**4.2.2 The IL-23/Th17 pathway**

238 Psoriasis

and in particular the data from the CD18hypo PL/J psoriasis mouse model demonstrate (Wang et al., 2009) that the psoriasis-form inflammatory skin disorder critically depends on

In human psoriasis, the number of epithelium-lining macrophages was reported to increase in lesional skin. These macrophages can play a role in the regulation of epidermal proliferation and differentiation (van den Oord & de Wolf-Peeters, 1994); also vigorous interactions between macrophages and keratinocytes (Djemadji-Oudjiel et al., 1996) may be

Macrophages, under different conditions, secrete various pro-inflammatory cytokines: TNF- , IL-1b, IFN-, IL-6, IL-10, IL-12, and IL-18, (Willment et al., 2003) and notably, in a recent study CD68+ macrophages were identified as important TNF-source in human psoriasis and upon treatment with anti-TNF- antibody macrophage levels decreased in the plaque psoriasis, with clinical psoriasis resolution (Marble et al., 2007). In according to this finding, it is also showed that CD68+ macrophages as important TNF- source in human psoriatic skin, which had distinctly decreased number and TNF- concentration following bath-PUVA therapy (Wang et al., 2009). This was also found in a T-cell-independent mouse

Based on literature data, an emerging model of psoriasis pathogenesis in humans suggests that dermal macrophages, activated by T-cell cytokines, produce large amounts of TNF-,

Until the 1990s, psoriasis was thought to be a disease of disordered keratinoctye proliferation and differentiation (G. G. Krueger et al., 1984) and epidermal hyperplasia was the most prominent clinical and histological feature. For this reason, the old psoriasis treatments using antimetabolites including methotrexate which limit epidermal hyperproliferation. However, successive evidence from clinical studies and, experimental models support the theory that psoriasis is a T cell-mediated inflammatory skin disease (Lew et al., 2004) affecting genetically predisposed individuals and the epidermal

The first evidence resulting in psoriasis being widely considered as a T cell mediated autoimmune disease came from the success in the psoriasis treatment of T cell-targeted therapies such as cyclosporine (Baker et al., 1987), tacrolimus (Jegasothy et al., 1992) or CD4-

A pivotal study involved the testing of IL-2-diphtheria-toxin fusion protein in psoriasis patients (S. L. Gottlieb et al., 1995). This agent selectively depleting activated T cells that express IL-2 receptors from psoriasis skin lesions and resulted in clinical remission of

Subsequently, administration of another fusion protein, cytotoxic T-lymphocyte antigen 4 (CTLA4)-antibody, was shown to reverse the clinical and cellular features of psoriasis

an appropriate activation of macrophages, with ample release of TNF-a.

model, with an increase of TNF- in macrophages (Stratis et al., 2006).

leading to skin changes (Clark & Kupper, 2006).

**4.2 Dysfunction of the adaptive immune response cells** 

hyperplasia is an effect of cellular immune infiltration.

specific monoclonal antibodies (Moabs) (J. Prinz et al., 1991).

**4.2.1 Role of T cells** 

psoriasis vulgaris.

involved in the psoriasis pathogenesis (van den Oord & de Wolf-Peeters, 1994).

The IL-23/Th17 pathway is an exciting area in psoriatic pathology (**Figure1**) because it has led to the development of promising innovative treatments which specifically target this pathway (D'Elios et al., 2010). The development, characterization and function of Th17 cells and the role of IL-23 in Th17-cell dependent chronic inflammation in psoriasis have been recently reviewed (Di Cesare et al., 2009). Briefly, IL-23 is a heterodimeric cytokine (Oppmann et al., 2000) composed of the subunits IL-23p19 and IL-12p40 (an IL-12 subunit). Intradermal injection of IL-23 in mice resulted in the development of a psoriasis-form phenotype with histopathological features (Chan et al., 2006). IL-23 can mediate epidermal hyperplasia, acanthosis, hyperparakeratosis and orthohyperkeratosis by way of TNF-, IL-20R2 and IL-22 (Chan et al., 2006; Zheng et al., 2007). These data are supported by findings in humans including an mRNA over-expression of IL-23p19 and IL-12p40 seen in psoriatic skin lesions, compared to uninvolved skin. Further other results indicate that IL -23 production occurs at inflammatory skin sites and is mediated by tissue-resident and/or recruited immune cells, such DCs and KCs (Piskin et al., 2006).

The pathogenic role of IL-23 in psoriasis is strongly supported by the clinical findings that anti-TNF- agents can reduce IL-23p19 and IL-12p40 mRNA levels also the reduction of IL-

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 241

Tregs express CD4, height CD25 and Foxp3 and are about the 1-5 % of the total population

Dysfunction of Tregs has been implicated in the pathogenesis of various autoimmune diseases such as multiple sclerosis and rheumatoid arthritis (RA) and in psoriasis; where Treg function and proliferation are both defective (Sugiyama et al., 2005). This combination may result in a failure to limit the activation and proliferation of pathogenic T cells, contributing to the ongoing inflammation seen in psoriasis; for this reason strategies that correct Treg function or increase the Treg/pathogenic T cell ratio may be potential treatments for psoriasis (Sugiyama et al., 2005). Phototherapy, for example, might induce Treg type suppressor cells as well as eliminate pathogenic T cells (Baadsgaard et al., 1990),

Today we know that during the time course of psoriasis, certain conditions may appear at somewhat unpredictable time points in a progressive fashion. These so-called comorbidities, often become manifest years after the onset of skin manifestations and are

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

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

Numerous clinical observations support these experimental data, particularly a number of clinical trials showed a significant inhibition of joint damage in patients who underwent

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

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

estimated to be approximately 30% (Gisondi et al., 2005; Zachariae et al., 2002).

process by obstructing osteoblast growth (Baron & Rawadi, 2007; Diarra et al., 2007).

anti-TNF therapy, confirming the role of TNF in altered bone remodeling.

supporting a possible role of Treg cells in protection against psoriasis.

of peripheral CD4+ cells.

**5. Principal co-morbidities** 

**5.1 Psoriatic arthritis** 

symptoms (Kana et al., 2003).

using the biological drugs (Ali et al., 2007).

frequently observed in severe forms of 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 al., 2004).

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 cells.

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

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

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

#### **4.2.3 Regulatory T cells**

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

Tregs express CD4, height CD25 and Foxp3 and are about the 1-5 % of the total population of peripheral CD4+ cells.

Dysfunction of Tregs has been implicated in the pathogenesis of various autoimmune diseases such as multiple sclerosis and rheumatoid arthritis (RA) and in psoriasis; where Treg function and proliferation are both defective (Sugiyama et al., 2005). This combination may result in a failure to limit the activation and proliferation of pathogenic T cells, contributing to the ongoing inflammation seen in psoriasis; for this reason strategies that correct Treg function or increase the Treg/pathogenic T cell ratio may be potential treatments for psoriasis (Sugiyama et al., 2005). Phototherapy, for example, might induce Treg type suppressor cells as well as eliminate pathogenic T cells (Baadsgaard et al., 1990), supporting a possible role of Treg cells in protection against psoriasis.
