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Overview

The Accelerating Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) launched in 2014 as one of the original components of the Accelerating Medicines Partnership (AMP). AMP RA/SLE, which was managed by the Foundation for the NIH, relies on a nationwide Network of research teams that work collaboratively to deepen our understanding of autoimmune diseases through a focus on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Funding came from NIAMS and the National Institute of Allergy and Infectious Diseases (NIAID), together with industry partners and non-profit organizations. The overall goal of the program is to identify relevant drug targets for treating autoimmune diseases.

Approach

The AMP RA/SLE program uses a molecular- and cellular-level approach (“disease deconstruction”) to uncover the biological pathways that play a role in RA and/or SLE. AMP RA/SLE investigators conducted more than 100 synovial biopsies in RA and more than 200 renal biopsies in SLE. From the biopsy tissues, the researchers characterized the protein, mRNA, and open chromatin sequences in thousands of single cells. By analyzing other tissues (blood, urine, skin) from the same patients, the investigators discovered new cell populations and states, and identified disease biomarkers. Subsequent follow-up of patients will further enhance our understanding of the course of these diseases.

To ensure standardization of procedures, the individual Network projects are proceeding according to the Research Phases shown below. Research Phase 0 and Phase I are complete, and Phase II studies are underway.

Image depicting the AMP RA/SLE Program Research Phases zero, one and two

Research Phase 0

Highlights of the Network’s Phase 0 work include the following:

  • Established Network infrastructure for communications and decision-making, as well as policies to allow for timely sharing of data.
  • Tested different means of obtaining and prepping tissue and, based on the results, developed standard operating procedures for preparation of synovial (joint) tissue for RA projects and kidney tissue for SLE projects.
  • Tested and validated cutting-edge technologies, such as CyTOF (Cytometry by Time of Flight) and RNA-seq (RNA sequencing), in synovial and kidney tissues.
  • Developed proposals for pilot projects to explore other emerging technologies and additional types of biological specimens.
  • Established clinical protocols and procedures for Phase I studies.
  • Established systems for data management and analysis, including databases for clinical data and biospecimen tracking, and storage of experimental data.

The Phase 0 standard operating procedures that were developed by the Network allow cross-tissue comparisons that would not otherwise be possible. These procedures are anticipated to be widely applicable to studies of human disease tissues and, already, the AMP RA/SLE initiative is serving as a demonstration of state-of-the-art analysis of human disease tissues.

X-ray image depicting joint damage from rheumatoid arthritis
A horizontal X-ray image depicting joint damage from rheumatoid arthritis. (Photographer: Camazine Scott)

Research Phase I

In Phase I, the Network used the standardized technologies established in Phase 0 to analyze samples from patients with RA and SLE. Research Phase I also included analysis of samples from individuals without RA or SLE, using a systems biology approach to identify pathways that distinguish disease and non-disease tissue. For example:

  • SLE Phase I study: The Network conducted a multi-center study in SLE patients with active renal disease requiring biopsy. Researchers compared the RNA-seq signature of kidney biopsies from SLE patients and living donors (controls). They also performed single-cell RNA-seq on paired urine and skin samples from SLE patients, and used CyTOF to analyze paired blood from SLE patients and control participants.
  • RA Phase I study: The Network conducted a multi-center study in RA patients and a comparison group of osteoarthritis (OA) patients. The RA researchers also established a program in the United States to obtain synovial biopsies using minimally invasive ultrasound-guided technology to enhance capacity for tissue acquisition for the AMP RA projects. The Phase I study compared RNA-seq and CyTOF signatures of RA and OA arthroplasties and biopsies. In addition, paired blood samples were analyzed by CyTOF.
  • The Network successfully completed sample accrual for Phase I studies in RA and SLE.
  • Investigators demonstrated the feasibility of the AMP methods for tissue and cell collection and processing, as well as for data analysis. Researchers are able to distinguish disease and control tissues using various technologies, and identify cell populations in tissue samples that may be relevant to pathological processes.

Progress was discussed at the NIAMS Advisory Council meeting on June 21, 2017. (The Council meeting can be viewed here. The AMP presentation begins at 03:08:28.) The Phase I results informed the feasibility and design of larger studies during Phase II.

Research Phase II

Phase II studies are being conducted with a larger number of patients. To improve understanding of disease variability, subgroups of patients are being compared within a disease. For example, people with recently diagnosed RA are being compared to those with established RA. Phase II studies include:

  • RA Phase II study: Prospective multi-center longitudinal study, using biopsies and arthroplasty tissue, of RA patients across the spectrum of disease from disease-modifying anti-rheumatic drug (DMARD)-naïve to end-stage disease.
  • SLE Phase II study: Prospective multi-center longitudinal study of SLE patients with active renal disease who require a biopsy.
  • Researchers continue to improve tissue processing, analytic methods and imaging technologies.

