Disease Awareness

Epidemiology

Psoriasis is a widespread and complex disorder that results from an interplay between multiple genetic and environmental factors (Parisi et al., 2013; Griffiths & Barker, 2007).

Psoriasis has a wide range of clinical manifestations and although worldwide incidence and prevalence is poorly understood, psoriasis is estimated to affect around 2–4% of the population in Western countries (Parisi et al., 2013).

Like many chronic inflammatory disorders, genetics plays a key role in psoriasis development (Parisi et al., 2013). In addition, the manifestation of psoriasis may also be dependent environmental factors (Griffiths & Barker, 2007). Monozygotic twins demonstrate a concordance rate of 65–72% for psoriasis, supporting this hypothesis (Boehncke & Schön, 2015; Chandra et al., 2015).

Suggested environmental triggers responsible for the pathogenesis or intensification of psoriasis (Boehncke & Schön, 2015; Chandra et al., 2015):

• Infections
• Psychological stress 
• Cigarette smoking 
• Alcohol consumption 
• Obesity
• Exposure to some pharmacologic agents

Learn more about some of the important factors in the variation of psoriasis incidence and prevalence rates: (Parisi et al., 2013)

Age

Globally, psoriasis prevalence increases with age. Studies from the United Kingdom, Germany, Russia, and United States found an increasing trend with age until around 60 years, after which the prevalence reduced (Parisi et al., 2013).

In a recent Mediterranean regional study, a corrected database analysis that included 6,868 patients with a psoriasis diagnosis, the highest prevalence of psoriasis was found in the 61–70 year old group (2.90%). Psoriasis prevalence was just 0.30% among those under 18 years of age (Fernández-Armenteros et al., 2019). However, further studies need to determine the relationship between patients age and psoriasis prevalence after accounting for confounders.

Find out how age influences treatment selection from Professor Andrew Blauvelt.

Geographical location and ethnicity

Higher prevalence rates have been reported at higher latitudes and in Caucasians compared with other ethnic groups. This is likely due to a combination of genetic and environmental factors (Parisi et al., 2013). In addition, prevalence estimates may depend on the sampling method (eg medical databases or patient questionnaires).

Figure 1. Prevalence of psoriasis by location (Lee et al., 2017; Richard et al., 2018; Valent et al., 2018).

Understanding country-specific prevalence and incidence of psoriasis provides useful insights and may allow future resources to be allocated appropriately and adequately (Parisi et al., 2013). 

Genetics

Areas of chromosomes thought to harbour psoriasis genes are named psoriasis-susceptibility (PSORS) loci. Understanding the genetic variations in psoriasis and how these may influence the immunological disease-causing pathways may help in the development of novel and targeted personalised psoriasis therapies (Gunter et al., 2019).

Find out more about targeted and personalised therapies from Professor Andrew Blauvelt. He describes targeting therapy as a challenge, and stresses the importance of onset of action.

The HLA-C gene

There are at least 15 different PSORS loci responsible for susceptibility of psoriasis and the HLA-C gene has been consistently indicated as the most likely ‘psoriasis-susceptibility region 1’ (PSORS1) gene associated with psoriasis. HLA-C is a class I major histocompatibility complex (MHC) molecule and the locus at 6p21 within the MHC region has been shown to exhibit the strongest association with psoriasis development; abnormalities in this locus account for 35–50% of psoriasis susceptibility (Lowes et al., 2014; Singh et al., 2019).

Genome-wide association study findings 

Genome-wide association studies (GWAS) have identified psoriasis-associated genes; a recent review of genomic databases found 424 genes to have single nucleotide polymorphisms (SNPs) associated with psoriasis (Singh et al., 2019). Many of these genes are involved in skin barrier defence and the induction of innate or adaptive immunity. This has allowed GWAS to provide insights into the biological mechanisms associated with psoriasis susceptibility (Capon et al., 2012; Boehncke & Schön, 2015; Chandra et al., 2015; Aterido et al., 2016). 

GWAS have also discovered psoriasis-linked genes outside of the PSORS segments. Epigenetic changes have also been associated with the development of psoriasis (Singh et al., 2019).

