Real‐Life Clinical Experience With SQ Grass, Tree, Ragweed, and House Dust Mite Sublingual Immunotherapy Tablets: A Review of Evidence From Non‐Interventional Studies

ABSTRACT

This review evaluates data from > 12,000 children, adolescents and adults (≥ 4 years) in non‐interventional studies to assess the real‐life effectiveness and safety of SQ sublingual immunotherapy (SLIT)‐tablets for allergic rhinitis (AR). Non‐interventional studies of SQ grass, tree, ragweed, and house dust mite (HDM) SLIT tablets were identified from PubMed (1 January 2006 to 11 February 2025) and supplemented by manual searches. Effectiveness was captured as patient‐reported change in AR symptoms; AR and/or asthma medication use, safety and treatment satisfaction were also evaluated. In total, 12,136 participants were enrolled across 22 SQ SLIT tablet studies (grass: n = 6744; HDM: n = 4323; tree: n = 1069; ragweed: n = 102). Across studies, a high proportion of participants reported improvements from baseline or the previous season across nasal (up to 87%), ocular (up to 81%), and bronchial symptoms (up to 78%) with SQ SLIT tablets. Compared to baseline, a lower proportion of patients reported use of symptom‐relieving medication, consistent across key drug classes including oral antihistamine, intranasal corticosteroids, short‐acting beta‐agonist, and inhaled corticosteroids. Discontinuations due to adverse events were low (0%–14.5%). Among studies reporting treatment satisfaction, 73%–96% of participants were found to be ‘satisfied’ or ‘very satisfied’ with this treatment. SQ SLIT tablets showed consistent effectiveness for AR, were well‐tolerated, and were associated with a high degree of patient satisfaction. These real‐life data from clinical practice are a valuable and important source of complementary evidence to the well established efficacy and safety from randomised clinical trials.

1. Background

Respiratory allergy is the most common form of allergy [1], and is mainly triggered by outdoor allergens, such as grass, tree and ragweed pollen, as well as indoor allergens, such as house dust mite (HDM) and animal dander [2]. The associated airway inflammation affects the upper airways—causing allergic rhinitis (AR) or allergic rhinoconjunctivitis—and the lower airways—manifesting as asthma [3]. AR is highly prevalent, affecting up to 40% of children and up to 30% of adults [4, 5, 6], and often coexists with asthma and atopic dermatitis [7]. Furthermore, in children with asthma and poorly controlled AR, adverse impacts on asthma severity have been observed [8]. AR poses a health problem on a global scale—one that is associated with a high burden of disease and disability [7, 9], and which is further compounded by the presence of comorbidities, such as asthma.

Alongside allergen avoidance, the management of AR typically comprises two types of pharmacological treatment: (1) symptom‐relieving medication, such as antihistamines (oral, ocular, and intranasal) and intranasal corticosteroids; (2) allergen immunotherapy (AIT) administered subcutaneously (by injection) or sublingually (as tablets or oral drops) [9]. Currently, AIT is the only treatment option with potential for disease modification for allergic airway diseases including AR [10, 11]. By inducing long‐term immunological tolerance to the allergen, AIT improves symptoms and quality of life, reduces the need for symptom‐relieving medication, and has the potential to halt the progression of allergic disease and prevent asthma [12]. To achieve long‐term efficacy, the European Academy of Allergy and Clinical Immunology guidelines recommend a minimum duration of 3 years of AIT for AR [10]. The efficacy and safety of SQ sublingual immunotherapy (SLIT)‐tablets for the treatment of AR triggered by respiratory allergens (grass, tree, ragweed pollen and HDM) have been demonstrated in Phase III randomised controlled trials (RCTs) involving adults, adolescents and children [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. In addition, the SQ grass SLIT‐tablet has shown benefits in preventing asthma symptoms and medication use in children with AR [26], and the SQ HDM SLIT‐tablet has been shown to prevent asthma exacerbations in adults [27].

Although RCTs provide the high internal validity for evaluating efficacy and safety that is required for regulatory approval, the data from these rigorously conducted trials may not be generalisable to routine clinical practice [28]. While there remains a need for evidence generated in clinical practice to complement the findings from RCTs [29, 30], real‐world data analyses have demonstrated the potential of AIT to reduce the need for symptom‐relieving allergy medications [31, 32, 33], and indicate long‐term benefits [31, 32].

