**5. Overview of psoriasis**

#### **5.1 Psoriasis – Genetic**

It is generally accepted that the genetic background for psoriasis susceptibility is pivotal for the appearance of the symptoms. Intensive family studies since the early 1950s and linkage analysis studies pointed out several genetic loci that play a role in psoriasis (Bhalerao et al., 1998). In the last decade, a molecular biology approach emerged to identify abnormally expressed genes and proteins contributing to psoriasis (Jackson et al., 1999) (Chen et al., 2000). Two major genes under investigation are IL12B on chromosome 5q, which expresses interleukin-12B; and IL23R on chromosome 1p, which expresses the interleukin-23 receptor, and is involved in T cell differentiation. T cells are involved in the inflammatory process that leads to psoriasis. These genes are on the pathway that ends up upregulating tumor necrosis factor-α and nuclear factor κB, two genes that are involved in inflammation (Nestle et al., 2009). Genome-wide association studies have also identified several new genomic loci, and compelling evidence has shown an interaction between the HLA-C and ERAP 1 loci, implicating pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis (Strange et al., 2010).

#### **5.2 Psoriasis – Keratinocytes**

Psoriasis is a chronic inflammatory disease characterized by epidermal keratinocytic hyper proliferation and abnormal differentiation (Abdou et al., 2008). The upper most layer of skin, the epidermis, consists primarily of keratinocytes (>90% of all epidermal cells) (Sun et al., 1979). The keratin intermediate filament network is responsible for the extremely high keratinocyte stiffness and resilience. This could manifest into the rugged protective nature of the human epidermis (Lulevich et al., 2010). Therefore, keratinocytes form an effective barrier to the entry of protein antigens, chemical irritants, and infectious agents in to the body (Fuchs 1995), all while resisting environment stress, external pressure, and sheer force. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines implicated in pathogenesis (Lowes et al., 2007).

#### **5.2.1 Keratinocytes – Dendritic & T cells**

Researchers have identified many of the immune cells involved in psoriasis, and the chemical signals they send to each other to coordinate inflammation. The immune system consists of an innate immune system, and an adaptive immune system. In the innate system, immune cells have receptors that have evolved to target specific proteins and other antigens which are commonly found on pathogens. In the adaptive immune system, immune cells respond to proteins and other antigens that they may never have seen before, which are presented to them by other cells. The immune cells, such as dendritic cells (Dendritic cells are present in tissues in contact with the external environment, such as the skin: Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response) and T cells, move from the dermis to the epidermis, secreting chemical signals, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6, which cause inflammation, and interleukin18, 22 which causes keratinocytes to proliferate (Banchereau et al., 1998) (Nestle et al., 2009). Recent studies indicate that various cytokines play an essential role in the induction and maintenance of psoriatic lesion.

#### **5.2.2 Keratinocytes – Cytokines**

196 Psoriasis

adaptive immune responses and impair effector functions of macrophages, NK cells and lymphocytes. For example, treatment of peripheral blood leukocytes (PBLs) with catecholamines *in vitro* results in the suppression of interleukin-12 (IL-12) synthesis and an increase in IL-10 production (Elenkove et al., 1996). Data from both human and animal studies show that the connections between the neuroendocrine system and immune system provide a finely tuned regulatory system required for health. However, the immune cells and cytokines influencing keratinocyte function play a major role in the development and

It is generally accepted that the genetic background for psoriasis susceptibility is pivotal for the appearance of the symptoms. Intensive family studies since the early 1950s and linkage analysis studies pointed out several genetic loci that play a role in psoriasis (Bhalerao et al., 1998). In the last decade, a molecular biology approach emerged to identify abnormally expressed genes and proteins contributing to psoriasis (Jackson et al., 1999) (Chen et al., 2000). Two major genes under investigation are IL12B on chromosome 5q, which expresses interleukin-12B; and IL23R on chromosome 1p, which expresses the interleukin-23 receptor, and is involved in T cell differentiation. T cells are involved in the inflammatory process that leads to psoriasis. These genes are on the pathway that ends up upregulating tumor necrosis factor-α and nuclear factor κB, two genes that are involved in inflammation (Nestle et al., 2009). Genome-wide association studies have also identified several new genomic loci, and compelling evidence has shown an interaction between the HLA-C and ERAP 1 loci, implicating pathways that integrate epidermal barrier dysfunction with innate and adaptive

