TNF-blockers are effectively used for various immune-mediated diseases such as psoriasis, rheumatoid arthritis, and, more recently, hidradenitis suppurativa (HS). However, **reactions, such as eczema and psoriasis-like lesions, and others***, have been reported
Some of these adverse effects are considered contradictory, in particular, 2 to 5 patients receiving TNF-antagonists** will develop paradoxical psoriasis** lesions. These reactions may require interruption of interpolable drugs, and no other biologic agents have been approved for conditions such as HS. Therefore, it is important to understand the pathogenesis of these reactions, and these patients should be examined for possible genetic predisposition.
Psoriasis is a chronic inflammatory disease mediated by autoreactive T cells, which causes excessive proliferation of epidermal keratinocytes and abnormal differentiation and aging. Early upstream events that occur in psoriasis include the induction of an innate immune response, which depends primarily on keratinocytes activated by mechanical trauma, pathogens, or drugs. In this initial phase, keratinocytes establish innate immune circuitry involving neutrophils, mast cells, and macrophages and, importantly, make plasmacytoid dendritic cells (PDCs) and myeloid DCs (MDCs) drive responses. PDC and MDC produce locally type I IFN as well as TNF- and IL-6, thereby releasing an adaptive immune response, and the expansion of T lymphocytes is usually Th17 and Th22 in the initial phase and Th1 cells in the chronic phase. Thus, the release of lymphokines in ** lesions, particularly IL-17, IL-22, and IFN-, further amplify the local immune response. Paradoxical psoriasis induced by TNF-blockers does not have a chronic immune response, and an innate inflammatory process predominates, while autoreactive T cells do not grow with it. These processes are accompanied by the accumulation of immature PDCs and the overexpression of type I IFNs.
Several studies have shown that intrinsic defects in genes that control T cell stereotyping and inflammatory activation of keratinocytes are associated with psoriasis. Among them, the HLA-CW6 allele represents the strongest genetic risk variant associated with psoriasis. The HLA-CW6 haplotype may affect antigen presentation and immune responses, especially when associated with a variant of the Erap1 gene, which encodes an aminopeptidase involved in the formation of peptide formation for MHC class I molecules. Interestingly, a number of allelic variants were found in genes encoding signal transducers associated with IL-17 or TNF-, such as NFKBIZ and TNFAIP3, which encode IKB and A20 proteins, respectively. Both IKB and A20 proteins regulate IL-17 and TNF-induced molecular signaling, and are activators and negative regulators of NF-B, respectively.
Here, we report the immunological and genetic characteristics of HS patients who develop a psoriasis response after the use of adalimumab anti-TNF-*. We found that paradoxical psoriasis** predominantly exhibited immunological features common to early psoriasis, characterized by a large infiltration of innate immune cells and local overproduction of innate immune molecules. Contrary to classic psoriasis,Psoriasis-like lesions show an infiltrated IL-22 [+ increased number of white blood cells. Finally, we found that all HS patients with paradoxical responses carried allele variants in typical psoriasis susceptibility genes, including SNPs in the HLA-C genomic region.