What causes psoriasis?

Causes of Psoriasis

Psoriasis is primarily caused by a complex interplay between genetic predisposition and environmental triggers that lead to dysregulated immune responses, resulting in chronic inflammation and hyperproliferation of keratinocytes in the skin. 1

Genetic Factors

• Psoriasis has a strong genetic component with multiple susceptibility loci identified:
  • HLA-Cw6 allele (PSORS1) is the major susceptibility gene 1
  • At least 8 chromosomal loci (PSORS I-VIII) have been linked to psoriasis 1
  • Family history is a significant risk factor, with higher concordance rates in monozygotic twins

Immune System Dysfunction

The pathogenesis involves several key immune mechanisms:

• IL-23/Th17 axis dysregulation is central to psoriasis development 1, 2

  • Inappropriate activation of cutaneous T cells and dendritic cells
  • Release of pro-inflammatory cytokines (TNF-α, IL-17, IL-22, IL-23)
  • These cytokines create a "feed forward" inflammatory response 2

• Immune cell interactions form an inflammatory loop:

  • Dendritic cells produce IL-23, activating Th17 cells
  • Th17 cells produce IL-17, IL-22, and other cytokines
  • Keratinocytes respond by hyperproliferating and releasing more inflammatory mediators 3
  • This creates a self-perpetuating cycle of inflammation

Environmental Triggers

Several environmental factors can initiate or exacerbate psoriasis in genetically predisposed individuals:

• Skin trauma (Koebner's phenomenon) 1
• Infections, particularly streptococcal infections (often triggers guttate psoriasis) 1
• Medications that can trigger or worsen psoriasis:
  • Beta-blockers
  • Lithium
  • Antimalarials
  • Interferons
• Stress - psychological stress can trigger flares 1
• Obesity - strong association with psoriasis development and severity 1
  • Higher BMI correlates with increased risk
  • Weight gain is a substantial risk factor for psoriasis development

Keratinocyte Abnormalities

• Hyperproliferation of epidermal keratinocytes
• Aberrant differentiation
• Shortened epidermal turnover time (3-5 days vs. normal 28-30 days)
• Keratinocytes also function as immune cells by secreting:
  • Antimicrobial peptides
  • Chemokines
  • Pro-inflammatory cytokines 3

Clinical Implications

Understanding the multifactorial nature of psoriasis explains:

• Why treatments targeting specific immune pathways (like IL-17, IL-23, or TNF-α inhibitors) are effective
• The chronic, relapsing nature of the disease
• The association with systemic comorbidities like psoriatic arthritis, cardiovascular disease, and metabolic syndrome 1

Common Pitfalls in Understanding Psoriasis

• Misconception: Psoriasis is merely a skin disease - In reality, it's a systemic inflammatory condition with multiple comorbidities
• Misconception: Psoriasis is contagious - It is not transmissible from person to person
• Misconception: Psoriasis is solely caused by stress - While stress can trigger flares, the underlying cause is much more complex
• Misconception: Psoriasis is just cosmetic - The disease significantly impacts quality of life and is associated with serious comorbidities including cardiovascular disease and depression 1

Understanding these complex mechanisms has led to the development of targeted therapies that have revolutionized psoriasis treatment, particularly biologics targeting specific cytokines in the inflammatory cascade.