Treatment of Rheumatoid Arthritis Part 4

New Therapeutic Advances

Recently, many new agents to treat rheumatoid arthritis have been developed or are under investigation. Traditional antirheumatic drugs suppress the inflammatory response and slow the process of joint destruction. Yet the mechanisms of action for these drugs are nonspecific. Newer drugs have been designed to target the inflammatory process and specific components in the inflammatory cascade. The newer biotechnology agents have been designed to target components of the immune system involved in inflammation, while preserving the integrity of the immune system to fight off infection. Another relatively new approach is the use of combination therapy with various DMARDs in the hope that combining drugs with different mechanisms of action will provide added benefit.

Cox Inhibitors: The variation in GI side effect profiles of NSAIDs may be due to the COX selectivity of individual drugs. COX serves as the rate-limiting enzyme in prostaglandin production. Inhibiting this enzyme decreases prostaglandin-induced initiation and maintenance of inflammatory responses. Two isoforms of COX have been identified (COX-1 and COX-2).27 COX-1 is beneficial in helping to maintain normal cellular physiologic processes in the GI tract, kidneys, and blood. In the gut, COX-1 stimulates the secretion of bicarbonate and mucus, and reduces stomach acid secretion. All of these actions are protective for the lining of the stomach against irritants. COX-2 is involved in selectively activating pro-inflammatory cytokines and does not have a gastroprotective effect. Therefore, the ideal agent would selectively inhibit COX-2 to reduce the inflammatory response but also maintain the GI and renal protective nature of COX-1.29 NSAIDs have been developed to be COX-2 selective, or combined with synthetic prostaglandins to minimize GI intolerance. Of the NSAIDs on the market, etodolac (Lodine) and nabumetone (Relafen) are the most selective agents for COX-2 and have the lowest incidence of GI and renal side effects. Piroxicam (Feldene), indomethacin (Indocin), naproxen (Naprosyn), and sulindac (Clinoril) have a greater affinity for inhibiting COX-1 and therefore an increased risk of GI and renal problems. Flurbiprofen (Ansaid), ibuprofen (Motrin), meclofenamate sodium (Meclomen), and diclofenac (Voltaren) show equal affinity for COX-1 and COX-2 inhibition. While the clinical relevance of COX-2-selective NSAIDs is unclear, these agents may prove beneficial in patients requiring long-term NSAID therapy who are predisposed to developing adverse GI effects. COX-2 selective agents would inhibit the inflammatory response but maintain the GI protective properties of COX-1. Studies using one of the first COX-2 inhibitors, meloxicam, demonstrated that selectively inhibiting COX-2 improved GI tolerability while maintaining therapeutic effectiveness. An FDA advisory panel has recommended approval of Celecoxib (Celebra), which in Phase III trials shows promising results for pain reduction and joint swelling. In a clinical trial enrolling 300 patients with active RA, celecoxib was administered to patients experiencing an acute flare. Patients given either 200 mg BID or 400 mg BID had a statistically significant improvement. Patient global assessment scores, duration of morning stiffness, and number of painful or tender joints all improved compared to placebo. A COX-2 inhibitor by the name of Vioxx will be undergoing clinical trials in late 1998. Preliminary research shows a significant improvement in preventing GI mucosal damage when compared to aspirin and ibuprofen.

Biotechnology: Biotechnology is playing an increasing role in the development of novel approaches to manage rheumatoid arthritis. Molecular technology has permitted the identification of specific cell components and cell surface markers that contribute to the immune-mediated response in rheumatoid arthritis. Although the etiology of rheumatoid arthritis remains unknown, this increased understanding of the pathogenesis provides opportunities to target the immune system with specific therapies. Several biologic agents developed for the treatment of rheumatoid arthritis include monoclonal antibodies, recombinant interleukin-1 receptor antagonists, and recombinant soluble tumor necrosis factor receptor.

