Top 10 Arthritis Advances 2006
1) Dramatic Surge in Arthritis Predicted
The prevalence of doctor-diagnosed arthritis is projected to increase to nearly 67 million by the year 2030. Of those 67 million affected people, 25 million are projected to report arthritis-related activity limitation.
The Centers for Disease Control and Prevention released new arthritis prevalence estimates in the January 2006 issue of Arthritis & Rheumatism. The prevalence of doctor-diagnosed arthritis is projected to increase from the current 46 million to nearly 67 million (25 percent of the adult population) by the year 2030. Of those 67 million, 25 million are projected to report arthritis-related activity limitation. In 2030, more than half of the people with arthritis will be older than age 65. Almost one-third of all cases will be in working-age adults, those 45 to 64 years old. Of the 25 million with arthritis-related activity limitation, 64 percent will be women and 54 percent will be 65 years old or older.
This large increase in the number of people with arthritis poses a major challenge to the health care and public health systems. This burden can be reduced by increasing the availability of current interventions aimed at prevention and improving quality of life through lifestyle changes and disease self-management. Programs, such as the Arthritis Foundation Aquatic Program, Arthritis Foundation Exercise Program and Arthritis Foundation Self-Help Program, are available throughout the country to help people with arthritis, or those at risk of developing arthritis, to take control.
2) Genetic Links with Rheumatoid Arthritis Identified
It has been determined that at least one gene, in addition to the HLA genes already linked to rheumatoid arthritis, affects the likelihood of developing RA. Possible connections were found for two others.
Although the exact cause of rheumatoid arthritis (RA) is not known, it has become increasing clear that this disease has both genetic and environmental origins. In December 2005, an international team of scientists released results of their study in the American Journal of Human Genetics examining several genes that may increase a person’s risk of developing RA. Although everybody has HLA-DR genes, those people who inherit a form of the HLA-DR gene called HLA-DRB1 (also known as the shared epitope) already were known to have an increased risk of developing RA. Now it has been determined that at least one other gene increases the likelihood of developing RA, and possible connections were found for two more.
Researchers verified a statistically significant association between having rheumatoid factor-positive RA and carrying a particular form of the gene called PTPN22. The presence of PTPN22 also influenced age of onset of RA; those with the gene developed RA two years earlier than those without it. Specific variations in two other genes, CTLA4 and PADI4, also had a positive association with the likelihood of developing RA, but the relationships were not as strong as with PTPN22, and the results will need to be confirmed in future studies.
Detecting the influence of genes on the disease in such a statistically significant way is a feat that has been difficult to achieve before now. The scientists had the power to succeed this time because they tested such a large number of people. In all, 17 genetic segments were tested in 2,370 people with RA and 1,757 people without RA from the North American Rheumatoid Arthritis Consortium, a research collaboration co-funded by the National Institutes of Health and the Arthritis Foundation, and the Swedish Epidemiological Investigation of Arthritis cohorts.
3) Effectiveness of Biologics in Arthritis
Rituximab’s (Rituxan) and adalimumab’s (Humira) FDA approvals were expanded to include RA and anklylosing spondylitis, respectively. Combining a biologic agent with methotrexate is safe and more beneficial than taking either drug alone. All of the biologics tested in juvenile arthritis were found to be safe and effective, and hold the potential of inducing remission.
Over the past year, biologic response modifiers – drugs that target specific products of the immune system – have continued to gain momentum as treatment for inflammatory arthritis. In February 2006, rituximab (Rituxan; a medication already approved for use in cancer treatment) was approved by the U.S. Food and Drug Administration for use in RA. Likewise, in August 2006, adalimumab (Humira), which was previously approved for RA treatment, was approved for the treatment of ankylosing spondylitis. Along with these new indication approvals, a great deal of research has been released throughout the year on biologic drugs’ safety, effectiveness and best use.
