Co-Chairs:
Stephen I. Katz, M.D., Ph.D., NIAMS
Susana A. Serrate-Sztein, M.D., NIAMS
Leslie J. Crofford, M.D., University of Kentucky

Introduction

The Arthritis and Rheumatic Diseases programs at the NIAMS cover basic, translational, and clinical research in a number of autoimmune and arthritis-related chronic disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, and ankylosing spondylitis (AS). The Institute is pursuing opportunities in genetics and genomics research, clinical trial design, pain, and biopsychosocial aspects of diseases in its portfolio. It also supports studies focused on the basic biology of autoimmunity and inflammation, to better understand the molecular mechanisms underlying these processes, with the goal of finding ways to interrupt them and improve patient outcomes.

The Arthritis and Rheumatic Diseases roundtable discussion expanded on the feedback compiled by its participants, as well as input that was submitted via a web-based Request for Comments. In particular, the panel focused on what they viewed to be the most promising areas of science.

Discussion

Mechanisms of Disease

Increased knowledge of autoimmunity and basic functioning of the immune system has opened new avenues of discovery, for understanding arthritis and rheumatic diseases, and developing targeted treatments. The identification of T cell subsets, such as regulatory T cells (Tregs) and T helper 17 cells (Th17), and specific cytokines associated with pathogenesis and inflammation (e.g., interferons, tumor necrosis factor, and interleukins 1, 6, 17, and 22), have already led to new therapies. Some of them are biologics, with high specificity for the targeted pathways and fewer side effects than the traditional, broadly immunosuppressive therapies. Further research and therapeutic development is expected to focus on these cytokine pathways, including a better understanding of fundamental mechanisms and more clinical trials in various disease populations.

Th17 cells have been found to preferentially express the arylhydrocarbon receptor, also known as the dioxin receptor. Its ligands can have diverse toxic effects, and it may be the link to environmental triggers of SLE and other autoimmune diseases. The plasticity of immune system components (such as the ability of Tregs to become Th17 cells, and, potentially, the reverse) shifts attention in disease pathogenesis and treatment from cellular and molecular targets to pathways, regulation, epigenomics, and system imbalances.

Research on the role of B cells and autoantibody production in rheumatic diseases has been important for exploring B cell-targeted therapies (e.g., B cell depletion). As well, autoantibodies are models for biomarker development; they can be used to identify disease subtypes, and track disease progression and response to therapy. There is new knowledge of the innate immune system's involvement in inflammatory diseases, particularly the inflammasome—a complex of proteins, intrinsic to the innate immune system's function, that drives a cascade of inflammatory cytokine activation. The role of the inflammasome and interactions between the innate and adaptive immune systems in rheumatic diseases are promising avenues for future research.

Further study of disease mechanisms and comorbidities will collectively inform both topics, and will also be important for evaluating drug safety. This is exemplified in the heart attack risk for RA patients who were taking Vioxx. The use of surrogate markers in clinical trials for potential or existing comorbidities, such as interleukin 6 (IL-6) or cholesterol, would be useful in efforts to detect, assess, and prevent adverse events.

Patient pain, which used to be referred to other medical specialties, is becoming a focus for the rheumatology community and integrated rheumatic disease management. Mechanisms of pain, and interactions between immune, nervous, endocrine, and musculoskeletal systems, are gaining attention in rheumatic diseases research. Discoveries in this field contribute to the emerging concept that acute pain leads to chronic pain via interactions between inflammatory pathways and the peripheral and central nervous systems, and development of central pain mechanisms. Further advances in understanding disease processes will rely on communications across multiple disciplines, which can be facilitated by workshops and conferences, and organized interactions within interdisciplinary research teams.

Genetics, Genomics, and Other 'Omics

Linkage association and genome-wide association studies (GWAS) have yielded important results for complex rheumatic disorders, such as RA, SLE, and AS, and have revealed genetic associations with other autoimmune diseases (e.g., multiple sclerosis, Crohn's disease) and comorbidities. The odds ratios (ORs) for individual single nucleotide polymorphisms (SNPs) from GWAS are frequently quite small; the collection of several gene variants appears to contribute to pathogenesis. At present, ORs from GWAS data are most useful for identification of pathogenic pathways and therapeutic targets, rather than genetic risk for disease.

