1. Inflammatory Skin Diseases

Inflammatory dermatoses represent the most common reason for dermatology referral. Understanding pathomechanisms — particularly the Th2/Th17/Th22 axis — is essential for selecting targeted biologics and systemic therapies. This section covers major inflammatory conditions at fellowship level, integrating 2025 guidelines (AAD, EDF) and landmark trials.

▼1.1 Atopic Dermatitis (Eczema)

Epidemiology: Affects 10–20% of children and 7–10% of adults worldwide. Prevalence increasing in urban/developing areas. Part of the atopic march (AD → allergic rhinitis → asthma). 70% have family history of atopy; FLG mutations (filaggrin) in ~30% of European AD but lower in Asian populations.

Pathogenesis

A two-hit model: (1) Skin barrier defect (filaggrin loss → trans-epidermal water loss → allergen penetration) + (2) Immune dysregulation. Acute phase: Th2 dominant (IL-4, IL-13 → IgE switching, eosinophilia). Chronic phase: Th2 + Th22 + Th17 (IL-17, IL-22 → acanthosis, lichenification). IL-31 mediates pruritus via sensory neuron activation. Staphylococcus aureus colonization (>90%) perpetuates inflammation via superantigens and barrier disruption.

Cytokine/Pathway	Role in AD	Targeted Therapy
IL-4 / IL-13 (via IL-4Rα)	Th2 skewing, IgE production, barrier impairment	Dupilumab, Tralokinumab
IL-13 (specific)	Barrier disruption, itch	Tralokinumab, Lebrikizumab
IL-31 (via IL-31RA)	Pruritus signaling to sensory neurons	Nemolizumab
JAK1 (downstream IL-4R, IL-31R)	Broad cytokine signaling	Upadacitinib, Abrocitinib
OX40/OX40L	T-cell co-stimulation, Th2 priming	Rocatinlimab (anti-OX40)

Diagnosis — Hanifin & Rajka Criteria (simplified)

Major (≥3 required): pruritus; typical morphology/distribution (flexural lichenification in adults; facial/extensor in infants); chronic/relapsing course; personal/family history of atopy.

Minor features include: xerosis; ichthyosis/palmar hyperlinearity/keratosis pilaris; elevated serum IgE; early age of onset; Dennie-Morgan infraorbital folds; periorbital darkening; pityriasis alba; anterior neck folds; itch when sweating; reactions to wool/lipid solvents; food intolerance; keratoconus; anterior subcapsular cataracts.

Disease Severity Assessment

Tool	Domain	Range	Use
EASI (Eczema Area Severity Index)	Signs: erythema/edema/excoriation/lichenification × area × weight	0–72	Clinical trials, biologic eligibility
IGA (Investigator Global Assessment)	0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe	0–4	Trial endpoint (IGA 0/1 = success)
SCORAD	Area + intensity + subjective (itch/sleep)	0–103	European standard
POEM (Patient-Oriented Eczema Measure)	7 items, patient-reported	0–28	Patient monitoring, PRO

Treatment Ladder

AAD/EDF 2023 AD Treatment Algorithm

All patients: Emollients (apply within 3 min of bathing — "soak and smear"), trigger avoidance, wet wrap therapy for flares, bathing with dilute bleach (sodium hypochlorite 0.005%) for S. aureus
Mild–moderate: Topical corticosteroids (TCS) — potency matched to site; Tacrolimus 0.03/0.1% or pimecrolimus 1% (calcineurin inhibitors, face/flexures, no atrophy risk); Crisaborole 2% ointment (PDE4-i, mild-moderate); Tapinarof 1% cream (AhR agonist, FDA 2022)
Moderate–severe systemic: Dupilumab 600mg SC loading then 300mg q2w (anti-IL-4Rα, FDA 2017, ≥6mo); Tralokinumab 600mg then 300mg q2w (anti-IL-13, FDA 2021, adults); Lebrikizumab 500mg×2 then 250mg q2w (FDA 2023)
JAK inhibitors (oral): Upadacitinib 15 or 30mg QD (JAK1-selective, Measure Up 1 & 2); Abrocitinib 100 or 200mg QD (JAK1-selective, JADE MONO-1 & 2); Black box warning: serious infection, malignancy, MACE, thrombosis
Conventional systemic: Cyclosporine 2.5–5mg/kg/day (fastest, short-term only); Methotrexate 10–25mg/wk; Azathioprine 1–3mg/kg/day (check TPMT); Mycophenolate 1.5–3g/day; Short-course oral prednisolone (rebound risk — avoid as maintenance)

🔑 Pearl — Eczema Herpeticum (Kaposi Varicelliform Eruption): HSV superinfection on atopic skin. Punched-out monomorphic erosions with hemorrhagic crust, clustered on eczematous skin. Systemically ill. Tzanck smear (multinucleated giant cells) + PCR confirmation. Rx: IV acyclovir 5mg/kg q8h → switch to oral when improving. Risk factors: severe AD, FLG mutations, low LL-37 antimicrobial peptide. Ophthalmic exam to exclude corneal involvement.

🔑 Pearl — Proactive Therapy: Twice-weekly TCS or tacrolimus to previously affected areas (even when clear) reduces relapse frequency. Best evidence for tacrolimus in this approach. Continue emollients daily.

Biologic	Target	Key Trial	EASI-75 (wk16)	Notable AE
Dupilumab	IL-4Rα (blocks IL-4+IL-13)	SOLO 1&2, LIBERTY AD CHRONOS	~51%	Conjunctivitis (10%), ISR, facial erythema
Tralokinumab	IL-13	ECZTRA 1&2	~56%	Conjunctivitis (less than dupilumab), URI
Lebrikizumab	IL-13	ADvocate 1&2	~59%	Conjunctivitis, ISR
Upadacitinib 30mg	JAK1	Measure Up 1	~71%	Acne, nasopharyngitis, herpes, CPK↑
Abrocitinib 200mg	JAK1	JADE MONO-1	~63%	Nausea, thrombocytopenia transient, herpes

▼1.2 Psoriasis

Epidemiology: 2–3% global prevalence; bimodal onset (type I: <40yrs, HLA-Cw6, strong family history; type II: >40yrs, less genetic). Affects all races; lower prevalence in East Asians and Sub-Saharan Africans.

Pathogenesis — IL-23/Th17 Axis

Key pathway: Dendritic cells produce IL-23 → drives Th17/Th22 differentiation → IL-17A, IL-17F, IL-22 → keratinocyte hyperproliferation (turnover 3–4 days vs 28 days normal) + neutrophil recruitment + angiogenesis. TNF-α amplifies this cascade. HLA-Cw6 (PSORS1 locus) is the strongest genetic risk factor.

Clinical Variants

Type	Key Features	Triggers/Notes
Plaque (Psoriasis vulgaris) 85%	Well-demarcated erythematous plaques, silver-white micaceous scale; Auspitz sign (pinpoint bleeding on scale removal); scalp, elbows, knees, lumbosacral	Koebner phenomenon; stress, infection, drugs (lithium, beta-blockers, antimalarials, IFN)
Guttate 10%	Drop-like 0.5–1.5cm papules/plaques, trunk/proximal extremities; self-limited 3–4 months	Post-streptococcal pharyngitis (GAS); throat culture, ASOT; NB-UVB
Pustular (GPP)	Generalized sterile neutrophilic pustules on erythrodermic background; fever, systemic illness, LIFE-THREATENING; IL36RN/CARD14 mutations	Pregnancy (impetigo herpetiformis); spesolimab (anti-IL-36R, FDA 2022 for GPP flares)
Erythrodermic	>90% BSA erythema; thermoregulation failure, high-output cardiac failure, protein loss; may arise from plaque or as initial presentation	Hospitalize; cyclosporine or infliximab for rapid disease control
Inverse/Flexural	Intertriginous areas (axillae, groin, submammary, intergluteal); NO scale (moist environment); well-demarcated bright red	DDx: candidiasis, intertrigo, Hailey-Hailey; may respond to calcipotriol/mild TCS
Nail Psoriasis	Pitting (most specific for psoriasis), oil-drop/salmon patch (subungual hyperkeratosis with yellow-brown discoloration), onycholysis, subungual hyperkeratosis, splinter hemorrhages, Beau lines	Present in 50% of plaque psoriasis; 80% of PsA patients; NAPSI score
Scalp Psoriasis	Beyond hairline; silvery thick adherent scale; DDx: seborrheic dermatitis (less scale, greasy)	Topical calcipotriol+betamethasone foam/shampoo; clobetasol solution
Palmoplantar	Hyperkeratotic plaques or pustular (PPP); PPP: female, smokers, HLA-B27; IL-36 driven	Topical TCS, acitretin, apremilast, IL-17i

Psoriatic Comorbidities

Psoriatic Arthritis (PsA): 15–30% of psoriasis patients; asymmetric oligoarthritis most common; enthesitis, dactylitis ("sausage digit"), spondylitis. Screen with PEST questionnaire. Early treatment prevents joint damage. Cardiovascular risk: 1.3–1.5× elevated MI risk due to chronic systemic inflammation; manage with statins/aspirin/lifestyle. Metabolic syndrome, IBD, uveitis, depression, lymphoma risk.

Biologic Therapy for Psoriasis

Drug	Target	PASI 90 (~wk16)	PASI 100	Key Notes
Adalimumab	TNF-α	~50%	~25%	Also for PsA; biosimilars available
Etanercept	TNF-α (soluble receptor)	~35%	~10%	Less effective vs IL-17/23; safer in MS concerns
Infliximab	TNF-α	~70%	~45%	IV; fastest acting TNF-i; use in erythrodermic/pustular
Ustekinumab	IL-12/IL-23 (p40)	~65%	~35%	Q12wk maintenance; favorable safety profile; also PsA
Secukinumab	IL-17A	~77%	~45%	ERASURE/FIXTURE; also AS, PsA; candida IBD caution
Ixekizumab	IL-17A	~80%	~55%	UNCOVER-2&3; Q4wk maintenance; also PsA
Bimekizumab	IL-17A+F	~91%	~67%	BE VIVID/BE READY; FDA 2023; candida↑ oral candidiasis
Brodalumab	IL-17RA	~83%	~60%	REMS due to suicidality signal; fastest onset in class
Guselkumab	IL-23 (p19)	~85%	~52%	VOYAGE 1&2; Q8wk maintenance; also PsA (DISCOVER)
Risankizumab	IL-23 (p19)	~90%	~60%	UltIMMa-1&2; Q12wk; also PsA, CD
Tildrakizumab	IL-23 (p19)	~66%	~35%	reSURFACE 1&2; Q12wk maintenance
Deucravacitinib	TYK2 (allosteric)	~58%	~30%	Oral; POETYK PSO-1&2; no JAK REMS; also PsA

Pre-Biologic Screening Checklist (ALL biologics)

TB: TST or IGRA (QuantiFERON); treat latent TB before starting anti-TNF (INH 9 months)
HBV: HBsAg, anti-HBc, anti-HBs; HBsAg+ or anti-HBc+ → antiviral prophylaxis (entecavir) with TNF-i
HIV, HCV
ANA, anti-dsDNA (drug-induced lupus risk with TNF-i)
CBC, LFT, creatinine
Vaccinations up to date (live vaccines contraindicated once on biologics)
Skin cancer check (especially prior PUVA, immunosuppression)
Pregnancy status/contraception counseling

Conventional Systemic Agents

Drug	Dosing	Monitoring	Key Contraindications/AE
Methotrexate	7.5–25mg/wk (oral/SC); folic acid 5mg/wk (not on MTX day)	CBC, LFT, creatinine q4–8wk; Fibroscan/liver biopsy if cumulative >3.5–4g or elevated enzymes	Teratogenic (Category X); hepatotoxicity/fibrosis; pneumonitis; myelosuppression; mucositis; avoid alcohol; NSAID interaction
Cyclosporine	2.5–5mg/kg/day (BID); max 5mg/kg/day; short-term courses ≤1–2yrs	BP (q2wk), creatinine (q2wk); drug interactions (CYP3A4)	Nephrotoxicity (dose-dependent, often reversible); hypertension; hypertrichosis; gingival hyperplasia; hyperlipidemia; avoid in immunosuppression/active infection
Acitretin	25–50mg/day	LFT, lipids q4–8wk	Teratogenic (3yr abstinence from pregnancy); chelitis, dry skin (all patients), alopecia, hyperostosis (long-term); good for GPP/PPP/erythrodermic
Apremilast	30mg BID (titrate over first week)	Weight monitoring; no labs required	Diarrhea/nausea (first 2 wks, usually resolves); depression; weight loss; no immunosuppression; useful in elderly/comorbidities

🔑 Pearl — Koebner Phenomenon: Psoriasis induced by trauma/injury to previously uninvolved skin. Also occurs in lichen planus, vitiligo, warts. Surgical scars can develop psoriatic plaques. Important counseling point — minimize trauma, scratching.

🔑 Pearl — Generalized Pustular Psoriasis (GPP) Emergency: Life-threatening. Admit to hospital. Spesolimab (anti-IL-36R) 900mg IV single dose — rapid resolution of pustules (Effisayil-1, NEJM 2021). Bridge with infliximab or cyclosporine while awaiting biologic. Avoid systemic steroids (rebound pustulation on withdrawal). Istradefylline and anakinra also used.

