Psoriasis Pathogenesis Overview

Psoriasis Pathogenesis

• Psoriasis is a chronic inflammatory skin disease causing discrete plaques with scales. It frequently affects nails and can co-occur with psoriatic arthritis, even without skin lesions.
• Historically, psoriasis was thought to stem from abnormalities in keratinocytes, immunocytes, and endothelial cells. While antimetabolites and UV radiation treatments suggested keratinocyte growth problems, they also have immunomodulatory effects.
• The involvement of lymphocytes was confirmed by the development of selective therapies. Cyclosporine, while modulating keratinocyte growth, didn't definitively exclude keratinocytes as a target. The lymphocyte-depleting agents denileukin diftitox and alefacept confirmed lymphocytes play a key role.
• Recent studies emphasize psoriasis as a systemic disease, with significant skin inflammation, rather than a disease localized to the skin.
• Histology reveals thickened, over-proliferating epidermis, reduced basal keratinocyte transit times, abnormal differentiation, neutrophilic and lymphocytic inflammation, and prominent capillary loops in the superficial dermis.

Treatments and Biologics

• Improved treatments and understanding of psoriasis have evolved with biologic therapies. Early testing with infliximab (anti-TNFα) in inflammatory bowel disease led to its testing and proven efficacy in severe psoriasis.

• TNFα is a key pro-inflammatory cytokine and its inhibition has proven effective against psoriasis.

• Lymphocyte-depleting agents demonstrated T-cell and cellular immunity perturbations are crucial. Prior to biologics, psoriasis and atopic dermatitis were associated with Th1 and Th2 pathways, respectively. The discovery of Th17 cells (and their cytokine IL-17), led to new research avenues.

• TNFα, IL-23, and IL-17 are elevated in psoriatic lesions, and effective treatments reduce their levels. An IL-17-dependent, TNFα-augmented feedback loop amplifies psoriasis-related inflammation. This supports the effectiveness of TNFα-targeting agents.

• Targeting IL-23 (with ustekinumab, anti-human p40) has shown dramatic efficacy in psoriasis. Likewise, anti-IL-17A monoclonal antibodies (secukiumab, ixekinumab) have also proven highly effective.

• The effectiveness of anti-IL-23 and anti-IL-17 therapies solidified the importance of these cytokines in psoriasis.

Genetic and Unanswered Questions

• Genetic studies (GWAS) have yielded insights into psoriasis. However, identified susceptibility loci only explain a minor portion of the genetic predisposition.
• Genetic susceptibility loci for atopic dermatitis and psoriasis are largely distinct, implying different disease causes. GWAS results vary by ethnicity, further supporting psoriasis' complexity.
• Genetic variants frequently occur in non-protein-coding regions, suggesting influence on gene regulation or expression.
• MHC Class I locus variants are related to the greatest genetic risk in both European and Chinese populations. Genes influencing innate immunity and the IL-23/IL-17 axis are also implicated.
• The initial trigger(s) and IL-23/IL-17 activation process remain unknown. Identifying the IL-17 source is vital.
• Studies are ongoing to characterize the precise cellular source of IL-17 in psoriatic skin and characterize innate lymphocytes (ILC1, ILC2, ILC3) involvement.
• Aggressive biologic therapy use is debated. Effectiveness has been observed in moderate-to-severe psoriasis, though cost is a factor. Long-term remissions are often absent.
• Potential health-promoting activities of biologics are possible and under study in cases of mild psoriasis, with comorbidities like cardiovascular disease, requiring further research.