**5.2 Inflammatory bowel disease (IBD)**

IBD commonly refers to ulcerative colitis (UC) and Crohn's disease (CD), which are chronic inflammatory diseases of the gastrointestinal tract with unknown etiology. UC and CD have significant clinical differences, however, both diseases share similar pathogenic mechanisms and many extra-intestinal manifestations, and frequently respond to the same treatments.

Many data indicate a stringent correlation between CD and psoriasis (Najarian & A. B. Gottlieb, 2003). Firstly, CD patients have been found to have a seven-fold higher risk of developing psoriasis than control subjects (Mrowietz et al., 2006). This association may be related to the following observations: a) it has been shown that TNF- has a key role in both conditions, valuing the hypothesis of common inflammatory pathways. This point has been further supported by the therapeutic efficacy of anti-TNF- antibodies; b) genetic evidences, such as polymorphisms in the TNF- promoter region and the close position of the susceptibility loci, link psoriasis to CD (Najarian & A. B. Gottlieb, 2003). In particular, a recent study demonstrated a significant association between CD and the IL-23 receptor gene (Duerr et al., 2006) and, as reported previously, IL-23 /IL-17 pathway is involved in psoriasis pathogenesis (Blauvelt, 2008; Rizzo et al., 2011).

On the other hand, the association between psoriasis and UC has been described in only in recent studies, even if the first studies regarding this connection trace back to the 60s and early 70s (Brewerton et al., 1974; McEwen et al., 1971). Most recently, Cohen et coll. (Cohen et al., 2009), in a case-control study with 12,502 psoriasis patients, demonstrated that even though not as high as CD (odds ratio 2.49), UC association is statistically significant and far from being negligible (odds ratio 1.64). This often undervalued correlation is biologically conceivable because chronic systemic inflammation and TNF- constitute core features of UC, as well as psoriasis (Torres & Rios 2008).

### **5.3 Metabolic Syndrome (MS) and Cardiovascular Diseases (CVD)**

Different overlapping guidelines have been proposed to define the MS: the cardiometabolic risk factors of obesity, impaired glucose tolerance (or type 2 diabetes), insulin resistance, dyslipidemia, and hypertension (Alberti et al., 2006; Grundy et al., 2005; Johnson & Weinstock, 2006). Just like psoriasis, MS is characterized by a pro-inflammatory state, characterized by a complex cytokines network.

In response to various metabolic signals the adipose tissue release the adipokines that modulate flogosis, lipid metabolism, and insulin sensitivity. A cluster of these adipokines is represented by pro-inflammatory cytokines (TNF-, IL-8 and IL-6) whose overproduction drives the psoriasis pathogenesis, as well as of certain basic features of MS like insulin resistance and diabetes (Arican et al., 2005; Nickoloff & Nestle, 2004; Rondinone, 2006). Consistent with this common pathophysiology, different studies have demonstrated that psoriasis patients show an increased risk of developing the metabolic syndrome (Henseler & Christophers, 1995; Neimann et al., 2006).

The multiple conditions that constitute the MS could very well be the main reasons for CVD in psoriasis patients.

IBD commonly refers to ulcerative colitis (UC) and Crohn's disease (CD), which are chronic inflammatory diseases of the gastrointestinal tract with unknown etiology. UC and CD have significant clinical differences, however, both diseases share similar pathogenic mechanisms and many extra-intestinal manifestations, and frequently respond

Many data indicate a stringent correlation between CD and psoriasis (Najarian & A. B. Gottlieb, 2003). Firstly, CD patients have been found to have a seven-fold higher risk of developing psoriasis than control subjects (Mrowietz et al., 2006). This association may be related to the following observations: a) it has been shown that TNF- has a key role in both conditions, valuing the hypothesis of common inflammatory pathways. This point has been further supported by the therapeutic efficacy of anti-TNF- antibodies; b) genetic evidences, such as polymorphisms in the TNF- promoter region and the close position of the susceptibility loci, link psoriasis to CD (Najarian & A. B. Gottlieb, 2003). In particular, a recent study demonstrated a significant association between CD and the IL-23 receptor gene (Duerr et al., 2006) and, as reported previously, IL-23 /IL-17 pathway is involved in

