25.1 Inflammatory Skin Disease, Immunobullous Disorders & Severe Drug Eruptions
Key Takeaways
- Pemphigus vulgaris causes flaccid blisters with mucosal involvement and a positive Nikolsky sign from intraepidermal desmoglein antibodies; bullous pemphigoid causes tense subepidermal blisters that usually spare the mouth.
- Toxic epidermal necrolysis involves more than 30% of body surface area, Stevens-Johnson syndrome less than 10%, and the commonest triggers are allopurinol, anticonvulsants, sulfonamides and NSAIDs.
- DRESS presents 2-8 weeks after the culprit drug with fever, rash, eosinophilia, lymphadenopathy and hepatitis.
Dermatology questions in MRCP(UK) Part 1 demand precise diagnostic pattern recognition, detailed knowledge of immunopathology, mastery of stepwise therapeutic ladders, and the immediate recognition of acute life-threatening dermatological emergencies. This section covers papulosquamous and eczematous disorders, immunobullous diseases, severe cutaneous adverse drug reactions (SCARs), and cutaneous malignancies.
1. Papulosquamous & Eczematous Disorders
Psoriasis
Psoriasis is a chronic, immune-mediated inflammatory dermatosis affecting 2–3% of the UK population. It is driven by abnormal T-lymphocyte activation (Th1 and Th17 cytokines: IL-23, IL-17A, TNF-α), stimulating excessive epidermal keratinocyte proliferation. Keratinocyte transit time from the basal layer to the stratum corneum is reduced from 28 days to 3–5 days, resulting in epidermal hyperplasia (acanthosis) and premature, incomplete cornification with retention of keratinocyte nuclei in the stratum corneum (parakeratosis).
- Clinical Subtypes:
- Chronic Plaque Psoriasis (Psoriasis Vulgaris, ~90%): Symmetrically distributed, sharply demarcated, erythematous plaques covered with thick, micaceous silvery-white scales. Classic predilection for extensor surfaces (elbows, knees), scalp, sacrum, umbilicus, and natal cleft.
- Auspitz Sign: Pinpoint bleeding elicited when surface scales are scraped off, caused by mechanical trauma to tortuous, dilated dermal capillaries within the thinned suprapapillary dermal plates.
- Koebner Phenomenon (Isomorphic Response): Development of characteristic psoriatic lesions at sites of cutaneous injury or trauma (scars, scratches, burns).
- Guttate Psoriasis: Widespread eruption of small (0.5–1.5 cm), 'teardrop-like' salmon-pink scaly papules over the trunk and proximal extremities. Typically affects children and young adults 1–3 weeks following an acute upper respiratory infection (Group A beta-haemolytic Streptococcus pharyngitis or tonsillitis); anti-streptolysin O (ASO) titre is elevated. Resolves spontaneously over 3–4 months or responds to phototherapy; ~30–50% progress to plaque psoriasis.
- Pustular Psoriasis: Generalized pustular psoriasis (von Zumbusch): Life-threatening acute dermatosis presenting with widespread sheets of sterile, non-follicular pustules coalescing on an intensely erythematous, painful base. Accompanied by high fever, leukocytosis, and systemic toxicity. Classically triggered by the abrupt withdrawal of systemic corticosteroids.
- Erythrodermic Psoriasis: Generalized inflammatory erythema involving >90% of total body surface area (BSA). Medical emergency producing catastrophic physiological instability: high-output cardiac failure (from massive cutaneous vasodilation), severe hypothermia, fluid and protein loss, and secondary sepsis.
- Chronic Plaque Psoriasis (Psoriasis Vulgaris, ~90%): Symmetrically distributed, sharply demarcated, erythematous plaques covered with thick, micaceous silvery-white scales. Classic predilection for extensor surfaces (elbows, knees), scalp, sacrum, umbilicus, and natal cleft.
- Psoriatic Nail Changes (in up to 50%):
- Pitting: Punctate surface depressions caused by parakeratotic cell shedding from the proximal nail matrix.
- Onycholysis: Painless separation of the nail plate from the underlying nail bed.
- Subungual Hyperkeratosis: Accumulation of chalky scale beneath the distal nail.
- 'Oil Drop' / 'Salmon Patch' Discolouration: Red-yellow translucent discolouration of the nail bed.
- Stepwise Management Ladder (NICE CG153):
- Topical Therapy (First-line for localized plaque disease):
- First-line: Once-daily potent topical corticosteroid (e.g. betamethasone dipropionate) PLUS once-daily topical vitamin D analogue (e.g. calcipotriol) applied together for up to 4 weeks (often prescribed as fixed-dose combination ointment/gel e.g. Dovobet).
