Psoriatic arthritis (PsA) is the most prevalent coexisting condition in PsO. In most cases, psoriasis precedes psoriatic arthritis [14]. Clinically, it can affect both axial and peripheral skeletons, with a wide range of clinical presentations including sacroiliitis, enthesitis, osteitis, and dactylitis.

Numerous pieces of evidence support the hypothesis that the IL-23/IL-17 axis plays a key role in the pathogenesis of PsA. High levels of Th17 cells have been found in psoriatic synovial fluid compared to rheumatic synovial fluid [44], similarly, high levels of IL-17A have been found in the synovial fluid and synovial membrane of patients with psoriatic arthritis [45]. Enthesitis, synovitis, and altered bone remodeling were observed in a mouse model after IL-23 administration. Inflammation and bone remodeling were mediated by TNF-α and IL-17 in this model [46]. Other studies have been reported in the literature on murine models with psoriasiform skin lesions, enthesitis, and arthritis were observed, and all of these models were linked to IL-23 [47].

A pathophysiologic model of psoriatic arthritis makes it resemble that of cutaneous psoriasis. A high ratio of myeloid to plasmacytoid dendritic cells was found in psoriatic synovial fluid. Inappropriate activation of dendritic cells triggers IL-23 production that activates IL-17-producing cells [48]. A second model, instead, supported by recent studies such as those mentioned above, attributes a fundamental role to the entheses, which have been proposed to be the site where the disease starts: IL-23 is released following biomechanical stress or trauma and activates IL-17 producing cells [14].

IL-17, acting in concert with other molecules produced in the process such as IL-22, IL-23, and TNF-α results in inflammation and pathological bone resorption and formation. Mesenchymal cells differentiate into osteoblasts in response to IL-22 and other signaling pathways, forming enthesophytes and syndesmophytes, involved in pathological bone formation [14]. IL-17 does not appear to directly activate osteoclasts, but stimulates osteoblasts to produce RANKL, which results, by binding to the RANK receptor on the surface of osteoclast precursors, in osteoclastogenesis [49].

We infer from current scientific evidence that both IL-17 and IL-23 play a key role in the pathogenesis of PsO and PsA, which might instead differ between skin and joints. is the “expression of the IL-23/IL-17 axis”.

For example, Belasco et al. [50] reported that gene expression patterns in skin and synovium are distinct, showing a stronger IL-17 signature in the skin than in synovium, while is an equivalent TNF-α signal across both tissues. Nerviani et al. [51] demonstrated that PsA synovial tissue shows a heterogeneous IL-23 axis profile when compared with matched skin. They reported that, while IL23A, IL12B, and IL23R are expressed at a high level in lesional skin, their expression in the synovium is hugely heterogeneous [51]. This could be the pathophysiological premise of the divergent skin-joints response, with less efficacy on the joint side, that is observed on a clinical base in patients under biological therapy. Recently, the existence of IL-23 producing cells in the axial involvement of PsA is gaining importance: the fact that IL-17 can be produced independently of IL-23, “outside the axis”, has relevant therapeutic consequences [52]. The relationship between osteoporosis, psoriasis, and psoriatic arthritis is still debated. Although these pathological conditions have common inflammatory pathways, such as TNF-α, INF-γ, IL-6, and although treatments used for PsO and PsA, such as methotrexate and cyclosporine, may induce bone rarefaction, studies on this subject are contradictory, and screening and management of osteoporosis in the psoriatic patient are still under debate [53]. A further link between osteoporosis and psoriasis could be IL-23, since this molecule induces osteoclastogenesis and receptor activator of kappa B ligand (RANKL) expression in T cells. Recent studies support the idea of a protective effect of anti-IL23 therapy, but further confirmatory studies are needed [54].

The association between psoriasis and cardiovascular disease has been known for a long time, but the cause-and-effect relationship is still not well established. Robust data show that patients with severe psoriasis have an increased cardiovascular risk and reduced life expectancy. On the other hand, psoriatic patients are more likely to have a high BMI, metabolic syndrome, and type 2 diabetes mellitus. Although the contribution of cardiovascular risk factors to an increased rate of cardiovascular disease cannot be excluded, large studies show an independent relationship between PsO and cardiovascular disease [55,56,57,58].

IL-17, according to current scientific evidence, appears to be more central than IL-23 in the genesis of cardiometabolic complications in psoriatic disease.