Psoriasis is a chronic inflammatory disease characterized by epidermal keratinocytic hyper proliferation and abnormal differentiation (Abdou et al., 2008). The upper most layer of skin, the epidermis, consists primarily of keratinocytes (>90% of all epidermal cells) (Sun et al., 1979). The keratin intermediate filament network is responsible for the extremely high keratinocyte stiffness and resilience. This could manifest into the rugged protective nature of the human epidermis (Lulevich et al., 2010). Therefore, keratinocytes form an effective barrier to the entry of protein antigens, chemical irritants, and infectious agents in to the body (Fuchs 1995), all while resisting environment stress, external pressure, and sheer force. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines

Researchers have identified many of the immune cells involved in psoriasis, and the chemical signals they send to each other to coordinate inflammation. The immune system consists of an innate immune system, and an adaptive immune system. In the innate system, immune cells have receptors that have evolved to target specific proteins and other antigens

pathogenesis of psoriasis.

**5.1 Psoriasis – Genetic** 

**5. Overview of psoriasis** 

**5.2 Psoriasis – Keratinocytes** 

immune dysregulation in psoriasis (Strange et al., 2010).

implicated in pathogenesis (Lowes et al., 2007).

**5.2.1 Keratinocytes – Dendritic & T cells** 

Various inflammatory cytokines and growth factors have been shown to be strongly induced in keratinocytes in psoriatic lesion. Although it is thought that the induction of cytokine production is the consequence of the activation of infiltrating immune cells rather than a triggering factor for the inflammatory process (Lowes et al., 2007). Three types of cytokines elaborated by keratinocytes are of particular interest in this context: growth factors for keratinocytes, endothelial cells and neutrophil-attracting chemokines. Several growth factors are able to induce keratinocyte proliferation and have been found to be highly expressed in lesional psoriatic epidermis. Transforming growth factor *α* (Elder et al., 1989) (Addison et al., 2010) and amphiregulin-epidermal growth factor (Cook et al., 1992) have been shown to induce epidermal proliferation and reproduce some aspects of the psoriatic phenotype when expressed in epidermal keratinocytes in transgenic animals (Cook et al., 1999) (Vassar et al., 1991). The epidermal growth factor (EGF) receptor ligand amphiregulin (AREG) has been implicated as an important autocrine growth factor in several epithelial malignancies and in psoriasis, a hyperproliferative skin disorder. In vitro, in vivo and clinical studies are well established the role of growth factors and neuropeptides in cutaneous innervation and there is substantial evidence that sensory neuropeptides contribute to the development of psoriasis (Saraceno et al., 2006).

#### **5.2.3 Keratinocytes & peripheral CRH/CRH-R1**

CRH is a central component of the local HPA axis, which has a functional equivalent in the skin. The ability of CRH to activate mast cells may explain its proinflammatory actions and the pathophysiology of certain skin conditions, which are precipitated or exacerbated by stress, such as atopic dermatitis, eczema, psoriasis, and urticaria (Theoharides et al., 1998). Mast cells are derived from stem cells in the bone marrow and migrate into tissues where they are prominently located just below the dermal–epidermal junction; they mature, depending on the tissue, under the influence of stem cell factor (SCF), interleukin 3 (IL-3), IL-4 and IL-9 (Wedemeyer et al., 2000). Mast cell infiltration and/or proliferation in the skin can be triggered by SCF released from fibroblasts and other immune cells, nerve growth factor (NGF) released from nerve endings, or RANTES (regulated on activation, normal T cells, expressed and secreted) (Conti et al., 1998) . Mast cells can also secrete SCF (de Paulis et al., 1999) and NGF (Xiang et al., 2000), thus affecting their own growth and activation (Gagari et al., 1997). The cytokines expressed by mast cells are primarily pro-inflammatory or are necessary for innate immunity [e.g. IL-1, IL-6, IL-8 and

