Psoriasis

Psoriasis involves a complex interplay of genetic predisposition, innate immunity activation, and abnormal keratinocyte proliferation

• HLA-associated genetic susceptibility with environmental triggers — Approximately 40 HLA alleles confer psoriasis risk, particularly HLA-Cw6, HLA-B57, and HLA-DR7, explaining the strong familial clustering (approximately 35-90% of patients report family history). Environmental triggers including streptococcal infection (typically β-hemolytic Group A Streptococcus in guttate psoriasis), trauma (Köbner phenomenon), psychological stress, medications (lithium, beta-blockers, NSAIDs, ACE inhibitors), smoking, alcohol, and cold weather activate disease through yet incompletely characterized mechanisms. The "two-hit hypothesis" suggests genetic predisposition requires environmental trigger(s) for disease manifestation, explaining variable penetrance and disease onset timing.

• Aberrant innate immune activation and dysregulation of plasmacytoid dendritic cells — Streptococcal antigens and tissue damage trigger pattern recognition receptors (TLRs 1, 2, 3, 7, 9) on dendritic cells and keratinocytes, leading to production of antimicrobial peptides (especially LL-37 cathelicidin) and increased interferon-alpha (IFN-α) secretion. LL-37 forms immunogenic complexes with self-DNA and RNA that cross-link TLR3 and TLR9 on plasmacytoid dendritic cells, driving massive IFN-α production in a positive feedback loop. This creates a self-amplifying circuit where IFN-α promotes additional TLR expression and myeloid dendritic cell activation, establishing chronic inflammation independent of the initial trigger.

• IL-23/IL-17 axis and T helper cell polarization — Activated dendritic cells secrete IL-23 (IL-12p40 + IL-23p19), IL-6, TNF-α, and IL-1β, which promote differentiation of naive CD4+ T cells toward TH17 cells that produce IL-17A and IL-17F. IL-23 also acts on tissue-resident memory T cells (TRM) and innate lymphoid cells (ILC3s) to amplify IL-17 production. IL-17A and IL-17F (along with TNF-α and IL-22 from TH22 cells) act on keratinocytes to stimulate further IL-6, IL-8, and TNF-α secretion, as well as antimicrobial peptide production and increased proliferation. This self-sustaining TH17 response is central to psoriasis pathogenesis and explains the therapeutic efficacy of anti-IL-17 and anti-IL-23 biologics.

• Keratinocyte hyperproliferation and altered differentiation — Psoriatic keratinocytes exhibit intrinsically altered responses to inflammatory cytokines, including increased proliferation rates (cell cycle shortens from ~28 days to 3-4 days) and impaired apoptosis due to altered Bcl-2 expression. TNF-α, IL-17, and IL-22 disrupt the normal epidermal differentiation program by suppressing expression of terminal differentiation markers (filaggrin, involucrin, loricrin) and accelerating keratinocyte transit through the epidermis. This results in incomplete keratinization, parakeratosis (retention of nuclei in stratum corneum), and thickening of the epidermis (acanthosis) with regular elongation of rete ridges—the histopathologic hallmark of psoriasis. Compromised barrier function secondary to altered lipids and impaired tight junction proteins increases transepidermal water loss (TEWL) and enhances penetration of pathogens and irritants.

• Dermal inflammation and vascular changes — TNF-α and other cytokines promote neovascularization through VEGF upregulation, resulting in dilated, tortuous dermal capillaries and venules arranged at the dermal-epidermal junction. Increased vascular permeability and recruitment of T cells (predominantly CD8+ and CD4+ TH17 cells) and neutrophils into the dermis perpetuate inflammation. The characteristic "dilated tortuous vessels" seen on dermoscopy reflect this vascular pathology and contribute to the erythema of psoriatic plaques.

Psoriasis is primarily a genetically predisposed condition triggered by environmental factors; understanding this multifactorial model is essential for counseling patients

• Genetic predisposition (non-modifiable) — Multiple genome-wide association studies (GWAS) have identified >60 genetic loci associated with psoriasis, with the HLA region accounting for ~50% of genetic risk. Non-HLA susceptibility genes include NFKBIA, IL12B, IL23A, IL23R, TNF, LCE (late cornified envelope), FBXL19, and TNFAIP3, many of which regulate immune responses. First-degree relatives of affected individuals have approximately 5-fold increased risk; concordance in monozygotic twins is ~65-70%, while in dizygotic twins approximately 15-20%, demonstrating substantial but incomplete genetic heritability.

