Sublingual immunotherapy (SLIT) has been shown to be safe and efficacious in treating allergic rhinitis. It has been used in Europe for more than 20 years, and interest in the United States is increasing. SLIT has been shown to elicit immunologic changes similar to subcutaneous injection immunotherapy. SLIT may prevent new sensitizations, improve asthma control, and decrease asthma development in allergic individuals. Although differences in antigen quantification and standardization make European dosing schemes difficult to translate in the United States, several new studies suggest the range for effective dosing. Further studies will help clarify optimal dosing.
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SLIT has been show in multiple studies to be efficacious in allergic rhinitis for adults and children.
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SLIT has also been shown to be helpful in asthma and in preventing the development of new sensitivities to allergens.
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Studies have shown immunologic changes in SLIT that are similar to SCIT, suggesting a similar mechanism of action.
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SLIT enjoys a good safety profile, allowing for the convenience of dosing in the home and in individuals unable to tolerate injections, such a young children, although a few cases of anaphylaxis have been reported.
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The majority of literature has been published in Europe, with multiple factors making the translation of dosing to the United States difficult. Future studies will help continue to clarify optimal dosing and schedule in the United States.
The incidence of allergic disease has increased significantly over the past 40 years. Allergic rhinitis is a very common health problem associated with considerable decreases in quality of life, and affects 5% to 22% of Americans. Although it is typically not a life-threatening disease, medical management costs are substantial. More than $1 billion are spent on management of allergic rhinitis every year in the United States. If the apparent trend of increasing atopy continues, a growing number of patients will be affected by the decreased quality of life associated with allergic rhinitis, and the increasing societal economic burdens associated with treatment of the disease and losses in worker productivity.
The mainstays of treatment for allergic rhinitis include avoidance of allergen, pharmacotherapy, and immunotherapy. Immunotherapy involves administering increasing concentrations of allergen to sensitized individuals to reduce allergic symptoms caused by natural exposures to these allergens. When immunotherapy is administered over an adequate duration, the body gradually adapts the immune response to the sensitized allergen and allows for increased tolerance.
Immunotherapy is an alternative for individuals who are refractory to avoidance of allergens or medical therapy. Unlike pharmacotherapy or avoidance, allergen-specific immunotherapy has the advantage of providing potential continued symptom suppression after discontinuation of therapy, preventing or halting progression of asthma, and preventing the development of new allergies. Currently, the most common form of allergen-specific injection immunotherapy in the United States is subcutaneous injection immunotherapy (SCIT), which not only has been proven to be efficacious in reducing symptoms but also effects measurable immunologic changes in individuals who have undergone this treatment.
Allergen-specific injection immunotherapy was introduced approximately 100 years ago, and currently 7 to 10 million allergy immunotherapy injections are administered annually in the United States. However, injection immunotherapy is associated with rare but real risks of anaphylaxis and death. Injection immunotherapy must be administered in an appropriately supervised physician’s office on a repeated basis, from once a week to once a month over several years. For many young children, needle-phobic patients, and areas with limited access to specialists, injection immunotherapy is not a realistic treatment option.
Over the years, different routes of allergen-specific immunotherapy administration have been investigated as alternatives to injection immunotherapy. Previous studies of oral immunotherapy found that this route was not efficacious, and the same is true of bronchial immunotherapy, which also confers a high risk of bronchospasm. Local nasal immunotherapy has been shown to significantly improve allergy symptoms and decrease the need for allergy medications. However, local nasal immunotherapy must be carefully administered to prevent bronchospasm, and it frequently provokes rhinitis on administration. None of these alternative dosing routes has gained popularity in the clinical arena. Sublingual immunotherapy (SLIT), in which the allergen is held under the tongue for an interval and then either swallowed or spit out, was first introduced in the United States in the 1940s, but it did not gain widespread acceptance at that time.
Concerns over safety, patient convenience, and patient tolerability of injection allergen immunotherapy led to renewed interest in alternative forms of immunotherapy. In 1986, the British Committee for the Safety of Medicine questioned the risk–benefit ratio of SCIT after several deaths occurred. Although subsequent investigation found the deaths to be from avoidable human error, this report greatly increased interest in developing alternative routes of immunotherapy. Interest in SLIT steadily increased after sublingual administration of dust mite allergen was reported in 1986. Since the early reports more than 2 decades ago, investigators have published increasing data on the safety and efficacy of SLIT, primarily in Europe. Data supporting the clinical use of SLIT began to increase, and in 1998 the World Health Organization (WHO) concluded that SLIT was an acceptable means of immunotherapy. Further publications by the European Academy of Allergy and Immunology and the Allergic Rhinitis and Its Impact on Asthma (ARIA) treatment guideline support the use of SLIT in allergen desensitization in children and adults.
