Delivering on the Promise
in
Rheumatoid Arthritis
Did You Know?
- Rheumatoid arthritis (RA) affects 2.1 million Americans,
including 1.5 million women.
- RA is characterized by chronic inflammation that begins in
the lining of joints, causing pain, stiffness, redness and swelling.
- RA can cause permanent joint damage with joint deformities
and loss of function.
- Mortality rates for people with RA are double that of the
general population.
- Medical costs and indirect expenses due to lost wages for RA
are estimated at over $3 billion annually.
- Less than 50 percent of working age adults with RA are still
employed 10 years after disease onset.
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Research Progress
While RA remains a complex disease and much remains to be
learned about how to prevent and cure it, research is yielding many insights:
Causes
It is now believed that multiple genetic and environmental factors interact to trigger the
onset of RA. Much progress has been made in the identification of genetic factors that
appear to increase one's risk for getting RA and that are associated with more severe
disease. Epidemiologic studies are helping to clarify the role of various environmental
factors, including infectious agents, reproductive status, smoking and coffee
intake.
Autoimmunity and Inflammation
What happens in RA can be described in terms of two inter-related, complex processes: (1)
a malfunctioning of the body's immune system, and (2) chronic inflammation within the
joint which can lead to destruction of joint cartilage and bone.
In RA, the body's immune system mounts an attack on joint tissues, in particular the
membrane lining of the joint called the synovium. Damage to the cartilage and bone in the
joint is caused by the accumulation of inflammatory cells and new blood vessel growth
(called angiogenesis) in the joint space.
Researchers have identified many different components of the immune system and steps in
inflammation, including immune cells called T- and B-lymphocytes, messenger molecules of
the immune system called cytokines such as tumor necrosis factor (TNF) and interleukin-1
(IL-1), and different proteins such as adhesion molecules, complement, chemo-kines and
various growth factors - many of which are now being studied as the targets of new
therapies.
Delivering on the Promise in
Rheumatoid Arthritis
New Therapies
Advances in basic research have led to a greater
understanding of the relevant genes, cells and molecules involved in RA, which has
dramatically increased the pipeline of different therapeutic options. Significant
breakthroughs have already occurred in the development of biologic response modifiers, a
new class of drugs that specifically block cytokines that may be harmful if present in
excess.
Commercially available biologic agents that inhibit the
cytokines, TNF and IL-1, have been shown in clinical trials to reduce joint inflammation
and damage in RA. Other TNF inhibitors may be available soon, including a fully humanized
and a longer-acting version. Biologics that target other cytokines, such as IL-6 and IL-8,
are in clinical trials. Several other approaches to therapy are showing promising results
in either animal models or early clinical trials:
- One novel approach to therapy focuses on the early stages of
the immune response. The discovery that only certain types of T cells behave abnormally in
RA has led to the development and testing of agents that block only those T cells involved
in autoimmune disease, including a drug in clinical trials called keliximab. Also under
study are many so-called "next generation biologics," including co-stimulatory
blockers that in-hibit receptors like CD 40, blocking the initial signaling and chain of
chemical reactions that turns on the immune system.
- Under development and testing are therapies that block blood
vessel formation, inhibit the migration of inflammatory cells into the joint tissues, or
prevent cartilage and bone destruction. Many of these therapies are small molecules that
can be taken as pills instead of injections and would be less expensive and more
convenient to take.
- Small clinical trials of gene therapy to interfere with the
cytokine IL-1 have also shown promising results.
- Combination therapy (for example, use of disease- modifying
drugs like methotrexate or leflunomide with a biologic agent) has also been shown to be
highly effective while causing minimal side effects, and early trials of combination TNF
and IL-1 biologic therapy appears to have promise.
Quality of Life Advances
While the search for better treatments and a cure
continues, other researchers are focusing on helping to improve the quality of life of
people with RA through studies that have provided insights about how to help people with
RA cope with their pain and depression and remain as functional as possible. Researchers
have also made advances in reconstructive surgery, including new techniques and materials
to reduce the failure rate of artificial joints.