The REAl‐world effeCtiveness in allergy immunoTherapy (REACT) study was a large and very comprehensive database study of AIT effectiveness, amassing data from 9 years of follow‐up in a broad population of more than 90,000 subjects with AR [34]. The REACT study demonstrated greater reductions in prescriptions for AR and asthma medications in subjects receiving AIT versus matched subjects not treated with AIT, with improvements in clinically relevant outcomes, such as asthma exacerbations and hospitalisations [7, 34, 35]. However, by nature, retrospective cohort studies dictate a reliance on data that have been routinely recorded in clinical practice. Non‐interventional studies are prospective studies that can be designed to closely follow normal clinical practice, whilst also allowing detailed data collection for the purposes of answering specific research questions. The use of SQ SLIT‐tablets in routine clinical practice has been assessed by appropriately designed non‐interventional studies, which: (1) allow continual evaluation of real‐life safety when administered at home; (2) provide complementary effectiveness data to existing RCTs and real‐world evidence (RWE) studies. This article reviews and summarises the evidence from published non‐interventional studies.

2. Methods

A search of PubMed was conducted in February 2025 to identify publications of non‐interventional studies of SQ SLIT‐tablets specific for grass (GRAZAX 75,000 SQ‐T/2800 BAU), tree (birch homologous group) (ITULAZAX 12 SQ‐Bet), ragweed pollen (RAGWIZAX 12 SQ‐Amb), and HDM (ACARIZAX 12 SQ‐HDM) in patients with AR and/or asthma. The following search string was used: (Product Surveillance, Post‐marketing[MH] OR post‐marketing OR post‐authorization OR cohort or case–control OR observational OR non‐interventional OR prospective OR real‐world OR ‘drug utilisation’ OR longitudinal) AND (grazax OR itulazax OR ragwizax OR acarizax OR grastek OR itulatek OR ragwitek OR miticure OR odactra OR ‘ALK’[AD] OR ‘ALK‐abellό’[AD]) AND (‘2006/01/01’[PDAT]: ‘2025/02/11’[PDAT]). Supplementary manual searching in ClinicalTrials.gov and the EU Clinical Trials Register was also conducted to identify relevant publications, plus searching of ALK's internal clinical study database for SQ SLIT‐tablets to ensure that no relevant studies were missed. All records returned from literature searching had the title and abstract screened by one reviewer for relevance and were excluded if they were: published before 2006 (i.e., year of the first marketing authorisation for an SQ SLIT‐tablet); reports of Phase I–III clinical trials, RWE or cross‐sectional studies without any prospective follow‐up, and cost‐effectiveness analyses; studies evaluating disease areas/medicinal products outside of allergy; publications not written in English. A second reviewer performed a quality check of the included publications. An overview of the literature searching process is provided in Figure 1.

FIGURE 1.

Literature searching conducted to identify publications of non‐interventional studies of SQ SLIT‐tablets. ^aFor each of the SQ grass SLIT‐tablet and SQ HDM SLIT‐tablet, two publications reported data from the same study (grass: Suárez‐Fueyo et al. [2014] and Varona et al. [2019]; HDM: Demoly et al. [2022] and Jaffuel et al. [2024]). ^bOne publication reported data for the co‐administration of grass and ragweed SQ SLIT‐tablets and has, therefore, been included in both categories (grass and ragweed). HDM, house dust mite; RCT, randomised controlled trial; RWE, real‐world evidence; SLIT, sublingual immunotherapy.

The 24 publications of non‐interventional studies selected [36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59] were screened for relevant outcome data pertaining, primarily, to the clinical effectiveness of SQ SLIT‐tablets—for example, a change in the symptoms of AR and in the use of medication to manage AR and/or asthma. Patient‐reported outcome data, such as treatment satisfaction, patient well‐being and ease of treatment use, were extracted from the selected publications where available and tabulated, as were data for adherence/compliance and immunology.

Safety and tolerability were assessed from the reporting of adverse events (AEs; events occurring after treatment initiation), and/or adverse drug reactions (ADRs; AEs that were considered related to study treatment); data for AEs/ADRs, including severity and seriousness, were collected where available, as were data for discontinuations due to AEs/ADRs. Publications were also screened for information relating to anaphylaxis and the use of adrenaline.

3. Results

3.1. Overview of Selected Studies

Table 1 summarises the key characteristics of the non‐interventional studies identified through the literature searching. A full list of the publications selected for data collection is presented in Table S1. Together, the dataset provides information on more than 12,000 participants (including 1317 children and adolescents [≥ 4 years], and 8899 adults [≥ 18 years] noting that not all studies provided age breakdowns or defined adult as ≥ 18 years) [36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59] and represents the four SQ SLIT‐tablet products available in Europe and North America for the treatment of AR due to pollen and HDM allergens. Safety and tolerability were the primary research objectives for most of the studies identified, and five studies evaluated the long‐term effectiveness of treatment over 3–5 years.

TABLE 1.