Very large cohorts are needed for GWAS in order to see subtle genetic differences across patients' entire genomes, relative to control populations without the disease. Epigenomics, gene-environment interactions, chromatin structure, copy number variants, and microRNAs may have roles in disease risk and pathogenesis, and may be important contributors to comorbidities. As with genetics and genomics research, technological improvements and advances in statistical analysis will be important drivers for discoveries in these fields.

Assembling these sizeable study cohorts requires multi-institutional and, frequently, international collaborations, which yield additional population genetics factors such as:

• genetically-mixed populations in large, multi-ethnic countries;
• large ethnic populations (e.g., Koreans), for identification of common, population-associated variants;
• isolated, homogeneous populations (e.g., Iceland).

Long-term efforts with disease registries have borne fruit with recent GWAS discoveries. Continued advances in RA and SLE, and understanding of other conditions, will depend on well-organized, well-phenotyped cohorts, and collaborative efforts. Studying selected rare diseases can still be very informative. Hence, researchers stress the need to catalogue as many human genetic defects as possible, to understand complex diseases.

Future research will pursue gene targets identified from GWAS and genetic linkage information with functional/mechanistic studies, proteomics, and metabolomics, for further understanding of pathogenic pathways. As well, these approaches will feed translational research and the nascent field of pharmacogenetics, and may lead to tailored treatments according to disease subtypes and individual differences in drug metabolism and adverse reactions. Educating clinicians in basic science, statistics, and understanding relative risk will be important for harnessing genomic and associated functional biology information, and will contribute to improved design of translational research projects.

Clinical Trials

Continuous engagement of the community healthcare services and early contact with patient populations can enhance the conduct and the ultimate adoption of translational research results into clinical practice. The information can add efficiency to trial recruitment strategies, study design, and study completion. A focus on outcomes and discussion of healthcare goals with the community will have a longer lasting effect than pursuing a new technology or scientific concept.

Clinical trials are always challenged by attaining enrollment goals. Collaboration among multiple sites is usually required in conducting clinical trials, presenting several instructional opportunities. Lead investigators can acquire critical management skills, which are not usually part of medical education, and young investigators can receive formal training in the conduct of clinical trials, and become part of the cultural change towards collaborative research.

Academic medicine is slowly shifting credit (as in publication authorship) from individuals to research groups or networks, which enhances the potential for productive, collaborative efforts. The success of some multi-site clinical trials has been attributed to shared credit models, sustained involvement of experienced principal investigators, and establishment of networks. Many networks have been started with initial funds from NIAMS and other NIH institutes and centers, but their infrastructures (e.g., study personnel, biorepositories) are maintained through creative partnerships (with industry and non-U.S. networks) and management of consecutive or concurrent trials, with support from a variety of sponsors.

Biorepositories are valuable resources for genomic and gene expression data, and conduct of trial-associated mechanistic studies and longitudinal investigations of biomarkers. Biomarkers are viewed as vitally important for therapeutic development and evaluating treatment outcomes. For long-term value, standards in data quality, collection, storage, nomenclature, and phenotyping—with detailed annotation from medical records—must be followed. Challenges in data sharing, such as ownership and confidentiality, should be anticipated in the development of informed consent documents and network management.

Clinical trials in rare rheumatic diseases invite innovative design, use of active comparators, and heavy reliance on collaborations. Some of these approaches may be ripe for an RA prevention trial.

Regulatory requirements are frequently cited as barriers to clinical research, causing delays in trial initiation that can make experimental interventions obsolete by the time the studies are completed. Agreement between institutional review boards (IRBs) in multi-site trials would ease many of these difficulties. Successful models of central IRBs could lead the way for harmonization of IRB requirements, but use of them raises liability concerns for local institutions.

Biopsychosocial Research

Efforts to improve outcomes in rheumatic diseases are driving changes in disease management strategies that include individualized care. Personalized medicine considers patient preferences, lifestyle, and health disparities. Listening to patients is critical to understanding patient pain and patient goals, in contrast to compartmentalized clinical models in which rheumatologists transfer patients to musculoskeletal or pain specialists. However, physicians are challenged by time limitations on individual clinic visits and minimal training in psychology. Although early treatment of RA has been shown to have positive effects on outcomes, these interventions may not address patient concerns about side effects. Further research into disease risk assessment and prevention strategies that target earlier parts of disease pathways may yield improved outcomes.

