Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

Different immunological effector cells are responsible for allergic inflammation [23‐25]. The allergic disease is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, IL-5 and IL-13 among others. These cells and their cytokines are responsible for the effects on other cells involved in the allergic response. The most important effector cells in the allergic immunological response are eosinophils, mast cells and basophils. Th2 cells play an essential role in the promotion of allergen-specific IgE synthesis by B cells.

The benefits and the clinical effects of SIT should be evaluated and analysed in terms of the immunological changes that follow the treatment. SIT acts by influencing basic immunological mechanisms [26] resulting in the suppression of the seasonal increase in eosinophilia [27], in reduction of the late-phase reactivity [28, 29] and a shift from a Th2- to Th1-like response is initiated and maintained [30‐33]. T regulatory cells play a central role in the mechanism of effective SIT with an important effect on the down regulation of the Th2 response [34]. One mechanism by which immunotherapy suppresses the allergic response is through an increase in the production of specific IgG antibodies, primarily of the IgG4 subtype. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells) [35]. Because the production of IgE against normally harmless antigens is the cause of the allergic responses, the production of antigen specific IgG antibodies, can antagonise and block the allergic inflammatory cascade resulting from antigen recognition by IgE. Therefore, the shift in balance between IgE and IgG4 is essential to successful allergen SIT. It has been demonstrated that allergen-specific IgG4 antibodies with potent inhibitory activity against IgE persist after treatment discontinuation and could account for long-term clinical tolerance [36]. Induction of specific IgG4 has the capacity to influence the allergic response in different ways (Figure 1), and is related to immunological effector mechanisms, also responsible for the reduced late-phase hyperreactivity and ongoing allergic inflammation. Details are described in Textbox 1.

Studies have shown that symptomatic improvement correlates with reductions in eosinophils and IL-5 expression in the nasal mucosa [32] during the pollen season, as well as with increased interferon-gamma (INF) production [37]. Immunotherapy induces an IL-12-response shown to be inversely related to IL-4 production and to promote a Th1-response estimated as interferon-gamma production which promotes B-cells into IgG production [31]. Several studies have shown that immunotherapy induces a new regulatory T-cell response characterised by induction of IL-10 [38, 39] which precedes the inhibitory IgG4 antibody activity [40]. TGF-β is also a T-regulatory cell mediator induced by immunotherapy [41] which is responsible for the down regulation of the Th2 response - reducing IL-5 production [33] and preventing allergen-exposure-induced eosinophilia and inflammation [32]. The importance of T regulatory cells in allergy and in relation to immunotherapy has been carefully reviewed [34, 42, 43]. The left side of Figure 1 summarises basic immunological changes during immunotherapy. The immunological mechanisms described here illustrate the close connection between the basic immunological response to immunotherapy and the humoral response, characterised by the induction of competitive specific antibodies accompanying and potentially leading to clinical benefits.

Different IgG4 related immunological effects acting as a competitive response to that of specific IgE, result in clinical effects as reduction in symptoms and the need for medication, and a reduced inflammatory response to allergen presentation (Figure 1).

The first priority for respiratory allergic patients is usually the treatment of allergic symptoms as these appear as a consequence of allergen exposure. Different symptomatic drugs have the capacity to reduce the symptoms either on a rescue basis or when taken daily [4, 22]. From a regulatory point of view the primary focus on the benefit from anti-allergic treatments is usually on the potential reduction in symptoms. Together with the potential range of benefits following SIT, reduction in symptoms is mandatory. Recently, an overview of how effective SIT is in reducing symptoms including a comparison to the effectiveness of symptomatic treatment options was published [50]. The data support that already during the first seasonal exposure after initiation of SCIT a reduction in symptoms at least as potent as the reduction following treatment with symptomatic drugs can be achieved.

