Lesson 6 of 8: Understanding Biologics

In recent years, there's been a revolution in Disease-Modifying Antirheumatic Drugs, known as DMARDs, available to control RA, driven largely by biologic therapies. What are these agents, exactly? Let's start with a few quick basics about what goes wrong in RA and then have a look at how biologics work to help correct it.

ALLAN GIBOFSKY: In rheumatoid arthritis, a person's immune system mistakenly attacks healthy cells, mainly in the lining of the joints, but in other parts of the body as well. We don't yet know the cause. But it sets in motion a cascade of events involving T-cells, B-cells, and various messenger proteins called cytokines that play a role in activating your immune system.

A normal immune system mounts an inflammatory response that attacks and removes an invading organism and then stops. With RA, your immune system is in overdrive.

Biologic therapies are genetically engineered proteins-- hence, the term "biologics"-- designed to inhibit or shut off overactive parts of your immune system that keep signaling the attack on healthy cells. Biologics are disease-modifying agents, or DMARDs, that can affect underlying joint damage and slow the course of RA.

NEKETIA HENRY: Conventional drugs, such as methotrexate and biologics, are both disease-modifying. However, they are different kinds of agents that operate in very different ways.

ALLAN GIBOFSKY: Conventional DMARDs, like methotrexate, offer a more broad approach that tends to suppress your body's entire immune system. In contrast, biologics zero in on specific pathways that are known to drive inflammation.

Current American College of Rheumatology guidelines recommend methotrexate as a starting point for DMARD therapy. If that proves insufficient in controlling disease activity, the next step is a biologic, which can work fairly quickly to ease pain and swelling and prevent further joint damage.

Inflammatory diseases, like RA, are often driven by several factors. So there is no one-size-fits-all therapy. A treat-to-target plan can help in selecting an appropriate biologic or a replacement if the first one a patient tries doesn't work or, at some point, stops working.

Biologic agents are divided into several classes based on which aspect or pathway in the inflammatory process they block. Many biologics target cytokines that can trigger inflammation or are responsible for signaling that keeps it going. Each works by preventing a particular cytokine from causing inflammation.

Tumor Necrosis Factor, or TNF, occurs naturally in the body. It has been called the body's fire alarm because of its role in initiating the response to any kind of local injury. At low levels, it is thought to have beneficial effects in fighting infections. But at high concentrations, TNF can lead to inflammation and organ injury.

The picture that has emerged for TNF is that it plays a central role in the network of cellular and molecular events involved in RA. Because of this, TNF inhibitors are often a first choice in a biologic. Five anti-TNF agents are approved for use in RA, each with different properties and mechanisms, but all of which block or reduce the availability of TNF.

Another major class of cytokines are the interleukin proteins, especially interleukin-1 and interleukin-6. Both of these have important roles in regulating the body's immunologic and inflammatory response. Agents in this class work by blocking the receptors where interleukin-1 or interleukin-6 need to bind in order to activate processes involved in RA inflammation.

Biologic agents are available that block T-cell or B-cell activity, both of which are central players in the body's immune system and the response to inflammation in RA. Let's have a look at this aspect of the process.

B-cells and T-cells are both white blood cells that have a major role in our immune system function. Both B-cells and T-cells patrol our bodies, looking for foreign invaders, or antigens. Following recognition of a foreign invader by the T-cell, B-cells produce proteins called antibodies that help identify and attack would-be invaders.

In RA, these immune system components become tissue-destructive cells that attack healthy cells in your own body. The signaling dysfunction that occurs in RA leads to a vicious cycle in which defective B-cells and T-cells activate each other, along with other inflammatory cytokines, such as TNF, that magnify the inflammatory disease process.

The B-cell inhibitor approved for use in RA works by attaching to a receptor on the B-cell surface and removing it from circulation. The T-cell inhibitor attaches to a receptor that prevents the T-cells from becoming activated.

Regardless of their mechanisms, all biologics suppress the immune system. As a result, all biologic therapies carry with them an increased risk of infection. And some may pose a potential risk for certain malignancies. Patients should work with their physicians in weighing the risks and benefits of therapy and in selecting an appropriate agent, either alone or in combination with other non-biologic treatments.

NEKETIA HENRY: Using a treat-to-target approach, the goal of therapy in RA is to achieve remission or a state of low disease activity. When that happens, is it appropriate to reduce treatment or, perhaps, stop it altogether? Join me next time, when we discuss this important topic.