Overview of study characteristics [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57].

	Total	SQ SLIT‐tablet
		Grass a , b	HDM a	Tree	Ragweed b
Total number of participants	12,136 (100.0) c	6744 (55.6)	4323 (35.6)	1069 (8.8)	102 (0.8)
Publications	24 (100.0)	16 (66.7)	7 (29.2)	1 (4.2)	1 (4.2)
Non‐interventional studies	22 (100.0)	15 (68.2) a , d	6 (27.3) a	1 (4.5)	1 (4.5)
Study population e
Adults (≥ 18 years)	11 (50.0)	8 (53.3)	3 (50.0)	1 (100.0)	1 (100.0)
Children and adolescents (≥ 4 years)	1 (4.5)	0 (0.0)	1 (16.7)	0 (0.0)	0 (0.0)
Both	10 (45.5)	8 (53.3)	1 (16.7)	0 (0.0)	0 (0.0)
Study duration e
Single season/1 year	17 (77.3)	11 (73.3)	5 (83.3)	1 (100.0)	1 (100.0)
Multiple seasons/> 1 year	5 (22.7)	4 (26.7)	1 (16.7)	0 (0.0)	0 (0.0)
Region e
Europe	19 (86.4)	14 (93.3)	4 (66.7)	1 (100.0)	0 (0.0)
North America	1 (4.5)	1 (6.7)	0 (0.0)	0 (0.0)	1 (100.0)
Asia	1 (4.5)	0 (0.0)	1 (16.7)	0 (0.0)	0 (0.0)
USA	1 (4.5)	0 (0.0)	1 (16.7)	0 (0.0)	0 (0.0)
Primary research objective e
Safety and tolerability	14 (63.6)	7 (46.7)	5 (83.3)	1 (100.0)	0 (0.0)
Clinical effectiveness	2 (9.1)	1 (6.7)	1 (20.0)	0 (0.0)	0 (0.0)
Treatment satisfaction/well‐being/ease of use	2 (9.1)	2 (13.3)	0 (0.0)	0 (0.0)	0 (0.0)
Adherence/compliance	1 (4.5)	1 (6.7)	0 (0.0)	0 (0.0)	0 (0.0)
Immunological response	1 (4.5)	1 (6.7)	0 (0.0)	0 (0.0)	0 (0.0)
Safety and tolerability of co‐administration	3 (13.6)	3 (20.0) f	0 (0.0)	0 (0.0)	1 (100.0)
Quality of life	1 (4.5)	1 (4.5)	0 (0.0)	0 (0.0)	0 (0.0)

Note: Data presented are n (%).

Abbreviations: AIT, allergen immunotherapy; HDM, house dust mite; NIS, non‐interventional study; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy.

^a For each of the SQ grass SLIT‐tablet and SQ HDM SLIT‐tablet, two publications reported data from the same study (grass: Suárez‐Fueyo et al. [2014] and Varona et al. [2019]; HDM: Demoly et al. [2022] and Jaffuel et al. [2024]).

^b One publication (Maloney et al. [2016]) reported data for the co‐administration of grass and ragweed SQ SLIT‐tablets and has, therefore, been included in both categories (grass and ragweed).

^c Participants of the co‐administration study (grass and ragweed SQ SLIT‐tablets; Maloney et al. 2016) were counted in the total number of participants once only.

^d In one study (Reiber et al. [2017]), only 21% of participants received SQ grass SLIT‐tablet in addition to existing SCIT.

^e Proportion calculated from the number of non‐interventional studies for that particular category (not from the number of publications).

^f Co‐administration: SQ grass SLIT‐tablet and concomitant AIT (Reiber et al. [2016]); SQ grass SLIT‐tablet and SQ ragweed SLIT‐tablet (Maloney et al. [2016]); primary SCIT and concomitant AIT (Reiber et al. [2017])^d.

3.2. Study Populations

Baseline demographics and clinical characteristics for the selected studies are summarised in Table 2. The data are well‐balanced across the studies and represent a young adult population, with a high frequency of comorbidities and high use of symptom‐relieving medication. Many participants were sensitised to more than one allergen.

TABLE 2.

Summary of baseline demographics and clinical characteristics [36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59].