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 199

axis and elevated SAM system responses to stress may be crucial in better understanding the inflammatory characteristics of psoriasis, particularly in stress-responders. For instance, decreased secretion of cortisol and increased levels of epinephrine (Zangeneh et al., 2008) and norepinephrine may stimulate the release of mast cells, affect skin barrier function, and upregulate proinflammatory cytokines, which could thereby maintain or exacerbate psoriasis severity (Evers et al., 2010). Some authors have commented that this decreased cortisol response may be similar to how psoriasis flares with steroid withdrawal, as evidenced by the well known phenomena of steroid-induced psoriasis

Glucocorticoids are essential for maintaining barrier competency, as exemplified in GR−/<sup>−</sup> mouse, where loss of GR function led to incomplete epidermal stratification, hyperproliferation and abnormal differentiation (Bayo et al., 2008). In addition, the cortisol analogue dexamethasone has been shown to acutely influence expression of genes regulating cell proliferation, differentiation, apoptosis and inflammation in primary human keratinocytes (PHK) (Elias 2005) (Stojadinovic et al., 2007). Accordingly, cortisol (hydrocortisone) is regarded as the most potent therapy for many inflammatory skin conditions including psoriasis and atopic dermatitis. Keratinocytes contain an abundance of cholesterol, the precursor to all steroids, as they are capable of synthesizing cholesterol de novo (Menon et al., 1985). Additionally, the cholesterol transporter, steroidogenic acute regulatory (StAR) protein has been identified in human epidermis by immunofluorescence

longitudinal study of patients with psoriasis to show a relationship between cortisol levels and daily stressors, these results suggest that patients who continuously experience higher levels of daily stressors are characterized by persistently lower cortisol levels and might thus be more vulnerable to the effects of stress on their disease (Everse et al., 2010). Hannen et al., in 2011 demonstrated that primary human Keratinocytes (PHK) express all the elements required for cortisol steroidogenesis and metabolite pregnenolone through each intermediate steroid to cortisol. They showed that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3βHSD1, CYP21 and CYP11B1) that are required for cortisol synthesis. Collectively these data show that PHK are capable of extraadrenal cortisol synthesis, which could be a fundamental pathway in skin biology with

HPA axis is a critical adaptive system that maximizes survival potential in the face of physical or psychological challenge. The principal end products of the HPA axis, glucocorticoid hormones, act on multiple organ systems, including the brain, to maintain homeostatic balance. The brain is a target of stress, and the hippocampus is the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids (Zangeneh et al., 2009). There is increasing evidence that the experience of stressful events is associated with the course of chronic inflammatory skin diseases. Buske-Kirschbaum et al., reported attenuated responsiveness of the HPA axis and further, an increased reactivity of the SAM system to stress in patients suffering from atopic dermatitis (AD) (Buske-Kirschbaum et al.,

s study in 2010 is the first

rebound (Richards et al., 2005).

**5.3.2 Psoriasis & stress axis** 

**5.3.1 Psoriasis & steroidogenic capabilities of keratinocytes** 

histochemistry (**b**Slominski, et al., 2004) (Tuckey 2005). Evers'

implications in psoriasis and atopic dermatitis (Hannen et al., 2011).

tumor necrosis factor α (TNF-α) (Wedemeyer et al., 2000). Human mast cells were recently shown to be particularly rich in both CRH and the structurally related peptide urocortin (Ucn) ( Kempuraj et al., 2004) and express multiple CRH receptor isoforms which suggests autocrine actions of CRH(Cao et al., 2003).

