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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 in response to the treatment itself.
The 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, has evolved into a viable treatment for allergic respiratory diseases. Sublingual immunotherapy (SLIT) offers several specific advantages over injection immunotherapy. SLIT can be self-administered by patients or caregivers, does not require injections, and carries a much lower risk of anaphylaxis compared with SCIT. This topic will discuss the mechanisms of action, advantages, and limitations of SLIT for allergic rhinitis and the most common methods of administering immunotherapy via an oral route: sublingual immunotherapy tablets (SLIT-tablets) and sublingual aqueous or glycerinated liquid preparations (SLIT-drops).
The use of SCIT for the treatment of allergic respiratory diseases is discussed separately. (See "Subcutaneous immunotherapy for allergic disease: Indications and efficacy" and "Allergen immunotherapy for allergic disease: Therapeutic mechanisms" and "SCIT: Standard schedules, administration techniques, and monitoring".)
Oral immunotherapy for the treatment of other allergic diseases is reviewed elsewhere. (See "Future therapies for food allergy" and "Latex allergy: Management", section on 'Immunotherapy'.)
Background — Oral immunotherapy was first proposed as a method of treatment for allergic disease in the early 1900s. In the 1980s, properly designed clinical trials first demonstrated a dose-dependent therapeutic response with specific and well-characterized aeroallergens. 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 [2,3].
DELIVERY SYSTEMS — Several types of allergen preparations have been studied in sublingual immunotherapy (SLIT). The following forms are most promising:
●Sublingual immunotherapy tablets (SLIT-tablets) – Allergen is formulated into a rapidly-dissolving tablet that is held under the tongue until completely dissolved. The majority of United States clinical studies have defined a single optimal dose based on prior dose-ranging safety studies. The tablets are self-administered, once daily.
●Sublingual aqueous or glycerinated liquid allergen extracts (SLIT-drops) – An aqueous or liquid (eg, glycerinated) extract of allergen, generally administered as drops, is held under the tongue for a specified period of time, and then the residual is swallowed. The allergen is taken up through the rich vascular lymphoid network of the mouth. Oral solutions that are held in the mouth for a period of time, but then spit out rather than swallowed, have also been evaluated in clinical trials. However, holding the extract under the tongue appears more efficient for delivery of active drug.
Other approaches to oral immunotherapy that have been investigated in research trials include administration of the allergen(s) as enteric-coated tablets, liposomal constructs, or microencapsulated polymers. These oral (swallow) delivery systems are intended to protect the allergenic proteins from breakdown in the stomach and then allow a pH-dependent release in the small intestine for processing by the gut-associated lymphoid tissue (GALT). However, research studies with these constructs have not, as of yet, demonstrated evidence for effective delivery [4,5].
Types of allergens — The majority of studies of SLIT have been performed with pollen allergens in patients with allergic rhinitis. There are a smaller number of studies of dust mite immunotherapy. The use of food allergens or latex allergens in oral immunotherapy is discussed separately. (See "Future therapies for food allergy" and "Latex allergy: Management", section on 'Immunotherapy'.)
AVAILABILITY — Sublingual immunotherapy tablets (SLIT-tablets) have been approved by the European regulatory authorities and are in use throughout the European Union and Japan. Some SLIT-tablets are available in Canada. In April 2014, the US Food and Drug Administration (FDA) announced approval of a 5-grass pollen sublingual tablet (Oralair) produced by Stallergenes , followed by a Timothy grass pollen sublingual tablet (Grastek) and a short ragweed pollen sublingual tablet (Ragwitek), both produced by Merck [7,8]. These are the first immunotherapy tablets to become available in the United States. (See 'Sublingual tablets' below.)
In the United States, there has been "off-label" use of liquid allergen extracts for sublingual immunotherapy (SLIT). The issues regarding this practice are discussed below. (See 'Sublingual drops' below.)
MECHANISMS OF ACTION — The gut is the largest mucosal organ of the body and is exposed to numerous foreign proteins on a constant basis. The normal response of the gut immune system to nonpathogenic proteins is tolerance, a fact which forms the basis for the concept of oral immunization.
The gut immune system is comprised of various physical barriers, secretory immunoglobulin A (IgA), the gut-associated lymphoid tissue (GALT), and lymphoid organs (mesenteric lymph nodes, spleen, and liver). Within the GALT, two areas of importance for antigen processing are the tonsils and adjacent ring of lymphoid tissue in the posterior pharynx and the Peyer's patches of the duodenum, jejunum, and small intestine. The GALT is essential for normal tolerance to most foreign proteins, as well as in the immunologic response to oral immunotherapy. The role of the GALT in the pathogenesis of food allergy is reviewed elsewhere. (See "Pathogenesis of food allergy".)
Allergens used in sublingual immunotherapy (SLIT) are usually intended for absorption either in the mouth or within the small intestine, as the conditions of the gastric environment (pH and other factors) destroy many allergenic proteins. Whether the immunologic response to allergens absorbed through the oral mucosa is different from that to allergens absorbed through the intestine is an area of ongoing investigation.
●Allergen extracts given sublingually are primarily taken up by dendritic cells in the mucosa and presented to T cells in the draining lymph nodes. Likely mechanisms of action include activation of T regulatory cells and downregulation of mucosal mast cells . Within the oral and sublingual mucosa, effector cells, such as mast cells, are less numerous . This characteristic of the oral mucosa is believed to be an important factor in the lower rates of adverse systemic allergic reactions seen with SLIT.
●Allergenic proteins that reach the small intestine are processed through columnar mucosal cells and presented to T lymphocytes within Peyer's patches . Allergen processing within the GALT is discussed in greater detail separately. (See "Pathogenesis of food allergy".)
●Under normal conditions, local tolerance is believed to arise through stimulation of antigen-specific T helper cells to increase IgA production with concomitant suppression of immunoglobulin G (IgG) and immunoglobulin M (IgM) production . Systemic tolerance occurs as a result of a decline in T helper mechanisms or stimulation of T suppressor cells involved in immunoglobulin E (IgE) production. Mechanisms of oral tolerance are discussed in more detail separately. (See "Pathogenesis of food allergy", section on 'Factors influencing sensitization or tolerance'.)
