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For more information, go to www.arthritisresearchuk.org

The science behind the success of anti-TNF therapy

Published on 15 November 2010
Source: Arthritis Today

Anti-TNF therapy, pioneered and developed by Arthritis Research UK, has transformed the treatment of inflammatory arthritis for millions of people across the globe. But how does this important class of drugs work? Dr Lisa Croucher explains the science behind its success.

Inflammation – the good and the bad

When the body is invaded by bacteria or viruses, our immune system recognises the threat and triggers a response – inflammation – to protect our tissues. The physical signs of inflammation – redness, heat and swelling – tell us that the immune system is doing its job properly.

Once the invasion is seen off, any damaged tissue is repaired, the debris is cleared away and the inflammation fades away. Our immune system protects us safely as long as it is able to recognise the difference between foreign invaders and our own tissues.

In autoimmune diseases, the clear dividing line between friend and foe becomes blurred, and the immune system becomes dangerously confused about the true identity of its enemy, turning inwards to attack the tissues of the joint.

In rheumatoid arthritis (RA) and other inflammatory joint diseases with an auto-immune dimension, the initial “mistaken identity” is compounded by defects, probably genetically inherited, in the way that the cells of the immune system communicate with each other. A vicious cycle of deranged cell communication, prolonged inflam-mation and tissue damage is set in motion that is very difficult to stop.

How to tackle this chaos? Painkilling analgesics relieve symptoms, non-steroidal anti-inflammatory drugs (NSAIDS) throw a “fire-blanket” over the inflammation, but neither will slow down or stop the underlying disease. Steroids interfere with the inflammatory process to some extent, and are often rapidly effective, but their long term use can be problematic. Conventional disease-modifying anti-rheumatic drugs (DMARDS) such as methotrexate have a marked effect on inflammation, but we are still not clear how they work.

Strangling the major “fuel lines” that feed the fire of inflammation has been the focus of scientists and clinicians over the last two decades, and a deeper understanding of the processes at work in inflammation, as well as major advances in drug development technology over this period, has helped to turn the goal into a reality. Biologic drugs are the result, and for inflammatory joint diseases, the most important of these has been anti-TNF alpha.

Tumor necrosis factor-alpha

TNF alpha–a major culprit

First recognised in the 1960s and 1970s for its toxic effects on cancer cells, research worldwide during the 1980s revealed the naturally occurring protein, tumour necrosis factor (TNF), to be an inflammation fuel-line – a master regulator of inflammation and an important cell-to-cell communicator, or cytokine, in the body’s defences against infection. But TNF has a dark side.

In the late 1980s and early 1990s, Professor Ravinder Maini, Professor Marc Feldmann and colleagues at the then Arthritis Research Campaign’s Kennedy Institute demonstrated that excessive production of a particular type of TNF, TNF alpha, drives the damaging inflammation characteristic of inflammatory joint disease. TNF alpha directs the production of several key immune molecules, including the cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6).

In turn, IL-1 and IL-6 stimulate the production of enzyme molecules, “biological scissors” that destroy cartilage and bone, and attract and activate more immune cells to perpetuate the cycle of inflammation. TNF alpha is at the very centre of this system – driving not only the recruitment and activation of inflammatory cells, but also controlling their destructive activities.

Targeting TNF alpha in the fight against inflammatory joint disease

In 1992, Professors Maini and Feldmann, with their colleague Dr Richard Williams, published laboratory research demonstrating a marked reduction in joint inflammation with a molecule that blocks the activity of TNF alpha. Not only did this ground-breaking work confirm the importance of TNF alpha in the inflammatory process, but it set in motion the development of a new generation of targeted drugs for joint disease.

In the same year, the Kennedy Institute carried out the world’s first trial of an anti-TNF alpha drug, infliximab, in a small group of people with rheumatoid arthritis; this was quickly followed by a larger trial in Europe. Both trials demonstrated the dramatic anti-inflammatory effects of anti-TNF alpha.

The remainder of the 1990s saw the development of other drugs designed to block the activity of TNF alpha and their approval over the last decade for the treatment of a range of inflammatory joint diseases, including RA, juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis.

What is anti-TNF alpha?

Within its large armoury of cells and molecules, the immune system has a very sophisticated weapon at its disposal – the antibody.

Antibodies are produced in response to “intelligence” gathered from the enemy, usually a molecule on the invader’s surface that alerts the immune system to its foreignness – or in the case of auto-immune diseases such as RA, a molecule that has been mistakenly identified as foreign. Each type of antibody is a unique weapon, designed specifically to neutralise only one type of target molecule.

Scientists and clinicians are now “borrowing” natural technology from the body’s own immune resources and exploiting the power of the antibody to control many diseases, including inflammatory joint diseases. The anti-TNF alpha drugs infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia) are all monoclonal antibodies, so-called because they are made in the laboratory by large populations of cells that are cloned, or copied, from a single parent cell, ensuring that every cell – and every antibody molecule made by the cloned cells – shows identical specificity for TNF alpha.

When these drugs find their way into the joint, each monoclonal antibody molecule binds tightly to a target TNF alpha molecule, blocking the communication pathways that stimulate the production of destructive molecules by immune cells. The anti-TNF alpha drug etanercept (Embrel) targets the TNF alpha molecule in a slightly different way, but the downstream effects of this drug are the same as the monoclonal antibody- based anti-TNF alpha drugs.

Despite its devastating effects in inflammatory joint disease, TNF alpha has a very important role in the body’s defences against infection. However, as TNF alpha is just one of many molecules known to be important in immunity, it seems that anti-TNF alpha therapy does not significantly compromise the immune system’s natural abilities to fight infection in most patients.

Coloured scanning electron micrograph (SEM) of a macrophage white blood cell Other biologic drugs for inflammatory joint disease

The success of anti-TNF alpha therapy and our greatly improved under-standing of the complexity of the inflammatory process have led to the development of several other biologic drugs for inflammatory joint disease. Currently, the first option for treatment with a biologic in the UK must be one of the anti-TNF alpha preparations.

It is not always clear why a patient does not respond to a particular anti-TNF alpha drug, telling us that the mechanisms by which the drugs work are still not fully understood. Second-line biologics for those patients who do not see a significant improvement in their disease with anti-TNF alpha target a range of different cells and molecules central to the inflammatory process.

The mono-clonal antibody rituximab (MabThera) destroys antibody-producing B cells, removing the source of the destructive auto-antibodies that target the body’s own tissues. Tociliuzimab (RoActemra) targets the activity of IL-6, and abatacept (Orencia) interferes with the processes involved in the activation of T cells, a key component of the immune response in inflammatory joint disease. Abatacept has recently been approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis in patients where other treatment options have failed.

The future

Most of the biologic drugs mentioned have been approved in the UK for the treatment of at least one type of musculoskeletal disease; the National Institute for Health and Clinical Excellence (NICE) has recently approved their use for a range of other musculoskeletal diseases, in isolation or in combination with other disease modifying drugs such as methotrexate.

Meanwhile, work is ongoing to develop new, more effective and better tolerated biologic drugs for inflammatory joint diseases.

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