What are the recent concepts about the pathogenesis of psoriasis?

Recent Concepts in Psoriasis Pathogenesis

Core Immunologic Mechanisms

Psoriasis is fundamentally an immune-mediated inflammatory disease driven by the IL-23/Th17 axis, representing a major paradigm shift from earlier models that focused primarily on Th1 cells. 1, 2

The IL-23/IL-17 Inflammatory Cascade

• The IL-23/type 17 T-cell axis is the central pathogenic driver, with pathogenic T cells producing high levels of IL-17 in response to IL-23 stimulation 2, 3
• IL-17 activation in prepsoriatic skin creates a "feed-forward" inflammatory loop that is self-amplifying, driving keratinocyte hyperproliferation, epidermal hyperplasia, and recruitment of inflammatory cells into the skin 2
• Th17 cells secrete IL-22, which directly promotes keratinocyte proliferation and augments production of antimicrobial peptides (AMPs) 1, 4
• While Th1 cells and their cytokines (TNF-α, interferon-γ) remain important contributors, they are now understood to work in concert with the dominant IL-23/Th17 pathway 1, 3

Innate Lymphoid Cells (ILC3)

• ILC3 cells represent a recently identified innate immune component that can induce psoriasis directly without T-cell/antigen interaction 3
• ILC3s express retinoic acid receptor-related orphan receptor gamma t (RORγt), mature in the presence of IL-7 and IL-23, and produce IL-17 and IL-22 3
• ILC3 numbers are increased in blood, psoriatic lesions, and even in non-lesional skin of psoriasis patients 3
• These cells respond to antimicrobial peptides released from activated keratinocytes and inflammatory cytokines, creating an additional inflammatory amplification loop 3

Tissue Resident Memory T Cells (TRMs)

• TRMs are a recently identified subset of memory T cells that persist in the skin and contribute to local disease memory and recurrence at previously affected sites 4
• These cells remain in the skin after clinical resolution and can rapidly reactivate upon triggering stimuli, explaining the tendency for psoriasis to recur in the same locations 4
• TRMs represent a potential new therapeutic target for preventing disease recurrence 4

Genetic Architecture

The HLA-Cw6 allele (PSORS1) remains the strongest genetic determinant of psoriasis, but over 80 susceptibility loci have now been identified 1, 5, 6

• At least 8 chromosomal loci (PSORS I-VIII) show statistically significant linkage to psoriasis 1, 5
• Key genetic variants include HLA-C*06:02, IL23R, and CARD14, highlighting the genetic basis of immune dysregulation 6
• The low penetrance of these genetic factors indicates that environmental triggers are required for disease expression, explaining why not all genetically susceptible individuals develop psoriasis 5
• Psoriasis shares common genetic susceptibility factors with Crohn's disease (particularly IL-23 genotypes), with the incidence of Crohn's disease among psoriatics being 3.8 to 7.5 times that of the general population 1, 7

Epigenetic and Environmental Modulation

• Epigenetic modifications influence gene expression and interact with environmental factors to modulate disease activity 6
• Environmental triggers include mechanical stress (Koebner phenomenon), infections (particularly streptococcal), medications (lithium, antimalarials, beta-blockers, NSAIDs, paradoxically TNF inhibitors), psychological stress, smoking, alcohol, and obesity 1, 5, 8
• Obesity is a strong risk factor for developing psoriasis, with a severity-dependent relationship—the pooled odds ratio for obesity in psoriatic patients is 1.66, increasing to 2.23 in moderate-to-severe disease 5
• Air pollution and ultraviolet exposure can exacerbate the inflammatory cascade 6

Keratinocyte Dysfunction and Antimicrobial Peptides

• Activated keratinocytes release antimicrobial peptides (AMPs) that serve as danger signals, activating both innate and adaptive immune responses 3, 4
• Keratinocytes in psoriatic skin exhibit altered expression of keratins, keratinocyte transglutamase, involucrin, filaggrin, and other structural proteins 9
• The dysregulated interplay between epidermis, dermis, cutaneous microvasculature, and immune system results in the characteristic scaling, thickened plaques, and erythema 1

Cellular Infiltration and Chemokine Networks

• Psoriatic lesions show infiltration of T cells, dendritic cells, macrophages, and neutrophils, orchestrated by altered levels of chemokines and integrins 1, 4
• Resolution of psoriasis correlates with decreased lesional infiltration of these cell types and decreased expression of TNF-α, interferon-γ, and IL-12/23-dependent genes 1
• Intralesional inflammation primes basal stem keratinocytes to hyperproliferate, perpetuating the disease process 1

Systemic Inflammation and Comorbidities

Psoriasis is now recognized as a systemic inflammatory disease with far-reaching health implications beyond the skin 1, 6

• Chronic systemic inflammation contributes to increased cardiovascular disease, metabolic syndrome, type 2 diabetes, obesity, and depression 1
• Patients with severe psoriasis have increased mortality risk, dying on average 5 years younger than those without psoriasis, largely due to cardiovascular death 1
• The similarity of gut enterobacteria in psoriasis patients to that in diabetic patients may contribute to metabolic comorbidities 3
• There is an increased incidence of lymphoma (particularly cutaneous T-cell lymphoma with RR 4.34) and possible links to multiple sclerosis 1, 7

Therapeutic Implications

The elucidation of the IL-23/IL-17 axis has revolutionized treatment, with biologics targeting IL-23p19 (guselkumab, risankizumab, tildrakizumab) and IL-17 signaling (secukinumab, ixekizumab, brodalumab) demonstrating superior efficacy 1, 2

• Ustekinumab targets the p40 subunit common to both IL-12 and IL-23 1
• TNF-α inhibitors (infliximab, adalimumab, etanercept, golimumab) remain effective by targeting upstream inflammatory mediators 1
• Emerging bispecific antibodies and small-molecule inhibitors offer potential for even better disease control and less costly long-term management 2
• The success of these targeted therapies validates the central role of the IL-23/Th17 axis in psoriasis pathogenesis 2, 6

Common Pitfalls

• Do not dismiss limited body surface area involvement as "mild" disease—psoriasis affecting palms, soles, genitals, or face can have disproportionate impact on quality of life and may warrant systemic therapy 1
• Screen for psoriatic arthritis in all psoriasis patients, as deforming arthritis may occur even with minimal cutaneous involvement 1
• Recognize that disease recurrence at previously affected sites is mediated by TRMs, not simply inadequate treatment 4
• Address cardiovascular risk factors, metabolic syndrome, and depression screening, as these comorbidities significantly impact morbidity and mortality 1, 7