Making a Difference
Arthritis Foundation-funded research is improving the lives
of people with RA by:
- Increasing our understanding of the role of ge- netic and
environmental factors in the develop- ment of RA;
- Identifying how immune cells and inflammatory molecules
contribute to joint damage and testing new therapies to block their effects; and
- Evaluating exercise and coping interventions to help people
with RA reduce their pain and im- prove their function.
The Arthritis Foundation is currently funding 107 studies
focused on RA, representing a total commitment of nearly $19 million. The following
sections highlight some of the current cutting-edge research activities.
Genetics and Environmental Triggers
Researchers funded by the Arthritis Foundation are using
different approaches to try to pinpoint the causes of RA:
- The North American Rheumatoid Arthritis Consortium (NARAC)
is a collaborative multi-center study funded by the National Institutes of Health (NIH)
and the Arthritis Foundation to learn more about the genes associated with RA by studying
families with more than one member affected by RA. The study is led by Peter Gregersen,
MD, at the North Shore University Hospital, Manhasset, N.Y.
- Employing a research technique called a meta-analysis, Jennifer
Gorman, MD, at the University of California in San Francisco, will attempt to clarify
the role of a set of genes that share a common sequence of amino acids, or "shared
epitope." This study could provide the basis for genetic testing to be used in
diagnosis of RA or testing to predict disease severity, allowing doctors to select how
aggressively to treat the disease.
- Michael Maldonado, MD, and his colleagues at the
University of Pennsylvania, are selectively manipulating the genes in mice to determine
which genes are necessary for initiating and perpetuating RA.
- How genetic and environmental factors interact to increase
the risk of RA is the focus of an epidemiology study co-led by Kenneth Saag, MD, at
the University of Alabama in Birmingham, and Lindsey Criswell, MD, at the
University of California in San Francisco. Using a population of women with elderly-onset
RA, they began analyzing environmental risk factors such as cigarette smoking, estrogen
use, and nutritional factors. Preliminary analysis has shown that smoking and intake of
decaffeinated coffee appears to increase the risk of RA in postmenopausal women. Next they
will be analyzing genetic factors and how they interact with the environmental factors
Reprogramming the Immune Process
Many Arthritis Foundation-funded researchers are trying to
manipulate the very early stages of the immune process in RA:
- David Fox, MD, and his colleagues at the University
of Michigan, are studying how two recently discovered receptor molecules (CD160 and CD245)
on the surface of T cells activate cells in the joint lining that contribute to joint
damage. Understanding how these receptors work could lead to therapy that blocks just the
T cells with these molecules. They also are studying unique immune cells called dendritic
cells that play a critical role in activating T cells. They have discovered that dendritic
cells that have been genetically engineered to express the anti-inflammatory cytokine
IL-4, can inhibit the onset and severity of arthritis in mice.
- In a study that could lay the basis for a RA vaccine, William
Robinson, MD, PhD, at Stanford University, is testing whether delivering protein
pieces (peptides) will block the autoimmune response of harmful T cells.
- Huang-Ge Zhang, DVM, at the University of Alabama at
Birmingham, and Donald Bellgrau, PhD, at University of Colorado in Denver, are using gene
therapy with a molecule known as Fas ligand to kill pro-arthritis T cells and joint lining
cells.
- Patricia Tam, PhD, at University of Minnesota in
Minneapolis, is studying whether RA can be prevented by using irradiation and chemotherapy
to eliminate a defective, RA-prone immune system in mice. After chemotherapy, she'll
immunize the mice with high levels of collagen, a protein found in cartilage, and then
infuse stem cells (cells that have the capacity to develop into any type of cell) that
were previously collected from the mice to regenerate normal immune cells.
The Arthritis Foundation is also supporting research aimed
at preventing the progressive destruction of joints in RA by learning more about how to
block the blood vessel growth and release of toxic enzymes and other molecules into
chronically inflamed joints:
- Gary Firestein, MD, at the University of California,
San Diego, has discovered that RA joints have high amounts of a protein kinase called JNK,
which appears to be especially important to the production of destructive enzymes. Use of
a new inhibitor that blocks JNK suppressed both inflammation and bone destruction in mouse
models of arthritis.