▼1.3 Contact Dermatitis (Allergic & Irritant)

Feature	Allergic Contact Dermatitis (ACD)	Irritant Contact Dermatitis (ICD)
Mechanism	Type IV delayed hypersensitivity (CD4+ Th1/Th17 mediated)	Direct cytotoxicity; no sensitization required
Onset	12–72h after re-exposure	Immediate to hours; cumulative with repeated exposure
Distribution	Follows allergen contact pattern precisely; may spread beyond	Sites of highest exposure (hands, perioral)
Morphology	Acute: vesicles, bullae, edema, weeping; chronic: lichenification, fissuring	Often dryness, fissuring, chapping; less vesiculation
First exposure reaction	NO (requires prior sensitization)	YES (first exposure can cause reaction)
Diagnosis	Patch testing (TRUE Test / extended series)	Clinical; patch test negative
Common causes	Nickel, fragrance mix, rubber (thiuram, carba mix, black rubber), preservatives (MCI/MI, parabens), dyes (PPD), epoxy resins, plants (Toxicodendron/urushiol), topical medications (neomycin, bacitracin, corticosteroids)	Soaps/detergents, water (wet work), solvents, acids/alkalis, friction, occlusion

Patch Testing

Standard method: Finn chambers applied to upper back, read at D2 (48h) and D4–7 (72–96h). A reaction at D2 only may be irritant; reactions strengthening at D4/7 suggest allergy. International Contact Dermatitis Research Group (ICDRG) grading:

Grade	Symbol	Finding
Negative	−	No reaction
Doubtful	?+	Faint erythema only
Weak positive	+	Erythema, infiltration, papules
Strong positive	++	Erythema, infiltration, papules, vesicles
Extreme positive	+++	Bullous reaction
Irritant reaction	IR	Pustule, necrosis, miliaria — not allergy

🔑 Pearl — Top Patch Test Allergens (NACDG Data): (1) Nickel sulfate — jewelry, belt buckles, coins; (2) Myroxylon pereirae (balsam of Peru) — fragrances, flavors; (3) Fragrance mix I; (4) Quaternium-15 (formaldehyde releaser); (5) Neomycin sulfate; (6) Formaldehyde; (7) Bacitracin; (8) Methylchloroisothiazolinone (MCI/MI) — cosmetics/wet wipes; (9) p-Phenylenediamine (PPD) — hair dye, "black henna tattoo" sensitization; (10) Cobalt chloride.

🔑 Pearl — Systemic Contact Dermatitis: Oral/systemic exposure to a previously skin-sensitized allergen causes generalized eczematous reaction, often with "baboon syndrome" (symmetric intertriginous involvement). Nickel (dietary), balsam of Peru (foods), thimerosal (vaccines in sensitized), mercury dental amalgam.

▼1.4 Lichen Planus & Lichenoid Reactions

Pathogenesis: Autoimmune CD8+ cytotoxic T-cell attack on basal keratinocytes (express modified self-antigens). Association with HCV infection (~20% of LP patients in endemic areas). Also: drugs, GVHD, lichen planus overlap with lupus (LPCL).

Classic LP — 6 Ps: Pruritic, Planar (flat-topped), Polygonal, Purple Papules and Plaques. Wickham striae (white reticular lines on surface — pathognomonic). Sites: flexor wrists, ankles, lower back, buccal mucosa. Koebner phenomenon.

Histology: Saw-tooth acanthosis, band-like lichenoid infiltrate (lymphocytes hugging basal layer), Max-Joseph spaces (clefts), colloid/civatte bodies (necrotic basal cells), hypergranulosis.

LP Variant	Features	Treatment
Hypertrophic LP	Thick verrucous plaques, anterior tibiae; severe pruritus; risk of SCC in long-standing lesions	Superpotent TCS under occlusion, IL triamcinolone, acitretin
Erosive/Ulcerative Oral LP	Painful erosions on buccal mucosa, gingivae, tongue; chronic; SCC risk (1–3% in >10 yrs)	Topical tacrolimus 0.1% or clobetasol gel; topical cyclosporine; systemic hydroxychloroquine or dapsone
Lichen Planopilaris (LPP)	Scarring alopecia of scalp; perifollicular erythema + scale; frontal fibrosing alopecia (FFA) is a variant — frontal hairline recession, loss of eyebrows, body hair; postmenopausal women	TCS, hydroxychloroquine, tetracyclines, 5α-reductase inhibitors for FFA
Vulvovaginal LP	Erosive LP; desquamative inflammatory vaginitis; introital stenosis; long-term complications (fusion, SCC)	Topical TCS, tacrolimus; systemic hydroxychloroquine; multidisciplinary (gynecology)
Nail LP	20-fingernail dystrophy, pterygium unguis (scar across nail = pathognomonic), nail loss; early treatment important	IL triamcinolone into nail matrix; systemic retinoids; hydroxychloroquine

🔑 Pearl: All patients with oral LP should be screened for HCV (anti-HCV ELISA). HCV-associated LP may improve with antiviral therapy (DAAs). Long-standing erosive oral LP requires annual oral SCC screening.

▼1.5 Urticaria & Angioedema

Definition: Wheals (hives) = transient, pruritic, erythematous swelling of superficial dermis, resolving <24h. Angioedema = deeper dermis/subcutaneous tissue, often non-pruritic/painful, facial/oropharyngeal. Acute <6 weeks; Chronic ≥6 weeks.

Type	Mechanism	Key Features	Treatment
Chronic Spontaneous Urticaria (CSU)	IgE/IgG anti-FcεRI or anti-IgE autoantibodies (autoimmune ~45%); mast cell activation	No identifiable trigger; CU-Q2oL QoL score; screen: anti-TPO (Hashimoto association); H pylori	Ladder: Non-sedating H1-antihistamine (cetirizine/loratadine/fexofenadine) → up to 4× dose → add omalizumab 300mg q4wk → add cyclosporine
Inducible Urticaria	Physical stimuli → mast cell degranulation	Dermographism (factitious urticaria — firm stroking), cold urticaria (cold water/air), pressure urticaria (delayed 4–6h), solar urticaria (UV), cholinergic (heat/exercise), aquagenic	Identify/avoid trigger; H1-AH; omalizumab (especially cold urticaria, solar urticaria)
IgE-mediated (allergic)	Specific IgE → FcεRI → mast cell → histamine	Acute (minutes–hours); specific allergen (food, drug, venom, latex); anaphylaxis risk	Allergen avoidance; auto-injectable epinephrine; specific immunotherapy if indicated

Hereditary Angioedema (HAE)

HAE — Types, Diagnosis & Treatment

HAE Type I (85%): C1-inhibitor deficiency (low C1-INH level + function); C4 always low (even between attacks); C1q normal (vs acquired AE). HAE Type II (15%): C1-INH dysfunctional (low function, normal/high level); C4 low. HAE Type III (rare): Normal C1-INH; FXII gene mutation; predominantly women, estrogen-triggered, bradykinin-mediated.

Triggers: Trauma (dental procedures, surgery), estrogens (OCP, HRT), ACE inhibitors (contraindicated!), stress, infections, medications (NSAIDs).

Clinical: Recurrent non-pruritic, non-pitting subcutaneous/submucosal swelling; abdominal attacks (colicky pain, nausea, vomiting — can mimic surgical abdomen); laryngeal attacks (life-threatening).

Treatment:

Acute attacks: Icatibant (bradykinin B2-receptor antagonist, SC, 30mg) or C1-INH concentrate (IV, Berinert/Ruconest) or Plasma kallikrein inhibitor (ecallantide); fresh frozen plasma if nothing available; epinephrine does NOT work well (not histamine-mediated)
Long-term prophylaxis: Lanadelumab 300mg SC q4wk (anti-plasma kallikrein, HELP OLE trial); C1-INH SC (Haegarda) twice weekly; attenuated androgens (danazol, tranexamic acid — older, less preferred); oral berotralstat (plasma kallikrein inhibitor)
Short-term prophylaxis (before procedures): C1-INH 1000U IV 1–2h before or fresh frozen plasma

🔑 Pearl — Differentiating HAE from Histaminergic Angioedema: HAE = no urticaria, no pruritus, C4 always low, bradykinin-mediated → antihistamines/epinephrine INEFFECTIVE → need kallikrein pathway drugs. Histaminergic AE = urticaria + pruritus usually present, C4 normal → H1-AH + epinephrine work. ACE inhibitor-induced AE = angiotensin II accumulation → bradykinin-like; C4 NORMAL; treatment = stop ACEi + icatibant if severe.

▼1.6 Key References & Guidelines

📚 Guidelines & Landmark Trials — Inflammatory Dermatoses

AAD-NPF Psoriasis Guidelines 2020 (JAAD) — systemic therapy recommendations
EDF/EADV Atopic Dermatitis Guidelines 2022
SOLO 1&2 (Dupilumab AD, NEJM 2016) — 38% IGA 0/1 vs 10% placebo at week 16
JADE MONO-1&2 (Abrocitinib, NEJM 2021) — dose-dependent AD response
Measure Up 1 (Upadacitinib, Lancet 2021) — EASI-75 70.8% at wk16 (30mg)
UltIMMa-1&2 (Risankizumab psoriasis, Lancet 2018) — PASI 90: 75% vs 42% (ustekinumab)
BE VIVID (Bimekizumab, Lancet 2021) — PASI 90 superior to ustekinumab and placebo
Effisayil-1 (Spesolimab GPP, NEJM 2021) — pustule clearance wk1: 54% vs 6% placebo
HELP OLE (Lanadelumab HAE, NEJM 2018) — 87% reduction in HAE attacks

2. Cutaneous Infections

Skin infections range from superficial bacterial colonization to life-threatening invasive disease. Recognition of clinical patterns, regional epidemiology (Southeast Asian pathogens), and appropriate culture/laboratory workup guide management. This section covers bacterial, viral, fungal, and parasitic infections at fellowship level.

▼2.1 Bacterial Skin Infections

Impetigo

Non-bullous (70%): S. pyogenes (GAS) ± S. aureus; honey-colored crusts; perifacial; children; spread by direct contact. Post-streptococcal glomerulonephritis (PSGN) complication (not rheumatic fever which is pharyngitis-related).

Bullous (30%): S. aureus phage group II (exfoliatin toxin cleaves desmoglein-1 locally) → flaccid bullae → thin "varnish-like" crust; neonates/young children.

Treatment: Topical mupirocin 2% or retapamulin (limited lesions); oral dicloxacillin/cefalexin for extensive/systemic; MRSA: oral TMP-SMX or doxycycline.

Cellulitis vs Erysipelas

Feature	Erysipelas	Cellulitis
Depth	Superficial dermis + upper subcutaneous	Deep dermis + subcutaneous fat
Demarcation	Sharp, well-demarcated raised border	Poorly demarcated, flat border
Causative organism	S. pyogenes (GAS) predominantly; facial erysipelas = GAS	S. aureus + S. pyogenes
Surface	Shiny, peau d'orange; may have vesicles/bullae	Warm, erythematous; no surface change
Location	Face (butterfly) or lower legs	Lower extremities (75%)
Treatment	Penicillin (amoxicillin) — GAS-specific; IV benzylpenicillin if severe	Dicloxacillin/flucloxacillin (MSSA); vancomycin if MRSA suspected

Necrotizing Fasciitis (NF)

Medical emergency — high mortality (20–40%) without prompt surgery.

Feature	Type I (Polymicrobial)	Type II (Monomicrobial)
Organisms	Mixed anaerobes + aerobes (Bacteroides, E.coli, Peptostreptococcus)	Group A Streptococcus (most common); also Vibrio vulnificus (saltwater injury, cirrhosis — very rapid, fatal)
Risk factors	Diabetes, immunosuppression, abdominal surgery, IV drug use, perianal disease	Healthy individuals; penetrating trauma; NSAID use may mask early symptoms
Special forms	Fournier's gangrene (perineal/scrotal NF)	Streptococcal toxic shock syndrome (STSS): shock + multi-organ failure

LRINEC Score (Lab Risk Indicator for Necrotizing Fasciitis): CRP (>150=4pts), WBC (>25=2pts; 15–25=1pt), Hb (<11=2pts; 11–13.5=1pt), Na (<135=2pts), Creatinine (>141=2pts), Glucose (>10=1pt). Score ≥6: suspect NF; ≥8: strongly suspect. Sensitivity 89%, specificity 97%.

Clinical clues: Pain out of proportion to examination, woody induration extending beyond erythema, skin necrosis/bullae (late), crepitus (gas-forming organisms), systemic toxicity disproportionate to local findings.

NF Management Algorithm

Immediate: IV access, broad-spectrum antibiotics (piperacillin-tazobactam + clindamycin [anti-toxin effect] ± vancomycin); fluid resuscitation
URGENT surgical debridement — do not delay for imaging; "finger test": probe wound under LA, if fascial planes separate easily without bleeding = NF confirmed → extend to OR
Repeat debridement every 24–48h until margins clear; HBO therapy adjunct in Type I
STSS: IVIG 2g/kg IV (neutralizes streptococcal superantigens) + clindamycin (inhibits toxin synthesis)
Reconstruction: Wound closure/skin grafting after source control

MRSA Skin & Soft Tissue Infections

Community-acquired MRSA (CA-MRSA): USA300 clone (USA); predominantly skin/soft tissue; Panton-Valentine Leukocidin (PVL) positive — associated with severe furunculosis/carbuncles, necrotizing pneumonia. Healthcare-associated MRSA (HA-MRSA): More antibiotic-resistant; less common in skin infections.

Condition	Treatment
Abscess (furuncle/carbuncle)	I&D is primary treatment (sufficient for simple abscess); TMP-SMX 1–2 DS tab BID × 5d if cellulitis or systemic illness (NEJM 2017 — TMP-SMX superior to placebo post-I&D)
Cellulitis ± abscess	TMP-SMX + amoxicillin (to cover beta-hemolytic Strep too); or clindamycin; or doxycycline
Severe/bacteremic MRSA	IV vancomycin (target AUC/MIC 400–600); alternative: daptomycin; linezolid for bacteriostatic coverage
Decolonization (recurrent)	Mupirocin 2% nasal ointment BID × 5d + CHG body wash daily × 5d for patient + household contacts; environmental decontamination

🔑 Pearl — Erythrasma: Corynebacterium minutissimum; intertriginous areas (groin, axillae, toe webs); coral-red fluorescence under Wood's lamp (coproporphyrin III). Treat with topical erythromycin or clindamycin; systemic erythromycin for extensive disease.

🔑 Pearl — Pitted Keratolysis: Corynebacterium, Kytococcus; hyperhidrotic plantar skin; multiple pits; malodorous; no fluorescence; treat with topical antibiotics (clindamycin/erythromycin) + antiperspirant.

▼2.2 Viral Skin Infections

Herpes Simplex Virus (HSV)

	HSV-1	HSV-2
Primary location	Orolabial, herpes labialis, herpetic whitlow, HSV encephalitis	Genital herpes (majority); neonatal herpes
Latency site	Trigeminal ganglion	Sacral dorsal root ganglia (S2-S5)
Recurrence rate	Lower than HSV-2	High (monthly recurrences in >50%)
Transmission	Oral/contact; asymptomatic shedding	Sexual; asymptomatic shedding (higher viral load)

Primary infection: More severe; grouped vesicles on erythematous base → painful erosions → crusting. Systemic symptoms (fever, malaise, lymphadenopathy).