	SQ SLIT‐tablet (n = 12,136 a )
	Grass (n = 6744) b , c	HDM (n = 4323)	Tree (n = 1069)	Ragweed (n = 102) c
Demographics
Mean/median (range) age, years d	20.0–41.0	34.0–39.3	36 (18–65)	40.0
Male	42.0–48.0	43.6–60.4	46.3	48.0
Clinical characteristics
Allergic rhinitis	87.9–100.0	82.9–100.0	99.1	100.0
Polysensitised	63.3–100.0	63.6–79.0	NR	100.0
Comorbidities
Asthma	19.7–67.0	28.1–41.9	38.6	23.5
Conjunctivitis	63.5–100.0	58.6–72.0	89.8	NR
Skin	6.7–10.0	6.0–17.0 e	AD: 14.3	NR
Use of symptom‐relieving medication
Total	68.2–99.0	85.7–96.1	100.0	NR
AH	73.0–97.7	NR	83.9	NR
INCS	44.4–63.2	NR	59.2	NR

Note: Data presented are % unless otherwise stated. For each parameter, the ranges represent the lowest and highest values reported in the selected publications for each SQ SLIT‐tablet product. Note that not all studies provided data for all parameters (see Table S2 for full details of the baseline demographics and clinical characteristics that were reported for each study). Unless stated in the table, data to further characterise the system organ class ‘skin’ (e.g., as AD, eczema or itching) were not reported in the publications, and AH data presented are for oral AH.

Abbreviations: AD, atopic dermatitis; AH, antihistamine; HDM, house dust mite; INCS, intranasal corticosteroid; NR, not reported; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy.

^a Participants of the co‐administration study (grass and ragweed SQ SLIT‐tablets; Maloney et al. 2016) were counted in the total number of participants once only.

^b In one study (Reiber et al. [2017]), only 21% of participants received SQ grass SLIT‐tablet in addition to existing SCIT.

^c One publication (Maloney et al. [2016]) reported data for the co‐administration of grass and ragweed SQ SLIT‐tablets and has, therefore, been included in both categories (grass and ragweed).

^d Age was reported as mean, years in the following studies: Sidenius et al. (2021); Armentia et al. (2012); Chivato et al. (2017); Janson et al. (2018); Kiotseridis et al. (2018); Reiber et al. (2016); Reiber et al. (2017); Suárez‐Fueyo et al. (2014); Varona et al. (2019); Wessel et al. (2012); Demoly et al. (2022)/Jaffuel et al. (2024); Tempels‐Pavlica et al. (2024); Zeiger et al. (2024); Maloney et al. (2016). Age was reported as median, years in the following studies: Horn et al. (2016); Kiotseridis et al. (2018); Schwab et al. (2013); Schwab et al. (2018); Sidenius et al. (2021); Vitzthum et al. (2014); Gronke et al. (2013); Tjan et al. (2017); Reiber et al. (2021); Pfaar et al. (2024); Kajiume et al. (2022).

^e Zeiger et al. (2024) reported 6.0% for urticaria and 6.1% for AD.

3.3. Clinical Effectiveness

Nine studies reported data for the change in AR symptoms from baseline (before treatment) or from the previous pollen season following treatment with SQ SLIT‐tablets, described by patients as ‘improved symptoms’, ‘decreased symptoms’, ‘no symptoms’ and/or being ‘symptom‐free’. A high proportion of participants who received treatment with SQ grass, HDM, or tree SLIT‐tablets reported an improvement in nasal (74.7%–86.9%), ocular (62.0%–80.9%), bronchial (39.3%–77.9%) and skin (15.7%–76.2%) symptoms (Figure 2A). One study reported the proportion of patients achieving a minimal clinically important difference on a validated clinical instrument. Jaffuel et al. (2024) showed a dramatic improvement in AR control with the SQ HDM SLIT‐tablet—71.3% of participants with AR reported an improvement equal to or greater than the minimal clinically important difference (i.e., 3 points) on the 5‐item Allergic Rhinitis Control Test [53].

FIGURE 2.

Effect of SQ SLIT‐tablets on: (A) AR, lower airway, and skin symptoms and (B) patient‐reported outcomes. Data were obtained from: ^aHorn et al. (2016); ^bSchwab et al. (2013); ^cSchwab et al. (2018); ^dVitzthum et al. (2014); ^eGronke et al. (2013); ^fTjan et al. (2017); ^gReiber et al. (2021); ^hSidenius et al. (2021); ⁱPfaar et al. (2024) (Europe = Denmark, Finland, Germany, the Netherlands, Norway and Sweden); ^jWessel et al. (2012); ^kTempels‐Pavlica et al. (2024). Data are missing for some non‐interventional studies due to heterogeneity in the reporting of data among the publications. AT, Austria; DE, Germany; DK, Denmark; FR, France; HDM, house dust mite; NL, the Netherlands; SE, Sweden; SLIT, sublingual immunotherapy.