• Streptococcal pharyngitis — β-hemolytic Group A Streptococcus (GAS) infection strongly associates with psoriasis onset or exacerbation, particularly in children and young adults. GAS antigens cross-react with keratin and other skin autoantigens through molecular mimicry, and streptococcal pyrogenic exotoxins (SPEs) act as superantigens bypassing normal T cell selection mechanisms. Up to 50% of guttate psoriasis cases follow streptococcal pharyngitis by 1-3 weeks; eradication of streptococcal colonization may improve disease in selected patients.

• Trauma and stress (Köbner phenomenon) — The isomorphic response occurs when psoriatic lesions develop at sites of cutaneous injury (scratching, surgery, tattoos, sunburn) typically within 1-2 weeks; approximately 25% of patients report this phenomenon. The pathophysiology involves TLR activation and antimicrobial peptide release by injured keratinocytes in genetically susceptible individuals. Psychological stress increases catecholamine sensitivity and promotes TH17 differentiation, explaining stress-induced flares; approximately 40% of patients report stress as a trigger.

• Medications — Lithium salts increase psoriasis risk through multiple mechanisms including impaired protein kinase C signaling and altered immune responses; beta-blockers (particularly non-selective agents like propranolol) impair cAMP-mediated immune suppression; NSAIDs may trigger disease through COX inhibition; ACE inhibitors are associated with drug-induced and exacerbated psoriasis; TNF-α inhibitor paradox occasionally causes psoriasiform eruptions despite use in psoriatic arthritis. Withdrawal of systemic corticosteroids precipitates rebound flares in approximately 20% of patients.

• Lifestyle and environmental factors — Smoking increases psoriasis risk 1.5-2 fold through immunological mechanisms and oxidative stress; excessive alcohol consumption (>30 grams/day) associates with worse disease; obesity (BMI >30) correlates with increased TNF-α and IL-6; and cold, dry climate exacerbates disease while sun exposure generally improves it through vitamin D effects and UVB-induced immunosuppression.

• Infections and immunologic triggers — Beyond GAS, HIV infection, candidal infection, and viral reactivation may trigger psoriasis; immunosuppression paradoxically may unmask latent disease. Immune reconstitution inflammatory syndrome (IRIS) in treated HIV patients can precipitate psoriasis flares.

Psoriasis presents across a broad clinical spectrum, with multiple morphologic variants reflecting underlying pathophysiologic mechanisms

• Well-demarcated erythematous plaques with silvery-white scale — The cardinal lesion is a planar, sharply circumscribed plaque with a violaceous to bright red color and adherent silvery-white scale; this reflects the underlying parakeratosis, dilated capillaries, and keratinocyte hyperproliferation. Auspitz sign (pinpoint bleeding after gentle removal of scale) indicates dilated dermal capillaries at the dermal-epidermal junction and is highly specific for psoriasis. Plaques typically measure 1-10 cm in diameter and may coalesce into large areas of involvement; they are typically symmetric and favor extensor surfaces (elbows, knees, scalp, lower back).

• Pruritus — Approximately 80% of patients experience pruritus, which is often severe and disproportionate to visible disease; severity correlates poorly with extent of disease and may be mediated by increased substance P, nerve fiber density, and nerve growth factor (NGF) in psoriatic lesions. Pruritus significantly impairs quality of life and may trigger additional trauma through scratching, perpetuating the Köbner phenomenon.

• Nail involvement (onychopathy) — Occurs in approximately 50% of plaque psoriasis and up to 80% of patients with psoriatic arthritis; manifestations include pitting (small punctate depressions from defective nail matrix), subungual hyperkeratosis (powdery material under the nail), onycholysis (separation of nail from nail bed), nail discoloration, and oil-drop sign (yellowish macule under the nail plate). These findings reflect involvement of the nail matrix and hyponychium by psoriatic inflammation and are important clinical clues linking skin disease to systemic manifestations.

• Erythrodermic psoriasis — Rare but severe variant involving >75% of body surface area (BSA) with generalized erythema, desquamation, and loss of normal skin barrier function; patients develop hypothermia, electrolyte abnormalities, dehydration, and secondary infection. This life-threatening presentation may occur spontaneously or from withdrawal of systemic corticosteroids; requires hospitalization and aggressive fluid/electrolyte management.

• Guttate psoriasis — Acute eruptive variant with numerous small droplet-shaped lesions (<1 cm diameter) typically following streptococcal pharyngitis by 1-3 weeks; may occur as initial presentation of psoriasis or in established disease. Approximately 33% of guttate cases progress to chronic plaque psoriasis.

• Pustular psoriasis — Rare but severe variant subdivided into generalized (von Zumbusch) and localized (palmoplantar, acropustulosis) forms; features sterile pustules on erythematous base. Generalized pustular psoriasis presents with fever, malaise, and widespread pustules that may coalesce; constitutes a dermatologic emergency with risk of sepsis, dehydration, and electrolyte abnormalities. Commonly triggered by medication withdrawal or infection; associated with mutations in CARD14 and IL36RN genes.

