INTRODUCTION — Allergen immunotherapy for the treatment of allergic respiratory diseases has traditionally been administered by subcutaneous injections. Subcutaneous immunotherapy (SCIT) has proven efficacy in allergic rhinoconjunctivitis and asthma, but it requires regular injections at a clinician's office (typically over a period of three to five years) and carries the risk of potentially serious systemic allergic reactions, including anaphylaxis, in response to the treatment itself.
Sublingual immunotherapy (SLIT) is an alternate approach of administering allergens orally, and more specifically with a sublingual methodology in which the allergen is given as either a dissolvable tablet (under the tongue) or as an aqueous or liquid extract. SLIT-tablets offer several specific advantages over injection immunotherapy. The tablet can be self-administered by patients or caregivers, does not require injections, and carries a much lower risk of serious systemic allergic reactions compared with SCIT. SLIT-drops (liquid extract) are used in other parts of the world but are not approved by the US Food and Drug Administration (FDA).
This topic will discuss the SLIT-tablet forms of treatment that have been approved by either the US FDA and/or Canadian, European, and Asian regulatory authorities. The article will focus on appropriate patient selection, dose regimens and method of administration, the evidence-based clinical data to support its safety and efficacy, its use in patients with asthma, and its advantages and limitations.
The use of SCIT for the treatment of allergic respiratory diseases is discussed separately:
Oral immunotherapy for the treatment of other allergic diseases is also reviewed separately. (See "Experimental therapies for food allergy: Immunotherapy and nonspecific therapies".)
Background — Oral approaches to immunotherapy were first tried in the early 1900s. Through the years, allergen materials became better characterized and various delivery systems were developed, including oral solutions that were either swallowed or swished in the mouth but then expectorated, administered as enteric-coated tablets, liposomal constructs, or microencapsulated polymers [1,2].
In 1998, the World Health Organization (WHO) recognized that SLIT was a promising alternate mode of immunotherapy and encouraged continued clinical investigation into this form of treatment . In 2009, the World Allergy Organization (WAO) published their opinion that the cumulative evidence showed SLIT represented a viable alternative to SCIT and encouraged continued clinical investigation to characterize optimal techniques [4,5].
The realization that the rich vascular bed localized under the tongue could serve as a novel approach for allergen delivery led to the development of rapidly dissolving tablets that could efficiently be taken-up, processed by local antigen presenting cells, and carried to regional lymph nodes for effective immunization through downregulation of mucosal mast cells, induction of blocking antibody, and activation of T regulatory cells [6,7]. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms".)
AVAILABILITY — In the United States, SLIT-tablets are the only form of sublingual aeroallergen immunotherapy that is approved by the US Food and Drug Administration (FDA). In the United States, grass pollen, ragweed pollen, and house dust mite (HDM) tablets are available. In Canada and Europe, a tree tablet has received approval, and in Japan, a cedar tablet is available. Availability of various SLIT-tablet products around the world is shown in the table (table 1).
In contrast, SLIT-drops (aqueous/liquid extracts) are not approved by the US FDA; however, they are increasingly being used off-label by allergists, otolaryngologists, and other physicians caring for allergic patients, and they are approved by regulatory bodies in other countries.
ADVANTAGES AND DISADVANTAGES OF SLIT — There are several potential advantages of SLIT compared with subcutaneous immunotherapy (SCIT):
●SLIT is safer, with fewer systemic allergic reactions than SCIT. (See 'Rare anaphylaxis' below.)
●SLIT is more comfortable for patients since allergens are ingested rather than injected.
●SLIT is more convenient for patients and clinicians because therapy is self-administered by the patient (or caregiver) at home.
The disadvantages of SLIT include:
●Benefit is reliant on consistent patient self-administration. Patients who regularly miss doses may not have satisfactory results. (See 'Compliance' below.)
●Patient education will be required to ensure that it is carried out safely and effectively. As an example, patients will require education about how to resume therapy after missed doses. (See 'Patient education' below.)
The relative efficacies of SLIT and SCIT are reviewed below. (See 'Efficacy compared with SCIT' below.)
Indications — SLIT-tablet immunotherapy is indicated for the treatment of allergic rhinitis (with or without conjunctivitis) induced by the allergen contained in the product. The approved age ranges differ somewhat among the products, with grass and ragweed pollen SLIT-tablets approved for use in children and all are approved through age 65 (table 2). Because patients are most often treated with a single type of allergen, SLIT is most appropriate for patients in whom one allergen seems to account for the majority of their symptoms. However, published data have shown the ability to sequentially administer grass and ragweed SLIT-tablets, as discussed below. (See 'Polysensitized patients' below.)
The decision to initiate allergen immunotherapy should be based upon a clinical evaluation and physical examination of the patient, complemented by appropriate in vivo or in vitro testing to identify specific allergen sensitivity to the relevant allergen(s), and a detailed discussion with the patient of goals, risks versus benefits, and long-term commitment to the treatment plan. Because SLIT involves long-term daily therapy that is self-administered, it requires a commitment by the patient or caregiver to help maximize compliance. Studies of compliance are reviewed below. (See 'Compliance' below.)
Safety in patients with asthma
●Mild to moderate asthma – Trials examining the safety and efficacy of SLIT in patients with rhinoconjunctivitis and concomitant asthma have mostly included patients with mild or intermittent asthma who only required bronchodilators or low-dose daily inhaled corticosteroids. These studies have consistently demonstrated that SLIT is safe in this population [8-20]. Fewer studies have included patients with moderate-persistent asthma [21-24]. These have also shown that SLIT is well tolerated. As an example, in a trial of 834 patients with allergic rhinoconjunctivitis and asthma that was not well controlled on inhaled corticosteroids alone or in combination with a long-acting beta agonist, only one possibly treatment-related moderate asthma exacerbation was observed .