The use of SLIT in clinical practice has increased in Europe over the past 2 decades. The European clinical experience includes SLIT in the form of oral aqueous and tablet formulations. Its excellent safety profile has allowed it to be administered in the convenience of the home, and the lack of needles makes it an attractive option in the pediatric population. Interest in SLIT has also been increasing in the United States, with some clinicians offering this treatment modality to patients. However, because no sublingual allergens are currently approved by the U.S. Food and Drug Administration (FDA), these practitioners are using allergens approved for injection immunotherapy in an off-label route of administration.
Immunologic response
Several articles have addressed the immunologic effects of SLIT, both local and systemic. Experts believe the interaction of the allergen in the sublingual mucosa may be important in the mechanism of action. A study involving radiolabeled SLIT found evidence of radioactivity in the oral cavity for 2 to 20 hours after initial administration of SLIT; this is thought to possibly be caused by the local uptake of antigen by dendritic cells. Other studies have focused on potential local immune changes in the oral submucosa. A study comparing sublingual mucosal biopsies of subjects receiving SLIT with those of controls found no difference in CD3+, CD1a+, or CD68+ cell counts. However, another study found that sublingual salivary eosinophil cationic protein was significantly reduced after 7 months of SLIT.
A larger number of studies have focused on the systemic immunologic responses induced by SLIT, particularly examining changes in serum inflammatory mediators. Several studies have shown that one of the most consistent changes in inflammatory mediators is the reduction of serum eosinophil cationic protein (ECP). This decrease has been seen in both children and adults after 6 to 24 months of treatment with SLIT. The decrease in ECP was found to correspond with a decrease in serum eosinophil counts. The most widely studied antibody responses to SLIT include changes in IgE and IgG4. Studies show decreases in antigen-specific IgE after treatment with SLIT; antigen-specific serum IgG4 has shown a dose–response increase to SLIT after the first year of use, and then a plateau in levels. SLIT has also been shown to suppress skin prick test after treatment, although this seems to be affected by duration of treatment, with suppression in skin responses seen after 18 to 24 months of use.
The immunologic changes seen after SLIT administration are similar to those seen after administration of SCIT. Both induce changes in skin testing, increases in allergen-specific IgG4, and decreases in antigen-specific IgE. These findings suggest a similar mechanism underlies both routes of immunotherapy. SCIT induces changes in regulatory T cells that lead to increased tolerance of antigen, and SLIT probably acts in a similar manner.
Efficacy
Several recent large reviews and meta-analyses discuss the efficacy of SLIT. In 2005, Wilson and colleagues published the first large-scale meta-analysis entitled “Sublingual Immunotherapy for Allergic Rhinitis,” which examined 979 pediatric and adult subjects pooled from 22 randomized, double-blind, placebo-controlled studies of SLIT. This meta-analysis found significant reductions in symptom and medication scores with SLIT, and concluded that it was effective in treating allergic rhinitis. The authors acknowledged, however, the large heterogeneity in dosages and treatment schedules among the studies.
In 2006, the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) formed a task force that was charged with providing a comprehensive, updated report on SLIT for the North American Allergy community. The ACAAI/AAAAI task force reviewed 104 articles addressing SLIT dosing, efficacy, immunologic response, and safety. The doses used in the studies varied by 30,000-fold, with frequency ranging from daily to weekly; few comparative studies were found regarding optimal dosing and schedules. Of the 47 studies that met criteria for clinical efficacy, most showed some evidence of this. Studies suggested a dose–response effect, but a consistent relationship among treatment dose, duration, and efficacy was not found. Although the task force found evidence for the efficacy of SLIT in treating allergic rhinitis, many questions remain regarding SLIT, including was is the effective dose and schedule.
Other SLIT studies have examined efficacy in specific subpopulations, such as asthmatics. In 2006, Calamita and colleagues performed a systematic review of the efficacy of SLIT in asthma. This review included randomized controlled clinical trials involving adult and pediatric patients and conducted from 1974 to 2005; 1706 patients from 25 studies met study inclusion criteria. The authors found that SLIT was beneficial for asthma treatment in terms of symptoms, medication use, lung function, and bronchial provocation. However, the authors concluded that the effects, although statistically significant, were small in scale.
The pediatric population is another subgroup in which the efficacy of SLIT is studied frequently. In 2006, Penangos and colleagues published a meta-analysis focusing on the use of SLIT in patients aged 3 to 18 years. Ten studies met selection criteria, and 484 patients from these studies were evaluated. The authors found a significant reduction in symptoms and medication use after SLIT. Subset analysis showed a greater improvement related to seasonal allergens as opposed to perennial, and for patients receiving therapy for greater than 18 months. The authors concluded that SLIT was an effective form of therapy for allergic rhinitisin the pediatric population. An updated review in 2008 found evidence of efficacy with SLIT for grass allergies in children, but the evidence of efficacy in dust mite allergy was inconsistent.