Diagnosis: Clinical (classic presentation); Tzanck smear (multinucleated giant cells — not HSV-specific, also VZV); PCR (gold standard, most sensitive); DFA; viral culture (less sensitive, slower).

Treatment:

Primary: Acyclovir 400mg TID × 7–10d or valacyclovir 1g BID × 7–10d (oral)
Recurrent: Valacyclovir 500mg BID × 3d or 1g QD × 5d (episodic); valacyclovir 500mg QD (suppressive — reduces shedding 50%)
Severe/IV: Acyclovir 5mg/kg IV q8h; acyclovir-resistant (thymidine kinase mutation) → IV foscarnet or topical cidofovir
Neonatal HSV: IV acyclovir 60mg/kg/day × 14–21d

Varicella-Zoster Virus (VZV)

Primary infection (Varicella/chickenpox): Highly contagious; centripetal distribution (face/trunk > extremities); pruritic macules → papules → "dewdrop on rose petal" vesicles → pustules → crusts — all stages simultaneously (pathognomonic). Complications: secondary bacterial infection (S. aureus/GAS), pneumonia (adults, immunosuppressed), encephalitis, cerebellar ataxia (children), Reye syndrome (aspirin use — avoid).

Herpes Zoster (Shingles): VZV reactivation from dorsal root/cranial nerve ganglia; dermatomal distribution; burning/stabbing pain precedes rash by 2–5d (pre-eruptive phase); vesicles on erythematous base in a dermatomal band (does NOT cross midline, but may in immunosuppressed). Elderly, immunosuppressed, stress, HIV.

Complication	Notes
Post-herpetic neuralgia (PHN)	Pain >90d after rash onset; most common in elderly; prevention: early antiviral treatment + vaccination; treatment: gabapentin, pregabalin, tricyclics, topical lidocaine 5% patch, capsaicin 8%
Herpes zoster ophthalmicus (HZO)	V1 branch (ophthalmic); Hutchinson sign (nose tip involvement = nasociliary branch = high risk of ocular involvement); ophthalmology URGENT; IV acyclovir for ocular involvement
Ramsay Hunt Syndrome (HZ Oticus)	VZV reactivation in geniculate ganglion; ear pain + vesicles (external ear canal/auricle/tympanic membrane) + ipsilateral facial palsy (CN VII) + CN VIII (hearing loss, vertigo); oral acyclovir + prednisolone; prognosis worse than Bell's palsy
VZV vasculopathy/CNS	Stroke (small/large vessel), myelopathy, meningitis, encephalitis; CSF PCR VZV; treat with IV acyclovir ± steroids

Antiviral treatment: Valacyclovir 1g TID × 7d (preferred oral); acyclovir 800mg 5×/day × 7d; famciclovir 500mg TID × 7d. Start within 72h of rash onset (or any time if new lesions appearing). IV acyclovir for disseminated/CNS disease, immunosuppressed.

Vaccination: Shingrix (RZV — recombinant zoster vaccine): 2-dose SC schedule 2–6 months apart; 97% efficacy against HZ; 91% efficacy against PHN; preferred over live Zostavax for adults ≥50y; can give immunosuppressed patients (non-live); not for acute HZ episode.

Human Papillomavirus (HPV)

HPV Type	Clinical Lesion	Treatment
HPV 1, 2, 4	Verruca vulgaris (common wart — rough, hyperkeratotic, fingers/periungual/plantar)	Salicylic acid; cryotherapy; PDT; bleomycin IL; CO2 laser
HPV 1 (deep), 2, 4	Plantar warts (myrmecia — deep, painful endophytic)	Salicylic acid; cryotherapy; intralesional bleomycin; surgical
HPV 3, 10	Flat warts (verruca plana — smooth, flat-topped, face/arms)	Tretinoin; salicylic acid; laser
HPV 6, 11	Condylomata acuminata (anogenital warts — low-risk, no cancer); Recurrent Respiratory Papillomatosis	Imiquimod 5%; podophyllotoxin; TCA; cryotherapy; surgical; sinecatechins
HPV 16, 18, 31, 33 (high-risk)	Bowenoid papulosis; cervical/vulvar/anal/penile/oropharyngeal SCC	Treatment of lesion + close follow-up; high-risk vaccine (Gardasil 9)
HPV 5, 8	Epidermodysplasia verruciformis (EV) — immunosuppressed or EVER2/TMC6 mutation; widespread flat warts + pityriasis versicolor-like lesions + high SCC risk on sun-exposed areas	Sun protection; surveillance; retinoids; imiquimod; limited surgical

🔑 Pearl — Molluscum Contagiosum: Poxvirus; umbilicated pearly papules; children (truncal/intertriginous) and adults (sexually transmitted — genital); giant mollusca (>1cm) in HIV/immunosuppressed. Expressive/curettage; liquid nitrogen; cantharidin; imiquimod; watch for "molluscum dermatitis" (eczematous reaction around lesions — sign of immune response → spontaneous resolution soon). Berdazimer gel (FDA 2024 — phosphodiesterase inhibitor) first approved Rx for molluscum.

▼2.3 Dermatophytosis (Tinea) & Superficial Fungal Infections

Dermatophytes (Trichophyton, Microsporum, Epidermophyton) infect keratinized tissue (skin, hair, nails). KOH prep: hyphae (branching septate hyphae in tinea; pseudohyphae in candida; yeast+hyphae "spaghetti and meatballs" in PV).

Tinea Type	Organism	Clinical Features	Treatment
Tinea corporis	T. rubrum, T. tonsurans	Annular scaly plaques, centrifugal spread, central clearing, raised scaly advancing border	Topical terbinafine/azoles × 2–4wk; systemic if extensive
Tinea capitis	T. tonsurans (endothrix, NA); M. canis (ectothrix, Europe/Asia)	Children; scaly patches ± alopecia; kerion (painful boggy mass — inflammatory); Wood's lamp: green fluorescence with M. canis only; must treat systemically	Oral griseofulvin 15–25mg/kg/day × 6–8wk (children); terbinafine 125–250mg × 4wk; selenium sulfide/ketoconazole shampoo (adjunct, not curative); treat contacts
Tinea pedis	T. rubrum, T. mentagrophytes	Interdigital (maceration, 4th/5th toe web most common); moccasin (hyperkeratotic plantar); vesicular/bullous; one-hand-two-feet (tinea manuum)	Topical terbinafine/clotrimazole BID × 2–4wk; systemic if extensive/moccasin
Tinea unguium (Onychomycosis)	T. rubrum (80%), T. mentagrophytes	DLSO (distal lateral subungual — most common): distal nail thickening, onycholysis, subungual debris, yellow-brown discoloration; SWO (superficial white — T. mentagrophytes); PSO (proximal subungual — HIV marker!); total dystrophic	Oral terbinafine 250mg/day × 6wk (fingers) or 12wk (toes); itraconazole pulse (400mg × 1wk/month × 2[fingers]/3[toes] months); efinaconazole 10% nail lacquer (topical, mild DLSO); confirm before treatment (KOH + culture + PCR)
Tinea versicolor (Pityriasis versicolor)	Malassezia furfur/globosa (commensal yeast, not dermatophyte)	Hypo/hyperpigmented (variable in darker skin), slightly scaly macules; trunk/upper arms; Wood's lamp: yellow-green fluorescence; KOH: "spaghetti and meatballs" (short curved hyphae + yeast)	Topical: selenium sulfide 2.5% shampoo, ketoconazole shampoo/cream, zinc pyrithione; systemic: fluconazole 400mg single dose or itraconazole 200mg/day × 5–7d; repigmentation slow (months); high recurrence rate

🔑 Pearl — Tinea Incognito: Atypical tinea modified by topical corticosteroid use → reduced scaling, less erythema, broader spread, loss of active advancing border, may become pustular. Always suspect fungal infection before prescribing topical steroids to scaly lesions. KOH mandatory before TCS for annular/scaly lesions.

🔑 Pearl — Terbinafine vs Azoles for Onychomycosis: Terbinafine (allylamine) has SUPERIOR mycological cure for dermatophytes (mechanism: ergosterol synthesis inhibition at squalene epoxidase step, fungicidal). Azoles (itraconazole) = fungistatic, broader spectrum including Candida. Do NOT use terbinafine for Candida onychomycosis → use itraconazole. Always confirm diagnosis before systemic antifungal (false positive rate high clinically).

▼2.4 Deep Fungal Infections (Including Southeast Asian Pathogens)

Talaromyces (Penicillium) marneffei — Thai Highly Relevant

Epidemiology: Endemic to Southeast Asia (Thailand, Vietnam, southern China, India). Thermally dimorphic fungus — hyphal form (25°C/room temp), yeast form (37°C/body). Most common systemic fungal infection in HIV-infected patients in northern Thailand. CD4 <100 cells/μL. Bamboo rat (Rhizomys) as reservoir.

Clinical features: Fever, weight loss, lymphadenopathy, hepatosplenomegaly, pulmonary infiltrates. Skin lesions (70–80%): umbilicated papules with central necrotic dell — resembling molluscum contagiosum on face, trunk, extremities; skin biopsy is a rapid diagnostic method. Also: papules on palate.

Diagnosis: Skin biopsy (touch prep or histology) — intracellular/extracellular yeast with central septum ("sausage cells," no capsule); blood culture (lysis-centrifugation); bone marrow biopsy; serum/urine Talaromyces Mp1p antigen; serum galactomannan. Culture: powder-blue colonial growth on SDA at 25°C with red diffusible pigment.

Treatment: IV amphotericin B deoxycholate or liposomal AmB (0.7–1mg/kg/day) × 2 weeks (induction), then oral itraconazole 200mg BID × 10 weeks (consolidation), then itraconazole 200mg/day (maintenance until CD4 >100 × 6 months on ART). Voriconazole = alternative. Start ART after 2–4 weeks of antifungal.

Sporotrichosis

Organism: Sporothrix schenckii complex; thermally dimorphic. Route: Implantation (rose thorns, sphagnum moss — "rose thorn disease," cat scratches). Lymphocutaneous sporotrichosis = classic form: initial papule/nodule at inoculation site → nodular lymphangitis following lymphatic chain ("rosary" of nodules). Fixed cutaneous sporotrichosis = single non-spreading lesion. Disseminated = hematogenous spread (immunosuppressed/alcoholism).

Diagnosis: Culture from lesion (gold standard); histology: cigar-shaped yeast, asteroid bodies (if present, pathognomonic but rare). Treatment: Itraconazole 200mg/day × 3–6 months (drug of choice); saturated potassium iodide (SSKI) — alternative, cheap, traditional; terbinafine 250–500mg/day; disseminated: AmB then itraconazole.

Chromoblastomycosis

Traumatic implantation; Fonsecaea pedrosoi and others (Dematiaceae); chronic warty/verrucous plaques usually lower extremities; "cauliflower-like" lesions; "Medlar bodies" (muriform cells — brown, thick-walled, septate cells in tissue — pathognomonic). Treatment: itraconazole + 5-flucytosine; voriconazole; liquid nitrogen (adjunct); surgical excision small lesions.

🔑 Thai Pearl — Opportunistic Fungal Infections in HIV: When CD4 <200: Pneumocystis, Cryptococcus. CD4 <100: Talaromyces marneffei, Histoplasma, disseminated candida, CMV, toxoplasmosis. Skin umbilicated papules in Thai HIV patient → Talaromyces vs Cryptococcus vs Molluscum (non-HIV) → skin biopsy + culture diagnostic. Cryptococcal skin lesions (umbilicated, molluscum-like) = disseminated cryptococcus → India ink, cryptococcal antigen (CRAG), LP.

▼2.5 Parasitic Infestations & Tropical Skin Infections

Scabies

Organism: Sarcoptes scabiei var. hominis; obligate human ectoparasite; female mites burrow in stratum corneum → lay eggs → sensitization (Type IV + Type I) → intense pruritus (worse at night).

Clinical features: Intensely pruritic papules/vesicles/burrows; interdigital web spaces, wrists (flexor), axillary folds, areolae, genitalia, periumbilical; SPARES face and scalp in adults (unlike infants). Burrows (pathognomonic — linear slightly elevated track 5–15mm with a dark dot at the end = female mite). Secondary eczematization, nodular scabies (firm pruritic brown nodules, genitalia/axillae — represent hypersensitivity, persist after treatment).

Norwegian (Crusted) Scabies: Immunocompromised (HIV, HTLV-1, transplant, Down syndrome); millions of mites (vs 10–15 in classical scabies) → hyperkeratotic crusts, generalized scaling, minimal pruritus, highly contagious; must isolate; requires systemic + topical treatment.

Diagnosis: Clinical; dermoscopy ("delta-wing jet" or "hang-glider" appearance of mite); skin scraping (mineral oil on burrow) → microscopy (mites/eggs/fecal pellets); PCR. Serology not useful.

Scabies Treatment Protocol (WHO/IACS)

First-line: Permethrin 5% cream — apply to entire body (neck down to soles, include under nails) at night × 8–12h → wash off; repeat at Day 7–14. Safe in pregnancy (>2 months), infants >2 months.
Alternative: Ivermectin 200mcg/kg oral, single dose; repeat at Day 7–14 (superior evidence for 2-dose); NOT approved in pregnancy or infants <15kg; preferred for Norwegian scabies
Norwegian scabies: Ivermectin oral + permethrin topical (combined); may need 3–7 doses ivermectin over 2 weeks; consider ivermectin every 2 weeks for severe cases
Household/close contacts: Treat simultaneously (even asymptomatic — incubation 4–8 weeks for new sensitization); wash all clothing/bedding/towels in hot water (>60°C) or bag for 72h (mites die within 72h off host)
Post-scabetic pruritus: May persist 2–4 weeks after successful treatment → oral antihistamines, mild TCS — do NOT re-treat unless re-infestation confirmed

Pediculosis

Type	Organism	Transmission	Clinical	Treatment
Pediculosis capitis (head lice)	Pediculus humanus capitis	Direct head contact; fomites; school children	Intense scalp pruritus; lice/nits (cemented to hair shaft, near scalp; DDx: dandruff = removable)	Permethrin 1% lotion × 10min; malathion 0.5% lotion × 12h; ivermectin 0.5% lotion; wet combing; oral ivermectin for resistance
Pediculosis pubis (crab lice)	Pthirus pubis	Sexual contact; shared bedding/towels	Pubic/genital pruritus; also axillae, eyelashes (phthiriasis palpebrarum); Macula cerulae (bluish-gray macules from mite feeding)	Permethrin 1% or malathion; eyelash: petrolatum (suffocation) or physostigmine ophthalmic ointment; treat partner
Pediculosis corporis (body lice)	Pediculus humanus corporis	Infested clothing (lice live in seams); homeless/displaced populations	Generalized pruritus, excoriations, lichenification; no lice on body (in clothing); vector for Bartonella quintana (trench fever), Rickettsia prowazekii (louse-borne typhus)	Improve hygiene; launder clothing; permethrin on clothing; doxycycline for bacterial complications

Cutaneous Larva Migrans (CLM)

Etiology: Larvae of animal hookworms (Ancylostoma braziliense — cat/dog hookworm, most common; A. caninum). Contact with contaminated soil/sand (beaches, sandboxes). Endemic: Southeast Asia, tropical Americas, Africa.

