What Causes Psoriasis
Psoriasis is a complex genetic disease of dysregulated inflammation caused by an interplay between genetic susceptibility (particularly the HLA-Cw6 allele) and environmental triggers including drugs, skin trauma, infection, and stress. 1
Genetic Factors
The strongest genetic determinant is the HLA-Cw6 allele (PSORS1), which represents the major susceptibility gene for psoriasis. 1 At least 8 chromosomal loci (PSORS I-VIII) have been identified with statistically significant evidence for linkage to psoriasis, though the mechanism of inheritance has not been completely defined. 1 The low penetrance of these genetic factors indicates that additional genetic risk factors and environmental triggers are required for disease expression. 2
Immunologic Mechanisms
Psoriasis is an immune-mediated organ-specific inflammatory disease in which intralesional inflammation primes basal stem keratinocytes to hyperproliferate and perpetuate the disease process. 1
The pathophysiology involves:
- Dysregulated T-cell activation, particularly TH1 and TH17 subsets, which play central roles in disease pathogenesis 1, 3
- TH17 cells secrete IL-17 and IL-22, which promote keratinocyte proliferation and augment production of antimicrobial peptides 1, 3
- Altered levels of chemokines and integrins affecting migration of T cells, dermal dendritic cells, macrophages, and neutrophils into plaques 1
- Increased expression of TNF-α, interferon-γ, and IL-12/23-dependent genes in lesional skin 1
Environmental Triggers
Multiple environmental factors play important roles in triggering or exacerbating psoriasis: 1
Medications
- Lithium can cause severe, even life-threatening deterioration of pre-existing psoriasis 4
- Antimalarials (chloroquine, hydroxychloroquine) can severely worsen psoriasis 4
- Beta-blockers can exacerbate disease, particularly with long-term use (≥6 years) 1, 4
- NSAIDs can worsen existing disease 4
- Certain cytokine therapies (interferons α, β, γ; IL-2; granulocyte colony-stimulating factor) can trigger exacerbations 1
Other Environmental Factors
- Skin trauma (Koebner's phenomenon) can trigger new lesions at sites of injury 1
- Infections, particularly streptococcal antigens acting as bacterial superantigens 1
- Stress can precipitate or worsen disease 1, 5
- Alcohol consumption can trigger or exacerbate psoriasis 4
Obesity as a Risk Factor
Obesity and weight gain are strong risk factors for developing psoriasis, with a severity-dependent relationship. 1 The Nurses Health Study II demonstrated that multiple measures of obesity (BMI, waist circumference, weight gain since age 18) were substantial risk factors, with the highest relative risk in those with highest BMIs. 1 The pooled odds ratio for obesity in psoriatic patients is 1.66, increasing to 2.23 in moderate-to-severe disease. 1
Clinical Implications
The multifactorial etiology means that genetic predisposition alone is insufficient—environmental triggers are required for disease expression. 5, 6 This explains why patients with genetic susceptibility may not develop psoriasis until exposed to specific triggers, and why identifying and avoiding modifiable risk factors (obesity, smoking, alcohol, certain medications) is clinically important for disease prevention and management. 6, 7