Together with the significant reduction in allergic symptoms, several studies on SIT have documented a significant reduction in the need for symptomatic drugs on short term as well as during long-term treatment [51‐54] even in patients with severe allergic rhinoconjunctivitis, who fail to respond adequately to symptomatic treatment [55]. The reduction in symptomatic medication achieved early after initiation of treatment with SIT has been shown for pollens [52] as well as perennial allergens [56]. Also, the long-term benefit even after termination of SIT has been shown [57, 58]. The most comprehensive overview of the outcome on reduction of the need for symptomatic medication is provided by the recent Cochrane reviews covering SIT studies with subcutaneous and sublingual application of SIT for rhinoconjunctivitis as well as asthma [59‐61]. If patients were sensitised to other allergens, this did not influence the response to the treatment for their grass allergy [55], suggesting that SIT can be efficiently used even in polysensitised patients. Both adults and children with house dust mite-induced allergic asthma, benefit from SIT which results in a steroid-sparing effect by following guideline-defined asthma control [62, 63]. This is of particular importance as allergic asthma is frequently associated with rhinitis [64] with the consequent need of simultaneous nasal steroid therapy as well as some concern arising from possible adverse effects of long-term treatment with inhaled steroids in children [65].

The World Allergy Organization has proposed a model for the standardisation of clinical trials of allergen specific immunotherapy for respiratory allergic symptoms [21]. They suggest defining the primary outcome of immunotherapy trials as the total clinical score, calculated as the sum of symptom score plus drugs usage calculated as one score. The European Medicines Agency (EMA guideline "Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases") has also described the issues that the use of rescue medication has a direct impact on symptom severity [18]. An estimate of the power as well as the number of subjects to be included is mandatory to the outcome of clinical studies and the primary endpoint of a clinical study should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial. It is also mandatory in confirmative clinical trials to define the endpoint up front. It may sometimes be desirable to use more than one primary variable, each of which could be sufficient to cover the range of effects of the therapies. For clinical trials on allergen specific immunotherapy this could be the use of symptom score as well as medication score reduction [66]. The extent of inter correlation among the proposed primary variables may be considered.

Different methods for combining symptom score and intake of rescue medication have been described [66, 67] but there is no guideline for how this combined score should be established, and from case to case the method used must be pre-specified and justified. In order to further develop the methods for one and only one final endpoint for trials on SIT, new methods to establish a clinical relevant score evaluating the potential reduction in allergic symptoms in combination with the potential reduced need for symptomatic medication have been assessed [51, 68, 69]. Recently, the first validation of a combined symptom/medication score strategy was published as the "Allergy-Control-SCORE™". Based on a comparison of the symptoms and need for medication during the pollen season between allergic subjects and healthy controls, they proved a reliable instrument in distinguishing between allergic patients and controls, which is also able to access the severity of disease [70]. After the final endpoint has been defined and the results obtained, it is possible to look for secondary parameters and explorative outcomes which are extremely useful for the establishment of new hypotheses and future research [66, 71].

In this paper the effects of immunotherapy are categorised into the following levels of benefit whose immunological characteristics are explained above.

These correspond to the different levels of clinical effects which can be claimed for the registration of products for SIT as defined by the EMA [18] (Textbox 2). Evidence for the different claims is summarised below.

Depending on the clinical documentation available and study duration different claims for efficacy are possible:

It is evident that very early on and during the first seasonal exposure after initiation of immunotherapy -or alternatively when patients have reached the top or maintenance dosage [30, 55, 72, 73], they experience an improvement in allergy symptoms (rhinoconjunctivitis and/or asthmatic symptoms) and a need for rescue medication. The early effect of SIT on rhinoconjunctivitis symptom scores has been confirmed in the so-called "big trials" which recruited hundreds of grass pollen allergic patients [55, 74, 75]. In sublingual tablet studies the positive effects of at least 16 weeks of treatment have been documented [74, 75] and a single study using an adjuvant (MPL) in combination with a grass allergen extract also indicate efficacy after only 4 weeks with 4 injections [76, 77].

Pre-seasonal short-term therapy normally including six weeks of treatment has been shown to be clinically effective as early as in the first season [51, 78‐80]. A six-month treatment period with recombinant grass pollen major allergens has also proved effective [81]. A combined symptom/medication score strategy has recently been used and confirmed the clinical efficacy for short term injection therapy [51, 68], as well as for sublingual tablet treatment [66].