Immunologic changes following SLIT — SLIT is less well-studied than subcutaneous immunotherapy (SCIT), although similar immunologic mechanisms appear to be involved .
The following changes in the humoral responses to allergens are seen with SLIT [13-20]:
●Increases in allergen-specific immunoglobulin G4 (IgG4) [13-15,17]. Several studies now suggest that IgG4 production is under the control of interleukin-10 (IL-10).
●Blunting of seasonal increases in allergen-specific IgE .
SLIT also results in changes in the cellular response to allergens, including [21-25]:
●Increases in CD8+ T cells and decreases in the CD4:CD8 T cell ratio .
●Increases in IL-10 production and IL-12/interferon-gamma by peripheral blood monocytes [21,22]. As mentioned previously, IgG4 production may be regulated by IL-10, and SCIT has been shown to induce T regulatory cells to produce IL-10. IL-10 downregulates T helper type 2-dependent inflammation and suppressed B cell isotype switching to IgE. (See "Pathogenesis of allergic rhinitis (rhinosinusitis)".)
●Decreases in IL-13 levels and in the ratio of serum eosinophil cationic protein (ECP):eosinophil. Serum ECP is an indicator of activated eosinophils, and reductions in the ECP:eosinophil ratio suggest that a smaller percentage of eosinophils are in an activated state as a result of successful immunotherapy. Furthermore, IL-13 changes are associated with airway remodeling, and its reduction is also a positive marker of successful immunotherapy.
The immunologic changes observed with SCIT are discussed in more detail elsewhere. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms".)
Administration of SLIT-tablets — Sublingual immunotherapy (SLIT)-tablet therapy is initiated with a full dose or a short escalation in dose, with the first dose given under medical supervision, and then administration continues once daily and is self-administered by the patient or caregiver at home.
SLIT-tablets are labeled as contraindicated in patients with severe, unstable, or uncontrolled asthma (table 1) [26-28]. Other contraindications include a history of eosinophilic esophagitis and hypersensitivity to any of the inactive ingredients. It is recommended that patients with asthma do not take SLIT-tablets when they are experiencing an acute asthma exacerbation and that they be reassessed after an asthma exacerbation, or if they have recurrent asthma exacerbations on therapy, to determine if it is appropriate to continue treatment.
If patients receiving SLIT-tablets develop oral inflammation (eg, thrush, mouth ulcers, oral lichen planus) or oral wounds (eg, following dental surgery or tooth extraction), SLIT therapy should be stopped to allow complete healing of the oral mucosa before resumption.
5-grass sublingual tablet — The 5-grass pollen sublingual tablet (Oralair, Stallergenes) is indicated for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis in patients aged 10 to 65 years of age. Sensitization to any of the 5-grass species contained in the tablet (Timothy, Orchard, Perennial Rye, Kentucky Blue Grass, 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.
The tablet is administered under the tongue and held there for at least one minute or until fully dissolved (table 1). The patient should be instructed not to ingest food or beverage for five minutes following dissolution of the tablet. The first dose is to be taken at the clinician's office under medical supervision, and patients should be observed for at least 30 minutes for signs of allergic reactions . Subsequent doses are to be administered once a day by the patient (or the patient's caregiver). 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 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 sublingual allergen immunotherapy; a history of eosinophilic esophagitis; or hypersensitivity to any of the inactive ingredients. Oralair was not studied in patients with moderate or severe asthma or patients requiring daily controller therapy .
Timothy grass sublingual tablet — The Timothy grass pollen sublingual tablet (Grastek, Merck) contains 2800 bioequivalent allergy units (BAUs) of Timothy grass pollen (approximately 15 mcg Phl p 5) and is indicated for the treatment of grass pollen-induced allergic rhinitis, with or without conjunctivitis, in patients aged 5 to 65 years. Prior to considering this therapy, allergy to Timothy or to a cross-reactive grass species (Sweet Vernal, Orchard, Perennial Rye, Kentucky Blue/June Grass, Meadow Fescue, or Redtop) should be confirmed by positive skin test or in vitro testing for pollen-specific immunoglobulin E (IgE) to Timothy grass or to one of the cross-reactive grass pollens. Patients living in geographic areas with other grass species that do not cross-react with the temperate family (eg, Bermuda, Bahia) may not have as complete a therapeutic response to the Timothy grass tablet, depending upon 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 at present that the 5-grass tablet provides superior efficacy over the Timothy tablet.
The tablet is administered under the tongue and held there until fully dissolved, after which the patient should not ingest food or beverages for five minutes (table 1). The first dose is to be taken at the clinician's office under medical supervision, and patients should be observed for at least 30 minutes for signs of allergic reactions . Subsequent doses are to be administered once a day by the patient (or the patient's caregiver). 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 Timothy grass 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 sublingual allergen immunotherapy; a history of eosinophilic esophagitis; or hypersensitivity to any of the inactive ingredients" (eg, fish-derived gelatin) . The most common adverse effects were oral pruritus, throat irritation, ear pruritus, and mouth edema (27, 23, 13, 11, percent respectively).
The product was not studied in patients with moderate or severe asthma or those requiring daily controller therapy.
Short ragweed sublingual tablet — The short ragweed pollen sublingual tablet (Ragwitek, Merck) contains 12 Amb a 1 units of short ragweed pollen (approximately 12 mcg Amb a 1) and is indicated for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, in patients aged 18 to 65 years. Allergy to short ragweed should be confirmed by positive skin test or in vitro testing for specific immunoglobulin E (IgE) to short ragweed pollen . There is extensive cross-reactivity among common ragweed species (ie, short, giant, false, and western) [30-33].
The tablet is administered under the tongue and held there until fully dissolved, after which the patient should not swallow for at least one minute and not ingest food or beverage for five minutes (table 1) . The first dose should be administered at the clinician's office under medical supervision, and patients should be observed for at least 30 minutes for signs of allergic reactions. Subsequent doses are to be administered once a day by the patient. 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 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 sublingual allergen immunotherapy; a history of eosinophilic esophagitis; or hypersensitivity to any of the inactive ingredients (eg, fish-derived gelatin, mannitol). The most common adverse effects were throat irritation, oral pruritus, ear pruritus, and oral paresthesias (17, 11, 10, 10 percent, respectively) .
