Efficacy vs Safety in Immunotherapy With Inhalant Allergens
Efficacy vs Safety in Immunotherapy With Inhalant Allergens
In the past 20 years, SLIT has emerged as a viable and efficacious alternative to SCIT and with an increased safety profile. SLIT has been extensively studied in Europe and in the USA, where it appears to carry a minor risk of severe systemic reactions. Actually, it is also widely used in clinical practice in many European countries and its practice is also increasing in the USA. It should be noticed that in the absence of the US FDA-approved extracts, the increase in SLIT use in the USA is off-label, unregulated and often performed by non-allergists. Moreover, in Europe too, the optimal dosage (differently from SCIT), duration and treatment schedule are not clearly established making a consensus on treatment difficult at present. However, the clinical efficacy has been evaluated in many trials performed with different SLIT extracts that can be administered in the form of drops or dissolving tablets and that can be standardized using both biologic or immunologic methods. Today, the most widely used system to classify and grade the strength of experimental evidence is that proposed by Shekelle et al. According to this system, the results of meta-analyses of randomized controlled trials (RCTs) offer robust evidence of the efficacy (or non-efficacy) of a treatment/intervention. Additional data can be obtained from meta-analyses, such as quality of the trials and heterogeneity of variables considered. Therefore in our review, we refer to the results of these studies concerning SLIT efficacy.
Several meta-analyses have been performed on SLIT, four in allergic rhinitis and three in allergic asthma ( Table 1 ). The first meta-analysis included 484 SLIT patients and 475 controls (adults and children) from 22 studies published up to September 2002. A significant reduction of symptom and medication score was only demonstrated in adults; in addition, the authors did not identify a greater improvement according to the treatment duration. The same group published recently an updated systematic review. The studies suitable for the inclusion were 49. A significant reduction of symptom and medication score compared with placebo was confirmed but in this paper a trend of greater symptom reduction in studies lasting more than 12 months was observed. Furthermore, better results were also recorded in studies treating house dust mite allergy compared with those treating grass pollen allergy. A meta-analysis only addressed the allergic conjunctivitis. Forty-two trials including 3958 participants were considered as suitable. SLIT induced a significant reduction of total ocular symptom score, but did not affect eye drops use. Subjects actively treated showed an increase in specific threshold dose. Lately, an Italian meta-analysis has evaluated only the allergic rhinitis due to grass pollens. SLIT significantly reduced symptom and medication score in comparison with placebo and was more effective in adults than in children. A pre-seasonal schedule lasting more than 12 weeks improved the clinical efficacy. According to these results, a recent systematic review, including adult and children, supports that SLIT improves asthma symptoms, as 8 of 13 studies reported more than 40% improvement with respect to comparator. The clinical result was less impressive in allergic rhinitis as 9 of 34 studies showed a more than 40% improvement.
The efficacy of SLIT in asthma has been evaluated by three meta-analyses. The first included 25 studies on 1706 adults and children. Eight studies were for mites, 14 studies for pollens, 1 study for latex and 2 for mixed allergens. A significant improvement in symptoms was reported in eight studies as well as an increase of FEV1 in four trials. A more focused meta-analysis of nine studies in 452 adults and children treated with house dust mite SLIT for their allergic asthma proved a significant improvement in symptom and medication scores. However, some drawbacks of meta-analyses and systematic review have to be considered. In fact, they are statistical procedures that incorporate the results of different independent studies pooled together in order to provide a quantitative estimate of treatment effects. Included studies have different indications, age groups and allergen preparations. Furthermore, schedule and duration of treatment are diverse and a high heterogeneity can weaken the final data. Therefore, the results of meta-analyses can give a general indication about a treatment but cannot give any indication about the single treatment. Very recently, Bachert et al. addressed this problem suggesting to specify the SIT product in any study including it in the title and to avoid unjustified general statements on application routes or patients group. More practically, the clinical benefit of immunotherapy has to be referred to a single brand and not generically to SLIT as a high number of different extracts are now available on the market with different clinical effect and safety profile. An overcoming of the heterogeneity of the meta-analyses and more practical indications come from the so-called big trials of immunotherapy (comprising more than 100 individuals per treatment arm) ( Table 2 ). In the first trial after a preliminary dose finding study, which identified as the best option the treatment with rapidly dissolving tablet (Grazax® ALK Abello, Denmark) containing 15 μg of Phl P5 (75.000 SQ-T), a second randomized study was performed using the optimized daily dose according to a pre-coseasonal schedule (4 months prior and during the grass pollen season). A significant reduction of symptom and medication scores was proved, observed for any individual nasal symptom, including nasal obstruction and eye symptoms, compared with placebo. A second study, using sublingual tablets (Oralair Grasses® Stallergenes, France) with five grass mix (orchard, meadow, ryegrass, seet vernal and timothy species) identified the 300-IR (25 μg of group five major grass allergens) as the optimal dosage for treatment. After a 4-month schedule, an efficacy comparable with the previous study was observed. A more prolonged trial (18 months) with sublingual drops at high dose (40 μg) of six grasses (Allergovit®, Allergopharma, Germany) confirmed the results of the previous studies. It should be noticed that the different timing of the assessment of clinical results makes the studies discussed above not fully comparable. Grazax was also evaluated in the USA with clinical efficacy comparable with the European study. However, all these studies were performed on allergic rhinitis due only to grass pollen. More recently, a multicenter study performed in the USA and in Europe including 784 adults evaluated the clinical efficacy of ragweed immunotherapy, using fast dissolving tablets (12 units of Ambrosia artemisiifolia). After 52 weeks with the active treatment, a 27% reduction of symptom score and 36% of medications score was detected. A marked placebo response was observed in these studies, shared with most of immunotherapy trials. The 'clinical trial effect' secondary to more intensive medical care in a therapeutic environment may account, at least in part, for this phenomenon. Nevertheless, there is a remarkable consistency in results among these trials. It is to note that effect sizes reported for SLIT compare favorably with those reported in a recent Cochrane review and meta-analysis of anti-allergic drugs that includes anti-leukotrienes, antihistamines and intranasal steroids.