Although individual studies found slightly different results, the overall conclusions drawn are as follows: 1) combining a biologic agent with the disease-modifying antirheumatic drug (DMARD) methotrexate is safe and effective; 2) combining two biologics is not considered safe; and 3) biologics are safe and effective when used in children and may even induce remission. Details of some of the most prominent studies follow.
Combination therapy with adalimumab plus methotrexate was found to treat early, aggressive RA more effectively than either medication alone (Arthritis & Rheumatism, January 2006). Similarly, improvement and remission rates were significantly higher with a combination of etanercept (Enbrel) plus methotrexate than with either therapy alone (Arthritis & Rheumatism, April 2006). A study of abatacept (Orencia) combined with other anti-arthritis drugs found that abatacept plus a DMARD (such as methotrexate, hydroxychloroquine, etc.) was well tolerated and improved disease outcomes. However, they found that abatacept should not be combined with another biologic agent (such as etanercept, infliximab, adalimumab, anakinra) because of an increased rate of serious adverse events, particularly infection (Arthritis & Rheumatism, September 2006).
Rituximab was found to be equally effective at treating RA when given at two 500-mg doses or at two 1,000-mg doses. More than half of study subjects achieved a 20 percent improvement in disease activity and more than one-third achieved a 50 percent improvement (Arthritis & Rheumatism, May 2006).
In addition to these published studies, preliminary reports at the 2006 meeting of the American College of Rheumatology addressed a number of important questions regarding use of biologic agents for the treatment of arthritis. Adalimumab was found to provide rapid, substantial and sustained improvement in symptoms of juvenile rheumatoid arthritis. Abatacept was found to have effectiveness similar to infliximab (Remicade) in people with RA, but abatacept had a better safety profile. Children with active juvenile arthritis who found relief while taking abatacept entered into a clinical trial in which they either stayed on abatacept or were given placebo. More than half of the placebo-treated children experienced a disease flare, whereas only 20 percent of the abatacept-treated children experienced a flare.
4) Importance of Anti-Cyclic Citrullinated Proteins in RA
Anti-CCP antibodies contribute to the development of RA, paving the way for targeted therapeutics that inhibit these antibodies. An important clue to the way that genetics and environment may interact to trigger RA was found when an association between anti-CCP antibodies, the “shared epitope” genetic marker, smoking and RA was discovered.
Although most people with RA test positive for rheumatoid factor, many people who do not have RA also test positive for rheumatoid factor, limiting the diagnostic value of this test. It has been found that testing for antibodies against cyclic citrullinated peptide, or anti-CCP, is much more specific for identifying people with RA. Furthermore, anti-CCP antibodies may be present for years before disease symptoms are apparent, making this antibody a potential predictor of who will develop disease. Although the relationship between anti-CCP antibodies and RA has been known for a few years, research studies released in 2006 have increased our understanding of the role and importance of anti-CCP.
In April 2006, a multicenter team of scientists published results in Journal of Clinical Investigation about the role of anti-CCP antibodies in the onset and continuation of RA. They found that antibodies against citrullinated proteins (proteins that have a citrulline molecule attached) do indeed contribute to the development of RA. The article’s senior author, V. Michael Holers, MD, stated, “knowing [this] may allow for the development of targeted therapeutics that inhibit these antibodies or their development. Such therapeutic approaches may reduce severity in patients with active disease or perhaps even prevent the onset of clinically significant arthritis in susceptible individuals.”
A Swedish group of scientists found important associations between anti-CCP antibodies, the shared epitope genetic marker, smoking and RA – providing an important clue about the way genetics and the environment may interact to trigger the onset of RA (Arthritis & Rheumatism, January 2006).
They found that the presence of the shared epitope increases the risk of developing RA only in the subgroup of people who are positive for anti-CCP antibodies. They also found that smokers with two copies of the shared epitope genes had a 21-fold greater risk of developing RA compared with nonsmokers who do not carry the genes. Importantly, they were able to determine what happens in the body that ties together the environmental trigger (smoking) with the genetic background (presence of the shared epitope). They found that an immune reaction to citrullinated proteins occurs almost exclusively in individuals with the shared epitope genes who also smoke. The lead study author Lars Klareskog, MD, PhD, notes in the article, “These findings may provide new opportunities to both predict and understand the onset of RA and to interfere with RA-inducing events before clinical symptoms are apparent.”