#### **5.2.4 Keratinocytes – CRH & Mast cells**

Skin and hypothalamic mast cells appear to have important physiological functions as sensors of stressful events with bidirectional regulation of the HPA axis; a local increase of the levels of CRH or Ucn in extracranial tissues under stress could adversely affect different disease states (Theoharides et al., 1998). Hypothalamic mast cells are located close to nerve endings that contain CRH and can be activated by acute stress (Rozniecki et al., 1999). Acute stress can trigger mast cell degranulation (Singh et al., 1999) and increased the number of skin mast cells and also can worsened delayed hypersensitivity, effects blocked by pretreatment with a CRH receptor antagonist (Kaneko et al., 2003). Neuropeptides can also activate mast cells in a receptor-independent manner by activating G proteins directly. Regardless of the mechanism of activation, mast cell-derived vasoactive, pro-inflammatory and neurosensitizing molecules could act on keratinocytes, endothelial cells or nerve endings to liberate additional molecules and lead to chronic inflammation and neuropathic hypersensitivity or pain. The Kempuraj et al., findings indicate that mast cells are not only the target, but also a potential source of CRH and Ucn that could have both autocrine and paracrine functions, especially in allergic inflammatory disorders (Kempuraj et al., 2004), atopic dermatitis and psoriasis exacerbated by stress (Theoharides et al., 2004).

#### **5.2.5 Keratinocytes – CRH & Stress**

The study of Mitsuma et al., in 2001 showed that CRH induces the proliferation of keratinocytes via interaction with CRH receptors (Mitsuma et al, 2001) and it may indicate the possible correlation of the proliferation of keratinocytes and the degree of stress. Therefore, activation of the stress system, via the direct and indirect effects of CRH, might affect the susceptibility of an individual to certain autoimmune, allergic, infectious, inflammatory or neoplastic diseases (Arbiser et al, 1999). The biological effects of CRH have been shown to include the inhibition of keratinocyte proliferation and regulation of adhesion molecules and cytokines (**c**Slominski et al, 2000)(Pisarchik et al., 2001)(Quevedo et al, 2001)(Zbytek et al, 2002). Dysregulation of the HPA and SAM systems has been proposed as one possible underlying cause of stress-induced flares of psoriasis (Heller et al., 2011).

#### **5.3 Psoriasis & stress**

Generally, in normal individuals, stress elevates stress hormones (i.e., increases cortisol levels). However, according to available studies, exposure to stress in psoriatic patients has been associated with diminished HPA responses and upregulated sympathic adernomedullary (SAM) responses (Richards et al., 2005). Evers et al., found psoriasis patients had significantly lower cortisol levels at moments when daily stressors are at peak levels. The study also reported that psoriasis patients with overall high levels of daily stressors exhibited lower mean cortisol levels, as compared to psoriatics with overall low levels of daily stressors (Evers et al., 2010) (Zangeneh et al., 2008). These blunted HPA

tumor necrosis factor α (TNF-α) (Wedemeyer et al., 2000). Human mast cells were recently shown to be particularly rich in both CRH and the structurally related peptide urocortin (Ucn) ( Kempuraj et al., 2004) and express multiple CRH receptor isoforms which suggests

Skin and hypothalamic mast cells appear to have important physiological functions as sensors of stressful events with bidirectional regulation of the HPA axis; a local increase of the levels of CRH or Ucn in extracranial tissues under stress could adversely affect different disease states (Theoharides et al., 1998). Hypothalamic mast cells are located close to nerve endings that contain CRH and can be activated by acute stress (Rozniecki et al., 1999). Acute stress can trigger mast cell degranulation (Singh et al., 1999) and increased the number of skin mast cells and also can worsened delayed hypersensitivity, effects blocked by pretreatment with a CRH receptor antagonist (Kaneko et al., 2003). Neuropeptides can also activate mast cells in a receptor-independent manner by activating G proteins directly. Regardless of the mechanism of activation, mast cell-derived vasoactive, pro-inflammatory and neurosensitizing molecules could act on keratinocytes, endothelial cells or nerve endings to liberate additional molecules and lead to chronic inflammation and neuropathic hypersensitivity or pain. The Kempuraj et al., findings indicate that mast cells are not only the target, but also a potential source of CRH and Ucn that could have both autocrine and paracrine functions, especially in allergic inflammatory disorders (Kempuraj et al., 2004),

atopic dermatitis and psoriasis exacerbated by stress (Theoharides et al., 2004).