●Severe asthma – SLIT has not been sufficiently studied in patients with severe asthma, although the limited data that are available are reassuring . Accordingly, all SLIT-tablet products available in the United States and Canada are labeled as contraindicated in patients with severe, unstable, or uncontrolled asthma (table 2).
Studies evaluating the benefit of SLIT on asthma symptoms and medication use are described below. (See 'Impact on asthma' below.)
Use in pregnancy — Published data addressing the safety of SLIT in pregnancy are lacking. However, reports of adverse outcomes or fetal harm have not emerged despite decades of use in various countries. European manufacturers suggest an approach similar to the one used for injection immunotherapy (ie, that treatment not be initiated in a pregnant patient, but if a woman becomes pregnant during treatment, therapy could be continued provided the patient has not had significant allergic reactions to therapy in the past).
●Asthma that is severe, unstable, or uncontrolled.
●A history of eosinophilic esophagitis.
●A history of any severe systemic reaction or severe local reaction after taking SLIT.
●Hypersensitivity to any of the inactive ingredients (table 2). Some tablets contain fish-derived gelatin, although this been shown to be tolerated by the vast majority of fish-allergic patients .
Pre-administration testing — Sensitization to the relative allergen should be confirmed by positive skin test or in vitro testing for allergen-specific immunoglobulin E (IgE) antibodies.
Patient education — Patients should discontinue SLIT therapy temporarily if any of the following occur:
●The patient develops oral inflammation (eg, thrush, mouth ulcers, oral lichen planus) or oral wounds (eg, following dental surgery or tooth extraction). Once the oral mucosa is completely healed, therapy can be resumed.
●A patient with asthma develops an asthma exacerbation. Once asthma is under control again, the patient should be reassessed to determine if it is appropriate to continue treatment.
Patients should be instructed not to take extra doses to "catch up" if they have had gaps in treatment. This may be particularly important at times when allergic rhinitis symptoms are severe.
Polysensitized patients — The most compelling data for use of SLIT are in the monosensitized pediatric or adult patient with seasonal allergic rhinoconjunctivitis with or without mild asthma. Nearly all of the high-quality studies available have shown benefit in this context. However, the typical patient in North America is sensitized to multiple aeroallergens. House dust mite (HDM) SLIT-tablet studies have shown significant symptom improvement in patients regardless of sensitization status [29,30]. A grass study likewise demonstrated similar clinical improvement in grass-allergic patients irrespective of their polysensitivity .
●Effect of SLIT on unrelated allergens – The "bystander effect" is a term used in immunotherapy research to describe improvement in allergic symptoms caused by allergen A (eg, grass), which results from immunotherapy with an unrelated, nonhomologous allergen B (eg, ragweed). A small number of studies have directly evaluated subjects for this and have not found an appreciable effect, indicating that the benefits of immunotherapy are specific to the allergen being administered. For example, a study of immunotherapy with Timothy grass SLIT tablets showed no benefit on allergic rhinoconjunctivitis caused by birch tree pollen, two nonhomologous pollens .
●Effect of SLIT on related allergens – Immunotherapy with allergen A may result in improvement in symptoms caused by allergen B if the two allergens share homologous proteins. For example, in a study of birch tree SLIT-tablets, symptoms related to exposure to oak tree pollen were also reduced in patients allergic to both, reflecting that the two pollens share homologous proteins .
●Effect of treating just one of the patient's allergies – Whether it is preferable or necessary to include all the allergens to which the patient is sensitized in their immunotherapy or just a single allergen that seems to be responsible for most of the patient's symptoms is an area of controversy in both SLIT and subcutaneous immunotherapy (SCIT). The data in SLIT are mixed. A post-hoc analysis of data from six randomized trials of grass pollen tablet immunotherapy, including 1871 adults and children, found no difference in the benefit reported by patients who were monosensitized to grass and those who were polysensitized to grass and other allergens during the grass pollen season . In another study, 54 grass-allergic patients were randomized to monotherapy with Timothy extract, Timothy extract plus nine additional unstandardized pollen extracts, or placebo . A modest positive trend was observed in clinical parameters in the multiple pollens group, which did not reach clinical significance. (See "SCIT: Preparation of allergen extracts for therapeutic use", section on 'Multiple allergen immunotherapy extracts'.)
●Treatment with multiple SLIT tablets – The administration of two SLIT tablets simultaneously appears to be well tolerated. In an open-label six-week study, 102 adults allergic to both grass and ragweed pollens received both types of SLIT-tablets in combination to assess tolerability . The respective tablets were each given for two weeks sequentially, followed by simultaneous administration of both tablets five minutes apart for the final two weeks. Another approach is to give one type of tablet in the morning and one in the evening. Treatment was generally well tolerated, with less than five percent of patients discontinuing treatment due to adverse effects. This study provides reassurance that in patients allergic to two pollens, immunotherapy with both tablets may be accomplished with a sequential dosing regimen. Further studies, especially combining pollens and HDM, are needed to assure that multiple tablets can be safely administered.
REFERRAL — SLIT should be prescribed and initiated by clinicians with expertise in allergy to ensure the optimal selection of patients and allergens. The performance and interpretation of skin test results and the interpretation of in vitro testing both require experience and clinical judgement. The small number of studies that have evaluated the use of SLIT in primary care settings have had disappointing results [36,37].
Oral and pharyngeal adverse effects — The most common adverse effects of SLIT are oral pruritus, ear pruritus, throat irritation, and swelling of the lips, tongue, and pharynx. A smaller percentage of patients may also experience edema of the tongue, uvula, lips, or throat that may occasionally require epinephrine [13,38,39]. In clinical trials, 4 to 7 percent of patients dropped out because of adverse effects [23,29,39-41].
