Sublingual Immunotherapy

Allergy Relief Under Your Tongue

Immunotherapy treats the cause of allergies by giving increasing doses of what a person is allergic to, which increases “immunity” or tolerance to those allergens and reduces the allergy symptoms. It is truly functional medicine in that it gets to the root cause of allergies instead of simply trying to control the symptoms.

History of Sublingual Immunotherapy

The concept of immunotherapy originated in the early 1900s and was based on the idea of vaccination against infectious agents. An attempt at vaccination against “airborne toxins” led to the subcutaneous route for administration1. This route remains the standard today, at least in America, where allergy specialists primarily oversee and administer subcutaneous immunotherapy (SCIT).

Attempts at other routes of immunotherapy included oral, nasal and bronchial but these were not successful or fraught with complications. In 1986 The British Committee for the Safety of Medicines reported several deaths caused by SCIT and raised concerns about the safety and the risk/benefit ratio of SCIT2. About the same time cheaper drugs (anti-histamines, inhaled steroids) were becoming widely available. Thus, interest in alternative routes for IT increased again.

That same year the first randomized controlled trial (RCT) with sublingual immunotherapy (SLIT) was published3. SLIT was soon confirmed to be effective in several controlled studies, including the first pediatric study4,5.

By 1993 the European Academy of Allergy and Clinical Immunology (EAACI) stated in it’s position paper that SLIT could be regarded as a “promising route” for desensitization6, and only few years later declared “the use of SLIT in clinical practice is justified because of the ascertained efficacy and the favorable safety profile”7. SLIT safety in adults and children (> age 5) was shown8-9 and The World Health Organization accepted SLIT use in adults in 199810.

In 2004 the first meta-analysis showed SLIT effective for allergic rhinitis11 and another study showed SLIT actually helps prevent the development of asthma12. 2006-2008 brought studies analyzing the mechanism of action behind SLIT efficacy and several meta-analyses conclude SLIT is significantly efficacious compared with placebo for rhinitis and asthma in adults and children13-17.

Finally, from 2006-2009 there were many large double blind, placebo controlled, randomized controlled trials (DBPC-RCTs) with SLIT in adults and children that were positively adequately powered to confirm benefits18-23.

How Immunotherapy Works

By definition, an allergy is an abnormal immune response to an otherwise harmless antigen. An antigen is a molecule recognized by the immune system, originally termed from antibody generator, and allergens are antigens that trigger allergies. The mechanisms that make immunotherapy a successful treatment involve a “recalibration” of the portion of the immune system that is hypersensitive.

The allergic response in the case of hayfever and asthma is the type-1 hypersensitivity reaction that involves an allergen binding to specific IgE receptors on mast cells which trigger the degranulation and release of histamine and leukotrienes, chemicals that cause blood vessel dilation and leaking, leading to the symptoms of swelling, itching and inflammation that accompany “allergies”. Mast cells are abundant in the skin and respiratory tract which explains why the symptoms of allergies present there. It also explains why SCIT side effects include pain, redness and swelling at the injection site and possible anaphylaxis from triggering mast cells in the skin.

The T-helper (Th) system is involved in the abnormal allergy response. The Th1 pathway is responsible for defense against intracellular pathogens, and a pathologic response in this pathway is associated with autoimmune disease and cell-mediated allergies. The Th2 pathway is responsible for defense against extra-cellular pathogens, and it is here that asthma and IgE-mediated allergies present when the Th2 system goes awry.

Note that Th3 or T-regulatory (T-reg) cells may control the Th1 or Th2 pathways by secreting certain chemical mediators called cytokines, which control the response of other immune pathways. In particular, interleukin-10 (IL-10) is secreted which leads to immuno-suppression and anti-inflammatory effects. Also note that the Th1 and Th2 pathways exert a negative feedback on one another – that is, by up-regulating one pathway it will lead to the down-regulation of the other pathway.