On the other hand, the association between psoriasis and UC has been described in only in recent studies, even if the first studies regarding this connection trace back to the 60s and early 70s (Brewerton et al., 1974; McEwen et al., 1971). Most recently, Cohen et coll. (Cohen et al., 2009), in a case-control study with 12,502 psoriasis patients, demonstrated that even though not as high as CD (odds ratio 2.49), UC association is statistically significant and far from being negligible (odds ratio 1.64). This often undervalued correlation is biologically conceivable because chronic systemic inflammation and TNF- constitute core features of

Different overlapping guidelines have been proposed to define the MS: the cardiometabolic risk factors of obesity, impaired glucose tolerance (or type 2 diabetes), insulin resistance, dyslipidemia, and hypertension (Alberti et al., 2006; Grundy et al., 2005; Johnson & Weinstock, 2006). Just like psoriasis, MS is characterized by a pro-inflammatory state,

In response to various metabolic signals the adipose tissue release the adipokines that modulate flogosis, lipid metabolism, and insulin sensitivity. A cluster of these adipokines is represented by pro-inflammatory cytokines (TNF-, IL-8 and IL-6) whose overproduction drives the psoriasis pathogenesis, as well as of certain basic features of MS like insulin resistance and diabetes (Arican et al., 2005; Nickoloff & Nestle, 2004; Rondinone, 2006). Consistent with this common pathophysiology, different studies have demonstrated that psoriasis patients show an increased risk of developing the metabolic syndrome (Henseler &

The multiple conditions that constitute the MS could very well be the main reasons for CVD

**5.2 Inflammatory bowel disease (IBD)** 

psoriasis pathogenesis (Blauvelt, 2008; Rizzo et al., 2011).

**5.3 Metabolic Syndrome (MS) and Cardiovascular Diseases (CVD)** 

UC, as well as psoriasis (Torres & Rios 2008).

characterized by a complex cytokines network.

Christophers, 1995; Neimann et al., 2006).

in psoriasis patients.

to the same treatments.

However, in various studies involving patients with psoriasis, the latter was identified as an independent risk factor for myocardial infarction regardless of the presence of the complete MS and an independent risk factor for coronary artery calcification (Gelfand et al., 2006).

Indeed, as of today there is forceful evidence that psoriasis, much like other systemic proinflammatory conditions (e.g. RA, SLE), may predispose to an increased CVD risk, following a nontraditional pathway to atherogenesis and premature vascular damage (Kimball et al., 2008c; Saphiro et al., 2007).

In conclusion, basic inflammatory activity in psoriasis could act independently of traditional risk factors, MetS included, and can increase the risk of CVD through its own underlying biological mechanisms (inflammation-driven atherogenesis).


↑ = Increase; ↓ = decrease; CRP = C-reactive protein; CV = Cardiovascular; DKK-1 = Dickkopf-1; LDL = Low-density lipoproteins; NGF = Nerve growth factor; NO = Nitric oxide; RANKL = Receptor-Activator of NFkappaB ligand; ROS = Reactive oxygen species; TF = Tissue Factor; VEGF = Vascular endothelial growth factor.

Table 1. Biological effects and clinical consequences of TNF- stimulation in different cells

al., 2009).