In addition to a significant early clinical effect, a sustained effect of SLIT after its discontinuation was demonstrated for all these grass studies, lasting currently up to 2 years. Besides the double-blind placebo-controlled trials mentioned above, some open studies have been performed. A long-lasting effect after SLIT discontinuation is confirmed, even if the different methodology doesn't allow a direct comparison. A prospective open controlled study including patients with different sensitizations with a 15 years follow-up period found that the effects of a 4-year course of immunotherapy persisted more than 5 years. Another 6-year randomized open trial by Tahamiler et al. showed that the improvements in allergy symptoms achieved with SLIT were maintained for 3 years after treatment discontinuation.
As SCIT, some open studies document that SLIT can modify the natural history of allergic diseases and limit the progression from allergic rhinitis to asthma, when used in pediatric age. A study used grass pollen SLIT according to a coseasonal schedule for 3 years and observed that the risk of asthma development was 3.8 times greater in control than in treated group. Another study performed on 216 children with allergic rhinitis with or without intermittent asthma were randomized to pharmaceutical treatment only or plus SLIT for 3 years. At the end of the study, the incidence of mild asthma was significantly lower in the SLIT-treated arm (odds ratio [OR]: 0.04; 95% CI: 0.01–0.17) along with a decrease of methacholine reactivity. Concerning the possibility that SLIT can prevent the onset of further sensitizations, controversial data are reported in literature.
Despite the favorable results, some unmet needs have to be addressed. The meta-analyses showing clinical efficacy of SLIT are mainly based on the results of RCT performed on grass and mite-allergic patients (68%), whereas only few controlled studies evaluated other relevant sensitizations, such as birch, ragweed, cat and Alternaria. Other two problems come currently out in the daily routine such as the patient with multiple sensitizations as well as the elderly allergic patient. Two recent post hoc analysis performed in two large studies conducted with grass allergen tablets showed that the clinical improvement is not different between mono- and polysensitized patients in large studies. The potential role of SLIT in elderly population has also been recently assessed. A similar trend of efficacy and safety between young (18–28 years) and older (55–65 years) patients was proved by an open Italian study as well as a significant improvement has been observed in a double-blind controlled trial performed in elderly patients with mite-allergic rhinitis. Additionally, the clinical improvement of SLIT seems to be less impressive in asthma. In fact, many studies were not formally sized and adequately powered for asthma. Several studies of SLIT for grass and mites have failed to show functional improvement or exacerbations reduction. However, it has to be considered that in some of these studies most of patients had minimal symptoms at baseline and throughout the study, likely precluding a detection of a beneficial effect of immunotherapy.
At last, it is worth pointing out that currently clinical efficacy of immunotherapy in patients with allergic asthma and/or rhinitis is mostly evaluated by means of symptoms and medication scores. These tools are not always validated and they are highly affected by variability. Moreover, clinical manifestations represent one of the faces of allergic respiratory diseases. Reliable predictive surrogate markers or biomarkers that may correlate with real clinical end points are necessary both for choosing a tailored immunotherapy treatment and for follow-up. At present, in vivo (early and late skin reaction) and in vitro (IgE levels, IgG subclasses, mucosal IgA, lymphocyte subsets, cytokines and systemic inflammatory markers) have been proposed as potential surrogate markers. However, an ideal surrogate marker is still not available, given the poor reproducibility, the high costs and the lack of extensive availability of most of these parameters in daily clinical practice.
