About 20–30 % of psoriasis patients develop psoriatic arthritis (PsA), a seronegative, chronic inflammatory muscoskeletal disorder, occurring in most cases about a decade after the appearance of psoriasis [14].

PsA has a complex aetiology mirrored in a wide spectrum of clinical disease presentation, expression and clinical course [15]. PsA can affect different tissues (synovium, cartilage, bone, entheses, tendons); it presents common involvement of distal joints, asymmetric articular distribution, erythema over affected joints, spinal involvement and enthesitis [14] and eventually leads to erosion and loss of function of the affected areas.

Since about 80 % of the patients develop PsA following psoriasis [16], PsA is sometimes considered as a disease within a disease with the skin manifestation being the parent disease [17]. PsA has a stronger genetic component than psoriasis (sibling recurrence risk (λ_s) of 27–47 for PsA v [18] vs. 4–11 for Ps [19]), however it is not as well defined as that of psoriasis due to phenotypic heterogeneity, disease overlap and smaller number of patients analyzed. Several PsA susceptibility genes, such as HLA–C, IL12B, IL23R, TNIP1, overlap with psoriasis [16, 20, 21]. On the other hand, differences in the genetic background of the two conditions do exist and unique genetic determinants have been identified, although not at a genome-wide significant level [21]. Nevertheless, PsA shares several key cellular and molecular mediators with psoriasis, such as lymphocytes infiltrating the inflamed skin or joint [22] and the pro-inflammatory cytokines TNF, IL-23, and IL17. TNF is a critical disease player and about 70 % patients successfully respond to anti-TNF therapy in terms of signs and symptoms improvement, and, in some cases also by radiographic progression [15]. Moreover, clinical trials showed efficacy for the anti IL-12/IL23p40 antibody ustekinumab [23–25] or anti-IL17 secukinumab [26] in the treatment of PsA.

The association of psoriasis with physical and psycho-social co-morbidities, such as cardiovascular disease (CVD, i.e. myocardial infarction (MI) and stroke), metabolic disorders (obesity, non-alcoholic fatty liver disease, dyslipidaemia and diabetes), depression and Crohn’s disease (CD), is increasingly being appreciated and results in a more modern definition of the disease as a systemic inflammatory disorder in which the chronic nature of the skin inflammation is likely to contribute to the development of associated co- morbidities [27]. In analogy with that occurring in atopic dermatitis, the concept of “psoriatic march” has been proposed to describe the synergistic interplay of psoriasis and its co-morbidities in the establishment of systemic inflammation [28].

Moreover, in analogy to hypertension being called the “silent killer”, psoriasis has been recently dubbed the “visible killer” [29] as patients with severe psoriasis have a 6-year reduction in life expectancy, mainly due to excess risk of CV death [30, 31]. The association between psoriasis and CVD has attracted considerable interest since a significant increased risk of death from CVD for psoriasis patients requiring hospital admission was reported in 2004 [32]. Nevertheless, it has been long known that psoriasis patients have a higher prevalence of traditional cardiovascular risk factors such as diabetes, hypertension, dyslipidaemia, obesity, and metabolic syndrome compared to the general population [33–35] that might account for some or all of the increased CVD risk. Therefore, a number of population-based epidemiological studies have been performed in the last decade to address this issue. Unfortunately, these studies are often heterogeneous in their data collection methods, outcomes, sample size and thus in statistical power, and display variable degrees of control for confounding factors [29, 36, 37]. This heterogeneity is likely to account for some conflicting results [38–40].

Nevertheless, a growing body of epidemiologic literature suggests that severe psoriasis (defined in most of the studies as affecting >10 % body surface area or requiring systemic treatment or phototherapy) confers a clinically significantly increased risk of CVD and cardiovascular mortality that is independent of conventional risk factors [39, 41]. A recent meta-analysis, including 14 previous epidemiological studies of which ten were population-based, showed increased risk of CVD in patients with severe disease, with OR relative to the general population of 1.37 for CVD mortality, 3.04 for myocardial infarction (MI) and 1.59 for stroke [42]. Thus, psoriasis has been included as an independent risk factor for CVD in recent guidelines for CVD prevention (Fifth Joint Task Force of the European Society of Cardiology, 2012).

Moreover, severe psoriasis has been shown to be an independent risk factor for atherosclerotic CV disease, as defined by outcomes such as imaging of coronary and carotid arteries, and measurements of endothelial function and arterial stiffness [43–45].

