Moving Toward Cures for RA, OA and JA

1.  New pathway for development of safe, effective medications for controlling inflammation in rheumatoid arthritis (RA).

An Arthritis Foundation-funded study at Brigham and Women’s Hospital in Massachusetts revealed a previously unknown mechanism that promotes inflammation in the joints of patients with rheumatoid arthritis (RA). It turns out that blood platelets, which are important for stopping bleeding, can enter joints affected by RA and form new structures called microparticles. These microparticles can affect the tissues’ lining, causing well-known characteristics of active RA including joint swelling, warmth and tenderness.

The relevance of this finding for future treatment of RA is substantial. It shows a new way by which blood platelets impact inflammation, helps explain why some newer medications are sometimes not effective in treating RA, and opens up a new target for drug development.

Platelets amplify inflammation in arthritis via collagen-dependent microparticle production.  Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O’Donnell E, Farndale RW, Ware J, Lee DM. Science. 2010 Jan 29;327(5965):580-3. Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. Study sponsored in part by the Arthritis Foundation.

2. Small reduction in body weight could mean better health for the joints.

It is well known that obesity has a strong association with osteoarthritis (OA), but it has been assumed that this association is  due to the strain on joints caused by excess body weight. This study, funded in part by the Arthritis Foundation, supports a different mechanism. Normally, fat cells secrete a substance known as leptin, which tells the brain that eating should stop. Using mutant mice that lacked the leptin receptor in their brains, researchers found that the mice kept eating as they became increasingly overweight. Surprisingly, these mice did not develop arthritis even in the face of marked obesity because cells in normal joint cartilage (chondrocytes) have the leptin receptor and can respond to leptin with changes in their metabolism in ways that promote OA. Therefore, the mutant mice have cartilage that is resistant to the effects of obesity that are mediated by leptin. This study supports the hypothesis that substances derived from fat tissue, such as leptin, directly harm articular cartilage and predispose individuals to the development of OA.

Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Griffin TM, Huebner JL, Kraus VB, Guilak F. Arthritis Rheum. 2009 Oct;60(10):2935-44. Duke University Medical Center, Durham, North Carolina 27710, USA. Study sponsored in part by the Arthritis Foundation.

3.  Radiographic features of osteoarthritis strongly associated with knee pain.

Pain is the major clinical symptom in osteoarthritis of the knee and a key reason for seeking medical care. Painful OA also limits activity, reduces quality of life and can lead to disability. Understanding how and why OA causes pain is a top priority for finding better ways to manage patients with OA. This study carefully demonstrates how radiographic findings correlate with pain in the knees of patients with OA. It shows that loss of joint cartilage correlates strongly with symptoms of pain, while bone spurs (osteophytes) were less likely to be associated with joint pain. Although researchers continue to search for information about how OA leads to pain in joints, this study certainly helps narrow the search. These findings are essential for improving our strategies to control the pain and disability caused by OA.

Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. Neogi T, Felson D, Niu J, Nevitt M, Lewis CE, Aliabadi P, Sack B, Torner J, Bradley L, Zhang Y. British Medical Journal 2009 Aug 21;339-346. Clinical Epidemiology Research and Training Unit, Boston University School of Medicine. Study sponsored in part by the Arthritis Foundation.

4.  New diagnostic test for a rare form of juvenile arthritis.

The cytokine known as interleukin-1 (IL-1) is a central mediator of inflammation. It exerts its effects through activating the IL-1 receptor on many cells that are important in producing inflammation. The effect of IL-1 on this receptor is blocked by another molecule known as the IL-1 receptor antagonist, which helps the body avoid excessive inflammatory responses. This study describes the clinical findings in families in which a genetic mutation causes the IL-1 receptor antagonist to be ineffective. The affected patients had severe rashes, skeletal abnormalities, enlargement of the liver and spleen, and inflammation in internal organs that were apparent at the time of birth or shortly thereafter. Treatment with a drug designed to block the IL-1 receptor (anakinra) resulted in rapid improvement. These exciting clinical findings reveal a new diagnostic test for a rare form of juvenile arthritis. The study also sheds light on the interactions of substances in the body that promote and inhibit inflammation in the body. Balancing these interactions is important for all inflammatory diseases.

An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgård U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R. N Engl J Med. 2009 Jun 4;360(23):2426-37. National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA. Dr. Kastner began his research career with support of an Arthritis Foundation Postdoctoral Fellowship.

