**5.1 Psoriatic arthritis**

240 Psoriasis

23 level caused by cyclosporin A, UV therapy and biological agents correlates to clinical improvements in psoriasis patients (A. L. Gottlieb et al., 2005; Haider et al., 2008; Piskin et

Transforming growth factor (TGF)-1, IL-6 and IL-21 are all required to transform naïve T cells into cells expressing the unique lineage-specific transcription factor, RORC variant 2 and IL-23 receptors with subsequent binding of IL-23 resulting in differentiation into Th17

Th17 cells in turn produce the pro-inflammatory cytokines IL-17A, IL-17F, IL-22 and IL-26 (Langrish et al., 2005) that activate KCs leading to hyperproliferation and production of proinflammatory cytokines / chemokines, which recruit and activate other immune cells in the inflamed skin, enlarging the inflammatory response and consequently the clinical disease features. Another support for a role of the IL-23/Th17 pathway in psoriasis comes from whole genome studies showing that genetic variants of the IL-23 receptor are

Regarding the clinical relevance of the IL-23/Th17 pathway, targeting the common subunit p40 of IL-12 and IL-23 demonstrated clinical improvement in psoriasis. Two anti-IL-12p40 Moabs, ustekinumab and ABT-874, have been recently developed as psoriasis cures. As we'll see in more detail later, ustekinumab and ABT-874 are humanized IgG1 Moabs that binding to the p40 subunit of human IL-12 and IL-23, prevents interaction with IL-12Rb1. Phase I (Kauffman et al., 2004) and phase II (Kimball et al., 2008b; G. G. Krueger et al., 2007) studies

The safety profile of ustekinumab in psoriasis has been evaluated in 2 phase III studies. Of these, PHOENIX I assessed the efficacy and safety of ustekinumab 45 and 90 mg administered subcutaneously at weeks 0, 4, and then every 12 weeks over 76 weeks of treatment (Leonardi et al., 2008). 67.1 % and 66.4 % of patients who received ustekinumab 45mg and 90 mg respectively, achieved PASI-75 at week 12 compared to placebo control (3.1 %). The observed adverse events were mild, non-life threatening and not significantly different from the placebo group. The most commonly reported adverse events were upper respiratory tract infections, nasopharyngitis, headache, and arthralgia. The PHOENIX II trial (Papp et al., 2008) was conducted to further assess if dosing intensification would increase the response to treatment in partial responder patients (between PASI-50 and PASI-75). It was found that dosing intensification resulted in increased clinical efficacy only in patients receiving 90mg, but not 45mg, of ustekinumab every 8 weeks (PASI-75 in 68.8 % of patients receiving 90mg every 8 weeks versus 33.3 % of patients receiving 90 mg every 12 weeks). The incidence and type of adverse events observed did not differ between PHOENIX I and II studies. Ustekinumab is also effective in the treatment of psoriatic arthritis and this study again confirmed that ustekinumab is

Regulatory T cells (Tregs) are characterized by their ability to suppress the activation and proliferation of effector T cells (CD4+/CD8+) by direct contact with antigen presenting cells (Gondek et al., 2005) or by releasing IL-10 (Annacker et al., 2003) and/or TGF-1 (Nakamura

supported the use of both antibodies as effective treatments for psoriasis.

al., 2004).

cells.

associated with psoriasis (Capon et al., 2007).

well tolerated (A. Gottlieb et al., 2009).

**4.2.3 Regulatory T cells** 

et al., 2004) (**Figure 3**).

PsA is traditionally included among common co-morbidities of psoriasis, even if it should be rather considered a component of the clinical spectrum of psoriatic disease. Skin manifestations occur before the onset of arthritis in the large majority of patients (A. B. Gottlieb et al., 2006), and in general, the prevalence of arthritis in psoriasis patients is estimated to be approximately 30% (Gisondi et al., 2005; Zachariae et al., 2002).

In PsA pathogenesis the TNF- plays a key role, promoting osteoclastogenesis and bone resorption by stimulating the receptor-activator of NFkB, expressed in bone marrow osteoclast precursors (Abu-Amer et al., 2000; Keffer et al., 1991). Moreover, TNF- has been noted to increase DKK-1 (dickkopf-1), a glycoprotein able to inhibit the bone apposition process by obstructing osteoblast growth (Baron & Rawadi, 2007; Diarra et al., 2007).

Numerous clinical observations support these experimental data, particularly a number of clinical trials showed a significant inhibition of joint damage in patients who underwent anti-TNF therapy, confirming the role of TNF in altered bone remodeling.

Approximately 20% of PsA patients are estimated to suffer from a severe and destructive form of arthritis, that leads to overall increased disability (D. D. Gladman et al., 1990; Queiro-Silva et al., 2003). Interestingly, different results indicate that the DMARDs (diseasemodifying antirheumatic drugs) might not be able to inhibit disease progression and osteoarticular damage, even though they are generally useful in providing relief of clinical symptoms (Kana et al., 2003).

There is also convincing evidence of increased mortality in PsA patients, which seems to be related to disease activity, characterized by high erythrosedimentation rate, high medication level, and significant radiological damage at early patient visits (D. D. Gladman et al., 1998). Fortunately, as we shall see later, the mortality in PsA patients has gradually improved by using the biological drugs (Ali et al., 2007).

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 243

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

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

> ↑ inflammatory cytokine/expression

cells/apoptosis

↑ release of VEGF

↑ expression of adhesion

maturation/activation) ↑ DKK-1 level (↓ osteoclast

glucose metabolism ↑ circulating levels of FFA

Hepatocytes Induction of IL-6 Raised CRP serum levels

proliferation NGF-induced

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

↑ = Increase; ↓ = decrease; CRP = C-reactive protein; CV = Cardiovascular; DKK-1 = Dickkopf-1; LDL =

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

Impaired NO Bioavailability Induction of TF expression

↑ Metalloproteinase synthesis

ROS release

molecules

(↑osteoclast

development)

and LDL

**Cell Types Biological Effects Clinical Consequences** 

↑ Inflammation Endothelial injury Epidermal Proliferation

↑ Angiogenesis

Articular erosion

infection

factors

dysfunction

↑ leukocytes recruitment Endothelian dysfunction Hemostasis impairment

Bone resorption promotion Bone apposition inhibition

Disadvantageous metabolic response to injury and

↑ in traditional CV risk

CRP-induced vascular

Neurogenic inflammation

(Kimball et al., 2008c; Saphiro et al., 2007).

biological mechanisms (inflammation-driven atherogenesis).

Leukocytes Activation/maturation

Endothelial cells Suppression of precursor

Osteoclast precursors ↑ RANKL expression

Adipocytes Dysregulation of lipid and

Neural cells Modulation of cell

endothelial growth factor.

Condrocytes/Synoviocytes Apoptosis