●Oral mucosal pruritus and irritation – These self-limited local reactions typically occur with the first dose of treatment and last 10 to 60 minutes. Symptoms tend to lessen in duration with continued therapy and resolve in the majority of patients within one to two weeks. Pollen SLIT-tablets induced oropharyngeal itching/irritation in between 10 and 40 percent of subjects in clinical trials [42,43]. These adverse effects were more pronounced in house dust mite (HDM) studies, in which up to 50 percent of patients initially experienced similar types of mild-to-moderate local reactions [44-46]. However, it should be recognized that this higher percentage of adverse events in the HDM clinical trials is reflective of a change in reporting adverse events by the regulatory agency to that of solicited rather than a true difference in the rate of occurrence.
●Transient angioedema – Transient angioedema of the sublingual tissues, tongue or oropharynx occurs in 6 to 11 percent of study subjects with pollens, and up to 14 percent with HDM . It is described as a swelling under the tongue at the site of tablet application and typically resolves within 5 to 10 minutes. This adverse effect tends not to appear with first dosing but rather is most likely to be observed at the end of the first week. It is self-limited in most patients, both with respect to severity and duration over the ensuing weeks of treatment.
In patients with persistence or worsening of oropharyngeal adverse effects and particularly in those patients experiencing more severe complexity (with laryngeal edema/obstruction), epinephrine may be indicated, and follow-up with the clinician is necessary to ascertain whether SLIT-tablet therapy should be continued [10,11,47-49].
Rare anaphylaxis — A small number of cases of anaphylaxis have been reported in patients receiving sublingual drops, a form of immunotherapy that is not approved in the United States by the US Food and Drug Administration (FDA) [50-53]. No longitudinal surveillance data have been reported to date for SLIT-tablets; therefore, only limited FDA-reported and clinical trial data can be reviewed. Data from 29 American clinical trials of SLIT-tablets revealed only two systemic reactions (none with airway compromise) and epinephrine use was 0.2 percent . However, because of the small risk of anaphylaxis, the manufacturers of the SLIT-tablet products available in the United States recommend that patients should be prescribed self-injectable epinephrine and instructed in its proper use [25-27]. There have been no fatalities reported to date with SLIT-tablets (versus seven fatalities with SCIT during the 2015 to 2017 surveillance period) [54,55].
Eosinophilic esophagitis — An association has been reported between eosinophilic esophagitis and SLIT, as well as with oral immunotherapy with food allergens [56-59]. However, reports are rare, with only six cases reported in the world's literature as of 2019 . SLIT should be discontinued in patients who develop severe or persistent gastroesophageal symptoms (including dysphagia or chest pain), and the diagnosis of eosinophilic esophagitis should be considered. Pre-existing eosinophilic esophagitis or a history of this disorder is a contraindication to the use of SLIT (table 2). (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)
Initiating therapy — SLIT-tablets are rapidly dissolving tablets that are held under the tongue until completely dissolved. SLIT-tablet therapy is initiated with a full dose in most cases. One grass pollen product stipulates a short escalation in dose when used in children 10 to 17 years of age (table 2). The first dose is given under medical supervision, and patients should be observed for at least 30 minutes for any signs of an allergic reaction. Subsequent doses are self-administered once daily by the patient or caregiver at home.
Hands should be clean and completely dry before handling the tablets. The tablet is placed under the tongue and held there for at least one minute or until fully dissolved, after which the patient should not swallow for at least one minute and not ingest food or beverage for five minutes.
Premedication with H1 antihistamines is not suggested in the product inserts of SLIT-tablets, and we do not specifically instruct patients to take an antihistamine prior to initiating sublingual immunotherapy. However, it is recommended that patients continue their usual medications when they are beginning SLIT-tablets, including antihistamines and any other medications taken regularly for allergic rhinoconjunctivitis.
Dosing — The majority of United States clinical studies have defined a single optimal dose based on prior dose-ranging safety studies [61-65]. In general, SLIT requires higher doses than subcutaneous immunotherapy (SCIT). In some SLIT studies, the daily dose of allergenic protein in micrograms is equivalent to the dose given every two to four weeks in SCIT. The cumulative amount of allergen administered in the course of one year is up to 30 times greater with SLIT-tablets compared with SCIT . Possible reasons for the higher dose requirements with SLIT may include loss of allergen from the sublingual site, processing differences of antigen uptake by lymphoid tissue within Waldeyer's Ring versus gut-associated lymphoid tissue (GALT), and other undefined mechanisms.
Timing relative to pollen seasons — SLIT-tablet therapy for pollen allergy is initiated three to four months prior to the allergen season (called "preseasonal treatment"), because clinical benefit begins within three to four months. Daily therapy is then maintained through the end of the pollen season. SLIT can also be safely started during pollen season (called "co-seasonal treatment") . Continuous year-round SLIT is another option for pollen allergy, although in open-label studies of grass pollen SLIT, this did not appear to be superior to preseasonal treatment after the first year [68,69]. However, the best approach is not clear, since the studies that showed persistent benefit two years after completion of a three-year course of therapy used continuous year-round treatment . (See 'Duration of therapy' below.)
House dust mite (HDM) SLIT-tablets can be safely started at any time of year, including during pollen seasons in patients who are also sensitized to pollens .
Labeling of specific products — Available products are shown in the table (table 2). Each has unique dosing units. All are approved for adults up to the age of 65 years. The grass and ragweed tablets are US Food and Drug Administration (FDA)-approved for children, whereas the HDM tablet is under study for this age group. Excipients should be reviewed to ensure that the patient has no history of allergies to these substances. Some tablets contain fish-derived gelatin, which is tolerated by the majority of fish-allergic patients .