The Th2 pathway is hyper-reacting in the case of environmental IgE-mediated allergies and asthma. While there is much research needed to fully understand the mechanisms of SLIT, there is a consensus that SLIT works by inducing a population of IL-10 producing Treg cells, inducing a Th1 immune response, increasing IgG4 which inhibits allergen-IgE binding to B cells, inhibiting eosinophils and reducing cellular adhesion molecules.

Unlike SCIT in which allergen is exposed to primed mast cells in the skin, SLIT delivers the allergen directly to antigen presenting cells in the tissue underneath the tongue. These cells “present” the allergen to the immune system, bypassing the Th2 pathway and progressively leading to the effects that begin to down-regulate the hypersensitive Th2 pathway.

Effectiveness of SLIT

During the last 3 years there have been numerous studies that are well-designed DBPC-RCTs of adequate power using standardized grass pollen tablets. In those studies the general effect of SLIT was a significant reduction in symptom severity and medication use.

The first meta-analysis of SLIT for allergic rhinitis included 22 trials and nearly 1000 patients. Overall, there was a significant reduction in both symptoms and medication requirements following immunotherapy24.

A meta-analysis of SLIT for asthma which included 25 trials and over 1000 patients found that SLIT is beneficial for asthma treatment albeit the magnitude of the effect is not very large. Moreover, it was noted as a safe alternative to the subcutaneous route with improvements in symptoms, medication use, pulmonary function, and overall well-being25.

A meta-analysis of SLIT for allergic rhinitis in children which included 10 trials and 484 patients showed that, compared with placebo, SLIT with standardized extracts is effective in pediatric patients with allergic rhinitis26. Another meta-analysis of SLIT for asthma in children included 9 trials and 441 patients and found SLIT with standardized extracts reduces both symptom scores and rescue medication use in children with allergic asthma compared with placebo27.

Comparison of SLIT with SCIT reveals that sublingual and injective therapies are equally effective according to subjective clinical parameters, with a statistically highly significant reduction of symptoms and drugs28. Interestingly, even though the clinical outcomes were equally successful, objective parameters (total specific IgG, specific IgG4, skin reactivity) changed only in patients treated with active injective therapy.

The clinical efficacy of SLIT is not statistically different from SCIT, and both treatments are clinically effective compared with placebo, however due to the advantageous safety profile SLIT may be favored29. Some studies even give SLIT the edge over SCIT for success in treatment of allergic rhinitis30.

Early research is showing potential for SLIT to treat other allergic reactions such as IgE-mediated food allergies, atopic dermatitis, and honeybee allergies. Future needs for SLIT efficacy determinations include evaluation of optimal allergen dosing and duration of treatment, efficacy and safety of no build-up regimens, duration of pre-seasonal induction, efficacy of SLIT in asthma and use of mixtures of unrelated allergens.

Safety of SLIT

The safety of SLIT over SCIT is perhaps the most exciting area worth noting. In a comprehensive review of 104 articles on SLIT31, there were 66 studies that provided some information on safety and tolerance, representing 4,378 patients who received approximately 1,181,000 SLIT doses. There were no fatalities or anaphylactic events reported. There were only 1.4 significant adverse events (SAE) per 100,000 SLIT doses.

Oral-mucosa reactions were the most common mild AE occuring in about 75% of patients, most frequently seen in the escalation phase. Moderate AEs occurred in 0.056% of SLIT doses. These included gastrointestinal symptoms, hayfever symptoms, and itching. 21% of SLIT patients reported AEs compared with 11.7% of placebo patients. AEs accounted for study withdrawal in 3% of SLIT patients compared with 1.4% of placebo patients. The most common SLIT-related SAEs were asthmatic reactions, followed by abdominal pain/vomiting, uvula edema and urticaria lasting 48 hours.

By comparison, according to the World Allergy Organization, it is estimated that 3.4 fatal and 22.8 near fatal reactions occur every year with SCIT. Local reactions at the injection site, such as redness, swelling, and warmth, are common, with about 10-20% of users experiencing large (>25mm) reactions.

