Assessment, Therapy and Prevention Of Autoimmune Disease

自身免疫性疾病的评估、治疗和预防

• 批准号: 7734522
• 负责人: Frederick Miller
• 金额: $ 128.85万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/7734522
• 关键词: Adolescent; Adoption; Adult; Anti-Inflammatory Agents; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Caring; Cells; Characteristics; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Companions; Condition; Conduct Clinical Trials; Consensus; Cutaneous; Cutaneous Involvement; Dermatomyositis; Development; Disease; Disease Outcome; Double-Blind Method; Educational Materials; End Point; Enrollment; Environmental Risk Factor; Flare; Flow Cytometry; Future; Gene Expression; Goals; Guidelines; Heterogeneity; Idiopathic Inflammatory Myopathies; Image; Immune; Immune Targeting; Immunosuppression; Individual; International; Intervention; Investigation; Laboratory Research; Learning; Lesion; Licensing; Life; Lupus; Measurement; Measures; Mediating; Methods; Morbidity - disease rate; Muscle; Muscle function; Myositis; Numbers; Onset of illness; Outcome; Outcome Assessment; Outcome Measure; Pathogenesis; Patient Recruitments; Patients; Pattern; Peripheral; Play; Prevention therapy; Randomized; Randomized Controlled Clinical Trials; Refractory Disease; Rehabilitation therapy; Reporting; Research Personnel; Resistance; Risk; Risk Factors; Role; Safety; Score; Scoring Method; Site; Skin; Specialist; Standardization; Standards of Weights and Measures; Syndrome; Therapeutic; Therapeutic Agents; Therapeutic Studies; Therapeutic immunosuppression; Therapy Clinical Trials; Tissues; Ultraviolet Rays; Uncertainty; United States Food and Drug Administration; Validity and Reliability; Week; design; disease characteristic; disorder prevention; double-blind placebo controlled trial; drug efficacy; efficacy evaluation; experience; genetic risk factor; immunopathology; improved; infliximab; interest; member; molecular imaging; mortality; novel; novel therapeutics; peripheral blood; placebo controlled study; prevent; prospective; rituximab; skin disorder; success; tool; week trial

For this project we are now focusing on the idiopathic inflammatory myopathies (IIM), also known as the myositis syndromes, as prototypic autoimmune diseases from which principles learned in these disorders may be applied generally to other diseases. The myositis syndromes are associated with substantial lifelong morbidity and mortality. Their treatment is unsatisfactory in many cases and drug efficacy evaluation is hampered by the lack of reliable and standardized measures of disease outcome. No agents are currently licensed for the treatment of IIM and few have been studied in randomized controlled clinical trials. Because of the lack of consensus on how to best measure disease in the myositis syndromes, and to enhance recruitment of patients for other studies, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children. We have organized a collaborative group of over 150 adult and pediatric specialists with special interest in myositis, known as the International Myositis Assessment and Clinical Studies Group (IMACS) to assist in this project. The goals of IMACS are to standardize the conduct and reporting of clinical studies in all forms of IIM. Achieving these goals should enhance the consistency by which clinical trials are performed, improve the capacity to compare different treatments, and encourage development of promising novel therapeutic agents. Therapeutic studies of novel biologic agents are in progress and others are being planned to utilize these outcome measures in prospective trials. Together, and with input from the FDA, IMACS has: 1) developed and validated new tools to assess myositis disease activity and damage; 2) achieved consensus on core set outcome measures to comprehensively describe disease activity; 3) delineated preliminary definitions of improvement for use as clinical trial outcomes, which provide clinically meaningful change in combinations of the core set measures in a composite endpoint; and 4) developed international consensus guidelines on details of the conduct of multi-center therapeutic trials for adult and juvenile IIM. We have created a website to consolidate all IMACS activities, including member lists and contacts, educational materials, meeting presentations, references, assessment tools and ongoing and future collaborative initiatives and studies (https://dir-apps.niehs.nih.gov/imacs/). Clinical care and therapeutic trials in myositis require accurate and consistent assessment of cutaneous involvement. We designed a Cutaneous Assessment Tool (CAT) to measure both skin activity and damage lesions in IIM. The CAT has shown good inter-rater reliability and validity in various studies. We have demonstrated that the total CAT skin disease activity and damage scores have moderate to good reliability, and that assessors generally agree on the presence of a variety of cutaneous lesions. The CAT appears to be a promising tool to reliably and quantitatively assess skin disease activity and damage in IIM. This year we validated the CAT by demonstrating it had good internal consistency, little redundancy, good construct validity, and appropriate responsiveness. We also showed that the maximum and binary methods of scoring an abbreviated version of the CAT have measurement characteristics similar to the original method. Adoption of one of these abbreviated scoring methods should increase its acceptability to clinicians and researchers. Taken together, these studies demonstrate that the CAT is a comprehensive, semiquantitative assessment tool for skin disease in juvenile dermatomyositis. The therapy of myositis is focused on immunosuppression to minimize effects from immune activation and rehabilitation to improve remaining muscle function. Given the poor outcomes of myositis patients with standard therapy, novel biologic anti-inflammatory agents, which have been shown to be safe and effective for other immune-mediated diseases and have rationale for use in myositis, are reasonable candidates for study and may represent important advances in the treatment of myositis in the future. Our experience is that conducting therapeutic trials also greatly enhances recruitment to our epidemiologic investigations. We are participating as one site in the Rituximab in Myositis (RIM) trial which, is a multicenter, double-blind, placebo-controlled study that will assess the efficacy and safety of rituximab in 202 treatment-resistant dermatomyositis, polymyositis, and juvenile dermatomyositis patients. The RIM study provides us a unique opportunity to study a number of myositis features, including gene expression patterns and imaging profiles of refractory disease and how they respond to a targeted immune intervention. Identifying such molecular and imaging features may not only allow early recognition of patients requiring more aggressive treatment but could enhance our understanding of the pathogenesis of myositis and related autoimmune syndromes. The goals of this study are to define molecular and imaging characteristics of disease responsiveness to rituximab therapy and to better understand the role of B cells and their subsets in the pathogenesis of myositis. We are taking advantage of this trial to identify changes in gene expression patterns in muscle, skin and peripheral blood and the imaging features and immunopathology of muscle, skin and peripheral cells before (week 0) and after (week 16) therapy. These will also be correlated with the large number of clinical, laboratory and research variables already planned to be collected in the core RIM study. Furthermore, knowing specifically which gene expression patterns are altered in resistant patients before rituximab, and which are changed after rituximab therapy -- in conjunction with flow cytometry of peripheral cells and immunopathology of the tissues -- will help in understanding more about the pathogenesis of myositis and the possible contribution of B lymphocytes and their subsets. We are also collaborating with Paul Plotz in NIAMS on a randomized, double-blind, placebo-controlled trial of infliximab in myositis using the IMACS outcome criteria. We have completed enrollment in this study and are following the remainder of enrolled subjects to the end of the 40-week trial. The identification of environmental risk factors for autoimmune diseases offers the hope of preventing some of these disorders by exposure avoidance in genetically susceptible individuals. Investigations underway in our companion study - ES101074 DIR, Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease which is focused on identifying environmental risk factors for autoimmune conditions, may offer approaches to disease prevention. Exposures that are known to be important in inducing disease exacerbations in established disease may be triggers for disease onset as well. One example is our recent finding that ultraviolet radiation, known to induce exacerbations of lupus and dermatomyositis, likely plays an important role in the development of dermatomyositis and related autoantibodies. Studies to assess the efficacy of ultraviolet radiation avoidance in reducing dermatomyositis disease flares are now under consideration.