- Building on advances in cancer treatment in which
anti-angiogenic agents have been successfully used to block blood vessel formation and
tumor growth, Arthritis Foundation-funded researchers are now looking at such agents as a
potential target for new RA drugs. Teruna Siahann, PhD, at the University of Kansas
and Chris Storgard, MD, at Scripps Research Institute have reported successfully
suppressing joint damage in animal models by using peptides that blocked blood vessel
growth. These types of studies are providing the scientific rationale for beginning
clinical trials in RA of anti-angiogenic medications, such as Vitaxin, previously tested
as a cancer therapy.
Improving Bone Metabolism in RA
Researchers have discovered that the chronic inflammation
in RA interferes with another body process, i.e., the balancing of cells that build up and
breakdown bone. Ellen Gravallese, MD, at Beth Israel Deaconess Medical Center in
Boston, is examining what factors regulate a cytokine within the TNF family called RANKL,
which appears to play a key role in the bone erosions that occur in RA and its antagonist,
osteoprotegerin (OPG). Such research could lead to the development of a new pathway of
therapies to prevent the disabling bone destruction in RA.
Improving Coping
Psychological stress can worsen pain and interfere with
functioning in people with RA. Several Arthritis Foundation studies are examining
questions related to coping:
- Bruce Smith, at Arizona State University in Tempe, is
studying whether positive factors like social support and an optimistic outlook can reduce
the negative effects of stress and pain in women with RA.
- Howard Tennen, PhD, at University of Connecticut Health
Center, is examining the effect of depression on RA pain, work loss and physician
visits.
- Mark Lumley, PhD, at Wayne State University in Detroit,
Mich. is studying whether writing in a journal about one's negative life events can reduce
pain, depression and disability.
- Francis Keefe, PhD, at Duke University, is assessing the
impact of sharing stressful life events with a clinician.
Reducing Work Disability
With the introduction of potent new therapies, there
is a greater potential to reduce the work disability that is so prevalent in RA. Susan
Reisine, PhD, and her colleagues at the University of Connecticut, are studying women with
early RA to explore the relationships among employment and unpaid family work and physical
and psychological health. The information from this study could be used to help identify
women who are at higher risk for disability so that they can receive early assistance to
help stay employed as long as possible.
Improving Long-Term Outcomes
Arthritis Foundation-funded researchers are also examining
ways to reduce complications of RA and premature death:
- Immaculada del Rincón, MD, at the University of
Texas, is studying a population of people with RA to determine what factors appear to
increase the risk of heart disease. Such information will lead to better ways to treat and
prevent heart disease.
- Ronenn Roubenoff, MD, at Tufts University, has shown
that increased production of tumor necrosis factor (TNF) is associated with a loss of
muscle mass and fat gain in people with RA. These changes can lead to complications such
as disability, reduced ability to fight infections, and increased mortality from diseases
like diabetes and heart disease. Dr. Roubenoff is now studying whether using a
TNF-blocking biologic agent will improve protein, carbohydrate and fat metabolism in
people with RA and help to reduce disability and mortality in RA.
Promoting Physical Activity
Although physical activity is a safe and effective
way of improving function and quality of life, many people with RA are inactive. Pamela
Semanik at the University of Illinois in Chicago, is studying older women with RA to
determine what factors impede or promote their physical activity behaviors. Understanding
these factors will lead to the design of more effective interventions to help these women
become more active.
Disability in Mexican Americans
Previous studies have shown that the amount of
disability that a person with RA experiences is not always directly related to the
severity of their disease. Some people with mild RA are very disabled, while others with
severe disease remain very functional. The reasons for these discrepancies are not well
understood. Agustin Escalante, MD, at the University of Texas in San Antonio will assess
how the extent of disability in Mexican Americans compared to Caucasians with RA is
affected by cultural and language differences, socioeconomic level, psychological factors
and genetics. The results of this study will help find ways to reduce disability and
improve quality of life in people with RA.
Improving Decision-Making
Liana Fraenkel, MD, at Yale University, is conducting
an Arthritis Foundation-funded study aimed at describing how patients perceive different
side effects and whether varying degrees of toxicity affect choice of treatment. A better
understanding about patient preferences will help physicians provide more relevant
information about risks and benefits of different options of care. Ultimately, this study
could improve patients' decision-making, satisfaction with and quality of care. |
