Rheumatologic disorders consist of a variety of conditions characterized by inflammation or pain in muscles, joints or fibrous tissue. The National Institutes of Health (NIH) estimates that more than 40 million Americans have been diagnosed with rheumatic related illnesses, half of which are due to osteoarthritis alone. This figure is expected to climb to 59.4 million by the year 2020, due to the predicted aging of America’s population. Although the risks for developing a rheumatic or arthritic condition grow with age, more than 50% of patients are under the age of 65. It has been estimated that the cost of treatment for rheumatic related conditions is well over $10 billion a year. There are more than 100 diseases treated under the care of rheumatologists. For most of these conditions, a cause is not known. The most common forms of rheumatic disease are Systemic lupus erythematosus, osteoarthritis, fibromyalgia, Sjögren’s syndrome, and rheumatoid arthritis. New areas of molecular discovery are slowly expanding into therapeutic research.

One approach, which has the potential to treat arthritis, involves a type of gene therapy in which genetically altered cells are injected into joints to block cartilage breakdown. Preliminary results in animal studies have shown some success in slowing down disease progression with this technique. Another procedure being tested is the replacement of damaged cartilage with stem cells taken from a patient’s own healthy tissue. Although these new therapeutic directions press the limits of cutting edge research, more holistic approaches are beginning to be explored by the scientific community as well. Alternative treatments such as acupuncture, energy therapy and herbal remedies are being examined for their possible therapeutic effects. The NIH and NCCAM (National Center for Complementary and Alternative Medicine) are currently sponsoring a number of these alternative treatments, however their efficacy is still uncertain.

The approximate prevalence of some of the more common rheumatologic disorders are as follows:

Condition	Prevalence (US)
Osteoarthritis	20.7 million
Fibromyalgia	4-6 million
Sjögren’s syndrome	1-4 million
Rheumatoid arthritis	2 million adults
Psoriatic arthritis	1.6 million
Systemic lupus erythematosus	1.5 million
Ankylosing spondylitis	1 million
Gout	8.4 out of 1000
Polymyalgia rheumatica	7.0 out of 1000
Giant cell arteritis	2.0 out of 1000
Pseudogout	1.3 out of 1000
Juvenile arthritis	285,000+
Lyme disease	100,000+
Autoimmune myopathies	1.0 out of 100,000
Scleroderma	1.5 out of 100,000

Osteoarthritis (OA) is the most prevalent arthritic disorder in the U.S., affecting more than 20 million people. OA is known to result from a degeneration of the cartilage surrounding joints, however the causes of this cartilage loss are varied. In most people, cartilage breakdown is due to both mechanical effects and biochemical effects. Nearly every person over the age of 75 will eventually suffer cartilage degeneration in at least one joint, and women have been shown to be affected at a younger age than men. Current therapy for OA includes treatments that help to relieve pain and improve joint function, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs make up the largest class of medications for any type of arthritis.

CenterWatch has identified more than 30 drugs in clinical trials specifically indicated for the treatment of OA. Research into the mechanisms of inflammation has led to the development of anti-inflammatory drugs called cyclooxygenase-2 (COX-2) inhibitors. YM-177 (Pharmacia/Yamanouchi Pharmaceutical) is COX-2 inhibitor and is currently being investigated in phase II trials. In addition, agents called COX/LO inhibitors not only block COX enzymes, but also inhibit another pro-inflammatory enzyme called lipoxygenase, have also shown promising results. Licofelone (Merkle) is one of these COX/LO inhibitors in development and is currently in phase III. An alternate strategy is to suppress the progressive degradation of cartilage that occurs in OA. One method is to develop oral inhibitors of protein-dissolving enzymes, called matrix metalloproteinases (MMPs). PG-530742, an experimental drug from Proctor & Gamble, inhibits some of these matrix metalloproteinases and is currently in phase II trials. Other synthetic small molecular weight inhibitors of MMPs have proven efficacious in pre-clinical trials of arthritis and may enter clinical trials in humans.

Fibromyalgia, sometimes called fibrositis, is a common condition that is associated with widespread aching, stiffness and fatigue, and originates in muscles and soft tissues. It is estimated that 4 to 6 million Americans have this disorder. Although fibromyalgia is not an arthritic disease, it is listed by the Arthritis Foundation due to a historical association. Since fibromyalgia does not exhibit inflammatory characteristics, NSAIDs and steroids deliver no therapeutic benefits. The cause of fibromyalgia is currently unknown, however researchers have several theories about the possible disease triggers. Some believe the syndrome may be caused by an injury or trauma, which then affects the central nervous system. Other researchers believe an infectious agent, such as a virus, may trigger the condition, but no such agent has ever been identified.