Efficacy
In the past 20 years, SLIT has emerged as a viable and efficacious alternative to SCIT and with an increased safety profile. SLIT has been extensively studied in Europe and in the USA, where it appears to carry a minor risk of severe systemic reactions. Actually, it is also widely used in clinical practice in many European countries and its practice is also increasing in the USA. It should be noticed that in the absence of the US FDA-approved extracts, the increase in SLIT use in the USA is off-label, unregulated and often performed by non-allergists. Moreover, in Europe too, the optimal dosage (differently from SCIT), duration and treatment schedule are not clearly established making a consensus on treatment difficult at present. However, the clinical efficacy has been evaluated in many trials performed with different SLIT extracts that can be administered in the form of drops or dissolving tablets and that can be standardized using both biologic or immunologic methods. Today, the most widely used system to classify and grade the strength of experimental evidence is that proposed by Shekelle et al. According to this system, the results of meta-analyses of randomized controlled trials (RCTs) offer robust evidence of the efficacy (or non-efficacy) of a treatment/intervention. Additional data can be obtained from meta-analyses, such as quality of the trials and heterogeneity of variables considered. Therefore in our review, we refer to the results of these studies concerning SLIT efficacy.
Several meta-analyses have been performed on SLIT, four in allergic rhinitis and three in allergic asthma ( Table 1 ). The first meta-analysis included 484 SLIT patients and 475 controls (adults and children) from 22 studies published up to September 2002. A significant reduction of symptom and medication score was only demonstrated in adults; in addition, the authors did not identify a greater improvement according to the treatment duration. The same group published recently an updated systematic review. The studies suitable for the inclusion were 49. A significant reduction of symptom and medication score compared with placebo was confirmed but in this paper a trend of greater symptom reduction in studies lasting more than 12 months was observed. Furthermore, better results were also recorded in studies treating house dust mite allergy compared with those treating grass pollen allergy. A meta-analysis only addressed the allergic conjunctivitis. Forty-two trials including 3958 participants were considered as suitable. SLIT induced a significant reduction of total ocular symptom score, but did not affect eye drops use. Subjects actively treated showed an increase in specific threshold dose. Lately, an Italian meta-analysis has evaluated only the allergic rhinitis due to grass pollens. SLIT significantly reduced symptom and medication score in comparison with placebo and was more effective in adults than in children. A pre-seasonal schedule lasting more than 12 weeks improved the clinical efficacy. According to these results, a recent systematic review, including adult and children, supports that SLIT improves asthma symptoms, as 8 of 13 studies reported more than 40% improvement with respect to comparator. The clinical result was less impressive in allergic rhinitis as 9 of 34 studies showed a more than 40% improvement.
The efficacy of SLIT in asthma has been evaluated by three meta-analyses. The first included 25 studies on 1706 adults and children. Eight studies were for mites, 14 studies for pollens, 1 study for latex and 2 for mixed allergens. A significant improvement in symptoms was reported in eight studies as well as an increase of FEV1 in four trials. A more focused meta-analysis of nine studies in 452 adults and children treated with house dust mite SLIT for their allergic asthma proved a significant improvement in symptom and medication scores. However, some drawbacks of meta-analyses and systematic review have to be considered. In fact, they are statistical procedures that incorporate the results of different independent studies pooled together in order to provide a quantitative estimate of treatment effects. Included studies have different indications, age groups and allergen preparations. Furthermore, schedule and duration of treatment are diverse and a high heterogeneity can weaken the final data. Therefore, the results of meta-analyses can give a general indication about a treatment but cannot give any indication about the single treatment. Very recently, Bachert et al. addressed this problem suggesting to specify the SIT product in any study including it in the title and to avoid unjustified general statements on application routes or patients group. More practically, the clinical benefit of immunotherapy has to be referred to a single brand and not generically to SLIT as a high number of different extracts are now available on the market with different clinical effect and safety profile. An overcoming of the heterogeneity of the meta-analyses and more practical indications come from the so-called big trials of immunotherapy (comprising more than 100 individuals per treatment arm) ( Table 2 ). In the first trial after a preliminary dose finding study, which identified as the best option the treatment with rapidly dissolving tablet (Grazax® ALK Abello, Denmark) containing 15 μg of Phl P5 (75.000 SQ-T), a second randomized study was performed using the optimized daily dose according to a pre-coseasonal schedule (4 months prior and during the grass pollen season). A significant reduction of symptom and medication scores was proved, observed for any individual nasal symptom, including nasal obstruction and eye symptoms, compared with placebo. A second study, using sublingual tablets (Oralair Grasses® Stallergenes, France) with five grass mix (orchard, meadow, ryegrass, seet vernal and timothy species) identified the 300-IR (25 μg of group five major grass allergens) as the optimal dosage for treatment. After a 4-month schedule, an efficacy comparable with the previous study was observed. A more prolonged trial (18 months) with sublingual drops at high dose (40 μg) of six grasses (Allergovit®, Allergopharma, Germany) confirmed the results of the previous studies. It should be noticed that the different timing of the assessment of clinical results makes the studies discussed above not fully comparable. Grazax was also evaluated in the USA with clinical efficacy comparable with the European study. However, all these studies were performed on allergic rhinitis due only to grass pollen. More recently, a multicenter study performed in the USA and in Europe including 784 adults evaluated the clinical efficacy of ragweed immunotherapy, using fast dissolving tablets (12 units of Ambrosia artemisiifolia). After 52 weeks with the active treatment, a 27% reduction of symptom score and 36% of medications score was detected. A marked placebo response was observed in these studies, shared with most of immunotherapy trials. The 'clinical trial effect' secondary to more intensive medical care in a therapeutic environment may account, at least in part, for this phenomenon. Nevertheless, there is a remarkable consistency in results among these trials. It is to note that effect sizes reported for SLIT compare favorably with those reported in a recent Cochrane review and meta-analysis of anti-allergic drugs that includes anti-leukotrienes, antihistamines and intranasal steroids.