As mentioned earlier, high prevalence of metabolic syndrome has been reported among psoriasis patients, with more than two-fold increased odds ratio (OR) in psoriasis patients, compared to matched healthy controls [46]. In particular, the association of type 2 diabetes with psoriasis is stronger in patients with severe disease (OR = 1.97) as compared to those with mild disease (OR = 1.53).

Clinical data and a better understanding of psoriasis immunopathogenesis also support these epidemiological observations. Elevated levels of nonspecific inflammation markers (e.g. as C-reactive protein), pro-inflammatory cytokines (such as TNF and IFN-γ) and immune cells (such as T helper type 1 (Th1) and Th17) in the circulation of psoriasis patients [47, 48], and the fact that most of these inflammatory markers are also increased in the skin lesions [49], strongly support that psoriasis is not only skin deep. Indeed, psoriasis patients have high levels of lipids and lipid peroxidation, altered adipokine function [50, 51] as well as abnormal coagulation profile [52, 53].

Despite a definitive biological link between co-morbidities and psoriasis has yet to be identified, it is reasonable to infer that the systemic inflammation and dyslipidaemia present in patients may predispose to impaired glucose tolerance and cardiovascular damage [27]. It has been suggested that the pro-inflammatory molecules produced by the skin could be released into the systemic circulation; in fact several genes differentially regulated in psoriasis are linked to functional pathways associated with metabolic diseases/diabetes and cardiovascular risk [49]. For instance renin, an enzyme involved in the renin–angiotensin pathway ultimately regulating blood pressure, is over-expressed in psoriatic skin, suggesting a functional link between expression profile at the skin level and peripheral functions. The presence of IL-17A/IL-17 F and CD4+ cells expressing IL-17 and IFN-γ in atherosclerotic lesions [54, 55], and risk alleles shared between psoriasis and its metabolic and cardiovascular co-morbidities [56], also lend support to the association between psoriasis and these diseases.

Epidemiological [57–59] and genetic [60, 61] studies support a close relationship between psoriasis and inflammatory bowel diseases (IBDs). Increased occurrence of psoriasis has been reported in patients with CD (8.9 %) yielding an aggregate relative risk of 7.1 (χ ² = 139, P < 1 × 10⁻⁹) [62]. Conversely, Li et al recently reported that women with psoriasis have a significantly increased risk of CD (relative risk (RR), 3.86, 95 % CI 2.23–6.67), but not ulcerative colitis (UC) (RR, 1.17, 95 % CI 0.41–3.36) [58].

Remarkably, psoriasis and IBDs share a number of common genetic determinants such as IL23R [60, 61].

Finally, psoriasis carries a severe psychosocial burden with anxiety, depression and perceived stress appearing at higher rate in psoriasis patients [63]. The impact of psoriasis on health-related quality of life is similar to that of other major medical diseases, including cancer, arthritis, hypertension, heart disease, diabetes, and depression [64]. Psoriasis patients find it hard to adapt to the chronic yet variable and unpredictable nature of the disease. Another major component of psychological distress is the anticipated negative reactions of others which can be of shame or stigmatization. Coping mechanisms include avoidance and seclusion which in turn affect their quality of life.

Changes in cognitive processing of facial expressions of disgust have been identified in psoriasis patients, who display smaller signal responses to disgusted faces to protect them from stressful emotional responses [65].

Depression, which is one of the stronger predictors of suicidal ideation, has been observed in more than 60 % of patients [66], and higher prevalence of suicidal ideation has been detected in psoriasis patients as compared to healthy controls and patients affected by other skin disease [67, 68].

Taken together, clinicians are presented with the challenging task of managing a multifaceted and lifelong disease which, although apparently not lethal, can severely affect patients’ quality of life and, in some cases, life expectancy.

Thus, the current focus is not to only treat but to manage psoriasis patients [69]. A multidisciplinary approach is needed, particularly in cases of severe psoriasis with multiple comorbidities or cardiovascular disease with dermatologists alerted to detect and react to early indications of cardiovascular risk factors and comorbidities in psoriasis patients. While all patients should be encouraged to correct their modifiable cardiovascular risk factors, particularly obesity and smoking, and to adopt healthy lifestyle behaviours, patients with moderate to severe psoriasis are to be recognized and managed as being at intermediate risk of CVD with appropriate counselling and treatment [70].

Moreover, a patient-centred therapeutic approach, undertaken early in the psoriasis treatment pathway (“early intervention”) aimed at complete clearance, has been advocated to improve control of cutaneous symptoms and modify disease course and burden [71].