The product was not studied in patients with moderate or severe asthma or those requiring more than daily controller therapy with low-dose inhaled glucocorticoids.
Doses — The cumulative amount of allergen administered in the course of a year is generally 20 to 200 times greater with SLIT compared with subcutaneous immunotherapy (SCIT) . The reason(s) that higher doses are needed have not been fully defined, although they may include loss of allergen through digestion, as well as the immunologic effects of high versus low levels of allergen exposure in the gut.
In some studies, the daily dose of allergenic protein in micrograms is equivalent to the dose given every two to four weeks in SCIT.
●A range of allergen doses was evaluated in dose-exploratory phase I and II safety studies of patients with seasonal allergic rhinoconjunctivitis treated with Timothy grass pollen sublingual tablets [18,35]. In these studies, 100,000 standardized-quality tablet (SQ-T) units was equivalent to approximately 20 mcg Phleum p 5, a dose similar to the effective maintenance dose for grass pollen SCIT. A randomized trial conducted in centers throughout Europe compared three different strengths of a Timothy grass sublingual tablet (Grazax) with placebo in 855 adults with grass pollen-induced rhinoconjunctivitis . Subjects received one of three doses of the major Timothy allergen (Phleum p 5): 2500 SQ-T units (0.5 mcg of major allergen), 25,000 SQ-T units (5 mcg), or 75,000 SQ-T units (15 mcg). Treatment was initiated 8 weeks prior to grass pollen season and continued daily throughout the season (mean duration of therapy was 18 weeks).
●A similar safety study of the 5-grass standardized allergen SLIT-tablet was performed to establish a tolerated dose for subsequent trials . Doses of 100 to 500 IR were evaluated for safety and tolerability in 30 grass-allergic adults over a 10-day treatment period. Through incorporation of a five-day up-dosing regimen, high-dose treatment with 500 IR (approximately 42 mcg group 5 major allergens) could be reached without significant untoward adverse events. The majority of adverse events were mild-to-moderate with the most common being oral pruritus, throat irritation, and tongue swelling. No serious adverse events occurred.
Schedules — Treatment is typically initiated 12 to 16 weeks prior to the allergen season and maintained through the end of the pollen season. As an example, SLIT-tablet treatment for seasonal allergens is generally started two to three months prior to the start of the relevant pollen season. Continuous year-round SLIT is another option, although in open-label studies of grass pollen SLIT, this did not appear to be superior to preseasonal treatment after the first year [37,38]. 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, as described below . (See 'Persistence of therapeutic benefit' below.)
Duration of therapy — The optimal duration of a course of SLIT has not been defined. However, one controlled, but nonrandomized, study of 78 patients undergoing dust mite SLIT for three, four, or five years found that patients experienced persistent reduction in symptoms lasting seven, eight, and eight years, respectively . Based on this, the authors suggested four years of therapy was a reasonable goal until more data are available. Other studies evaluating the persistence of benefit after stopping therapy are reviewed below. (See 'Persistence of therapeutic benefit' below.)
SPECIFIC STUDIES AND EFFICACY DATA — The efficacy and safety of sublingual immunotherapy (SLIT), using products designed for oral use, has been demonstrated in a number of properly designed European trials, for both children and adults with allergic rhinitis. Trials involving each of the main forms of SLIT are reviewed below.
In a 2011 systematic review of 60 randomized trials (published through 2009) that included approximately 2300 adults and children receiving active SLIT treatment (tablets or drops) or placebo, treatment with SLIT resulted in a statistically significant reduction in symptoms (standardized mean difference [SMD] of -0.42 [95% CI -0.69 to -0.15]) and in medication requirements (SMD of -0.43 [95% CI -0.63 to -0.23]) . Most studies involved treatment with single pollens (most commonly grass) or house dust mite preparations, at a range of doses. Fifteen studies included only children, with results that were similar to those in adults. There was a trend for greater improvement with treatments lasting longer than one year. Local side effects (oral pruritus and swelling, throat irritation) and nausea were more common with active treatment, although systemic adverse effects (rhinitis or rhinoconjunctivitis) were equal in active treatment and placebo groups. No trial reported anaphylaxis or the need to administer epinephrine. Effects on quality of life could not be assessed because a variety of different measurements were used. Publication bias could not be excluded, as with any systematic review.
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 [3,42,43].
●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 agent to get approved by the US Food and Drug Administration (FDA), two statistical efficacy criteria must be met: (1) the TCS must demonstrate an average relative difference of 15 percent compared with placebo, and (2) the upper bound of the 95% confidence interval must be ≤-10 percent. These statistical tests were selected after rigorous internal evaluation by the agency and have been mandated to more clearly identify and define a statistically significant and clinically meaningful therapeutic effect when comparing allergen immunotherapy with placebo.
Sublingual tablets — Some of the best results in studies of SLIT have been obtained with tablet formulations, particularly those using grass pollen preparations.
Efficacy compared with pharmacotherapy — Based on indirect comparisons, the efficacy of SLIT-tablets for seasonal allergic rhinitis to pollens appears to be slightly less than that of glucocorticoid nasal sprays, but superior to antihistamines and montelukast, while the efficacy of dust mite SLIT-tablets appears to be superior to all medical therapies for perennial allergic rhinitis. This is based on 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 and found that SLIT-tablet treatment resulted in an overall improvement in total nasal symptom scores (TNSS) of 16 to 17 percent . By comparison, trials of mometasone furoate nasal spray (n = 8), desloratadine (n = 9), and montelukast (n = 7), all at full strength, resulted in improvements in TNSS 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 placebo
Grass — 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.
Single grass allergen tablet — European and North American studies with the Timothy grass SLIT-tablet have demonstrated clinical benefit in grass-allergic subjects [18,47-51].
●In a trial of 634 European adults with grass-induced seasonal allergic rhinoconjunctivitis, subjects were treated with once daily treatment with a Timothy SLIT-tablet (Grazax) containing 15 mcg Phleum 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. (See 'Persistence of therapeutic benefit' below.)
In this initial study, there were no serious or life-threatening adverse events, and <4 percent of patients withdrew. A fivefold higher adverse event rate probably or possibly related to drug was observed with active drug versus placebo, including oral pruritus (46 versus 4 percent), mouth edema (18 versus 1 percent), ear itch (42 versus 1 percent), and throat irritation (9 versus 1 percent), respectively.