5.  Crucial process in the development of the immune system illuminated.

T cells represent a very important part of our immune defense system. Like all other white blood cells, these cells are formed from stem cells in a life-long process. The transformation of stem cells into T cells is guided by mechanisms that precisely turn on and turn off specific genes. Understanding how this process is controlled is fundamental for understanding human biology and for applying stem cells to the treatment of a broad variety of human diseases. In this study, a protein referred to as NKAP is identified as a key regulator of the process that guides the transformation of a bone marrow stem cell into a T cell that can distinguish molecules of the person’s own body from foreign molecules, such as those on an invading pathogen. The experiments showed how NKAP is required for regulating a mechanism that permits cells to pick up signals in their environment through sensors on the cell surface and deliver those messages to the nucleus of the cell. These messages govern a specific set of genes required for T cell development, and are essential for development of a specific group of T cells known as alphabeta T cells. This study illuminates a crucial process in the development of the immune system. This insight is important because subtle abnormalities in the function of this process are likely to be associated with both cancer and autoimmunity. A full understanding of this process is also essential for making the best use of stem cell treatments for autoimmune diseases in the future.

NKAP is a transcriptional repressor of notch signaling and is required for T cell development. Pajerowski AG, Nguyen C, Aghajanian H, Shapiro MJ, Shapiro VS. Immunity 2009 30(5):696-707. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Study sponsored in part by the Arthritis Foundation.

6. Osteoarthritis involves specific metabolic and immune mechanisms that are amenable to pharmacological intervention.

It has long been accepted that rheumatoid arthritis (RA) is an autoimmune disease, a condition in which the immune system is attacking components of the body’s own tissues. In this study, the investigators used powerful new technologies to examine proteins from joints of patients with both RA and osteoarthritis (OA). Two important new findings emerged. First, it is clear that autoantibodies are present in patients with RA and OA and that these autoantibodies target different sets of self molecules in these two diseases.

Second, fundamental structural elements of our genetic material deposit on the surfaces of joints and serve as targets for autoantibodies in patients with RA but not OA. Knowing the targets of autoimmune responses that cause tissue injury is essential for developing new approaches to manipulating the immune system to turn off specific unwanted autoimmune diseases (e.g., vaccines). The study also provides new insight into what is happening in joints of patients with OA – here is clear evidence that autoimmune responses occur in OA and may be amenable to pharmacological intervention.

A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis. Monach PA, Hueber W, Kessler B, Tomooka BH, BenBarak M, Simmons BP, Wright J, Thornhill TS, Monestier M, Ploegh H, Robinson WH, Mathis D, Benoist C. Proc Natl Acad Sci U S A. 2009 106(37):15867-72. Section on Immunology and Immunogenetics, The Joslin Diabetes Center, Boston, Massachusetts, USA. Study sponsored in part by the Arthritis Foundation.

7.  Early knee OA associated with series of inflammatory cytokines typically seen in RA.

Deterioration of the medial or lateral meniscus – structures within the knee that help maintain proper alignment during joint motion – is often an early feature of osteoarthritis (OA). In the present study, patients with degenerative meniscal tears and minimal cartilage thinning were studied as a model for early OA. These patients were found to produce a series of inflammatory cytokines in their joints as has been shown for patients with rheumatoid arthritis (RA) and to a lesser extent advanced OA. The key observation is that one cytokine known as IL-15 was more likely to be elevated in knee joints of patients with early OA as compared to patients with advanced OA. This study defines a new approach to the study of OA at a time when the disease is relatively early in its course – a time when OA is most likely to be treatable with medical interventions. The important finding that early OA is associated with elevated IL-15 suggests that processes that drive production of IL-15 are active in early OA. Medications that block inflammation, especially if they reduce expression of IL-15, may slow or stop progression of OA if applied early in the course of the disease.

Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease. Scanzello CR, Umoh E, Pessler F, Diaz-Torne C, Miles T, Dicarlo E, Potter HG, Mandl L, Marx R, Rodeo S, Goldring SR, Crow MK. Osteoarthritis Cartilage. 2009 Aug;17(8):1040-8. Rush University Medical Center, Section of Rheumatology. Study sponsored in part by the Arthritis Foundation.

8.  Autoimmune response to citrulline an important driver of the inflammation that damages joints in patients with RA.

Proteins are made up of amino acids, one of which is arginine. Under certain circumstances arginine is converted to an alternative amino acid know as citrulline. This conversion process occurs in joints of patients with rheumatoid arthritis (RA) who frequently develop anti-citrulline autoantibodies. Measurement of these antibodies has become an important clinical tool for diagnosing RA. The present study demonstrates that inducing anti-citrulline antibodies causes joint inflammation in a special strain of mice engineered to have genetic risk factors comparable to those associated with RA in humans. The results of this study indicate that the autoimmune response to citrulline is an important driver of the inflammation that damages joints in patients with RA. This study is an important step toward finding new treatments for RA that focus on controlling specific harmful autoimmune responses in RA. This approach promises to be more effective, safer and longer lasting than presently available medications for RA.

Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. Hill JA, Bell DA, Brintnell W, Yue D, Wehrli B, Jevnikar AM, Lee DM, Hueber W, Robinson WH, Cairns E. J. Exp Med. 2008 Apr 14;205(4):967-79. Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada. Supported in part by the Canadian Arthritis Society.

