Towards endotype-specific therapy
Phenotypes vs Endotypes
One way to classify asthma involves identifying the phenotypes of asthma – that is the clusters of properties observed in different types of asthma. Criteria related to clinical aspects (e.g. severity and frequency of exacerbations, airflow restriction, age of onset, treatment effect), type of inflammatory cells (eosinophils or neutrophils) or environmental triggers have been grouped into clusters using 2D or 3D representations (cluster analysis).
Asthma endotypes are a new approach to classify disease entities within the asthma syndrome. While phenotypes rely on observable characteristics, endotypes relate to the underlying functional or pathological mechanisms. As such, endotypes are distinct disease entities, not equivalent to phenotypes, but which may be present within clusters of phenotypes.1
Speaking at FRONTIERS of Respiratory Medicine in Maynooth, Prof Jan Lötvall, Professor of Clinical Allergy, University of Gothenburg, Sweden, explained how he and his team came up with a classification of asthma based on its endotypes. They defined five subgroups associated with different immune processes (Table 1).2 There is emerging evidence that asthma patients should be treated differently depending on their endotype. This is the case in particular for Th2-driven asthma, as highlighted by a number or clinical trials.
Table 1: Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome 2
| Asthma endotypes* | Mechanism | Treatment |
| Endotype 1 | Allergen driven | Inhaled GCS, LABA, anti-LTs, anti-IgE |
| Endotype 2 | Severe eosinophilic non-allergic | Inhaled GCS, LABA, oral GCS |
| Endotype 3 | Aspirin sensitive | Inhaled GCS, LABA, anti-LTs, intense treatment often required |
| Endotype 4 | Broncho-pulmonary mycosis | Inhaled GCS, oral GCS, anti-IgE |
| Endotype 5 (or more) | Not yet identified or rare** | Conventional treatments o
new endotype specific approaches |
GCS: Glucocorticosteroids; LABA: Long acting beta2 agonists; anti-LT: Anti-leukotrienes; anti-IgE: anti-immunoglobulin E.
* Distinct disease entities which are present in clusters of phenotypes and each having a specific biological mechanism. As with asthma phenotypes, the distinction between different endotypes is not necessarily clear cut and there are some overlaps.
** Rare endotypes include sport-associated asthma, whose mechanism is not clear and whose symptoms fade away when sport is discontinued.
Th2-driven asthma
Mechanistic studies conducted in asthma of similar severities identified two types of immunological responses or ‘immunophenotypes’: low eosinophils and high eosinophils.
Evidence indicates that these two types of asthma have similar levels of circulating T helper cells, except for one subtype, the Th2 subtype.3 While non eosinophilic asthma has a very low level of Th2-associated transcription factors, this level is very high in high eosinophils asthma – which can thus be considered as ’Th2-driven’. The authors concluded that at least one of the five endotypes described in Table 1 must be Th2-driven.
In fact, it is generally considered that Th2 driven infammation defines a major subtype of asthma. This subtype is likely to respond to agents targeting Th2 related processes – i.e. inhibitors of cytokines produced by Th2 cells (i.e. interleukins IL-4, IL-5 and IL-13) as well as CRTH2-antagonists. However recent evidence also suggests that there is a subtype of asthma with low Th2 which is not likely to respond to these therapies4 (see Table 2).
Table 2: Agents targetting Th2-driven asthma
| Agent | Mechanism | Results |
| Pitrakinra | IL-4 variant, potently inhibits binding of IL 4 and IL 13 to their receptors (Anti IL-4 and Anti IL-13) | Administered locally could substantially diminish the symptoms of asthma.5 |
| Lebrikizumab | Anti-IL-13. Periostin production is induced by IL13; it may contribute to mechanisms of airway remodelling in asthma | Improves lung function in patients with high periostin levels, while having no effect when periostin levels are low. This suggests that lebrikizumab efficacy is enhanced in Th2 driven endotype(s).6 |
| Mepolizumab | monoclonal antibody to IL-5 | Limited results in the general asthmatic population, but reduces exacerbations and improves quality of life in a subgroup of asthmatic patients with eosinophilic asthma. 7,8 |
| CRTH2 blocker | CRTH2 is a prostaglandin D2 receptor expressed by Th2 cells | Reduces asthmatic response to bronchial allergen challenge by 25%.9 Effect seen in patients with high sputum eosinophils, while those who do not have a Th2 driven disease are unlikely to respond. |
Many questions remain to be answered: How to find the right patients? Can we identify Th2 endotypes in random samples? How stable are asthma phenotypes and endotypes? But Prof Jan Lötvall’s message is very clear. If we are to advance in asthma treatment and eventually cure asthma, we need to design therapies that are endotype-specific and identify the responders. As he put it, future therapies will be endotype specific.
Key message:
- Asthma can be identified and classified by its phenotype – that is by its observable characteristics including asthma symptoms or related personality traits. More recently, asthma has been classified by its endotype – this is more closely associated to the underlying mechanisms.
- This mechanistic approach offers unexpected therapeutic opportunities for patients with specific endotypes. The identification of asthma endotypes, including Th2 driven asthma, along with the targeting of responders, has the potential to improve treatment efficacy substantially and eventually lead to a cure for asthma.
‘Asthma – Towards endotype-specific therapy?’ was presented among other respiratory topics at the 2011 Frontiers in Respiratory Medicine meeting, October 21st, 2011.
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