The study of Mitsuma et al., in 2001 showed that CRH induces the proliferation of keratinocytes via interaction with CRH receptors (Mitsuma et al, 2001) and it may indicate the possible correlation of the proliferation of keratinocytes and the degree of stress. Therefore, activation of the stress system, via the direct and indirect effects of CRH, might affect the susceptibility of an individual to certain autoimmune, allergic, infectious, inflammatory or neoplastic diseases (Arbiser et al, 1999). The biological effects of CRH have been shown to include the inhibition of keratinocyte proliferation and regulation of adhesion molecules and cytokines (**c**Slominski et al, 2000)(Pisarchik et al., 2001)(Quevedo et al, 2001)(Zbytek et al, 2002). Dysregulation of the HPA and SAM systems has been proposed as one possible underlying cause of stress-induced flares of psoriasis (Heller et al., 2011).

Generally, in normal individuals, stress elevates stress hormones (i.e., increases cortisol levels). However, according to available studies, exposure to stress in psoriatic patients has been associated with diminished HPA responses and upregulated sympathic adernomedullary (SAM) responses (Richards et al., 2005). Evers et al., found psoriasis patients had significantly lower cortisol levels at moments when daily stressors are at peak levels. The study also reported that psoriasis patients with overall high levels of daily stressors exhibited lower mean cortisol levels, as compared to psoriatics with overall low levels of daily stressors (Evers et al., 2010) (Zangeneh et al., 2008). These blunted HPA

autocrine actions of CRH(Cao et al., 2003).

**5.2.4 Keratinocytes – CRH & Mast cells** 

**5.2.5 Keratinocytes – CRH & Stress** 

**5.3 Psoriasis & stress** 

axis and elevated SAM system responses to stress may be crucial in better understanding the inflammatory characteristics of psoriasis, particularly in stress-responders. For instance, decreased secretion of cortisol and increased levels of epinephrine (Zangeneh et al., 2008) and norepinephrine may stimulate the release of mast cells, affect skin barrier function, and upregulate proinflammatory cytokines, which could thereby maintain or exacerbate psoriasis severity (Evers et al., 2010). Some authors have commented that this decreased cortisol response may be similar to how psoriasis flares with steroid withdrawal, as evidenced by the well known phenomena of steroid-induced psoriasis rebound (Richards et al., 2005).

#### **5.3.1 Psoriasis & steroidogenic capabilities of keratinocytes**

Glucocorticoids are essential for maintaining barrier competency, as exemplified in GR−/<sup>−</sup> mouse, where loss of GR function led to incomplete epidermal stratification, hyperproliferation and abnormal differentiation (Bayo et al., 2008). In addition, the cortisol analogue dexamethasone has been shown to acutely influence expression of genes regulating cell proliferation, differentiation, apoptosis and inflammation in primary human keratinocytes (PHK) (Elias 2005) (Stojadinovic et al., 2007). Accordingly, cortisol (hydrocortisone) is regarded as the most potent therapy for many inflammatory skin conditions including psoriasis and atopic dermatitis. Keratinocytes contain an abundance of cholesterol, the precursor to all steroids, as they are capable of synthesizing cholesterol de novo (Menon et al., 1985). Additionally, the cholesterol transporter, steroidogenic acute regulatory (StAR) protein has been identified in human epidermis by immunofluorescence histochemistry (**b**Slominski, et al., 2004) (Tuckey 2005). Evers' s study in 2010 is the first longitudinal study of patients with psoriasis to show a relationship between cortisol levels and daily stressors, these results suggest that patients who continuously experience higher levels of daily stressors are characterized by persistently lower cortisol levels and might thus be more vulnerable to the effects of stress on their disease (Everse et al., 2010). Hannen et al., in 2011 demonstrated that primary human Keratinocytes (PHK) express all the elements required for cortisol steroidogenesis and metabolite pregnenolone through each intermediate steroid to cortisol. They showed that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3βHSD1, CYP21 and CYP11B1) that are required for cortisol synthesis. Collectively these data show that PHK are capable of extraadrenal cortisol synthesis, which could be a fundamental pathway in skin biology with implications in psoriasis and atopic dermatitis (Hannen et al., 2011).

