What is the pathogenesis of psoriasis?

From the Guidelines

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes and immune dysregulation, involving a complex interplay between genetic predisposition and environmental triggers, with the TH17 subset of T-helper cells playing a central role in its pathogenesis. The pathogenesis of psoriasis is multifactorial, involving both genetic and environmental factors [ 1 ]. In the skin, scaling, thickened plaques, and erythema can be attributed to hyperproliferation of epidermal keratinocytes and to a dysregulated interplay among the epidermis and dermis, the cutaneous microvasculature, and the immune system [ 1 ].

Key Factors in Pathogenesis

• Genetic predisposition: Multiple susceptibility loci have been identified, particularly HLA-Cw6 [ 1 ]
• Environmental triggers: Such as trauma, infection, stress, or medications, which activate dendritic cells in the skin [ 1 ]
• Immune dysregulation: Involving the activation and proliferation of T helper cells, particularly Th1, Th17, and Th22 cells [ 1 ]
• Cytokine release: Pro-inflammatory cytokines including TNF-α, IL-17, IL-22, and IL-23 create an inflammatory cascade [ 1 ]

Immunopathogenesis

The activated T cells release pro-inflammatory cytokines, which stimulate keratinocytes to proliferate abnormally, resulting in the characteristic thickened, scaly plaques of psoriasis [ 1 ]. The normal skin cell turnover rate of 28-30 days is dramatically accelerated to 3-4 days in psoriatic lesions. Additionally, the inflammatory process attracts neutrophils, forming microabscesses in the epidermis. Angiogenesis is also stimulated, creating the dilated blood vessels responsible for the erythema seen in psoriatic plaques [ 1 ].

Treatment Implications

Understanding this immunopathogenesis has led to targeted biologic therapies that block specific cytokines in the inflammatory pathway, revolutionizing psoriasis treatment [ 1 ]. Biologics that have received regulatory approval for psoriasis and/or PsA include two that interfere with T-cell function (alefacept and efalizumab), 3 monoclonal antibodies that inhibit tumor necrosis factor (TNF)-alfa (infliximab, adalimumab, and golimumab), one soluble receptor that inhibits TNF-alfa (etanercept), and one monoclonal antibody directed at the p40 subunit common to IL-12 and IL-23 (ustekinumab) [ 1 ].

From the FDA Drug Label

The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.

The pathogenesis of psoriasis is not directly addressed in the provided drug label. The label discusses the adverse reactions and side effects associated with the use of cyclosporine in patients with psoriasis, but it does not provide information on the underlying causes or mechanisms of the disease itself. The FDA drug label does not answer the question.

From the Research

Pathogenesis of Psoriasis

The pathogenesis of psoriasis is a complex process involving the interplay of multiple factors, including:

• The immune system, specifically T cells, dendritic cells, and keratinocytes 2, 3, 4
• Psoriasis-associated susceptibility loci and autoantigens 2
• Environmental factors 2
• Cytokines, such as IL-17, IL-23, and TNF-α, which play a central role in the development of psoriasis 2, 3, 5, 4

Key Players in Psoriasis Pathogenesis

The following cells and cytokines are key players in the pathogenesis of psoriasis:

• T cells, particularly TH17 cells, which produce IL-17 in response to IL-23 2, 3
• Dendritic cells, which produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells 3
• Keratinocytes, which are activated by IL-17 and produce inflammatory products 2, 4
• Innate lymphoid cells (ILCs), particularly ILC3, which induce psoriasis rashes directly without T-cell/antigen interaction 5

Signaling Pathways and Cytokines

The following signaling pathways and cytokines are involved in the pathogenesis of psoriasis:

• The IL-23/type 17 T-cell axis, which is central to the development of psoriasis 2
• The IL-17A axis, which is involved in the pathogenesis of psoriasis 5
• TNF-α, which is produced by dendritic cells and promotes T cell activation and inflammation 3, 4
• IL-22, which is produced by TH17 cells and ILC3 and promotes skin inflammation and keratinocyte activation 3, 5