## 2 Discussion
### Specific Drug Targets  
The discovery of gene associations enabled the development of safe and effective drugs that directly target genes responsible for psoriasis, such as biologics antagonizing tumor necrosis factor (TNF), the p40 subunit of both interleukin (IL)12 and IL23, and the p19 subunit of IL-23 (IL23p19) and IL17 (Table 2) [5]. These drugs may be well tolerated and improve the PASI-75 (Psoriasis Area and Severity Index reduction >/= 75%) score at week 12 [4]. Treatments such as ustekinumab and briakinumab target the p40 subunit of IL12/23 and are highly effective, underscoring the role of IL12 and IL23 in the pathophysiology of psoriasis [1,3,5,6]. In the case of ustekinumab, the mechanism of action prevents the interaction between IL12/23 and IL12-\(\beta\)-3, not only preventing downstream cascades but also gene activation and cytokine production. IL12 is primarily produced by dendritic and phagocytic cells in response to microbial infection to activate NK cells and T-lymphocytes. IL12 also mediates Th1 cells, which play a vital role in cell-mediated immunity and macrophage infiltration. Furthermore, IL23 is crucial to Th17 differentiation. Th17 cells produce a variety of pro-inflammatory cytokines in humans, such as the IL17 necessary for neutrophil recruitment, IL21 for B cell function, and IL23 for additional Th17 differentiation [24]. Therefore, both ustekinumab and briakinumab block the inflammatory cascade triggered by Th1 and Th17 lymphocytes. Dysregulation in both of these inflammatory processes is linked to psoriasis, as well as other immune disorders such as rheumatoid arthritis and multiple sclerosis [1,6,24,25]. Treatments such as guselkumab, tildrakizumab, and risankizumab target the p19 subunit of IL23 [1,3,5,6]. This subsequently blocks the release of other cytokines, as IL23 facilitates Th17 differentiation. Given the role of Th17 in triggering pro-inflammatory cascades such as that of IL17 and IL21, the aforementioned biologics serve to halt the immune dysregulation contributing to disease pathophysiology. Notably, these drugs have no affinity for IL12 and, thus, allow the IL12/Th1 axis to remain intact, as IL12 initiates the differentiation of naive CD4+ T cells to Th1 cells necessary for cell-mediated immunity. This particular characteristic of these three drugs may be important, given that the literature suggests that dysregulated IL23 may play a larger role than IL12 overproduction in psoriasis pathogenesis. Notably, IL23p19 mRNA is elevated in skin samples from psoriatic patients [26]. IL23 is also involved in IL-C3 cell activity, which causes epidermal thickening in psoriasis. Intradermal injections of IL23 were shown to cause psoriatic skin lesions to develop in mice models [27,28]. Guselkumab, tildrakizumab, and risankizumab selectively inhibit IL23, unlike ustekinumab, which is a non-selective IL23 inhibitor. \begin{table}
\begin{tabular}{l l l} \hline \hline
**Type** & & **Gene(s)** \\ \hline Interleukins & Pro-inflammatory & IL1B, IL2, IL6, IL15, IL17, IL18, IL20, IL23 \\ \cline{2-3}  & Anti-inflammatory & IL1 RN, IL4, IL10, IL13, IL19 \\ \hline Interleukin receptor proteins & IL20 RA, IL28 RA, IL36 RN \\ \hline Mediators of HLA class I function & HLA-C, ERAP-1 \\ \hline NF-kB pathway regulators & \
\begin{tabular}{l} TNFAIP3, TNFRsF1B, TNIP1, TRAF1 IP2, \\ NFkBIA \\ \end{tabular} \\ \hline Interferons and mediators & IFN-gamma, IFH1 \\ \hline JAK/STAT pathway & STAT3, STAT4, JAK2, TYK2 \\ \hline Other &
\begin{tabular}{l} APOE, CTLA4, DEFB4, GBP6, LCE, MCP1, \\ VDR, ZNF313 \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Genetic mediators associated with psoriasis. Additionally, infliximab, etanercept, and adalimumabb target TNF-\(\alpha\), which induces the production of proinflammatory cytokines and mediators such as IL1 and IL6 and helps recruit immune cells to sites of inflammation [1; 5; 6; 29]. The inhibition of TNF-\(\alpha\) leads to a reduction in inflammation [1; 6].