9.  Medical decision making in patients with knee pain, meniscal tear, and osteoarthritis.

An estimated 27 million Americans have osteoarthritis (OA), and this number is on the rise. Up to 80 percent of individuals with knee OA will have meniscal tears detectable in MRI studies.

This problem is often treated surgically with an arthroscopic partial meniscectomy (APM) in which the surgeon uses an arthroscope to remove a damaged or loose portion of the damaged meniscus. At present, about 500,000 of these operations are done annually in the United States. The problem, however, is that we do not know which patients will benefit from this surgery and which will not. This study sought to answer the question by using a mathematical model based on published data regarding mechanical symptoms (such as locking and giving way), pain patterns, the type of meniscal injury as established by MRI, and the presence of bone marrow lesions to estimate who will benefit from the surgical procedure. In this analysis, individuals with a displaced tear, locking, increased pain, and no bone marrow lesions were judged to be the most likely to benefit from the procedure. Knowing which patients will benefit from APM is crucial for addressing a staggering public health dilemma. While a large scale clinical trial is needed to address this question definitively, the present study can help guide decision making when patients are considering the option of APM intervention.

Medical decision making in patients with knee pain, meniscal tear, and osteoarthritis. Suter LG, Fraenkel L, Losina E, Katz JN, Gomoll AH, Paltiel AD. Arthritis Rheum. 2009 Nov 15;61(11):1531-8. Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, Room TAC S541, PO Box 208031, New Haven, CT 06520-8031, USA. Study sponsored in part by the Arthritis Foundation.

10.  Important Conceptual Advances – In addition to new understanding of the cost-effectiveness of certain medications in the treatment of rheumatoid arthritis (RA), 2009 also culminated in the development of A National Public Health Agenda for Osteoarthritis, which provides opportunities to collaborate and alter the trajectory of osteoarthritis (OA).

Treatment of Very Early Rheumatoid Arthritis with Symptomatic Therapy, Disease-Modifying Antirheumatic Drugs, or Biologic Agents: A Cost-Effectiveness Analysis: While it is known that long-term control or remission of RA may be possible with very early treatment, no optimal first therapeutic strategy has been determined. This study assessed the potential cost-effectiveness of three major therapeutic strategies for very early RA:

• A“pyramid” strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, low-dose glucocorticoids and DMARDs at one year for nonresponders
• Early DMARD therapy with methotrexate
• Early therapy with biologics and methotrexate

By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the “pyramid” strategy and save long-term costs. This study establishes that very early intervention with disease-modifying antirheumatic drugs (DMARDs) is very cost-effective in terms of improving the quality of life for people with RA and provides a strong case for both physicians and insurers that early intervention in RA is essential. Further studies are needed to define the optimal time to begin treatment with newer biologic medications due to their substantial incremental cost.

Treatment of Very Early Rheumatoid Arthritis with Symptomatic Therapy, Disease-Modifying Antirheumatic Drugs, or Biologic Agents: A Cost-Effectiveness Analysis. Axel Finckh, MD, MS; Nick Bansback, MS; Carlo A. Marra, PharmD, PhD; Aslam H. Anis, PhD; Kaleb Michaud, PhD; Stanley Lubin, MD; Marc White, PhD; Sonia Sizto, BA; and Matthew H. Liang, MD, MPH. Ann Intern Med. 2009;151:612-621. Study sponsored in part by the Arthritis Foundation.

A National Public Health Agenda for Osteoarthritis, which provides opportunities to collaborate and alter the trajectory of osteoarthritis (OA): A decade ago, the Centers for Disease Control and Prevention and the Arthritis Foundation launched the National Arthritis Action Plan: A Public Health Strategy, a landmark document that put arthritis on the public health map and laid out a plan for marshalling the nation’s resources to confront the greatest single cause of chronic pain and disability among Americans. Ten years later, the partnership is still strong. In collaboration with a large and diverse group of stakeholder organizations, we are proud to announce the 2010 publication of A National Public Health Agenda for Osteoarthritis. The recommendations presented in A National Public Health Agenda for Osteoarthritis provide an opportunity for us to work together to alter the trajectory of this disease so the millions of Americans who struggle with this painful and important public health problem can live fuller and more independent lives.

Debra Lubar, Patience H. White, Leigh F. Callahan, Rowland W. Chang, Charles G. Helmick, Debra R. Lappin, Amy Melnick, Roland W. Moskowitz, Erica Odom, Jeffrey Sacks, Susan Baker Toal, Mary B. Waterman: A National Public Health Agenda for Osteoarthritis 2010. Seminars in Arthritis and Rheumatism 2010 in press. Available on line at www.cdc.gov/arthritis/docs/OAagenda.pdf. A joint initiative led by the Arthritis Foundation and the Centers for Disease Control and Prevention.