Other pediatric studies have examined the potential protective effects of SLIT on the pediatric population. For example, Novembre and colleagues studied whether short-term coseasonal SLIT for grass allergen would benefit children compared with a control group taking standard allergy and asthma medications. The SLIT group underwent 3 years of therapy. At the conclusion of the study, the control group was found to be 3.8 times more likely to have developed asthma than the SLIT-treated group. The authors concluded that SLIT not only improved seasonal allergic rhinitis symptoms but also reduced the development of seasonal asthma in children with grass pollen allergy.
Another study by Marogna and colleagues in 2008 also focused on the preventative effects of SLIT in children. In this study, 216 children were randomized to receive either medications alone or SLIT plus medications for 3 years. New sensitizations to allergens were found in 34.8% of controls compared with 3.1% receiving SLIT. Mild persistent asthma also occurred less frequently in the SLIT group. The number of children with positive methacholine challenge tests decreased significantly after 3 years in the SLIT group only, suggesting that SLIT reduces both new sensitizations and bronchial hyperreactivity. Di Rienzo and colleagues also evaluated the duration of these positive SLIT effects in children The children in this study received either 4 to 5 years of SLIT (n = 35) or allergy medications (n = 25). The patients were evaluated at baseline, end of SLIT, and 4 to 5 years after SLIT discontinuation. The SLIT group was found either to be less likely to have asthma or to have improved asthma. The positive clinical effects were maintained for 4 to 5 years after discontinuation of SLIT.
Several recent publications have focused on the efficacy of a specific form of SLIT, the grass tablet. The sublingual grass antigen tablet is currently available in Europe, and efforts seem to be underway to bring it to the United States. These multicenter, double-blind, and placebo-controlled studies have shown a significant reduction in allergy symptoms in grass-sensitized patients. The grass tablet has also decreased the need for medication, improved asthma, and improved disease-specific quality of life. Efficacy seems to be greater if the grass tablet is given preseason. Administration of the grass tablet has also led to corresponding immunologic changes seen with allergen-specific immunotherapy, such as an increase in antigen-specific IgG.
Similar to the grass tablet studies, most SLIT studies have been single allergen studies; however, most allergic patients in the United States are polysensitized. In the United States, most practitioners use multiantigen treatment when using allergy-specific immunotherapy to treat polysensitized patients. Of the few studies performed on the use of SLIT in polysensitized patients, one published in the United States in 2009 evaluated the quality of life using multiantigen SLIT. Patients undergoing multiantigen SLIT were found to have statistical improvement in 12 of 14 domains of the Mini Rhinoconjunctivitis Quality of Life Questionnaire. This study, although small, offered encouraging pilot results of multiantigen SLIT. A subsequent larger European study of SLIT in polysensitized subjects found similar gains in disease-specific quality of life.
The literature has attempted to answer the important question of how SLIT compares with SCIT in terms of efficacy. Although studies have found both modalities to be efficacious, no agreement has been reached on which treatment is more effective. In a double-blind, placebo-controlled study performed in 2004 comparing SLIT and SCIT in birch pollen–sensitive subjects, both therapies decreased symptoms and medication scores compared with placebo. Although SLIT had a higher safety profile, a nonsignificant greater improvement occurred in the SCIT group. Among the varied findings in multiple studies, no clear cut answer seems to exist regarding the efficacy of SLIT versus SCIT; this is an area that would benefit from future, large-scale, randomized, placebo-controlled studies.
Efficacy
Several recent large reviews and meta-analyses discuss the efficacy of SLIT. In 2005, Wilson and colleagues published the first large-scale meta-analysis entitled “Sublingual Immunotherapy for Allergic Rhinitis,” which examined 979 pediatric and adult subjects pooled from 22 randomized, double-blind, placebo-controlled studies of SLIT. This meta-analysis found significant reductions in symptom and medication scores with SLIT, and concluded that it was effective in treating allergic rhinitis. The authors acknowledged, however, the large heterogeneity in dosages and treatment schedules among the studies.
In 2006, the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) formed a task force that was charged with providing a comprehensive, updated report on SLIT for the North American Allergy community. The ACAAI/AAAAI task force reviewed 104 articles addressing SLIT dosing, efficacy, immunologic response, and safety. The doses used in the studies varied by 30,000-fold, with frequency ranging from daily to weekly; few comparative studies were found regarding optimal dosing and schedules. Of the 47 studies that met criteria for clinical efficacy, most showed some evidence of this. Studies suggested a dose–response effect, but a consistent relationship among treatment dose, duration, and efficacy was not found. Although the task force found evidence for the efficacy of SLIT in treating allergic rhinitis, many questions remain regarding SLIT, including was is the effective dose and schedule.