Clinical: Intensely pruritic serpiginous (snake-like) erythematous track that advances several cm/day as larvae burrow through epidermis. Larvae cannot penetrate basement membrane (no enzyme). Self-limited (6 weeks to months, larvae die).

Treatment: Ivermectin 200mcg/kg single dose (first-line; 97% cure rate); albendazole 400mg/day × 3–7 days (alternative); topical thiabendazole (difficult to apply adequately).

🔑 Thai Pearl — Gnathostomiasis: Gnathostoma spinigerum; acquired from raw freshwater fish (pla ra, pla som), frogs, chicken; migrating worm causes serpiginous subcutaneous swellings (intermittent, migratory, painful) — similar to CLM but deeper, in subcutis; may migrate to CNS (eosinophilic meningoencephalitis — bloody CSF); ocular involvement. Diagnosis: clinical + eosinophilia + ELISA antibody. Treatment: Albendazole 400mg BID × 21 days (preferred over ivermectin for this indication). Surgical removal if accessible.

▼2.6 Key References

📚 Cutaneous Infections — Key Guidelines

IDSA Guidelines — SSTI Management 2014 (updated 2017)
AAD Clinical Practice Guidelines — Superficial Fungal Infections
WHO Guidelines for Scabies Management (2020)
ACAMBIS/NEJM 2017 — TMP-SMX vs Placebo post I&D for MRSA abscess: superior outcomes with TMP-SMX
ZOE-50/ZOE-70 (Shingrix RZV, NEJM 2015/2016) — 97.2% VZV protection ≥50y; 91.2% PHN prevention
Thai HIV Treatment Guidelines — Talaromyces marneffei Management (HIVNAT/MOPH Thailand)
ACTG A5360 — Itraconazole maintenance for Talaromyces: definitive consolidation therapy

3. Autoimmune Blistering Diseases

Autoimmune blistering diseases (AIBD) are grouped by the target antigen, blister plane (intraepidermal vs subepidermal), and immunofluorescence patterns. Mastery of DIF/IIF patterns, antigen targets, and clinical correlates is critical for board examination.

🎨 Skin Blister Plane Diagram

Disease	Target Antigen	Blister Plane	DIF Pattern	IIF / Salt-Split
Pemphigus vulgaris (PV)	Dsg3 ± Dsg1 (IgG)	Suprabasal (intraepidermal)	ICS "chicken-wire" IgG + C3	IIF monkey esophagus (Dsg3 mucosal); no salt-split needed
Pemphigus foliaceus (PF)	Dsg1 only (IgG)	Subcorneal (intraepidermal)	ICS IgG (upper epidermis)	IIF normal skin (Dsg1 throughout epidermis)
Bullous pemphigoid (BP)	BP180 (type XVII collagen) + BP230 (IgG, IgE)	Subepidermal (lamina lucida)	Linear IgG + C3 at BMZ	Salt-split: epidermal roof
Mucous membrane pemphigoid (MMP)	BP180, laminin-332, α6β4 integrin, BP230	Subepidermal	Linear IgG/IgA ± C3 at BMZ	Salt-split: roof (most) or floor (anti-laminin-332)
Dermatitis herpetiformis (DH)	Transglutaminase 3 (TG3); IgA	Subepidermal (papillary dermis)	Granular IgA at papillary dermis tips	Not applicable
Linear IgA bullous dermatosis (LABD)	LAD-1 (97kDa cleaved BP180); IgA	Subepidermal	Linear IgA at BMZ	Salt-split: roof
Epidermolysis bullosa acquisita (EBA)	Type VII collagen (IgG)	Subepidermal (sub-lamina densa)	Linear IgG ± C3 at BMZ	Salt-split: dermal floor
Paraneoplastic pemphigus (PNP)	Envoplakin, periplakin, desmoplakin, BP230, plectin (IgG)	Variable (suprabasal + subepidermal)	ICS + BMZ (both)	IIF rat bladder (pathognomonic — transitional epithelium)

▼3.1 Pemphigus Group

Pemphigus Vulgaris (PV)

Pathogenesis: IgG (primarily IgG4) autoantibodies against desmosomal cadherins Dsg3 (mucosa) and Dsg1 (skin) → sterically inhibit Dsg binding → acantholysis (loss of intercellular adhesion) → suprabasal split. Nikolsky sign positive (lateral pressure on perilesional skin causes skin to slide/shear).

Dsg compensation theory: Dsg1 expressed throughout epidermis + mucosa (low in mucosa). Dsg3 expressed in lower epidermis + mucosa (high in mucosa). Anti-Dsg3 only → mucosal-dominant PV (erosions in mouth, no skin blisters — Dsg1 compensates in skin). Anti-Dsg3 + anti-Dsg1 → mucocutaneous PV (skin + mucosa).

Clinical: Painful oral erosions (first sign in 60%); flaccid bullae on normal/erythematous skin → rupture rapidly → painful erosions; most common sites: scalp, face, trunk. Histology: Suprabasal acantholysis ("tombstone row" of basal cells at bottom); eosinophilic spongiosis in early lesions.

Treatment:

PV Treatment — PEMPHIX Trial-Based Approach

Induction (new/active disease): Prednisone 0.5–1mg/kg/day (monotherapy insufficient for long-term); Rituximab 1g IV × 2 doses 2 weeks apart (anti-CD20; depletes B cells) — PEMPHIX trial (NEJM 2017): Rituximab + short-course prednisone SUPERIOR to long-course prednisone alone for sustained remission
Adjuvants/Steroid-sparing: Mycophenolate mofetil 2–3g/day (preferred); azathioprine 1–3mg/kg/day (check TPMT); IVIG; dapsone (for mild mucosal)
Monitoring after rituximab: Anti-Dsg ELISA levels (correlate with disease activity — use to guide retreatment); CD19 B-cell counts
Recurrence (rising anti-Dsg titers): Retreatment with rituximab before clinical relapse
Efgartigimod alfa (FcRn antagonist): Reduces IgG (including pathogenic autoAbs) — FDA approved 2023 for PV; reduces anti-Dsg levels

Pemphigus Foliaceus (PF)

Anti-Dsg1 only → skin-only disease (no mucosal involvement — mucosa protected by Dsg3 compensation). Superficial blistering (subcorneal) → fragile, rupture rapidly → shallow erosions with scale/crust. Seborrheic distribution (face, scalp, upper chest/back). Nikolsky positive. Fogo Selvagem ("wild fire"): Endemic PF in Brazil (Rio São Francisco valley) — autoimmune triggered by black fly (Simulium nigrimanum) bites → similar IgG anti-Dsg1 response. Treatment: similar to PV but often milder; acitretin sometimes used.

Paraneoplastic Pemphigus (PNP)

Autoantibodies against plakin family proteins (envoplakin, periplakin, desmoplakin, BP230, plectin) + anti-Dsg3. Associations: Non-Hodgkin lymphoma (most common), CLL, Castleman disease, thymoma, Waldenström macroglobulinemia, retroperitoneal sarcoma. Bronchiolitis obliterans: Fatal complication; anti-plakin antibodies attack bronchial epithelium → respiratory failure even after tumor removal. DIF: ICS + BMZ (both). IIF on rat bladder (transitional epithelium): positive = pathognomonic. Treatment: treat underlying malignancy; immunosuppression (rituximab); prognosis poor.

🔑 Pearl: If patient with known lymphoma develops painful stomatitis that doesn't respond to steroids + severe bullous/lichenoid skin lesions + dyspnea → think Paraneoplastic Pemphigus. Check IIF on rat bladder. Prognosis largely determined by underlying malignancy and bronchiolitis obliterans.

▼3.2 Bullous Pemphigoid (BP)

Most common AIBD globally. Elderly (mean 80 years); autoimmune. Target: BP180 (type XVII collagen, NC16A domain — primary epitope) + BP230 (cytoplasmic plaque protein of hemidesmosomes). IgG (mainly IgG4) + IgE antibodies.

Pathogenesis: Anti-BP180 IgG → complement activation → eosinophil/neutrophil recruitment → proteases → separation at lamina lucida (subepidermal blister).

Clinical phases:

Pre-bullous phase: Intense pruritus + urticarial/eczematous plaques for weeks-months before bullae — often misdiagnosed as eczema/urticaria → biopsy both urticarial AND bullous lesions
Bullous phase: Tense bullae on normal or urticarial/erythematous base; NOT fragile like PV; Nikolsky NEGATIVE; flexural > extensor; lower legs, abdomen, groin; mucosa: 10–30% mild involvement (vs severe oral PV)

Diagnosis: Perilesional skin for DIF (linear IgG + C3 at BMZ); ELISA anti-BP180 NC16A (most sensitive/specific; correlates with disease activity); anti-BP230 ELISA (less sensitive). Salt-split skin IIF: epidermal roof. Histology: subepidermal blister with eosinophilic infiltrate.

BP Treatment — Evidence-Based

Mild-moderate localized: Superpotent TCS (clobetasol propionate 0.05% cream 40g/day to entire body) — JDFI trial (Joly, NEJM 2002): whole-body TCS = superior or equal to systemic prednisone with better safety in elderly; topical tacrolimus for face
Moderate-severe generalized: Prednisone 0.5mg/kg/day (with gastric protection, bone protection); taper over 6–12 months guided by anti-BP180 titers
Steroid-sparing agents: Doxycycline 200mg/day + nicotinamide 1.5–2g/day (anti-inflammatory, reduces eosinophil activation, safer in elderly — Williams/Chalmers trials); azathioprine; mycophenolate
Refractory BP: Rituximab; IVIG; omalizumab (anti-IgE, rationale for IgE-mediated BP); dupilumab (increasing evidence for eosinophilic pruritic phase)
Novel: Efgartigimod (FcRn antagonist — FDA approved 2023 for BP); beremagene geperpavec (gene therapy for EB)

🔑 Pearl — Drug-Induced BP: Most common triggers: gliptins (DPP-4 inhibitors — vildagliptin, sitagliptin; non-inflammatory variant; older patients; resolves on stopping), furosemide, spironolactone, penicillins, fluoroquinolones, checkpoint inhibitors (PD-1/PD-L1 — increasing frequency). Anti-BP180 ELISA usually positive. DPP-4i BP: linear IgG at BMZ, but unique anti-BP180 epitope outside NC16A.

▼3.3 Dermatitis Herpetiformis (DH)

Gluten-sensitive skin disorder — virtually 100% have celiac disease (subclinical in many). IgA anti-transglutaminase-3 (TG3) and anti-transglutaminase-2 (TG2) antibodies. HLA-DQ2 (95%) or DQ8.

Clinical: Intensely pruritic grouped papulovesicles (herpetiform = grouped like herpes) on extensor surfaces (elbows, knees, buttocks, shoulders, posterior scalp); vesicles so pruritic they are often excoriated before biopsy — only erosions may be visible. May have GI symptoms (iron/folate deficiency, osteoporosis from malabsorption).

Diagnosis: Perilesional skin DIF: granular IgA deposits at papillary dermis (tips of dermal papillae) — pathognomonic. Anti-TG2 IgA serology (correlates with celiac). Anti-TG3 IgA (more specific for DH). Small bowel biopsy: villous atrophy (even without GI symptoms). Anti-endomysial IgA, anti-gliadin IgA.

Treatment:

Gluten-free diet (GFD): Definitive treatment — sustained GFD leads to remission of skin disease and normalization of bowel histology; reduces lymphoma risk; takes 12–24 months for skin response
Dapsone (diaminodiphenylsulfone) 25–100mg/day: Rapid control of pruritus/blistering within days; does NOT treat underlying celiac or reduce lymphoma risk; monitor for hemolytic anemia (especially G6PD deficient), methemoglobinemia, peripheral neuropathy, agranulocytosis; check CBC q1–2wk initially then monthly
Sulfapyridine: Alternative if dapsone intolerant

🔑 Pearl: DH patients have significantly increased risk of intestinal T-cell lymphoma (enteropathy-associated T-cell lymphoma, EATL) if gluten exposure continues. GFD reduces this risk to near-normal. Screen for celiac-related complications (DEXA, B12/folate/iron levels, thyroid function — celiac autoimmune associations).

▼3.4 Key References

📚 Autoimmune Blistering Diseases

EDF Guidelines for BP (JEADV 2022)
AAD Guidelines for Pemphigus (JAAD 2020)
PEMPHIX (Ritchie, NEJM 2017) — Rituximab superior to prednisone monotherapy for new PV; 89% vs 34% complete remission at 24 months
Joly et al. (NEJM 2002) — Clobetasol TCS = oral prednisone for BP, superior safety
CHAMPION BP trial (Efgartigimod) — IgG reduction → DAS reduction vs placebo
BSG Guidelines for Coeliac Disease (2017) — includes DH management

4. Cutaneous Drug Reactions

Cutaneous adverse drug reactions (CADRs) occur in 2–3% of hospitalized patients. Recognition of pattern, latency, and implicated drugs is life-saving — particularly for severe cutaneous adverse reactions (SCARs: SJS/TEN, DRESS, AGEP).

