Novel Routes for Allergen Immunotherapy
Safety, Efficacy and Mode of Action
Immunotherapy. 2012;4(2):201-212. © 2012 Future Medicine Ltd.
Immunotherapy. 2012;4(2):201-212. © 2012 Future Medicine Ltd.
Wouldn’t it be nice to put some drops under your tongue and say goodbye to those painful shots for good? Allergy treatment under the tongue (sublingual drops and now tablets) have actually been around for a long time. Until recently, the science behind allergy drops has been lacking. As you read this review, consider the following:
Specific allergen immunotherapy has been practiced for allergic rhinoconjunctivitis for over 100 years and is the only treatment option that is disease modifying. In the USA, immunotherapy is usually administered via subcutaneous injection; this is the only route with a US FDA-approved formulation. There is growing interest in developing US-standardized formulations for the sublingual route, but up until recently there have been few US trials. Most of the experience with sublingual immunotherapy (SLIT) comes from Europe, where it is widely used and there is a large body of literature supporting its use. The purpose of this review is to summarize recent adult and pediatric clinical trials of SLIT in the USA. Most of the trials are for inhalant allergies, but there is some early work on SLIT as a novel therapy for food allergies.
Presently, only subcutaneous immunotherapy is approved by the US FDA for inhalant and stinging insect allergies in the USA. Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is being viewed with increased interest by US allergists as an alternative to subcutaneous immunotherapy.
The first published double-blind, placebo-controlled, randomized clinical trial (DBPC-RCT) with inhalant SLIT came from London, UK in 1986. This was followed by numerous studies from Europe in the last two decades, which confirmed the efficacy and safety of SLIT. Some novel studies include the first DBPC-RCT on allergoid SLIT tablets in 1998 and the first DBPC-RCT of SLIT successfully treating atopic dermatitis in dust mite-sensitized children.
Important work has also gone into elucidating the underlying mechanism of SLIT. The current thought is that tolerogenicity is induced by oral dendritic cells, which reside on the uppermost layers of oral tissue and in the context of SLIT, capture allergen and produce IL-10 and IL-12 cytokines. This thereby promotes a tolerogenic pathway and a T-cell shift from a Th2 to a Th1 and Treg phenotype. Treg cells further propagate the Th1 pathway by producing IL-10 and TGF-β that negatively feedback on Th2 cytokines and subsequently cause a decrease in IgE levels and an increase in IgG4 levels.
In the USA, there was early work performed on SLIT for cat allergy in 1993; however, this aside, there were no other published DBPC-RCTs until the past few years. Renewed interest may be, in part, due to the advent of two SLIT grass pollen tablets – Grazax®[7,8] and Oralair®, approved for use in Europe in the late 2000s. These SLIT tablets are currently undergoing trials in the USA. Here we review those and other recent US clinical trials for inhalant and food SLIT.
SLIT has been demonstrated in US studies to be efficacious and safe in the limited number of allergens evaluated so far. Hopefully this will lead to FDA approval for this treatment in the near future. It appears from the studies discussed that SLIT by tablet will have a higher likelihood of FDA approval compared with SLIT drops. We should see the development of other common allergens in tablet form for SLIT, including dust mites, tree pollen and cat hair over the next several years. Studies will need to be performed to determine if mixed unrelated allergens given together by the SLIT method will demonstrate clinical efficacy and safety. We may likely see further studies looking at the disease-modifying aspects of SLIT and whether early treatment with SLIT in children at risk for allergy and asthma may prevent their development. Food studies will continue to assess the role of SLIT versus OIT that will hopefully lead to better and safer means of inducing desensitization and tolerance to improve the lives of the increasing growing population of people with food allergy in the USA.
Purpose of review To update safety information regarding allergen-specific immunotherapy (ASIT) in clinical practice and highlight the risk factors associated with the adverse reactions, product and each dose.
