Psoriasis (PsO) and atopic dermatitis (AD) are the most prominent immune-mediated inflammatory skin diseases, traditionally viewed as polar opposites in their underlying pathology. While PsO is primarily driven by Th17 dysregulation, AD is characterized by a Th2 imbalance. With the advent of targeted biologic therapies, such as those inhibiting the IL-17/23 axis for PsO or the IL-4/13 axis for AD, patients have experienced remarkable clinical improvements. However, these treatments occasionally trigger a paradoxical reaction, where suppressing one immune pathway causes a phenotypic shift toward the opposite disease. This “immune drift” occurs because of a dynamic balance and mutual inhibition between Th1/Th17 and Th2 axes; when one side is strongly suppressed, the other may become dominant. JAK inhibitors have recently emerged as a potential solution for these reactions because they act as intermediate modulators, simultaneously blocking multiple downstream signals (JAK1, JAK2, JAK3, TYK2) to rebalance the immune system.
Methods
This review systematically summarizes the underlying immunological mechanisms of both PsO and AD while compiling all currently reported cases of paradoxical reactions induced by biological therapies. The authors integrated findings from advanced sequencing technologies, such as single-cell RNA sequencing and transcriptomics, to delineate local inflammatory signatures. By analyzing these cases alongside epidemiological and genomic data, the study explores the complexity of pathogenesis and identifies potential therapeutic targets for managing immune imbalances.
Key Findings
• Contrasting Pathways: PsO is centered on the IL-23/Th17 axis, leading to excessive keratinocyte proliferation, while AD is driven by Type 2 immunity (IL-4, IL-13, IL-31), which disrupts the skin barrier and causes intense pruritus.
• Mutual Antagonism: A bidirectional inhibitory network exists where IFN-γ (Th1) suppresses Th2 differentiation at the transcriptional level, and IL-4/IL-13 (Th2) can inhibit Th17 cell function through the STAT6 pathway.
• Paradoxical Reactions: Clinical data show that drugs like dupilumab (targeting Th2) can induce psoriasis-like eruptions, while IL-17 inhibitors used for PsO can trigger AD-like dermatitis.
• Genetic Insights: GWAS and Mendelian randomization indicate a negative genetic correlation between the two diseases, suggesting that an individual’s innate genetic background often predisposes them to one pattern while protecting against the other.
• The Role of JAK Inhibitors: Unlike single-pathway biologics, JAK inhibitors serve as versatile modulators that can simultaneously act on Th1, Th2, and Th17 pathways, offering an effective approach to resolve paradoxical reactions.
• Molecular Signatures: Single-cell sequencing reveals that paradoxical eczema is not a simple shift to Th2 polarization but involves a global upregulation of TNF and IFN-γ.
The novelty of this research lies in its status as the first comprehensive compilation of all reported paradoxical reaction cases combined with an integration of cutting-edge transcriptomic and genomic data to explain these phenomena. These findings challenge the traditional Th1/Th17 vs. Th2 dichotomy and highlight the plasticity of the skin’s immune system. In the future, these insights will likely drive a shift toward precision medicine, where treatment selection is guided by a patient’s specific immune endotype—using biomarkers like cytokine profiles or transcriptomic signatures—rather than just a clinical diagnosis.
Link to the study: https://www.tandfonline.com/doi/full/10.2147/CCID.S574980#abstract
