The “Dark Side” of Anti-Tumor Necrosis Factor Therapy

27 May

Anti-Tumor NecrosisThe introduction of biological agents in recent years for the treatment and possible reversal of the progression of some serious chronic diseases was heralded as a breakthrough in therapy, in which the benefits seemed to outweigh the risks. Although carefully controlled clinical trials demonstrated several adverse effects, the benefits of these agents led to the Food and Drug Administration’s (FDA’s) approval. After several years on the market and with the widespread use of these biological agents throughout the world, some serious adversities have emerged. This article presents some of the potential problems associated with the long-term use of these agents.


Etanercept (Enbrel®, Immunex, marketed by Amgen) and infliximab (Remicade®, Centocor) are tumor necrosis factor (TNF) antibodies that are used to treat severe cases of rheumatoid arthritis (RA) and Crohn’s disease (CD).
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Infliximab is the first product that has been documented to reduce the number of open fistulas that burrow through the bowel wall into nearby organs or through the surface of the skin in patients with CD. On August 24, 1998, the FDA approved this product for marketing to treat moderately to severely active CD in patients who had responded inadequately to conventional therapy. Infliximab is also indicated for patients with fistulizing CD to reduce the number of draining enterocutaneous fistulas. Overproduction of TNF-a leads to inflammation in conditions such as CD, RA, and other autoimmune diseases. Infliximab seems to reduce intestinal inflammation in patients with CD by binding to and neutralizing TNF-a on cell membranes and in the blood.

Seminal basic science work identified the importance of the proinflammatory cytokines (TNF-a) and interleukin-1|3 (IL-1p) by showing that they had an active role in the pathogenesis of RA. IL-1p is also a potent immunomodulator that mediates a wide range of immune and inflammatory responses, including the activation of B and T cells. These discoveries rapidly led to the development ofbiological agents that inhibited these cyto-kines and suppressed disease in patients with RA.

Etanercept is a soluble p75 TNF receptor that inhibits the action of TNF. Infliximab is a chimeric monoclonal antibody to TNF-a, approved for the treatment of severe RA.

Anti-interleukin-1|3 (anti-IL-1|3) is a well-validated cytokine target in inflammatory disease with in vivo neutralization of IL-1| that suppresses the arthritic process and confers beneficial effects on joint erosion. Controlled clinical trials have demonstrated the efficacy of chronic administration of etaner-cept and infliximab with methotrexate in slowing the progression of disease activity and joint damage in patients with early RA, with emphasis on the importance of early treatment.

Antibodies to pegylated IL-1p have the potential to complement anti-TNF-a treatment of RA, and one agent is currently under investigation (anti-IL-1p or CDP 484 [Cistron, Cell-tech]).

Another agent, anakinra (Kineret™, Amgen), is a synthetic protein that is similar to a naturally occurring protein in the body called interleukin-1 receptor antagonist (IL-IRa). In patients with RA, the body produces a high amount of IL-1Ra and other proteins that lead to joint damage. High concentrations of one of these proteins, IL-1, contribute to the pain, swelling, and stiffness associated with RA. Therapy with anakinra, which can block the action of IL-1, has been found to be safe and effective against RA.

Etanercept has also received FDA approval for patients with ankylosing spondylitis (AS). This condition is characterized by inflammation of the spinal joints and causes painful stiffening of the spine, often leading to fusion of the vertebrae that can leave the back curved and inflexible. Treatment of AS with etanercept is safe and efficacious, with significant improvement noted in as early as two weeks and continuing for 24 weeks.
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The FDA has also approved etanercept for the improvement of physical function in patients with moderately to severely active RA. The approval was based on results from three placebo-controlled trials in which etanercept improved patients’ physical functioning and disability scores for up to four years.

Adalimumab (Humira®, Abbott), previously known as D2E7, is the latest anti-TNF-a agent to be approved by the FDA for “reducing the signs and symptoms and inhibiting the progression of structural damage in adults with moderately to severely active RA who have had insufficient response” to one or more disease-modifying anti-rheumatic drugs (DMARDs).