Paradoxical Psoriasis in Patients Receiving Therapy with Tumor Necrosis Factor Inhibitors: Potential Pathogenic Mechanisms and the Role of Genetic Factors

Abstract

TNF inhibitors (TNFi) have revolutionized the therapeutic management of various chronic immune-mediated inflammatory diseases. Despite their known benefits, these therapies are related to paradoxical adverse effects (PAEs), including paradoxical psoriasis (PP). Although the underlying mechanism remains somewhat unclear, some theories suggest that genetic factors, particularly certain single-nucleotide polymorphisms (SNPs), may play an important role. The present review aimed to research and analyze recent findings regarding the pathomechanisms involved in the appearance of PP and the association between various genetic factors and PP in individuals treated with TNFi. We performed a literature search and found that certain genes (IL23R, TNF, FBXL19, CTLA4, SLC12A8, TAP1) are strongly associated with the occurrence of PP in pediatric and adult patients during therapy with TNFi. The identification of the specific SNPs involved in the appearance of PP and other PAEs in patients treated with TNFi for various diseases and in different populations may later favor the recognition of those patients at a high risk of developing such adverse effects and could guide personalized therapeutic strategies in future years.

Keywords: gene; genetic polymorphisms; genetic predisposition; paradoxical adverse effects; paradoxical psoriasis; tumor necrosis factor-alpha inhibitors.

Figure 1

Schematic representation of the most common theories regarding the pathogenesis of paradoxical psoriasis (partial explanation) [9]. In classical psoriasis, a trigger factor (such as an injury to the skin, smoking, stress, or some drugs) leads to the production of antimicrobial peptides (AMPs) by keratinocytes. These AMPs form complexes with nucleic acids (NAs) which activate pDCs. These cells play an important role in the early phase of classic psoriasis pathogenesis, as they release IFNα. The early phase of classic psoriasis has similar immunological features to PP. Subsequently, IFNα activates cDCs, which produce TNFα and IL-23, which are crucial for the activation of autoimmune T cells. In PP, the use of TNFi disrupts this process. TNFi blocks TNFα, which is involved in the maturation and activation of dendritic cells and leads to unregulated IFNα production. In addition, without TNFα, cDCs cannot mature properly, which means they cannot elicit a T cell-mediated autoimmune response. This suggests that PP is independent of T cells, contrasting with the T cell-dependent mechanism seen in classical psoriasis [9]. The mechanism that connects IFNα overproduction to increased IL-17 and IL-22 production in the context of TNFi treatment is not fully established and may involve several immune pathways and cell types.