- Alternatives: Topical coal tar preparations, dithranol (short-contact therapy), or topical calcineurin inhibitors (tacrolimus) for sensitive facial/flexural areas.
- Phototherapy (Second-line for widespread plaque or guttate disease):
- Narrowband UVB (NB-UVB) phototherapy (3 times weekly).
- Photochemotherapy (PUVA: oral/bath Psoralen + UVA radiation); monitor lifetime exposure for non-melanoma skin cancer risk.
- Oral Systemic Non-Biologic Agents (Third-line for extensive/refractory disease or severe arthritis):
- Methotrexate: First-line systemic; dihydrofolate reductase inhibitor; co-prescribe folic acid (5 mg once weekly 24h post-dose). Monitoring: FBC, LFTs, Procollagen III Peptide (PIIINP) for hepatic fibrosis, CXR for pneumonitis.
- Ciclosporin: Calcineurin inhibitor offering rapid disease control. Toxicities: Nephrotoxicity, hypertension; limited to 1–2 years of continuous use.
- Acitretin: Oral retinoid, highly effective in pustular and erythrodermic psoriasis. TERATOGENICITY WARNING: Strictly contraindicated in women of childbearing potential. Pregnancy must be avoided for at least 3 years following treatment cessation due to long-lived active metabolite etretinate stored in fat.
- Biologic Therapies (Fourth-line: PASI ≥10 and DLQI >10 refractory to systemic therapy):
- Anti-TNF agents: Adalimumab, infliximab, etanercept.
- Anti-IL-17A inhibitors: Secukinumab, ixekizumab.
- Anti-IL-23 inhibitors: Guselkumab, risankizumab.
- Anti-IL-12/23 inhibitor: Ustekinumab.
- Mandatory Pre-Treatment Screening: Chest X-ray and IGRA (Quantiferon) to rule out latent tuberculosis, plus viral hepatitis B/C serology.
- Topical Therapy (First-line for localized plaque disease):
Atopic Eczema (Atopic Dermatitis)
- Pathophysiology: Complex interplay of genetic skin barrier dysfunction and Th2 immune dysregulation. Loss-of-function mutations in the Filaggrin (FLG) gene impair stratum corneum integrity, increasing transepidermal water loss and allergen penetration. Associated with the 'atopic march' (eczema → food allergy → allergic rhinitis → asthma).
- Clinical Features: Intractable pruritus, dry scaly erythema, excoriations, and lichenification (thickened, leathery skin with exaggerated markings from chronic rubbing). Classic flexural distribution (antecubital and popliteal fossae, neck, wrists, ankles) in older children and adults; infants display facial and extensor surface involvement.
- Management: Liberal, frequent emollients; topical corticosteroids (mild to potent) for acute flares; topical calcineurin inhibitors (tacrolimus, pimecrolimus) for face/neck (avoiding corticosteroid-induced skin atrophy); systemic dupilumab (anti-IL-4Rα) or JAK inhibitors (upadacitinib, baricitinib) for severe refractory disease.
- LIFE-THREATENING COMPLICATION — Eczema Herpeticum:
- Disseminated cutaneous Herpes Simplex Virus (HSV-1) infection on eczema-affected skin.
- Clinical Triad: High fever, systemic malaise, and a rapid eruption of monomorphic, clustered, 'punched-out' circular erosions and umbilicated pustules.
- Emergency Action: Immediate oral or IV aciclovir. Temporarily withhold topical corticosteroids until systemic antiviral therapy is established. Urgent ophthalmology review if lesions involve the periorbital region (risk of dendritic corneal ulceration and scarring).
