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

描述(由申请人提供)： 应聘者是风湿学的初级研究员，在临床流行病学方面接受过高级培训，专注于以患者为中心的慢性风湿病研究。他在费城退伍军人管理局有很长的临床工作历史，最近被任命为临床教员。在整个训练过程中，他一直致力于照顾退伍军人，并建议在退伍军人管理局发展自己的职业生涯。候选人提出了一个全面的跨学科职业发展计划，将为他提供技能和经验，使他发展成为一名独立的临床研究员。他的联合导师是来自宾夕法尼亚大学和弗吉尼亚州的NIH K24资助的高级调查人员，他们在各种慢性病的骨骼和关节健康方面拥有专业知识。他的多学科团队包括NIH资助的生物统计学、流行病学、骨代谢、身体成分和风湿病方面的其他领导人，每个人都致力于协调努力，以期取得事业上的成功。他将利用杰出的资源，包括退伍军人事务部类风湿性关节炎国家登记以及CTSA支持的临床和翻译研究中心，以及附近宾夕法尼亚大学的临床流行病学和生物统计中心。他还将完成与这项提议相关的方法方面的额外正式教学培训。拟议的项目将以他的流行病学培训和以前的研究经验为基础，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RA发病率很高的原因，导致国家花费数十亿美元。1最近的研究表明，与非退伍军人相比，美国退伍军人的关节炎患病率和严重性更高。2此外，退伍军人管理局将关节炎、疼痛、肥胖和骨质疏松症确定为 妇女；每个问题都在本申请中涉及。低体重与RA的许多不良后果有关，包括骨折、关节损伤和死亡。然而，疾病本身对BMI的动态影响还没有被表征，身体成分改变对RA预后的影响也没有被表征。这种慢性炎症性疾病对体重的长期影响尚不清楚，可能有助于解释这些联系。同样，低BMI与低瘦身质量有关。申请者证明，在健康成年人中，低瘦体重和较大脂肪质量与骨皮质变薄有关。鉴于1)类风湿性恶病质的特征是瘦质量减少，脂肪质量正常或增加，以及2)低瘦质量与皮质骨变薄相关，类风湿关节炎瘦质量的丧失可能是该人群过度骨折风险的原因之一。关键的知识差距是1)骨骼和BMI之间的联系是否与疾病的长期影响造成的混淆有关，2)瘦肉和脂肪质量(而不是BMI)的变化在多大程度上解释了骨骼缺陷。进一步说，瘦质量对皮质骨的积极影响可能是重要的，对于防止炎性血管膜的侵袭，以及对覆盖软骨的健康是不可或缺的。因此，通过对皮质骨的机械作用或产生肌源性因子，逆转类风湿性关节炎瘦体重不足的干预措施可能会对疾病结局产生有价值的影响。申请者的目标是：1)与对照组相比，量化类风湿性关节炎患者骨结构和身体成分的变化，并评估与基线水平的类风湿性关节炎参与者中的生长因子、细胞因子和结构性关节损伤的相关性；2)确定与ALM、骨密度和结构、关节损伤和残疾的纵向恶化相关的基线疾病特征、身体功能、血清学测量和身体成分测量；以及3)确定疾病活动性较低是否与非糖皮质激素治疗的VARA参与者的BMI增加更大有关。

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.