B is for Biologic

Autoimmune Disorders

Many of the most common chronic illnesses are autoimmune disorders. All are characterised by an uncontrolled inflammatory response.

Diseases as diverse as type 1 diabetes, rheumatoid arthritis, lupus, multiple sclerosis and inflammatory bowel disease (IBD) are all thought to have some underlying defect that leads to an unregulated immune response that triggers attack of self-antigens, cells and tissues. In the vast majority of cases, although the underlying clinical consequences are devastating and clearly evident, the trigger of the disease remains to be elucidated and often either remains hidden or is difficult to prove.

Natural immune processes are extremely complex and the critical component is that they have evolved in balance. The immune system needs to be proactive in its response to infection and foreign antigens that could potentially harm the body. On the other hand it needs to dampen down attack so that our own cells and tissues are not damaged when it responds.

As our bodies are habitually exposed to vast quantities of food and other antigens, bacteria, viruses and other microbes that may not necessarily harm us it is important that the immune system is kept in check and regulated.

We have evolved efficient and complex mechanisms involving inflammatory mediators called cytokines and special regulatory cells called T-cells to ensure our immune system is kept in balance. Regulatory pathways are turned on or off in the local environment by specific critical cytokines. This balance goes awry and the wrong pathways are switched on and off when autoimmune processes occur.

So in an autoimmune disease the secretion and release of cytokines that induce certain specific biochemical pathways may lead to a threshold response and thus trigger disease. For example, TNF alpha is known to be an extremely important cytokine in a number of autoimmune diseases with deleterious systemic inflammatory components such as RA, IBD and psoriasis. TNF alpha switches on certain regulatory pathways in the immune system. It may be at very high concentrations or low concentrations it switches on alternate pathways that may lead to less severe or more severe disease. Similarly it may be that the presence of high TNF alpha and perhaps high levels of another cytokine such as IL-10 may lead for example to Crohn’s disease (CD) as opposed to ulcerative colitis (UC).

It is not known why individual cytokines are increased or are decreased in autoimmune disorders. Various genetic factors may lead to a predisposition to have higher TNF alpha release in the joint for example. Autoimmune disorders are not completely genetic and some environmental impact or exposure, most likely some sort of infection, is crucial to the triggering of disease. Many autoimmune diseases seem to be clusters of disease and this is particularly evident in IBD, where CD and UC although similar in some aspects of the clinical presentations may be very different in terms of the drivers of the inflammatory processes involved. NOD2 for example is associated with CD but not UC. It is not present in all CD patients and may only play a role in a subset of patients or it may be that CD requires further sub-classification.

Treatment of Autoimmune Disorders

The treatment of autoimmune disorders has been fraught with the complexity of the symptoms seen in the individual. Recently it has emerged however, that there seems there may be a small number of dominant cytokines that are central to the immune processes of specific disease. One of these cytokines is TNF alpha and the development of anti-TNF treatments has revolutionised the approach to autoimmune disorders. Currently anti-TNF alphas are the most effective treatments available for dampening down the unregulated immune response. The effectiveness of these agents has led to the investigation into the potential therapeutic use of a whole spate of inflammatory cytokines mediators. The new cytokine therapeutics may eventually supersede the use of the current generation of TNF alphas, may be used for specific diseases in which these agents are not useful or may be used in combination with them in the future if they improve efficacy and are proven safe to use together.

The New Biologics

TNF alphas belong to a new class of drugs which are called biologics. They are in a sense novel medicines in that they are not chemical drugs synthesised in a laboratory and are derived from living sources. Treatment with biological medicines, however, is not a new concept, as vaccines, blood replacement products and insulin are all well established medicines.

The term ‘new biologics’ is different in that it refers to medicines generated through biotechnological techniques, such as DNA manipulation and cell culture. These biologics can be substances, such as proteins and sugars, which occur naturally in our bodies or even cells or tissues but using cells and tissues remains controversial experimental treatments for the most part except for in bone marrow transplantation.

Stem cells are biologics and have attracted much media attention and to a certain extent as with other biologics their potential remains essentially an unfulfilled promise. The use of biologics is still in its infancy, but the new treatments that have reached the clinic have a profound impact, particularly in oncology and in chronic conditions such as rheumatoid arthritis.