The role of cytokines in rheumatoid arthritis is a concept that has been explored for many years. Identifying a T-cell mediated immune response was the first step in targeting the inflammatory response in rheumatoid arthritis. The concept of activated T-cells both initiating rheumatoid synovitis and maintaining chronic RA has focused new attention on specific pro-inflammatory cytokines such as IL-1 and TNF-a. These cytokines are believed to be directly responsible for the clinical manifestations of rheumatoid arthritis, and therapies are being developed to specifically target these areas.

Monoclonal Antibodies: Monoclonal antibodies (MAbs) have been developed to bind to receptors on the surface of T-cells, thus interfering with their function or making the T-cells unavailable for binding. By binding to T-cells, MAbs disable the autoimmune response involved in inflammation and tissue destruction. This may slow the disease progression. Some trials of monoclonal antibodies (MAbs) have shown a resultant reversible depletion of T-cells that would prevent the patient from mounting a T-cell mediated immune response. IDEC Pharmaceuticals and SmithKline Beecham have partnered to develop a chimeric combination of human and monkey antibodies. This agent has proven to be less allergenic than previous products made with mouse antibody. Phase II trial results indicate an improvement >20% by American College of Rheumatology criteria in 42%–47% of patients receiving therapy with 40 mg and 80 mg, respectively. Dosages of 140 mg were also evaluated but had to be discontinued due to the development of rash. No other adverse effects were reported, and rash was not observed in patients receiving the lower dosages. Patients receiving this therapy sustained benefit for 2–3 months following discontinuation before arthritis symptoms worsened.
Other MAbs are being developed, such as an antibody that would be coupled with a cytotoxin that, when taken up into the target cell, would cause cell destruction and decrease the immune response. No agents are currently available using these techniques.

Cytokines: Tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) are two proinflammatory cytokines that appear to be dominant in the inflammatory response in rheumatoid arthritis. In patients with rheumatoid arthritis, there is an imbalance between proinflammatory and anti-inflammatory mediators, which may or may not be cytokines. This leads to increased activity of the proinflammatory components (TNF-a and IL-1) and inflammation at the site. By providing exogenous inhibitors such as antagonists or antibodies or soluble receptors, one may achieve an anti-inflammatory state within the joint. When administered over 6 months to patients with rheumatoid arthritis, IL-1 receptor antagonists have been shown to decrease C-reactive protein, as well as improve responses based on American College of Rheumatology clinical response criteria. Monoclonal antibodies to TNF provided the first evidence that TNF inhibitors may be useful agents in treating rheumatoid arthritis. Both open-label and double-blind, placebo controlled trials using MAbs to TNF have demonstrated significant decreases in CRP levels and number of swollen joints. Agents used to inhibit the activity of TNF-a and IL-1 have only been used as monotherapy. Combination biologics is in its infancy at this time.

TNF Receptors: The identification and isolation of soluble TNF receptors (sTNFRs) is also being pursued. sTNFRs are a naturally occurring counter-regulation mechanism to the activity of TNF. Levels of soluble receptors are elevated in both plasma and synovial fluid samples of rheumatoid arthritis patients and patients with other autoimmune and inflammatory conditions. A recombinant human TNFR fusion protein (TNFR:Fc) has been developed by Immunex to neutralize TNF. Etanercept (Enbrel) is a product of recombinant DNA technology in which the extracellular portion of two TNF receptors is linked to the Fc fragment of human IgG1 molecules and then expressed in mammalian cells. The product acts as a noncompetitive inhibitor of TNF, preventing binding of TNF to the cell surface receptor, thus reducing TNF activity.
Both Phase II and Phase III clinical trials have been conducted using etanercept. Etanercept was administered as 10–25 mg SC twice weekly. Subjects had active RA and had failed to respond to therapy with DMARDs at least once. Results show a statistically significant reduction in disease activity, which was determined using clinical endpoints (American College of Rheumatology clinical response criteria); biological markers (CRP, ESR); and quality of life assessments (health assessment questionnaire, visual analog pain scale). Clinical improvement was seen in these areas within 2 weeks of initiating therapy. Treatment was generally well tolerated, with the most common side effect reported as redness and discomfort at the injection site. There appeared to be an increased incidence of upper respiratory tract infections in patients receiving etanercept; however, this difference was not significant when the data was analyzed over time.