Patient education is an important factor in disease management. Social science research contributes to the understanding of patient motivation in adoption of healthy behaviors and medication compliance, and cultural sensitivity to these efforts. It may also be applied to patient recruitment in clinical trials participation.

Rheumatic disease research may benefit from intervention models in other disorders. Heart disease, cancer, and depression are significant comorbidities with rheumatic diseases. Partnerships with the NIH Roadmap's Clinical and Translational Science Awards (CTSA) network, may provide novel approaches to these disorders, as well as access to existing cohorts. The diabetes medical community has been successful in motivating exercise and healthy behaviors. Prevention and management strategies developed around human immunodeficiency virus (HIV) infection are important examples for addressing risk behavior. In turn, further research in the life-long course of risk and behavioral factors, environmental exposures, and disease management in rheumatic diseases may be applicable to other chronic diseases.

Patient-reported outcomes (PRO) instruments, which have traditionally been used for disease-specific, quality of life (QOL) assessments, are very popular among patients. They are embraced by some physicians and parts of the clinical research community, but broad-scale educational efforts have been lacking. The NIH Roadmap's Patient-Reported Outcomes Measurement Information System (PROMIS) initiative is creating a psychometrically-robust PRO instrument to gather information on many health-related concerns, such as pain, fatigue, and physical functioning, across a wide range of disorders. This information will be used to classify symptoms, and assess changes over time and in response to treatment. The component questions of the PROMIS instrument undergo rigorous testing in culturally- and ethnically-diverse populations, with a particular focus on individual use of language to describe PROs.

Outcomes Research

Administrative (e.g., billing, pharmacy) databases can be used to evaluate outcomes in care and therapies, such as differences when specialists or behavioral interventions are involved, the emergence of health disparities among populations, and medication compliance.

New technologies may be adopted to improve patient care. A large, systems approach to disease modeling could lead to better clinical decision-making and more efficient clinical trial design. For example, analysis of an early intervention can evaluate cost effectiveness, potential toxicity versus prevention, and the QOL impact over time. History of inflammatory disease, environmental exposures, as well as disease-associated differences in pain tolerance, could be components of disease modeling, and would require multidisciplinary collaborations. Similar to systems biology approaches at a molecular level, current efforts are limited by the quality and amount of data, such as well-defined phenotypes, validated biomarkers, and the size of patient populations.

Non-NIH Participants

BEACH, George
Patient Advocate
Philadelphia, Pennsylvania

BINGHAM, Clifton O., III, M.D.
Assistant Professor, Department of Medicine
Division of Rheumatology
Director, Johns Hopkins Rheumatology Clinics and Johns Hopkins Arthritis Website
The Johns Hopkins University School of Medicine

BOACKLE, Susan A., M.D.
Associate Professor, Departments of Medicine and Integrated Immunology
Division of Rheumatology
University of Colorado Health Sciences Center

BORENSTEIN, David G., M.D.
Clinical Professor, Department of Medicine
The George Washington University Medical Center
Arthritis and Rheumatism Associates

CROFFORD, Leslie J., M.D. (Co-chair)
Gloria W. Singletary Professor
Department of Internal Medicine
Chief, Division of Rheumatology
University of Kentucky

KATZ, Jeffrey, M.D., M.S.
Associate Professor, Departments of Medicine and Orthopedic Surgery
Brigham and Women's Hospital

MAMULA, Mark, Ph.D.
Professor, Department of Internal Medicine
Section of Rheumatology
Yale University School of Medicine

MERKEL, Peter, M.D., Ph.D., M.P.H.
Professor, Department of Medicine
Section of Rheumatology and the Clinical Epidemiology Unit
Director, Vasculitis Center
Boston University School of Medicine

RAMSEY-GOLDMAN, Rosalind, M.D., Dr.PH.
Professor, Department of Medicine
Division of Rheumatology
Feinberg School of Medicine
Northwestern University

SALMON, Jane, M.D.
Professor, Department of Medicine
Weill Medical College of Cornell University
Collette Kean Research Chair
Co-Director Kirkland Center for Lupus Research
Hospital for Special Surgery

SANDBORG, Christy, M.D.
Professor and Associate Chair, Department of Pediatrics
Chief, Division of Pediatric Rheumatology
Lucile Salter Packard Children's Hospital
Stanford University School of Medicine

ST. CLAIR, E. William, M.D.
Professor, Department of Medicine
Division of Rheumatology and Immunology
Duke University