Causes & pathophysiology of psoriasis

Date of preparation: December 2024

Causes & pathophysiology of psoriasis

Psoriasis is mainly studied as an autoimmune condition, and it is now well established that psoriasis is the result of interactions between environmental factors and a complex genetic background.¹ 

At the cellular level, psoriatic plaques are characterised by:¹ 

1. Abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia. 
2. Infiltration of the dermis by various immune cells, causing inflammation and damage. 
3. Increased dermal capillary density, with enhanced permeability in wide-calibre vessels. 

The epidermis has been identified as a key player in the early pathogenic steps of psoriasis by contributing to the activation of the immune response as well as the recruitment of inflammatory and endothelial cells.¹

Risk factors

Psoriasis is a multifactorial disease that is associated with both genetic and environmental triggers or risk factors.² It is estimated that approximately 10% of people inherit one or more of the genes associated with psoriasis, but only a fraction of them (2–3%) will go on to develop the disease.³ 

Several environmental risk factors have been associated with psoriasis.^2–4 

1. Medications including lithium, antimalarials, beta-blockers, quinidine and indomethacin can trigger flares or make psoriasis worse.^2,3 
2. Skin injury or trauma such as scratching, tattoos, burns and vaccinations can trigger the development of psoriasis.^2,3 
3. Smoking tobacco doubles the risk of developing psoriasis.³ 
4. Drinking alcohol may impair skin barrier function and trigger psoriasis.² 
5. Recurring strep throat or upper respiratory tract infections may trigger or exacerbate psoriasis.^1,2 Those with HIV/AIDS may experience more severe psoriasis.^2,3 
6. Stress can trigger or worsen psoriasis.^2,3 
7. Obesity is linked with psoriasis development and increased severity.³ 
8. Sunlight exposure may exacerbate psoriasis in some people, but it is usually beneficial.² 
9. Cold temperatures and dry weather can make psoriasis worse.³ 

The elimination of psoriasis risk factors is important for controlling the disease.⁴

Underlying pathophysiology

The understanding of the pathogenesis of psoriasis has evolved significantly over several decades.⁵

Figure 1: Evolution of psoriasis pathophysiology^5,8

The role of cytokines: TNF and IL-17/23

Psoriasis is thought to be a cytokine-led disease.^5,6 Tumour necrosis factor (TNF) was one of the first cytokines to be defined as pathogenic in psoriasis. In synergy with TNF, the interleukin (IL)-17/23 axis is now known to also be central to psoriasis pathogenesis.⁷ 

The roles of IL-17 and IL-23 in the psoriasis inflammatory cascade have traditionally been illustrated by a waterfall hypothesis. 

1. IL-23 is an upstream regulatory cytokine, which acts at the top of the cascade and stimulates the production of IL-17 by T cells.^5,7 
2. IL-17 binds to its receptor, IL-17R, inducing the proliferation of keratinocytes and the production of 
pro-inflammatory cytokines that drive inflammation in psoriasis.^5,7

Figure 2: The IL-23/IL-17 axis waterfall hypothesis

However, we now understand that the processes involved in the pathophysiology of psoriasis are far more complex. Research into keratinocyte-produced factors shows that a feedback amplification loop drives the IL-17/23 axis and further amplification arises from the production of chemokines, which recruit immune cells to the lesion.^8–11

Figure 3: Psoriasis pathophysiology involves an amplification cycle that contributes to the development and maintenance of chronic inflammation^12–15

The role of intracellular signalling: JAK/STAT

The JAK-STAT (Janus kinase–signal transducer and activator of transcription) pathway plays a crucial role in the intracellular signalling of many cytokines. Cytokines bind to extracellular receptors, causing the 
JAK-STAT cascade to activate downstream effects (e.g., producing inflammatory cytokines).¹¹

Figure 4: The role of the JAK-STAT pathway in psoriasis¹¹

The role of PDE4

Phosphodiesterase 4 (PDE4) is involved in regulating the inflammatory response at the molecular level and plays a key role in chronic plaque psoriasis and other inflammatory conditions. Degradation of cyclic adenosine monophosphate (cAMP) to adenosine monophosphate (AMP) by PDE4 leads to the production of pro-inflammatory cytokines (TNF, IL-23).¹⁶

Figure 5: The role of PDE4¹⁶

The importance of intercellular and intracellular mechanisms

Intercellular and intracellular mechanisms drive the pathogenesis of psoriasis together, and both can be targeted for treatment.^{5,6,8–11,16–19}

Figure 6: Key mechanisms of psoriasis pathophysiology