Currently there are three different types of new biologic drug treatments that are being used: biosimilars, receptor proteins, and monoclonal antibodies.

Biosimilars are homologous to natural substances in our body and used to treat conditions where these substances are missing, depleted or defective or perhaps through increasing their concentration they can positively impact symptoms of disease. Some insulins used to treat diabetics are biosimilars. Other examples include the immunomodulator inteferons and interleukins, the blood production protein Epoetin and growth hormone.

Receptor proteins are special proteins that bind molecules with a specific function and take them out of action or inhibit them from functioning, for example, Enbrel and Amevive.

Monoclonal antibodies harness innate immune mechanisms and these biologics have shown great clinical potential already. A monoclonal is a clone of one type of antibody to a specific body substance and binding to it stops its function. The big advantage of monoclonals is that they are highly specific and targeted thus minimising the side-effects of the more systemic acting drugs.

Biologics have major applications in cancer and it is this specialty that has the way in development. Interleukins, interferons and colony stimulating factors, such as Epogen, have all been used to treat a variety of cancers and they often enable using more aggressive therapies, as they reduce the side-effects of potent cancer drugs.

Monoclonal antibody therapies used in cancer treatment, include Herceptin for breast cancer, and Rituxan for Non-Hodgkin’s lymphoma. New cancer vaccines have also been developed using recombinant DNA technology. One example is the cervical cancer vaccine Gardasil much in the news.

The second major application of monoclonals is in diseases with profound immunological involvement. The major successes have been altering the function of a tumour necrosis factor called TNFalpha, which is a cytokine central to the inflammatory response. By downgrading the inflammatory component of the disease through inhibiting TNFalpha, patients have improved rapidly and dramatically. Responses have been most significant often in those with the most severe intransigent disease.

Rheumatologists were first to harness the potential of a monoclonal antibody directed against TNFa, but now it is used for those with diseases as diverse as inflammatory bowel disease and psoriasis. There are currently three anti-TNF drugs on the market with slightly different actions and indications. Many new monoclonal drugs, particularly to interleukins and specials molecules called Tolls, are likely to be onstream in the next decade or so and it is predicted that the management of many more diseases will be based on using these therapies.

The big advantages of biologics are that they are very specific and you can avoid systemic side-effects and improve compliance, as they tend to have a very narrow spectrum of activity. In the future it is hoped that new biologics are developed that target the disease process and don’t just alleviate symptoms. Major disadvantages are that they are expensive and difficult to make, they are powerful drugs and many patients don’t respond or after a while develop tolerance.

The potency of biologics is the major reason why many clinicians were reticent to use them initially. Rapid clinical responses were the plus side, but the risk of hidden destructive side-effects seemed too big a risk.

These concerns seemed justified when rare side-effects led to the withdrawal of Irish company Elan’s drug Tysabri used for the treatment of MS because of the association with four cases of a rare lymphoma. Prior to its withdrawal many experts were getting very excited about Tysabri, as in trials it seemed to be much more efficacious than the already effective anti-TNF drugs at controlling inflammation.

Recent research casts doubts as to whether it is the monoclonal itself or the fact that it was given with other commonly used immunosuppressants that led to the occurrence of the rare cancers. Since Tysabri has been given a limited license and is used under strict controls and monitoring for MS patients.

The upshot of this is that it is recommended that people given monoclonal treatments should all be monitored carefully for rare side-effects. Most monoclonal biologics are currently indicated for people with moderate to severe disease, but as our experience with these drugs increases it may be that specific treatments will be targeted to specific stages of disease. For example, as Crohn’s disease progresses in severity it is now thought the immunological mechanisms themselves evolve so some patients may benefit more from earlier biologic therapy with anti-TNFs.

Future research in this area is to focus on why people don’t respond or become tolerant to a specific biologic treatment. The ideal will be to have a whole range of biologic treatments and to screen people for who will benefit most from which treatment and to be able to treat patients early to prevent their disease before it progresses in severity.

Examples of Biologics

Herceptin – breast cancer

Remicade – rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, psoriasis

Humira – rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, psoriasis

Epogen – Anaemia associated with chemotherapy, chronic renal failure

Enbrel – rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis

Orencia – rheumatoid arthritis

Amevive – psoriasis