Rheumatoid Arthritis: Introduction to the Tumor Necrosis Factor-Alpha

In recent years, doctors have heralded a "new era" in the treatment of rheumatoid arthritis (RA) with the introduction of a class of medications called biologic response modifiers. Among these "biologics" are medications that take an entirely different route to treating the disease than previous therapies. They target a specific component of the immune system called the tumor necrosis factor-alpha (TNF-alpha).

Tumor necrosis factor-alpha is a type of cytokine or small protein that is released by cells in the body and serves many functions. One of its most important roles is the effect it has on the communication between the cells that trigger inflammation and respond to infections. It has been linked to several chronic inflammatory conditions, including rheumatoid arthritis, and its presence in the synovial fluid of joints is now considered to be an important indicator of the disease.

Understanding the Immune System
To understand the role of TNF-alpha, it is first necessary to understand how the body's immune system works. The immune system is a complex network of cells and organs whose overall job is to protect the body against attacks by foreign invaders, such as infections with bacteria and viruses. When a foreign substance, also known as an antigen, is present, it activates a specific type of white blood cell called T lymphocytes or T cells. These cells circulate through the body to protect it from infection, and they coordinate the immune response in order to neutralize the foreign substance.

When an autoimmune disease is present, the immune system malfunctions and can no longer distinguish between self and non-self cells. As a result, it starts attacking the body's own healthy tissues and organs. This response stimulates the overproduction of T cells. When the T cells are overproduced and "activated" by the overstimulated immune system, they begin to release chemicals that bring about the destruction of the tissues surrounding the joints. This results in the pain, inflammation and damage to bone and cartilage that are the typical signs and symptoms of rheumatoid arthritis.

One part of this activation includes the release of interleukins, which are the types of cytokines that the immune system uses to communicate messages between cells. TNF-alpha is one of these cytokines.

Tumor necrosis factor-alpha is naturally produced in the body. Its job is to mobilize white blood cells to fight infections and other invaders. This mobilization temporarily causes inflammation in the affected area. A healthy body can rid itself of excess TNF-alpha, but the body of a patient with rheumatoid arthritis cannot. As a result, more and more white blood cells travel to the affected area. The build up of TNF-alpha, particularly in the rheumatoid joint, is what causes inflammation, pain and tissue damage.

New Drugs Target Tumor Necrosis Factor-Alpha
Because TNF-alpha has pro-inflammatory effects, researchers have discovered that inhibiting it is clinically useful in treating rheumatoid arthritis. In recent years, drugs called biologic response modifiers, which have the ability to target or block a particular cytokine, have proven successful at reducing inflammation, pain and morning stiffness in the tender or swollen joints that are typically associated with rheumatoid arthritis. In most cases, these drugs usually start working within one to two weeks after treatment begins.

Biologics, as they are often referred to, are the newest class of drugs on the market to treat rheumatoid arthritis, and they are considered by many to be the most promising. In addition to halting the inflammation caused by the disease, studies show they can improve the quality of life and function of patients who have rheumatoid arthritis. Further studies also indicate they may slow down and, in some cases, halt the progression of the disease.

Some of these drugs, which are made from human or animal proteins, work by binding to the TNF-alpha and preventing it from communicating with other cells. By doing so, they are able to block the action of TNF-alpha, which, in turn, halts the inflammation, pain and joint damage caused by rheumatoid arthritis. Other biologics target different mechanisms in the immune system. Biologics, as a whole, are not considered a cure—when the treatment stops, their therapeutic effect tapers off, although not as rapidly as with shorter-acting drugs.

There are several biologic medications that are considered TNF-alpha blockers, and they are available and approved for the treatment of rheumatoid arthritis. They include adalimumab (Humira®), etanercept (Enbrel®), and infliximab (Remicade®). These drugs haven't been tested against each other, so no one knows which one is the most effective. However, extensive clinical trial data has confirmed that these drugs are well-tolerated and effective. They are commonly used alone or in combination with methotrexate.

Because these biologics target TNF-alpha, the specific mechanism in the immune system that causes inflammation, they are thought to spare the body from the potentially serious side effects that have been associated with other rheumatoid arthritis treatments. However, they carry their own set of side effects that range from minor infections at the site of the injection to more serious concerns. Use of these biologics has been linked to tuberculosis, lymphoma and severe blood disorders. Scientists are still investigating this connection; clinical trials continue to look at the long-term safety of these agents, because it is still relatively unknown.

Opting for treatment with these newer agents involves serious consideration. They have not proven effective for everyone, and because of their complexity, they are very expensive, sometimes costing upwards of $12,000 per year. For these reasons, and because long-term data is still unavailable, biologics are usually recommended for use in patients who have not responded to more conventional treatments, or who have experienced side effects as a result of other medications.

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