#### **5.3.2 Psoriasis & stress axis**

HPA axis is a critical adaptive system that maximizes survival potential in the face of physical or psychological challenge. The principal end products of the HPA axis, glucocorticoid hormones, act on multiple organ systems, including the brain, to maintain homeostatic balance. The brain is a target of stress, and the hippocampus is the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids (Zangeneh et al., 2009). There is increasing evidence that the experience of stressful events is associated with the course of chronic inflammatory skin diseases. Buske-Kirschbaum et al., reported attenuated responsiveness of the HPA axis and further, an increased reactivity of the SAM system to stress in patients suffering from atopic dermatitis (AD) (Buske-Kirschbaum et al.,

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 201

and "non-stress responders," respectively (Koo 1995). Psoriasis itself can serve as a stressor for patients. Psoriasis can be a disfiguring skin disease causing social stigma. Accordingly, patients often suffer significant interpersonal and psychological distress. Patients commonly experience difficulties in social interactions, especially in meeting new individuals and forming romantic relationships. In general, most patients demonstrate adverse psychological consequences, including poor self-esteem, anxiety, depression, and for some, even develop suicidal ideation (Russo et al 2004). As psoriasis can cause considerable stress for patients and increased levels of stress are likely to exacerbate psoriasis, the disease process, thus, becomes a self-perpetuating, vicious cycle (Kimball et al., 2005). Therefore, treatment considerations for psoriasis stress responders should integrate methods of

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**6. References** 

245–52.

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2006) and psoriasis (Buske-Kirschbaum et al., 2010). It has been indicated that the redistribution of leukocytes in response to acute stress is mediated by the SAM, since adrenalectomy or blockade of β-adrenergic receptors has been found to mitigate this effect (Dhabhar et al., 1995) (Engler et al., 2004). It is widely accepted that the SAM system represents a major immunoregulatory system that controls various aspects of immunity (Sanders et al., 2002).

#### **5.3.3 Psoriasis & SAM system: Aspect of psychoneuroimmunology**

It has been suggested that a dysfunctional sympathoadernomedulatory (SAM) system may increase the risk of an aberrant immune response, especially under stressful conditions when the system is activated. In fact, altered leukocyte distribution to acute stress, for example, increased numbers of NK cells, monocytes, CD4+ and CD8+ cells have been reported in psoriasis patients (Schmid-Ott et al., 2001). Under non-pathological conditions, this process may optimize immunoprotection in the case of wounding or infection. However, in the psoriatic patient, leukocyte trafficking to the (chronically inflamed) skin has been found to be a major step in the development of psoriatic eruption (Mehlis et al., 2003). Thus, the finding of a stress-induced increase of leukocyte trafficking with a potentially increased influx of leukocytes into the skin could be of clinical significance, and could at least partly explain the often observed stress-induced exacerbation of psoriatic lesions. However, there is growing evidence that T cell mediated autoimmune processes and action of proinflammatory cytokines cause hyperproliferation of keratinocytes and assume the psoriatic phenotype (Krueger et al., 2005). When exposed to psychosocial stress, psoriasis patients showed increased monocyte and (activated) T cell number when compared to healthy controls. Further, a shift towards a TH1-derived cytokine profile could be identified. These findings suggest that in psoriasis patient's stress may change immune functions towards a pathological relevant immune profile which could explain the often observed aggravation of psoriatic plaques in psoriasis patients under stressful conditions. Just as in many dermatologic conditions, psoriasis appears to worsen with stress in a significant segment of patients. For example, more than half of patients with psoriasis retrospectively report having experienced stressful life events before an exacerbation of the disease (Gupta et al., 1989) (Fortune et al., 1998). Studies report that the proportion of psoriasis patients who are "stress responders" ranges from 37% to 78% (Picardi et al., 2001).