5) Results of Largest Glucosamine-Chondroitin Trial to Date
Taking a glocosamine-chondroitin combination relieves osteoarthritis pain no better than placebo. Another phase of GAIT is ongoing investigating whether the supplements affect cartilage loss.
Over the past decade, the dietary supplements glucosamine and chondroitin have been widely promoted and used to relieve the pain associated with knee OA. In addition, some studies suggest that glucosamine and chondroitin may reduce the loss of joint cartilage that occurs with the disease. The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) – the most comprehensive clinical trial of these supplements to date – is a landmark study conducted to clarify the role of glucosamine and chondroitin in the treatment of knee OA. Results from GAIT were published in the New England Journal of Medicine in February 2006.
Funded by the National Institutes of Health and conducted at 16 U.S. rheumatology centers, GAIT was designed to evaluate rigorously the efficacy and safety of these agents alone and in combination when taken over a 24-week period. The study measured the effects of taking glucosamine alone, chondroitin alone, a glucosamine-chondroitin combination or celecoxib (Celebrex) alone versus placebo in 1,258 people with mild or moderate-to-severe pain from knee OA.
The glucosamine-chondroitin combination showed no greater effectiveness overall than placebo. Only when patients with moderate-to-severe knee OA pain were evaluated could an effect be discerned: these participants experienced 25 percent greater pain relief than those taking either supplement alone.
GAIT is ongoing and the findings of the portion of the trial examining the effect of glucosamine and chondroitin on cartilage loss within the knee should be available in the near future. There is speculation that the supplements may alter the course of the disease even if they do not relieve mild OA pain.
6) High Rate of Relapse in Juvenile Arthritis
Some medications used to treat juvenile idiopathic arthritis have been able to induce periods of remission. However, relapse can be expected in up to 85 percent of children, highlighting the urgent need for improved treatments.
Juvenile idiopathic arthritis (JIA) refers to a group of diseases that share the common feature of chronic joint inflammation. Some of the disease-modifying antirheumatic drugs and the biologic agents used to treat JIA have been able to induce periods of disease remission. In November 2005, an international team of scientists released results in Arthritis & Rheumatism showing that although remission can be achieved, relapse can be expected in up to 85 percent of children.
During a follow-up period of at least four years, children with JIA spent between 16 percent and 60 percent of their time with inactive disease, depending on the type of JIA they had. Patients with persistent oligoarticular (few joints) JIA spent the least amount of time in a heightened disease state, whereas children with rheumatoid factor-positive polyarticular (many joints) JIA spent the most time with active disease. Unfortunately, once a child achieved clinical remission off medication (defined as having 12 months of inactive disease without anti-arthritis medications), that child had a 40 percent to 69 percent chance of having a disease flare within the next two years. That same child’s chances of having a flare increased to 49 percent to 85 percent in the next five years.
The study’s lead author, Carol A. Wallace, MD, voiced her concerns in the article’s summary. “The small percentage of time spent in clinical remission off medication was disappointing, as was the lack of durability of this state. These data highlight the urgent need for improved treatments of JIA that are capable of inducing extended periods of clinical remission off medication.”
7) Immune Cell Involvement in Juvenile Arthritis Better Defined
In children with polyarticular JIA, the genes that initiate neutrophil (white blood cells involved in immunity) activation are much more active than in children without JIA, suggesting that medications to inhibit neutrophil activity may limit polyarticular JIA.
Polyarticular JIA is a form of arthritis that begins in children under the age of 16 and involves the inflammation of several joints. Because neutrophils (a type of white blood cell that is involved in immunity) are the most abundant cells within the synovial fluid of children with JIA, a multicenter team of scientists worked together to understand the role of neutrophils in polyarticular JIA (Arthritis Research & Therapy, September 2006).