Current treatments mainly center on the pain management approach, which provides a wide variety of choices. Nonhabituating medications such as tricyclic antidepressants with low anticholinergic profiles (doxepin 10-20 mg and protriptyline 5-10 mg) or mild benzodiazepines (temazepam) for some recalcitrant cases have been effective. Soporifics, which improve the quality of sleep, are often helpful for pain tolerance. Reliable studies have not demonstrated that chiropractic manipulation, acupuncture, hypnotherapy, or nutritional supplements help most people.

There are very few drugs currently in clinical development specifically indicated for fibromyalgia. Some studies have shown that persistent pain may be due to abnormalities in neuropeptides that convey pain messages. Preliminary findings have revealed that people with fibromyalgia exhibit changes in the levels of certain types of neuropeptides. In addition, studies have demonstrated that subjects who had high levels of pain anxiety reported higher levels of pain. Researchers are further examining how pain anxiety and the nervous system lead to a heightened pain response. More recent results show that abnormally low levels of the hormone cortisol may be associated with the disease.

Sjögren’s syndrome is an immunological disorder characterized by dry eyes, nose and throat. Like many arthritic diseases, the body’s immune system turns against itself and attacks tissue. Sjögren’s syndrome causes lymphocytes to attack the glands that produce moisture. The decreased production of tears and saliva is caused when the glands that produce these fluids are damaged. Between 1 and 4 million Americans have Sjogren’s syndrome and it is 10 times as likely to occur in women. There is currently no cure for this disease.

The most common treatments for Sjögren’s syndrome attempt to deal with the loss of body moisture by replacing it with artificial compounds. Prescription drugs such as Lacriserts can be used by some to alleviate dry eyes, and Salagen (pilocarpine hydrochloride) or Evoxac (cevimeline) are available to treat dry mouth. Over-the-counter products include artificial tears, artificial salivas, unscented skin lotions, saline nasal sprays, and vaginal lubricants. Almost all of the current research studies are still highly experimental and have not yet entered into human trials. Some strides have been made in transferring corrective genes into salivary gland cells, utilizing adenoviruses or adeno-associated viruses as vectors. In addition, research into artificial glands has investigated biodegradable substrates that can be lined with a monolayer of epithelial cells and engineered to secrete salivary fluid.

Rheumatoid Arthritis (RA) is a chronic and often debilitating disease that causes stiffness, pain and inflammation throughout the body. The most common areas of swelling are in the joints and tissues of the limbs. Over 2 million people in the U.S. are afflicted with RA, with more than 75% of them being women. The total costs of RA treatment and research reached $65 billion in 1992. Peak onset of the disease is between age 20 and 45; however, nearly 300,000 children have juvenile arthritis (JA), a form of arthritis that arises before the age of 16. While the ultimate causes of rheumatoid and juvenile arthritis are not known, the proximate mechanisms that result in inflammation and joint damage are being discovered.

Treatments for arthritis include nonsteroidal anti-inflammatory drugs such as ibuprofen; disease modifiers like methotrexate, azalthioprine, corticosteroids; etanercept and total joint replacement surgery for advanced disease. Treatments for JA parallels that of adult onset except in dose and formulation. Steroids, such as cortisone, must be used with caution because of the possible side effects on growth and maturation. Physical therapy has been shown to greatly enhance the benefits of arthritis medication.

CenterWatch has identified over 40 active trials specifically indicated for the treatment of RA. Current drug research has focused mainly on the areas of inflammation, immune response, and cell migration. The discovery of cyclooxygenase-2 (COX-2) inhibitors has greatly enhanced the effectiveness of anti-inflammatory medications. While drugs that utilize the COX-2 mechanism have fewer side effects and are an improvement over the traditional NSAIDs, they do not address the overall cause of the disease. There are a number of second-generation COX-2 inhibitors presently in clinical trials, including COX 189 (Novartis) and CI-1004 (Pfizer). The ability to create antibodies to specific disease-causing elements has led to some recent success. The drug Humira (adalimumab), approved in December 2002, is an anti-tumor necrosis factor (TNF) antibody that selectively binds TNF in RA patients decreasing its deleterious effects. Humira is also in development for juvenile arthritis and Crohn’s disease. Other immune blockers in clinical development are anti-interferon-gamma (anti-IFN-g), a monoclonal antibody that inhibits the C5 protein in the complement system (5G1.1) and a monoclonal antibody that blocks the chemokine receptor known as CCR2 (MLN-1202).

