## 3 Expression and Role of IL-36 Cytokines in Inflamed Skin and Joints
### Are IL-36 Cytokines a Good Target in Skin- and Joint-Related Inflammation? Biological agents have been introduced about two decades ago and have since then carried a significant improvement in the clinical outcome of patients affected by a range of diseases, such as psoriasis, PsA and RA. Biologics include drugs targeting proinflammatory molecules and pathways (e.g., TNF, IL-6, or the IL-17/IL-23 axis), specific population of cells (e.g., B cells) or immune mechanisms (e.g., T cell costimulation). However, up to 30 to 40% of the treated patients do not respond adequately to the available agents, either immediately after the initial treatment (primary failure) or by losing efficacy over time (secondary failure). The sequential use of the available molecules is currently based on \"trial-and-error\" but a stratified and personalized approach would certainly increase the rate of responders and reduce both the exposure to side effects and the economic impact related to the use of inappropriate drugs [77]. Importantly, different organ-dependent (i.e., skin versus joints) rates of response have been observed in PsA and thoroughly discussed in a recent review published by our group [5]. Moreover, distinct pathogenic mechanisms driving the development of skin or synovial inflammation must be considered when assessing the divergent efficacy of the biologics in PsA. A better characterization of the pathways contributing to the chronic inflammation in psoriasis, PsA and RA would facilitate the development of new effective drugs. Here, we discuss the potentiality of targeting IL-36 in both skin- and joint-related inflammation. It is now well accepted that IL-36 cytokines are paramount in psoriasis pathogenesis, and IL-36 receptor inhibition represents a promising therapeutic strategy for treating generalized pustular psoriasis (GPP) and palmoplantar pustulosis (PPP). Two phase I trials are currently evaluating the safety and pharmacokinetics of two different IL-36R blocking antibodies (ANB019 and BI655130) [78, 79]. In the attempt to develop additional strategies to target the activation of the IL-36 cytokines, small molecules inhibiting the elastase have been generated. Since their efficacy to reduce IL-36  
Figure 2: IL-36 agonists drive skin and joint inflammation. IL-36 cytokines are cleaved and activated by neutrophil proteases and act on multiple immune and resident stromal cells through their specific receptor complex IL-36R to initiate and amplify the inflammatory cascade. FLS = fibroblast-like synovioocytes; Th = T helper. activation has been proven [80], they might represent a novel approach to inhibit IL-36-driven inflammation in psoriasis and other IL-36-dependent inflammatory diseases [81]. Whether or not the same pathogenic mechanisms sustain psoriasis and PsA is still under debate. Nevertheless, the significant neutrophil component characterizing the PsA synovium [82] and the well-known relevance of the Th17-related cytokines in the PsA development suggest that the IL-36 axis is a potential new therapeutic target in PsA with synovial inflammation (manuscript in preparation). Several preclinical studies failed to demonstrate a pivotal role of the IL-36 cytokines in driving synovial inflammation in RA. However, analysis of human rheumatoid synovial tissue emphasized that at least a subset of patients defined by a high IL-36 agonists/antagonists ratio, similar to the lesional skin in psoriasis, might benefit from the inhibition of the IL-36 pathway [40]. Even if preliminary data on the effectiveness of IL-36 neutralization are encouraging, combined inhibition of the IL-1/IL-36 axis would be even more efficient and, possibly, necessary for obtaining a meaningful clinical effect. We learned indeed that the single inhibition of IL-1\(\alpha\)/\(\beta\) was of limited efficacy in treating RA patients, despite extremely promising preclinical data [83]; likely, this discrepancy relates to the redundancy of other proinflammatory compensatory pathways such as TNF\(\alpha\), IL-6, or other IL-1 family members like IL-36.