They found that in children with polyarticular JIA, the genes that initiate neutrophil activation are much more active than in children without JIA. They also discovered that even when their disease is well controlled, these abnormalities in neutrophil gene expression persist. Their findings suggest that developing medications to inhibit neutrophil activity may limit the development and progression of polyarticular JIA.
8) Help for Seniors Buying Medications
January 2006 marked the beginning of the Medicare Part D prescription drug plan, representing the most significant expansion of the Medicare program since its inception in 1965.
January 2006 marked the beginning of the Medicare Part D prescription drug plan, representing the most significant expansion of the Medicare program since its inception in 1965. For seniors and people with disabilities who previously had not been able to afford their medications, this historic government program expansion provides access to life-changing medications. With more effective drug therapies available for arthritis than ever before, seniors and people with disabilities have access to these medications and greater opportunities for self-sufficiency and mobility.
9) New Treatment Possibilities for Systemic Sclerosis
Scleroderma results in damage to the skin, blood vessels, lungs, heart, kidneys and gastrointestinal tract. Researchers identified antibodies they believe are important in the development of scleroderma, and another group found that the drug cyclophosphomide can be used to successfully treat interstitial lung disease, a leading cause of death among people with scleroderma.
Systemic sclerosis (also known as scleroderma) is an autoimmune disease that results in damage to and hardening of the skin, blood vessels, lungs, heart, kidneys and gastrointestinal tract. One group of researchers has found a potential clue to the development of the condition, and another group has had success in treating a leading cause of death among people with scleroderma.
The primary cause of systemic sclerosis is not known, but an Italian research team identified antibodies against platelet-derived growth factor receptors (PDGFR) in people with scleroderma (New England Journal of Medicine, June 22, 2006). These antibodies may trigger a chemical cascade that results in increased collagen production, which is the hallmark of scleroderma and causes organ damage. Their experiments strongly indicate that these PDGFR antibodies have a role in causing scleroderma; with that knowledge, therapies that block the action of the antibodies can now be developed.
Interstitial lung disease is a consequence of scleroderma and is a leading cause of death among people with scleroderma. The Scleroderma Lung Study Research Group, a large multicenter group of scientists, released results of a well-controlled clinical trial of oral cyclophosphamide (Cytoxan) on lung function in people with scleroderma interstitial lung disease (New England Journal of Medicine, June 22, 2006). After one year of treatment, people in the trial had a significant but modest improvement in lung function, less shortness of breath, reduced skin thickening, and a higher health-related quality of life. Treatment of scleroderma has been challenging, and this study provides evidence for the treatment of scleroderma lung disease, one of the most severe complications of the disease.
10) Anakinra Effective Against Genetic Form of Juvenile Arthritis
Neonatal-onset multisystem inflammatory disease is a rare disease characterized by rash, deforming arthritis, meningitis, vision loss, mental retardation and hearing loss. Anakinra (Kineret) was found to significantly decrease symptoms and organ damage.
Results from a 2006 trial of a biologic found it to be useful in treating a rare form of juvenile arthritis. Neonatal-onset multisystem inflammatory disease (NOMID) is a rare chronic inflammatory disease characterized by rash, deforming arthritis, meningitis, vision loss, mental retardation and hearing loss. Mutations in a gene that encodes cryopyrin, a protein involved in inflammation, are responsible for about 60 percent of cases of the disease. It affects many aspects of a person’s life and is one of a family of diseases called hereditary systemic autoinflammatory disorders. Results of a 2006 trial of the interleukin-1–receptor antagonist anakinra (Kineret) found the drug significantly decreased disease symptoms and organ damage in both children and adults with the disease. The trial revealed that rash, measures of inflammation, intracranial pressure and hearing all improved with treatment (New England Journal of Medicine, August 10, 2006).