2. Immunobullous Diseases: Pemphigus vs Pemphigoid
Autoimmune blistering diseases are high-yield MRCP Part 1 questions. Differentiating Pemphigus Vulgaris from Bullous Pemphigoid requires mastery of blistering semiology, histopathology, and immunofluorescence:
| Feature | Pemphigus Vulgaris | Bullous Pemphigoid |
|---|---|---|
| Target Antigen & Locus | Desmoglein 3 (mucosa) and Desmoglein 1 (skin), components of epithelial desmosomes | BP180 (type XVII collagen) and BP230 (dystonin), components of basement membrane hemidesmosomes |
| Blister Cleavage Plane | Intraepidermal (suprabasal layer) | Subepidermal (dermo-epidermal junction) |
| Microscopic Hallmark | Acantholysis (loss of intercellular keratinocyte adhesions); basal cells remain attached to BM like a "row of tombstones" | Intact blister roof of full-thickness epidermis with a dense eosinophil-rich dermal inflammatory infiltrate |
| Blister Semiology | Flaccid, thin-walled, fragile bullae that rupture easily, leaving weeping, painful, non-healing denuded erosions | Tense, firm, thick-walled bullae on an erythematous or urticarial base; resistant to rupture |
| Mucosal Involvement | Severe & Universal (>90%); oral ulceration characteristically precedes cutaneous blisters by months | Rare / Mild (10–20%); cutaneous blisters dominate |
| Nikolsky's Sign | POSITIVE (gentle lateral sliding pressure on perilesional or normal skin induces epidermal shearing/blistering) | NEGATIVE (lateral pressure does not shear the epidermis) |
| Direct Immunofluorescence (DIF) | Intercellular IgG and C3 deposition throughout the epidermis in a "chicken-wire" / "fishnet" pattern | Continuous linear IgG and C3 deposition along the dermo-epidermal basement membrane zone (BMZ) |
| Patient Demographics | Middle-aged adults (40–60 years); equal gender ratio | Elderly adults (>70 years); associated with neurological disease (stroke, PD, dementia) and DPP-4 inhibitors (gliptins) |
| First-Line Management | High-dose oral prednisolone (1.0–1.5 mg/kg/day) combined with Rituximab (anti-CD20; first-line disease-modifying therapy); azathioprine or mycophenolate | High-potency topical corticosteroids (clobetasol propionate cream 20–40 g/day) to entire body (preferred in elderly to minimize systemic steroid mortality); or oral prednisolone |
3. Severe Cutaneous Adverse Reactions (SCARs)
Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)
SJS and TEN are life-threatening mucocutaneous reactions characterized by extensive keratinocyte apoptosis and full-thickness epidermal necrolysis, mediated by cytotoxic CD8+ T-lymphocytes and NK cells releasing granulysin and perforin/granzyme B.
- Spectrum Classification by Body Surface Area (BSA) of Epidermal Detachment:
- SJS: <10% BSA epidermal detachment.
- SJS/TEN Overlap: 10–30% BSA epidermal detachment.
- TEN: >30% BSA epidermal detachment.
- Clinical Presentation: Onset occurs 1–3 weeks (latency 7–21 days) following initiation of the offending drug. Flu-like prodrome (fever, malaise, sore throat, cough) followed by painful, dusky erythematous macules and atypical targetoid lesions that rapidly coalesce into flaccid bullae. The epidermis sloughs off in sheets, leaving extensive raw, bleeding dermis resembling severe scald burns. Nikolsky's sign is positive. Severe mucosal involvement (≥2 sites in >90%): hemorrhagic crusted lips, severe stomatitis, pseudomembranous conjunctivitis (risk of symblepharon, corneal scarring, and blindness), and genital/urethral erosions.
- Common Culprit Medications: Allopurinol (HLA-B5801), Carbamazepine (HLA-B1502 in Han Chinese/SE Asians), Lamotrigine, Phenytoin, Sulfamethoxazole-trimethoprim (Co-trimoxazole), Nevirapine, and oxicam NSAIDs.
SCORTEN Severity-of-Illness Score for SJS/TEN
SCORTEN is a validated prognostic score calculated within the first 24–48 hours of admission. Each parameter scores 1 point:
| SCORTEN Prognostic Factor | Value Indicating 1 Point |
|---|---|
| 1. Age | ≥40 years |
| 2. Heart Rate | ≥120 beats/min |
| 3. Associated Malignancy | Yes (haematologic or solid tumor) |
| 4. Detached Body Surface Area | >10% BSA at day 1 |
| 5. Serum Urea | >10 mmol/L (BUN >28 mg/dL) |
| 6. Serum Bicarbonate | <20 mmol/L |
| 7. Serum Glucose | >14 mmol/L (>252 mg/dL) |
- Mortality Prediction: Score 0–1 = 3.2% mortality; Score 2 = 12.1%; Score 3 = 35.3%; Score 4 = 58.3%; Score ≥5 = >90% mortality.
- Management: Immediate cessation of all suspect medications; urgent transfer to a specialized Burn Centre or Intensive Care Unit; supportive fluid resuscitation, ambient temperature maintenance (30–32°C to prevent hypothermia), non-adherent silicone dressings, nutritional support; daily ophthalmology review with aggressive ocular lubrication and symblepharon lysis; immunomodulatory therapies: IVIG, ciclosporin, or anti-TNF (etanercept).
DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)
- Pathophysiology: Severe drug-induced hypersensitivity accompanied by reactivation of latent human herpesviruses, predominantly Human Herpesvirus 6 (HHV-6), HHV-7, EBV, and CMV.
- Clinical Diagnostic Triad:
- Prolonged Latency: Symptoms emerge 2 to 8 weeks after commencing the culprit drug (distinctly slower than SJS/TEN).
- Cutaneous & Facial Manifestations: High spiking fever (>38.5°C), widespread confluent morbilliform exanthem, and striking facial oedema (periorbital and facial swelling present in >70%).
- Haematological & Visceral Involvement: Marked peripheral eosinophilia (≥1.5 × 10^9/L), atypical lymphocytosis, and internal organ injury:
- Hepatitis: Most common organ complication (50–80%), ranging from elevated transaminases to fulminant liver failure.
- Nephritis: Acute interstitial nephritis (proteinuria, rising creatinine).
- Myocarditis / Pneumonitis: Myocarditis can present insidiously weeks after cutaneous clearing, carrying high mortality.
- Culprit Drugs: Allopurinol, carbamazepine, lamotrigine, phenytoin, phenobarbital, sulfasalazine, minocycline, vancomycin.
- Management: Immediate cessation of culprit drug; high-dose systemic corticosteroids (oral prednisolone 0.5–1.0 mg/kg/day or IV methylprednisolone) with a prolonged, slow taper over 2 to 3 months (rapid tapering precipitates catastrophic rebound flares); serial monitoring of LFTs, troponin, and renal function.
Erythema Nodosum
- Pathology: Delayed-type hypersensitivity reaction occurring in subcutaneous adipose tissue; classic histopathology shows septal panniculitis without vasculitis.
- Clinical Presentation: Exquisitely tender, painful, warm, erythematous subcutaneous nodules, classically distributed symmetrically over the anterior shins. Lesions do NOT ulcerate and resolve over 3–6 weeks like bruises (erythematous → violaceous → yellowish-green) without scarring. Accompanied by fever, malaise, and ankle arthralgia.
- High-Yield Causes:
- Streptococcal Pharyngitis: Most common infectious trigger in young adults.
- Sarcoidosis: Classic acute presentation: Löfgren's Syndrome (triad of erythema nodosum, bilateral hilar lymphadenopathy on CXR, and acute polyarthritis/ankle periarthritis).
- Primary Tuberculosis: Must be ruled out before steroid administration.
- Inflammatory Bowel Disease (IBD): Crohn's disease > Ulcerative Colitis. Lesion activity directly parallels luminal bowel inflammation.
- Pregnancy & Oral Contraceptive Pills.
- Drugs: Sulfonamides, penicillins.
A 52-year-old woman presents with painful oral ulcerations that have persisted for 4 months, making swallowing solids difficult. Over the past 3 weeks, she has developed multiple fragile, fluid-filled blisters across her scalp, upper chest, and back. On examination, several thin-walled, flaccid bullae are visible, but the majority have ruptured to leave extensive, painful, weeping denuded erosions. Gentle lateral sliding pressure applied with a finger to normal-appearing perilesional skin readily induces epidermal shearing and blister formation (positive Nikolsky's sign). Direct immunofluorescence (DIF) microscopy of a perilesional skin biopsy demonstrates deposition of IgG and C3 in an intercellular, net-like 'chicken-wire' pattern throughout the epidermis. Autoantibodies targeting which anatomical structure are primarily responsible for the pathogenesis of this condition?
A 48-year-old man who commenced oral allopurinol 100 mg daily 5 weeks ago for recurrent gout presents to the acute medical unit with high spiking fevers up to 39.1°C, a sore throat, and a progressive cutaneous eruption. Examination reveals severe, tender facial oedema, particularly involving the periorbital tissues, accompanied by bilateral cervical and axillary lymphadenopathy. A widespread, confluent, dark erythematous morbilliform maculopapular exanthem covers approximately 75% of his total body surface area, sparing only his distal lower extremities; there is no mucosal ulceration or epidermal detachment, and Nikolsky's sign is negative. Laboratory investigations reveal: White cell count 18.6 x 10^9/L, Absolute eosinophil count 2.9 x 10^9/L (reference 0.04–0.40), Atypical lymphocytes noted on blood film, Serum ALT 520 IU/L (reference <45), Serum AST 410 IU/L (reference <35), Serum Creatinine 178 μmol/L (baseline 84). Serology for acute hepatitis A, B, and C is negative, and blood cultures show no growth. Which pathological mechanism is most intimately linked to the systemic visceral complications and protracted clinical course of this disorder?