• Inverse (flexural) psoriasis — Occurs in intertriginous areas (axillae, groin, inframammary folds, gluteal cleft) with loss of typical scale due to moisture, maceration, and friction; presents as well-demarcated erythematous plaques that may resemble dermatitis or candidiasis. Clinically significant for delayed diagnosis and challenges with topical therapy due to moisture and occlusion.

• Palmoplantar involvement — Presents with hyperkeratotic plaques, transgressive erythema (extending beyond expected distribution), and pustular variant (pustulosis palmaris et plantaris); causes significant functional impairment due to involvement of weight-bearing and manipulative surfaces.

Diagnosis is primarily clinical, supported by selective use of confirmatory tests; understanding diagnostic criteria and ruling out mimickers is essential

• Clinical diagnosis criteria — The NICE (National Institute for Health and Care Excellence) criteria require typical morphology (well-demarcated erythematous lesions with silvery-white scale, with or without pruritus) plus at least one of the following: family history of psoriasis, lesions on extensor surfaces, involvement of nails, or psoriatic arthritis. Diagnosis is clinical based on characteristic morphology and distribution in most cases; biopsy is reserved for atypical presentations or diagnostic uncertainty.

• Dermoscopy findings — Dermoscopy reveals white lines (parakeratosis), red dots or globules (dilated capillaries), red/yellow patches (inflammation), and regular or irregular psoriasiform pattern; particularly helpful in distinguishing psoriasis from seborrheic keratosis or other mimickers, though not required for diagnosis.

• Histopathology (when biopsy performed) — Microscopy shows regular acanthosis (uniform thickening of epidermis with elongated rete ridges), parakeratosis (retained nuclei in stratum corneum), hypogranulosis (thinned or absent granular layer), and dilated tortuous capillaries in elongated dermal papillae. Additionally, there is dermal inflammation predominantly with CD8+ T cells and neutrophilic microabscesses in the stratum corneum (Munro microabscesses). Histology is pathognomonic but not necessary for diagnosis if clinical presentation is classic.

• Laboratory tests — No specific laboratory tests diagnose psoriasis; routine labs are used for baseline assessment before systemic therapy and to monitor for comorbidities. HLA-Cw6 typing is not clinically useful for diagnosis or prognosis. Streptococcal serology (anti-streptolysin O titer, anti-DNase B) may support diagnosis in guttate cases with recent pharyngitis. Inflammatory markers (ESR, CRP) correlate loosely with disease severity but are not diagnostic.

• Imaging — Imaging is not required for diagnosis; however, plain radiographs of hands may reveal psoriatic arthropathy changes (juxta-articular new bone formation, asymmetric joint space narrowing, "pencil-in-cup" deformity in severe cases) if arthritis is clinically suspected. Ultrasound can detect subclinical joint and entheseal involvement in psoriatic arthritis.

• Severity assessment and scoring systems — PASI (Psoriasis Area Severity Index) integrates body surface area involvement and severity of erythema, induration, and scale (range 0-72; >10 typically indicates need for systemic therapy); however, PASI doesn't capture disease burden in hidden areas and has limited correlation with patient quality of life. BSA (Body Surface Area) is calculated using the "rule of nines" or handprint method (patient's palm equals approximately 1% BSA). DLQI (Dermatology Life Quality Index) assesses quality of life impact. PGA (Physician Global Assessment) provides clinician-reported severity. Mild disease is typically <3% BSA or localized; moderate is 3-10% BSA or significant involvement of visible areas; severe is >10% BSA or significant facial/genital involvement or inadequate response to topical therapy.

• Differential diagnosis considerations — Seborrheic dermatitis presents with less sharply demarcated lesions, yellow rather than silvery scale, and prominent scalp/intertriginous involvement; contact dermatitis shows variable morphology and resolves with allergen avoidance; lichen planus displays violaceous flat-topped papules with Wickham striae and mucosal involvement; mycosis fungoides (cutaneous T cell lymphoma) is insidious with ill-defined patches and atypical histology; drug reactions to lithium or beta-blockers may mimic psoriasis but improve with drug withdrawal; pityriasis rosea is self-limited with herald patch and Christmas tree distribution; tinea corporis demonstrates active border with KOH positivity; secondary syphilis presents with maculopapular rash including palms/soles with positive RPR/FTA-ABS.

