Posted by: Indonesian Children | April 6, 2010

Sub-Lingual Immunotherapy: World Allergy Organization Position Paper 2009

Sub-Lingual Immunotherapy: World Allergy Organization Position Paper 2009

HISTORICAL BACKGROUND TO SUBLINGUAL IMMUNOTHERAPY

* Subcutaneous immunotherapy (SCIT) currently represents the standard immunotherapy modality, with well ascertained clinical efficacy.

* The first SLIT randomized DBPC-RCT was published in 1986. The rationale proposed for SLIT was to improve the safety and to make the treatment more convenient.

* The first DBPC-RCT trial with tablets was published in 1986.

* SLIT was firstly accepted as a viable alternative to SCIT in the World Health Organization (WHO) position paper, published in 1998, and then included in the ARIA guidelines.

* Since 1986, 60 DBPC-RCT trials have been published.

* The available meta-analyses are in favor of SLIT (rhinitis in adults, asthma, and rhinitis in children), although the conclusions are limited by the great heterogeneity of the studies.

* Adequately powered, well-designed DBPC-RCTs involving hundreds of patients, published in the last 3 years have clearly confirmed the efficacy and the dose-dependent effect of SLIT for grass allergens in both adults and children.

 

Allergen-specific immunotherapy (SIT), or allergen vaccination is the practice of administering to allergic subjects increasing amounts of allergen(s) (the allergenic extract or vaccine) to achieve hyposensitization, that is to reduce the symptoms occurring during the natural exposure to the allergen(s) itself. The history of SIT began in the first years of the twentieth century, based on the idea of the vaccination against infectious agents. In fact, Leonard Noon1 aimed at achieving a vaccination against “airborne toxins,” and for this reason he chose the subcutaneous route of administration. Although the theoretical background was incorrect, SIT was immediately found to be effective in reducing symptoms of hay-fever, its use spread rapidly, and the subcutaneous route (SCIT) remained therefore the standard practice.

Indeed, the idea of administering the allergenic extracts via noninjection routes is not as recent as commonly believed. The first descriptions of the “oral” route of administration also appeared in the early 1900s2 and the first clinical attempts with this administration were carried out only a few years later.3,4 Subsequently, other routes of administration were proposed, that is, local bronchial during the 1950s5,6 and local nasal7,8 during the 1970s. The overall rationale of these attempts was of course that of finding a safer and more convenient route of administration for SIT. Those routes have been variously named, that is, alternative, nonparenteral, noninjection, or local routes. Presently, it is agreed that the most proper terms are local and noninjection, which are equivalent; whereas the word alternative has been abandoned because it might generate confusion with other unconventional medicines. The oral route was investigated in several clinical trials performed during the 1980s,9–12 but the clinical results were controversial and, in some cases, important gastrointestinal adverse events were reported. For these reasons, oral administration was gradually abandoned. In 1986, the British Committee for the Safety of Medicines13 reported several deaths caused by SCIT, and raised serious concerns about the safety and the risk/benefit ratio of SIT, also because cheaper and effective drugs (eg, oral H1-antihistamines and topical corticosteroids) had become available for the treatment of respiratory allergy. In this scenario, the interest in noninjection routes of immunotherapy (IT) increased again,14 and in 1986 the first randomized controlled trial with the sublingual route (SLIT) was published.15 This study was conducted with very low doses of a mite extract. The original idea supporting SLIT was to achieve a prompt absorption of the vaccine through the sublingual mucosa as happens, for instance with nitroglycerine or nifedipine. Indeed, 10 years later, biodistribution studies with radiolabeled allergens in humans,16,17 consistently showed that the direct absorption of the extract through the oral mucosa is absent or negligible, and that the clinical effect should be rather ascribed to the interaction of the allergen with the mucosal immune system. Nonetheless, from a clinical point of view, SLIT was confirmed to be effective in several controlled studies utilizing either drops or tablets,18,19 and the first pediatric study appeared in 1990.18

In the subsequent years, the number of DBPC-RCTs of SLIT rapidly increased, and SLIT began to be mentioned in official documents. In 1993 the European Academy of Allergy and Clinical Immunology (EAACI) stated in its position paper that SLIT could be regarded as a “promising route” for desensitization.14 Five years later, the WHO, based on the results of 8 DBPC-RCTs, stated that SLIT “may be considered as a viable alternative to the injection route in adults.”20 In the same year, EAACI produced a position paper on noninjection routes, stating that the use of SLIT in clinical practice is justified because of the ascertained efficacy and the favorable safety profile.21 In 2001, the ARIA position paper accepted the use of SLIT in adults and children, as a valid alternative to SCIT22 and this was confirmed by the ARIA update in 2008.23 In SLIT, the allergen extract (prepared as drops or tablets) is kept under the tongue for 1 to 2 minutes and then swallowed; thus, this route is also called sublingual-swallow. In some studies a different method was adopted, the allergen was kept under the tongue and then spat out (sublingual-spit).24 Presently, only the sublingual-swallow route is used, therefore the acronym SLIT refers to the sublingual-swallow modality.

