Sublingual Immunotherapy for Allergic Rhinitis and Conjunctivitis

Giovanni Passalacqua; Valentina Garelli; Francesca Sclifò; Giorgio Walter Canonica

Disclosures

Immunotherapy. 2013;5(3):257-264. 

In This Article

SLIT for Allergic Rhinoconjunctivitis

Efficacy

To date, the principal indication to SLIT remains allergic rhinoconjunctivitis and most of the clinical data derive from trials conducted in patients with that disease. More than 60 randomized double-blind placebo-controlled trials have been published so far (for review see [6]), two-thirds of them in dust mites and grass allergy.

The majority of trials assessed the effects of SLIT in allergic rhinitis; however, some also evaluated the effects in asthma, although only in few studies was asthma the primary outcome. Only six studies produced completely negative results (no difference vs placebo).[8–13] In the 60 positive studies, the degree of clinical effect ranged from 10 to 45% over placebo with greater than 20% in about two-thirds. When analyzing the available trials, it was noted that some meta-analyses were continued, subdividing patients for age, allergen or disease ( Table 1 ).[14–21] Four meta-analyses evaluated the use of SLIT considering only allergic rhinitis for symptoms and drug intake[14,17,19,20] (three included patients of all ages[14,19,20] and the fourth only patients aged 5–18 years[17]), all providing results consistently in favor of SLIT versus placebo.[22] The same was evidenced in the two meta-analyses that only took asthma into account.[15,17] Nieto et al. questioned the reliability of these meta-analyses, underlining the possible publication biases, the incorrect reporting and the high heterogeneity testified by the large CIs (certainly owing to the variability in the inclusion criteria, doses, regimens and outcome measures).[23] Some of the concerns expressed by Nieto et al. (especially heterogeneity) remained, nonetheless, valid, even after more recent meta-analyses were published. However, meta-analysis is so far the only way to summarize the results of studies when they are not comparable with each other. In addition, more recent meta-analyses, restricted to house dust mite and grasses[19,20] confirmed the results with a lesser heterogeneity grade. Finally, the superiority of SLIT over placebo was confirmed, also limiting the analysis to conjunctivitis symptoms.[21]

Relevant information on SLIT (grass tablets) in allergic rhinitis was obtained in the so-called 'big trials', where more than 200 individuals were enrolled in each study (in some cases up to 600).[12,24–31] Some of these trials had a dose-ranging design, thus it was possible to demonstrate a dose-dependent clinical effect of SLIT and to identify the optimal maintenance dose for grasses in 15–25 µg major allergen per day (approximately 50-times the monthly dose of SCIT). Finally, a magnitude of clinical effect of 20% or greater over placebo is considered clinically relevant[32] and in the quoted studies this magnitude ranged from 25 to 50% ( Table 2 ).[12,24–31]

The comparison between immunotherapy and drugs is still a matter of debate. In particular, the clinical effects of SLIT can be appreciated only in the long term (months), whereas traditional drugs act immediately. The only available head-to-head trials comparing SLIT as add-on therapy versus inhaled budesonide[33] and montelukast[34] in patients with asthma and rhinitis, respectively, consistently showed a favorable outcome for SLIT, in nasal and bronchial symptoms, and nasal inflammation.

Finally, there are very few randomized trials directly comparing SLIT with SCIT. The first was randomized, double-blind and double-dummy, but without a placebo arm, which failed to find significant difference between SLIT and SCIT.[35] Another was randomized, double-blind, double-dummy and placebo-controlled, and showed no significant difference in clinical efficacy between the two routes of administration over 2 years in birch-allergic patients.[36] Another recent, randomized, open controlled trial in children with asthma and rhinitis due to mite provided similar results.[37] Finally, a meta-analysis-based comparison between SLIT and SCIT for grass pollen allergy reported a more prominent effect in favor of SCIT, although this comparison was totally indirect and with high data heterogeneity.[38] Thus, the few head-to-head comparison trials (with a small number of subjects) could not demonstrate a difference between the two routes, whereas an indirect comparison pooling together all the grass pollen studies was in favor of SCIT. In conclusion, no robust evidence so far exists to suggest that one route is superior to the other.

Safety

After more than 25 years of clinical use, the satisfactory safety profile of SLIT has been well acknowledged.[6,39] In general, the vast majority (>90%) of side effects of SLIT are represented by local adverse reactions such as oral itching/swelling/burning, nausea and stomach ache. These side effects are usually mild and tend to disappear after the first doses (<10 days).[40,41] Systemic side effects, such as rhinitis, asthma and urticaria, are reported to be very rare, and to occur in less than 1% of patients. Only six cases of anaphylaxis[42–46] have been described so far, with some of them not using standardized extracts. Finally, no fatal event has ever been described. Due to the rarity of severe adverse events, no risk factor has so far been clearly identified. Nonetheless, based on common sense and transferring our knowledge about SCIT to SLIT, it is recommended to not administer SLIT to patients with severe/uncontrolled asthma. Also, it is recommended that the first dose of SLIT is administered under medical supervision.[6] Below 5 years of age is generally considered a relative contraindication to SCIT owing to safety concerns;[4] however, postmarketing surveys have clearly shown that SLIT-induced side effects are no more frequent or severe in small children than in older age groups,[47–49] even when multiple allergens are administered.[50]

There is a certain dose-dependence in side effects, since their occurrence increases as the dose increases; however, so far there is no clear demonstration of a 'maximum tolerated dose'. A controlled dose-finding study involved 48 grass pollen allergic patients outside pollen season.[51] They received SLIT for 28 days at progressively increasing doses, up to 200 µg Phl p 5 allergen (approximately 40-times the dose given subcutaneously). The incidence of side effects was 74%, all of mild or moderate intensity, the most frequent being irritation of the throat and oral itching. An updosing phase, as is usually carried out with SCIT, seems to be unnecessary with SLIT and the treatment course can be started immediately with the maintenance dose.[24,26,52,53]

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