Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile

Allergen immunotherapy reorients inappropriate immune responses in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical tolerance. Although 40-75% of patients receiving SLIT experience mild, transient local reactions in the oral mucosa, these primary reactions rarely necessitate dose reduction or treatment interruption. We discuss 11 published case reports of anaphylaxis (all nonfatal) diagnosed according to the World Allergy Organization criteria and relate this figure to the approximately 1 billion SLIT doses administered worldwide since 2000. Anaphylaxis risk factors associated with SCIT and/or SLIT should be characterized further.     

Economic evaluation of sublingual vs subcutaneous allergen immunotherapy.

BACKGROUND: Sublingual allergen immunotherapy (SLIT) is a commonly used alternative route of administration to standard subcutaneous immunotherapy (SCIT) in Europe. Despite its wide use, the cost-effectiveness of SLIT vs SCIT has not been well established. OBJECTIVE: To evaluate the cost and effectiveness of SLIT compared with SCIT in patients with allergic rhinoconjunctivitis during a 3-year specific allergen immunotherapy (SIT) from a third-party payer's, a patient's, and society's perspectives. METHODS: We performed an open-label randomized clinical trial of patients receiving SLIT (n = 19), patients receiving SCIT (n = 23), and a control group (n = 22). The outcome measures were Rhinoconjunctivitis Quality of Life Questionnaire score, visual analog scale score, symptomatic medication reduction, and direct and indirect costs. RESULTS: SLIT offered clinical benefits to patients comparable to those provided by SCIT. From the perspective of a third-party payer, the total average direct medical cost per patient of 3-year SIT was estimated at Euro 416 vs Euro 482 in the SLIT and SCIT groups, respectively. A patient who received SLIT paid less than a patient who received SCIT for all out-of-pocket costs (Euro176 for SLIT vs Euro 255 for SCIT) but more for sole allergen extracts (Euro 72 for SLIT vs Euro 55 for SCIT). When both direct and indirect costs were considered, the 3-year SIT expenditures per patient reached Euro 684 vs Euro 1,004 in the SLIT and SCIT groups, respectively. CONCLUSIONS: SLIT represents a less expensive alternative relative to subcutaneous administration from all perspectives. However, from a patient's perspective, SCIT offers a less expensive alternative for patients who do not experience loss of income and travel costs associated with treatment.     

A bright future for sublingual immunotherapy--contra

Defining the role of sublingual immunotherapy (SLIT) for the treatment of allergic rhinoconjunctivitis and allergic asthma is hampered for various reasons: Heterogeneity in study designs, different allergen extracts and dosages, imperfect assessment strategies and partially inconclusive results. A number of questions need to be addressed before replacing subcutaneous immunotherapy (SCIT) by the sublingual route: Ideal dose, treatment duration, magnitude of improvement, modification of the immune response, long-term and preventive effects. At present, SLIT might be used in adults with pollen related rhinoconjunctivitis, particularly if SCIT is not suitable for the patient (i.e. systemic effects). Only few data support SLIT for house dust mite allergy or bronchial asthma. Due to a lack of convincing results SLIT for children should only be applied in controlled studies and not in the daily routine. A more substantiated and conclusive judgment of SLIT is possibly warranted in a few years, when more studies with larger patient groups have addressed open questions concerning SLIT.     

Dose dependence of immunological response to sublingual immunotherapy

BACKGROUND: Sublingual-swallow immunotherapy (SLIT) is an accepted treatment for allergic rhinitis but its optimal dosage is scantly investigated. We studied the dose dependence of clinical efficacy and immunological response to SLIT by administering two different dosages of the same allergen in rhinitic children monosensitized to grass pollen. METHODS: Seventy-one patients with comparable age and symptoms were randomized to receive SLIT by the same grass pollen extract from Stallergenes (Antony, France), 40 of them with the 100 IR and 31 with the 300 IR extract. All patients recorded diary cards for symptoms, medications and side-effects of the treatment, and had measurements of specific IgE and IgG4 in serum by the CAP System FEIA (Pharmacia, Uppsala, Sweden) and in nasal secretion by an in situ incubation method with the same reagents of CAP System FEIA. RESULTS: Symptom/medication scores during the pollen season were significantly higher in patients treated with the lower dosage compared with those treated with the 300 IR dosage. Side-effects occurred with a comparable rate (25.8%vs 27.5%) in the two groups. Serum-specific IgE and IgG4 had no significant changes after 3 months of SLIT in both groups, while a significant seasonal increase of nasal IgE (P = 0.015) and IgG4 (P = 0.019) was found only in patients treated with the lower dosage. CONCLUSIONS: A rise of specific IgG4 and a blunting of seasonal increase of specific IgE in serum was repeatedly reported during subcutaneous immunotherapy (SCIT) with pollen extracts. Our findings show such blunting of specific nasal IgE along with a low symptom/medication score in patients treated with SLIT with the higher dosage, but not a concomitant rise of specific nasal IgG4. This suggests a local immunological effect of SLIT, different from systemic mechanisms of SCIT.     

