought to have autoantibodies against the muscarinic acetylcholine receptors (mAChR). These antibodies may contribute to the salivary gland dysfunction but are very difficult to detect. We are evaluating several methods for the large scale detection of these antibodies. Since acetylcholine receptors are also expressed on activated lymphocytes we started a project to analyze the effects of Ach on various lymphocyte subsets such as regulatory and effector T cells. Any such affect may play an important role in the local inflammatory response seen in the salivary gland of Sjogren?s patients. We also initiated several collaborations with laboratories within and outside the NIH. Future directions Autonomic nervous system (ANS) dysfunction in SS The range of symptoms in SS suggests that there may be perturbations in the nervous and immune systems and in multiple physiological pathways through which these systems communicate and mediate each other. Compared to normal healthy individuals impaired ANS function (which regulates the homeostasis via effects on the smooth muscle, glands and cardiovascular system) is more common in SS patients However, little is known, about the incidence and prevalence, underlying mechanisms and importance of the ANS in SS patients. Since majority of the exocrine glands producing the SS phenotype have autonomic nervous system regulation, one can hypothesize that ANS dysfunction is central to the exocrinopathy observed in SS. We are developing a study to investigate ANS function in patients with SS, association between ANS failure and autoimmunity, and design therapeutic interventions based on the pathogenic mechanisms underlying ANS dysfunction. This clinical study will be complemented by the functional lymphocyte studies described above. Long-term plans We plan to develop several early stage clinical studies (Phase I/II) to establish the safety and toxicity of an intervention, and at the same time, collect data about its possible efficacy. Our goal is to attempt the ?immunodissection? of human SS by targeting specific components of the immune system. We will combine these clinical trials with thorough basic science evaluations to learn about the pathogenesis of SS and the biologic effects of the intervention.

摘要：干燥综合征（SS）是一种自身免疫性疾病，其特征是外分泌腺和其他器官的广泛炎症导致身体内膜表面干燥，最明显的是口干和眼干。此外，它还可能涉及许多其他器官，如关节、皮肤和神经系统。在这个项目下，GTTB- SS诊所进行临床调查和临床试验，并与GTTB、其他NIH实验室和NIH以外的机构的实验室研究人员合作，以了解这种疾病的潜在机制。