TNF-α : Inhibitors
Two recently introduced biological therapies were de-signed to interfere with the inflammatory cascade initi-ate by TNF-α . Etanercept (Enbrel) is indicated for the treatment of moderate to severe rheumatoid arthritis in individuals over age 4. Infliximab in conjunction with methotrexate (Remicade) is approved for use by adults in the treatment of rheumatoid arthritis. It is also indi-cated for therapy of Crohn’s disease. Over the short term, the efficacy of these drugs in the treatment of rheumatoid arthritis appears to be superior to that of methotrexate alone; however, their ability to prevent bone erosion for longer than 24 months must be further studied. The cost of both drugs is significantly higher than that of the other DMARDs.
Etanercept is a recombinant fusion protein produced in Chinese hamster ovary cells. It consists of the intracel-lular ligand-binding portion of the human p75 TNF re-ceptor linked to the Fc portion of human immunoglob-ulin (Ig) G1. Two p75 molecules are attached to each Fc molecule. Etanercept binds to soluble TNF-α and TNF-α and forms inactive complexes, effectively lowering circulating levels of these cytokines. It is administered subcutaneously, generally twice weekly.
Infliximab is a chimeric monoclonal antibody tar-geted against TNF-α . It consists of a human IgG1 Fc heavy chain and partial -light chain fused to a murine hypervariable region. Infliximab binds to both soluble and transmembrane forms of TNF-α and inhibits their ability to bind to TNF receptors. It does not inhibit TNF-α , which binds to the same receptors as TNF-α . Infliximab is administered intravenously, usually at 4- to 8-week intervals.
The most common adverse reaction to etanercept is mild to moderate erythema, pain, or pruritus at the in-jection site (37%). Headaches and abdominal pain can also occur. New positive autoantibodies, such as antinu-clear antibodies (ANA), anti-dsDNA antibodies, and anticardiolipin antibodies, can develop in patients treated with etanercept. Although there is so far no as-sociation between this and the development of autoim-mune diseases or malignancies, long-term studies have yet to be done. Rare cases of pancytopenia may be as-sociated with this drug. Although clinical trials showed no increased risk of infection with etanercept treat-ment, postmarketing reports of serious infections, sep-sis, and associated fatalities exist.
Infliximab produces an acute infusion-related reac-tion consisting of fever and chills in approximately 20% of patients. Other common side effects include headache, nausea, and diarrhea. Persons given inflix-imab with methotrexate may have a greater elevation of hepatic enzyme levels than those given methotrex-ate alone. Because it is a human–mouse fusion protein, infliximab seems to be more immunogenic than etaner-cept. During infliximab treatment, autoantibodies (anti-dsDNA, ANA) and antibodies to the drug itself (human antichimeric antibodies) can develop. Con-comitant therapy with methotrexate or immunosup-pressive drugs decreases this risk somewhat. It is possi-ble that infliximab may increase the incidence of autoimmune diseases and malignancies; however, long-term data are needed to determine whether this is the case. As with etanercept, a low risk of serious infection was seen in clinical trials of infliximab; however, sepsis, disseminated tuberculosis, and other potentially fatal infections have been reported in patients taking this drug.
Etanercept therapy should not be initiated in patients with active infection. If an infection develops in a per-son taking etanercept, he or she should be closely mon-itored. If a serious infection or sepsis occurs, the drug should be discontinued. Etanercept should be used with caution in individuals who have conditions predis-posing them to serious infection (e.g., uncontrolled diabetes, hematological abnormalities). Data on drug interactions are limited. Live virus vaccines are con-traindicated because of the potential for secondary transmission of the infection by the vaccine. Myelo-suppressive antirheumatic agents have been associated with pancytopenia in some patients treated with etan-ercept.
Infliximab should not be given to individuals with known hypersensitivity to murine proteins. As with etanercept, precautions for the prevention of serious in-fections must be taken, and live virus vaccines are con-traindicated.