General safety issues for SLIT include identifying known risk factors for side effects which would include asthma, especially if not optimally controlled, and previous significant reaction to SCIT. Safety of SLIT in children has been shown down to age 3 and several studies have shown safety of multi-allergen mixtures. There has not been a consistent correlation between SAE and SLIT dose or induction schedule.

Future areas surrounding safety need to address how to handle treatment interruptions, seasonal variations, escalation schedules and what clinical conditions warrant holding therapy. Use in pregnant and nursing women is uncertain.

Treatment Guidelines

Recommendations from various allergy organizations to minimize risk and improve efficacy suggest these considerations for initiating immunotherapy: 1) demonstrating the presence of IgE-mediated disease, 2) documentation that specific sensitivity is involved in symptoms, 3) documention of the severity and duration of symptoms and 4) the availability of standardized or high quality vaccines32-34.

After more than 20 years of administering SCIT in my office I am very familiar with the protocol, success and risks of SCIT. We have observed SCIT working quite well in controlling asthma and hayfever conditions and we’ve had a fair share of significant adverse reactions including anaphylaxis.

Our protocol for SLIT involves the initial history along with respiratory allergen testing by either serum RAST or skin tests. We then inform the patient about the risks and benefits, educate on home use, administer a 60 day supply of allergen drops and include an epinephrine kit for safety and peace of mind, albeit the risk of anaphylaxis is almost nil. The patient takes drops under the tongue daily. During the first 10 days, called the “escalation phase,” the dosage is gradually increased. After that, in the “maintenance phase,” the patient takes the same dose of drops each day.

Our allergen manufacturer is GREER® labs, which has specialized in immunotherapy for over 100 years. Wellness Pharmacy, which is family owned and has been in business since 1922, provides the packaging and distribution of the allergen drops either mailing directly to our office or to the patient. Wellness Pharmacy and GREER® have worked closely together to formulate the universal allergen mixture containing 70 allergens and is formulated to insure extract compatibility and stability. This insures a consistent industry standard of excellence in the allergen product. By contrast, SCIT involves specific allergens being sent directly to physicians, who then mix allergens and make the serial dilutions necessary for SCIT.

Treatment for allergies is a very big business! In 2005 Americans spent $11 billion on doctors’ bills, prescription drugs, and other medical care to relieve allergy symptoms, according to data from the Agency for Healthcare Research and Quality (AHRQ).  AHRQ’s data indicated that in 2005 about 22 million Americans reported visiting a doctor, obtaining a prescription drug, being hospitalized, getting home care, or experiencing allergy symptoms. Visits to doctors’ offices and hospital outpatient departments for allergy care accounted for $4 billion. The remaining roughly $7 billion was spent mostly on prescription drugs. Between 2000 and 2005, average annual spending on treatment of allergies jumped from $350 per person to $520 per person.

Most insurance plans do not cover sublingual immunotherapy and it is considered an FDA “off-label” use.  Some patients note symptom improvement within 3-4 months but immunotherapy is recommended for 3-5 years in order to confer long lasting immunity. It is important to note that when compared with the cost of allergy shots, SLIT may be a more economical choice and is certainly more convenient to the patient.

SLIT is the most common method of immunotherapy outside of the US, where SCIT remains the standard. I predict this is going to change soon, as prestigious centers such as Johns Hopkins Sinus Center are already offering SLIT, and one can envision the expansion of allergy treatment into the primary care arena due to SLIT offering an effective, safe, and affordable treatment option. SLIT is patient-friendly functional medicine at its finest.

References

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2 Committee on the safety of medicines. CSM update. Desensitizing vaccines. BMJ. 1986;293:948.

3 Scadding GK, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy. 1986;16:483– 491.

4Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A doubleblind study. Allergol Immunopathol. 1990;18:277–284.

5Sabbah A, Hassoun S, Le Sellin J, Andre C, Sicard H. A double-blind placebo-controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy. 1994;49:309 –313.

6Malling H, Weeke B, eds. Immunotherapy. Position Paper of the European Academy of Allergy and Clinical Immunology. Allergy. 1993; 48(Suppl 14):9 –35.

7Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, Bjorksten B, Bousquet J, et al. EAACI Position Paper on local immunotherapy. Allergy. 1998;53:933–944.

8Di Rienzo V, Pagani A, Parmiani S, et al. Post-marketing surveillance study on the safety of sublingual immunotherapy in children. Allergy 1999; 54:1110-1113.

9Lombardi C, Gargioni S, Melchiorre A, et al. Safety of sublingual immunotherapy in adults: a post marketing surveillance study. Allergy 2001; 56:889-892.

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11Wilson DR, Torres L, Durham SR. Sublingual immunotherapy for allergic rhinitis Allergy 2005;60:3– 8. Cochrane Database Syst Rev. 2003;(2):CD002893.

12Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004; 114:851– 857.

13Cosmi L, et al. Sublingual immunotherapy with Dermatophagoides monomeric allergoid downregulates allergen-specific immunoglobulin E and increases both interferon-gamma and interleukin-10-production. Clin Exp Allergy. 2006; 36:261–272.

14Bohle B, et al. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol. 2007;120:707–713.

15Penagos M, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in children. Meta analysis of randomized controlled trials. Ann Allergy Asthma Immunol. 2006;97:141–148.

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17Penagos M, et al. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008;133:599–609.

18Pfaar O, Klimek L. Efficacy and safety of specific immunotherapy with a high-dose sublingual grass pollen preparation: a double-blind, placebo controlled trial. Ann Allergy Asthma Immunol. 2008;100:256–63.

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20Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118:434–440.

21Didier A, Malling HJ, Worm M, Horak F, Jager S, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol. 2007;120:1338 –1345.

22Wahn U, Tabar A, Kuna P, Halken S, Montagut A, et al. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123:160 –166.

23Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123:167–173.

24Wilson DR, Torres L, Durham SR. Sublingual immunotherapy for allergic rhinitis. Allergy. 2005;60:3– 8.

25Calamita Z, Saconato H, Bronhara Pela` A, Nagib Atallah A. Efficacy of Sublingual Immunotherapy in asthma. Systematic review of randomized clinical trials. Allergy. 2006;61:1162–1172.

26 Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in children. Meta analysis of randomized controlled trials. Ann Allergy Asthma Immunol. 2006;97:141–148.

27Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE, Orozco S, et al. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008;133:599–609.

28Quirino T, Iemoli E, Siciliani E, Parmiani S, Milazzo F. Sublingual vs injective immunotherapy in grass pollen allergic patients: a double-blind double-dummy study. Clin Exp Allergy. 1996;26:1253–1261.

29Khinchi S, Poulsen LK, Carat F, Andre´ C, Malling HJ. Clinical efficacy of sublingual swallow and subcutaneous immunotherapy in patients with allergic rhinoconjunctivitis due to birch pollen. A double-blind doubledummy placebo-controlled study. Allergy. 2004;59:45–53.

30Bernardis P, Agnoletto M, Puccinelli P, Parmiani S, Pozzan M. Injective VS sublingual immunotherapy in Alternaria tenuis allergic patients. J Inv Allergol Clin Imm. 1996;6:55–62.

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32Malling H, Weeke B. Immunotherapy. Position Paper of the European Academy of Allergy and Clinical Immunology. Allergy. 1993;48(Suppl 14):9 –35.

33Global strategy for asthma management and prevention. GINA. Update from NHLBI/WHO Workshop Report 1995, Revised 2006. www.ginasthma. com 2006.

34Bousquet J, Van Cauwenberge P, eds. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108(Suppl):S147–S334.


Author

Scott Rollins, MD, is Board Certified with the American Board of Family Practice and the American Board of Anti-Aging and Regenerative Medicine.  He specializes in bioidentical hormone replacement for men and women, thyroid and adrenal disorders, fibromyalgia and other complex medical conditions.  He is founder and medical director of the Integrative Medicine Center of Western Colorado (www.imcwc.com) and Bellezza Laser Aesthetics (www.bellezzalaser.com).   Call (970) 245-6911 for an appointment or more information.

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