Tobacco

Despite its decline since the 1960s, smoking remains a common part of westernised culture and is increasing in developing countries. A 2018 review paper by Pezzolo & Naldi reported smoking to be a risk factor for the development of psoriasis and a possible reduction to treatment adherence (Pezzolo & Naldi, 2019). One study included in the review – a pooled analysis of three studies (the Nurses’ Health Study [NHS], the Nurses’ Health Study II [NHS II], and the Health Professionals’ Follow-Up Study [HPFS]) – found that current smokers were twice as likely to develop psoriasis than non-smokers (adjusted OR 1.94, 95% CI 1.64–2.28). The likelihood of developing psoriasis was also seen to increase with an increase in the number of daily cigarettes (Armstrong et al., 2014).

Obesity

Obesity has also been associated with the risk of developing psoriasis. A recent systematic review confirmed that different adiposity measures such as BMI, waist circumference, waist-to-hip ratio, and weight gain positively correlated with increased risk of psoriasis (Aune et al., 2018).

A retrospective study of medical records between 1970–2014 found children diagnosed with psoriasis were more likely to be obese at the time of diagnosis than a control group without psoriasis (OR = 2.58, 95% Cl 1.48–4.52) (Hunjan et.al., 2018).

A previous study found obesity preceded psoriasis in 93% of paediatric patients with psoriasis who were either overweight or obese (Becker et.al., 2014)

Cross-talk between adipocytes and the immune system via various mediators such as adipokines have been proposed as a pathological explanation for the association between obesity and psoriasis (Wong et al., 2019).

Psoriatic arthritis

Psoriatic arthritis (PsA) occurs in around 20% of psoriasis patients as a systemic, polymorphic disease of the joints that varies in presentation and clinical course. (Zachariae et al., 2003; Goldenstein-Schainberg et al., 2012; Alinaghi et al., 2018). Skin involvement is not required to establish the diagnosis. PsA is diagnosed based on specific joint symptoms (such as enthesitis, present in 60–80%, and dactylitis, present in 30%) and serology (usually negative for rheumatoid factor and cyclic citrullinated peptide) (Coates & Helliwell, 2017). 

Prevalence of PsA differs with age. While the overall pooled proportion of PsA among psoriasis patients in a meta-analysis of 266 studies was 19.7% (95% CI, 18.5%–20.9%), this dropped to 3.3% (95% CI, 2.1%–4.9%) among patients <18 years of age (Alinaghi et al., 2018).

Prevalence of PsA also differs with ethnicity (Alinaghi et al., 2018).

Professor Andrew Blauvelt describes why psoriatic arthritis is an important factor to consider in treatment selection.

Genetics and psoriatic arthritis

It remains to be established why some patients with psoriasis develop PsA whilst others do not, but there are genetic differences between purely cutaneous psoriasis and PsA (O'Rielly et al., 2019).

Although the most dominant genetic effect for both psoriasis and PsA exists within the MHC region located on chromosome 6p21.3 (Rahman et al., 2012), dedicated GWAS and meta-analyses of psoriasis and PsA reveal differences in their genetic architecture and provide insights into the pathogenetic similarities and differences between cutaneous psoriasis and PsA (Stuart et al., 2015). Putative functional coding variants in TYK2 and TRAF3IP2 within psoriasis susceptibility genes have been strongly associated with cutaneous psoriasis and PsA (O'Rielly et al., 2019).

Genomics and serological factors may predict treatment response in tumour necrosis factor inhibitors in PsA. Detecting the genetic variants that create a predisposition to psoriatic disease may also be valuable in predicting response to biological therapy (O'Rielly et al., 2019).

Burden of disease

Psoriasis continues to have a significant impact on quality of life, health-care resource utilisation, costs and productivity. A US study suggested that despite treatment, many psoriasis patients continue to experience clinical symptoms and impaired functioning (Schaefer et al., 2015).

Find out from Professor Andrew Blauvelt the importance of quality of life for patients with psoriasis.

Patients with more severe psoriasis have a greater reduction in quality of life (QoL) and work productivity (Korman et al., 2016). A study evaluating real-life experiences revealed that patients often suffer in ways not recorded by typical severity measures (Pariser et al., 2015). Patients reported that itching/scratching, flaking/scaling and skin pain had a significant impact on their social and emotional lives (Pariser et al., 2015). 

Furthermore, the visible disfiguration associated with psoriasis, particularly when on exposed areas of the body, leads to a significant psychological impact and reduction in quality of life which can include relationship difficulties, employment problems and low self-esteem as well as avoidance of social situations and isolation (Boehncke & Boehncke, 2014; Cohen et al., 2012). 