The symptoms of AR can interfere with an individual's sleep and negatively impact quality of life [37]. Two studies identified for this review reported an improvement in sleep problems/disorders following treatment with SQ SLIT‐tablets. Horn et al. (2016) reported a reduced overall mean ± standard deviation score (−1.31 ± 0.96) and clinically important improvement on the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) following treatment with the SQ grass SLIT‐tablet, indicating an improved quality of life [38]. The effect was observed across all domains, including sleep problems (RQLQ sleep problem mean ± standard deviation scores of 2.26 ± 1.27 versus 1.19 ± 1.01 in the first versus second grass pollen seasons, respectively) [38]. Jaffuel et al. (2024) reported data from the CARIOCA study showing that a clinically meaningful improvement in sleepiness (with the minimally clinically important difference [MCID] defined by a 2‐point reduction in the Epworth Sleepiness Scale) and insomnia (MCID defined by a 6‐point reduction in the Insomnia Severity Index score) was experienced by 59.7% and 48.3% of patients, respectively [53].

Oral allergy syndrome, also known as pollen–food syndrome (PFS), is another common symptom related to AR, caused by cross‐reactivity between structurally similar pollens and food allergens [2, 41]. One study has shown that the proportion of participants experiencing symptoms of PFS reduced from 43.0% at baseline to 4.3% at the last visit following treatment with the SQ tree SLIT‐tablet [41].

Seven SQ SLIT‐tablet studies reported data on treatment satisfaction or well‐being, with more than 70% (range, 72.8%–95.9%) of patients reporting treatment satisfaction rated as ‘satisfied/very satisfied’ and more than 65% (range, 67.4%–90.4%) reporting improved or better well‐being (Figure 2B). Four studies reported data on ease of use, with more than 85% (range, 89.6%–93.7%) of patients reporting treatment as easy and convenient (Figure 2B). However, we did observe a high degree of heterogeneity in the wording reporting this outcome. The high rating for treatment satisfaction from participants was supported by physician opinion—where data were reported, ≥ 80% (range, 80.0%–96.4%) of physicians were ‘satisfied’ or ‘very satisfied’ [39, 46, 51, 57]. A long‐term study of the SQ grass SLIT‐tablet also showed that the proportion of physicians rating highly on treatment satisfaction increased during the second and third years of treatment [51]. Together, these findings support the favourable effectiveness of SQ SLIT‐tablets and the convenience of self‐administration at home.

Across seven studies that reported the use of any symptom‐relieving medication, SQ SLIT‐tablets showed a concurrent and consistent reduction in medication use from baseline to the end of the study across three SQ SLIT‐tablet products (Figure 3). Four studies provided data by drug class, allowing for an evaluation of effect on the use of key medications for AR—oral antihistamine and intranasal corticosteroids—and for asthma—inhaled corticosteroids and short‐acting beta agonist. Consistent reductions in the use of AR and asthma medication following treatment with grass, HDM and tree SQ SLIT‐tablets were observed (Figure S1).

FIGURE 3.

Reduction in symptom‐relieving medication following treatment with SQ SLIT‐tablets. Data were obtained from: ^aHorn et al. (2016); ^bSchwab et al. (2013); ^cSchwab et al. (2018); ^dGronke et al. (2013); ^eReiber et al. (2021); ^fTempels‐Pavlica et al. (2024); ^gPfaar et al. (2024) (Europe = Denmark, Finland, Germany, the Netherlands, Norway and Sweden). Data are missing for some non‐interventional studies due to heterogeneity in the reporting of data among the publications. AT, Austria; DE, Germany; HDM, house dust mite; NL, the Netherlands; SLIT, sublingual immunotherapy.

Two publications presented data from a study designed to characterise the kinetics of individual changes in the immunological response to the SQ grass SLIT‐tablet [47, 49]. The study showed that the progressive development of a regulatory T‐cell response during the first 2 years of treatment is linked to the sustained regulatory T‐cell response observed after completion of a 3‐year treatment course and a 2‐year follow‐up period [47, 49].

3.4. Safety and Tolerability

From the 17 publications reporting safety data for SQ SLIT‐tablets, 18%–79% of participants experienced AEs and/or ADRs with the grass tablet, 32%–80% with the HDM tablet, 58% with the tree tablet, and 54% with the ragweed tablet (Figure S2). The most frequently reported AEs/ADRs were expected local application site reactions, including oral pruritus, throat irritation, ear pruritus, and mouth edema (Figure 4). Across the three SQ‐SLIT tablets, most AEs/ADRs were mild or moderate in severity (up to 75%), the rate of discontinuations due to AEs/ADRs was low (0%–14.5%; Figure S2), and few studies reported serious AEs/ADRs (≤ 2%; Figure S2). The majority of these publications defined severity and seriousness of AEs/ADRs using language consistent with the International Conference on Harmonisation Harmonised Tripartite Guideline E2A, Step 5 [60]. No deaths were reported in the publications.

