RECENTLY LAUNCHED! – The Arthritis and Autoimmune and Related Diseases Knowledge (ARK) Portal

The ARK Portal is a virtual resource that accumulates, organizes, and links core datasets generated by research teams focused on arthritis, skin, autoimmune, and related diseases. Directed by NIAMS and developed and maintained by Sage Bionetworks, the ARK Portal will house a broad and diverse portfolio of datasets – the first of which will come from the Accelerated Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE). The ARK Portal will host all data and analytical tools generated by the AMP RA/SLE research teams, which will be added on a rolling basis as quality control is completed. Datasets from other research programs with a focus on arthritis, skin, autoimmune, and related diseases will also be added in the future.

Access to the datasets on the portal is free to the public; however, some datasets will require users to register and agree to a data-use agreement.

Explore data in the ARK Portal.

Overview

The Accelerating Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) program 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, relied on a nationwide network of research teams that worked 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 was to identify relevant drug targets for treating autoimmune diseases.

About Rheumatoid Arthritis and Lupus

Rheumatoid arthritis (RA) and lupus are relatively common, severe autoimmune disorders. About 1.3 million people or about 0.6 percent of the U.S. adult population have rheumatoid arthritis. Estimating how many people in the U.S. have lupus is difficult because symptoms vary widely and onset is often hard to pinpoint. Both conditions are autoimmune diseases that occur when the immune system mistakenly attacks parts of the body that it is designed to protect. They represent just two of a larger number of autoimmune disorders, including multiple sclerosis, Crohn’s disease, ulcerative colitis, type 1 diabetes, and psoriasis. These diseases share common flaws in immune function and regulation, leading to inflammation that destroys tissues. They can last a lifetime, cause severe disability, greatly affect quality of life, and are associated with increased risk of death.

Need for New Therapies

Treatments for these diseases typically aim to decrease inflammation and pain by slowing down tissue damage and reducing complications. Most people with RA have only a partial response to available drugs, and many only respond to drugs for a limited period of time. 

In the case of lupus, no effective targeted therapies exist for the most severe forms of the disease. Research is needed to better understand the underlying disease process and identify parts of the immune system that aren't functioning correctly. This insight will help reveal the most promising new biological targets for drug development and match existing drugs to patients with specific molecular profiles who are most likely to benefit.

Approach

The AMP RA/SLE program used 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 (joint) 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. 

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

Governance

The steering committee (SC) for RA and lupus is comprised of representatives from NIH, FNIH, and participating companies and non-profit organizations. The SC operates under the direction of the overall AMP Executive Committee comprised of representatives from NIH, FNIH, participating companies, the U.S. Food and Drug Administration, and non-profit organizations.

Funded Projects

PI NameAwardee OrganizationProject Title

Paul J. Utz and V. Michael Holers

Stanford UniversityAMP RA/SLE Leadership Center

Jennifer H. Anolik

University of RochesterCellular Dynamics at the Synovium-Bone Interface in RA

Jill Buyon; Chaim Putterman; Thomas Tuschl

New York University School of MedicineMulti-Ethnic Translational Research Optimization (METRO) Lupus Consortium

Vivian Bykerk; Lionel B. Ivashkiv; Alessandra B. Pernis; Robert B. Darnell

Hospital for Special SurgeryMolecular Pathways in Treatment Response and Flare in RA
Betty A. Diamond and David WofsyFeinstein Institute for Medical ResearchPEARL: Pathway Exploration and Analysis in Renal Lupus
Peter K. Gregersen and Michael B. BrennerFeinstein Institute for Medical ResearchMolecular and Cellular Dissection of Early Rheumatoid Arthritis
Michael HolersUniversity of Colorado, DenverEvolving Adaptive and Effector Mechanisms from Pre-RA Through Established Disease
Larry W. Moreland and Mandy J. McGeachyUniversity of Pittsburgh at PittsburghUPITT Rheumatoid Arthritis Combined Center (UPITT RACC)
Michelle A. PetriJohns Hopkins UniversityAccelerating Medicines Partnership in RA and Lupus: Network Sites (UH2/UH3)
Soumya Raychaudhuri and Michael B. BrennerBrigham and Women’s HospitalRA-SLE Molecular Deconstruction Leadership Center
William H. Robinson and Paul J. UtzStanford UniversityStanford Technology Accelerating Medicines Partnership Center

Project Structure

The steering committee (SC) for RA and lupus is comprised of representatives from NIH, FNIH, and participating companies and non-profit organizations. The SC operates under the direction of the overall AMP Executive Committee comprised of representatives from NIH, FNIH, participating companies, the U.S. Food and Drug Administration, and non-profit organizations.

The steering committee (SC) for RA and lupus is comprised of representatives from NIH, FNIH, and participating companies and non-profit organizations. The SC operates under the direction of the overall AMP Executive Committee comprised of representatives from NIH, FNIH, participating companies, the U.S. Food and Drug Administration, and non-profit organizations.

The steering committee (SC) for RA and lupus is comprised of representatives from NIH, FNIH, and participating companies and non-profit organizations. The SC operates under the direction of the overall AMP Executive Committee comprised of representatives from NIH, FNIH, participating companies, the U.S. Food and Drug Administration, and non-profit organizations.

Image
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 allowed cross-tissue comparisons that would not otherwise have been possible. These procedures are anticipated to be widely applicable to studies of human disease tissues. The AMP RA/SLE initiative demonstrated state-of-the-art analysis of human disease tissues.

Image
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

The Arthritis and Autoimmune and Related Diseases Knowledge Portal

  • The ARK Portal will house a broad and diverse portfolio of datasets including those from the Accelerated Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE).

Budget: 6 Years ($52.9 Million Total Project Funding)

Disease area

Total NIH funding ($M)

Total Industry funding ($M)

Total non-profit funding ($M)

Total project funding ($M)

Rheumatoid Arthritis and Lupus

24.9

27.1

1.2

53.2

 

 

 

 

 

 

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.

AMP RA/SLE Partners

Government:

  • NIH

Industry:

  • AbbVie
  • Bristol-Myers Squibb
  • GlaxoSmithKline
  • Janssen
  • Merck
  • Pfizer
  • Sanofi
  • Takeda

Non-Profit Organizations

  • Arthritis Foundation
  • Foundation for the NIH
  • Lupus Foundation of America
  • Lupus Research Alliance
  • Rheumatology Research Foundation

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.

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