Body composition, bone structure, and joint damage in rheumatoid arthritis

描述（由申请人提供）： 该候选人是一名初级研究员在风湿病与先进的培训，在临床流行病学和重点病人为导向的研究，在慢性风湿性疾病。他在费城退伍军人事务部有着悠久的临床工作历史，最近被任命为临床教师。在他的整个训练过程中，他表现出对退伍军人的关怀，并建议在退伍军人事务部发展他的职业生涯。候选人提出了一个全面的跨学科职业发展计划，将为他提供发展成为独立临床研究者的技能和经验。他的共同导师是来自UPENN和VA的NIH K24资助的高级研究人员，他们在各种慢性疾病的骨骼和关节健康方面具有专业知识。他的多学科团队包括其他NIH资助的生物统计学，流行病学，骨代谢，身体成分和风湿性疾病的领导者，他们每个人都致力于协调努力，以推动他的职业生涯的成功。他将利用优秀的资源，包括VA风湿性关节炎国家登记处以及CTSA支持的临床和转化研究中心，以及附近的UPENN临床流行病学和生物统计学中心。他还将完成与本提案相关的方法的额外正式教学培训。拟议的项目将建立在他的流行病学培训和先前的研究经验，以促进他向独立过渡。他的长期目标是进行临床试验，以改善类风湿性关节炎（RA）的身体成分，骨骼健康和相关结果。这里提出的研究是为这些试验提供信息的必要的第一步。骨质疏松性骨折和关节损伤是类风湿关节炎的主要发病原因，导致数十亿美元的国家成本。1最近的研究表明，与非退伍军人相比，美国退伍军人关节炎的患病率和严重程度更高。2此外，VA将关节炎、疼痛、肥胖和骨质疏松症确定为 妇女;在本申请中，对其中每一个都进行了说明。低体重与RA的许多不良结局相关，包括骨折、关节损伤和死亡。然而，疾病本身对BMI的动态影响尚未得到表征，也没有改变身体成分对RA结局的影响。这种慢性炎症性疾病对体重的长期影响尚未阐明，可能有助于解释这些关联。同样，低BMI与低瘦体重相关。申请人证明，低瘦体重和较高脂肪量与健康成人的骨皮质变薄相关。鉴于1）类风湿性恶病质的特征是瘦体重减少，脂肪量正常或增加，2）低瘦体重与皮质骨变薄有关，RA中瘦体重的减少可能导致该人群中骨折风险过高。关键的知识差距是1）骨骼和BMI之间的关联是否与疾病的长期影响有关，2）瘦体重和脂肪量（而不是BMI）的改变在多大程度上导致了骨骼缺陷。更进一步，瘦体重对皮质骨的积极影响可能对预防炎性血管翳的侵袭很重要，并且对上覆软骨的健康不可或缺。因此，通过对皮质骨的机械作用或肌肉源性因子的产生，逆转类风湿关节炎瘦体重不足的干预措施可能对疾病结局产生有价值的影响。申请人的目的是1）与对照相比，量化RA中骨结构和身体组成的改变，并评估基线时RA参与者中与生长因子、细胞因子和结构性关节损伤的相关性，2）鉴定与ALM、骨密度和结构的纵向恶化相关的基线疾病特征、身体功能、血清学测量和身体组成测量，关节损伤和残疾超过2年，和3）确定较低的疾病活动是否与BMI的较大增加相关，独立于VARA参与者的糖皮质激素治疗。

DESCRIPTION (provided by applicant): The candidate is a junior investigator in rheumatology with advanced training in clinical epidemiology and a focus on patient-oriented research in chronic rheumatic diseases. He has a long history of clinical work within the Philadelphia VA and has recently been appointed here as clinical faculty. Throughout his training he has shown dedication to the care of veterans and proposes to develop his career within the VA. The candidate proposes a comprehensive interdisciplinary career development plan that will provide him with the skills and experience for his development into an independent clinical investigator. His co-mentors are NIH K24-funded senior investigators from the UPENN and VA, who have expertise in bone and joint health in varied chronic diseases. His multidisciplinary team includes additional NIH-funded leaders in biostatistics, epidemiology, bone metabolism, body composition, and rheumatic disease, each of whom is dedicated to a coordinated effort to ward the success of his career. He will draw on outstanding resources, including the VA Rheumatoid Arthritis national registry as well as the CTSA-supported Center for Clinical and Translational Research, and the Center for Clinical Epidemiology and Biostatistics at nearby UPENN. He will also complete additional formal didactic training in methods relevant to this proposal. The proposed project will build on his epidemiology training and prior research experience to promote his transition to independence. His long-term goals are to conduct clinical trials to improve body composition, bone health, and related outcomes in rheumatoid arthritis (RA). The study proposed here is the necessary first step to inform these trials. Osteoporotic fractures and joint damage account for significant morbidity in RA, resulting in billions of dollars in national costs.1 Recent studies suggest a greater prevalence and severity of arthritis in US veterans, compared with non-veterans.2 Furthermore, the VA identified arthritis, pain, obesity, and osteoporosis as priority conditions in women; each of these is addressed in this application. Low body weight has been associated with many adverse outcomes in RA, including fractures, joint damage, and death. However, the dynamic effect of the disease itself on BMI has not been characterized nor have the effects of altered body composition on RA outcomes. The long-term effects of this chronic inflammatory disease on body weight have not been clarified and may help explain these associations. Similarly, low BMI is associated with low lean mass. The applicant demonstrated that low lean mass and greater fat mass are associated with cortical thinning of bone among healthy adults. Given that 1) rheumatoid cachexia is characterized by reduced lean mass with normal or increased fat mass and 2) low lean mass is associated with thinning of cortical bone, loss of lean mass in RA likely contributes to the excess fracture risk in this population. The critical knowledge gaps are 1) whether associations between bone and BMI are related to confounding by long-term effects of disease and 2) to what extent altered lean and fat mass (rather than BMI) account for bone deficits. Taken further, the positive effects of lean mass on cortical bone may be important for prevention of invasion of inflammatory pannus, and integral to the health of overlying cartilage. Interventions to reverse lean mass deficits in RA could therefore have a valuable impact on disease outcomes through mechanical effects on cortical bone or production of muscle- derived factors. The applicant aims to 1) quantify alterations in bone structure and body composition in RA, compared with controls, and to evaluate associations with growth factors, cytokines and structural joint damage within RA participants at baseline, 2) identify baseline disease characteristics, physical function, serologic measures, and body composition measures associated with longitudinal deteriorations in ALM, bone density and structure, joint damage and disability over 2 years, and 3) To determine if lower disease activity is associated with greater increases in BMI, independent of glucocorticoid therapy in VARA participants.