5-grass sublingual tablet — The 5-grass pollen sublingual tablet (Oralair) is indicated for the treatment of grass pollen-induced allergic rhinitis (with or without conjunctivitis) in patients 5 to 65 years of age (table 2). Sensitization to any of the 5-grass species contained in the tablet (Timothy, Orchard, Perennial Rye, Kentucky Blue, Sweet Vernal) should be confirmed by positive skin test or in vitro testing for pollen-specific immunoglobulin E (IgE) antibodies to any of the 5-grass species contained in the tablet.
●Dosing is expressed in index of reactivity (IR) units. For children 10 to 17 years of age, a two-day dose escalation is stipulated (100 IR tablet on day 1, two 100 IR tablets on day 2, one 300 IR tablet daily thereafter, if tolerated). Patients 18 years and older start with the full 300 IR tablet, which contains approximately 25 mcg/mL of group 5 major allergens.
●Treatment should be started four months (16 weeks) prior to the expected onset of the respective grass season and continued through the grass season.
●The most common adverse effects were oral pruritus, throat irritation, ear pruritus, and mouth edema (25, 22, 8, and 8 percent, respectively).
●Oralair was not studied in patients with moderate or severe asthma or patients requiring daily controller therapy .
Timothy grass pollen sublingual tablet — The Timothy grass pollen sublingual tablet (Grastek) is indicated for the treatment of grass pollen-induced allergic rhinitis (with or without conjunctivitis) in patients 5 to 65 years of age . Prior to considering this therapy, allergy to Timothy or to a cross-reactive temperate grass species (Sweet Vernal, Orchard, Perennial Rye, Kentucky Blue/June, Meadow Fescue, or Redtop) should be confirmed by positive skin test or in vitro testing for pollen-specific IgE to Timothy grass or to one of the cross-reactive grass pollens. Patients living in geographic areas with other grass species, such as Bermuda or Bahia, which do not cross-react with Timothy and other temperate grasses, may not have as complete a therapeutic response to the Timothy grass pollen sublingual tablet, depending on the degree to which they are sensitive to these other grasses. In addition, there is some evidence that although grass allergens are highly homologous across species, individual allergens may be differentially recognized by T cells, and therefore, a 5-grass tablet may provide a broader array of clinically relevant epitopes . However, there is no evidence that the 5-grass tablet provides superior efficacy over the Timothy grass pollen sublingual tablet.
●Dosing is expressed in bioequivalent allergy units (BAUs) of Timothy grass pollen. Each tablet contains 2800 BAUs of Timothy grass pollen (approximately 15 mcg Phl p 5).
●Treatment should be started three months (12 weeks) prior to the expected onset of the respective grass season and continued through the grass season. It may be taken throughout the year and for three consecutive years, although the optimal schedule of treatment has not been determined.
●The most common adverse effects were oral pruritus, throat irritation, ear pruritus, and mouth edema (27, 23, 13, and 11 percent, respectively).
●Grastek was not studied in patients with moderate or severe asthma or those requiring daily controller therapy .
Short ragweed pollen sublingual tablet — The short ragweed pollen sublingual tablet (Ragwitek) is indicated for the treatment of short ragweed pollen-induced allergic rhinitis (with or without conjunctivitis) in patients 5 to 65 years of age (table 2). Allergy to short ragweed should be confirmed by positive skin test or in vitro testing for specific IgE to short ragweed pollen . It should be noted that there is extensive cross-reactivity among common ragweed species (ie, short, giant, false, and western) [73-76]. There is a reasonable assumption that the available product would be useful for treating allergy caused by any ragweed species.
●Dosing is expressed in units of major allergen. Each tablet contains 12 Amb a 1 units of short ragweed pollen (approximately 12 mcg Amb a 1).
●Treatment should be started at least three months (12 weeks) prior to the expected onset of the respective ragweed season and continued through the ragweed season.
●The most common adverse effects were throat irritation, oral pruritus, ear pruritus, and oral paresthesias (17, 11, 10, and 10 percent, respectively) .
●The short ragweed pollen sublingual tablet is labeled as contraindicated in patients with severe, unstable, or uncontrolled asthma; a history of any severe systemic allergic reaction; a history of any severe local reaction after taking SLIT; a history of eosinophilic esophagitis; or hypersensitivity to any of the inactive ingredients.
Dust mite sublingual tablet — The house dust mite sublingual tablet (Odactra) is indicated for the treatment of dust mite-induced allergic rhinitis (with or without conjunctivitis) in patients 12 to 65 years of age (table 2) . Allergy to HDM should be confirmed by positive skin test to licensed HDM allergen extracts or in vitro testing for specific IgE to Dermatophagoides farinae or D. pteronyssinus.
●Dosing is expressed in standardized-quality house dust mite (SQ-HDM) units of HDM allergen. Each tablet contains 12 SQ-HDM units of HDM allergen.
●The most common adverse effects were oral pruritus, ear pruritus, and throat irritation (47, 40, and 36 percent, respectively) . The rates of adverse reactions in this study were higher than in other studies, probably because the study design actively solicited symptoms of local reactions from patients on their electronic daily diary cards, rather than relying on spontaneously reported symptoms.
●The HDM sublingual tablet is labeled as contraindicated in patients with severe, unstable, or uncontrolled asthma; a history of any severe systemic reaction or severe local reaction after taking SLIT; a history of eosinophilic esophagitis; or hypersensitivity to any of the inactive ingredients.
EFFICACY FOR ALLERGIC RHINOCONJUNCTIVITIS — The efficacy and safety of SLIT has been demonstrated in a number of properly designed European trials for both children and adults with allergic rhinitis.
Outcome measures for immunotherapy trials — There have been efforts to standardize the outcome measures in trials of immunotherapy for respiratory allergy, to use validated tools that can be compared across studies, and to reach consensus about what degree of therapeutic benefit should be considered clinically meaningful [5,78,79].
