Surrogate Markers of Efficacy of Allergen Immunotherapy
Purpose of review The assessment of clinical efficacy of immunotherapy in patients with respiratory allergy is highly affected by variability and lack of validated outcome measures such as symptom and medication scores. At the same time, there is a need to identify reliable predictive surrogate markers or biomarkers that may correlate with real clinical endpoints and lead to individually tailored immunotherapy treatment.
Recent findings In-vivo markers, such as early and late skin reaction as well as immunological parameters such as IgE levels, IgG subclasses, mucosal IgA, lymphocyte subsets, cytokines and local and systemic inflammatory markers, have been proposed as potential surrogate markers.
Summary Given the poor reproducibility and surrogacy to clinical outcomes shown in various clinical trials, the decreased availability in daily practice and anticipated high costs, an ideal surrogate marker is still not available to allergists.
Allergen-specific immunotherapy (SIT) is a well established treatment option for patients with allergic rhinitis with or without associated asthma. Compared with pharmacological therapies, which provide only temporary relief of symptoms, SIT is the only currently available treatment that can modify the allergic disease process. Its clinical efficacy has been shown in many clinical trials and further confirmed in several meta-analyses.
The majority of randomized clinical trials, in order to provide evidence of clinical efficacy of SIT, investigate the effect on symptoms and on the use of rescue medications as 'primary outcome' parameters. However, standardized symptom/medication scores are not currently available and different scoring systems are used in different studies.
There is a need for surrogate markers that can objectively measure the response to immunotherapy for use in everyday clinical practice as well as in clinical trials. The National Institutes of Health defines a surrogate endpoint/marker as 'a biomarker intended to substitute for a clinical endpoint'. It is a measure of effect of a treatment that may correlate with a real clinical endpoint but does not have a guaranteed relationship.
It is anticipated that identification of potential surrogate markers will assist in distinguishing responders from nonresponders early on so that immunotherapy can be targeted to those more likely to benefit. Furthermore, surrogate markers may be useful in not only monitoring response and adjusting treatment accordingly but also deciding when to discontinue treatment or predict relapse after discontinuation. The increased knowledge of the underlying mechanisms of initially subcutaneous immunotherapy and more recently sublingual immunotherapy has given rise to novel potential in-vivo and in-vitro markers (given below).
Potential surrogate markers in allergen-specific immunotherapy (adapted from the study by Canonica et al.):
1. In vivo
2. In vitro
Abstract and Introduction
Abstract
Purpose of review The assessment of clinical efficacy of immunotherapy in patients with respiratory allergy is highly affected by variability and lack of validated outcome measures such as symptom and medication scores. At the same time, there is a need to identify reliable predictive surrogate markers or biomarkers that may correlate with real clinical endpoints and lead to individually tailored immunotherapy treatment.
Recent findings In-vivo markers, such as early and late skin reaction as well as immunological parameters such as IgE levels, IgG subclasses, mucosal IgA, lymphocyte subsets, cytokines and local and systemic inflammatory markers, have been proposed as potential surrogate markers.
Summary Given the poor reproducibility and surrogacy to clinical outcomes shown in various clinical trials, the decreased availability in daily practice and anticipated high costs, an ideal surrogate marker is still not available to allergists.
Introduction
Allergen-specific immunotherapy (SIT) is a well established treatment option for patients with allergic rhinitis with or without associated asthma. Compared with pharmacological therapies, which provide only temporary relief of symptoms, SIT is the only currently available treatment that can modify the allergic disease process. Its clinical efficacy has been shown in many clinical trials and further confirmed in several meta-analyses.
The majority of randomized clinical trials, in order to provide evidence of clinical efficacy of SIT, investigate the effect on symptoms and on the use of rescue medications as 'primary outcome' parameters. However, standardized symptom/medication scores are not currently available and different scoring systems are used in different studies.
There is a need for surrogate markers that can objectively measure the response to immunotherapy for use in everyday clinical practice as well as in clinical trials. The National Institutes of Health defines a surrogate endpoint/marker as 'a biomarker intended to substitute for a clinical endpoint'. It is a measure of effect of a treatment that may correlate with a real clinical endpoint but does not have a guaranteed relationship.
It is anticipated that identification of potential surrogate markers will assist in distinguishing responders from nonresponders early on so that immunotherapy can be targeted to those more likely to benefit. Furthermore, surrogate markers may be useful in not only monitoring response and adjusting treatment accordingly but also deciding when to discontinue treatment or predict relapse after discontinuation. The increased knowledge of the underlying mechanisms of initially subcutaneous immunotherapy and more recently sublingual immunotherapy has given rise to novel potential in-vivo and in-vitro markers (given below).
Potential surrogate markers in allergen-specific immunotherapy (adapted from the study by Canonica et al.):
1. In vivo
skin prick test reactivity, late cutaneous response.
2. In vitro
immunological parameters,
total and allergen-specific ige, igg subclasses, mucosal iga, lymphocyte subsets, cytokines,
local and systemic inflammatory markers,
adhesion molecules, urinary leukotrienes, serum eosinophil cationic protein (ECP), FeNO and
evaluation of quality of life (QoL).