Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseases

Abstract

A rapidly developing paradigm for modern health care is a proactive and individualized response to patients' symptoms, combining precision diagnosis and personalized treatment. Precision medicine is becoming an overarching medical discipline that will require a better understanding of biomarkers, phenotypes, endotypes, genotypes, regiotypes, and theratypes of diseases. The 100-year-old personalized allergen-specific management of allergic diseases has particularly contributed to early awareness in precision medicine. Polyomics, big data, and systems biology have demonstrated a profound complexity and dynamic variability in allergic disease between individuals, as well as between regions. Escalating health care costs together with questionable efficacy of the current management of allergic diseases facilitated the emergence of the endotype-driven approach. We describe here a precision medicine approach that stratifies patients based on disease mechanisms to optimize management of allergic diseases.

Figure 1. Factors influencing disease endotypes and precision medicine.

(A) A multitude of factors can induce or suppress certain genes or pathways and may play a role in the development of certain phenotypes and endotypes as well as control of asthma. (B) Methodologies addressing the dynamic and complex interaction between risk factors, disease phenotype and endotypes, and expression modulators in allergic diseases in the context of precision medicine.

Figure 2. The dynamic and complex interaction between risk factors, disease phenotypes and endotypes, and expression modulators in allergic diseases in the context of precision medicine.

In type 2 asthma, four main pathways can be targeted: the IgE pathway (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), the IL-4/IL-13 pathway (dupilumab, tralokinumab, lebrikizumab), and the CRTH2 receptor (fevipiprant and timapiprant). In non–type 2 asthma, three main pathways can be targeted: the inflammasome pathway (anti–TNF-α interventions such as etanercept, infliximab, and adalimumab; anti–IL-1β interventions such as anakinra; anti–IL-6 targeting with tocilizumab or atlizumab; negative feedback with IL-37; or CD80-CD28 blockade with abatacept), the IL-17 pathway (brodalumab), or the anti–IL-33 pathway, with CXCR2 and HMGB1/RAGE blockade as additional approaches. For the mixed complex endotypes, a combination of anti–type 2 interventions with antiinflammatory macrolides or anti-CXCR2 can be indicated. As an alternative, PI3Kδ/JAK/MyD88 inhibitors might block the upstream effects of type 1, type 2, and type 17 cytokines.

Figure 3. The role of innate lymphoid cells in allergic diseases.

Type 1, 2, and 3 ILCs play different roles in different endotypes of asthma. The findings mostly come from mouse models and detection of cells in body fluids.