●In 2012, the World Allergy Organization (WAO) proposed that a 20 percent mean reduction in total combined score (TCS) compared with placebo be considered the minimum change that corresponds to a clinically meaningful benefit . The decision as to what represents a sufficient therapeutic effect must be tempered by the risk:benefit ratio of the therapeutic agent. Traditionally, the bar has been set somewhat higher for a treatment such as injection immunotherapy, where the risks (ie, anaphylaxis induced by the injections) were perceived as relatively significant.
●For an allergen immunotherapy therapeutic to be approved by the US Food and Drug Administration (FDA), two statistical efficacy criteria must be met: a) Criterion 1 (point estimate): a difference of 15 percent in the TCS between active treatment and placebo must be demonstrated; b) Criterion 2 (confidence interval): a lower bound of the 95 percent confidence interval of that difference demonstrating at least a 10 percent separation between the two groups must be demonstrated. These statistical tests were selected after rigorous internal evaluation by the agency and have been mandated to identify and define a statistically significant and clinically meaningful therapeutic effect more clearly when comparing allergen immunotherapy with placebo.
Efficacy compared with pharmacotherapy — Based on indirect comparisons, the efficacy of SLIT-tablets for seasonal allergic rhinitis to pollen appears to be similar to that of corticosteroid nasal sprays but superior to either antihistamines or montelukast , while the efficacy of house dust mite (HDM) SLIT-tablets appears to be superior to any single pharmacologic therapy for perennial allergic rhinitis .
A 2016 study that compared pooled efficacy data from 10 randomized trials of SLIT-tablets (for treatment of seasonal or perennial allergic rhinitis) with data from studies of pharmacotherapy found that SLIT-tablet treatment resulted in an overall improvement in total nasal symptom scores of 16 to 17 percent relative to placebo .
By comparison, trials of mometasone furoate nasal spray, desloratadine, and montelukast, all at full strength, resulted in improvements in total nasal symptom scores of 22, 9, and 5 percent, respectively, for seasonal allergic rhinitis and 11, 5, and 4 percent, respectively, for perennial allergic rhinitis. Limitations of this analysis included the fact that most SLIT studies allowed for use of rescue medications, while trials of pharmacotherapy generally did not, which would potentially underestimate the effect of SLIT. However, this study design also provides evidence for the additive effects of SLIT beyond pharmacotherapy. Another limitation of the analysis was the lack of trials employing combinations of pharmacotherapies, which would more closely simulate "maximal medical therapy."
Efficacy compared with SCIT — A 2021 network meta-analysis (NMA) of 26 randomized double-blind clinical trials reached a similar conclusion . Clinical symptoms and medication improvement was ascertained for each type of immunotherapy (directly for each agent against placebo, and indirectly for comparisons between types of therapy), with the NMA providing data to suggest that subcutaneous immunotherapy (SCIT) was more effective than SLIT-tablets and SLIT-drops.
A small number of trials have directly compared SLIT and SCIT [66,84-91]. Three randomized trials involved head-to-head, double-dummy protocols [66,84,85]. Although each study had methodologic issues and small numbers of patients, two of three found SCIT to be at least somewhat more effective than SLIT.
Efficacy compared with placebo — In multiple randomized trials, SLIT tablets have been shown to reduce symptom scores and medication requirements in patients with allergic rhinoconjunctivitis.
In a 2017 systematic review that included 41 randomized trials and approximately 4500 adults and children receiving active SLIT treatment (tablets or drops) or placebo, treatment with SLIT resulted in a reduction in symptom scores (standardized mean difference [SMD] –0.48 [95% CI –0.61 to –0.36]) and in medication requirements (SMD –0.31 [95% CI –0.44 to –0.18]) . Nine studies reported on TCS, which were also reduced (SMD –0.47 [95% CI –0.81 to –0.12]). Most studies involved treatment with single pollens (most commonly grass) or HDM preparations at a range of doses. Effects on quality of life could not be assessed because a variety of different measurements were used. There was some evidence of publication bias. However, this systematic review did not include subsequent important studies of HDM-SLIT. (See 'House dust mite tablet' below.)
Grass tablet — A 2015 systematic review and meta-analysis of all randomized trials (through 2014) evaluating grass pollen SLIT-tablet immunotherapy found a treatment benefit on symptom score (SMD –0.28; 95% CI –0.37 to –0.19) and medication score (SMD –0.24; 95% CI –0.31 to –0.17) . Representative studies are discussed below.
Timothy grass pollen tablet — European and North American studies with the Timothy grass pollen SLIT-tablet have demonstrated clinical benefit in grass-allergic subjects [44,47,48,61,94,95]. Pivotal trials are described below.
●In a trial of 634 European adults with grass-induced seasonal allergic rhinoconjunctivitis, subjects received once-daily treatment with a Timothy SLIT-tablet (Grazax) containing 15 mcg Phl p 5 or placebo . Treatment was initiated 16 weeks preseason and continued during the season within a study design that was extended to incorporate a two-year maintenance phase and a two-year follow-up after discontinuation of therapy (ie, five years in total) [44,96]. (See 'Duration of therapy' below.)
Mean rhinoconjunctivitis symptom scores and medication scores improved 30 and 38 percent, respectively, compared with placebo. There were also significant increases in the number of well days (53 versus 44 percent) and improvements in quality of life in the treatment group. After the first year, the study was continued, demonstrating that three years of continuous daily therapy conferred sustained benefit over the three years of treatment (ie, reductions in total rhinoconjunctivitis combined scores of 33; 41; and 36 percent over the three years), with a persistence of clinical benefit in the fourth and fifth grass seasons (off treatment) (reductions of 27 and 23 percent, respectively).
