Vincent St Aubyn Crump FRACP - April 8, 2013
Immunotherapy is defined as ‘the treatment of diseases by inducing, enhancing, or suppressing an immune response’. Simply put, immunotherapy modifies or avoids diseases by influencing the immune system. The immune system is the body’s defence mechanism, and immunotherapy mainly acts as a reinforcement of this mechanism. Immunotherapy that enhances the immune response is classified as activation immunotherapy, while immunotherapy that suppresses the immune response is classified as suppressive immunotherapy.
The active agents used in immunotherapy are known as immuomodulators, and include cytokines, chemokines and interferons. Cancer immunotherapy uses these agents to stimulate the immune system to destroy tumours. This is a relatively new treatment, which is shaping up to be the future for treating cancers. By comparison, vaccination against infectious diseases by stimulating the immune system to produce antibodies to offer protection against infectious foreign invaders is an example of an old form of activation immunotherapy, which has led to the worldwide eradication of smallpox and reduced prevalence of several other diseases.
Allergen-specific immunotherapy, a suppressive immunotherapy, previously known as desensitization and hyposensitisation, and now also known as allergy vaccination, is also a treatment of the past, it is the oldest treatment we have for allergies – first used 100 years ago, in 1911 by Leonard Noon & Freedman at St Mary’s Hospital in London – which has stood the test of time, and is presently a very useful treatment for many allergic diseases. This paper will only be discussing Allergen immunotherapy and will try to give arguments to support why Allergen-specific immunotherapy, which is an old treatment, will be the future of treating allergies.
How does allergen Immunotherapy work?
The role of the immune system is to protect the body from harmful foreign substances. The immune system has 2 different modes of attack based on the invader. Th1 (T Helper 1) lymphocytes goes after invaders that get into our cells, cell mediated immunity. The other the Th2 (T Helper2) lymphocytes attack extracellular invaders that are outside the cell, in blood and other body fluids, antibody-mediated immunity. The atopic or allergic individual has an imbalance in their immunity towards the Th2 immune response. The immune response is orchestrated via the T lymphocytes and with the help of antibodies. There are several classes of antibodies including IgG, which are useful in fighting bacterial infections. The IgE class of antibodies is involved in allergic reactions and also some parasitic infections. An allergic reaction is caused by the fact that the immune system of the allergic individual is malfunctioning and is over-reacting to a supposed foreign invader protein. The allergic individual produces an excessive amount of IgE antibodies against the substances that they are allergic to. IgE antibodies respond to allergenic proteins by causing the release of histamine and other allergic mediators. The concept of immunotherapy is to retrain the immune system to tolerate these allergens. Allergen-specific immunotherapy involves the administration of gradually increasing quantities of an allergen product to an individual with IgE-mediated allergic diseases, in order to achieve tolerance of those allergens that cause symptoms. Immunotherapy will only work for IgE-mediated diseases, and this is the main reason why IgE antibodies have to be identified to the specific allergen either in the blood (Specific IgE, RAST-type blood tests) or in the skin through skin prick tests, before immunotherapy can be considered.
The efficacy of immunotherapy was confirmed 100 years ago, and even though the basic principle of immunotherapy has not changed, the mechanisms responsible for its efficacy are still being worked out. On the whole, immunotherapy causes “immune deviation”, from the typical “Th2” predominant lymphocyte subset seen in allergies to the “Th1” predominant subset. Immunotherapy leads to a reduction in the number of allergen specific IgE antibodies and increases the allergen specific IgG (considered blocking antibodies) antibody levels. There is a blunting of seasonal increase in pollen specific IgE in patients with hay fever. There is also inhibition of the recruitment and activation of other immune cells including mast cells, and eosinophils.
The most popular immunotherapy protocol in New Zealand involves weekly injections (under the skin) of gradually increasing doses of the allergen over a 12 week interval, up to a maintenance dose, which is then injected monthly for three to five years. Most patients will see some improvement in their symptoms within six months, but the 3-5 year length of the program is necessary to achieve the long-lasting effect, which persists long after the treatment is stopped.
Treatment options for allergies
A carefully taken history guides the physician to the appropriate allergy tests (skin prick tests, specific IgE (RAST-type) blood tests, and allergen challenges) in order to confirm the trigger/s for the allergic disease. Once the specific trigger/s are identified the options for management of the allergic disease includes – usually in a step-wise or pyramid manner - allergen avoidance (when this possible), drug therapy, including antihistamines, steroids, and more powerful immunosuppressive drugs like cyclosporine.
Traditionally immunotherapy has usually been the last choice on the list. For reasons which will be discussed later this position has recently been challenged. The main advantage of immunotherapy over the ‘symptomatic’ drug therapy is the fact that immunotherapy alters the patient’s immune response to the allergenic trigger rather than just suppressing the symptoms. Therefore after the end of a course of immunotherapy when the treatment stops the patient continues to be symptom-free when the allergen is encountered, instead of the symptoms recurring when drug therapy (antihistamines, steroids & immunosuppressives) is stopped.
What allergies can be treated with immunotherapy & why?