#### **5.3.4 Psoriasis & "stress responders"**

#### Does stress cause or exacerbate psoriasis?

The answer is both, because the stress response disrupts physiological homeostasis and body function and contributes to disease production (Burchfield, 1979). This disruption of physiological homeostasis in the skin barrier is the trigger and stressors may contribute directly to the production of psoriasis disease or it contributes to the development of stress behavior, which increases the risk of disease. Stress has been indicated as a trigger in many dermatologic conditions and with each of these conditions, one encounters both patients who experience a close chronologic association between stress and exacerbation of their skin disease, and patients for whom their emotional states seem to be unrelated to the natural course of their cutaneous disorder. These two groups are considered "stress responders" and "non-stress responders," respectively (Koo 1995). Psoriasis itself can serve as a stressor for patients. Psoriasis can be a disfiguring skin disease causing social stigma. Accordingly, patients often suffer significant interpersonal and psychological distress. Patients commonly experience difficulties in social interactions, especially in meeting new individuals and forming romantic relationships. In general, most patients demonstrate adverse psychological consequences, including poor self-esteem, anxiety, depression, and for some, even develop suicidal ideation (Russo et al 2004). As psoriasis can cause considerable stress for patients and increased levels of stress are likely to exacerbate psoriasis, the disease process, thus, becomes a self-perpetuating, vicious cycle (Kimball et al., 2005). Therefore, treatment considerations for psoriasis stress responders should integrate methods of psychotherapy and pharmacotherapy that can decrease stress.

#### **6. References**

200 Psoriasis

2006) and psoriasis (Buske-Kirschbaum et al., 2010). It has been indicated that the redistribution of leukocytes in response to acute stress is mediated by the SAM, since adrenalectomy or blockade of β-adrenergic receptors has been found to mitigate this effect (Dhabhar et al., 1995) (Engler et al., 2004). It is widely accepted that the SAM system represents a major immunoregulatory system that controls various aspects of immunity

It has been suggested that a dysfunctional sympathoadernomedulatory (SAM) system may increase the risk of an aberrant immune response, especially under stressful conditions when the system is activated. In fact, altered leukocyte distribution to acute stress, for example, increased numbers of NK cells, monocytes, CD4+ and CD8+ cells have been reported in psoriasis patients (Schmid-Ott et al., 2001). Under non-pathological conditions, this process may optimize immunoprotection in the case of wounding or infection. However, in the psoriatic patient, leukocyte trafficking to the (chronically inflamed) skin has been found to be a major step in the development of psoriatic eruption (Mehlis et al., 2003). Thus, the finding of a stress-induced increase of leukocyte trafficking with a potentially increased influx of leukocytes into the skin could be of clinical significance, and could at least partly explain the often observed stress-induced exacerbation of psoriatic lesions. However, there is growing evidence that T cell mediated autoimmune processes and action of proinflammatory cytokines cause hyperproliferation of keratinocytes and assume the psoriatic phenotype (Krueger et al., 2005). When exposed to psychosocial stress, psoriasis patients showed increased monocyte and (activated) T cell number when compared to healthy controls. Further, a shift towards a TH1-derived cytokine profile could be identified. These findings suggest that in psoriasis patient's stress may change immune functions towards a pathological relevant immune profile which could explain the often observed aggravation of psoriatic plaques in psoriasis patients under stressful conditions. Just as in many dermatologic conditions, psoriasis appears to worsen with stress in a significant segment of patients. For example, more than half of patients with psoriasis retrospectively report having experienced stressful life events before an exacerbation of the disease (Gupta et al., 1989) (Fortune et al., 1998). Studies report that the proportion of psoriasis patients who

**5.3.3 Psoriasis & SAM system: Aspect of psychoneuroimmunology** 

are "stress responders" ranges from 37% to 78% (Picardi et al., 2001).