The first year of this study of the Timothy grass product was accepted by the US FDA as pivotal data for approval, and the complete data set of the study was reviewed and accepted as the basis for the multiple year approval of the product in grass-allergic patients . Data for maintaining sustained effectiveness beyond this timeframe have not been established. (See 'Duration of therapy' below.)
●A European study in grass-allergic children demonstrated similar efficacy and safety .
●American trials of Timothy grass pollen SLIT-tablets used a dose of 15 mcg Phl p 5 in both adults and children [47,48]. These trials were large (300 to 400 patients each), and 85 to 90 percent of patients were sensitized to multiple allergens in addition to grass pollen. The primary endpoint, the combined daily symptom plus medication score, improved (was reduced) by 20 percent (difference versus placebo –1.31 [95% CI –2.8 to –0.36]) in adults and 26 percent (difference versus placebo –1.63 [95% CI –2.60 to –0.66]) in adolescents and children.
●In the largest United States SLIT study of 1501 children and adults, the Timothy grass pollen sublingual tablet showed efficacy in both primary and secondary outcomes similar to that demonstrated in the positive trials performed earlier .
Multiple grass pollen tablet — There are a number of high quality studies with the 5-grass pollen tablet in both children and adults [40,97-101].
●A randomized, placebo-controlled trial performed on 473 American adults used the 300 index of reactivity (IR) dose 5-grass pollen sublingual tablet . Compared with placebo, active treatment patients showed a 28 percent improvement in the primary efficacy measure of total combined score plus medication score (figure 1). Similar improvements were observed in the secondary outcome measurements, including daily rhinitis total symptom score (23 percent), daily rhinitis rescue medication score (46 percent), overall rhinoconjunctivitis quality of life questionnaire score, and respective individual symptom scores (except nasal itch).
●In a multinational dose-ranging trial performed in 784 adults with allergic rhinitis caused by ragweed (with or without conjunctivitis or mild asthma), subjects were randomly assigned to placebo or to three different doses of ragweed SLIT-tablet (containing 1.5, 6, or 12 units of Amb a 1 protein, where 1 unit is approximately equal to 1 mcg) . Therapy was initiated four months prior to the ragweed pollen season and continued for one year (for safety monitoring). The primary endpoint was the total combined symptom/medication score (TCS) during peak ragweed season. The 6 and 12 unit tablets reduced TCS by 19 percent (difference versus placebo –1.58 [95% CI –2.8 to –0.36]) and 24 percent (difference versus placebo –2.04 [95% CI –3.30 to –0.79]), respectively (figure 2). Only the 12 Amb a 1 U dose met the 95 percent lower bounds of the confidence interval criterion required by the US FDA.
●In the second trial performed in North America, 565 ragweed allergic patients were randomized to two strengths of tablet (6 or 12 units of Amb a 1) or to placebo, and a similar degree of improvement in TCS was demonstrated (21 and 27 percent, respectively) versus placebo during the peak season .
House dust mite tablet — Randomized trials have demonstrated the efficacy and safety of HDM SLIT-tablets for the treatment of allergic rhinitis [21,23,29,30,102,103]. The Odactra (ALK) product has received FDA approval. Other products are under review .
In a representative trial of 1482 subjects (aged ≥12 years) with HDM-induced allergic rhinitis with or without either conjunctivitis and/or asthma, subjects were randomized to one year of daily treatment with a 12 unit standardized-quality HDM (SQ-HDM) SLIT-tablet or placebo . The primary endpoint was the average total combined rhinitis score, which was defined as the daily rhinitis symptom score plus rhinitis daily medication score, during the last two months of treatment. Active treatment improved the total combined rhinitis score by 17 percent (95% CI 10-25 percent) versus placebo and was well tolerated.
Studies of HDM SLIT in patients with asthma are discussed below. (See 'Impact on asthma' below.)
●In a randomized trial using the Vienna environmental exposure chambers (VEEC), 219 European patients with birch pollen-related allergic rhinoconjunctivitis received three different strengths of birch pollen SLIT-tablets for 24 weeks, followed by exposure to birch pollen in a chamber challenge, and then to oak pollen, which shares homologous proteins with birch . The highest dose most effectively reduced symptoms to both pollens in the VEEC, with effects apparent at 16 weeks of treatment.
●In a randomized trial of 634 birch and oak allergic patients treated with the sublingual birch homologous tree pollen tablet, significant improvements in the TCS (25 percent), daily symptom score (22 percent), and daily medication score (32 percent) compared with placebo were observed over the course of the oak tree pollen season. In addition, the immunizing regimen induced oak-specific protective antibody. This natural exposure seasonal trial demonstrated that the tree pollen tablet provided meaningful clinical improvement not only against birch allergy but also in oak-sensitive patients who share Bet v 1 cross-reactivity .
Japanese red cedar tablet — Japanese red cedar is the predominant seasonal allergen in Japan and is recognized as a major cause of allergic rhinoconjunctivitis in the Japanese population. The 5000 JAU (allergy unit) SLIT-tablet received approval from the Japanese Ministry of Health Labor and Welfare in 2017 for patients aged 5 to 64 years.
In a trial of 1042 patients with Japanese cedar pollinosis, subjects were randomized to three different dosing regimens of active drug (2000, 5000, 10,000 JAU) or placebo. The primary clinical endpoint of Total Nasal Symptom and Medication Score was reduced by 21, 32, and 32 percent respectively versus placebo. Both the 5000 and 10,000 JAU regimens were comparable and statistically superior to the 2000 JAU dose, which served as the basis for 5000 JAU being selected as the optimal treatment dose [106,107].