Depression and anxiety

Psoriasis is strongly associated with depression and anxiety (Dalgard, 2015).

A UK primary care cohort study that assessed psychiatric morbidity and suicidal behaviour among 56,961 patients with psoriasis and 876,919 patients without psoriasis found that patients with psoriasis had higher prevalence ratios (PR) for (Parisi et al., 2019):

• A history of alcohol misuse 
• Bipolar disorder 
• Depression
• Anxiety disorders
• Self-harm
• Psychotropic medication prescription

Adolescence

Many cases of psoriasis begin in adolescence. In addition to the challenges seen in adult psoriasis patients, adolescents are also faced with additional and complex issues inherent to adolescence. It is therefore imperative that dermatologists and primary care physicians assess the psychosocial impact of psoriasis in adolescent patients to better identify the impact of the disease (Gonzalez et al., 2016).

Work absenteeism and lost productivity

A French national survey comparing people with and without psoriasis using an online questionnaire found that:(Claudepierre et al., 2018):

• Patients with psoriasis being treated with systemic therapies (PsoST) had greater sickness and absenteeism rates than those with psoriasis only (PsO)
  • 48% vs. 31% in the last 12 months, respectively 
• Sick leave within the previous 12 months was highest in patients with psoriasis and psoriatic arthritis (PsO + PsA) but sickness in both the PsO + PsA group and the PsoST group was significantly higher than the control group
  • 66% vs. 35%, respectively; p<0.05
• The impact on work productivity, measured by an estimated mean decrease in productivity over the previous 7 days in those with active psoriasis, was significantly higher for those in the PsoST group and the PsO + PsA group compared to the controls
  • 43.3% and 57.6% vs. 27.9%, respectively (p<0.05 for both)

Figure 2. Impact on absenteeism and work productivity over the past 7 days (Claudepierre et al., 2018).
a, active psoriasis skin lesions; b, active psoriasis skin lesions and/or psoriatic arthritis; ^* significantly higher compared to controls (p<0.05); ^** significantly lower compared to controls (p<0.05).

Mortality

A 12-study systematic review and meta-analysis found the following pooled relative risks (RR) for all-cause mortality (Dhana et al., 2019):

• 1.13 (95% CI 1.09–1.16) in mild psoriasis 
• 1.52 (95% CI 1.35–1.71) in severe psoriasis

The pooled RRs for cardiovascular mortality were

• 1.05 (95% CI 0.92–1.20) in mild psoriasis 
• 1.38 (95% CI 1.09–1.74) in severe psoriasis

For noncardiovascular causes, mortality risk from liver disease, kidney disease, and infection was significantly increased in psoriasis, regardless of disease severity. There was also a significantly increased mortality risk associated with neoplasms in severe psoriasis patients and chronic lower respiratory disease in all and mild psoriasis patients (Dhana et al., 2019). 

Pathophysiology

Psoriasis is more than a dermatological disorder. It is a chronic immune-mediated disease in which genetically susceptible individuals develop cutaneous inflammation and keratinocyte hyperproliferation (Nestle et al., 2009; Boehncke & Schön, 2015).

Psoriasis is associated with epidermal thickening and keratinocyte hyperproliferation. As a result, the skin becomes inflamed and has raised plaques with silvery scales (as shown in the figure below), which can cover large areas of the body (Nestle et al., 2009; Boehncke & Schön, 2015; Palfreeman et al., 2013).

Clinical course 

The clinical course of psoriasis can be divided into two stages: an initiation phase and a maintenance phase that perpetuates the inflammatory state (Sabat et al., 2007). This separation may be helpful when considering treatments that act in the trigger phase and those that block the self-perpetuating cycle of inflammation (Diani et al., 2015).

The histological features of psoriasis include epidermal (keratinocyte) hyperplasia, leukocyte infiltrates and an increased number of leaky vessels in the dermis of the skin (see Figure 3). Recently, lymphoid-like tissues have also been identified in the psoriatic plaques (Diani et al., 2015).

Figure 3. Psoriasis pathophysiology (adapted from Palfreeman et al., 2013).

Initiation phase

An interplay between environmental and genetic factors facilitates disease-initiating events and the initiation of the complex and dynamic psoriatic cascade within skin and immune cells (Nestle et al., 2009).