FIGURE 4.

Most frequently reported AEs/ADRs with SQ SLIT‐tablet treatment. Publications reported data for AEs that occurred after treatment initiation and/or for AEs that were considered related to study treatment (i.e., ADRs). Data were obtained from: ^aWessel et al. (2012); ^bSchwab et al. (2018); ^cReiber et al. (2016); ^dArmentia et al. (2012); ^eTjan et al. (2017); ^fDemoly et al. (2022); ^gReiber et al. (2021); ^hSidenius et al. (2021); ⁱKajiume (2022); ^jPfaar et al. (2024) (Europe = Denmark, Finland, Germany, the Netherlands, Norway and Sweden). Data are missing for some non‐interventional studies due to heterogeneity in the reporting of data among the publications. ADR, adverse drug reaction; AE, adverse event; DE, Germany; DK, Denmark; ES, Spain; FR, France; HDM, house dust mite; JP, Japan.

Among the more than 12,000 participants enrolled across the 22 studies, eight cases of anaphylactic reactions were reported—two for the SQ grass SLIT‐tablet and six for the SQ HDM SLIT‐tablet [44, 50, 55, 58]. One participant experienced a reaction 2 min after administration of the SQ grass SLIT‐tablet, self‐administered adrenaline (from an auto‐injector), and fully recovered [50]. In a study of the SQ HDM SLIT‐tablet, four serious ADRs were reported as anaphylactic reactions; however, adrenaline was not required, and all participants fully recovered [55]. A second SQ HDM SLIT‐tablet study reported serious allergic reactions (occurring at the first administration of the SQ SLIT‐tablet) in two adolescents that were coded as anaphylaxis; adrenaline was administered, participants were discharged within 1 h, and recovered quickly after treatment [58].

One SQ HDM SLIT‐tablet study evaluated the incidence of eosinophilic esophagitis (EoE) and reported one case of mild‐to‐moderate EoE among 521 participants over 5 years of follow‐up [58]. The participant experienced gastroesophageal reflux disease (GERD) and dysphagia 17 months after starting SQ HDM SLIT‐tablet therapy (no recent history of GERD or food allergy); eosinophilia was confirmed on biopsy [58].

Safety data were reported for more than one pollen season in a long‐term study of SQ grass SLIT‐tablet [51]. The rate of AEs was highest in the first year (53.8%) and lower in each subsequent year (Year 2: 17.7%; Year 3: 4.7%) [51]. Co‐administration of the SQ grass SLIT‐tablet and subcutaneous immunotherapy was the focus of two non‐interventional studies, and no safety concerns were reported in either study [43, 44]. Similarly, co‐administration of the grass and ragweed SQ SLIT‐tablets was found to be well‐tolerated [59]. Three studies also investigated the feasibility of an intra‐seasonal start of SQ SLIT‐tablets (grass and tree) [41, 45, 46]. These studies concluded that the intra‐seasonal start of the SQ SLIT‐tablet was well‐tolerated [41, 45, 46], with a high degree of treatment satisfaction reported by patients and physicians [45, 46].

3.5. Adherence and Compliance

Twelve studies reported data for either adherence or compliance across the four SQ SLIT‐tablet products. Various definitions of adherence/compliance were used among the studies. For example, taking the tablet 6–7 times per week [41, 42]; taking the tablet regularly in all documented prescription intervals [38, 39, 50]; ≥ 75 to 80% of tablets taken daily [43, 44, 45, 46, 57] proportion of number of days on therapy to the number of days the patient should be on therapy [59]. Overall, adherence/compliance was reported in ≥ 60% of participants across studies (including two long‐term studies of SQ grass SLIT‐tablet) [38, 39, 41, 42, 43, 44, 45, 46, 50, 51, 57, 59].

4. Discussion

This narrative review of 22 non‐interventional studies involving more than 12,000 participants provides substantial and consistent evidence for the real‐life effectiveness and safety of SQ SLIT‐tablets for the treatment of AR. The findings complement the evidence from RCTs and other RWE studies, confirming the short‐ and long‐term clinical benefits of SQ SLIT‐tablets in several respiratory allergies. The novel aspect of this review is that it focuses on the effectiveness data from non‐interventional prospective studies of SQ SLIT‐tablets that were designed to predominantly evaluate safety and tolerability.