A number of outstanding questions arise from the study of psoriasis and its comorbidities, including what is the effect of systemic therapy for psoriasis on CVD and diabetes [42, 72] and whether an association exists between specific subtypes of psoriasis and co-morbidities.

Genetic predisposition to psoriasis is supported by population and family studies, as well as, higher concordance rates in monozygotic twins, compared with dizygotic twins (up to 73 vs. 20 %, depending on the population studied) [73–76]. Lack of complete concordance between monozygotic twins and familial occurrence of disease not following a clear inheritance pattern, support the definition of psoriasis as a complex genetic trait, resulting from gene–gene and gene–environment interactions [77, 78]. Large efforts to understand the genetic architecture of psoriasis have resulted in the identification of a number of psoriasis genetic determinants. The psoriasis genetic landscape emerging from recent genome-wide association studies (GWAS) and their meta-analysis [20, 60, 79–86], as of mid-2014, includes 36 independent psoriasis-associated genetic regions in individuals of European ancestry (Table 21.1), plus five more uniquely associated in the Chinese population [87]. Psoriasis- susceptibility genes encompass skin and immune-related genes, with the latter belonging to either the innate or the adaptive immunity, as well as bridging the two arms of the immune system. SNPs and Copy Number Variation (CNV) [85, 86] in genes of the late cornified envelope (LCE) family within the epidermal cell differentiation complex, a cluster of genes involved in skin barrier formation, support a critical role for skin-specific genes in psoriasis susceptibility. Among immune genes, the over-representation of four pivotal immunological processes and pathways strongly points towards their critical contribution to disease susceptibility: antigen presentation (HLA–C and ERAP1), NF-kb signalling (e.g. TNFAIP3, TNIP1, TRAF3IP2, CARD14), type I IFN pathway (e.g. IL28RA and RNF114), and IL-23/IL-17 axis (e.g. IL23A, IL12B, and IL23R) [77]. Psoriasis susceptibility region 1 (PSORS1) within the major histocompatibility complex is the strongest susceptibility locus [88, 89] and the HLA- Cw*0602 allele of the MHC class I molecule HLA-C is considered to be the primary associated allele, as confirmed by early sequence and haplotype analysis [90], and more recently by GWASs [81, 82, 86], and analysis of high density SNP data [91]. The HLA-C association has not only the greatest statistical significance observed in GWAS studies [86] but also accounts for about 6 % of the total genetic variance [92], which is at least ten fold more than that explained by any other known psoriasis susceptibility locus [86]. The expression pattern of MHC class I molecule on all nucleated cells makes HLA-C capable of regulating both innate and adaptive responses [93]. Nevertheless, despite the strong genetic evidences and the obvious immunological function of HLA-C, functional studies addressing the precise mechanism by which -Cw*0602 alleles predispose to psoriasis are still missing and no -Cw*0602 specific antigen or interacting protein has been identified to date. Among genes of the innate immunity, more than half belong to the NF-kB pathway, which has a pivotal role in amplifying and sustaining chronic inflammation. Two recent studies have identified and evaluated the functional consequences of rare and common gene variants [86, 94] and missense mutations [12] in CARD14, an activator of NF-kB primarily expressed in skin epidermis. Genes belonging to the type I IFN pathway support clinical and experimental findings indicating an important role for antiviral responses in psoriasis [95, 96]. Finally, several susceptibility genes belong to the IL-23/IL17 pathway, whose critical involvement in disease pathogenesis has been extensively documented by a wealth of studies showing a pivotal role for IL-23-induced and IL-17-mediated responses in psoriasis [97]. Moreover, the genetic association with IL23R is one of the very few supported by functional evidence with reduced IL-17 responses in carriers of the protective Arg381Gln IL23R allele [98, 99]. Interestingly, some genes from the above pathways influence multiple phenotypic traits, in particular other immune-mediated conditions such as Crohn’s disease (CD), celiac disease and ankylosing spondylitis [86], thus confirming the presence of a shared genetic basis among immune-mediated inflammatory diseases.

The signals identified in the European population collectively account for approximately 20 % of estimated psoriasis heritability, and the gene variants identified have only modest- effect size [86]. It has been hypothesized that rare variants with bigger effects may explain this “missing heritability” [100]. However, two recent re-sequencing studies in individuals of European or Chinese descent, have shown that rare variants at known immune-related loci have a negligible role in psoriasis genetic susceptibility [101, 102], suggesting that the estimated missing heritability either results from the co-existence of many common variants of weak effect, or has been overestimated, owing to the existence of gene-gene and gene-environment interactions [103].