Mean rhinoconjunctivitis symptom scores and medication scores (30 and 38 percent, respectively) improved significantly compared with placebo. Additionally, there were significant increases in the number of well days (53 versus 44 percent) and improvements in quality of life in the treatment group.
●A study in grass-allergic children demonstrated similar efficacy and safety .
●The first United States randomized trials to demonstrate positive clinical outcomes with this Timothy grass pollen SLIT-tablet were completed in 2009 [48,49]. The protocol was similar to the European studies and used a dose of 15 mcg Phleum p 5 in both adults and children. Both 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 .
A 2014 United States SLIT study with the Timothy grass tablet showed efficacy in both primary and secondary outcomes and provided further assurance on safety, as it evaluated 1501 grass-allergic children and adults, the largest published trial of immunotherapy . Efficacy was similar to that demonstrated in the positive trials performed earlier [48,49].
Multiple grass allergen tablet — There are a number of high-quality studies with the 5-grass pollen tablet [53-58]:
●An initial and pivotal study established dosing in 628 grass-allergic adults with rhinoconjunctivitis, who were randomized to three different doses: 100 IR units (approximately 8.3 mcg group 5 major grass allergen), 300 IR (approximately 25 mcg), or 500 IR (approximately 42 mcg) . Treatment was initiated 16 weeks prior to the grass season and continued through the grass season. A statistically significant benefit was seen in the primary efficacy variable (rhinoconjunctivitis total symptom score) for both the 300 IR and the 500 IR treatment arms versus placebo (37 percent and 35 percent, respectively), but not in the lower 100 IR dose arm . Reliance on "rescue" medication was also significantly less in the active treatment groups. Improvements were observed for rhinoconjunctivitis quality of life and individual rhinitis symptom scores.
●A study in grass-allergic children demonstrated similar efficacy and safety .
●A randomized, placebo-controlled trial performed on 473 American adults used the 5-grass pollen sublingual tablet at the 300 IR dose and reproduced the findings from a similar European study . Compared with those receiving placebo, active treatment patients showed a 28 percent improvement in the primary efficacy measure of total combined symptom plus medication score (difference versus placebo -0.13 [95% CI -0.19 to -0.06]) (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). Despite the fact that many patients in this study were highly grass-allergic, the most frequent adverse events in this trial were again oral pruritus, throat itch, and nasopharyngitis. There were no anaphylactic events, and no patients required epinephrine.
In this study, an interesting observation was made about the choice of patients for SLIT. Inclusion was based upon clinical history and a positive skin test reactivity reaction to Timothy pollen (prick skin test wheal >5 mm versus control), although Timothy-specific serum IgE levels were also measured. Eleven percent of skin test-positive study subjects had undetectable Timothy grass-specific serum IgE (<0.1 kU/L). This subgroup of patients was essentially asymptomatic during the grass pollen season and thus did not benefit from therapy, suggesting that the combination of skin test sensitivity and serum-specific IgE can identify a more appropriate population of study patients for inclusion in clinical trials of immunotherapy and for treatment (figure 1).
Single ragweed allergen — Efficacy and safety have been demonstrated with a ragweed SLIT-tablet standardized on the basis of the major ragweed allergen, Amb a 1. In a multinational trial of 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 preseason and continued for one year (for safety monitoring). The primary endpoint was 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, which was statistically significant compared with placebo (figure 2). Similar findings were shown for the entire ragweed season (18 and 27 percent reduction, respectively). The 1.5 unit dose also reduced TCS, but not to a statistically significant degree. As discussed previously, the World Allergy Organization (WAO) has proposed that a 20 percent mean reduction in TCS compared with placebo be considered a clinically meaningful benefit. Therefore, this dose-ranging study demonstrated meaningful clinical benefit for the 12 unit tablet. No serious systemic allergic reactions, anaphylaxis, or asthma exacerbations were reported. Approximately one-half of subjects receiving the 6 and 12 unit tablets noted itching and swelling of the mouth, throat, or ears, mostly of mild-to-moderate severity and limited in duration.
In another study of ragweed SLIT-tablet, in which patients were randomized to two strengths of tablet (6 or 12 units of Amb a 1) or to placebo, a similar degree of improvement in TCS was demonstrated (21 and 27 percent, respectively) versus placebo during the peak season . The tablets were well-tolerated, as the majority of treatment-related adverse events were mild, and no systemic reactions were reported. One patient receiving the lower dose tablet did receive epinephrine for the sensation of localized pharyngeal edema. This points to the need to carefully educate patients on the types of adverse events that can occur with SLIT and the importance of clearly outlining patient instructions on when to seek medical evaluation. It also raises the question of whether an epinephrine autoinjector should be prescribed to patients undergoing this form of self-administered home therapy.
House dust mite tablet — In a multinational trial of over 500 adults with moderate-to-severe allergic rhinitis and sensitization to house dust mite, subjects were randomized to treatment with a 300 index of reactivity (IR), 500 IR, or placebo SLIT-tablet for one year and observed for one additional year after the conclusion of treatment . The 300 IR tablets contained 16 mcg of Der p 1 and 68 mcg of Der f 1, and the 500 IR tablets contained 28 mcg and 120 mcg, respectively. The primary endpoint was the reduction in average adjusted daily symptoms score (AAdSS), which accounted for use of rescue medication. The authors did not report the results using the now accepted TCS methodology. At one year, there was a reduction of AAdSS of 20.2 and 17.9 percent for the 500 IR and 300 IR groups, compared with the placebo group. The difference between the two active treatment arms was not statistically significant. Benefit was apparent by the fourth month of treatment. The reduction in AAdSS was maintained during the year of observation (ie, 19.1 and 17 percent, compared with placebo).
Persistence of therapeutic benefit — The two-year house dust mite study  and the five-year study with the Timothy grass tablet (Grastek) (three years of treatment followed by blinded assessment of symptom control in the two grass seasons following discontinuation of treatment), which demonstrated a sustained treatment effect over two years of treatment [63,64], have provided evidence of disease modification [64,65] as a result of long-term year-round therapy. Hence, SLIT appears to be similar to SCIT with respect to conferring persistent clinical remission [66-71].
