| Continued…
Conventional Therapies: Many of the therapies for OA and RA have the inflammatory component as their target. Glucocorticoids (steroids) have long been employed to control inflammation. Their use over the long-term is discouraged because of potential severe toxicities to muscle and other organs. However, over the past 20 years, treatment regimens have indicated that the commonly employed steroid prednisone in low doses of 7.5 mg or less may be employed over long periods and are usually well tolerated and safe. Non-steroidal anti-inflammatory drugs (NSAIDs) are also commonly used in initial treatment of RA and OA.
NSAIDs (i.e., diclofenac, tenoxicam, indomethacin, tenidap, ibuprofen, to name just a few) are powerful anti-inflammatory drugs that act by inhibiting several components of the inflammatory pathways, including macrophage function and by the pharmacological inhibition of prostaglandin synthesis, in general. Long-term use of NSAIDs can produce gastrointestinal side effects, and the gastrointestinal mucosa can be injured so that bleeding occurs without warning. However, NSAIDs may be the most common drug therapy in the treatment of OA. The so-called Disease Modifying Anti-Rheumatic Drugs (DMARDs) are usually not the first line of treatment in RA because of associated toxicity with long-term use. However, x-rays and clinical evidence of aggressive joint damage with progression in patients treated only with steroids or NSAIDs usually requires DMARDs to be employed in RA therapy. DMARDs are less commonly used in OA treatment. The DMARDs commonly employed in RA include, sulfasalazine (Azulfidine), hydroxychloroquine (Plaquenil) and methotrexate (Rheumatrex). These DMARDs appear to be less toxic than previously commonly employed DMARDs such as gold, penicillamine and azathioprine (Imuran). Methotrexate appears to be particularly effective in RA and combination therapy where multiple DMARDs may be required to fully regulate clinical symptoms of RA at different disease stages. Thus, DMARDs appear to alter the activity of inflammatory and immune cells active in the progression of RA.
Status of Novel Therapies:
Cox-2 inhibitors. NSAIDs inhibit the activity of enzymes, termed cyclooxygenase, required for the synthesis of prostaglandins and other eicosanoids. Prostaglandins synthesized by macrophages and other inflammatory cells are, in part, responsible for significant inflammation in arthritis. The finding in 1991 that a least two forms of cyclooxygenases exist, called Cox-1 and Cox-2, resulted in numerous experimental and clinical studies that showed that Cox-1 was a normal enzyme involved in tissue homeostasis, whereas Cox-2 was induced in that it was synthesized only at sites of inflammation. Thus, according to Dr. David Gotlieb, a South African rheumatologist, “Inhibition of Cox-1 is therefore undesirable… while the inhibition of Cox-2 is desirable.” Cox-2 inhibitors, such as celecoxib (Celebrex) are about 375-fold more selective for Cox-2 than Cox-1. Celebrex is effective in controlling the inflammation of arthritis with no significant complications when compared to placebo.
Inhibitors of tumor necrosis factor-alpha. Inflammatory arthritis is characterized, in part, by an increase in the amount of soluble mediators of inflammation called cytokines. One of these cytokines is tumor necrosis factor-alpha (TNF-alpha). Some RA patients resistant to conventional therapies with steroids, NSAIDs and even DMARDs have been treated with an anti-TNF-alpha antibody called infliximab (Remicade), which is a genetically engineered hybrid molecule made by combining human and mouse cell proteins or with another genetically engineered, human-derived molecule, etanercept (Enbrel). According to Drs. Maini and Taylor (Kennedy Institute of Rheumatology, London, UK) randomized phase II and III clinical trials of anti-TNF reagents have shown an acceptable safety profile and significant clinical efficacy in cases of RA that have not responded to conventional therapy. Anti-TNF combined with methotrexate appears to be particularly effective in RA patients whose disease persists even after therapy with DMARDs. However, RA patients with co-morbid conditions, including serious infection or cancer, are not advised to use anti-TNF therapies.
Oral Collagen. “Ingesting low doses of Type II collagen (the collagen type found in articular cartilage of synovial joints) may help relieve the severe joint pain, swelling and stiffness of the disease. In a clinical trial to determine the efficacy of oral collagen, RA patients continued on NSAIDs or oral steroids, but prednisone use did not exceed 10 mg. daily. The mechanism of the action of oral collagen presumably involves a reduction in the severity of the immune response associated with RA. According to Dr. John Stuart, a rheumatologist at the University of Tennessee in Memphis, oral collagen, “has the tremendous advantage in that it has no side effects.” The use of oral collagen therapy as an adjunctive treatment in RA continues to be studied.
According to an article published on The Lancet Interactive, the device worked so well that a phase III trial was halted early. Almost 50 percent of the 109 RA patients on the study, who had RA for a mean of 15.5 years, have significant improvement in symptoms. Additional studies are needed to further ascertain the mechanism of action of the Prosorba column and whether or not it will be useful in treating other autoimmune disorders in addition to RA.
B Cell Depletion. RA is perpetuated by a chronic cycle in which “autoreactive B lymphocytes generate their own antigen, called IgG rheumatoid factor,” according to Dr. Jonathan C. Edwards (University College, London, UK). Studies were designed by his group to determine whether or not B lymphocyte depletion would lead to clinical remission in RA patients. A monoclonal antibody, called anti-CD20 was employed in combination with prednisolone and cyclophosphamide (Cytoxan) to treat 20 patients who had RA refractory to other therapies for about 20 years. The results of these studies were reported this month at the American College of Rheumatology annual meeting in Philadelphia. The majority of RA patients responded to B-lymphocyte depletion brought about by anti-CD20 and were able to discontinue DMARDs. Reappearance of RA symptoms in some patients correlated with increased levels of B lymphocytes. Side effects of this novel therapy were reported to be minimal. A formal controlled clinical trial is planned.
Both conventional and novel therapies for the medical treatment of OA and RA provide an increased armamentarium for use by physicians in the care of patients with these diseases. More recently, novel therapies are directed at altering specific pathways implicated in both the pathogenesis and progression of OA and RA. The discovery of new pathways in these diseases will offer additional targets for drug intervention and perhaps even gene therapy. A better understanding of the relevance of these pathways integral to the inhibition of immune system dysfunction and inflammation should provide us with important new treatments for OA and RA in the next few years.