▼4.1 Classification of Drug Reactions

Type	Mechanism	Onset	Common Culprits	Features
Maculopapular exanthem (MPE)	T-cell mediated (Type IVa/b); most common CADR (~90%)	5–14 days (1st exposure); 1–3d (re-exposure)	Aminopenicillins, sulfonamides, cephalosporins, allopurinol, anticonvulsants	Symmetric erythematous macules/papules; trunk→extremities; pruritic; rule out DRESS/SJS early
Fixed drug eruption (FDE)	CD8+ T-cell (epidermal tissue-resident); Type IVc	30min–8h after re-exposure; same site each time	Trimethoprim-SMX, NSAIDs, tetracyclines, pseudoephedrine, phenolphthalein	Round/oval dusky-red/violaceous plaque → erosion; heals with hyperpigmentation; genital FDE common; generalized FDE = bullous FDE (TEN mimic)
Urticaria / angioedema	IgE-mediated (Type I) or direct mast cell degranulation	Minutes–hours	Penicillins, cephalosporins, NSAIDs (aspirin), opiates, radiocontrast	Wheals; angioedema (face/lips/tongue); risk of anaphylaxis
Drug-induced lupus (DIL)	Drug-specific anti-histone Ab (IgG)	Months–years	Hydralazine, procainamide, isoniazid, minocycline, TNF-i (anti-dsDNA more with TNF-i)	SCLE-like rash; arthralgia; serositis; ANA+, anti-histone Ab+; anti-dsDNA rarely+; reverses on stopping drug
Photosensitivity (phototoxic)	Direct photo-damage (no sensitization needed)	Hours after UV exposure	Doxycycline, amiodarone, voriconazole, psoralens, NSAIDs (benoxaprofen)	Exaggerated sunburn in sun-exposed areas; no itch initially; dose-dependent
Photosensitivity (photoallergic)	Type IV (UV activates hapten → TCD)	1–14 days; prior sensitization required	Topical sunscreens (oxybenzone, PABA), topical NSAIDs, TCS, fragrances	Eczematous eruption; photopatch testing to diagnose; may persist (persistent light reaction)
Lichenoid drug reaction	Cytotoxic T-cells targeting basal keratinocytes	Months–years	Gold, antimalarials, thiazides, ACE-i, TNF-i, checkpoint inhibitors	Lichen planus-like (violaceous papules, Wickham striae may be absent); photodistributed often; oral involvement; drug rechallenge confirms
Serum sickness-like reaction (SSLR)	Immune complex-like; not true serum sickness	7–21 days	Cefaclor (#1), minocycline, bupropion, rituximab	Fever + urticarial rash + arthralgia; complement NORMAL (vs true SS); resolves spontaneously; no glomerulonephritis

▼4.2 Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis

SJS/TEN Spectrum: SJS = <10% BSA epidermal detachment; SJS/TEN overlap = 10–30%; TEN = >30%. Life-threatening mucocutaneous emergency — mortality TEN ~30–35%, SJS ~5%.

Pathogenesis

CD8+ cytotoxic T-lymphocytes + NK cells → keratinocyte apoptosis via perforin/granzyme B and FasL–Fas pathway + granulysin (major cytotoxin). HLA associations are critical for risk prediction in Asians:

Drug	HLA Association	Population	Odds Ratio
Allopurinol	HLA-B*58:01	Han Chinese, Thai, Korean, Vietnamese, Filipino	~580× in carriers
Carbamazepine	HLA-B*15:02	Han Chinese, Thai, Malaysian, Vietnamese (SJS/TEN); HLA-A*31:01 (Europeans — DRESS)	~2500× (B*15:02)
Phenytoin	HLA-B*15:02 (weaker association)	Southeast Asian	~10×
Abacavir	HLA-B*57:01	All (mainly European)	~900× (hypersensitivity syndrome)
Nevirapine	HLA-B35:05, DRB101:02	Asian, African	High

🔑 Thai Clinical Pearl: Thailand has mandated HLA-B*58:01 screening before allopurinol and HLA-B*15:02 screening before carbamazepine to prevent SJS/TEN. If HLA-B*58:01 positive, avoid allopurinol → use febuxostat instead. If HLA-B*15:02 positive, avoid carbamazepine/phenytoin → use alternative anticonvulsants (valproate, levetiracetam, lamotrigine — lower risk).

Common Culprit Drugs (Overall)

High-risk: Allopurinol (#1 cause globally), aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital, lamotrigine), sulfonamides (TMP-SMX, sulfasalazine, dapsone), nevirapine, oxicam NSAIDs (piroxicam, meloxicam), sertraline.

SCORTEN — Mortality Prediction Score

Parameter	Points
Age >40 years	1
Malignancy (active)	1
Heart rate >120 bpm	1
BSA involved >10% at Day 1	1
Serum urea >10 mmol/L (>28 mg/dL)	1
Serum bicarbonate <20 mEq/L	1
Serum glucose >14 mmol/L (>252 mg/dL)	1

SCORTEN 0–1: 3.2% mortality | 2: 12.1% | 3: 35.3% | 4: 58.3% | ≥5: 90%

SJS/TEN Management (Burns/ICU Approach)

Step 1 — Identify and STOP causative drug immediately (each day of continuation increases mortality)
Step 2 — Transfer to burns unit or ICU with dermatology; barrier nursing
Step 3 — Wound care: Non-adhesive dressings (Mepitel/Mepilex); avoid rupturing intact bullae; debride only necrotic tissue; daily wound assessment; BSA calculation daily
Step 4 — Supportive: IV fluid resuscitation (Parkland formula for TEN >30%); nasogastric feeding (high protein: 1.5–2g/kg/day); temperature control (warm environment 30–32°C); analgesia; thromboprophylaxis; PPI
Step 5 — Eyes: Ophthalmology consultation DAILY (pseudomembrane lysis, amniotic membrane grafting, topical steroids + antibiotics); ocular sequelae (symblepharon, corneal scarring) major long-term morbidity
Step 6 — Specific therapies (evidence summary):

Treatment	Evidence	Recommendation
Cyclosporine 3–5 mg/kg/day	Multiple retrospective studies + meta-analysis; reduced mortality vs supportive care; Schneck et al. 2008; Kirchhof et al. 2014	Reasonable option; most evidence among specific therapies; avoid if renal failure/sepsis
Etanercept (TNF-α inhibitor) 50mg SC ×1–2	RCT (Wang et al. Ann Int Med 2018): lower mortality vs systemic steroids; beneficial in multiple series; low side-effect profile	Increasingly preferred; especially if cyclosporine contraindicated; rapid epithelialization
IVIG 2–3 g/kg over 3–4 days	Conflicting data; high-dose IVIG contains anti-Fas antibodies (blocks keratinocyte apoptosis in vitro); clinical benefit uncertain in RCTs; SJS-TEN ConsORTium (2020): no benefit	Not recommended as first-line; consider early in mild SJS if no access to above
Systemic corticosteroids	Controversial; may increase infection/delay epithelialization; some data for early brief courses in SJS	Not recommended for TEN; possibly short course for SJS in early phase only

▼4.3 DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

Also termed DIHS (Drug-Induced Hypersensitivity Syndrome). Long latency (2–8 weeks), multi-organ involvement, HHV-6 reactivation, mortality ~10%.

RegiSCAR Diagnostic Criteria (≥4 points = probable/definite DRESS)

Criterion	Score
Hospitalization	Required
Reaction suspected to be drug-related	Required
Acute skin rash	0–2
Fever >38°C	0–1
Enlarged lymph nodes (≥2 sites)	0–1
Internal organ involvement (liver/kidney/lung/heart/muscle)	0–2
Blood count abnormality: eosinophilia and/or atypical lymphocytes	0–2

Key Features

Skin: Morbilliform/maculopapular rash (90%) → may progress to erythroderma; facial edema (characteristic, >50%); follicular accentuation; purpura if vasculitic; does NOT blister significantly
Systemic: Fever (high, 38–40°C, early); lymphadenopathy; liver involvement most common (hepatitis; AST/ALT 2–5× ULN; rarely fulminant hepatic failure); renal (interstitial nephritis, proteinuria); lung (interstitial pneumonitis, eosinophilic); cardiac (myocarditis — arrhythmia, heart failure); thyroiditis (delayed, 2–3 months after onset)
Hematology: Eosinophilia (>1.5×10⁹/L in 90%); atypical lymphocytes (CD8+ activated); thrombocytopenia; relative lymphopenia early
HHV-6 reactivation: HHV-6 IgM or rising IgG or PCR in blood; correlates with disease severity; thought to drive immune activation in a "second wave"

Common Causative Drugs

Aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital, lamotrigine — cross-reactivity within class ~30–50%); allopurinol (#1 globally); dapsone; minocycline; vancomycin; abacavir; nevirapine; sulfonamides; mexiletine.

Treatment

Stop causative drug immediately
Systemic prednisolone 1–2 mg/kg/day for severe organ involvement; taper SLOWLY over 3–6 months (rapid taper → flare)
Topical TCS for skin; emollients; antihistamines for pruritus
Monitor: LFT weekly ×4wk; CBC; renal function; thyroid at 3 months (delayed thyroiditis)
Avoid drug cross-reactors (anticonvulsant DRESS: avoid all aromatic anticonvulsants)
Long-term: autoimmune sequelae (Hashimoto thyroiditis, type 1 diabetes, autoimmune hepatitis) in 10–15%; monitor for years

🔑 Pearl — DRESS vs MPE: Key distinguishing features of DRESS: long latency (2–8wk vs 5–14d for MPE), fever, facial edema, lymphadenopathy, organ involvement, eosinophilia. If eosinophils >1.5 or any organ involvement with drug rash → think DRESS. Drug with latency >3 weeks before rash is highly suspect.

▼4.4 AGEP (Acute Generalized Exanthematous Pustulosis)

Sterile neutrophilic pustules on erythematous skin — dramatic appearance but self-limited (unlike TEN). SCAR with ~5% mortality (mostly from infection/organ failure in elderly).

Key Features

Onset: Very rapid — <24h for beta-lactams/macrolides; up to 10–14 days for others. Morphology: Hundreds of non-follicular sterile pustules (1–3mm) on bright erythematous edematous skin; begin in flexures/face → generalize; facial edema; mild mucositis in 20%; may develop superficial desquamation. Systemic: High fever (38–39°C), neutrophilia (>7×10⁹/L), eosinophilia in 30%.

Histology: Subcorneal/intraepidermal spongiform pustules with neutrophils; eosinophils often present; papillary edema; perivascular mixed infiltrate.

Common culprits: Aminopenicillins (amoxicillin #1), pristinamycin, quinolones, terbinafine, carbamazepine, imidazole antifungals, diltiazem, hydroxychloroquine. Also: infections (enterovirus, CMV, Mycoplasma — rare), spider bites.

Feature	AGEP	Generalized Pustular Psoriasis (GPP)
History of psoriasis	Absent (usually)	Often present
Drug trigger	Yes, recent	Yes (steroids withdrawal, infections), but not essential
Onset	Days (often <24h for beta-lactams)	Days–weeks (often after stopping steroids)
Resolution	Self-limited, 1–3 weeks after stopping drug	May recur chronically; not self-limited
Histology	Spongiform pustules + eosinophils	Kogoj spongiform pustules (deeper, larger); no eosinophils
Genetics	No IL-36RN/CARD14 mutations	IL-36RN, CARD14, AP1S3 mutations (GPP)
Treatment	Stop drug; supportive; TCS; resolves spontaneously	Spesolimab (IL-36R inhibitor), cyclosporine, infliximab

▼4.5 Other Important Drug Reactions

Reaction	Drug	Features
Pseudoporphyria	NSAIDs (naproxen), tetracyclines, furosemide, voriconazole, dapsone	Porphyria cutanea tarda-like (skin fragility, blistering on dorsal hands); porphyrins NORMAL; sun-exposed; stop drug
Drug-induced vasculitis (LCV)	Propylthiouracil, hydralazine, minocycline, allopurinol, penicillins, cefaclor	Palpable purpura, DIF IgA or IgG in vessel walls; ANCA (propylthiouracil → p-ANCA, anti-MPO); stop drug; ± short prednisone
Drug-induced SCLE	Hydrochlorothiazide (#1), terbinafine, TNF-i, PPI, calcium channel blockers, leflunomide	Anti-Ro/La positive; photosensitive annular/papulosquamous plaques; resolves on stopping drug (months)
Checkpoint inhibitor dermatitis	Anti-PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab), anti-CTLA-4 (ipilimumab)	Maculopapular rash (most common); vitiligo (melanoma patients — good prognosis marker); lichen planus; bullous pemphigoid; SJS/TEN (rare); psoriasiform; manage with TCS; hold/stop for Grade 3–4
Hyperpigmentation	Amiodarone (blue-grey, sun-exposed), minocycline (blue-black in scars/skin, grey-green nails/teeth), bleomycin (flagellate hyperpigmentation after trauma), busulfan (diffuse browning), hydroxychloroquine (blue-grey pretibial)	Pattern and distribution guide drug identification; mostly cosmetic; some irreversible (amiodarone, minocycline Type 3)
Chemotherapy-specific	5-FU, capecitabine — Hand-foot syndrome (palmar-plantar erythrodysesthesia); taxanes — nail changes, alopecia; EGFR inhibitors (cetuximab, erlotinib) — acneiform rash (correlates with tumor response); BRAF inhibitors (vemurafenib) — photosensitivity, keratoacanthomas, SCC	Grading by CTCAE; dose reduction/hold for Grade 2–3; prophylactic skincare (EGFR rash: doxycycline + TCS)

▼4.6 Key References

📚 Drug Reactions

EDF/RegiSCAR Guidelines for DRESS/SJS/TEN (JEADV 2022)
Wang et al. Ann Intern Med 2018 — Etanercept RCT in TEN: superior to cyclosporine in mortality reduction
Chung et al. NEJM 2004 — HLA-B*15:02 and carbamazepine SJS/TEN in Han Chinese
Hung et al. NEJM 2005 — HLA-B*58:01 and allopurinol SJS/TEN/DRESS in Han Chinese
Thai FDA Pharmacogenomics Guidelines 2014 — Mandatory HLA testing before allopurinol/carbamazepine

5. Skin Malignancy

Skin cancer is the most common malignancy worldwide. Melanoma, BCC, and SCC account for >99% of primary skin cancers. Targeted therapies and immunotherapy have transformed advanced melanoma outcomes from near-zero to durable remissions.

