Other immunomodulating agents

Anakinra (Kineret)

Anakinra is a recombinant human variant of the naturally occurring interleukin (IL)-1 receptor antagonist (IL-1Ra), which blocks the IL-1 signal and inhibits IL-1, which mediates synovial damage and inhibits repair in RA. Half-life is 4 to 6 hours and it is administered as daily subcutaneous injections. Anakinra has a favorable safety profile but poor long-term efficacy in adults and may be of limited use [15]. Infections occur at a similar rate as that of the placebo groups [16,17].

Rituximab (Rituxin)

Rituximab is a chimeric human-mouse monoclonal antibody against CD20 on pre-B lymphocytes and mature B lymphocytes. Binding induces B-lymphocyte lysis, depleting B-cell lineages. B lymphocytes mediate path-ogenesis of RA at multiple points in the inflammatory response and are associated with chronic synovitis. Administration for RA is two infusions

2 weeks apart. Half-life is 3.5 to 17 days with B-cell depletion enduring for several months, being detectable in serum 3 to 6 months after treatment. Rituximab is approved for non-Hodgkin's lymphoma and RA. Infectious concern surrounds hepatitis B virus (HBV) and HCV reactivation, and susceptibility to such viruses as cytomegalovirus, herpes simplex virus, varicella-zoster virus, parvovirus B19, and JC virus. Severe fatal infections have occurred up to 1 year after treatment. Live vaccine administration is not recommended [18].

Abatacept (Orencia)

Abatacept is a fully humanized soluble fusion protein that mimics the naturally occurring CTLA-4. CTLA-4 circulates and down-regulates T-cell activity by binding to CD28 on T lymphocytes. This action blocks the costimulatory signal between CD28 and antigen-presenting cell proteins CD80 or CD86, thereby decreasing T-cell activation and proliferation and subsequent B-cell effects with inhibition of TNF-a, IL-2, IL-6, and possibly interferon-g [19]. Administration is as an infusion at weeks 0, 2, and 4 and then every 4 weeks. Half-life is 8 to 25 days with biologic effects lasting up to

3 months. Live vaccines should not be given until 3 months after treatment. Abatacept is in early postmarketing stages, and establishing trends of associated infectious disease requires time. An increased risk for TB and bacterial pneumonia, however, may exist. One case each of sepsis, aspergillosis, and septic arthritis was reported [20].

Natalizumab (Tysabri)

Natalizumab is a chimeric monoclonal antibody directed at a4-integrin, a membrane protein on all leukocytes except neutrophils. Leukocytes migrate from the vascular space and into parenchyma by a4-integrin-recogniz-ing receptors on various cell adhesion molecules. Natalizumab competitively binds a4-integrin preventing transmigration of inflammatory cells across endothelial cells and into tissue. Half-life is 7 to 15 days administered at four weekly infusions for multiple sclerosis. It is approved for treatment of relapsing-remitting multiple sclerosis and may soon be approved for RA and Crohn's disease. In addition to progressive multifocal leukoencephalop-athy (see later), for which there is now black box and bold warnings, premarketing trials identified cases of Aspergillus, Pneumocystis jiroveci (formerly carinii) pneumonia, pulmonary Mycobacterium avium complex, and a fatal case of herpes encephalitis [21].

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