**7. Biological drugs** 

**7.1 TNF- inhibitors** 

Adalimumab (REVEAL)

Adalimumab (CHAMPION)

Adalimumab (ADEPT)

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 245

A supplementary tool to evaluate clinical remission in psoriatic patients is the Disease Activity Score (DAS) comprising the number of swollen and tender joints, the erythrocyte sedimentation rate and the general health of the patient (measured on a visual analogue scale) (Montecucco, 2006). The DAS measures 44 swollen joints, whereas the modified DAS 28 measures only 28 swollen and tender joints (Prevoo et al., 1995). The effect of psoriasis on the patient's quality of life is measured by the 10-item Dermatology Life Quality Index (DLQI) questionnaire. DLQI scores range from 0 (not at all) to 30 (very much) (Pathirana et

Biological therapies for the treatment of psoriasis are defined by their mode of action and are classified into 3 groups, the inhibitors of TNF- (adalimumab, certolizumab, etanercept, golimumab, and infliximab), the T-cell modulating agents (such as alefacept) and the

The TNF- inhibitors adalimumab, etanercept and infliximab have been approved by the FDA and EMEA for psoriasis and PsA treatment; they have been reviewed quite extensively in the past and the table 2 summarizes the clinical outcome for primary endpoints (e.g. PASI

In this chapter, instead will focus on the new TNF- blockers such as golimumab and

(50)

(46)

(814)

(108) MTX (110) Placebo (53)

(151)

**(n° of patients)**

A 40 mg weekly

A 40 mg eow

Placebo (52)

A 40 mg eow

Placebo (398)

A 40 mg eow

A 40 mg eow

Placebo (162)

**Major Results** 

PASI 75 at week 12: 80 PASI 75 at week 12: 53 PASI 75 at week 12: 4

PASI 75 at week 16: 71 PASI 75 at week 16: 7

PASI 75 at week 16: 80 PASI 75 at week 16: 36 PASI 75 at week 16: 19

ACR 20 at week 12: 58 ACR 20 at

**References** 

Gordon *et al*.,2006 *J Am Acad Dermatol* 55: 598–606.

Menter *et al*.,

Saurat *et al*., 2008

*Br J Dermatol* 

Mease *et al*., 2005

*Arthritis Rheum* 

2008 *J Am Acad Dermatol* 58: 106–115.

158: 558–566.

inhibitors of IL-12 and IL-23 (ustekinumab and briakinumab).

certolizumab (Mössner et al., 2008; Pathirana et al., 2009).

Psoriasis 16-week

Psoriasis 16-week

Psoriasis arthritis

**Drug Disease Trial Type Treatment**

RDBPC OLE until week 60

RDBPC OLE until week 52

RDBPC

24-week RDBPC OLE

and ACR) in randomized controlled studies.

Adalimumab Psoriasis 12-week

Recently, some studies have also shown that in psoriasis patients, the increased risk for myocardial infarction varies by age (higher in younger individuals) and disease severity (higher in severe forms) (Gelfand et al., 2006; Kremers et al., 2007; Mallbris et al., 2004). As such, a young patient with severe psoriasis is burdened by a CVD risk comparable with what is seen in the presence of traditional risk factors such as diabetes and hypertension.

Moreover, a variety of data indicates that psoriasis and CVD (mostly atherosclerosis) share common pathogenic features: both Th1 mediated, with an up-regulation of Th1 cytokines (TNF-, IFN-) and a systemic expression of adhesion molecules, neoangiogenesis factors, and superantigens, these latter potentially able to activate the T cells (Biedermann et al., 2004; Ettehadi et al., 2004; Gudjonsson et al., 2004). The table 1 summarizes the consequences of the TNF- over-expression in promoting inflammatory conditions such as psoriasis and atherogenesis.

Overlapping of genetic susceptibility loci between psoriasis and atherosclerosis is also worth mentioning, even though its role has yet to be fully understood (Becker et al., 1998).

Lastly, the two conditions also show similar histological aspects, mainly involving T cells, macrophages, mast cells and connective tissue matrix. (Nickoloff et al., 2007a; Nickoloff et al., 2007b).

Alongside the similar pathogenesis, other indirect factors might be responsible for psoriasis-CVD association; in fact some authors have found that a number of conventional systemic psoriasis treatments (e.g. methotrexate, acitretin, cyclosporine) might increase the effects of specific CVD risk factors (Katz et al., 1994; Strober & Menon, 2005; Taler et al., 1999).
