Psoriasis
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I now have comprehensive material from Fitzpatrick's and Andrews' dermatology, plus the latest guidelines and PubMed evidence. Here is the full answer:
Psoriasis
Definition & Overview
Psoriasis is a common, chronic, recalcitrant inflammatory skin disease characterized by discrete erythematous plaques with adherent micaceous (silvery) scales. It affects approximately 2-3% of the world's population and is now recognized as a systemic inflammatory disease - not merely a skin disorder - with significant metabolic, cardiovascular, and articular comorbidities. - Fitzpatrick's Dermatology, p. 227
Pathogenesis
The modern understanding centers on a dysregulated immune axis involving Th1 and Th17 T-cell subsets:
- Keratinocyte hyperproliferation: Basal keratinocyte transit time is markedly reduced, driving epidermal thickening (acanthosis) and hyperkeratosis.
- Th1/Th17 axis: The inflammatory infiltrate is predominantly Th1- and Th17-polarized memory T cells, plus neutrophils, macrophages, and dendritic cells.
- Key cytokines: TNF-α, IL-17, and IL-23 are the primary drivers. Dermal dendritic cells co-produce TNF-α and IL-23; IL-23 promotes Th17 differentiation; IL-17 drives neutrophilic inflammation and keratinocyte gene expression changes.
- IL-23 structure: It is a heterodimer of IL-23-specific p19 and p40 (shared with IL-12, the Th1-promoting cytokine) - this explains why anti-p40 antibodies target both pathways.
- Chemokines: CXCL8 (IL-8) attracts neutrophils to form Munro abscesses; various chemokines recruit lymphocytes (epidermotropism). - Fitzpatrick's, p. 213-228
The central role of T lymphocytes was confirmed by the efficacy of cyclosporine (calcineurin inhibitor), denileukin diftitox (IL-2 receptor-directed cytotoxin), and alefacept (CD2-binding agent) in clearing psoriasis. - Fitzpatrick's, p. 228
Clinical Features
Psoriasis presents as circumscribed, erythematous, dry, scaling plaques - symmetrically distributed with a predilection for:
- Scalp
- Nails
- Extensor surfaces (elbows, knees)
- Umbilical region
- Sacrum
Key signs:
- Auspitz sign: Removal of scales reveals pinpoint bleeding points (dilated capillary loops in the superficial dermis)
- Koebner (isomorphic) phenomenon: New lesions at sites of skin trauma
- Scales: Micaceous (peel in layers), looser peripherally, adherent centrally
Symptoms include pruritus and burning; lesions increase in size by peripheral extension and coalescence. - Andrews' Diseases of the Skin, p. 230
Morphological Variants
| Variant | Description |
|---|---|
| Plaque (psoriasis vulgaris) | Most common; stable, chronic plaques on trunk/extremities |
| Guttate | Droplike lesions; sudden onset; often post-streptococcal |
| Inverse | Intertriginous areas (axillae, groin, submammary); lacks scale due to moisture |
| Pustular (localized) | Palms and soles; chronic |
| Pustular (generalized, von Zumbusch) | Acute; fever, erythroderma, hypocalcemia, cachexia; life-threatening |
| Erythrodermic | >90% BSA involvement; systemic toxicity; temperature dysregulation |
| Psoriasis ostracea | Thick, oyster-shell-like lamellar plaques |
| Acrodermatitis continua (Hallopeau) | Acral pustular plaques; nail loss (anonychia) |
| Impetigo herpetiformis | Pustular psoriasis of pregnancy |
Andrews' Diseases of the Skin, p. 230-232
Guttate psoriasis:
Classic plaque psoriasis:
Erythrodermic psoriasis:
Histopathology
| Feature | Description |
|---|---|
| Acanthosis | Epidermal thickening (hyperplasia) |
| Parakeratosis | Nuclei retained in stratum corneum |
| Munro microabscesses | Neutrophilic collections in stratum corneum |
| Spongiform pustule of Kogoj | Neutrophils in spinous layer (pustular psoriasis) |
| Dilated capillary loops | Extend into superficial dermis - explains Auspitz sign |
| Reduced granular layer | Absent or thinned stratum granulosum |
| Lymphocytic infiltrate | Predominantly Th1/Th17 memory T cells in dermis |
Nail Changes (Psoriatic Nails)
Present in ~50% of patients; virtually universal in psoriatic arthritis. Features include:
- Pitting (most common)
- Onycholysis ("oil drop" or salmon patch sign)
- Subungual hyperkeratosis
- Leukonychia
- Splinter hemorrhages
Psoriatic Arthritis (PsA)
Occurs in ~30% of psoriasis patients. Five patterns:
- Asymmetric oligoarthritis (most common)
- Symmetric polyarthritis (resembles RA)
- Distal interphalangeal predominant
- Arthritis mutilans (severe, destructive)
- Axial (sacroiliitis/spondylitis)
PEST questionnaire is used for annual joint screening before irreversible damage occurs.
