**4. Immune therapeutical outlines in Ps**

Although diagnosis and therapy in skin pathologies have beneficiated from novel investigation assays [129, 130] and new therapies are emerging [18], there are still many immune niches that can be explored in the quest to find the best biomarker in diagnostic and therapy efficacy improvement [131].

A recent meta-analysis of biologics treatment in Ps has shown that the biological treatments that target IL-17, IL-12, IL-23, and TNF-α were significantly more effective in comparison to small molecules/conventional systemic agents [132]. Slowing down the pro-inflammatory biological processes using early intervention with anti-IL-17 and anti-IL-23 agents might positively change the course of Ps, especially in the current pandemic era, where chronic patients can reduce their hospital visits [133].

IL-17 inhibitors, namely secukinumab, ixekizumab, brodalumab and IL-23 inhibitors, namely guselkumab, tildrakizumab, risankizumab show increased effectiveness compared to other biologicals [134]. A recent meta-analysis has shown that these are the best choices in order to achieve PASI 90 in patients with moderate-to-severe psoriasis. The authors point out that future trials are needed to evaluate directly the biological agents in order to establish the best choice in terms of type and timing. Therefore, trials on anti-IL-17 versus anti-IL-23, anti-IL-23 versus anti-IL-12/-23, anti-TNF-α versus anti-IL-12/-23, and so on are to be expected (Cohrane skin group, 2021). Despite the therapeutical success of recent drugs, there are still a reactive patients to these treatments. Therefore, the combination of multiple immune-modulatory drugs can be an appropriate alternative strategy to improve the quality of life in Ps [135, 136]. Moreover, new biomarkers should personalize treatment with IL-17 inhibitors and IL-23 inhibitors and should stratify patients in Ps subgroups that could best beneficiate from these new biologics [137].

Historically, TNF-α inhibitors were the first biologicals approved in PsA. Now, targeting IL-12/IL-23 p40 common subunit, IL-17A, T cells co-stimulation, is proving an increased efficacy in Ps therapy. Moreover, additional drugs targeting phosphodiesterase-4 and JAK/STAT pathways are recently being developed [138]. Many cytokines are related to the pathways controlled by JAK/signal transducers and activators of transcription (STATs). JAK inhibitors have been approved in PsA [139]. In 2020, data from the Phase II trial of several selective TYK2 inhibitors in Ps were published [140] and new drugs targeting the JAK/STAT3 axis in Ps treatment are awaited [141]. Berberine was reported to inhibit CDK4/6-RB-CDC6 signaling in KCs, reducing their proliferation. This alkaloid extracted from Berberis plants represses JAK1, JAK2, and TYK2, inhibiting STAT3 activation [109].


#### **Table 1.**

*Main drugs approved in Ps and/or that are in various testing stages.*

Co-stimulatory molecules (CD28, CD40, OX40, CD27, DR3, LFA-1, LFA-3) and co-inhibitory molecules (CTLA-4, PD-1, TIM-3) regulate T cells functions, including cytokines production and Tregs differentiation. In 2021 it was shown that co-signaling molecules targeting can be developed in future Ps' drugs [142].

Biologics targeting TNF, IL-17s, and IL-23 in Ps are associated with adverse immune effects. In a recent study, high antinuclear antibodies (ANA), high eosinophils, and high IgE were reported. Therefore, in Ps, careful observation is required when patients are subjected to these new biologics [143]. Due to these adverse effects, several other compounds are tested in Ps, like prostaglandin D2 inhibiting Th2 cells [144]. Vitamin D3 analogs, corticosteroids, or a combination of these compounds are tested as future drugs in Ps [145]. Flavonoids like luteolin can suppress proinflammatory cytokines (e.g., IL-1β, IL-6, IL-8, IL-17, IL-22, TNF-α) and regulate the signaling pathways that are highly involved in Ps [146].

**Table 1** summarizes the main drugs that are already approved and/or are in various development stages in Ps.