Recent findings Efforts in recent years have focused on increasing our understanding of the efficacy and safety of ASIT, especially the sublingual variety (SLIT), in multicenter studies. Moreover, new Clinical Practice Guidelines (CPGs) and an international consensus concerning ASIT have been published recently. Although no deaths as a result of subcutaneous immunotherapy or SLIT have been reported in the last 2 years, systemic reactions mainly arising from administration errors still appear. Recent studies support the safety of new forms of specific immunotherapy.
Summary An understanding of the risk factors for each patient, product and dose, and the implementation of CPGs are the main factors that could improve the safety of ASIT. The standardization of all procedures for prescribing and administering ASIT, and the systematic collection of standardized safety data in a multicenter database (postmarketing surveillance), may be required to generate new information on the safety of ASIT.
Allergen-specific immunotherapy (ASIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), has been shown to be effective for the treatment of allergic respiratory disease in randomized controlled trials and meta-analyses. Indeed, SCIT is the treatment of choice for preventing anaphylaxis in patients with systemic reactions to hymenoptera (bee stings).
The greatest drawback to the more widespread use of ASIT is the associated risk of severe side-effects, as the dose which has been shown to be well tolerated and effective in a group of patients may not be so for a specific patient. Here again, everyone is different and what may be the best dose for one patient, may cause an adverse reaction for someone else.
Systemic reactions are those which produce symptoms and signs far from the administration site. They may be immediate systemic reaction (ISR), appearing in the first 30 min postadministration, or delayed systemic reaction (DSR), occurring after the first 30 min, with the former tending to be more severe.
The incidence of systemic reactions has been estimated at between 1 and 34% of patients and around 0.2–0.3% of doses, depending on the type of study, patient, diagnosis, extract or treatment scheme.
Historical reviews of ASIT-related mortalityhighlighted severe or poorly controlled asthma and administration errors as the main causes of fatal systemic reactions. These findings led to the drafting of Clinical Practice Guidelines (CPGs) for ASIT treatment,and their subsequent updates, in the 1990s. Adherence to such guidelines is the main reason behind the reduced frequency and severity of systemic reactions in the past 20 years. The statistics regarding mortality and systemic reactions prior to these CPGs are no longer applicable.
In the case of SCIT with airborne allergens, the use of fast regimens (rush and cluster) has been associated with a higher number of systemic reactions, although more recent studies have shown their safety to be similar to that of conventional schemes. Patients tend to like the rapid schedule because they can avoid the prolonged build-up of conventional treatment.
Omalizumab (Xolair) has been used to reduce the systemic reaction incidence in patients receiving SCIT with inhaled allergens and VIT (venom shots), with good results.
It is possible, but not confirmed, that systemic reactions increase during the pollen season, but patients generally do not decrease their dose at this time.
Together with poorly controlled asthma, the presence of a prior systemic reaction during AIT is the main risk factor associated with a new systemic reaction.
There is currently no evidence that the dose adjustments recommended in clinical guidelines reduce recurrent systemic reaction in a patient.
Premedication with antihistamines or omalizumab has been shown to be useful in some studies, although such treatment is not recommended as standard.
Local reactions do not predict the appearance of a systemic reaction, although some studies have suggested them to be a risk factor. The dose adjustments subsequent to major local reactions recommended in the clinical guidelines do not reduce the frequency of future systemic reactions. For additional information regarding the safety of allergy shots, refer to the reference below:
The clinical efficacy of SCIT (typical shots) is well established for both rhinitis and asthma. SLIT (sublingual drops) has also been validated in regards to rhinitis and asthma. Two recent meta-analyses in children showed that sublingual delivery of allergen vaccination constitutes a safe and effective alternative to the injectable route to reduce allergic respiratory symptoms and drug intake. Assessment of possible long-term benefits, including long-term disease remissions, suppression of new allergic sensitizations, and reduction of progression from rhinitis to asthma in children, as has been shown for the subcutaneous route, are future requirements for “proof” of benefits for sublingual drops.
The immunological effects of SLIT and how these relate to clinical efficacy are yet incompletely understood. Large-scale trials have confirmed the induction of allergen-specific IgG antibodies to be dose dependent. There is no early suppression of allergen-specific IgE antibodies and a transient early increase in specific IgE antibodies as in SCIT.