IL-17 overexpressing mouse models had shorter life expectancy, and hypertrophic cardiomyopathy, and altered vascular endothelium compatible with increased cardiovascular risk [59]. IL-17 could have potentially opposite effects at the level of atherogenesis. IL-17 may promote the recruitment of neutrophils and monocytes to the plaque and their transformation into foam cells; at the same time, it may inhibit the expression of adhesion molecules and promote smooth muscle proliferation [60,61]. From a therapeutic point of view, instead, the CARIMA study showed that the administration of the IL-17 inhibitor secukinumab leads to a significant improvement in flow-mediated dilatation (FMD), an index of endothelial function [62]. Elnabawi et al. demonstrated that the IL-17 inhibitor was superior to biologics of other classes in reducing non-calcified plaques burden, through angiographic studies [63]. Although there are studies supporting the anti-atherogenic action of IL-17 [64,65], and the relationship between atherosclerosis and psoriasis is far from clear, overall, many authors believe it is pro-atherogenic, and, generally, the key molecule in the cardiovascular involvement of psoriasis, and as such, although still lacking controlled studies, the most promising “target” [58,66]. However, there is also a role for IL-23 in the cardiometabolic comorbidities of psoriasis, although, according to current evidence, less crucial than IL-17. The increased carotid intima-media thickness (IMT) could be considered to be a marker of generalized arteriosclerosis. Studies suggest that the carotid IMT may benefit from treatment with biological drugs, particularly anti-IL-12/23, in patients suffering from moderate-to-severe psoriasis. However, larger longitudinal studies should be performed to fully confirm these results [67].

Obesity, diabetes, and metabolic syndrome also seem to be linked to psoriasis via IL-17.

Studies show that IL-17 and cytokines secreted in response to its stimulus are relevant in the pathogenesis of obesity [68]. Obesity is associated with elevated serum levels of free fatty acids, which sensitize DCs to amplify the Th17 response [69]. In both visceral adipose tissue and other peripheral tissues of obese individuals, increased IL-17-producing T cells were detected, and elevated levels of IL-17 were found in serum [70,71].

Supporting the implication of IL-17 in the metabolic syndrome is the finding that IL-17R levels in the liver and muscle correlate with insulin resistance [72], and that blockade of IL-17 leads to decreased hepatic inflammation in non-alcoholic steatohepatitis syndrome [73].

Worthy of mention is that IL-17 interferes at the molecular level with insulin signaling. Since IL-17 activates the IκB kinase (IKK)/NFκB pathway, inhibitory phosphorylation of IRS-1 directly by IKK and indirectly by JNK activation in response to other proinflammatory cytokines is able to attenuate insulin sensitivity [74]. The opposite is also true, as shown by epidemiological studies mentioned earlier, namely that insulin resistance can worsen psoriasis. From a molecular point of view, we know that, under conditions of hyperinsulinemia, adipocytes secrete large amounts of VEGF. VEGF has been shown to activate keratinocyte inflammation, in interaction with IL-17 [75].

The complex pathogenesis of psoriasis is intertwined with that of inflammatory bowel and neurodegenerative diseases, with important therapeutic implications. Psoriasis and Chron’s Disease, or Ulcerative Colitis, for example, show similarities from a pathogenesis perspective, and a higher rate of co-occurrence [76,77,78]. Again, the IL-23/IL-17 axis plays a crucial role and, again, is expressed differently than in other body sites. In “intestinal comorbidity” of psoriasis IL-23 has a decisive pathogenic role compared with IL-17.

Increased levels of IL-17 and IL-23 are found in the intestinal lamina propria of patients with Crohn’s disease. A growing body of literature demonstrates that IL-17, as opposed to IL-23, in the intestine has a role in maintaining homeostasis rather than as a driver of inflammation [79]. In murine models of intestinal disease, treatment with IL-23 inhibitors improved colic symptoms, increased the Treg/Th17 ratio, and improved epithelial barrier integrity, whereas treatment with IL-17 increased the number of proinflammatory cytokines, decreased the Treg/Th17 ratio, and worsened epithelial barrier integrity [80,81]. Manasson et al. demonstrated that in patients with psoriatic arthritis pharmacological blockade of IL-17 induced subclinical intestinal inflammation and dysbiosis [82]. Finally, gut dysbiosis could trigger IL-23-mediated inflammation, although a recent systematic review concludes that the relationship between psoriasis and the gut microbiome is still far from being understood and brought into clinical practice [14,83,84].

Court studies also report a statistically significant association between multiple sclerosis and psoriasis, an association that is denied by a few other studies [85,86,87]. The pathogenetic mechanism is unclear; however, a recent study attributing a key role to IL-17 in the genesis of neurodegenerative diseases is worthy of mention. It is able to activate microglia, astrocytes, oligodendrocyte precursors. What results is an inflammatory cascade that causes loss of dopaminergic neurons, glutamate excitotoxicity, and apoptosis of oligodendrocytes [88].