Allergen-Specific Sublingual Immunotherapy for Respiratory Allergy

Present knowledge regarding the clinical efficacy and safety of sublingual immunotherapy (SLIT) for the treatment of respiratory allergy is reviewed. Allergenspecific immunotherapy is presently considered a ‘biological response modifier’ for the treatment of respiratory allergy, to be used in association with drug therapy and allergen avoidance. Its value in the treatment of these conditions has been established in position papers from the World Health Organization and the European Academy of Allergology and Clinical Immunology. Immunotherapy is usually administered subcutaneously (SCIT), and with this route several severe adverse events and fatalities have been described. Therefore, in the last 15 years, novel and safer routes of administration (local routes) have been developed. SLIT, in particular, has been investigated in 18 randomised controlled clinical trials. SLIT’s clinical efficacy (improvement in symptoms and reduction in drug intake) in both asthma and rhinitis has been clearly assessed in 16 of these studies and for the most common allergens. SLIT’s safety profile, derived from the clinical trials and from post-marketing surveillance studies, was shown to be satisfactory in both adults and children. The most frequently reported adverse events are gastrointestinal complaints, which can be avoided through appropriate dosage adjustment. For these reasons, SLIT has been accepted as a viable alternative to SCIT in recent position papers. The main advantages of SLIT are its safety (no severe systemic adverse event has ever been described) and good patient acceptance, especially in children; in addition, SLIT is a self-administered treatment that can be carried out at home by the patient. In contrast to injection immunotherapy, knowledge of the mechanisms of action of SLIT is still developing, albeit rapidly, although interesting data about its pharmacokinetics in humans are available. Data are also required concerning the possible preventive and long-lasting effects. SLIT is a viable alternative to SCIT, with the same rationale and indications. It is intended to be used in association with proper pharmacological treatment, at the earliest stages of the disease, for optimal management of respiratory allergy.     

Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial

Background In children, the clinical efficacy and immunological mechanisms of sublingual immunotherapy (SLIT) compared with subcutaneous immunotherapy (SCIT) is still to be elucidated. Objectives To compare SLIT, SCIT and pharmacotherapy in relation to clinical efficacy and immunological mechanisms that govern its effect in asthmatic/rhinitis children who were sensitized to house dust mite (HDM). Methods In this single centre, prospective, randomized, controlled, open labelled, three parallel group trial, 48 patients mono‐sensitized to HDM were randomized to receive either SLIT (n=16), SCIT (n=16) or pharmacotherapy alone (n=16). Symptom, medication and visual analogue score (VAS) were collected and bronchial‐nasal hyper‐reactivity, skin prick tests, total‐specific IgE were performed at baseline and 12 months after treatment. In addition, peripheral blood mononuclear cells were cultured with recombinant Der p 1 and Bet v 1 extracts and allergen‐specific IL‐4, IL‐5, IL‐13, IFN‐γ, IL‐10, and TGF‐β secretions were measured. Results SLIT and SCIT demonstrated a significant reduction of total rhinitis and asthma symptom score, total medication score, VAS and skin reactivity to HDM (P<0.05) when compared with pharmacotherapy. A significant reduction of serum‐specific HDM‐IgE in SCIT and SLIT were observed. Moreover, titrated nasal provocative dose significantly increased in both immunotherapy groups when compared with the pharmacotherapy group. No adverse effects were reported in SLIT, while two patients demonstrated serious adverse events in SCIT. After 1 year of treatment, Der p 1‐driven IL‐10 significantly increased in SLIT compared with pharmacotherapy, whereas Bet v 1‐driven TGF‐β (negative control) increased significantly in SLIT only. No changes were observed for Th1–Th2 cytokines. Conclusion Both SLIT and SCIT demonstrated clinical improvement compared with pharmacotherapy in asthma/rhinitis children sensitized to HDM.     

Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3‐expressing cells and elevated allergen‐specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E‐facilitated allergen binding to B cells

Background The mechanisms of sublingual immunotherapy (SLIT) are less well understood than those of subcutaneous immunotherapy (SCIT). Objectives To determine the effects of grass‐pollen SLIT on oral mucosal immune cells, local regulatory cytokines, serum allergen‐specific antibody subclasses and B cell IgE‐facilitated allergen binding (IgE‐FAB). Methods Biopsies from the sublingual mucosa of up to 14 SLIT‐treated atopics, nine placebo‐treated atopics and eight normal controls were examined for myeloid dendritic cells (mDCs) (CD1c), plasmacytoid dendritic cells (CD303), mast cells (AA1), T cells (CD3) and Foxp3 using immunofluorescence microscopy. IL‐10 and TGF‐β mRNA expression were identified by in situ hybridization. Allergen‐specific IgG and IgA subclasses and serum inhibitory activity for binding of allergen‐IgE complexes to B cells (IgE‐FAB) were measured before, during and on the completion of SLIT. Results Foxp3⁺ cells were increased in the oral epithelium of SLIT‐ vs. placebo‐treated atopics (P=0.04). Greater numbers of subepithelial mDCs were present in placebo‐treated, but not in SLIT‐treated, atopics compared with normal controls (P=0.05). There were fewer subepithelial mast cells and greater epithelial T cells in SLIT‐ compared with placebo‐treated atopics (P=0.1 for both). IgG₁ and IgG₄ were increased following SLIT (P<0.001). Peak seasonal IgA₁ and IgA₂ were increased during SLIT (P<0.05). There was a time‐dependent increase in serum inhibitory activity for IgE‐FAB in SLIT‐treated atopics. Conclusions SLIT with grass pollen extract is associated with increased Foxp3⁺ cells in the sublingual epithelium and systemic humoral changes as observed previously for SCIT. Cite this as: G. W. Scadding, M. H. Shamji, M. R. Jacobson, D. I. Lee, D. Wilson, M. T. Lima, L. Pitkin, C. Pilette, K. Nouri‐Aria and S. R. Durham, Clinical & Experimental Allergy, 2010 (40) 598–606.     

Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study

BACKGROUND: Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed. OBJECTIVE: To investigate the clinical efficacy of SLIT vs SCIT and secondary to compare SLIT and SCIT with placebo and to evaluate the relative clinical efficacy in relation to systemic side-effects. METHODS: A 3-year randomized, placebo-controlled, double-blind, double-dummy study including 71 adult birch pollen hay fever patients treated for two consecutive years after a baseline year. Allocation to treatment groups was based on disease severity in the baseline season, gender and age. RESULTS: Clinical efficacy was estimated in 58 patients completing the first treatment year by subtracting baseline data and by calculating the ratio first treatment season vs baseline. SLIT diminished the median disease severity to one-half and SCIT to one-third of placebo treatment. No statistical significant difference between the two groups was observed. Both for symptoms and medication scores actively treated patients showed statistically significant and clinical relevant efficacy compared with placebo. SLIT treatment only resulted in local mild side-effects, while SCIT resulted in few serious systemic side-effects. CONCLUSION: Based on the limited number of patients the clinical efficacy of SLIT was not statistically different from SCIT, and both treatments are clinically effective compared with placebo in the treatment of birch pollen rhinoconjunctivitis. The lack of significant difference between the two treatments does not indicate equivalent efficacy, but to detect minor differences necessitates investigation of larger groups. Due to the advantageous safety profile SLIT may be favored.     

Safety of immunotherapy with therapeutic vaccines containing depigmented and polymerized allergen extracts

BACKGROUND: The major complication of allergen immunotherapy is a severe reaction. OBJECTIVE: To evaluate the safety of depigmented and glutaraldehyde-modified allergen extracts in a large group of patients undergoing immunotherapy treatment. MATERIAL AND METHODS: Seven hundred sixty-six patients, having rhinoconjunctivitis and/or asthma, were entered in a prospective, multi-centre, observational cohort study, to evaluate the safety of immunotherapy with modified allergen vaccines. Patients were sensitized to mites and/or pollen and received a therapeutic vaccine containing depigmented and polymerized allergen extracts of mites and/or pollens adsorbed onto aluminium hydroxide. The schedule of administration consisted of a build-up phase of 4- to 6-weekly injections, followed by 12-monthly injections of the maintenance dose. Tolerance was assessed by recording all side reactions related to immunotherapy. RESULTS: All patients completed the study. Fifty-four clinically relevant local reactions (43 immediate and 11 delayed) were observed (0.4% of injections). The systemic reactions were 34 in 12 patients. Six reactions were immediate (all of grade 2) and 28 delayed (18 of grade 1 in two patients, nine of grade 2 and one of grade 3). The systemic reactions of grade 2 or 3 occurred in 0.12% of the injections. All systemic reactions were mild and resolved spontaneously without the need for medication. CONCLUSION: Specific immunotherapy using modified allergen vaccines is safe to treat allergic patients. The percentage of adverse reactions detected is lower than those reported in the literature with native-unmodified allergen extracts.