Sublingual drops — Another approach to the delivery of SLIT involves aqueous or glycerinated liquid allergen extracts that are initially held under the tongue for two to three minutes and then swallowed (ie, SLIT-drops). This construct has gained acceptance in Europe and is being studied in United States clinical trials. In the United States, phase I studies on safety and tolerability have been carried out with ragweed, grass, house dust mite, and cat glycerinated extracts .
A 2013 systematic review, which included 63 randomized controlled trials and 5131 subjects, was performed to determine if there was evidence that SLIT with aqueous or liquid drops, performed with products equivalent to those available in the United States for use in SCIT, were safe and effective for allergic asthma and rhinoconjunctivitis . Studies were only included if the methods could be replicated using allergen extracts available in the United States. A meta-analysis of efficacy could not be performed because of the heterogeneity among studies. Instead, the authors judged the quality of the evidence that SLIT-drops improved symptoms scores, need for medication, and quality of life for allergic asthma, rhinitis, and conjunctivitis. There were no reports of anaphylaxis, confirming that SLIT-drops are well-tolerated. For allergic rhinitis and conjunctivitis, the quality of the evidence that SLIT was effective was deemed "moderate," as defined in the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines . The same analysis performed on studies of children found that the evidence that SLIT-drops improved asthma scores was of high quality, and the evidence that it improved allergic rhinitis and conjunctivitis scores was of moderate quality .
However, we believe that there are several factors limiting what can be learned from the above systematic review, including lack of standardized methods for conducting clinical trials, lack of uniformity regarding what defines a clinically meaningful effect, and variations in allergen selection (standardized versus nonstandardized allergens), allergen dose, and duration of therapy. Furthermore, many of the studies included were smaller phase 1 or 2 studies intended to evaluate safety, clarify dose, or examine mechanisms of action. In several instances, the clinical trials did not achieve significance for their primary endpoint and were only able to show an effect for secondary endpoints or upon subgroup analyses. This type of evidence does not meet the more rigorous standards required by various regulatory bodies and task forces [42,44,76].
Additional important limitations noted by the authors of the review, and which directly impact the ability of clinicians to create protocols with proven efficacy using SLIT-drops, included the following:
●Conclusions about effective dose ranges could not be drawn because the dosing units used in European products and American products are not interchangeable.
●The effectiveness of multiple allergen immunotherapy was not clear, which is important because most patients receiving subcutaneous injection immunotherapy in the United States are sensitized to multiple allergens and are treated with multiple allergens.
●Many of the patients included had allergic rhinoconjunctivitis with mild intermittent asthma, rather than asthma requiring maintenance controller therapy. This is discussed more below. (See 'Patients with concomitant asthma' below.)
Thus, there are several fundamental issues with SLIT-drops that require further study before clinicians can be confident that SLIT-drops using available American products represent an effective alternative to SCIT . Of primary importance is the question of effective dose.
It is our opinion that the only definitive way to evaluate newer forms of immunotherapy, including SLIT-drops, is to use products with doses defined in well-established units (eg, micrograms of major allergen or bioequivalent allergy units [BAU]). A small number of studies have been performed on North American or European populations that meet this requirement [78-85]. These studies used the commercially available standardized glycerinated extracts licensed for SCIT. However, the data from most of these more rigorous studies do not demonstrate consistent or clinically meaningful benefit. It is clear that further work is required with standardized allergens, as well as with mixes of multiple allergens to determine effective dose, tolerability, and clinical evidence of effect.
●Ragweed – The most advanced clinical trials have been performed with ragweed in a series of studies conducted by Greer Laboratories, Inc [78,79,84]. These clinical studies used the commercially available standardized glycerinated ragweed extract licensed for SCIT.
A randomized dose-response clinical trial was conducted in 115 adult patients with a history of ragweed-induced seasonal allergic rhinoconjunctivitis with or without asthma . In this study, a modest (approximately 15 percent) improvement in the primary endpoint (the total rhinoconjunctivitis symptom score for the entire pollen season) was observed with both active treatment arms. However, this was not statistically significant.
In 2014, the first large scale confirmatory clinical trial to demonstrate the efficacy of a sublingual liquid extract with a standardized (short ragweed) allergen extract was completed in North America. In this phase 3 clinical trial, 429 adults were randomized to either active treatment or placebo, with treatment initiated 8 to 16 weeks before and continued through the ragweed season . The study drug was administered sublingually, via a calibrated dropper, and held under the tongue for two minutes, with any residual liquid swallowed. Ninety-four percent of study subjects achieved the maximum tolerated dose (50 mcg Amb a 1). As consistent with accepted methods for assessment of SLIT studies, the primary endpoint was the total combined daily rhinoconjunctivitis symptom and medication scores, and the active treatment arm reported a 43 percent improvement in the primary endpoint as compared with the placebo group (difference versus placebo -0.83 [95% CI -1.30 to -0.37]). Expected increases in ragweed-specific IgG4, the predictive biomarker associated with symptom improvement in SCIT, were also observed in the active treatment group. No serious adverse events or anaphylaxis occurred. This North American study provides the first conclusive evidence that sublingual allergen immunotherapy with a liquid preparation, using well-established (standardized) allergen units (ie, mcg Amb a 1), can result in highly significant and clinically meaningful therapeutic benefit in the treatment of seasonal allergic rhinoconjunctivitis.
●Grass – In a multicenter, randomized trial of 207 children with grass pollen-induced rhinoconjunctivitis (with or without asthma), subjects received 40 mcg daily of grass pollen from six grass species or placebo in SLIT-drops, held under the tongue for three minutes and then swallowed . Treatment was administered daily January through August initially, and then all patients received daily active open-label treatment for two additional years. The primary endpoint was the change of the area under the curve of the symptom medication score (SMS) from the baseline season to the first season after start of treatment. The area under the curve of the SMS was approximately twofold lower in the active treated group. Allergen-specific IgG4 increased significantly in the active group also. No systemic allergic reactions occurred.