▼5.1 Melanoma

Clinical Subtypes

Subtype	Frequency	Features	Notes
Superficial spreading melanoma (SSM)	70%	Flat/slightly raised; asymmetric; irregular border; variegated color (brown/black/pink/white/blue); radial growth phase then vertical	Most common in Caucasians; back (men), legs (women)
Nodular melanoma (NM)	15–20%	Rapidly growing blue-black nodule; ulceration early; no radial growth phase; vertical growth from start; amelanotic in 5%	Worst prognosis per thickness; BRAF mutation ~50%
Lentigo maligna melanoma (LMM)	5–10%	Elderly; sun-damaged face (cheek, temple); large (cm) irregular pigmented macule (LM = in situ) → LMM when invasive	Prolonged in situ phase; Mohs or staged excision; imiquimod for LM
Acral lentiginous melanoma (ALM)	2–3% overall; 50–70% of melanoma in Asians and Africans	Palms, soles, subungual; subungual: pigmentation of nail plate (melanonychia) + Hutchinson sign (periungual skin pigmentation = pathognomonic invasive)	No UV association; BRAF wild-type more common; KIT mutations; poor prognosis (late diagnosis); relevant for Thai population
Mucosal melanoma	1%	Oral, nasal, anorectal, vulvovaginal; deeply invasive at diagnosis; no staging by Breslow; poor prognosis	KIT mutations (imatinib); immunotherapy

Staging — AJCC 8th Edition (2017)

Primary tumor staging by Breslow thickness (mm), ulceration, and mitotic rate:

T Category	Breslow Thickness	Ulceration
T1a	<0.8mm	Without ulceration, <1 mitosis/mm²
T1b	<0.8mm with ulceration; OR 0.8–1.0mm	With or without ulceration
T2a/b	1.0–2.0mm	a=no ulceration; b=ulceration
T3a/b	2.0–4.0mm	a/b as above
T4a/b	>4.0mm	a/b as above

Sentinel Lymph Node Biopsy (SLNB): Discuss for T1b (≥0.8mm or ulcerated T1), strongly recommend T2+. Positive SLN → Stage III → consider completion lymph node dissection or observation with US surveillance.

🎨 Breslow Thickness & 5-Year Survival

Systemic Therapy for Advanced/Metastatic Melanoma

Treatment Selection by BRAF Status

BRAF V600E/K mutation (~50% of cutaneous melanoma) → targeted therapy:

Dabrafenib (BRAF-i) + trametinib (MEK-i): PFS ~11–12 months; 5-yr OS ~34%; COMBI-d/v trials. AE: fever/chills (pyrexia), rash, serous retinopathy, QTc. Cutaneous SCC/keratoacanthoma from paradoxical MAPK activation in BRAF-WT keratinocytes.
Vemurafenib + cobimetinib: Similar efficacy; photosensitivity (vemo); coBRIM trial
Encorafenib + binimetinib: COLUMBUS trial; longest PFS; less fever

All patients (regardless of BRAF) → immunotherapy:

Nivolumab (anti-PD-1) + ipilimumab (anti-CTLA-4): CheckMate 067: 5-yr OS 52% combo vs 44% nivo vs 26% ipi; highest toxicity (irAE Grade 3–4 in 59% combo)
Pembrolizumab (anti-PD-1): KEYNOTE-006: superior to ipilimumab; 5-yr OS 38%; well tolerated
BRAF-mutant: Targeted therapy vs immunotherapy — generally immunotherapy preferred first if fit (durable response); targeted if rapid response needed (high tumor burden, symptomatic)

Adjuvant therapy (Stage III/IV resected): Nivolumab or pembrolizumab × 1 year; or dabrafenib+trametinib (BRAF+) × 1 year.

🔑 Pearl — Acral Lentiginous Melanoma in Asians: ALM accounts for ~50–70% of melanoma in Thai/East Asian patients. Subungual melanoma: Hutchinson sign (pigment spreading to periungual skin) = invasive until proved otherwise → nail matrix biopsy. KIT amplification/mutation (~15–20% of ALM) → imatinib/nilotinib response. BRAF V600E less common in ALM (~15–20% vs 50% overall). Screen feet/palms in ALL skin exams of Asian patients.

▼5.2 Basal Cell Carcinoma (BCC)

Most common human cancer. UV-induced; PTCH1 (Hedgehog pathway) mutation; cumulative sun exposure. Rarely metastasizes (<0.1%) but locally destructive.

Clinical Subtypes & Dermoscopy

Subtype	Appearance	Dermoscopy	Risk
Nodular BCC	Pearly translucent papule/nodule; telangiectasias; rolled border; ulceration ("rodent ulcer")	Arborizing (tree-like) vessels; blue-gray ovoid nests; leaf-like structures; ulceration; spoke-wheel areas	Low-intermediate
Superficial BCC	Scaly erythematous plaque; thin rolled border; multiple lesions; trunk	Short fine telangiectasias; shiny white-red areas; maple leaf-like structures	Low; treats well topically
Morpheaform/Sclerosing BCC	Scar-like indurated white/yellow plaque; ill-defined margins; atrophic; may resemble scar	White shiny structureless areas; few vessels; difficult to delineate margin	HIGH — aggressive, subclinical extension, perineural invasion
Infiltrative BCC	Similar to morpheaform; may be skin-colored; firm	White structureless + arborizing vessels	HIGH

Treatment

BCC Treatment by Risk Category

High-risk features (Mohs surgery indicated): H-zone (face: periocular, perinasal, perioral, ear, temple), morpheaform/infiltrative/sclerosing subtype, recurrent BCC, perineural invasion, large size (>2cm trunk/ext; >1cm face), immunosuppressed patient, site with tissue preservation critical (nose, eyelid)
Low-risk BCC: Electrodesiccation & curettage (ED&C); cryotherapy; standard excision 4mm margins; PDT (photodynamic therapy — superficial BCC); imiquimod 5% cream × 6 weeks (superficial only; 80% clearance)
Advanced/metastatic BCC: Vismodegib 150mg/day or sonidegib 200mg/day (Hedgehog pathway inhibitors, Smoothened inhibitors — PTCH1 loss → constitutive SMO activation → GLI transcription); AE: muscle cramps, alopecia, dysgeusia, weight loss, teratogenic; ERIVANCE/BOLT trials
Refractory to HHI: Cemiplimab (anti-PD-1) — FDA approved 2021 for advanced BCC after HHI failure; ORR ~31%

🔑 Pearl — Gorlin Syndrome (Basal Cell Nevus Syndrome): PTCH1 germline mutation; autosomal dominant. Features: multiple BCCs (appearing in teens/20s), odontogenic keratocysts (jaw), calcified falx cerebri, bifid ribs, palmar/plantar pits (pathognomonic), medulloblastoma (desmoplastic; childhood), meningioma, ovarian fibromas. Management: vismodegib for BCCs; MDT; strict sun protection; avoid radiation (triggers BCCs in radiation field).

▼5.3 Squamous Cell Carcinoma (SCC)

Second most common skin cancer. UV-induced (most), HPV-related (anogenital), chronic immunosuppression (transplant recipients: 65–250× increased risk; SCC > BCC in transplant), chronic wounds (Marjolin ulcer), arsenic, ionizing radiation.

Precursor Lesions

Actinic Keratosis (AK): UV-induced keratinocyte dysplasia; rough scaly papule on sun-damaged skin; progression to SCC ~0.025–16%/year per lesion; "field cancerization" — treat field not just individual lesions. Treatment: cryotherapy (single); 5-FU 5% cream ×4wk; imiquimod 5% ×4–16wk; ingenol mebutate; diclofenac 3%; PDT (methyl-aminolevulinate, most effective for field — cosmetically superior).

Bowen's Disease (SCC in situ): Full-thickness epidermal dysplasia; erythematous scaly plaque (well-demarcated); may arise on sun-exposed or covered (HPV) skin; treat with excision, 5-FU, imiquimod, cryotherapy, PDT.

High-Risk Features for Metastasis

Feature	High-Risk Criterion
Size	>2cm diameter (head/neck); >2cm any site (some guidelines)
Depth	>6mm invasion below granular layer; invasion into subcutaneous tissue
Differentiation	Poor/undifferentiated; spindle cell SCC; acantholytic SCC; desmoplastic
Perineural invasion (PNI)	Especially named nerve involvement → adjuvant RT; high recurrence/metastasis
Location	Ear, lip, non-sun-exposed (mucosa, genital, chronic wound/scar — Marjolin)
Immunosuppression	Transplant, HIV, CLL — markedly aggressive; early aggressive treatment
Recurrent SCC	After prior treatment — higher risk

Treatment: Mohs surgery for high-risk; standard excision 4–6mm margin (low-risk); adjuvant RT for PNI/positive margins. Advanced/metastatic: Cemiplimab (anti-PD-1, FDA 2018 — first approved for CSCC, ORR ~47%, EMPOWER-CSCC-1); pembrolizumab (FDA 2020 for unresectable CSCC); platinum-based chemotherapy + cetuximab (EGFR) older option.

▼5.4 Cutaneous T-Cell Lymphoma (CTCL)

Heterogeneous group of primary cutaneous lymphomas. Mycosis fungoides (MF) most common (50%); Sézary syndrome (SS) = leukemic variant. CD4+ CD45RO+ clonal T-cell proliferation.

MF Clinical Stages

Stage	Skin	Lymph Node/Blood	5-yr Survival
IA (T1)	Patches/plaques <10% BSA	No LN/blood	~97%
IB (T2)	Patches/plaques ≥10% BSA	No LN/blood	~83%
IIA (T1-2 N1)	Any patch/plaque	LN enlarged, not involved	~75%
IIB (T3)	≥1 skin tumor (>1cm)	LN ± involved	~42%
IIIA/B (T4)	Erythroderma ≥80% BSA	LN ± involved; B0/B1 blood	~40%
IVA1 (B2)	Any T	Blood: Sézary cells ≥1000/mm³ (Sézary syndrome)	~26%
IVB (N3 or visceral)	Any T	LN effaced; visceral involvement	~15%

Diagnosis

Skin biopsy (multiple biopsies from different lesions): Pautrier microabscesses (collections of atypical lymphocytes in epidermis — pathognomonic, present in <50%), epidermotropism, lichenoid band, cerebriform lymphocyte nuclei. Immunohistochemistry: CD4+, CD3+, CD45RO+, CD26−, CD7− (loss of CD7/CD26 — important for diagnosis). TCR gene rearrangement (PCR or NGS) in skin ± blood. Blood: Sézary cells (cerebriform cells), CD4:CD8 ratio >10 (SS), flow cytometry (CD4+CD26−, CD4+CD7−).

Treatment by Stage

Stage	Treatment
IA–IIA (Early, skin-directed)	NB-UVB (patches); PUVA (plaques); superpotent TCS; nitrogen mustard (mechlorethamine) gel; bexarotene gel 1%; local RT (single lesion/tumor)
IIB (Tumors)	PUVA or total skin electron beam (TSEB) ± systemic; low-dose MTX/bexarotene; romidepsin; local RT for tumors
III (Erythroderma)	ECP (extracorporeal photopheresis) — first-line for erythrodermic MF/SS; + bexarotene oral; + interferon-α; combination
IVA–IVB / refractory	Mogamulizumab (anti-CCR4, FDA 2018 for MF/SS — MAVORIC trial: superior PFS vs vorinostat); Brentuximab vedotin (anti-CD30, for CD30+ MF/pcALCL — ALCANZA trial); Romidepsin/vorinostat (HDAC inhibitors); Alemtuzumab; allogeneic SCT for fit patients

🔑 Pearl — Sézary Syndrome: Triad: erythroderma + lymphadenopathy + peripheral blood involvement (Sézary cells ≥1000/mm³ or CD4:CD8 >10 or CD4+CD26− cells >30%). Intense pruritus, ectropion, palmoplantar keratoderma, leonine facies, alopecia. Immunophenotype: CD4+ CD26− CD7− (loss of CD26 most specific). ECP cornerstone of treatment.

▼5.5 Merkel Cell Carcinoma & Other Rare Tumors

Merkel Cell Carcinoma (MCC)

Rare but aggressive neuroendocrine carcinoma of skin. Merkel cell polyomavirus (MCPyV) drives ~80% of cases (viral oncoprotein); UV-induced mutations drive ~20% (UV-signature). Elderly (>70y), immunosuppressed (HIV, organ transplant, CLL — disproportionately high risk).

AEIOU features: Asymptomatic, Expanding rapidly, Immunosuppressed, Older (>50y), UV-exposed site.

Histology: Small blue cells with scant cytoplasm; salt-and-pepper chromatin; high mitotic rate; necrosis. IHC: CK20+ (perinuclear dot pattern, pathognomonic), CK7−, TTF1−, synaptophysin+, chromogranin+, neurofilament+.

Treatment: Wide excision + SLNB; adjuvant RT to primary site; advanced disease: Avelumab (anti-PD-L1, FDA 2017) or pembrolizumab — ORR ~40%; chemotherapy (carboplatin+etoposide) for rapid response needs.

🔑 Pearl: CK20 positive (dot-like perinuclear staining) is the KEY IHC marker for MCC. CK7-negative distinguishes from small-cell lung cancer (CK7+, TTF1+). MCPyV-positive MCC has better prognosis and higher response to immunotherapy.

▼5.6 Key References

📚 Skin Malignancy Guidelines

NCCN Melanoma Guidelines 2025
CheckMate 067 (Larkin, NEJM 2015/5-yr update 2019) — Nivo+Ipi vs Nivo vs Ipi; 5-yr OS 52% combo
COMBI-d (Long, Lancet 2015) — Dabrafenib+trametinib vs dabrafenib alone; improved PFS/OS
ERIVANCE (Sekulic, NEJM 2012) — Vismodegib for advanced BCC; ORR 30–43%
EMPOWER-CSCC-1 (Migden, NEJM 2018) — Cemiplimab for advanced SCC; ORR 47%
MAVORIC (Kim, Lancet Oncol 2018) — Mogamulizumab vs vorinostat in MF/SS; PFS 7.7 vs 3.1 mo
ALCANZA (Prince, Lancet 2017) — Brentuximab vedotin vs physician choice in CD30+ CTCL

6. Hair & Nail Disorders

▼6.1 Androgenetic Alopecia (AGA)

Pathogenesis: Dihydrotestosterone (DHT) — converted from testosterone by 5α-reductase type II in follicle dermal papilla — binds androgen receptor → progressive follicular miniaturization → vellus-like hairs → eventual follicle loss. Polygenic inheritance; androgen receptor gene on X chromosome (maternal inheritance pattern). Female AGA: Ludwig pattern (diffuse crown thinning, preserved frontal hairline); etiology includes PCOS, hyperandrogenism — investigate if rapid onset, hirsutism, or menstrual irregularity.