Psoriasis management is tailored to disease severity, extent, and patient factors, progressing from topical to systemic to biologic therapies

Disease-related complications

• Psoriatic arthritis: occurs in roughly a third of patients, driven by the same IL-23/IL-17 axis acting at entheses rather than epidermis. Signals include dactylitis ("sausage digit"), enthesitis (Achilles, plantar fascia), inflammatory back pain, and DIP-predominant disease; nail pitting is the strongest cutaneous predictor. Radiographic pencil-in-cup deformity indicates established erosive disease. Early rheumatology referral prevents irreversible joint destruction (ACR/National Psoriasis Foundation psoriatic arthritis guideline).
• Erythrodermic psoriasis — emergency: loss of barrier function causes massive transepidermal water loss and cutaneous vasodilation. Watch for hypothermia, tachycardia, hypoalbuminemia, hypocalcemia, high-output cardiac failure, and secondary bacteremia. Requires admission, fluid/electrolyte repletion, and warming.
• Generalized pustular psoriasis (von Zumbusch) — emergency: IL-36 driven neutrophilic influx; fever, leukocytosis, sheets of sterile pustules, and risk of sepsis and acute kidney injury. Classically precipitated by systemic corticosteroid withdrawal.
• Cardiometabolic and psychiatric burden: chronic systemic inflammation accelerates atherosclerosis, insulin resistance, and hepatic steatosis. The ACC/AHA cholesterol and primary prevention guidelines list chronic inflammatory conditions such as psoriasis as risk-enhancing factors favoring statin therapy in intermediate-risk adults. Screen for depression and suicidality, uveitis, and inflammatory bowel disease.

Treatment-related complications

• Topical corticosteroids: atrophy, telangiectasia, striae, tachyphylaxis, and HPA-axis suppression with high-potency occluded use.
• Methotrexate: antifolate effect causes myelosuppression, hepatic fibrosis, and rare pneumonitis; teratogenic. Trimethoprim-sulfamethoxazole markedly increases toxicity — pancytopenia is the classic stem.
• Acitretin: teratogenic with prolonged pregnancy avoidance after discontinuation, plus hypertriglyceridemia and transaminitis.
• Cyclosporine: dose-dependent nephrotoxicity, hypertension, and cutaneous squamous cell carcinoma — limited to short courses.
• Phototherapy/PUVA: cumulative photocarcinogenesis and cataract risk.
• TNF inhibitors: reactivation of latent tuberculosis and hepatitis B, serious infection, demyelinating disease, drug-induced lupus, and worsening of NYHA class III-IV heart failure; paradoxical psoriasiform eruptions occur.
• IL-17 inhibitors: blocking mucosal IL-17 predisposes to Candida infection and may exacerbate inflammatory bowel disease.

• Buzzword cluster: Auspitz sign (pinpoint bleeding after scale removal), Köbner/isomorphic phenomenon, and histologic Munro microabscesses with parakeratosis, hypogranulosis, and regular acanthosis. If a stem gives silvery scale on extensor surfaces plus nail pitting, no biopsy is needed — the diagnosis is clinical.
• The single most tested "next step": a child or young adult with abrupt drop-like papules on the trunk after a sore throat has guttate psoriasis — obtain throat culture/rapid strep testing (with ASO or anti-DNase B if remote) and treat streptococcal infection; guttate lesions often respond to topicals or narrowband UVB and may remit spontaneously.
• The trap examiners set most often: do not give systemic corticosteroids for plaque psoriasis. Withdrawal precipitates rebound erythroderma or generalized pustular (von Zumbusch) psoriasis — a dermatologic emergency. "Oral prednisone taper" is the wrong answer even when the rash is extensive.
• Before any TNF inhibitor: screen for latent tuberculosis (IGRA or PPD plus chest radiograph) and hepatitis B; avoid in NYHA class III-IV heart failure and in demyelinating disease. This pre-treatment screening question appears repeatedly.
• The association to know: nail disease — pitting, onycholysis, oil-drop sign — predicts psoriatic arthritis. Asymmetric oligoarthritis with dactylitis, DIP involvement, and a seronegative (RF-negative) profile is the classic pairing; pencil-in-cup on radiograph seals it.
• Drug triggers: lithium, beta blockers, antimalarials, NSAIDs, ACE inhibitors, and interferon. A new psoriasiform eruption after starting one of these is drug-provoked until proven otherwise.
• Systemic risk: per ACC/AHA prevention guidance, psoriasis is a risk-enhancing factor supporting statin therapy in intermediate-risk adults; also screen for metabolic syndrome and depression at follow-up.
• Common distractor: seborrheic dermatitis on the scalp — greasy yellow scale, indistinct borders, nasolabial folds — versus psoriasis with sharply demarcated plaques and dry silvery scale extending past the hairline.