In addition to a significant early clinical effect, a sustained effect of SLIT after its discontinuation was demonstrated for all these grass studies, lasting currently up to 2 years. Besides the double-blind placebo-controlled trials mentioned above, some open studies have been performed. A long-lasting effect after SLIT discontinuation is confirmed, even if the different methodology doesn't allow a direct comparison. A prospective open controlled study including patients with different sensitizations with a 15 years follow-up period found that the effects of a 4-year course of immunotherapy persisted more than 5 years. Another 6-year randomized open trial by Tahamiler et al. showed that the improvements in allergy symptoms achieved with SLIT were maintained for 3 years after treatment discontinuation.
As SCIT, some open studies document that SLIT can modify the natural history of allergic diseases and limit the progression from allergic rhinitis to asthma, when used in pediatric age. A study used grass pollen SLIT according to a coseasonal schedule for 3 years and observed that the risk of asthma development was 3.8 times greater in control than in treated group. Another study performed on 216 children with allergic rhinitis with or without intermittent asthma were randomized to pharmaceutical treatment only or plus SLIT for 3 years. At the end of the study, the incidence of mild asthma was significantly lower in the SLIT-treated arm (odds ratio [OR]: 0.04; 95% CI: 0.01–0.17) along with a decrease of methacholine reactivity. Concerning the possibility that SLIT can prevent the onset of further sensitizations, controversial data are reported in literature.
Despite the favorable results, some unmet needs have to be addressed. The meta-analyses showing clinical efficacy of SLIT are mainly based on the results of RCT performed on grass and mite-allergic patients (68%), whereas only few controlled studies evaluated other relevant sensitizations, such as birch, ragweed, cat and Alternaria. Other two problems come currently out in the daily routine such as the patient with multiple sensitizations as well as the elderly allergic patient. Two recent post hoc analysis performed in two large studies conducted with grass allergen tablets showed that the clinical improvement is not different between mono- and polysensitized patients in large studies. The potential role of SLIT in elderly population has also been recently assessed. A similar trend of efficacy and safety between young (18–28 years) and older (55–65 years) patients was proved by an open Italian study as well as a significant improvement has been observed in a double-blind controlled trial performed in elderly patients with mite-allergic rhinitis. Additionally, the clinical improvement of SLIT seems to be less impressive in asthma. In fact, many studies were not formally sized and adequately powered for asthma. Several studies of SLIT for grass and mites have failed to show functional improvement or exacerbations reduction. However, it has to be considered that in some of these studies most of patients had minimal symptoms at baseline and throughout the study, likely precluding a detection of a beneficial effect of immunotherapy.
At last, it is worth pointing out that currently clinical efficacy of immunotherapy in patients with allergic asthma and/or rhinitis is mostly evaluated by means of symptoms and medication scores. These tools are not always validated and they are highly affected by variability. Moreover, clinical manifestations represent one of the faces of allergic respiratory diseases. Reliable predictive surrogate markers or biomarkers that may correlate with real clinical end points are necessary both for choosing a tailored immunotherapy treatment and for follow-up. At present, in vivo (early and late skin reaction) and in vitro (IgE levels, IgG subclasses, mucosal IgA, lymphocyte subsets, cytokines and systemic inflammatory markers) have been proposed as potential surrogate markers. However, an ideal surrogate marker is still not available, given the poor reproducibility, the high costs and the lack of extensive availability of most of these parameters in daily clinical practice.
Source...