Soluble cytokine receptors such as etanercept may have a therapeutic advantage over other TNF agents since immunogenicity does not appear to be an issue. Nonhuman or chimeric MAb therapy often stimulates the production of antibodies which deactivate the therapeutic agent, limiting long-term use or inducing allergic reactions. In the previously mentioned Phase II and III studies involving etanercept, neutralizing antibodies were not detected. The information gathered on etanercept is promising in its therapeutic applications in rheumatoid arthritis. At press time etanercept was recommended for approval by the FDA arthritis advisory committee as a mono agent or in combination for the treatment of active rheumatoid arthritis.

Immunosuppression: Suppressing the immune response to a particular antigen can be induced by oral administration of certain antigens. This may be beneficial in treating rheumatoid arthritis since oral administration of antigens including collagen have been shown to be effective in blocking the induction of, or ameliorating, established disease. Proposed mechanisms of action include induction of anti-inflammatory cytokines (i.e., IL-4 and IL-10) and the stimulation of growth factor at the site of joint injury. Several studies have investigated oral collagen. Patients given chicken type II collagen showed statistically significant improvements in the number of swollen or tender joints while patients receiving bovine type II collagen showed only minor clinical response. More controlled trials are needed to evaluate the efficacy of orally administered type II collagen in treating rheumatoid arthritis.
Immunosuppressive agents are another growing area of development in treatments for rheumatoid arthritis. Leflunomide (Arava) is an isoxazole derivative similar to methotrexate. Current studies with the drug are focused on treating autoimmune diseases such as rheumatoid arthritis. The mechanism of action of leflunomide is not completely known; however, it is believed to interfere with T-cell proliferation, which then inhibits synthesis of pyrimidines. This decrease in pyrimidine synthesis leads to a reduced number of proinflammatory cytokines within the body. The mild anti-inflammatory effect seen with leflunomide may be attributed to this activity.
Leflunomide dosing is one 100 mg tablet daily for three days, followed by a maintenance dose of one 20 mg tablet each day. Data on the use of leflunomide in patients with RA are promising. Both Phase II and Phase III double-blind, placebo-controlled, clinical trials showed statistically significant improvement versus placebo. Patients receiving leflunomide had a decreased number of tender or painful joints, improved global patient assessment scores, and improved clinical response criteria. Clinically significant results were seen after 1 month of therapy and benefit was retained for up to 18 months. Side effects associated with leflunomide include diarrhea, reversible alopecia, and hypertension. Six percent of patients discontinued therapy due to these side effects. Leflunomide has now been approved by the FDA for the treatment of inflammatory arthritis. This new agent will provide yet another approach to treat RA and add to possible combination therapies with other DMARDs.

Combination Therapy: By combining several drugs with different mechanisms of action, a greater benefit may be achieved than if the same drugs were used independently. It may also be possible to use lower doses of the medications, therefore minimizing the toxicities associated with each drug. Combinations of DMARDs that have been evaluated in the literature include MTX and HCQ; MTX, AZA, and HCQ; MTX and gold; MTX and cyclosporin A; MTX and SSZ; MTX, SSZ, and HCQ; HCQ and cyclosporin A; and MTX and DP. Studies indicate that the combination of antimalarials and DP shows antagonism within the body. While the effectiveness of combination therapy is difficult to evaluate, these therapies have provided relief when other medications used alone failed to do so.

Rheumatoid arthritis: Conclusion

New therapies and modifications on old therapies are constantly being explored in order to improve the treatment of rheumatoid arthritis. As more is learned about the disease process and the pathophysiology behind it, improved, targeted therapies can be developed. While there is no cure yet for rheumatoid arthritis, the future is promising for finding the treatments necessary to control and suppress the disease, enabling rheumatoid arthritis patients to continue to work and more comfortably perform their daily activities.