Biomarkers for chronic hand eczema: Could etiological and clinical subtypes truly be the starting point? An open question

Chronic hand eczema (CHE), the most common form of hand eczema, is a highly heterogeneous skin condition that is empirically categorized based on both aetiology (e.g., irritant contact dermatitis (ICD), allergic contact dermatitis (ACD) and atopic dermatitis (AD)) and clinical presentation (e.g. vesicular, fissured and hyperkeratotic HE).1 However, there is no consistent correlation between aetiology and clinical presentation, and despite allergology testing and thorough patient interrogation, more than one in five CHE patients cannot be classified based on aetiology.1 Eczema may persist chronically even after an initial diagnosis of ICD or ACD and avoidance of triggering irritants and/or allergens. Additionally, distinguishing hyperkeratotic CHE from non-pustular palmar psoriasis in some patients can be clinically challenging, with anatomopathological examination often providing limited contribution. Taken together, these factors suggest a complex interplay of immunological, environmental, and genetic factors underlying CHE pathophysiology. In their article titled 'Inflammatory plasma signature of chronic hand eczema: Associations with etiological and clinical subtypes', Quaade et al.2 utilized the cutting-edge Olink Proseek® Multiplex Assay (Olink Bioscience) to investigate 266 inflammatory plasma biomarkers in 51 CHE patients and 40 healthy controls. The authors sought to determine whether specific biomarkers could typify a unique aetiology and/or clinical presentation of CHE. A significant proportion of patients had unspecified aetiology (30%) and/or mixed clinical phenotypes (37%). Furthermore, most CHE patients with ACD and ICD had atopic comorbidities such as asthma or allergic rhinitis suggesting a type 2 immune background. They found that severe chronic ACD on the hands was associated with a mixed type 1/type 2 plasma signature as compared with controls, which positively correlated with clinical disease severity. However, no biomarkers were identified to discriminate between etiological subtypes. Interestingly, hyperkeratotic CHE exhibited a distinct type 1 exclusive signature, different from both vesicular and chronic fissured CHE, while no difference was observed between the latter two subtypes. These results suggest that profiling inflammatory plasma proteins in CHE patients may have some potential interest in the diagnosis process of CHE, helping to identify certain subtypes such as hyperkeratotic CHE. It remains to be determined whether such an approach can discriminate hyperkeratotic CHE from non-pustular palmar psoriasis. Nevertheless, this study highlights the difficulty of associating plasma proteins with specific aetiology (perhaps due to the limited size of some CHE subgroups). It may seem appealing, at first glance, to conduct biomarker analyses on unique etiological or clinical subtypes to define very specific inflammatory signatures. However, the present cohort and routine practice show that the vast majority of CHE patients display mixed etiological and clinical presentations, meaning that unique phenotypes do not represent CHE patients' diversity. In the present study, although many patients exhibited mixed clinical subtypes (37% of the entire cohort), analyses on clinical subtypes were limited to unique subtypes. Even if we could expect more sensitive markers from skin proteomic or transcriptomic exploration rather than plasma approaches, one can wonder if starting from clinically-based classifications could seriously limit the capacity to identify strong biomarkers associated with tailored therapeutic strategies in CHE patients. Of note, recent studies have shown that in-depth gene profiling of active skin lesions can aid in stratifying patients suffering of ACD, ICD or AD not affecting the hands.3, 4 These reflections highlight the importance of conducting high-throughput, unbiased, non-clinically based molecular analyses of plasma and, ideally, skin samples to gain deeper insights into multifactorial and heterogeneous conditions such as CHE. Relying solely on clinical or etiological triggering factors for CHE patient classification may limit our understanding of molecular data and impede progress toward achieving precision medicine goals. None. MT served as an investigator, speaker or advisor for AbbVie, Sanofi, Leo Pharma, Almirall, Medac, Janssen, E. Lilly. MV has no COI to declare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.