The efficacy of subcutaneous (injection under the skin) immunotherapy was first established just over a century ago by the pioneers Noon & Freedman, who first described successful treatment of grass pollen-induced hay fever with grass pollen inoculations. Noon believed that the pollen ‘toxin’ was the cause of hay fever and was able to demonstrate effective treatment of hay fever patients with a protocol of increasing doses of grass pollen extract injected under the skin. He also established that anaphylaxis could be caused by subcutaneous immunotherapy if the dose is too high. This study done even back then showed that the clinical benefits may persist for at least 1 year after stopping the treatment.
In 2007 Caledron et al published the first Cochrane systematic review and meta-analysis evaluating the effect of immunotherapy on seasonal allergic rhinitis (hay fever). Fifty-one randomised controlled trials published between 1984 and 2006 were included. There were a total of 2871 patients: 1645 active and 1226 placebo. There was significant improvement in symptoms score and medication score in the actively treated groups. The clinical efficacy of immunotherapy in asthma was evaluated by Abramson and colleagues in 3 systematic reviews and meta-analysis. This meta-analysis showed significant reduction in asthma symptoms and medication and improvement in bronchial hyper-reactivity following immunotherapy.
Immunotherapy to insect venoms has been shown to be most effective in the prevention of future anaphylaxis to insect stings in individuals who were previously susceptible. Ross et al conducted and published meta-analysis in 2000, looking at the effect of immunotherapy in treating venom anaphylaxis. Eight studies published between 1966 and 1996 were included. The authors found that symptoms of venom hypersensitivity were prevented in 79% of the 101 patients receiving immunotherapy versus 36% of the comparison patients.
There are also several studies showing efficacy of aeroallergen immunotherapy (mainly dust mites) in treating atopic eczema. In 2012 Darsow reviewed Allergen specific Immunotherapy for Atopic Eczema and noted that patients with house dust mite sensitisation have been studied extensively, and found that better effects are seen in patients with severe eczema. Some studies have also shown benefit of birch and grass pollen immunotherapy in eczema.
At the present time the efficacy & safety of immunotherapy for the treatment of food allergy is investigational.
Other reasons why allergen immunotherapy is better than drug therapy for treating allergies?
- It stops the allergic march by modifying the course of the allergic disease by reducing the risk of new allergic sensitization and inhibits the development of clinical asthma in children treated for allergic rhinitis. In 1997 Des Roches et al demonstrated that immunotherapy may prevent new sensitisations and in 2002 Moller et al demonstrated that immunotherapy may prevent progression of allergic rhinitis and asthma in children.
- Long-lasting effects: existing data suggest that immunotherapy achieves long lasting relief of allergic symptoms, unlike the benefit of drugs which only last as long as they are continued. In 2007 Jacobsen et al showed that the asthma preventative effect of immunotherapy was still significant 7 years after the treatment discontinuation.
- Cost-effectiveness of immunotherapy: A review study by Betro published in 2008 looking at immunotherapy in comparison to standard pharmaceutical treatment, have shown that immunotherapy may be very beneficial to the healthcare systems, in that either it could bring more clinical outcome at a reduced cost, versus standard therapy alone, or it could bring extra benefit at a very acceptable extra cost. This is even more attractive when indirect costs of lost productivity are considered & included in the economic analysis
Since allergen immunotherapy was first described 100 years ago, it has traditionally been given by injections. The main draw backs to injection immunotherapy is the inconvenience, in that it has to be given in a doctor’s office, and the patients wait for 30 minutes after the injection to observe for reactions to the injection.
All the studies on allergen immunotherapy over the years have shown that the efficacy of immunotherapy is dose-dependent. Oral or sublingual immunotherapy even though safer than injection needs a much higher dose than injection as the absorption is much reduced via this route. This is the reason why earlier studies of sublingual immunotherapy were no better than placebo. More recent blinded, placebo-controlled sublingual immunotherapy studies, with much higher doses have shown efficacy. Most studies done comparing injection immunotherapy with sublingual show that sublingual is inferior to injection as far as efficacy, but much safer.
A very recent meta-analysis on sublingual immunotherapy done by Lin et al concluded that the overall evidence provides a moderate grade level of evidence to support the effectiveness of sublingual immunotherapy for the treatment of allergic rhinitis and asthma, but high quality studies are still needed to answer questions regarding optimal dosing strategies. There were also limitations in the standardization of adverse event reporting, but no life-threatening events were noted in the review. At the present time in New Zealand, the cost of sublingual immunotherapy –along with the inferior efficacy- does not make it an attractive alternative to injection immunotherapy.
Practical advice on immunotherapy
If you suffer from severe hay fever, asthma, eczema or have had any reactions to bee or wasp sting apart from local reactions, ask your doctor about immunotherapy.
Allergen immunotherapy is one of the oldest treatments for allergies. It has lasted 100 years and unlike other treatment for allergies it treats the cause of the problem and not just the symptoms, and the effects persists long after the treatment is discontinued. It has also been shown to prevent allergies in children and stop the progression of allergies, the “allergic march”. Also over the years the side effects, including anaphylaxis are improving as the allergen extracts (vaccines) and the methods for administering the vaccines have improved. Allergen immunotherapy is an allergy treatment of the past, present and future.
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