●Birch – The efficacy of SLIT-drop immunotherapy with birch pollen was demonstrated in a randomized trial of 574 adults with birch pollen-induced rhinoconjunctivitis, one-half of whom had oral allergy syndrome . This study also showed sustained effects during the subsequent pollen season. Subjects received a 300 IR solution daily, beginning four months before and continuing through birch pollen season, and self-recorded symptoms and medication use for two consecutive seasons. The AAdSS (which adjusts symptom scores for the use of rescue medication) in the treatment group was reduced by 19 and 30.6 percent, relative to the placebo group, in the first and second seasons, respectively. The authors did not comment on the therapeutic effect on the treatment on oral allergy syndrome symptoms.
●House dust mite – SLIT-drops with house dust mite allergen can induce the immunologic changes associated with clinical improvement. However, significant reductions in clinical symptom scores and medication use have not been clearly demonstrated [80,81,87-89].
SAFETY — Sublingual immunotherapy tablets (SLIT-tablets) are safer than subcutaneous immunotherapy (SCIT) because anaphylaxis is rare with sublingual immunotherapy (SLIT). The main adverse effects of SLIT are oral-mucosal itching and swelling. The European literature has provided extensive data on the safety of various forms of SLIT [90,91]. Well-designed clinical trials in Europe and North America are providing important safety information on research subjects receiving the newer sublingual constructs [92,93]. Postmarketing surveillance data will be an important source of information about real world issues that were not addressed in clinical trials, such as the safety of initiating treatment in season and reinitiating drug after missed doses.
Rare anaphylaxis — Anaphylaxis is uncommon to rare with SLIT, although a small number of cases have been reported [94-97]. One report suggested that a patient who had previously tolerated SLIT subsequently developed anaphylaxis after sustaining minor oral lacerations, emphasizing the importance of an intact oral mucosa for safe administration. Product inserts specify that patients should temporarily discontinue therapy if oral inflammation (eg, thrush, mouth ulcers, oral lichen planus) or oral wounds (eg, following dental surgery or tooth extraction) are present. Therapy can be resumed once healing of the mucosa is complete. Because anaphylaxis is possible, all manufacturers of SLIT-tablets recommend that patients be prescribed epinephrine for self-injection. (See 'Administration of SLIT-tablets' above.)
Oral and pharyngeal adverse effects — The main adverse effects of SLIT are self-limited local effects, such as throat irritation, oral pruritus, ear pruritus, and mouth edema, which are seen in up to one-quarter of patients.
●Oral mucosal pruritus and irritation typically last 10 to 30 minutes with each tablet administration and begin on the first day. These symptoms may recur on the next couple of days, but usually subside within the first week.
●Sublingual swelling, tongue swelling, or oropharyngeal edema occur in 6 to 11 percent of study subjects and is described as a swelling under the tongue at the site of application that lasts 5 to 10 minutes before resolving. This adverse effect appears later than oral pruritus (day 8 in trials) and may recur over several weeks. Although the latter symptoms are also self-limited in most patients, they may evolve in complexity and lead to manifestations of laryngeal obstruction [48,49,59,60,92]. Published SLIT-drops studies also are consistent with these observations [84,86].
Eosinophilic esophagitis — A possible association has been reported between eosinophilic esophagitis and aeroallergen SLIT, as well as with oral immunotherapy with food allergens [98-101]. SLIT should be discontinued in patients who develop severe or persistent gastroesophageal symptoms (including dysphagia or chest pain) and the diagnosis of eosinophilic esophagitis considered.
Combined with other immunotherapy — The grass pollen tablets available in the United States were not studied in patients already receiving SCIT or additional SLIT treatments, and combining different forms of immunotherapy may increase likelihood of local or systemic reactions .
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). The 5-grass pollen sublingual tablet (Oralair) was assigned a category B rating for use in pregnancy . The Timothy grass pollen sublingual tablet (Grastek) was assigned a category B rating, while the short ragweed pollen sublingual tablet (Ragwitek) was assigned a category C rating [27,28].
Use in primary care settings — SLIT should be prescribed 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 [103,104].
COMPLIANCE — Sublingual immunotherapy (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 .
A United States study reported an attrition rate of approximately 40 percent over four years .
Several European studies have assessed the compliance and adherence with SLIT:
●A study of 300 children (6 to 16 years of age), who received either grass or house dust mite sublingual drops or tablets over two years of treatment, revealed that discontinuation rates were clearly tied to follow-up visits to the study site . The dropout rate was 30, 68, and 82 percent in patients evaluated in the clinic every 3, 6, and 12 months, respectively.
●Another study, which focused on young children (three to six years of age) reported that 46 percent of 150 children discontinued SLIT within three months of initiation . The most frequent reasons for discontinuation were lack of effect, time commitment, and adverse events.
●A third study addressed a more realistic measure of surveillance: drug sales figures (as opposed to marketing surveys, which can overestimate compliance due to contact of patients by the surveyor). In postmarketing surveys, compliance ranges from 50 to 90 percent depending on age and duration of treatment. In contrast, data on SLIT prescription refills shows a different picture: sales decreased from 100 percent to 44, 28, and 13 percent, in the first, second, and third years, respectively . Of the total prescriptions for SLIT from the two major manufacturers that participated in the survey, less than 20 percent of prescriptions were continued after three years.
●In a retrospective analysis of a community pharmacy database, of 6486 patients beginning subcutaneous immunotherapy (SCIT) or SLIT, 23 percent of SCIT patients and only 7 percent of SLIT patients completed three years of treatment .
Although these rates of treatment adherence are not dramatically different from those for other chronic diseases, they may significantly impact efficacy.
Noncompliance should not impact safety, provided patients are clearly instructed not to take extra doses in an attempt to "catch up" if they have had gaps in treatment. This may be particularly important at times when symptoms are severe. Long-term surveillance reporting will be needed to ascertain with the impact of stopping-restarting therapy.
PATIENTS WITH CONCOMITANT ASTHMA — Trials examining the safety and efficacy of sublingual immunotherapy (SLIT) in patients with rhinoconjunctivitis and concomitant asthma have mostly included patients with mild or intermittent asthma. A 2015 systematic review concluded that SLIT was well-tolerated in patients with mild asthma, but data about patients with moderate-to-severe asthma were limited. In addition, the reviewers found that studies examining patient-important outcomes of efficacy were limited .
Mild asthma — Multiple studies have demonstrated that SLIT is safe in many patients with milder asthma [52,80,86,112-118]. These trials included patients who only required bronchodilators or low-dose daily inhaled glucocorticoids [41,59,60]. Studies specifically evaluating the impact of SLIT on asthma symptoms and medication use are described below.