IMPACT ON ASTHMA
Improvement in asthma symptoms — SLIT has been shown in randomized trials to be safe for patients with concomitant mild-to-moderate asthma, and most studies have reported improvements in asthma symptom scores and medication use, while a smaller number have not. However, improvement in several patient-important asthma outcomes has not been conclusively demonstrated. In a 2020 systematic review of 66 studies including nearly 8000 children and adults, several patient-important primary outcomes were evaluated: Asthma exacerbations requiring a visit to the emergency department or admission to hospital, validated measures of quality of life, and all-cause serious adverse events . Secondary outcomes were asthma symptom scores, exacerbations requiring systemic glucocorticoids, response to provocation tests, and dose of inhaled glucocorticoids. However, with the exception of all-cause serious adverse events, which were not increased in patients receiving SLIT, these outcomes were not included or commented on in most of the studies, limiting the ability of the review to assess them. Trials that did include relevant outcomes mostly found a trend towards improvement in asthma symptoms.
In contrast to the systematic review of all types of SLIT, studies in house dust mite (HDM)-induced allergic asthma have provided consistent evidence that treatment improves asthma symptoms , reduces the risk of moderate-to-severe asthma exacerbations, nocturnal awakenings, relief medication use, and minimizes deterioration in lung function [23,109]. Based on these data, a 2019 guideline from the European Academy of Allergy and Clinical Immunology (EAACI) and a 2020 update to the Global Initiative for Asthma (GINA) guideline both endorse the use of HDM-SLIT tablets (and HDM subcutaneous immunotherapy [SCIT]) as add-on therapy for patients with mild-to-moderate allergic asthma and HDM allergy to decrease symptoms and medication use [110,111]. The GINA guideline suggests that clinicians "Consider adding HDM SLIT for sensitized patients with allergic rhinitis and an FEV1 >70 percent predicted" .
Reduced risk of asthma development — Both SCIT and SLIT-tablets appear to reduce the risk of developing asthma, particularly in children [112,113].
In a randomized trial, 812 children (5 to 12 years) with grass pollen-allergic rhinoconjunctivitis and without asthma were randomized to three years of treatment with a grass SLIT-tablet or placebo and followed for an additional two years . Treatment with the SLIT-tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial, during the two-year follow-up, and during the five-year study period (odds ratio [OR] 0.66 [95% CI 0.45-0.97]), corresponding to a relative risk reduction of 29 percent.
The preventative effects of SCIT on the development of asthma are discussed separately. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy", section on 'Preventive effects'.)
COMPLIANCE — SLIT requires a commitment by the patient to a long-term daily maintenance therapy that is self-administered, and compliance is likely to be lower than that obtained in supervised clinical trials . Past surveillance studies showed poor real-world compliance with all forms of allergen immunotherapy, with up to one-half of patients discontinuing therapy, and studies in both children and adults indicate that long-term compliance with SLIT is similarly low [115-118]. However, frequent follow-up, particularly in the first months of treatment, may encourage patients to remain on therapy. A 2010 study of 300 children (6 to 16 years of age) who received either grass or house dust mite (HDM) sublingual drops or tablets over two years of treatment demonstrated that discontinuation rates were clearly tied to the frequency of follow-up . In patients evaluated in the clinic every 3, 6, and 12 months, the dropout rate was 8, 15, and 29 percent, respectively, at the end of one year and worsened to 10, 18, and 41 percent at the end of two years. Similarly, when looking at prescription refills, a marker of real-world use, SLIT sales decreased to 44, 28, and 13 percent over three years .
A 2018 open-label observational study of adherence in a real-world practice setting in Scandinavia showed 55 percent of their 399 patients (59 percent adults, 41 percent children) completed three years of year-round treatment with the Timothy grass SLIT-tablet, and those patients adhering to the defined protocol (per-protocol) exhibited marked improvement in adherence (year 1: 94 percent; year 2: 93 percent; year 3: 89 percent) . Sixty-five percent of dropouts occurred before completion of the first year of treatment, which again emphasizes the importance of explaining to the patient the expected side effects with SLIT-tablet treatment, the likelihood of adverse effects occurring in the first several weeks but diminishing with continued dosing, and knowing the signs that alert the patient to follow up with the medical office.
The following measures may help optimize compliance:
●Ensure there is good understanding of the expected benefit and time course of improvement before starting therapy.
●Clearly explain the adverse effects that are possible and how to handle each of these, including knowing when to call the allergist's office, administer epinephrine, or proceed to an emergency department.
●Schedule regular follow-up visits to assess progress and problems.
Patient information is provided. (See 'Information for patients' below.)
DURATION OF THERAPY — The optimal duration for a course of SLIT has not been fully defined. Based on available studies reviewed below, we would suggest to grass-allergic patients that if they find the Timothy grass SLIT-tablet helpful after the initial grass season, and the daily regimen was not burdensome to maintain, then the grass literature supports that three years of continuous daily therapy is likely to confer some lasting benefit after treatment is discontinued, and the product is approved for use in this manner [96,98]. However, for house dust mite and other allergen SLIT-tablets, longer-term clinical data are needed to establish the optimal duration of therapy, and in the case of pollens, gain approval for continuous use.
●Three years of continuous daily therapy with the Timothy grass SLIT-tablet conferred benefit over the three years of treatment (ie, reductions in Total Rhinoconjunctivitis Combined Scores of 33, 41, and 36 percent) with sustained symptom control in the fourth and fifth grass seasons (off treatment) (reductions of 27 and 23 percent, respectively) .
●Similarly, three years of continuous therapy with the Timothy grass SLIT-tablet in 812 children (ages 5 to 12 years) with asthma demonstrated sustained efficacy in the two grass seasons following completion of a three-year period of daily treatment in the GAP study . Treatment reduced the risk of experiencing asthma symptoms or using asthma medications at the trial's end, during the two-year follow-up (off treatment), and over the full five-year course of the study (odds ratio: 0.66).