The observed effectiveness of SQ SLIT‐tablets presented in this review of non‐interventional studies complements a number of RCTs that have demonstrated reductions in symptoms and medication use [14, 16, 20, 26]. These include short‐term RCTs with SQ SLIT‐tablets, e.g., in HDM–induced AR [20], tree pollen–induced allergic rhinoconjunctivitis [16] and long‐term RCTs in grass pollen‐induced allergic rhinoconjunctivitis with or without allergic asthma [14, 26]. Further, improvements in RQLQ scores observed in a study included in this review are consistent with those in a pooled analysis of 11 RCTs across SQ grass, tree, ragweed, and HDM SLIT tablets [61]. The presented results are also consistent with subgroup analyses of the REACT study, which have also demonstrated the long‐term effectiveness of SQ grass SLIT‐tablet on AR prescriptions [35].

Non‐interventional studies follow normal clinical practice—patients are followed prospectively as in an RCT but, unlike RCTs, data collection and patient participation do not interfere with the choice of treatment, procedures, or with the treatment itself, thereby providing greater generalisability of the results. Furthermore, unlike retrospective RWE studies, the prospective nature of the data collection minimises the risk of confounding and increases the granularity of the data. Consequently, the findings of non‐interventional studies substantiate the suitability of treatment in normal clinical practice, and the wealth of evidence summarised in this review demonstrates that this is the case for SQ SLIT‐tablets. In addition, non‐interventional studies offer an opportunity to evaluate complementary measures, such as patient‐reported outcomes, which are increasingly considered important by the regulatory authorities to confirm clinical relevance, and to assist healthcare professionals in making treatment decisions. Indeed, the patient‐centric outcomes discussed in this review (treatment satisfaction, patient well‐being, and ease of treatment use) provide an important source of evidence to complement the well established efficacy and safety in RCTs for SQ SLIT‐tablets [14, 16, 20, 26]. A higher degree of treatment satisfaction and well‐being can be supported by the benefits of individuals experiencing fewer AR symptoms after treatment with SQ SLIT‐tablets.

The consistent reduction observed in symptom burden and the use of medication for AR and for asthma indicates similar effectiveness of SQ SLIT‐tablets in treating conditions of both the upper and lower airways and improving disease control. This consistent effect was also observed across the different SQ SLIT‐tablets. Clinical symptoms associated with HDM allergy may be less prominent than for seasonal allergy [62]. Therefore, the favourable data for the SQ HDM SLIT‐tablet from the non‐interventional studies presented in this review are reassuring and further extend the evidence for the SQ HDM SLIT‐tablet. The preliminary data indicating that SQ SLIT‐tablets can improve sleep (likely due to relief from nasal inflammation/congestion) is of particular relevance since AR‐associated sleep problems, such as sleep‐disordered breathing [63], can have a considerable impact on patients' quality of life, especially in young adults and children [64]. Indeed, for two‐thirds of children (with HDM allergy) who present for medical care, impaired sleep is stated as one of the main reasons for seeking help [65].

In line with RCT data and RWE, the findings of non‐interventional studies confirm that SQ SLIT‐tablets are well‐tolerated; the most common AEs were as expected and no new safety concerns were identified. Discontinuation rates due to AEs reported in RCTs of SQ SLIT‐tablets are generally within the range reported for the non‐interventional studies (0%–14.5%) [20]. Of note, data from the long‐term study indicated that the safety and tolerability of SQ grass SLIT‐tablet improved over time. In addition, the data showed that intra‐seasonal initiation of SQ tree SLIT‐tablets seems to be well‐tolerated in individual patients. However, pre‐seasonal treatment is the usual and recommended posology to ensure that patients have a clinical effect in the first pollen season [10]. The rates of adherence and/or compliance reported in the various studies were generally high, even after 3 years of treatment, which may be reflective of the good effectiveness, tolerability and treatment satisfaction of SQ SLIT‐tablets. However, the limited data and heterogeneity in reporting must be considered. In 2023, Pfaar and colleagues published a checklist to serve as a pragmatic guide for researchers when designing or interpreting studies evaluating adherence to AIT [66]. The checklist focuses on retrospective studies and, therefore, is not directly applicable to non‐interventional prospective studies, but the ethos underlying the checklist applies to any evaluation of adherence to AIT and is worth keeping in mind [66].

Limitations of this review include the lack of comparators resulting from the uncontrolled nature of non‐interventional studies, heterogeneity in the data extracted from the identified study publications, and inconsistent reporting of statistical methodology for missing data generally across the observational studies. To reduce heterogeneity, the review was restricted to SQ SLIT‐tablets and excluded other AIT formulations. Furthermore, other real‐life aspects of SQ SLIT‐tablets, such as cost‐effectiveness, were not specifically assessed in this review. Compared to RCTs, the data from non‐interventional studies are less stringently documented and rely on self‐reported endpoints. As with any patient‐reported outcome, there is a risk of recall bias, which may lead to either over or underestimation of effectiveness and tolerability.