Adults — A randomized trial of 114 adult subjects (aged 18 to 65) with mostly mild grass pollen-induced asthma and rhinoconjunctivitis, assigned subjects to treatment with 75,000 standardized-quality tablet (SQ-T) (15 mcg Phleum p 5), Timothy grass allergen sublingual tablet (Grazax), or placebo . The primary endpoints were average asthma symptom and medication scores during the grass pollen season.
During the grass season, asthma symptom and medication scores rose slightly in both active and placebo groups, but no discernible differences were observed between groups. Consistent with other trials with the SLIT-tablet construct, significant improvements in mean rhinoconjunctivitis symptom scores, medication scores, and well days (37, 41, and 54 percent, respectively) were observed in the group receiving active SLIT-tablet. No serious adverse events were reported in the study and the number of adverse events linked to asthma was reported as similar between groups.
This clinical trial provided data on the safety of self-administration of the grass allergen tablet in asthmatic subjects and showed that allergen treatment did not impair asthma control, although there was no significant improvement in asthma symptoms either.
Children — A randomized trial of 253 children (5 to 16 years of age) with seasonal allergic rhinoconjunctivitis with or without mild asthma, demonstrated that the same Timothy grass sublingual tablet formulation (75,000 SQ-T units [15 mcg Phleum p 5]) was safe and effective and did appear to have a positive impact on asthma symptoms and medication use .
Treatment was initiated 8 to 23 weeks prior to the grass season and continued through the season. Ninety-two percent of children completed the trial. No serious adverse events were assessed as being treatment-related .
In the grass tablet-treated group, the primary endpoints of median improvement of rhinoconjunctivitis symptom scores and medication scores were met . The active treatment also showed a significantly greater number of "well days" versus placebo treatment. During the study, 105 children (42 percent) reported asthma (5 percent severe, 48 percent moderate). Although only 23 percent used any asthma medications, a relative difference in median asthma symptom score was observed in the active treatment group versus placebo-treated children, and use of asthma "relief" medication was nominally lower in the active treatment group.
Moderate-persistent asthma — Fewer studies have included patients with moderate-persistent asthma [62,88,119]. These have shown that SLIT is well-tolerated, although the degree of improvement in asthma symptoms appears to be relatively modest.
●One trial that did include such patients evaluated whether SLIT-tablet therapy could reduce the need for inhaled glucocorticoids. This trial enrolled 604 adolescent and adult patients with mild-to-moderate asthma, allergic rhinitis, and sensitization to house dust mite who required low-to-medium doses of inhaled budesonide (100 to 800 mcg/day) . Patients were randomized to one of three doses of house dust mite SLIT-tablet or to placebo. The minimal dose of inhaled budesonide required to control asthma symptoms was measured at the outset and after one year of house dust mite SLIT-tablet therapy. There was a modest but statistically significant reduction in the amount of budesonide required (81 mcg/day) in the group receiving the highest dose of house dust mite SLIT (6 standardized-quality units, SQ) compared with placebo, but not in the groups receiving the lower doses (3 and 1 SQ). Thus, based on this limited data, SLIT appears to be well-tolerated and possibly helpful in patients with asthma requiring low-to-moderate doses of inhaled glucocorticoids.
●A randomized trial of 484 house dust mite-allergic asthmatics performed in China provided evidence for safety in moderate-persistent asthmatics receiving a 300 index of reactivity (IR) house dust mite sublingual extract [88,120]. The primary outcome of achieving well-controlled asthma occurred in 85.4 and 81.5 of active treatment and placebo patients, respectively, which was not statistically significant. However, subsequent posthoc analysis did demonstrate meaningful clinical benefit in those with moderate-persistent asthma (reduced steroids) in actively treated subjects. There were also no significant intergroup differences or intragroup changes in lung function, respiratory adverse events, or asthma-related quality of life over the course of the one year study. However, treatment was well-tolerated, and no treatment-related adverse events were reported, and those in the active treatment group were able to reduce their dose of inhaled budesonide by a mean of 92 mcg more than those in the placebo group, which was statistically significant.
●Another study also found SLIT to be safe and to have measurable benefits in patients with moderate-persistent asthma. This randomized trial included 834 adults with mild or moderate asthma not well-controlled by inhaled budesonide and short-acting beta agonists, given one of two doses of house dust mite SLIT-tablet or placebo . About 40 percent of patients required high doses (800 to 1200 mcg) of budesonide daily at enrollment. Patients received house dust mite SLIT or placebo for 7 to 12 months, after which budesonide therapy was reduced by 50 percent for 3 months, then discontinued entirely for the next 3 months. The primary outcome was time to first moderate or severe asthma exacerbation during the period of budesonide withdrawal. Both doses of house dust mite SLIT prolonged this time compared with placebo. The absolute risk for a first moderate-to-severe exacerbation during budesonide reduction/discontinuation was 26 and 24 percent for the lower and higher dose SLIT, respectively, which were statically significant differences compared with placebo (32 percent). The absolute risk difference in the higher dose SLIT group compared with placebo was 0.10 (95% CI, 0.02-0.16). However, asthma-related quality of life assessment were not different among the three groups. Thus, in patients with mild or moderate asthma not controlled on inhaled glucocorticoids, house dust mite SLIT was safe, and delayed time to exacerbation during steroid withdrawal, although a clinically meaningful improvement in asthma symptoms, was not clearly demonstrated.
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. (See 'Administration of SLIT-tablets' above.)
COMPARISON OF SLIT AND SCIT
Advantages and disadvantages of SLIT — There are several potential advantages of sublingual immunotherapy (SLIT) compared with subcutaneous immunotherapy (SCIT):
●SLIT is safer, with fewer local and systemic allergic reactions than SCIT. (See 'Safety' above.)
●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 upon consistent patient self-administration. Patients who regularly miss doses may not have satisfactory results. (See 'Compliance' above.)
●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. Postmarketing surveillance studies should be performed to identify the frequency and severity of untoward reactions/adverse events that may be observed at an increased rate in the "real world" use of these products.