The histological features of cutaneous psoriasis are due to the interactions between T cells, dendritic cells and keratinocytes, giving rise to sustained inflammation in the skin (Figure 4) (Becher et al., 2012; Diani et al., 2015). It is now well accepted that T cells, particularly T helper (Th) 17 lymphocytes, play an important role as effector cells in the pathogenesis of psoriasis (Büchau et al., 2007; Sabat et al., 2007).

Early events in psoriasis involve the following steps (Becher et al., 2012):

• People who are genetically predisposed to develop psoriasis (such as those with HLA-C*06:02, the main psoriasis risk allele) seem to show melanocyte-specific autoimmunity (Prinz, 2017). In these patients, skin insults activate dendritic cells (DCs) through pattern recognition receptors (PRRs) or cytokines interleukin 1 (IL-1), TNFα and IL-36. Meanwhile, a subset of DCs called plasmacytoid dendritic cells (pDCs) that typically mount a type 1 interferon (IFN) response to viral/microbial DNA have also been implicated in psoriasis
  • Research has suggested that combination of self-DNA with an antimicrobial peptide called LL37 (also called CAMP) can lead to a pDC-mediated immune response against self-DNA and subsequent activation of T cells. Infiltration of psoriatic skin has been observed for pDCs and it has been hypothesised that skin damage and subsequent release of self-DNA can lead to local pDC activation and drive autoimmunity and inflammation in psoriasis (Lande et al., 2007)
• Activated DCs produce IL-23, which activates T cells and innate lymphoid cells (ILCs) to produce TNFα, IL-17 and IL-22
  • IL-22 induces keratinocyte hyperproliferation
  • TNFα and IL-17 activate DCs and keratinocytes, leading to up-regulation of adhesion molecules by the skin epithelium, angiogenesis and chemokine production
  • IL-17–induced chemokines CXCL1 and CXCL8 which recruit neutrophils
• IL-17R engagement by keratinocytes leads to production of CCL20, which attracts more circulating CCR6+ γδ T cells and ILCs. This escalates into a self-amplifying inflammatory loop that can also be mediated by the adaptive immune system (Becher et al., 2012) 

Figure 4. Initiation of psoriasis (adapted from Becher et al., 2012).
CCL20, chemokine ligand 20; CCR6, chemokine receptor 6; CLA, cutaneous lymphocyte antigen; CXCL, chemokine (C-X-C motif) ligand; IFN-γ, interferon-gamma; IL, interleukin; ILC, innate lymphoid cells; PRRs, pattern recognition receptors; RORγt, retinoid-related orphan receptor γt; T_H, T helper cell; TNF-α, tumour necrosis factor-alpha.

Maintenance phase

Key processes during disease maintenance involve ‘cross talk’ between epithelial and immune cells and the transition from innate to adaptive immunity as described in Figure 5 (Nestle et al., 2009).

Figure 5. Maintaining psoriasis – transition from adaptive to innate immunity (adapted from Nestle et al., 2009).
CCL, chemokine ligand; CXCL, chemokine (C-X-C motif) ligand; IFN-α, interferon-alpha; IFN-γ, interferon-gamma; IL, interleukin; T_H, T helper cell; TNF-α, tumour necrosis factor-alpha.

The cells and cytokines involved in the perpetuation/maintenance of psoriasis represent key therapeutic targets (Sugiyama et al., 2005; Nestle et al., 2009; Chandrakumar et al., 2014; Boehncke & Schön, 2015; Diani et al., 2015).

• Secretion of IL-23 and IL-12 by DCs within the lymph nodes induces naïve T cells to differentiate into Th17 or Th1 cells, respectively
• T cells migrate to skin and produce further cytokines (IFNγ, IL-17 and IL-22) which drive epidermal cell proliferation

These cytokines lead to over-activity of keratinocytes and this leads to the release of cytokines and chemokines that continue to recruit and activate inflammatory cells. The balance between regulatory and effector functions is lost and regulatory T cells (Tregs) are unable to control ongoing inflammation.

Cytokines in psoriasis

Cytokines are small polypeptides (8–80 kDa) produced in response to antigens, microorganisms or other non-infectious stimuli that can regulate immune and inflammatory reactions (Brotas et al., 2012). 

A large number of inflammatory cytokines are elevated in psoriasis and, in a subset of these cytokines, their serum concentrations correlate with disease severity (Baliwag et al., 2015).

The combined effects of the cytokines found in psoriasis lesions may explain most of the clinical features of psoriasis: (Baliwag et al., 2015).

