Biomarkers for phenotype-endotype relationship in atopic dermatitis: a critical review

Abstract

Atopic dermatitis (AD) is the most common form of chronic skin inflammation with diverse clinical variants. Historically, various AD phenotypes have been grouped together without considering their heterogeneity. This approach has resulted in a lack of phenotype- and endotype-adapted therapeutic strategies. Comprehensive insights into AD pathogenesis have enabled precise medicinal approach for AD. These efforts aimed to redefine the endophenotype of AD and develop various biomarkers for diverse purposes. Among these endeavours, efforts are underway to elucidate the mechanisms (and related biomarkers) that lead to the emergence and progression of atopic diseases originating from AD (e.g., atopic march). This review focuses on diverse AD phenotypes and calls for a definition of endophenotypes. While awaiting scientific validation, these biomarkers ensure predicting disease onset and trajectory and tailoring therapeutic strategies for the future.

Keywords: Atopic dermatitis; Atopic march; Biomarker; Endo-phenotype; Precision medicine.

Fig. 1

Potential biomarkers for AD and AM. The left panel represents the current candidates of biomarkers for AD. Genotypes of the specific genes, chemokines and cytokines which reflect the Th2 immune responses, innate immune responses, and other biomarkers could be a potential biomarkers of AD. The right panel represents the current candidates of biomarkers for AM. Skin and serum biomarkers include FABP5, IL-17A, VEGF, and IL-13. Oxidative stress-related biomarkers also could be used as biomarkers for AM. (SPINK5; Serine peptidase inhibitor Kazal type 5, TARC; Thymus and activation-regulated chemokine, MDC; Macrophage-Derived Chemokine, CTACK; Cutaneous T cell-attracting chemokine, PARC; Pulmonary and activation-regulated chemokine, DPP-4; Dipeptidyl peptidase-4, ECP; Eosinophil cationic protein, LDH; Lactate dehydrogenase, CA2; Carbonic anhydrase II, NELL2; Nel-like protein 2, EDN; Eosinophil-derived neurotoxin, SCCA2; Squamous Cell Carcinoma Antigen 2, FABP5; Fatty acid binding protein 5, VEGF; Vascular endothelial growth factor).

Fig. 2

Endo/phenotypic classification with biomarkers could enable the application of “precision medicine” concept in AD. The left panel represents the current ‘one-size-fits-all’ strategy for AD management. Clinical judgment according to disease severity with visual inspection of the skin lesions (EASI, SCORAD), consideration of comorbidities, and other complications which could limit the use of systemic immunosuppressants are primarily used in current clinical environments. After the assessment of those factors, management strategy usually follows the standardized protocol which mainly consider the disease severity only. This approach could neglect the individual characteristics of immunological pathophysiology which might differ between various disease endo/phenotypes. The right panel represents the application of “precision medicine” concept in AD. By considering multiple aspects of AD pathogenesis, including the molecular immunologic mechanisms of AD development, micro/mycobiome profiles, and genetic susceptibility, patients might be accurately differentiated. Although the validation is needed with large cohort study, several endo/phenotypic biomarkers which could differentiate the AD patients for the specific therapeutic options have been proposed. Those endo/phenotypic classifications and biomarkers could be used to enable the personalized treatment of AD. (EASI; The Eczema Area and Severity Index, SCORAD; SCORing Atopic Dermatitis).