Treatment	Mechanism	Evidence/Notes
Minoxidil (2% women; 5% men; topical; 1mg/5mg oral)	Potassium channel opener → vasodilation → prolongs anagen; also direct follicle stimulation (prostaglandin E2↑)	FDA approved; 12–16 weeks to see effect; must use continuously; oral (low-dose) superior efficacy but systemic AE (fluid retention, hypertrichosis)
Finasteride 1mg/day (men); 2.5–5mg/day (women, post-menopausal)	5α-reductase type II inhibitor → ↓ DHT scalp/serum	FDA approved men; 66% halt progression; 33% regrowth; sexual AE in 1–2% (libido, ED); Post-finasteride syndrome controversial; contraindicated in pregnancy (feminization)
Dutasteride 0.5mg/day	5α-reductase type I + II inhibitor (more complete DHT suppression)	FDA approved for BPH only; off-label AGA (superior to finasteride in trials); lower sexual AE rates than expected; approved for AGA in South Korea/Japan
Spironolactone 100–200mg/day (women)	Androgen receptor antagonist; blocks DHT; also reduces testosterone production	Off-label but widely used female AGA; also for PCOS/hirsutism; monitor K+, BP; contraception required
PRP (Platelet-Rich Plasma)	Growth factors (VEGF, PDGF, IGF-1) → follicle stimulation	Adjunct; monthly × 3 then q3–6 monthly; moderate evidence; 3–6 injections needed
Hair transplant (FUE/FUT)	Permanent redistribution of DHT-resistant occipital follicles	FUE (individual follicle extraction, no linear scar) vs FUT (strip); combined with medical therapy for best results

▼6.2 Alopecia Areata (AA)

Pathogenesis: CD8+ NKG2D+ T-cell collapse of "immune privilege" of hair follicle → autoimmune attack on anagen follicle matrix. JAK-STAT signaling pathway drives IFN-γ and IL-15 production. HLA-DQ, HLA-DR associations; 20% family history; associated with thyroid disease, vitiligo, atopy.

Clinical: Well-demarcated oval/round patches of non-scarring alopecia; skin appears completely normal (unlike scarring); exclamation mark hairs (tapered proximally — pathognomonic active disease); nail pitting (20%; fine geometric pitting = most common nail finding in AA); trachyonychia (rough nails); Ophiasis pattern = band-like loss at periphery (poor prognosis); Sisaipho = inverse ophiasis; Alopecia totalis (AT) = complete scalp loss; Alopecia universalis (AU) = scalp + body.

AA Treatment — 2023 FDA Approvals (JAK Inhibitors)

Limited patchy AA (S1 — <25% scalp): IL triamcinolone acetonide 10mg/mL (first-line); superpotent TCS (clobetasol) under occlusion; DPCP (diphenylcyclopropenone) immunotherapy; minoxidil 5% topical (adjunct)
Extensive (≥50% or AT/AU): Baricitinib (JAK1/2 inhibitor) 2–4mg/day — BRAVE-AA1&2: 38.8% SALT≤20 at wk36 (4mg); FDA approved 2022; Ritlecitinib (JAK3/TEC family) 50mg/day — FDA 2023 (ALLEGRO trial); Deuruxolitinib (JAK1/2) — FDA 2024; Tofacitinib/ruxolitinib off-label
Screening before JAK-i: CBC, LFT, lipids, TB screening, HPV vaccination, live vaccine completion before starting
Conventional: Oral minipulse prednisolone (5mg Sat+Sun); methotrexate; cyclosporine; hydroxychloroquine (limited evidence)
DPCP (contact immunotherapy): Sensitize with 2% DPCP then weekly application to scalp of increasing concentration → induces contact allergy that "distracts" autoimmune attack; requires close monitoring; effective in 40–60% extensive AA

▼6.3 Scarring (Cicatricial) Alopecias

Permanent follicular destruction with fibrosis. Scalp biopsy ESSENTIAL — obtain from active margin (erythematous/scaly border, not central scar). Bisect: half for H&E, half in saline for DIF.

Disease	Infiltrate	Clinical Clues	Treatment
Lichen planopilaris (LPP)	Lymphocytic	Perifollicular erythema + scale (hallmark); violaceous papules around follicles; multifocal; painful/pruritic burning; Wickham striae absent on scalp	TCS potent + IL TCA; hydroxychloroquine 200–400mg/day; tetracyclines; pioglitazone (PPARγ agonist)
Frontal Fibrosing Alopecia (FFA)	Lymphocytic (LPP variant)	Postmenopausal women; symmetric frontal/temporal hairline recession; eyebrow loss (early, often presents first); facial papules (lichen planus pigmentosus); facial vellus hair loss; sunscreen association controversial	5α-reductase inhibitors (finasteride/dutasteride — most evidence); hydroxychloroquine; TCS; doxycycline
Discoid Lupus Erythematosus (DLE)	Lymphocytic	Follicular plugging (pathognomonic); central atrophic scar + peripheral hyperpigmentation; ANA+ in 5–10% (most DLE is skin-limited); scalp, face; Wood's lamp: follicular plugs fluoresce	Superpotent TCS; antimalarials (HCQ ± quinacrine); thalidomide; belimumab for SLE-associated
Folliculitis decalvans	Neutrophilic	Recurrent pustules → crusting; tufted folliculitis (multiple hairs from one follicle — doll's hair); S. aureus culture positive; men more common	Rifampicin 300mg + clindamycin 300mg BID × 3 months (combination); doxycycline; zinc sulfate; isotretinoin
Central Centrifugal Cicatricial Alopecia (CCCA)	Lymphocytic/fibrosing	African women; begins vertex/crown → centrifugal spread; traction from chemical relaxers/heat styling implicated; early: perifollicular fibrosis; may present with scalp pain; Association with uterine fibroids (JAAD 2020)	Stop traction/heat; TCS; tetracyclines; 5α-reductase inhibitors; minoxidil (adjunct)

▼6.4 Nail Disorders

Finding	Associated Condition	Notes
Pitting (small, geometric)	Psoriasis (#1), AA, eczema	Psoriasis pits: larger, irregular; AA: small, geometric, regular rows
Oil-drop/salmon patch	Psoriasis (pathognomonic)	Translucent yellow-brown subungual discoloration; also called "onycholysis with oil drop"
Onycholysis	Psoriasis, onychomycosis, trauma, hyperthyroidism, photo-onycholysis (doxy/psoralens)	Separation of nail plate from bed; white discoloration distally
Pterygium unguis	Lichen planus (pathognomonic)	Scar extending from proximal nail fold onto plate; irreversible; IL TCA early to prevent
Terry's nails	Cirrhosis, CHF, DM, aging	White nails with distal 1–2mm pink/brown band; loss of lunula
Lindsay's half-and-half nails	Chronic kidney disease (CKD)	Proximal white, distal red-brown (50:50); loss of lunula; transverse demarcation
Muehrcke's lines	Hypoalbuminemia (nephrotic, cirrhosis, chemo)	Paired transverse white bands; disappear with digital pressure (in soft tissue, not plate)
Beau's lines	Any systemic illness/stress (surgery, MI, severe infection, chemotherapy)	Transverse depressions traversing entire nail; location = time of insult (nail grows ~1mm/wk)
Melanonychia (brown/black streak)	Benign melanocytic activation (most common in Asian/dark skin); lentigo; nevus; melanoma	ABCDef: Age (peak 5th–7th decade malignant), Band (irregular width/color), Change (rapid), Digit (thumb/hallux/index), Extension (Hutchinson sign), Family history. Biopsy if: single band, new/changing, thumb/hallux/index, irregular color/width, Hutchinson sign
Yellow nail syndrome	Lymphedema + pleural effusion + respiratory disease (bronchiectasis)	Triad; slow-growing yellow thickened nails; onycholysis; also sinusitis; mechanism unknown; oral vit E/itraconazole/triazole

▼6.5 Key References

📚 Hair & Nail

BRAVE-AA1&2 (King, NEJM 2022) — Baricitinib for AA: 38.8% SALT≤20 at wk36 (4mg)
ALLEGRO Phase 2b/3 (Shapiro, NEJM 2022) — Ritlecitinib 50mg: 23% SALT≤20 at wk24
AAD Guidelines for AA Management (JAAD 2023)
North American Hair Research Society — Cicatricial Alopecia Guidelines

7. Photodermatology

▼7.1 UV Radiation Biology & Skin Phototypes

UV Type	Wavelength	Penetration	Biological Effects
UVA (long)	320–400nm	Deep dermis	Immediate pigment darkening (UPD); photoaging (elastosis, collagen degradation); MMP induction; indirect DNA damage (ROS); causes photoallergy; tanning; MSC indirect oxidation; less erythemogenic than UVB; major component of phototherapy (UVA1 for sclerotic disease)
UVB (medium)	280–320nm	Epidermis + upper dermis	Sunburn (main cause); cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts → DNA damage; p53 mutation; skin carcinogenesis; vitamin D3 synthesis; NB-UVB (311nm) for psoriasis/vitiligo/MF; MED = minimal erythemal dose
UVC (short)	200–280nm	Blocked by ozone layer	Germicidal; artificial sources (germicidal lamps); highly cytotoxic to exposed skin

Fitzpatrick Type	Description	MED (NB-UVB)	Example
I	Always burns, never tans	200–300 mJ/cm²	Very fair, freckles, red/blonde hair
II	Usually burns, sometimes tans	250–350	Fair skin, light hair
III	Sometimes burns, usually tans	300–450	Medium complexion (most Southeast Asians)
IV	Rarely burns, always tans	450–600	Olive/light brown skin (most Thai)
V	Very rarely burns	600–800	Brown skin
VI	Never burns	>800	Very dark skin

▼7.2 Photodermatoses

Condition	Key Features	UV Trigger	Treatment
Polymorphic Light Eruption (PLE)	Most common photodermatosis; young women; spring/early summer; pruritic papules/vesicles/plaques on exposed skin 30min–hours after sun; face often spared (hardening); papular form most common	UVA > UVB	Photoprotection; NB-UVB spring "hardening" course; hydroxychloroquine prophylaxis; short TCS for flares
Solar Urticaria	Rare; wheals within minutes of sun exposure; resolves within 1h shade; anaphylaxis if large BSA exposure; IgE-mediated (chromophore in serum)	UVA or visible light	H1-AH; omalizumab; PUVA desensitization; afamelanotide; plasma exchange (severe)
Chronic Actinic Dermatitis (CAD)	Elderly men; severe photosensitivity; eczematous/lichenified; very low MED; may involve covered areas; patch test positive (usually fragrance/plants); CT lymphocyte infiltrate → may progress to lymphoma-like	UVB + UVA + visible	Strict photoprotection; TCS; azathioprine; cyclosporine; PUVA desensitization; dupilumab emerging
Erythropoietic Protoporphyria (EPP)	FECH (ferrochelatase) mutation; painful burning/stinging within minutes of sun (NOT blistering initially); "burning on fire"; eventually scarring; liver disease (porphyrin accumulation); no blistering unlike PCT	Visible light (400–420nm)	Beta-carotene (modest); Afamelanotide (α-MSH analogue, implant SC, FDA 2019) — increases protective melanin, reduces pain; avoid hepatotoxic drugs
Porphyria Cutanea Tarda (PCT)	UROD deficiency; skin fragility, blistering on dorsal hands/sun-exposed areas, milia, hypertrichosis (periorbital/cheeks), hyperpigmentation, sclerodermoid plaques; elevated urine/plasma/stool porphyrins; triggers: alcohol, iron, estrogen, HCV, HIV	UVA (Soret band 400nm)	Phlebotomy (deplete iron); low-dose HCQ/CQ (chelate porphyrins); treat HCV; stop alcohol/estrogens; sun protection
Xeroderma Pigmentosum (XP)	NER (nucleotide excision repair) defect; 8 complementation groups (XPA-XPG + XPV); severe photosensitivity in infancy; freckling → actinic damage → multiple skin cancers (<10 years old); neurological degeneration (XPA/XPD/XPG most severe)	UVB + UVA	Extreme lifelong photoprotection; regular surveillance + early excision; vismodegib for BCC burden; gene therapy trials; neurological management

▼7.3 Drug-Induced Photosensitivity

Feature	Phototoxic	Photoallergic
Mechanism	Direct photo-damage (no sensitization needed); drug absorbs UV → reactive oxygen species → keratinocyte damage	Type IV (CD4+) — drug hapten activated by UV; requires prior sensitization
Onset on first exposure	Yes	No (requires sensitization)
Morphology	Exaggerated sunburn; may blister; demarcated to sun-exposed areas; pseudoporphyria (doxycycline)	Eczematous; can spread beyond sun-exposed; lichenoid (chronic)
Examples	Doxycycline, voriconazole (highest risk), amiodarone, NSAIDs, psoralens, phenothiazines, furosemide, quinolones	Topical sunscreens (oxybenzone, PABA), topical NSAIDs, ketoprofen, diclofenac, fragrances, TCS
Diagnosis	Clinical history + drug exposure timing + UV exposure	Photopatch test (patch test with UV provocation — read D2 and D4 with and without UV irradiation)
Treatment	Stop drug; strict photoprotection; emollients; TCS; time	Stop causative agent; TCS; photoprotection; persistent light reaction risk (CAD evolution)

▼7.4 Sun Protection & Phototherapy

SPF (Sun Protection Factor): Measures UVB protection only. SPF 30 blocks ~97% UVB; SPF 50 blocks ~98%; no sunscreen blocks 100%. PA system (Japan/Asia): PA+/++/+++/++++ measures UVA protection (PPD = Persistent Pigment Darkening test). Broad-spectrum = protection against both UVA + UVB (critical to specify "broad spectrum").

