# Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease
## 1 Introduction  
Psoriasis is a chronic and recurrent immune-mediated disease that affects approximately 3% of the US population, with a similar prevalence in European countries [1]. The most common presentation is plaque psoriasis, which is characterized by scalp, sharply demarcated plaques affecting extensor surfaces, often with a symmetrical distribution. Pustular psoriasis is rare and presents with sterile, neutrophil-rich pustules that can be localized or generalized [2]. Pustular psoriasis phenotypes include generalized pustular psoriasis (GPP), palmoplantar pustular psoriasis (PPP), and acro dermatitis continua of Hallopeau (ACH) [3]. Association between pustular psoriasis and plaque psoriasis is common, with patients often presenting with pustules and plaques altogether. However, clinical, histopathological, and genetic differences suggest that these two might be different entities [3, 4, 5, 6]. Psoriasis is a multisystem disorder with a great impact on quality of life and important comorbidity. Psoriatic arthritis (PsA) is a complex inflammatory joint disease included in the spondylworthy spectrum that affects approximately one-third of psoriasis patients, especially those with moderate-to-severe psoriasis [7]. Psoriasis symptoms precede PsA in 85% of patients, although they can occur simultaneously or, more rarely, be followed by cutaneous symptoms [8]. PsA produces stiffness, pain, and swelling of joints, and it can progress to debilitating joint destruction. Enthesitis and ductility are observed in 30 to 50% and 40 to 50% of patients, respectively [9]. Clinical presentation is variable, and different patterns of involvement have been described: oligorticular, polyarticular, distal, arthritis mutilans, and axial [10]. These may change over time within the same patient [11]. The pathogenesis of psoriasis is not completely understood. Genetic, epigenetic, and non-genetic factors--mainly the microbiome and environmental factors--altogether participate in psoriasis and PsA susceptibility [12]. The innate and adaptive immune systems play a critical role, especially CD4 and CD8 cells and the interleukin (IL)-23/IL-17 immune axis [13]. More recently, the identification of specific mutations in the IL36 RN gene encoding the IL-36 receptor antagonist (IL-36 Ra) have been linked to an autoinflammatory condition characterized by a severe form of GPP called \"deficiency of interleukin-36-receptor antagonists\" (DITRA); this highlights the importance of IL-36 family cytokinesas critical mediators of psoriaticatic disease [14; 15]. Other genes with mutations associated with pustular psoriasis include caspase-activating recruitment domain member 14 (CARD14), adaptor protein complex 1 subunit sigma 3 (AP1S3), TNFAIP3-interacting protein 1 (TNIP1), and serpin family A member 3 (SERPINA 3) [16]. All of them are involved in IL-1/IL-36 signaling pathways, further underscoring the relevance of these cytokines in pustular psoriasis. Phenotype/genotype correlation in pustular psoriasis is complicated, and controversial results have been published. II.36 RN mutations are the genetic variant most frequently observed in patients with pustular psoriasis (5-24%), followed by AP1S3 in 7-11% and CARD14 in a very small number of subjects [17]; the highest rates correspond to patients with GPP, and the lowest correspond to PPP in all cases. While earlier reports found earlier ages of onset and higher risks of systemic inflammation in patients with IL36 RN mutations [14], more recent studies have shown no difference in disease severity between patients with IL36 RN single heterozygous mutations and homozygous or compound heterozygous mutations [18; 19]. To further complicate this matter, a significant association of IL-36 RN mutations with early age of onset, regardless of phenotype, was found in a recent study including 863 patients with pustular psoriasis [17; 20]. The percentage of patients harboring IL36 RN mutations varies among studies, and different reports indicate that the sites of mutation differ among ethnicities.