In September 2014, the participating members of the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus (AMP RA/Lupus) Program funded a research Network to implement the program. The Network comprises a Leadership Center and several research sites that will work collaboratively to define shared and disease-specific biological pathways in order to identify relevant drug targets for the treatment of RA, lupus, and related autoimmune diseases.
The AMP RA/Lupus Network Leadership Center, led by Paul J. Utz, M.D., at Stanford University and V. Michael Holers, M.D., at the University of Colorado, will organize all aspects of the AMP Network and serve as the main interface between the Network research sites, NIH, and other sponsors. It will draw on the strengths of each of the participating investigators—leading scientists with overlapping expertise in basic, clinical, and translational research—to achieve the program goals. The Leadership Center includes two subcomponents—a Leadership Center Research, Coordination, Management and Statistics Program that will provide resources and expertise to support the design, conduct, analysis, and reporting of clinical studies, and a Tissue Acquisition Research Group that will assist with the procurement, processing, and distribution of biological samples.
The RA/Lupus Network includes clinical research sites, technology research sites, and sites that combine the two aspects. Clinical research sites will primarily assemble patient cohorts and obtain comprehensive clinical and laboratory data and relevant specimens. Some also include access to analytic facilities, which may be particularly useful as the network develops protocols and approaches. Technology research sites will develop, test, standardize, and validate advanced and new technologies to identify critical signaling pathways in cells and tissues. Combined sites will conduct both clinical and technology development activities. Rather than conducting independent projects, the sites will work collaboratively through the Network Leadership Committee to define shared research goals.
Additional information about each research site is provided below. Each of these brings unique capabilities to the network: which of these will be utilized will be determined collectively by the Leadership Committee based on the needs of the Network.
Clinical Research Site, led by Jennifer H. Anolik, M.D., Ph.D., University of Rochester
An approved protocol is in place to obtain synovial tissue in RA. This can be used to apply advanced histomorphometric and transcriptome analytics to define the microscopic structure and function of and interactions between tissues and cells affected by RA, including immune cells (B cells and T cells) and rarely studied tissues, such as synovium, subchondral bone, and bone marrow. The approach of characterizing both the location and function of key cell populations in affected joints will contribute to Network efforts to improve understanding of mechanisms of tissue damage in RA.
Technology Research Site, led by Michael B. Brenner, M.D., Soumya Raychaudhuri, M.D., Ph.D., Brigham and Women's Hospital
The site will conduct high-level bioinformatics and computational analyses for the AMP. When appropriate, it will develop new methodologies to analyze AMP data. It will also develop and apply cutting-edge systems biology approaches to improve understanding of autoimmune diseases. The systems level analyses will bolster Network efforts to develop a multi-dimensional model of the numerous biological and environmental factors involved in lupus and RA.
Combined Clinical and Technology Research Site, led by Jill P. Buyon, M.D., New York University School of Medicine, Chaim Putterman, M.D., Albert Einstein College of Medicine, and Thomas Tuschl, Ph.D., Rockefeller University
The site will study kidney inflammation (nephritis) in lupus. The site will leverage the Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium cohort to investigate the effects of race and ethnicity on specific biological pathways and potential drug targets. It will enable studies to understand the biological processes that contribute to endothelial (blood vessel) cell abnormalities in lupus patients. The site will bring expertise in coding and non-coding RNA sequencing (RNA-seq) analysis that can be used to identify unique patterns of RNA expression in tissues from lupus patients. It will provide nonlesional (normal) skin samples from lupus nephritis patients, which will facilitate Network efforts to predict kidney disease less invasively and at an earlier stage than is now possible.
Clinical Research Site, led by Vivian Bykerk, M.D., Lionel B. Ivashkiv, M.D., and Alessandra B. Pernis, M.D., Hospital for Special Surgery (HSS); and Robert B. Darnell, M.D., Ph.D. New York Genome Center
The site will facilitate research in RA. The site will leverage unique cohorts of RA patients and a well-integrated multidisciplinary team of clinicians and scientists at the HSS, the New York Genome Center, and Mount Sinai Hospital at the University of Toronto to obtain paired samples of peripheral blood and synovial tissues from RA and control patients undergoing surgical procedures. The site will contribute to Network efforts to identify molecular processes that distinguish patients who experience worsening of disease (flares) from those who do not, and RA patients who respond to specific drugs from those who do not.
Combined Clinical and Technology Research Site, led by Betty A. Diamond, M.D., Feinstein Institute for Medical Research, and David Wofsy, M.D., at the University of California, San Francisco
The site focuses on lupus nephritis. The site will work with the recently established Lupus Nephritis Trials Network, a large, multi-disciplinary organization of lupus clinicians and researchers, to facilitate patient enrollment and characterization and collection of biological samples. It will employ new methods, such as kidney microdissection and dissociation, to acquire kidney tissue. It also will conduct a pilot study of cell distance mapping to investigate interactions between cells and tissues. Other cutting edge technologies that this site will employ include RNA-seq and Assay for Transposase-Accessible Chromatin Sequencing (ATAC-seq), immunophenotyping, and mass cytometry (CyTOF).
Clinical Research Site, led by Peter K. Gregersen, M.D., Feinstein Institute for Medical Research
The site will focus on RA. Collaborating investigators have experience in performing synovial biopsies. Other researchers at this site have expertise in the use of several cutting-edge technologies, including single cell RNA sequencing of synovial tissue cells, epigenetic studies using ATAC-Seq, CyTOF for multi-dimensional analysis of cellular phenotypes, and RNA-seq analysis. This site will include researchers in the European Union who will contribute unique analytic capabilities and tissue samples.
Combined Clinical and Technology Research Site, led by V. Michael Holers, M.D., University of Colorado
The site will enable the Network to study the evolution of cellular and molecular changes that occur as RA progresses from an early asymptomatic phase to an established late-stage chronic disease. To develop expertise in ultrasound-guided synovial biopsy techniques, the site will also develop a "hands-on" procedural education and evaluation program to train U.S.-based investigators in the technique. The site will bolster Network efforts to understand disease development, enable early intervention, and identify therapeutic targets.
Clinical Research Site, led by Larry W. Moreland, M.D., University of Pittsburgh
The site will facilitate research on RA. Researchers working with this site have a wealth of experience in recruiting patients for clinical registries and studies with accompanying sample storage. This site will leverage a large cohort of RA patients under the care of a single network of rheumatologists located in Pittsburgh. Around one-quarter of the cohort is already enrolled in an active, NIH-funded research registry through which clinical disease activity, labs, and blood are collected. The site will facilitate initial validation and optimization of methods for tissue acquisition.
Clinical research site, led by Michelle A. Petri, M.D., M.P.H., at Johns Hopkins University
The site will bolster Network efforts to understand kidney inflammation in lupus. It will work with the Hopkins Lupus Cohort, a large, ethnically diverse and well-characterized cohort of lupus patients to obtain specimens and patient data. The site also will add clinical and epidemiologic expertise to the Network. The site also is expected to provide samples from individuals with osteoarthritis, gout, or other autoimmune diseases to facilitate comparisons between lupus and other conditions.
Technology Research Site, led by William H. Robinson, M.D., Ph.D., and Paul J. Utz, M.D., Stanford University
The site will identify—at the single cell level—genes, proteins, and pathways that are abnormal in lupus and RA. It will use cutting-edge technologies, including single cell RNA sequencing, ATAC-seq, and CyTOF. Advanced technologies such as Antibody Repertoire Capture and T cell receptor Repertoire Sequencing and Epitope Discovery will be used to study immune cells (B and T cells) in blood and tissues.