Systemic Lupus Erythematosus (SLE), often called lupus, is a chronic inflammatory disease resulting from the production of too many abnormal antibodies that can react negatively with the patient’s organs and tissues. The disease can cause various problems such as skin rashes, arthritis, anemia, seizures and often affects internal organs like the kidneys and heart. Neurologic disorders can affect up to 25% of those with SLE, with blood disorders affecting up to 85%. The ultimate cause of lupus is not known, but it is thought to have genetic, environmental and hormonal components. Although the survival rate today is more than 97%, more than million people in the U.S. alone suffer the debilitating symptoms. More than 85% of lupus patients are women and the disease seems to occur more often in certain minorities, such as African Americans and Asians.

Current treatments for lupus include the standard anti-inflammatory and anti-pain medications seen with other arthritic disorders such as NSAIDs, antimalarials, and corticosteroids. Cytotoxic (chemotherapy) drugs such as cyclophosphamide (Cytoxan), azathioprine (Imuran), and methotrexate (Rheumatrex) are fairly effective but produce persistent side effects such as severe nausea, vomiting and hair loss.

CenterWatch has identified fewer than 10 drug trials specifically indicated for the treatment of lupus. New drug research currently focuses on controlling the body’s attack against its immune system and thus preventing damage. Dehydroepiandrosterone (DHEA), a naturally occurring hormone, has been shown to decrease the immune response in animal studies. Prasterone (Prestera), from Genelabs Technologies contains DHEA and has shown considerable benefit in human trials. As disease models emerge for lupus, novel strategies are beginning to surface. LJP 394 (La Jolla Pharmaceuticals), a B-cell antibodies inhibitor that is thought to attack double-stranded DNA. Studies show LJP 394 reduces renal flares in lupus subjects with poor renal function and the drug has had some success in human trials. Future SLE research could include treatments based on gene therapy, vaccines or novel immunosuppressives.

Other less common, but still occasionally debilitating arthritic diseases include ankylosing spondylitis, gout, pseudogout, polymyalgia rheumatica, giant cell arteritis (GCA), and scleroderma. Ankylosing spondylitis (AS) is a rheumatic disease that causes arthritis of the spine and sacroiliac joints and can cause inflammation of the eyes, lungs and heart valves. Although gout and pseudogout have similar symptoms, characterized by acute localized swelling and pain, they are in fact caused by completely different phenomena. Gout is caused by an excess of uric acid in the body and can have many underlying causes such as poor kidney function, diets rich in purines, or other metabolic abnormalities. The deposit of calcium pyrophosphate crystals in joint tissues causes pseudogout. The reason that these crystals form is not certain but can include enzyme deficiency, glandular problems, or genetic disorders. TMX-67 is a novel, xanthine oxidase/dehydrogenase (XO/XDH) inhibitor being developed for the treatment of the hyperuricemia associated with gout. Polymyalgia rheumatica, and its related disorder giant cell arteritis (GCA), are inflammatory disorders that can affect the blood vessels.

The rarest rheumatic disorder is scleroderma, which affects fewer than 1.5 out of 100,000 Americans. Scleroderma is an autoimmune disease that is characterized by thickening of the skin from deposits of collagen. The underlying causes of the disorder are unknown and presently there are few drugs in development that are specifically indicated to treat it.

The rheumatology therapeutic area encompasses a wide range of chronic and painful disorders, usually characterized by inflammation. New anti-inflammatory drugs would have a direct benefit to patients with these diseases. The management of pain and inflammation could represent one of the largest research areas in the future. Although rheumatic diseases affect people of all ages, the predicted aging of America will drastically increase the need for more treatments. In total, CenterWatch has identified more than 70 drugs in clinical trials that are specifically indicated to treat these disorders. Future advances in stem cell research, gene therapy, immunosuppressives and combinational drugs could change the face of rheumatic disease for patients worldwide.