Comparative efficacy — One group compared various meta-analyses of SLIT (via sublingual extracts or tablets) and SCIT studies that measured changes in symptom scores and medication use in patients with allergic rhinitis due to grass pollen treated with grass pollen immunotherapy . The analysis included 36 randomized controlled trials of over 3000 treated patients and a similar number of placebo-treated controls. To account for the methodologic variation among the studies, results were converted to standardized mean differences. Although indirect and limited by a very high degree of heterogeneity, this analysis showed greater overall benefit with SCIT compared with SLIT.
A small number of trials have directly compared SLIT and SCIT [34,122-129]. Three randomized trials involved head-to-head, double-dummy protocols [34,122,123]. 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.
●The earliest study included 20 adults monosensitized to grass (and without asthma) treated with SLIT-drops or SCIT, which found that both therapies resulted in reductions in symptoms and medication scores of at least 50 percent after one year of therapy. However, there was no placebo arm . In contrast, immunologic measures of efficacy, such as allergen-specific immunoglobulin G4 (IgG4), changed only in the group receiving SCIT.
●A subsequent trial involved 58 birch-allergic adults (one-third with asthma) treated with either SLIT-aqueous or SCIT . Some were also sensitized to other allergens. Rhinitis disease severity was significantly reduced in both treatment arms compared with placebo, although the two therapies were not statistically different from each other.
●In a third trial, 30 children, all with both rhinitis and asthma and monosensitized to house dust mite, were randomized to SLIT-drops, SCIT, or placebo . SCIT significantly reduced rhinitis and asthma symptoms and medication use. SLIT modestly reduced symptoms for both rhinitis and asthma and medication use for rhinitis, but the changes with SLIT were not statistically significant compared with placebo. The doses given were also not quantified in terms of micrograms of allergen, so it was difficult to assess whether SLIT dosing was adequate.
Other reviews have identified a few additional studies, although these studies were not as rigorous as those described already and reached the same conclusion [130-132].
Issues requiring further study — Further research is needed in several areas, in addition to optimizing dosing and delivery systems. Incompletely answered questions include the following [42,92]:
●Can SLIT alter the progression of allergic disease? – No studies have addressed the question of whether oral forms of immunotherapy can be used to alter disease progression or prevent the onset of other allergic diseases. Specifically, it is not known if SLIT will prove to have the same potential to prevent the development of asthma in children that has been shown with SCIT. Until well-controlled clinical trials determine this, clinicians and parents may be unwilling to substitute SLIT for SCIT.
●What is the optimal duration of therapy? – Both SLIT [47-49,52,53,56,92] and SCIT [133-135] can produce clinical benefit within three to four months, and both appear to have some persistent benefit after therapy is discontinued, although the optimal duration of SLIT has yet to be defined. (See 'Persistence of therapeutic benefit' above.)
●How effective is SLIT for the polysensitized patient? – The most compelling data for use of SLIT is 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, both seasonally and perennially. At present, the few multiple allergen studies performed in the United States have not shown clinical benefit. In one study, 54 grass-allergic patients were randomized to placebo, monotherapy with Timothy extract (19 mcg Phleum p 5 daily), or Timothy extract plus nine additional unstandardized pollen extracts . A modest positive trend was observed in clinical parameters in the multiple pollens group, which did not reach clinical significance.
However, a posthoc analysis of data from six randomized trials of grass pollen tablet immunotherapy, including 1871 adults and children, found no significant 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 . This analysis does not address the question of whether SLIT with one allergen has any effect on patients' symptoms from exposure to other allergens, a controversy that also applies to SCIT. (See "SCIT: Preparation of allergen extracts for therapeutic use", section on 'Multiple-allergen immunotherapy extracts'.)
In addition, until a full range of oral products has been produced, tested, and made commercially available, it is not clear that it would be practical or cost-effective to combine SLIT (eg, grass SLIT-tablet) with SCIT in a patient with multiple allergen sensitivities, as opposed to simply continuing SCIT to cover all the allergens relevant to that patient.
●What is the minimal amount of time required to see a clinical effect? – The minimal amount of time required to see a clinical effect with SLIT may vary somewhat depending upon the allergen (seasonal versus perennial), as well as the type of study design used to address the question. For example, clinical trials of grass or ragweed tablets have shown that treatment effect is optimized with initiation of treatment 12 to 16 weeks prior to the onset of pollen season [48-50,55,56,59,60]. In contrast, an environmental chamber study design with house dust mite SLIT demonstrated an early onset of action at eight weeks , whereas a natural field trial showed an onset of action at four months .
SUMMARY AND RECOMMENDATIONS
●Sublingual immunotherapy (SLIT) involves the application of allergen to the sublingual tissue. There are two forms of SLIT with inhalant allergens that have been widely studied: dissolvable sublingual tablets (SLIT-tablet) and sublingual allergen extracts (SLIT-drops). The most consistent results have been obtained with SLIT-tablet formulations. (See 'Delivery systems' above.)
●SLIT has been shown in randomized trials to be effective for allergic rhinitis (with or without conjunctivitis) and safe for patients with concomitant mild-to-moderate asthma. However, efficacy in reducing the symptoms of persistent, not well-controlled allergic asthma has not been conclusively demonstrated. (See 'Specific studies and efficacy data' above and 'Patients with concomitant asthma' above.)
●SLIT has been used in Europe and some other countries for decades for the treatment of allergic rhinoconjunctivitis. The first sublingual products, a 5-grass pollen tablet, a single grass pollen tablet, and a short ragweed pollen tablet, became available in the United States in 2014 (table 1). (See 'Availability' above.)
●SLIT is self-administered by patients (or their caregivers) at home, although the initial dose is usually given under medical supervision. A significant percentage of patients experience local application site reactions (eg, oral pruritus, throat irritation, tongue swelling), but systemic allergic reactions are markedly fewer as compared with subcutaneous immunotherapy (SCIT). Local reactions subside in many patients within a few days to a week. (See 'Administration' above.)
●The main advantages of SLIT over SCIT are safety and the comfort and convenience of an oral therapy that is self-administered. SLIT appears to be somewhat less effective than SCIT, based upon meta-analyses and a small number of direct comparison studies. The main disadvantage of SLIT is that it requires the patient to be consistently compliant with therapy, and the impact of missed doses on efficacy is difficult to assess. (See 'Compliance' above and 'Comparison of SLIT and SCIT' above.)
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