Real‐life clinical data from non‐interventional studies are often used to develop clinical guidelines and are, increasingly, being used by the regulatory authorities to inform decision making [29, 30]. Consequently, this type of data are of great importance, and the findings presented here bridge the evidence gap between RCTs and RWE studies for SQ SLIT‐tablets in the treatment of AR, providing a comprehensive body of evidence for the real‐life clinical effectiveness of SQ‐SLIT therapy to further support clinical decision‐making. A key strength of these data are the consistency and robustness of data derived from the studies, recruiting more than 12,000 participants allowing for evaluation of all four SQ SLIT‐tablet products in populations reflecting a wide range of ages and geographies.

In conclusion, the findings from non‐interventional studies complement the existing data from RCTs and RWE studies—together, providing compelling evidence to support the use of SQ SLIT‐tablets as an efficacious and well‐tolerated treatment option for AR in daily clinical practice.

Author Contributions

All authors contributed to the study concept and design, and/or the analysis or interpretation of data. All authors reviewed and revised the content critically and approved the final version for submission. All authors agree to be accountable for all aspects of the work.

Conflicts of Interest

Pascal Demoly: has received non‐personal fees directed to research and teaching purposes from ALK‐Abelló A/S, AstraZeneca, Chiesi, Ménarini, GlaxoSmithKline, Puressentiel, Stallergenes Greer, Thermo Fisher Scientific, Viatris, and Zambon. Christer Janson: has served on an advisory board and/or served as a speaker and/or participated in educational activities arranged by ALK‐Abelló A/S, AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Orion, Stallergenes Greer, and Thermo Fisher Scientific. Andreas Horn: has received grants for studies and/or personal fees from ALK‐Abelló A/S, Allergopharma, Almirall, ASIT Biotech, AstraZeneca, BerlinChemie, HAL Allergie GmbH, Immunotek, IQVIA, LETI Pharma, Meinhardt Congress GmbH, Novartis, Sanofi Aventis, and Stallergenes Greer. André C. Knulst: has received institutional sponsoring for research or consultancy from ALK‐Abelló A/S, Thermo Fisher Scientific, Nutricia/Danone, DBV technologies, Novartis, EUROIMMUN, Stallergenes Greer, TNO, FARRP, NVWA, and STW. Oliver Pfaar: has received grants, and/or personal fees, and/or travel support from AEDA, Alfried Krupp Krankenhaus, ALK‐Abelló A/S, Allergopharma, Almirall, Altamira Therapeutics, ASIT Biotech, AstraZeneca, Bencard Allergie GmbH/Allergy Therapeutics, Blueprint, Breazy Health GmbH, Cliantha, Deutsche AllergieLiga e.V., Deutsche Forschungsgemeinschaft, Dustri‐Verlag, ECM Expro&Conference Management GmBH, Forum für Medizinische Fortbildung, Georg‐Thieme‐Verlag, GSK, HAL Allergy Holding B.V./HAL Allergie GmbH, Immunotek, Ingress Health, Institut für Disease Management (Essen, Germany), IQVIA Commercial, Japanese Society of Allergology, Königlich Dänisches Generalkonsulat, Laboratorios LETI/LETI Pharma, Lilly, Lofarma, Medizinische Hochschule Hannover, med update europe GmbH, Meinhardt Congress GmbH, Novartis, Paul‐Ehrlich‐Institut, Paul‐Martini‐Stiftung, PneumoLive, Pohl‐Boskamp, Procter & Gamble, Red Maple Trials Inc., Regeneron, RG Aerztefortbildung, ROXALL Medizin, Sanofi Aventis, Sanofi Genzyme, Springer Publisher, Stallergenes Greer, streamedup! GmbH, Technical University Dresden, Wiley Publishers, Wort & Bild Verlag, Verlag ME; outside the submitted work, O.P. is Vice President of the European Academy of Allergy and Clinical Immunology (EAACI), a member of EAACI Excom as well as a member of the external board of directors of the German Society of Allergy and Clinical Immunology (DGAKI); coordinator, main‐ or co‐author of different position papers and guidelines in rhinology, allergology and allergen immunotherapy; and he is Editor‐in‐Chief of Clinical Translational Allergy and Associate Editor of Allergy.

Supporting information

Table S1: Non‐interventional studies identified through literature searching, according to the type of SQ SLIT‐tablet.

Table S2: Summary of baseline demographics and clinical characteristics.

Figure S1: Reduction in symptom‐relieving medication by key drug class, following treatment with SQ SLIT‐tablets.

Figure S2: Overview of safety.

Data Availability Statement

The authors have nothing to report.