Psoriasis

Disease definition & pathophysiology

Psoriasis is a chronic, immune-mediated inflammatory skin disorder. It involves rapid proliferation of the main cells of the outer skin layer (keratinocytes), dysfunctional maturation of the outer skin layer (epidermal differentiation), and infiltration by immune cells (T-helper cells, dendritic cells, neutrophils). Key inflammatory mediators driving psoriasis include cytokines like TNF-α, IL-17, and IL-23.

Commonly used Pharmacodynamic (PD) Models

• Disease progression models (e.g., turnover models for raised, scaly skin patch (plaque) development and resolution)
• Indirect response models (cytokine-driven inflammatory response)
• Target engagement models (cytokine suppression, receptor occupancy models for biologics)

Typical patient population

• Commonly presents in adults aged 15–35 and 50–60 years
• Equal prevalence among genders
• Worldwide prevalence approximately 2–3%

Risk factors & disease progression indicators

• Family history and genetic predisposition (e.g., HLA-Cw6 allele)
• Environmental triggers: infections, stress, medications, trauma
• Co-occurring diseases (comorbidities): joint inflammation linked to psoriasis (psoriatic arthritis), cardiovascular disease, metabolic syndrome
• Disease progression indicated by extent/severity of skin involvement and responsiveness to initial therapies

Key Clinical Biomarkers

• Clinical evaluation of skin lesions (plaque thickness, redness, scaling)
• Imaging rarely used, except to evaluate psoriatic arthritis (MRI, X-ray)
• Non-specific inflammation markers (C-reactive protein, erythrocyte sedimentation rate) sometimes elevated

Disease Severity Classification

• Psoriasis Area and Severity Index (PASI):
  • Mild: PASI < 10
    
  • Moderate-to-severe: PASI ≥ 10
• Body Surface Area (BSA) involvement:
  • Mild: <3%, Moderate: 3–10%, Severe: >10%
• Physician Global Assessment (PGA) commonly used

Treatment aim (PD-targets)

• Suppression of inflammation, reduction of epidermal hyperproliferation, and normalization of immune dysregulation
• Primary targets: TNF-α, IL-17, IL-23, IL-12 pathways

Common Drug Classes & Regimens

The classes below sit in ATC D05 Antipsoriatics and D07 Dermatological corticosteroids; the biologics are L04A Immunosuppressants.

Commonly used PK-models

• One- or two-compartment pharmacokinetic models (particularly for biologics)
• Population PK-models incorporating covariates (body weight, immunogenicity, PASI scores)
• Exposure-response models linking drug concentration/exposure to PASI improvement

Modeling PASI and PGA

In a phase 3b trial of ustekinumab, PASI was a near-continuous score from 0 to 72 in steps of 0.1, while the primary endpoint was based on the 6-point physician’s global assessment (PGA), an ordered categorical score. A latent-variable indirect response model of the PGA alone had a substantial structural bias, which was corrected by modeling PGA jointly with PASI [2].

In a phase 2a study of brepocitinib in plaque psoriasis, PASI, a score bounded between 0 and 72, was modeled with a zero-inflated beta distribution to handle its bounds and its observations at 0. The model also predicted the derived responder endpoints PASI75, PASI90 and PASI100 (75%, 90% and 100% improvement) [3]. PASI has also been fitted with a bounded integer model, which respects the discrete and bounded nature of the score [4].

Clinical pharmacology studies

For a drug applied to the skin, the EMA guideline asks that pharmacokinetics be explored after repeated application to psoriatic versus healthy skin, together with systemic exposure in relation to BSA, the effect of the drug stored in the skin (skin reservoir) on how often it must be applied, and differences between skin sites such as skin folds (flexures) and other areas. Comparisons within the same patient (for example left versus right side) should be restricted to exploratory trials, where the psoriasis plaque test is another way to compare doses and formulations. Because psoriasis is thought to be driven by persistent T-cell activation and cytokine production, the guideline asks, for systemic drugs that modulate the immune system, for pharmacodynamic studies of the levels of the different lymphocyte types in the blood (lymphocyte subpopulations) or of cytokine responses, which could include studies in the skin [1].