• Keratinocyte hyperproliferation 
• Increased neovascularisation 
• Skin inflammation 

An understanding of which cytokines play a pivotal role in the disease process has revealed potential therapeutic targets, and several cytokines have been successfully targeted, revolutionising treatment (Baliwag et al., 2015).

Find out more about the challenge of targeted treatments for psoriasis from Professor Andrew Blauvelt.

TNFα

TNFα is the most studied psoriasis cytokine due to its increased expression in skin lesions/serum/synovial fluid of psoriasis/PsA and the therapeutic efficacy of its specific inhibitors (fusion proteins, monoclonal antibodies) (Brotas et al., 2012).

Tumour necrosis factor-alpha (TNFα) is an important Th1 pro-inflammatory cytokine that is up-regulated in psoriasis (Brotas et al., 2012; Lowes et al., 2014). It is often described as a ‘primary cytokine’ since it can independently initiate a number of mechanisms capable of triggering inflammation.

What TNFα-mediated mechanisms trigger inflammation?

TNFα has been demonstrated to be involved in (Brotas et al., 2012; Lowes et al., 2014):

• Endothelial activation
• Immunocyte recruitment
• Immunocyte-keratinocyte recruitment
• Amplification of inflammation
• Keratinocyte hyperproliferation

Where is TNFα detected? TNFα is present in psoriatic dermal CD45(+)HLA-DR(+) leukocytes consisting of CD11c(+) dendritic cells and CD163(+) macrophages. In peripheral blood, an increase in the TNFα-producing myeloid subsets of CD14(-) 6-sulfo-LacNac(+) dendritic cells and CD14(+)CD16(+) "intermediate" monocytes was observed in psoriasis compared with healthy control subjects. Detectable levels of TNFα are not present in other cells, including keratinocytes or T cells, making these cell types unlikely targets of TNFα blockers (Brunner et al., 2013).

What causes the reduction in inflammation during anti-TNFα therapy?

The decrease in tissue inflammation during anti-TNFα therapy is not due to immediate killing of TNFα-producing cells but rather results from a rapid downregulation of the pathogenic IL-12/IL-23-driven immune response (Brunner et al., 2013).

IL-17

The cytokine family IL-17 plays a central role in the promotion of an inflammatory response, activating dendritic cells to release a variety of cytokines and chemokines to promote neutrophil chemotaxis, enhancing the production of antimicrobial peptides, while also stimulating fibroblast release of vascular endothelial growth factor (VEGF) to support angiogenesis and endothelial cell proliferation (Amatya et al., 2017; Roman & Chiu, 2017).

The IL-17 family of cytokines consists of six members (IL-17A to IL-17F), which exist as a combination of homo- and heterodimers. The most influential cytokine in the family is believed to be IL-17A, which is found as a homodimer or as a heterodimer with IL-17F, while IL-17C, E and F also function as homodimers.

IL-17 cell surface receptors

Further complexity is added to the IL-17 cytokine family by the presence of five cell surface receptors (IL-17-RA–RE). IL-17RA forms heterodimers with IL-17RB, IL-17RC, and IL-17RE with the IL-17RA/RC heterodimer capable of binding both IL-17A and IL-17F. Meanwhile, IL-17E has been shown to bind to the IL17-RA/RB heterodimer and IL-17C binding to the IL-17RA/RE heterodimer (Amatya et al., 2017; Roman & Chiu, 2017).

IL-17 and psoriasis

IL-17 sustains inflammation in psoriatic plaques by stimulating production of antimicrobial peptides leading to the recruitment of inflammatory cells, enhanced proliferation of keratinocytes and inhibition of keratinocyte differentiation (Soler et al., 2011; Lowes et al., 2014; Diani et al., 2015).

IL-17A as a therapeutic target

The role of IL-17A in the pathogenesis of psoriasis and as targets for the IL-17 antagonists secukinumab and ixekizumab is described in Figure 6 (Lønnberg et al., 2014). These IL-17A antagonists have shown promising activity in clinical studies, supporting the role of IL-17A in disease pathogenesis (Langley et al., 2014; Blauvelt et al., 2015; Mrowietz et al., 2015; Paul et al., 2015a; Reich et al., 2015a; Thaci et al., 2015; Gottlieb et al., 2017). Indeed, secukinumab has been shown to decrease keratinocyte activation and improve keratinocyte differentiation in skin biopsy samples from psoriasis patients investigated using histology and transcriptomics (Krueger et al., 2019).