In contrast to the fast-growing list of psoriasis susceptibility genes, the environmental component concurring in initiating the disease is still ill-defined. Among known environmental triggers of psoriasis there are drugs, infections, physical trauma, smoking, alcohol and stress.

Drugs, such as the anti-viral and anti-proliferative agent imiquimod, anti-depressants (lithium), anti-hypertensives (beta-blockers), cytokines (IFN-α) and anti-cytokine therapies (anti-TNF) have all been clinically associated with initiation, exacerbation and worsening of psoriasis [104]. Imiquimod, a Toll Like Receptor (TLR) 7/8 agonist used to treat genital warts and non-melanoma skin tumours, represents one of the best investigated examples of psoriasis triggers so far. The initial clinical observation of a case of psoriasis exacerbated by topical treatment with imiquimod [105] has prompted research into plasmacytoid DC (pDC) and type I IFN pathway, which is downstream of TLR7/8 signaling [95]. Moreover, it has also been translated into the imiquimod-induced psoriasiform skin inflammation mouse model, which faithfully reproduces most of the features of the human disease and has quickly become one of the most widely used experimental models to study psoriasis [106].

An association between preceding streptococcal throat infection and psoriasis [107] has been reported, mainly with guttate psoriasis [108] and homologous T cell clones have been found in both the tonsils and skin lesions of plaque-type psoriasis patients [109].

Tattoos and surgical incisions give rise to the Koebner phenomenon with psoriasis plaques appearing at the site of the trauma [110].

The association of modifiable behavioural risk factors, such as smoking and alcohol consumption, as well as co-morbidites such as stress, are traditionally more difficult to investigate. Although a number of studies have offered evidence linking stress and smoking with psoriasis [33, 111, 112] there is no consensus on whether these factors do actually cause or aggravate psoriasis [113].

While more often included among risk factors, environmental cues can also have a protective role against disease. We have recently uncovered an unexpected protective role in psoriasis for the ligand-activated transcription factor Aryl hydrocarbon receptor (AhR) [114], an environmental sensor which responds to a wide range of stimuli including environmental pollutants (e.g. dioxin), but also more physiological ones (e.g. tryptophan metabolites of dietary or light-exposure origin), by inducing detoxifying enzymes belonging to the cytochrome P450 family. In particular, physiological ligands are believed to mediate the beneficial effect exerted by AhR, via short-term activation of the receptor in contrast to the prolonged and deleterious activation sustained by dioxin and tobacco smoke [115]. By combining data from the imiquimod model of psoriasis-like skin inflammation in mice lacking AHR, with the analysis of human psoriasis skin biopsies treated ex vivo with AhR ligands we found that absence of AhR signalling results in an exacerbation of psoriasis [114]. In particular AhR exerts its beneficial effect in keratinocytes as in its absence they become over-reactive to pro-inflammatory stimuli and release a greater amount of cytokines and chemokines, thus instigating an excessive inflammatory reaction. Thus, physiological AhR activation acts as an immunological brake that prevents dysregulation of the inflammatory response. Based on this data it is tempting to speculate that psoriasis patients might have impaired activation of the AhR pathway, possibly due to genetic variants in genes of the AhR pathway or perhaps shortage of physiological ligands, and ongoing studies are addressing these hypotheses.

The first biologics to be approved for psoriasis treatment were anti-T cell therapies targeting T cell adhesion or activation.

The first biologic to be approved was alefacept in 2003, a LFA-3/IgG1 fusion protein binding CD2 on T cells and thus, selectively inducing apoptosis of CD2(+) human memory-effector T cells [156]. Clinical efficacy was shown in phase III studies with 40 % of patients achieving a PASI75 response (75 % reduction of the PASI) [157] and more that 50 % achieving PASI 50 (50 % reduction of the PASI) [158]. A further antibody, anti-T cell strategy was approved in 2003 and consisted in a humanized antibody (efalizumab) binding and blocking CD11a, a key molecule for T-cell activation and migration through the circulation into the skin [159]. Despite a good efficacy profile, [160–166], efalizumab has been withdrawn from the market in 2009, due to three cases of progressive multifocal leukoencephalopathy [167], highlighting the importance of carefully monitoring the long-term safety of immunomodulatory therapies.