During a long-term treatment period of up to four years, persistent effects and further increased clinical and immunological benefits are achieved. This has been shown for grass, cat and dog, and house dust mites [28, 82, 83]. In a study using two consecutive pre-seasonal short-courses of a grass pollen allergoid, using a combined symptom medication score it was clear that although the treatment was clinically effective in the first season, its clinical efficacy was even better in the second seasonal [51]. An open continuation of this study including a third pre-seasonal treatment period confirmed the increased efficacy potential which prolonged immunotherapy treatment provides [54]. When continuing the treatment for more than 12 months it is possible to introduce non-specific efficacy parameters, seen as a decrease in the patient's non-specific bronchial hyper responsiveness as an indicator of inflammation. This was shown in patients suffering from house dust mite related allergic asthma, who increased their tolerance to bronchial challenge with house dust mite allergen after six months, but it was only after 18 months of SIT that a persistent reduced bronchial inflammation and hyperresponsiveness measured by bronchial challenge with metacholine was found [84]. It has also been observed that two years of immunotherapy prevented the seasonal onset of bronchial hyperresponsiveness in grass pollen allergic patients with rhinitis and asthma [29]. According to a meta-analysis on asthma, SCIT significantly reduced allergen specific bronchial hyperresponsiveness, which was evaluated in the majority of the studies done after one year of treatment [61]. The finding that SIT is able to improve specific bronchial hyperreactivity is important from a clinical point of view. Indeed, patients with brittle allergic asthma are at risk of sudden deterioration when exposed to increased levels of an aeroallergen to which they are sensitive, as in the case of mould allergic patients. Currently, the measurement of BHR is the only accurate method of assessing such a risk and any intervention which reduces the risk of an acute episode of asthma under these circumstances would be clinically useful. Moreover, a high percentage of children and adults also develop a late asthmatic response after an allergen specific bronchial challenge [85], the presence of which is considered an experimental model close to resembling chronic bronchial allergic inflammation. Subcutaneous SIT is able to decrease not only early, but also late asthmatic responses following allergen specific bronchial challenge, thus confirming the anti-inflammatory effect of the treatment in the lung [53].

A Th2/Th1 response towards normal balance is usually associated with a positive clinical effect of immunotherapy. In grass pollen allergic patients undergoing injection immunotherapy it has been shown that a significant change towards a Th1 response measured by the level of interferon-gamma in peripheral blood was achieved after a 12-month treatment period, but not after just three months treatment -despite a well-documented symptomatic effect being found after three months [30]. Administering a short four-week therapy with a grass allergen extract together with an MPL adjuvant showed that specific IgG and IgG4 levels increased only slightly in year one of SIT, but which became highly significant in year two [86]. A progressive immunological change as indicated by the significant induction of non-IgE competitive antibodies was also observed in year two of treatment with a sublingual tablet for grass pollen allergy whose clinical efficacy comparable to the benefits of year one [87]. In a three-year long-term SIT study in grass allergic patients with both rhinoconjunctivitis and asthma the asthma symptoms had completely cleared after 3 years with a general progression in clinical effect over the years. Symptoms and the need for medication was generally reduced from the beginning although nasal symptoms were not reduced during the first season - again indicating that continuing the treatment will increase the benefits [88].

Recently, wider studies have confirmed the long-term clinical potential of SIT after termination of treatment. In the Preventive Allergy Treatment Study (PAT) children treated for 3 years with pollen immunotherapy (grass and/or birch) showed a consistent reduction in their symptom score rated by Visual Analogue Score (VAS) and by objective measures of conjunctival sensitivity (CPT). The children were tested respectively two and seven years after discontinuation of treatment [89, 90]. The sustained long-term and disease-modifying effects of immunotherapy have also been confirmed in a large-scale randomised, double-blind, placebo-controlled sublingual trial with a two-year follow-up after three consecutive years of treatment with a sublingual grass allergen tablet [58, 91]. The key study which confirms the long-term persistent clinical and also immunological effect measured on late-phase skin response to an allergen, is the double blind randomised study where patients treated for grass pollen allergy with SCIT over a three-to-four year span were followed up to three years after cessation of therapy and compared to a SCIT naive matched group of patients [57]. Other studies have shown up to eight years persistent long-term clinical effects after termination of two to three years of SIT for grass pollen, tree pollen, animal hair and dander and house dust mites [92‐96]. In cat allergic patients with mild to moderate asthma not only was the reactivity to cat allergen reduced following immunotherapy, but also a reduction in specific as well as non-specific hyperresponsiveness occurred during the five-year follow up period [94]. In a small open controlled three year consecutive pre-seasonal treatment study with an allergoid persistent clinical efficacy in children for as long as up to 12 years after discontinuation of the treatment was shown [97, 98].