Rheumatoid arthritis (RA) is a highly progressive and destructive disease of synovial joints. Changes in the structure and function of the synovium in the joint are a hallmark of the disease process. Inflammation contributes significantly to the destruction of cartilage and bone in RA.
Treatment of the inflammatory component of RA is a first step in the therapy of the disease. However, an article, published in “UpToDate” by Drs. Harris, Schur and Maini stated that the duration of active RA treated with conventional therapies without significant remission makes it more difficult to treat RA long-term with disease-modifying antirheumatic drugs (DMARDs) and anticytokine drugs. The available evidence suggests that early aggressive therapy with DMARDs and anticytokine agents designed to inhibit pathways that contribute to cartilage and bone destruction in RA can be very effective in limiting the bad outcomes occurring when only first-line conventional therapies are employed early in disease management.
Remicade (Infliximab), Enbrel (Etanercept) and Arava (Leflunomide) are three FDA-approved drugs for the treatment of RA. They are among the first in a class of agents designed specifically to neutralize or inhibit two important components of the RA process; expression of cartilage- and bone-destroying enzymes and proliferation of thymus-derived lymphocytes (T-cells) within the synovial joint.
Remicade and Enbrel: Anti-TNF-Alpha Therapy
TNF-alpha is a cytokine that plays a critical role in RA because TNF-alpha induces pro-inflammatory cytokines such as interleukin-1 and interleukin-6, increases migration of inflammatory leukocytes into the synovial joint, activates polymorphonuclear leukocytes (PMNs), eosinophils and acute phase proteins produced in the liver, as well as inducing resident synoviocytes and articular chondrocytes to synthesize enzymes that when activated have the capacity to destroy the matrix of cartilage and bone. Activated PMNs also release enzymes capable of cartilage and bone destruction. Remicade neutralizes the biological activity of TNF-alpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha, which inhibits TNF-alpha binding to its receptor on the surface of inflammatory cells. This results in a decrease in the amount of TNF-alpha circulating in the peripheral blood. In contrast, Enbrel competitively inhibits the binding of TNF-alpha to the TNF-alpha receptor sites on cells. Since TNF-alpha must bind to its receptor with strong avidity, blocking this pathway neutralizes the downstream effects of TNF-alpha.
The safety and efficacy of Remicade has been assessed in RA patients treated with methotrexate. Several outcome measurements employed for assessing the destructive component of RA have been modified by treatment with Remicade. These include, a retardation of joint erosions and stabilization of joint space narrowing, the latter an indicator of cartilage loss. Other indicators of clinical effects include the Sharp score for hand and feet RA, which shows a stabilization of structural changes when compared to methotrexate alone.
Enbrel was the first in a new class of RA disease-modifying drugs approved by the FDA. Enbrel has shown efficacy in the treatment of RA and several clinical objective measures of its effectiveness have been indicated. These include, decreased pain, the number of tender joints and duration of morning stiffness. Enbrel has also been shown to slow the radiographic progression of cartilage and bone loss in RA.
The original statement of the manufacturer’s contraindications for Remicade and Enbrel clearly stated that patients with serious infections, including those with sepsis or those patients showing allergic reaction to these drugs, should not use them for RA therapy. A strong warning from the FDA (http://www.fda.gov/bbs/topics/ANSWERS/ANS00954.html) indicated safety concerns for Enbrel that extended the adverse reaction report to include any patients with active infection, including chronic or localized infections. It was also recommended by the FDA that their physician should closely monitor any RA patients receiving Enbrel who develop a new infection. Whether Enbrel therapy contributes to the incidence of significant infection must now be considered in the treatment management strategy for RA. However, controlled clinical trials have not shown an increase in serious infections in patients receiving Enbrel. It is worthwhile noting that both Remicade and Enbrel were approved by the FDA to treat patients with symptoms of moderate to severe RA who had not responded well to other more conventional therapies, including methotrexate. With the potential that more RA patients will commence anti-TNF-alpha therapy early in their disease, physicians and patients must work closely to ensure that any signs of infection be closely monitored.
Arava: An Inhibitor of DNA Synthesis
Proliferation of activated T-cells of the immune system is a critical step in the autoimmune process. Experimentally, elimination of T-cells from the inflamed synovial joint has been shown to reduce the severity of bone destruction in animal models of RA. Although the mechanism for the action of Arava is not fully understood, Arava is thought to inhibit T-cell proliferation by inhibiting the enzyme, dihydroorotate dehydrogenase (DHODH) whose activity is required for the synthesis of pyrimidines and the replication of DNA. Arava may also inhibit tyrosine kinase(s), a class of phosphorylating enzymes, whose activity is required for T-cell effector function.
Arava has been compared to methotrexate therapy for RA. While many RA patients improve on methotrexate therapy when compared to placebo in multi-center, randomized, double-blinded clinical trials, RA patients appeared to respond somewhat better to Arava. An elevation in liver enzyme levels in RA patients receiving Arava has been reported, but this is generally transient. Nevertheless, liver enzyme levels should be closely monitored. Arava is not recommended for patients with serious hepatic involvement or in patients with evidence of Hepatitis B or C viruses, or those patients immunocompromised from other treatments.