Links to Program Data & Results

Phase I data are available at:

dbGaP

ImmPort:

  • SDY997 - AMP Lupus Network Project: Molecular Characterization of Lupus Nephritis and Correlation with Response to Therapy
  • SDY998> - AMP Rheumatoid Arthritis Phase 1
  • SDY1299 - Identification of Three Rheumatoid Arthritis Disease Subtypes By Machine Learning Integration of Synovial Histologic Features and RNA Sequencing Data

Major AMP RA/SLE Program Publications

The immune cell landscape in kidneys of patients with lupus nephritis. Arazi A, Rao DA, Berthier CC, Davidson A, Liu Y, Hoover PJ, Chicoine A, Eisenhaure TM, Jonsson AH, Li S, Lieb DJ, Zhang F, Slowikowski K, Browne EP, Noma A, Sutherby D, Steelman S, Smilek DE, Tosta P, Apruzzese W, Massarotti E, Dall'Era M, Park M, Kamen DL, Furie RA, Payan-Schober F, Pendergraft WF 3rd, McInnis EA, Buyon JP, Petri MA, Putterman C, Kalunian KC, Woodle ES, Lederer JA, Hildeman DA, Nusbaum C, Raychaudhuri S, Kretzler M, Anolik JH, Brenner MB, Wofsy D, Hacohen N, Diamond B; Accelerating Medicines Partnership in SLE network. Nat Immunol. 2019 Jul;20(7):902-914. doi: 10.1038/s41590-019-0398-x. Epub 2019 Jun 17. Erratum in: Nat Immunol. 2019 Aug 13;: PMID: 31209404; PMCID: PMC6726437.

Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Der E, Suryawanshi H, Morozov P, Kustagi M, Goilav B, Ranabothu S, Izmirly P, Clancy R, Belmont HM, Koenigsberg M, Mokrzycki M, Rominieki H, Graham JA, Rocca JP, Bornkamp N, Jordan N, Schulte E, Wu M, Pullman J, Slowikowski K, Raychaudhuri S, Guthridge J, James J, Buyon J, Tuschl T, Putterman C; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium.  Nat Immunol. 2019 Jul;20(7):915-927. doi: 10.1038/s41590-019-0386-1. Epub 2019 May 20. Erratum in: Nat Immunol. 2019 Nov;20(11):1556. PMID: 31110316; PMCID: PMC6584054.

Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, Goodman SM, Tabechian D, Hughes LB, Salomon-Escoto K, Watts GFM, Jonsson AH, Rangel-Moreno J, Meednu N, Rozo C, Apruzzese W, Eisenhaure TM, Lieb DJ, Boyle DL, Mandelin AM 2nd; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Boyce BF, DiCarlo E, Gravallese EM, Gregersen PK, Moreland L, Firestein GS, Hacohen N, Nusbaum C, Lederer JA, Perlman H, Pitzalis C, Filer A, Holers VM, Bykerk VP, Donlin LT, Anolik JH, Brenner MB, Raychaudhuri S. Nat Immunol. 2019 Jul;20(7):928-942. doi: 10.1038/s41590-019-0378-1. Epub 2019 May 6. PMID: 31061532; PMCID: PMC6602051.

Funding Opportunity Announcements [now expired] and Funded Projects

Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus: Network Leadership Center (UM2) RFA-AR-14-015

AMP RA/SLE Leadership Center,
PI(s): Paul J. Utz, M.D., Stanford University, and V. Michael Holers, M.D., University of Colorado

Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus: Network Research Sites (UH2/UH3) RFA-AR-14-016

Cellular Dynamics at the Synovium-Bone interface in RA,
PI(s): Jennifer H. Anolik, M.D., Ph.D., University of Rochester

Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium,
PI(s): 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

Molecular Pathways in Treatment Response and Flare in RA,
PI(s): Vivian Bykerk, M.D., Lionel B. Ivashkiv, M.D., and Alessandra B. Pernis, M.D., Hospital for Special Surgery; and Robert B. Darnell, M.D., Ph.D., New York Genome Center

PEARL: Pathway Exploration and Analysis in Renal Lupus,
PI(s):  Betty A. Diamond, M.D., Feinstein Institute for Medical Research, and David Wofsy, M.D., University of California, San Francisco

Molecular and Cellular Dissection of Early Rheumatoid Arthritis,
PI(s): Peter K. Gregersen, M.D., Feinstein Institute for Medical Research, and Michael B. Brenner, M.D., Brigham and Women's Hospital

Evolving Adaptive and Effector Mechanisms from Pre-RA Through Established Disease,
PI(s): V. Michael Holers, M.D., University of Colorado

UPITT Rheumatoid Arthritis Combined Center (UPITT RACC,
PI(s): Larry W. Moreland, M.D., and Mandy J. McGeachy, Ph.D. University of Pittsburgh

Accelerating Medicines Partnership in RA and Lupus: Network Sites (UH2/UH3),
PI(s): Michelle A. Petri, M.D., M.P.H., Johns Hopkins University

RA-SLE Molecular Deconstruction Leadership Center,
PI(s): Soumya Raychaudhuri, M.D., Ph.D., and Michael B. Brenner, M.D., Brigham and Women's Hospital

Stanford Technology Accelerating Medicines Partnership Center,
PI(s): William H. Robinson, M.D., Ph.D., and Paul J. Utz, M.D., Stanford University

Related Information

AMP RA/SLE News

Accelerating Medicines Partnership and AMP are registered service marks of the U.S. Department of Health and Human Services.

Last Updated: February 2022