Category: Arthritis

Overview Despite the relatively low efficacy of the interleukin (IL)-lβ antagonist anakinra and the relative lack of success of this agent in the rheumatoid arthritis market, companies continue to study IL-1 and other interleukins in the hope of finding a novel drug for rheumatoid arthritis. Three interleukin-based therapies that have advanced to comparatively late-stage development are discussed here, including Chugai/Roche’s atlizumab (MRA) and Amgen’s AMG-714 (HuMax IL-15), which target IL-6 and IL-15 respectively. Abbott’s ABT-874, an anti-IL-12 mAb currently in Phase II studies, is not discussed owing to a lack of clinical data in rheumatoid arthritis. Regen-eron’s IL-1 inhibitor RGN 303 was also in clinical …

Overview A new class of biological agents has emerged that specifically target T and B lymphocytes, the main cells involved in an adaptive immune response. Most currently available biological agents target the products of activated macrophages, cytokines. However, T cells help activate macrophages, and both types of lymphocytes have been implicated in the inflammation and joint destruction found in rheumatoid arthritis. The rheumatoid synovium contains activated T and B cells, and immunoglobulin produced by B cells, such as rheumatoid factor and antinuclear or anticytoplasmic autoantibodies, serve as diagnostic markers for rheumatoid arthritis that may also be involved in the disease process. This section discusses one emerging therapy that …

Overview The conventional Disease-modifying antirheumatic drug class includes a wide range of agents as diverse as antimalarials, cytotoxics, and immunosuppressants. Unlike anti-inflammatories, which provide symptomatic relief without altering the natural course of the disease, Disease-modifying antirheumatic drugs typically lack a direct analgesic effect but have the potential to slow or prevent joint damage in rheumatoid arthritis patients. In 2002, the ACR published revised guidelines for the treatment of rheumatoid arthritis advocating more aggressive use of conventional Disease-modifying antirheumatic drugs earlier in the rheumatoid arthritis treatment regimen in an effort to limit joint damage and minimize loss of joint function and disability. As a result, the use …

Overview The first generation of selective COX-2 inhibitors, such as rofecoxib (Merck’s Vioxx) and celecoxib (Pfizer’s Celebrex), demonstrated their ability to reduce gastrointestinal (GI) side effects in comparison with traditional nons-teroidal anti-inflammatory drugs (NSAIDs), which suppress the isoforms of COX, COX-1 and COX-2, less discriminately. These agents still cause some degree of GI upset, however, so R&D efforts have been focused on developing a second generation of inhibitors that have an even higher degree of selectivity for COX-2. Valdecoxib (Pfizer’s Bextra) and etoricoxib (Merck’s Arcoxia) were the first of this second generation of selective COX-2 inhibitors to be launched; they are reviewed in “Current Therapies.” Concerns regarding …

Overview Even though immunosuppressive agents such as azathioprine (Glax-oSmithKline’s   Imuran,   generics)  and  cyclosporine   (Novartis’   Sandimmune/Neoral, generics) have been used for decades to treat the signs and symptoms of rheumatoid arthritis, development of novel agents in this class for rheumatoid arthritis has been sluggish because of efficacy and safety concerns that have arisen in clinical trials of agents under development. Nonetheless, companies are pursuing development of immunosuppressive therapies. Excluded from this analysis are immunomodulators currently in Phase II trial programs but for which large-scale trial data are currently lacking, including Androclus Therapeutics’ AT-001 and Wyeth’s temsirolimus. Mechanism Of Action Immunosuppressants function through a variety of mechanisms, but …

Overview Biotechnology companies such as Scios (a subsidiary of John-son&Johnson), Vertex, Celgene, and Cephalon dominate the field of mitogen-activated protein (MAP) kinase-based therapeutics. These companies are developing oral small-molecule inhibitors of MAP kinase for the treatment of inflammatory disorders such as rheumatoid arthritis and Crohn’s disease as well as oncology indications. This section discusses those agents that have advanced to Phase II trials, the most advanced stage of development for members of this class. Mechanism Of Action The enzyme p38 MAP kinase is part of an intracellu-lar signal transduction cascade involved in regulating the expression of several proinflammatory cytokines, including IL-1β and tumor necrosis factor-alpha. Patients …

Prosorbd Column Developed by Cypress Bioscience as a novel blood-filtering device, the Prosorba column was licensed for comarketing in the United States, Europe, and Japan to Fresenius Hemotechnology. The column received FDA approval in 1999 for patients unresponsive to or intolerant of Disease-modifying antirheumatic drug therapy, and it was launched in the United States and Europe in 2000. This device uses approximately 200 mg of protein A (a component of the Staphylococcus bacterium that selectively binds IgG and IgG-bound antigens) covalently bound to an inert silica matrix. In a process similar to kidney dialysis, a patient’s blood is removed from a vein in one arm and passed through …

Overview Corticosteroids have long been employed in the treatment of rheumatoid arthritis and remain a key component of symptom management. They produce potent, rapid suppression of inflammation with consequent improvements in joint pain and swelling. Studies showing that corticosteroids can reduce the rate of joint damage in rheumatoid arthritis patients led to their initial classification as disease-modifying agents. However, rheumatologists caution that the disease-modifying properties of corticosteroids are limited, and they should not be administered as a monotherapy to rheumatoid arthritis patients with active disease. Instead, true Disease-modifying antirheumatic drugs, either conventional or biological, should be initiated, and corticosteroids used as supplemental therapy to control symptoms as …

Oral prednisone (Pfizer’s Deltasone, generics) is commonly prescribed in low doses (less than 10 mg daily) to treat the signs and symptoms of rheumatoid arthritis. Oral corticosteroids — including prednisone — can be used as a short-term therapy during periods of high disease activity or as a bridge therapy and can be administered for long-term use in combination with Disease-modifying antirheumatic drugs. Corticosteroids act as anti-inflammatory and immunosuppressive agents through multiple effects: inhibiting synthesis of proinflammatory mediators (prostaglandins, leukotrienes, and cytokines); disrupting cellular activation, migration, and proliferation; and blocking edema formation. Corticosteroids can also inhibit the expression of COX-2 and block the activity of collagenase and other cartilage-damaging enzymes. Low-dose oral …