Blocking the IL-4/IL-13 Axis versus the JAK/STAT Pathway in Atopic Dermatitis: How Can We Choose?

Abstract

Atopic dermatitis (AD) is an immune-mediated skin disorder with a chronic-relapsing course and a multifactorial pathogenesis. In contrast to the traditional concept of AD as solely a type 2 immune-activated disease, new findings highlight the disease as highly heterogeneous, as it can be classified into variable phenotypes based on clinical/epidemiological or molecular parameters. For many years, the only therapeutic option for moderate-severe AD was traditional immunosuppressive drugs. Recently, the area of systemic therapy of AD has significantly flourished, and many new substances are now marketed, licensed, or in the last step of clinical development. Biological agents and small molecules have enriched the therapeutic armamentarium of moderate-to-severe AD, such as dupilumab, tralokinumab, lebrikizumab (monoclonal antibodies targeting the IL-4/13 pathway), abrocitinib, upadacitinib, and baricitinib (JAK inhibitors). Indeed, the AD treatment paradigm is now split into two main approaches: targeting the IL-4/13 axis or the JAK/STAT pathway. Both approaches are valid and have strong evidence of preclinical and clinical efficacy. Therefore, the choice between the two can often be difficult and represents a major challenge for dermatologists. Indeed, several important factors must be taken into account, such as the heterogeneity of AD and its classification in phenotypes, patients' comorbidities, age, and personal preferences. The aim of our review is to provide an overview of the clinical and molecular heterogeneities of AD and to explore the factors and parameters that, in clinical practice, may help inform clinical decision-making.

Keywords: JAK inhibitors; anti IL-4/13 monoclonal antibodies; atopic dermatitis; personalized medicine.

Figure 1

Schematic representation of the major cytokines that signal through the JAK/STAT pathways and the selectivity of JAK inhibitors approved for AD. AD, atopic dermatitis; INF, interferon; IL, interleukin; OSM, oncostatin M; LIF, leukemia inhibitory factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; C-CSF, granulocyte colony-stimulating factor; EPO, erythropoietin; TPO, thrombopoietin; GH, growth hormone. EPO: erythropoietin; G-CSF: granulocite-colony stimulating factor; GH: growth hormone; GM-CSF: granulocite macrophage-colony stimulating factor; IFN: interferon; LIF: leukemia inhibitory factor; OSM: oncostatin M; TPO: thrombopoietin.

Figure 2

Schematic representation of the special AD populations and main factors that could orient the clinician’s choice towards a monoclonal antibody targeting the IL-4/13 axis.

Figure 3

Schematic representation of the special AD populations and main factors that could orient the clinician’s choice towards a JAK inhibitor.