对于这个项目，我们现在专注于特发性炎症性肌病（IIM），也称为肌炎综合征，作为典型的自身免疫性疾病，从这些疾病中学习的原理可以普遍应用于其他疾病。肌炎综合征与大量的终生发病率和死亡率相关。在许多情况下，他们的治疗并不令人满意，由于缺乏可靠和标准化的疾病结果措施，药物疗效评估受到阻碍。目前还没有药物被许可用于治疗IIM，也很少有药物在随机对照临床试验中进行研究。

项目成果

Developing international consensus on measures of improvement for patients with myositis.

就肌炎患者的改善措施达成国际共识。

• DOI: 10.1177/0962280206070652
• 发表时间: 2007
• 期刊: Statistical methods in medical research
• 影响因子: 2.3
• 作者: Lachenbruch,PeterA;Miller,FrederickW;Rider,LisaG
• 通讯作者: Rider,LisaG

Autologous stem cell transplantation for pediatric rheumatic diseases.

自体干细胞移植治疗小儿风湿病。

• 发表时间: 2001
• 期刊: The Journal of rheumatology
• 作者: Barron,KS;Wallace,C;WoolfreyCEA;Laxer,RM;Hirsch,R;Horwitz,M;Siegel,J;Filipovich,L;Wulffraat,N;Passo,M;Rider,LG
• 通讯作者: Rider,LG

Neopterin and quinolinic acid are surrogate measures of disease activity in the juvenile idiopathic inflammatory myopathies.

• DOI: 10.1093/clinchem/48.10.1681
• 发表时间: 2002-09
• 期刊: Clinical chemistry
• 影响因子: 9.3
• 作者: L. Rider;Adam Schiffenbauer;M. Zito;K. L. Lim;A. Ahmed;L. Zemel;R. Rennebohm;M. Passo;R. Summers;J. Hicks;P. Lachenbruch;M. Heyes;F. Miller

Defining Clinical Improvement in Adult and Juvenile Myositis.

• 发表时间: 2003-03
• 期刊: The Journal of rheumatology
• 作者: L. Rider;E. Giannini;M. Harris-Love;G. Joe;D. Isenberg;C. Pilkington;P. Lachenbruch;F. Miller