What are the recent concepts in the pathogenesis of psoriasis and its treatment options in dermatology?

Recent Concepts in Psoriasis Pathogenesis

The IL-23/Th17 Axis: The Central Pathogenic Mechanism

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 This discovery has revolutionized both our understanding of disease pathogenesis and therapeutic development.

Core Immunologic Triad

The pathogenesis centers on three key cellular players working in an amplifying inflammatory loop 2, 3:

• Dendritic cells produce TNF-α and IL-23, which drive T cell differentiation toward the Th17 phenotype 2
• Th17 cells secrete IL-17A, IL-17F, IL-22, and IFN-γ, which are the primary effector cytokines in psoriatic inflammation 1, 2
• Keratinocytes respond to these cytokines with hyperproliferation and production of antimicrobial peptides (AMPs), chemokines, and additional inflammatory mediators that further recruit immune cells 4, 2

IL-17 Family: The Key Effector Pathway

IL-17A is the dominant pathogenic cytokine in psoriasis 3, 5:

• IL-22 (produced by Th17 cells) directly promotes keratinocyte proliferation and augments antimicrobial peptide production 1
• IL-17 induces keratinocyte production of inflammatory cytokines (IL-6, IL-8, TNF-α) and chemokines (CXCL1, CXCL2, CCL20) that recruit neutrophils and additional T cells 2, 5
• This creates a self-perpetuating inflammatory cycle where keratinocytes amplify the immune response 6, 2

IL-23: The Master Regulator

IL-23 (composed of p19 and p40 subunits) maintains and expands Th17 cell populations in psoriatic skin 5:

• IL-23 is produced by activated dendritic cells and macrophages in response to danger signals from stressed keratinocytes 2, 3
• Blocking IL-23p19 prevents Th17 cell survival and cytokine production, explaining the superior efficacy of IL-23 inhibitors 1

Beyond Th17: Additional Immune Cell Populations

Recent research has identified other contributing immune cells 2, 3:

• Innate lymphoid cell 3 (ILC3) produces IL-17 and IL-22 without requiring antigen presentation, providing a T-cell-independent pathway for psoriatic inflammation 3
• Th1 cells produce TNF-α and IFN-γ, which work synergistically with the Th17 pathway 1, 6
• Th22 cells produce IL-22 independently of Th17 cells, contributing to keratinocyte hyperproliferation 6, 2
• γδ T cells are early producers of IL-17 in psoriatic lesions and may initiate the inflammatory cascade 6, 2
• CD8+ cytotoxic T cells infiltrate the epidermis and contribute to keratinocyte damage 6, 2
• Neutrophils form characteristic Munro microabscesses in the stratum corneum and release additional inflammatory mediators 2

Genetic Architecture and Environmental Triggers

Genetic Susceptibility

Over 80 genetic susceptibility loci have been identified, but disease penetrance remains low 1, 7:

• HLA-Cw6 (PSORS1) remains the strongest genetic determinant, conferring a 9-fold increased risk and associated with earlier disease onset 1, 7
• At least 8 chromosomal loci (PSORS I-VIII) show statistically significant linkage 1, 7
• Many susceptibility genes encode proteins involved in IL-23/Th17 signaling (IL23R, IL12B, TRAF3IP2, IL23A) or NF-κB activation (TNIP1, TNFAIP3, CARD14) 5
• The low penetrance indicates that environmental triggers are required for disease expression 1, 7

Environmental and Lifestyle Triggers

Multiple environmental factors can precipitate or exacerbate psoriasis 7:

• Mechanical trauma (Koebner phenomenon) induces lesions at sites of skin injury 7
• Infections, particularly streptococcal pharyngitis, can trigger guttate psoriasis 7
• Medications including lithium, antimalarials, beta-blockers, NSAIDs, and paradoxically TNF inhibitors can worsen disease 7
• Obesity is a strong risk factor with a severity-dependent relationship; pooled odds ratio is 1.66 overall and 2.23 in moderate-to-severe disease 7
• Smoking and alcohol consumption increase disease risk and severity 7
• Psychological stress can trigger flares through neuroimmune mechanisms 7

Epigenetic Mechanisms

Recent studies have identified epigenetic dysregulation as a contributing factor 6:

• DNA methylation patterns are altered in psoriatic keratinocytes and immune cells 6
• Histone modifications affect expression of inflammatory genes 6
• MicroRNAs (miR-21, miR-31, miR-203) are dysregulated and modulate keratinocyte proliferation and immune responses 6

Systemic Inflammation and Comorbidities

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

• Chronic systemic inflammation contributes to increased cardiovascular disease, metabolic syndrome, type 2 diabetes, 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
• Psoriatic arthritis occurs in 20-30% of psoriasis patients and may develop even with minimal cutaneous involvement 1
• Increased risk of lymphoma, particularly cutaneous T-cell lymphoma (RR 4.34) and Hodgkin's lymphoma (RR 1.48), with risk correlating to disease severity 4

Therapeutic Implications of Pathogenic Understanding

Biologic Therapies Targeting Key Pathways

The elucidation of the IL-23/IL-17 axis has revolutionized treatment, with biologics targeting these pathways demonstrating superior efficacy 1:

• IL-23p19 inhibitors (guselkumab, risankizumab, tildrakizumab) block the master regulator of Th17 responses 1
• IL-17 inhibitors (secukinumab, ixekizumab, brodalumab) directly neutralize the key effector cytokine 1, 8
• IL-12/23p40 inhibitors (ustekinumab) block both IL-12 and IL-23 signaling 1
• TNF-α inhibitors (infliximab, adalimumab, etanercept) target upstream inflammatory mediators 1, 9

Clinical Considerations for Biologic Use

When selecting biologic therapy, consider the following 8, 9:

• IL-17 inhibitors may increase risk of oral candidiasis, upper respiratory infections, and inflammatory bowel disease exacerbations 8
• TNF inhibitors carry increased risk of serious infections including tuberculosis reactivation, bacterial sepsis, and invasive fungal infections 9
• Pre-treatment tuberculosis screening is mandatory before initiating TNF inhibitors or IL-17 inhibitors 8, 9
• Avoid live vaccines in patients on biologic therapy 8
• Monitor for malignancies, particularly lymphoma in patients on long-term immunosuppression 4, 9

Topical Therapies Based on Pathogenic Mechanisms

For mild disease, topical therapies target specific pathogenic steps 4:

• Vitamin D analogues inhibit keratinocyte proliferation and modulate T-cell function 4
• Topical corticosteroids suppress multiple inflammatory pathways including NF-κB activation 4
• Topical retinoids (tazarotene) normalize keratinocyte differentiation and reduce inflammatory marker expression 4
• Topical calcineurin inhibitors (tacrolimus, pimecrolimus) are effective for facial and intertriginous psoriasis by blocking inflammatory cytokine synthesis 4

Common Pitfalls and Clinical Caveats

• Do not assume all psoriasis is purely cutaneous—screen all patients with moderate-to-severe disease for psoriatic arthritis, cardiovascular risk factors, and metabolic syndrome 1
• Do not overlook infection screening before initiating biologics, particularly tuberculosis and hepatitis B/C 4, 8, 9
• Do not continue ineffective biologics—if a patient fails to respond adequately to one IL-17 or IL-23 inhibitor, switching to a different mechanism (e.g., from IL-17 to IL-23 inhibitor) may be more effective than trying another drug in the same class 1
• Do not ignore the role of obesity and lifestyle factors—weight loss and smoking cessation can significantly improve treatment responses 7
• Do not perform surgery on active psoriatic plaques without considering potential wound healing complications, though evidence is limited 4