●Three years of discontinuous treatment (16 weeks prior to the season, throughout the season, and stopping at the end of the season) was evaluated in a five-year study of the 5-grass SLIT-tablet . Subjects were blinded and maintained symptom diaries during the subsequent fourth and fifth grass pollen seasons. This study also demonstrated clinical benefit across the five grass seasons, although it did not meet the full requirements of the US Food and Drug Administration, and the drug was approved for a seasonal indication only.
●In contrast to the three-year studies above, two years of continuous treatment with the Timothy grass SLIT-tablet did not provide sustained benefit. In a nasal provocation study of grass-allergic patients with moderate-to-severe seasonal allergic rhinitis treated continuously for two years, the nasal response to allergen challenge at year 3 (one year off treatment) showed no difference between SLIT and placebo-treated patients, thus suggesting that a minimum of three years of treatment with the SLIT-tablet is necessary to induce longer-term clinical tolerance once treatment is stopped .
These studies are consistent with clinical trials of subcutaneous immunotherapy (SCIT) that have been the hallmark studies providing evidence that three years of "maintenance" treatment confers a persistent therapeutic benefit once subcutaneous injections have stopped [123-125]. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy", section on 'Persistence of benefit after discontinuation'.)
Data on other SLIT products are limited. In a randomized trial, one full year of treatment with house dust mite SLIT in patients with moderate-to-severe allergic rhinitis conferred a treatment benefit that persisted through the second year (during which patients were blinded and received no further immunotherapy) . However, longer-term studies are needed. (See 'House dust mite tablet' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Allergen immunotherapy for the treatment of respiratory allergy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
SUMMARY AND RECOMMENDATIONS
●Available products – Sublingual immunotherapy (SLIT) involves the application of allergen to the sublingual tissue. The most consistent benefit has been obtained with SLIT-tablet formulations using rapidly dissolving tablets, which are the only form of SLIT that is approved by the US Food and Drug Administration (FDA). Specific SLIT-tablet products available around the world are shown in the table (table 1). (See 'Availability' above.)
●Comparison to subcutaneous immunotherapy (SCIT) – The main advantages of SLIT over SCIT are safety (ie, anaphylaxis is rare) and the comfort and convenience of an oral therapy that is self-administered. The main disadvantages of SLIT are that it relies on the patient to self-administer the therapy daily and is slightly less effective than SCIT. (See 'Advantages and disadvantages of SLIT' above.)
●Patient selection and pretreatment testing – SLIT-tablet immunotherapy is best suited for patients with allergic rhinoconjunctivitis with or without mild-to-moderate controlled asthma, in whom one allergen seems to account for the majority of their symptoms, since patients are treated with one type of tablet at a time. However, studies of sequential administration (eg, pollen tablets during pollen season, followed by dust mite tablets during winter) are ongoing, which may impact future recommendations. Sensitization to the relative allergen should be confirmed by positive skin test or in vitro testing for allergen-specific immunoglobulin E (IgE) antibodies. The approved age ranges differ somewhat among the products, with some pollen SLIT-tablets approved for use in children and most products approved through age 65 (table 2). (See 'Patient selection' above.)
●Contraindications and adverse effects – All SLIT-tablets are labeled as contraindicated in patients with severe, unstable, or uncontrolled asthma. Other contraindications include a history of eosinophilic esophagitis and hypersensitivity to any of the inactive ingredients (table 2). The most common adverse effect of SLIT-tablet therapy is itching of the mouth, lips, tongue, or ears and mild swelling of the sublingual tissues, which occurs in up to 50 percent of patients at the start of treatment and generally resolves within one to two weeks. Anaphylaxis and eosinophilic esophagitis are rare side effects. (See 'Adverse effects' above and 'Patient selection' above.)
●Administration – SLIT is self-administered by patients (or their caregivers) at home, although the first dose is usually given under medical supervision. For the treatment of rhinitis due to pollen allergy, SLIT should be initiated three to four months before the onset of the relevant pollen season. (See 'Administration' above.)
●Efficacy for allergic rhinoconjunctivitis:
•The efficacy of SLIT-tablets for seasonal allergic rhinitis to pollens appears to be similar to that of glucocorticoid nasal sprays but superior to antihistamines or montelukast, based on indirect comparisons. The efficacy of house dust mite SLIT-tablets appears to be superior to any single pharmacologic therapy. However, SLIT therapy has not been compared to maximal medical therapy using combinations of medications. (See 'Efficacy compared with pharmacotherapy' above.)
•SLIT appears to be somewhat less effective than SCIT. (See 'Efficacy compared with SCIT' above.)
•Compared with placebo, SLIT-tablet therapy reduces symptoms of allergic rhinoconjunctivitis between 15 and 30 percent. (See 'Efficacy compared with placebo' above.)
●Impact on asthma – Most studies that have included patients with mild-to-moderate asthma have found improvements in asthma symptom scores and medication use. However, improvements in other patient-important asthma outcomes, such as reductions in exacerbations requiring emergency care or oral corticosteroids, have not been demonstrated and few studies have included these outcomes in the study designs. (See 'Impact on asthma' above.)
●Compliance – Compliance with all forms of immunotherapy is relatively low, and this is true of SLIT-tablet therapy as well. Close follow-up in the initial months of treatment can reassure patients experiencing local oral side effects and help them remain compliant until they experience benefit, which typically begins after three to four months. (See 'Compliance' above.)
●Duration of therapy – The optimal duration of therapy has not been fully defined. For pollen SLIT, three years of consecutive therapy, but not shorter periods, confers at last two additional years of benefit. This is consistent with observations in other forms of allergen immunotherapy, which are usually administered for three to five years. For patients who are responding well to SLIT-tablet therapy and are willing to continue it, we advise three years of treatment. (See 'Duration of therapy' above.)
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