Clinical and immunological response patterns to the anti-IL-17A antibody secukinumab in patients with moderate-to-severe psoriasis are indicative of a neutrophil-keratinocyte axis in psoriasis involving neutrophil-derived IL-17 (Reich et al., 2015b).

IL-17 receptor as a therapeutic target

Brodalumab disrupts IL-17 signalling by targeting the IL-17 receptor itself, rather than binding the IL-17 cytokine. This means brodalumab blocks the signalling of not just the IL-17A cytokine, but also IL-17F, the IL-17A/F heterodimer and IL-17E (also called IL-25).

In addition, large amounts of IL-17C are produced in keratinocytes (production in psoriasis is about 100 times greater than IL-17A), inhibiting IL-17C may therefore be beneficial for psoriasis patients. To date, brodalumab is the only anti-IL-17 treatment that affects IL-17C, since it blocks the shared IL-17 receptor (Galluzzo et al., 2019).

Figure 6. IL-17A in the pathogenesis of psoriasis, and targets for brodalumab, secukinumab, and ixekizumab (adapted from Lønnberg et al., 2014).
IFN-γ, interferon-gamma; NK, natural killer; Tc, cytotoxic T cell; TGF-β, transforming growth factor-beta; Th, T helper cell; TNFα, tumour necrosis factor-alpha.

IL-23

IL-23 is a heterodimeric cytokine with two subunits (p19 and p40) that is highly expressed in psoriatic skin lesions. IL-23 – which is produced mainly by dendritic cells and macrophages – has emerged as a key pro-inflammatory cytokine, driving autoimmunity and the development of IL-17A-producing Th17 cells (Di Meglio & Nestle, 2010; (Haugh et al., 2018; Fotiadou et al., 2018).

Essentially, IL-23 activates and maintains the Th17 pathway that drives psoriasis (Fotiadou et al., 2018). IL-23 modulates immune responses mediated by type 1-polarised T cells in peripheral tissues. Patients with psoriasis show increased numbers of type 1-polarised T cell in lesions and their peripheral circulation (Haugh et al., 2018). 

IL-23 triggers the differentiation of Th17 and Th22 cells. These, in turn, upregulate the inflammatory cascade that underlies the development of psoriatic lesions. For instance, Th17 cells produce IL-17, IL-22, IL-21 and TNFα, which induces a self-amplifying inflammatory response in the keratinocytes of pre-psoriatic skin (Fotiadou et al., 2018; Haugh et al., 2018).

IL-17 recruits leucocytes to the lesion (Haugh et al., 2018). Eosinophils, mast cells, basophils and epithelial cells produce IL-25 (also known as IL-17E). IL-25 signals through IL-17 receptors to augment Th2 cell immune responses (Sakkas et al., 2019). In the ‘IL-23/Th17 axis’ model of psoriasis, Th17 cells interact with skin-resident cells contributing to the psoriatic disease phenotype. 

As mentioned, IL-23 is a heterodimer – the cytokine consists of two subunits. The P19 subunit is specific to IL-23. IL-12 and IL-23 both contain p40 (Haugh et al., 2018; Fotiadou et al., 2018). Drugs that selectively target the IL-23p19 offer a new biologic treatment for moderate–to–severe psoriasis (Fotiadou et al., 2018).

Ustekinumab, which inhibits IL-12 and IL-23, and the IL-23 inhibitors, guselkumab, mirikizumab, risankizumab and tildrakizumab, have demonstrated efficacy in psoriasis (Langley et al., 2015; Blauvelt et al., 2017a; Reich et al., 2017a; Gordon et al., 2018b; Gisondi et al., 2019).

Find out more about treatment selection and head-to-head studies with IL-17 and IL-23 inhibitors from Professor Andrew Blauvelt.

IFNγ

Interferon gamma (IFNγ) also plays a role in the pathogenesis of psoriasis, and is thought to activate antigen-presenting cells, lead to the production of IL-23 from dendritic cells and favour IL-17-producing cell recruitment and activation (Lowes et al., 2014; Diani et al., 2015). Biologics targeting TNF can cause skin lesions that resemble psoriasis - an adverse event known as paradoxical psoriasis. Type 1 interferons seem to drive paradoxical psoriasis by inducing autoimmune reactions to T cells (Mylonas and Conrad, 2018). 