Other SLIT studies have examined efficacy in specific subpopulations, such as asthmatics. In 2006, Calamita and colleagues performed a systematic review of the efficacy of SLIT in asthma. This review included randomized controlled clinical trials involving adult and pediatric patients and conducted from 1974 to 2005; 1706 patients from 25 studies met study inclusion criteria. The authors found that SLIT was beneficial for asthma treatment in terms of symptoms, medication use, lung function, and bronchial provocation. However, the authors concluded that the effects, although statistically significant, were small in scale.
The pediatric population is another subgroup in which the efficacy of SLIT is studied frequently. In 2006, Penangos and colleagues published a meta-analysis focusing on the use of SLIT in patients aged 3 to 18 years. Ten studies met selection criteria, and 484 patients from these studies were evaluated. The authors found a significant reduction in symptoms and medication use after SLIT. Subset analysis showed a greater improvement related to seasonal allergens as opposed to perennial, and for patients receiving therapy for greater than 18 months. The authors concluded that SLIT was an effective form of therapy for allergic rhinitisin the pediatric population. An updated review in 2008 found evidence of efficacy with SLIT for grass allergies in children, but the evidence of efficacy in dust mite allergy was inconsistent.
Other pediatric studies have examined the potential protective effects of SLIT on the pediatric population. For example, Novembre and colleagues studied whether short-term coseasonal SLIT for grass allergen would benefit children compared with a control group taking standard allergy and asthma medications. The SLIT group underwent 3 years of therapy. At the conclusion of the study, the control group was found to be 3.8 times more likely to have developed asthma than the SLIT-treated group. The authors concluded that SLIT not only improved seasonal allergic rhinitis symptoms but also reduced the development of seasonal asthma in children with grass pollen allergy.
Another study by Marogna and colleagues in 2008 also focused on the preventative effects of SLIT in children. In this study, 216 children were randomized to receive either medications alone or SLIT plus medications for 3 years. New sensitizations to allergens were found in 34.8% of controls compared with 3.1% receiving SLIT. Mild persistent asthma also occurred less frequently in the SLIT group. The number of children with positive methacholine challenge tests decreased significantly after 3 years in the SLIT group only, suggesting that SLIT reduces both new sensitizations and bronchial hyperreactivity. Di Rienzo and colleagues also evaluated the duration of these positive SLIT effects in children The children in this study received either 4 to 5 years of SLIT (n = 35) or allergy medications (n = 25). The patients were evaluated at baseline, end of SLIT, and 4 to 5 years after SLIT discontinuation. The SLIT group was found either to be less likely to have asthma or to have improved asthma. The positive clinical effects were maintained for 4 to 5 years after discontinuation of SLIT.
Several recent publications have focused on the efficacy of a specific form of SLIT, the grass tablet. The sublingual grass antigen tablet is currently available in Europe, and efforts seem to be underway to bring it to the United States. These multicenter, double-blind, and placebo-controlled studies have shown a significant reduction in allergy symptoms in grass-sensitized patients. The grass tablet has also decreased the need for medication, improved asthma, and improved disease-specific quality of life. Efficacy seems to be greater if the grass tablet is given preseason. Administration of the grass tablet has also led to corresponding immunologic changes seen with allergen-specific immunotherapy, such as an increase in antigen-specific IgG.
Similar to the grass tablet studies, most SLIT studies have been single allergen studies; however, most allergic patients in the United States are polysensitized. In the United States, most practitioners use multiantigen treatment when using allergy-specific immunotherapy to treat polysensitized patients. Of the few studies performed on the use of SLIT in polysensitized patients, one published in the United States in 2009 evaluated the quality of life using multiantigen SLIT. Patients undergoing multiantigen SLIT were found to have statistical improvement in 12 of 14 domains of the Mini Rhinoconjunctivitis Quality of Life Questionnaire. This study, although small, offered encouraging pilot results of multiantigen SLIT. A subsequent larger European study of SLIT in polysensitized subjects found similar gains in disease-specific quality of life.
The literature has attempted to answer the important question of how SLIT compares with SCIT in terms of efficacy. Although studies have found both modalities to be efficacious, no agreement has been reached on which treatment is more effective. In a double-blind, placebo-controlled study performed in 2004 comparing SLIT and SCIT in birch pollen–sensitive subjects, both therapies decreased symptoms and medication scores compared with placebo. Although SLIT had a higher safety profile, a nonsignificant greater improvement occurred in the SCIT group. Among the varied findings in multiple studies, no clear cut answer seems to exist regarding the efficacy of SLIT versus SCIT; this is an area that would benefit from future, large-scale, randomized, placebo-controlled studies.
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