An alternative strategy to anti-T cell targeting aims at interfering with the psoriasis cytokine network using anti-cytokine biologic drugs. TNF blockade was serendipitously found to ameliorate psoriasis in a patient with IBD treated with the anti-TNF drug infliximab and had concomitant psoriasis [168]. Currently there are three anti-TNF biologics approved for psoriasis: etanercept, a human p75 TNF receptor fusion protein (approved in 2004), infliximab, a humanized chimeric anti-TNF monoclonal antibody (approved in 2006), and adalimumab, a fully human monoclonal antibody (approved in 2008). The efficacy of TNF inhibitors has been tested in phase III clinical trials, showing up to 80 % of treated patients achieving PASI75 within 10–12 weeks of treatment [169–176]. TNF neutralization causes early down- modulation of myeloid cell-related genes, with decrease of Th17 cell products and downstream molecules in just 2 weeks after commencing therapy [125, 177, 178]. The latest biologic to be approved for psoriasis in 2009, ustekinumab, is a monoclonal antibody simultaneously blocking the heterodimeric proteins IL-12 and IL- 23 via its binding to the shared subunit p40. Its efficacy is quite high, with 67 % of patients achieving PASI75 at 12 weeks of treatment [179, 180].

Some serious adverse events, such as opportunistic infections and reactivation of latent tuberculosis, have been reported for these monoclonal antibodies [181]. Long term safety data (up to 4 and 5 year treatment) are now available for etanercept and ustekinumab [169–171, 182, 183], suggesting a safe use of these drugs.

A number of other biologic drugs is currently being investigated in clinical trials, as of mid-2014 (see also Chap. 43) (Table 21.3). In line with the prominent role of IL-23/IL-17 axis in psoriasis, there are three antibodies (BI655066, tildrakizumab, and guselkumab) specifically targeting the IL-23p19 subunit which are currently being tested in phase II [184], III [185] or have recently completed phase II [186] clinical trials, respectively. Data from a small phase 1 study showed between 50 (10 mg) and 100 % (300 mg) of guselkumab-treated patients achieving PASI75, with improvements generally maintained through week 24 and rate of adverse event similar to placebo-treated patients [187]. Preliminary phase IIb data presented at the American Academy of Dermatology (AAD) meeting 2014 showed up to 81 % of patients receiving the highest dose achieving PASI75 response [188]. Phase 3 data for tildrakizumab presented at AAD 2013 showed PASI75 response rates of 64–74 % [189].

Monoclonal antibodies blocking either IL-17A (ixekizumab and secukinumab) [190–192] or IL-17R brodalumab [193], have shown remarkable efficacy in phase 2 clinical trials with more than 70 % of patients achieving PASI 75, and more than half achieving a striking PASI 90. While phase 3 clinical trials are currently ongoing, initial molecular data showed that the effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF is greater than in previous studies with anti-TNF therapy [194].

Notwithstanding the efficacy of the biologic drugs currently available in the clinic, at least one third of patients do not respond to biologic therapy [195] or lose initial responsiveness, due to the development of anti-drug antibodies (ADA), which causes decreased drug efficacy and/or induction of adverse events [196, 197]. Moreover, biologic drugs pose a considerable economic burden due to their cost of about £10 k per patient/per year. Finally, a sizable number of patients with mild-to-moderate psoriasis still rely only on traditional topical treatments to manage their disease. Thus, other therapeutic options are being explored, such as small molecules, i.e. low molecular weight organic compounds targeting key molecules involved in cellular signalling. Based on the importance of cytokine- driven inflammatory pathways in psoriasis, the most promising small molecules currently under testing are targeting key cellular components in cytokine signalling, such as Janus kinases (JAK), as well as enzymes involved in cytokine production. Among JAK inhibitors, tofacitinib, which specifically inhibits JAK1 and 3 and is approved for RA treatment, has showed good efficacy in phase II trials for both its oral and topical formulation [198, 199] with 66.7 % of patients treated with the highest dose of oral tofacitinib reaching PASI 75 at 12 weeks in a phase 2b study [200]. Apremilast, a phosphodiesterase four inhibitor which inhibits an enzyme involved in the breakdown of cAMP, thus suppressing the production of pro-inflammatory cytokines is also been tested in Phase IIb clinical trials [201, 202] showing 41 % of patients achieving PASI75 at week 16 with the highest dose. A cheaper manufacturing process, a route of administration (oral or topical vs injectable) which ensures high patient compliance and an overall good safety profile, makes the use of these small molecules in mild-to-moderate psoriasis foreseeable