IL-1

IL-1 is a proinflammatory cytokine principally expressed by keratinocytes and involved in the homeostasis of the skin. Various activating, promoting and inhibitory agents are involved in the regulation of IL-1 signalling including different IL-1 isoforms, competitive inhibitors and decoy receptors. These all function together to prevent excessive inflammatory responses. Typically, IL-1 signalling is active during stress, inflammatory and immune responses, however, various factors have been shown to result in IL-1 pathway dysregulation, including (Gómez-Garcia et al., 2018):

• Viral infection
• Ultraviolet a and b exposure
• Chemical exposure
• Skin barrier integrity

Dysregulation of IL-1 has been associated with the development of a variety of chronic, autoinflammatory skin diseases, including psoriasis. Recent data suggests that IL-1β-IL-1R signalling may contribute to this process via regulation of IL-17 producing cells within the skin, in addition to stimulation of keratinocytes, resulting in amplification of the inflammatory cascade (Cai et al., 2019). IL-1R signalling appears to correlate with psoriasis disease progression and treatment response (Cai et al., 2019).

IL-22

A member of the IL-20 family of cytokines, IL-22 is produced by Th17 and Th22 cells and has been implicated in several inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis and psoriasis. IL-22 acts as a homodimer binding to a receptor complex of IL-10R2 and IL-22R1 resulting in activation of members of the signal transducer and activator of transcription (STAT) family of transcription factors (Hao, 2014; Chiricozzi et al., 2018).

Expression of the IL-22 receptor is increased in psoriatic lesional skin and IL-22 signalling in psoriasis has been linked to enhanced keratinocyte migration, increased epidermal thickness, reduced keratinocyte differentiation and higher expression levels of various molecules such as chemokines and chemoattractants, although not as strongly as IL-17 (Chiricozzi et al., 2018). IL-22 may collaborate with other soluble factors and cells together forming inflammatory circuits that become pathologically amplificated in psoriasis. Targeting IL-22 may be a promising potential therapeutic for plaque psoriasis (Wawrzycki et al., 2019).

IL-36

A member of the IL-1 family of cytokines, IL-36 comprises IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by both TNF-α and IL-17. In contrast, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36 (Madonna et al., 2019).

Chemokines in psoriasis

CXC chemokine ligand 1 (CXCL1) and CXCL8 are neutrophil chemoattractants that are produced by keratinocytes in response to IL-17 and IL-22 signalling. The cytokine-mediated upregulation of chemokines, including CXCL1 and CXCL8, has been shown to promote the recruitment of neutrophils to psoriatic lesions (Reich et al., 2015b). The presence of neutrophils may be an important driver of the induction phase of psoriasis due to their secretion of proinflammatory cytokines, including IL-17, and the formation of neutrophil extracellular traps, which contain high-levels of self-DNA/nucleic acids (Steffen et al., 2018).

Click here to view the Treatment section for further details on TNFα, IL-17, IL-12 and IL-23 inhibitors.

Trigger factors for psoriasis

Figure 7. Common psoriasis trigger factors (Lowes et al., 2014; Marshall et al., 2015).

Emotional stress

Between 26–88% of patients with psoriasis reported stress in a meta-analysis of the relationship between stress and psoriasis (Rousset & Halioua, 2018).

Research suggests that the activation of corticotropin-releasing hormone in stress provokes the degranulation of mast cells, which in turn release pro-inflammatory cytokines, exacerbating psoriasis (Theoharides & Cochrane, 2004; Harvima et al., 2008; Evers et al., 2010; Heller et al., 2011;). It has also been suggested that stress can modify the permeability of the epidermal barrier, which maintains the inflammatory skin reaction (Elias et al., 1999; Garg et al., 2001).

Continuous exposure to stress could also be a trigger for psoriasis, as one study found flares to be more frequently reported in patients with psoriasis who were experiencing permanently high levels of stress, particularly related to stressful family events (Evers et al., 2010).

Infection

The association between bacterial (streptococcal) throat infection and psoriasis is thought to be due to activation of T cells in the tonsils, which then move to the skin, where CD8+ T cells cross-recognise keratin determinant on keratinocytes, and CD4+ T cells interact with dendritic cells and amplify the response, with IL-23 induced IL-17 responses giving rise to the clinical psoriasis (Diani et al., 2015).