The answer is both, because the stress response disrupts physiological homeostasis and body function and contributes to disease production (Burchfield, 1979). This disruption of physiological homeostasis in the skin barrier is the trigger and stressors may contribute directly to the production of psoriasis disease or it contributes to the development of stress behavior, which increases the risk of disease. Stress has been indicated as a trigger in many dermatologic conditions and with each of these conditions, one encounters both patients who experience a close chronologic association between stress and exacerbation of their skin disease, and patients for whom their emotional states seem to be unrelated to the natural course of their cutaneous disorder. These two groups are considered "stress responders"

**5.3.4 Psoriasis & "stress responders"**  Does stress cause or exacerbate psoriasis?

(Sanders et al., 2002).


Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 203

Dobson H, Smith RF. What is stress, and how does it affect reproduction. Anim Reprod Sci.,

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Fortune DG, Richards HL, Main CJ, Griffiths CE. What patients with psoriasis believe about

Gagari E, Tsai M, Lantz CS, Fox LG, Galli SJ. Differential release of mast cell interleukin-6

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Goldstein DS, Kopin IJ. Adrenomedullary, adrenocortical, and sympathoneural responses to

Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and

Gupta MA, Gupta AK, Kirkby S, et al. A psychocutaneous profile of psoriasis patients who are stress reactors. A study of 127 patients. Gen Hosp Psychiatry 1989; 11:166-73. Hannen RF, Michael AE, Jaulim A, Bhogal R, Burrin JM, Philpott MP. Steroid synthesis by

Heller MM, Lee ES, Koo JY. Stress as an influencing factor in psoriasis. Skin Therapy Lett.

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**11** 

*1Spain* 

**Personality in Patients with Psoriasis** 

Carmen Brufau Redondo1 and Francisco-Javier Corbalán Berná1

It has been known since antiquity that a connection exists between the skin and the mind. In fact, the first documented case of psychodermatosis dates to 1700 BC, when the physician to the prince of Persia speculated that the prince's psoriasis was caused by anxiety over succeeding his father to the throne (Shafii & Shafii, 1979). However, it was not until 1891 that Brocq and Jacquet coined the term neurodermatitis and hypothesised that there was a pathological association between the skin and the autonomic nervous system, given that itching precipitates the appearance of lesions (Braun-Falco, Plewig, Wolff, & Winkelmann). A further 62 years passed before "Emotional Factors in Skin Disease" (Wittkower & Russell, 1953) was published. Since then, physicians, and dermatologists in particular, have been steadily becoming aware of the impact of an individual's emotional state on skin disease and how this organ can reflect, like a mirror, their psychological state. It should come as no

Psychological factors have traditionally been associated with the onset, development, and persistence of skin disease (Alexander, 1951) and there is evidence to suggest an association between stress and the exacerbation of skin lesions (Kimyai-Asadi & Usman, 2001; Robles, 2007; Vileikyte, 2007). Recent longitudinal studies of a general hospital population show the involvement of psychological factors, such as stress, depression, and anxiety, in individuals who present skin disease (Magin, Sibbritt, & Bailey, 2009). In addition to depression or anxiety (da Silva, Müller, & Bonamigo, 2006; Fried, Gupta, & Gupta, 2005; Lotti, Buggiani et al., 2008; Morell-Dubois et al., 2008; Radmanesh & Shafiei, 2001; Richards & Fortune, 2006), higher rates of dissociative disorders (Konuk, 2007; Gupta, 2006), sexual dysfunction (Mercan, 2008) or problems of excessive alcohol consumption attributed to psychological distress (Kirby et al., 2008) have been found in this group than in the healthy population. Psoriasis has been associated with psychological distress, such as feelings of shame, shyness,

low self-esteem, and stigmatization (Magin, Adams, Heading, Pond, & Smith, 2009).

Psychological stress occupies a special place among the factors that trigger psoriasis, of which patients are very aware. They openly identify it as underlying many of their

surprise that these two structures have a common origin in the ectoderm.

**1. Introduction** 

**1.1 Skin diseases and psychological factors** 

Ramón Martín-Brufau1, Jorge C. Ulnik2,

*1Universidad de Murcia 2Universidad de Buenos Aires* 

*2República Argentina* 