Current models of SCIT propose the induction of antigen-specific Tregs (cell type in the body), which then orchestrate the observed antibody and mucosal changes observed during treatment. As of yet there is only scarce evidence that such mechanisms operate during SLIT. Comparative clinical studies of sublingual and subcutaneous treatment yielded heterogeneous results demonstrating efficacy of both modes, but SLIT to be a safer approach.
In conclusion, understanding of the interaction of allergen and antigen-presenting cells within the oral mucosa may allow improved targeting of SLIT vaccines. In the near future the combination of allergen products with adjuvants may improve efficacy of immunotherapy via the sublingual route.
So here’s the bottom line:
This issue isn’t going away, so stay tuned!
It’s time for my allergy shot, but I don’t wanna! If getting shots makes you nervous, watch this girl….a real trooper and funny at that:
Please review the following information on allergy shots…you’ll save some time and learn a lot.
Questions patients ask:
1. How often can I get shots? Once you are at the maintenance dose, you may receive shots every 2-4 weeks. Please adjust your shots based on your allergy symptoms. (ie, shots every 2 weeks during the spring/fall and every 4 weeks during the winter)
2. How long does it take to “build up?” I’m glad you asked that. You can build-up with weekly shots like we’ve always done it and take 4-6 months to reach the maintenance dose–conventional. If you want to reach the maximum benefit earlier, I prefer the “rapid desensitization” which will achieve maintenance in one month. Big difference in convenience!
3. What to do about local reactions? Don’t ignore them. Local swelling doesn’t mean you will develop more severe reactions, but talk to your allergy shot nurse about air lock, application of ice, diluting your serum, just to name a few. I want to know if your arm swells after your shots….the only bad question is–you get the hint.
4. Do shots really work?–I tell patients that after 3-5 years on allergy shots at high dilutions, 70 to 80% of patients don’t have to go back on injections. What this means is that symptoms of allergy go down and need for medication also goes down, leaving you free to enjoy the outdoors!
5. Here’s what allergy serum should look like at the maintenance concentration–if your serum is clear, you may not be receiving the full benefit of shots in the first place. Notice the dark, cola-colored allergy serum…should be your maintenance if tolerated.
Last but not least…..are shots safe long-term? This study published in 2011 is very encouraging. Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality. J Allergy Clin Immunol 2011. Subcutaneous allergen-specific immunotherapy (SCIT) is a well-documented treatment of IgE-mediated allergic disease. In this registry-based observational study, receiving SCIT (allergy shots) compared with medications only was associated with lower risk of autoimmune disease and heart disease, as well as decreased all-cause mortality (early death).
Sooo….pull up your sleeve and let’s get you feeling better!
For the last 100 years, the pioneering technique of subcutaneous allergen desensitization first developed by Noon and Freeman has proven quite resilient and, in fact, central to the practice of clinical allergy. It remains the only therapeutic modality by which long-term immune modification can be achieved and has afforded not only symptomatic relief to untold numbers of allergic patients, but also life-saving benefit in the case of venom hypersensitivity. So while we are indebted to generations of scientists and physicians for their outstanding contributions to the understanding of the mechanisms and clinical application of immunotherapy, we embrace the many new technological approaches that hold promise for the treatment of allergic patients and that perhaps one day may give rise to a cure for atopic diseases.
happy, healthy, safe
Navigating the healthcare system
Solo family practice: I may be going the way of the dinosaur, but I'm not dead yet.
oversharing on the internet since 2011
Better Health...Easy As 123
An apple a day might keep the doctor away, but what is modern hospital medicine really like? Follow Dr. Benjamin Kirkland - a Doctor working in Australia - through the pinnacles and pitfalls of everyday hospital medicine!
PREVENTIVE HEALTH MAGAZINE
MANAGING ALLERGIES AND ECZEMA WITHOUT LOSING SANITY OR STYLE POINTS