Nowadays, more than 50 DBPC-RCTs are available in the literature.25 Their results were also pooled and evaluated in several meta-analyses, which concluded that SLIT is significantly efficacious compared with placebo for rhinitis and asthma in adults and children.26–29 In the last 2 years, some adequately powered, well-designed DBPC-RCTs with grass drops30 or tablets31–33 including hundreds of patients, were published. These studies have confirmed the efficacy of SLIT for these allergens and, more importantly, have demonstrated a dose-effect relationship. In parallel to the clinical trials, postmarketing surveys,34 mechanistic investigations,35,36 prevention studies,37,38 and pharmaco-economic assessments39 were also published in the last 10 years, so that several aspects of SLIT were gradually clarified. Concerning safety, all clinical trials and postmarketing surveys have consistently agreed that SLIT is safe, and the majority of side effects are local and mild. In more than 20 years of clinical trials and everyday use, only 6 cases of anaphylaxis with SLIT have been reported, some of which were with mixtures of multiple unrelated allergens using nonstandardized extracts, but 2 patients had a severe reaction after the first dose of a grass tablet. It has also been reported that use of multiple allergens for SLIT does not increase the rate of side effects in children.40 Furthermore, it has been suggested41 that the safety profile of SLIT does not differ in children below the age of 5 years (a relative contraindication to SCIT).

SLIT is currently commercialized and used in most European and South American countries, and in Australia and Asian countries, but not in the United States. After an initial skepticism, because of the paucity of data, the US scientific community also acknowledged the efficacy and safety of SLIT.42 Nevertheless, because there is so far no Food and Drug Administration (FDA)-approved product for SLIT, this modality is not currently recommended in clinical practice in the US, where the Practice Parameter states that “…there is no US Food and Drug Administration (FDA)-approved formulation for sublingual or oral immunotherapy in the United States. Therefore sublingual and oral immunotherapy should be considered investigational at this time.”43 Clinical trials for FDA registration in the US are currently ongoing.

There are several aspects of SLIT still needing investigation and confirmation, including the optimal dose, the long-lasting effect, the preventive action and the exact mechanisms of action. This relative lack of information is not surprising if we consider that the history of SLIT is only 20 years in duration, and that the majority of studies were aimed at demonstrating the efficacy and safety of the treatment. Furthermore, despite the number of clinical trials available, the value of SLIT in pediatric patients was a matter of debate,44 until the new positive adequately powered, well-designed DBPC-RCTs in children were reported.45,46 The most important concern that still remains is to determine the optimal dose of allergen for SLIT, because the treatment has been shown effective over a very large range of doses (from 5–300 times the dose used for SCIT). However, it is clear that the effective doses of allergens for SLIT must be higher than for SCIT (in fact, we commonly speak of high-dose SLIT). On the other hand, the recently published large trials have indicated the correct direction for research; that is, dose-finding studies, standardization, and uniformization of administration schedules, and the use of no-updosing regimens, which are more simple and patient-friendly. In the meantime, new opportunities are being explored with SLIT, including the possibility of using it in conditions other than respiratory allergy, namely food allergy47 or Hymenoptera venom allergy48 and the use of adjuvants and mucoadhesive substances. Other issues concern the indication of SLIT because there is no study assessing its efficacy in patients uncontrolled despite optimal pharmacotherapy (Slide 1).

Slide 1
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41.Di Rienzo V, Minelli M, Musarra A, Sambugaro R, Pecora S, et al. Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy. 2005;35:560–564.

 

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46.Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123:167–173.

 

47.Enrique E, Pineda F, Malek T, Bartra J, Basagaña M, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005;116:1073–1079.

 

48.Severino MG, Cortellini G, Bonadonna P, Francescato E, Panzini I, et al. Sublingual immunotherapy for large local reactions (LLRs) caused by honeybee sting: a double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2008;122:44–48.

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