Triggering/Exacerbating Factors
- Infections: Streptococcal pharyngitis (guttate), HIV
- Drugs: Beta-blockers, lithium, antimalarials (chloroquine), NSAIDs, corticosteroid withdrawal, iodides, terbinafine
- Trauma (Koebner phenomenon)
- Stress
- Alcohol and smoking
- Obesity
Treatment
Severity Assessment (PASI/BSA/DLQI)
- Mild: BSA <10%, PASI <10, DLQI <10
- Moderate-to-severe: BSA >10%, PASI >10, or DLQI >10
1. Topical Therapy (Mild Disease)
| Agent | Mechanism/Notes |
|---|---|
| Topical corticosteroids | First-line; high-potency (clobetasol 0.05%) for thick plaques |
| Calcipotriene (Vitamin D analog) | Inhibits keratinocyte proliferation; often combined with steroids |
| Coal tar | Antiproliferative; useful for scalp/nails |
| Tazarotene (retinoid) | Normalizes differentiation |
| Calcineurin inhibitors | Tacrolimus/pimecrolimus for inverse/facial psoriasis |
2. Phototherapy (Moderate Disease)
- Narrowband UVB (NB-UVB): First-line phototherapy; safe in pregnancy
- PUVA (Psoralen + UVA): More effective but higher skin cancer risk
- Excimer laser (308 nm): Localized resistant plaques
3. Conventional Systemic Agents
| Drug | Notes |
|---|---|
| Methotrexate | Weekly dosing; monitor LFTs; teratogenic; first-line systemic |
| Cyclosporine | Rapid onset; nephrotoxic long-term; not for >1-2 years |
| Acitretin | Drug of choice for generalized pustular psoriasis; teratogenic |
| Apremilast | PDE4 inhibitor; oral; avoids lab monitoring |
4. Biologics (Moderate-to-Severe Disease)
TNF-α inhibitors:
- Etanercept, adalimumab, infliximab, certolizumab
- Historical first-line biologics; still widely used; avoid in TB/demyelinating disease
IL-12/23 inhibitor (anti-p40):
- Ustekinumab - effective for both skin and PsA; useful in IBD patients
IL-17 inhibitors:
- Secukinumab, ixekizumab, bimekizumab (also inhibits IL-17F)
- Highest efficacy in plaque psoriasis; avoid in IBD
IL-23 inhibitors (anti-p19):
- Guselkumab, risankizumab, tildrakizumab
- Among the most effective agents; favorable dosing intervals; safe in IBD
Updated 2025-2026 guidance: The 2026 German S3 guideline (updated from EuroGuiDerm) and new French guidelines now position biologics (especially IL-17 and IL-23 inhibitors) as first-line options for moderate-to-severe disease, equivalent to methotrexate, with biosimilars making this economically feasible. IL-17 inhibitors are recommended against in psoriasis with concurrent IBD; TNF inhibitors, IL-12/23, and IL-23 inhibitors are preferred in that setting.
Generalized Pustular Psoriasis
- Acitretin is the drug of choice; isotretinoin also effective
- Cyclosporine, methotrexate, and biologics are alternatives
- Dapsone 50-100 mg/day in some cases
- Andrews' Diseases of the Skin, p. 232
Comorbidities
Psoriasis is a systemic disease. Key associations:
- Cardiovascular disease (increased MI, stroke risk - related to systemic inflammation)
- Metabolic syndrome (obesity, dyslipidemia, hypertension, T2DM)
- Psoriatic arthritis (~30%)
- Inflammatory bowel disease (Crohn's, UC)
- Non-alcoholic fatty liver disease
- Depression and anxiety (significant QoL impact)
- Uveitis
Recent Evidence (2024-2025)
A 2025 Cochrane network meta-analysis (PMID 40767824) on systemic pharmacological treatments for chronic plaque psoriasis confirmed that IL-17 and IL-23 inhibitors achieve the highest rates of PASI 90/100 clearance among available agents. A 2026 study in BJD found that initiating biologics as first-line systemic treatment (rather than stepping through conventional agents first) is associated with greater clinical improvement.
Note: The Cochrane network meta-analysis (PMID 40767824, published August 2025) may update hierarchy of treatment efficacy - if selecting a biologic, IL-17/IL-23 inhibitors rank highest for skin clearance.
Sources:
- Fitzpatrick's Dermatology in General Medicine, 9th ed., pp. 213-230
- Andrews' Diseases of the Skin: Clinical Dermatology, pp. 230-232
- 2026 German S3 Guideline (EuroGuiDerm)
- Cochrane NMA 2025 - Systemic treatments for plaque psoriasis (PMID 40767824)
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