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Evolving
Concepts of RA: Progressing from Bench to Bedside
RA is a complex disease--several different disease mechanisms contribute to its
development and progression. Hence, different therapeutic agents may be
necessary to target the different processes involved in the disease. Previous
research uncovered the important role of proteins, called cytokines, which
promote inflammation, such as tumor necrosis factor alpha (TNF) and
interleukin-1 (IL-1). These discoveries led to the advent of new biologic agents
that target TNF and IL-1, reducing inflammation and the risk of joint damage.
New insights about other underlying disease mechanisms are paving the way for
other novel approaches to therapy.
RA: A 3-D Perspective
RA causes pain and joint damage through a chronic, destructive inflammatory
process that includes the accumulation of immune cells in the joint. As
described by Cornelia Weyand, MD from the Mayo Clinic and Nancy Ruddle,
PhD of Yale University, progress has been made in understanding why immune
cells infiltrate into the joint, how they acquire the capacity to injure tissue
and why this abnormal immune response persists and leads to chronic
inflammation.
It is now recognized that the
immune cells that migrate into joints can organize into several distinct
patterns including structures like lymph nodes, which are organs normally
concerned with defense against disease. It appears that the type of lymphoid
structure that occurs in the joint plays an important role in determining the
severity of inflammation and risk of joint and cartilage damage, and more
importantly may require different approaches to treatment.
What's the relevance to
people with arthritis? Increased insights about how different immune
cells affect the RA disease process provide a rationale for new approaches to
therapy. The recognition that patients with RA can be further classified based
on how cells of the immune system organize within their joints has major
implications for better understanding of the disease and the development of new
approaches to treatment.
Fighting Bone Destruction
Chronic inflammation in RA can destroy bone and cartilage in the joint. Existing
evidence suggests that certain cells called osteoclasts play an important role
in the bone destruction in RA. Studies being conducted by Ellen Gravallese,
MD and Allison Pettit, MD and their colleagues at Beth Israel
Deaconess Medical Center and Harvard Institutes of Medicine, have found in
animals and recently in patients with RA that a cytokine called RANKL
helps to activate the osteoclasts, resulting in bone loss. As reported as the
conference, these mechanisms that lead to bone destruction are distinct from
those that lead to cartilage destruction. Moreover, it appears that RANKL plays
a more important role in bone destruction than tumor necrosis factor alpha (TNF),
the inflammatory protein that is targeted by some of the new biologic agents.
What's the relevance to
people with arthritis? Documenting that there is a distinct pathway that
contributes to bone loss may lay the basis for even more effective therapeutic
approaches for arthritis that target osteoclasts, protecting patients with RA
from bone destruction.
Targeting Cell Signaling Pathways
In order for immune cells to appropriately respond to stress and carry out their
defensive functions, they rely on various proteins called "enzymes"
that transmit signals received at the cell surface to molecules inside the cell.
Some of these signaling pathways play a critical role in the inflammation seen
in RA and similar conditions. Gary Firestein, MD,
from the University of California, San Diego, reviewed recent advances in our
understanding of these pathways that have implications for potential therapeutic
targets. Two families of enzymes called the NF-kB and mitogen-activated protein
(MAP) kinases have been identified as especially attractive targets for new
therapeutics because of their role in stimulating inflammation. Inhibitors of
these enzymes have been shown to suppress arthritis in experimental animals.
What’s
the relevance to people with arthritis?
An increased understanding of targets within cells that regulate the
inflammatory process in RA could potentially lead to more effective therapeutic
interventions.
Cancer Treatment Shows Promise in RA
The overgrowth of the joint lining in RA has been likened to a tumor-like
growth, and indeed, as in cancer, this growth is fueled by the development of
new blood vessels within the joint (called "angiogenesis"). Hence,
building on successes in the cancer field in which so-called anti-angiogenic
drugs are being tested to "starve" tumors, researchers are showing
their potential benefit in arthritis. Laurie
Davis, PhD from
the University of Texas, Southwestern Medical Center in Dallas, reported a study
in which one such drug, a synthetic monoclonal antibody called vitaxin, was
tested on mice to determine its effects on the joint lining. Dr. Davis and her
colleagues found that vitaxin can selectively reduce blood vessel formation and
limit the growth of inflamed joint tissues.
What's the relevance to
people with arthritis? A better understanding of how such anti-angiogenic
agents affect the overgrowth of tissue in RA can help in the further development
and refinement of this new type of potential therapy for RA.
Research Update is compiled by
Michele Boutaugh, BSN, MPH, Medical and Scientific Affairs Department,
National Office.
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