Chemical vs Physical filters: Organic/chemical absorb UV (oxybenzone, avobenzone, octinoxate — photoallergy risk); Inorganic/physical scatter/reflect UV (zinc oxide, titanium dioxide — preferred in photosensitive/pregnancy/children, no photoallergy).

Phototherapy Overview:

Type	Wavelength	Indications	Key Points
NB-UVB (Narrowband)	311–313nm	Psoriasis, vitiligo, MF (patch/plaque), atopic dermatitis, PLE, urticaria pigmentosa	2–3×/week; 20–30 sessions for response; lower carcinogenic risk than PUVA; preferred in pregnancy; clearance rates: psoriasis ~75%
PUVA (Psoralen + UVA)	UVA after oral/topical psoralen (8-MOP)	Psoriasis, MF (CTCL), vitiligo, palmoplantar, chronic hand eczema	More effective for thick plaques; cataracts risk (eye protection mandatory); higher SCC/melanoma risk with >200 treatments; nausea (oral psoralen)
UVA1 (340–400nm)	340–400nm (long UVA)	Morphea, atopic dermatitis (acute flare), CTCL, urticaria pigmentosa, systemic sclerosis	High dose (60 J/cm²) or medium dose; penetrates dermis; affects collagen metabolism (morphea)
308nm Excimer Laser/Lamp	308nm (targeted)	Focal psoriasis, vitiligo, AA (scalp)	High dose to targeted areas; faster response; useful for localized recalcitrant lesions; no full-body exposure
PDT (Photodynamic Therapy)	Red light ~630nm after ALA/MAL	AKs (field), superficial/nodular BCC, Bowen's, acne (blue light), photorejuvenation	MAL cream under occlusion 3h → red light; painful procedure (cooling/analgesia needed); excellent cosmetic results; tumor selective

▼7.5 Key References

📚 Photodermatology

EADV Guidelines on Photoprotection 2022
SCENESSE EPP Trial (Langendonk, NEJM 2015) — Afamelanotide: 6.4h/day more sun tolerance vs placebo
British Association of Dermatologists — Phototherapy Guidelines 2019

8. Connective Tissue & Vascular Skin Diseases

▼8.1 Cutaneous Lupus Erythematosus (CLE)

CLE Subtype	Clinical Features	Serology/DIF	Treatment
ACLE (Acute CLE)	Butterfly/malar rash (fixed erythema, spares nasolabial folds); photodistributed diffuse maculopapular eruption (generalized ACLE); bullous lupus (anti-type VII collagen, linear IgG BMZ); often active SLE	ANA+, anti-dsDNA+, anti-Sm+; DIF: granular IgG/C3/IgM at BMZ (lupus band test — positive in lesional + non-lesional sun-exposed skin in SLE)	Photoprotection; hydroxychloroquine; systemic therapy for active SLE
SCLE (Subacute CLE)	Photosensitive annular/psoriasiform papulosquamous; upper trunk, shoulders, arms; heals WITHOUT scarring; ±mild arthralgias	Anti-Ro/SSA (95%); anti-La/SSB (40%); ANA+ 70%; weakly associated with SLE risk; neonatal lupus (fetal congenital heart block from anti-Ro crossing placenta)	Photoprotection; HCQ 200–400mg/day (first-line); topical TCS/tacrolimus; quinacrine (additive); thalidomide for refractory; SCLE from drugs: stop drug (same appearance — drug-induced SCLE: HCT, terbinafine, PPIs, CCBs)
DLE (Discoid LE / CCLE)	Indurated disc-shaped plaques; follicular plugging (carpet-tack sign on undersurface); central atrophic scar; peripheral hyperpigmentation; heals with SCARRING; scalp → scarring alopecia; 5–10% progress to SLE; localized (above neck) vs generalized (below neck = higher SLE risk)	ANA+ only 5–10% (localized DLE); DIF: granular IgG/C3 at BMZ (in lesional skin only)	Superpotent TCS (first-line); IL TCA; antimalarials; oral retinoids (acitretin); dapsone; thalidomide; belimumab (SLE-associated)
Lupus Profundus (Panniculitis)	Deep subcutaneous nodules/plaques → lipoatrophy; firm, rubbery; cheeks/face, proximal extremities; overlying DLE in 50%; painful	ANA+ 50%; DIF of overlying skin	Antimalarials; dapsone; belimumab; avoid trauma (lipodystrophy worsens)

🔑 Pearl — Hydroxychloroquine Monitoring: Annual ophthalmology exam after 5 years of use (Marmor AAO guidelines 2016 revised). Dose: ≤5mg/kg/day (actual body weight) to minimize retinopathy risk. Risk factors for retinopathy: cumulative dose >1000g, renal disease, tamoxifen use, pre-existing macular disease. Baseline 10-2 visual fields + SD-OCT. HCQ retinopathy = bulls-eye maculopathy on fundoscopy (late, irreversible). Stop drug if early changes on SD-OCT.

▼8.2 Dermatomyositis (DM)

Idiopathic inflammatory myopathy with characteristic skin findings. Classic DM = skin + muscle; Clinically Amyopathic DM (CADM) = skin only (no muscle weakness ≥6 months).

Pathognomonic/Characteristic Skin Signs

Sign	Description	Notes
Gottron papules	Erythematous/violaceous papules OVER knuckles (MCP/PIP/DIP); flat-topped; may have scale	Pathognomonic; distinguish from rheumatoid nodules (BETWEEN knuckles, not over); OVER vs BETWEEN = DM vs RA
Heliotrope rash	Periorbital violaceous/lilac erythema + edema; eyelids (upper > lower); associated pruritus	Pathognomonic when periorbital; bilateral; subtle early
Gottron sign	Similar flat violaceous erythema over elbows, knees, medial malleoli (extensor bony prominences)	Characteristic; may be overlooked
V-sign	Photodistributed erythema in V-shaped pattern over anterior chest/neck	Characteristic
Shawl sign	Photodistributed erythema over posterior neck/shoulders	Characteristic
Mechanic's hands	Roughened, cracked, fissured lateral/palmar fingers; hyperkeratosis; resembles manual laborer's hands	Associated with anti-Jo-1 (antisynthetase syndrome); ILD risk high
Periungual changes	Periungual erythema; dilated/tortuous nailfold capillaries (capillaroscopy: giant loops, avascular areas); ragged cuticles	Also in systemic sclerosis and MCTD; DM capillaries: fewer, larger, "bushy" loops
Calcinosis cutis	Subcutaneous calcium deposits; extensor surfaces; especially Juvenile DM; milia-en-plaque calcifications	Diltiazem, probenecid, warfarin (low evidence); surgical removal for painful deposits

Myositis-Specific Antibodies (MSAs) — Clinical Correlations

Antibody	Clinical Association	Cancer Risk
Anti-Jo-1 (anti-histidyl tRNA synthetase)	Antisynthetase syndrome: myositis + ILD + mechanic's hands + Raynaud + arthritis + fever	Lower
Anti-MDA5 (anti-CADM-140)	CADM (amyopathic DM) + rapidly progressive ILD (high mortality); skin: palmar papules, skin ulcers, oral ulcers; RP-ILD poor prognosis	Lower; ILD mortality high
Anti-TIF1γ (anti-p155/140)	Classic DM + erythroderma; highest cancer association (75% in adults >45y → cancer-associated DM); V-sign/shawl sign prominent	Very high
Anti-NXP-2 (anti-MJ)	Juvenile DM (calcinosis cutis most common); adult: cancer association; edema, dysphagia	Moderate-high in adults
Anti-Mi-2	Classic DM; V-sign; photodistributed rash; heliotrope; good response to treatment; low ILD; lowest cancer risk	Low
Anti-SAE	Adult DM; dysphagia; skin before muscle; Japanese more common	Moderate

🔑 Pearl — Cancer Screening in DM: ALL adult DM patients require malignancy screen (cancer-associated DM 15–30%): CT chest/abdomen/pelvis; PET-CT superior if available; nasopharyngeal endoscopy (Asian patients — NPC association); colonoscopy/gynecology/PSA per age/gender. Highest risk: anti-TIF1γ+, older age, DM onset after 45y, rapid onset, dysphagia, cutaneous necrosis. Repeat screen annually for 3–5 years (malignancy may precede DM or appear later).

▼8.3 Systemic Sclerosis (Scleroderma)

Feature	Limited SSc (lcSSc)	Diffuse SSc (dcSSc)
Skin involvement	Distal extremities + face only (hands, feet, forearms)	Trunk + proximal extremities + face; rapidly progressive
Antibody	Anti-centromere (ACA) — 80% sensitivity; anti-PM-Scl	Anti-Scl-70 (anti-topoisomerase I) — 40% sensitivity; anti-RNA pol III
CREST syndrome	Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasias	Not applicable
Pulmonary HTN (PAH)	Later complication (15–20%); more common in lcSSc	Less common; ILD dominates
ILD	Less common	More common (40–60%); NSIP pattern; nintedanib/mycophenolate
Renal crisis (SRC)	Rare (<1%)	More common (10–15%); anti-RNA pol III associated; rapid onset hypertension, AKI — ACE inhibitor immediately

Skin Features Progression

Early (inflammatory): Puffy/swollen fingers (sausage digits — edematous phase), non-pitting edema; may be mistaken for UCTD or RA. Fibrotic: Skin thickening → sclerodactyly (tethered, shiny), "praying hands" deformity, mask-like face, microstomia, telangiectasias (mat-like). Raynaud phenomenon: Triphasic color change (white → blue → red) on cold/emotional stress; earliest feature; vasospasm + structural vessel changes → digital ulcers → gangrene. Nailfold capillaroscopy: "scleroderma pattern" (giant loops, avascular areas, microhemorrhages).

Key Treatments: Bosentan (endothelin-1 antagonist) for digital ulcer prevention; Nifedipine/calcium channel blockers for Raynaud; Sildenafil/macitentan for PAH; Nintedanib or mycophenolate for SSc-ILD; ACE inhibitor (captopril) STAT for SRC — do not withhold for renal crisis despite AKI; methotrexate for early dcSSc skin; autologous SCT for severe progressive dcSSc (ASTIS trial).

▼8.4 Cutaneous Vasculitis

Type	Vessel Size	Clinical/DIF	Associations
Leukocytoclastic vasculitis (LCV)	Small (post-capillary venules)	Palpable purpura (lower legs); non-blanching; DIF: fibrin + IgM/C3 in vessels; "nuclear dust" (neutrophil debris)	IgA vasculitis (HSP): IgA in vessel wall DIF; children; preceded by URI; IgAV triad: purpura + arthralgia + abdominal pain ± nephritis
IgA Vasculitis (Henoch-Schönlein Purpura)	Small	Palpable purpura below waist (buttocks, legs); DIF: IgA+ in vessel wall (pathognomonic); hematuria, nephritis (mesangial IgA deposits similar to IgA nephropathy)	GAS/virus trigger; self-limited in children; adults: more severe renal involvement; prednisone for severe abdominal/renal; poor prognosis if crescentic GN
Urticarial vasculitis	Small	Wheals persisting >24h (unlike ordinary urticaria); burn/ache rather than itch; residual purpura/hyperpigmentation; DIF: LCV pattern; normocomplementemic vs hypocomplementemic (anti-C1q: SLE association)	Hypocomplementemic UV: SLE, COPD (obstructive lung disease), anti-C1q antibodies
Polyarteritis nodosa (PAN)	Medium	Cutaneous PAN: nodules + livedo racemosa along extremities + ulcers; does NOT involve small vessels/glomeruli; NOT ANCA-associated; Hepatitis B association (classic)	Skin biopsy of nodule: transmural necrotizing inflammation of medium artery; no glomerulonephritis; no ANCA; treat: prednisone; ± cyclophosphamide for systemic PAN

🔑 Pearl — Pyoderma Gangrenosum (PG): NOT a true vasculitis — neutrophilic dermatosis. Rapid-onset painful ulcer with undermined violaceous border; pathergy (minor trauma triggers new ulcer — surgical debridement is contraindicated initially); associated: IBD (UC > CD), RA, hematologic malignancy (AML, MDS, MGUS), monoclonal gammopathy. Treatment: systemic steroids 1mg/kg/day first-line; cyclosporine (fastest response); infliximab (FDA approved); dapsone; tacrolimus topical (mild). "Do not debride acutely" — will expand ulcer via pathergy.

▼8.5 Key References

📚 CTD & Vascular Diseases

EULAR Recommendations for Management of DM/PM 2017
ACR/EULAR Classification Criteria for SSc 2013
ASTIS Trial (van Laar, JAMA 2014) — Autologous SCT vs cyclophosphamide for early diffuse SSc: event-free survival at 5yr 74% vs 47%
SENSCIS (nintedanib SSc-ILD, NEJM 2019) — 44% reduction in FVC decline
EULAR Lupus Nephritis Guidelines 2019

9. Acne, Rosacea & Follicular Disorders

▼9.1 Acne Vulgaris

Pathogenesis (4 factors): (1) Follicular hyperkeratinization (microcomedone formation); (2) Excess sebum (androgen-driven, IGF-1); (3) Cutibacterium acnes (formerly Propionibacterium acnes) colonization → TLR2 activation → IL-1/IL-8/TNF-α → inflammation; (4) Inflammation (innate + adaptive). Diet: high glycemic index foods + dairy (esp. skim milk) associated with acne worsening.

Treatment Ladder

AAD Acne Guidelines 2016 (Updated 2024) — Evidence-Based Ladder

Mild comedonal: Topical retinoid (adapalene 0.1/0.3% or tretinoin 0.025–0.1% or tazarotene) — normalizes follicular keratinization; apply nightly; combine with moisturizer; takes 6–8 weeks; the cornerstone of acne therapy
Mild-moderate inflammatory: Topical retinoid + topical benzoyl peroxide (BPO, 2.5–10%) — anti-C. acnes, comedolytic, NO resistance; ± topical antibiotic (clindamycin, erythromycin — ALWAYS with BPO to prevent resistance); topical dapsone 5/7.5% (females better); clascoterone 1% cream (androgen receptor antagonist, FDA 2020)
Moderate-severe: Oral antibiotic (doxycycline 100mg BID or 50–100mg QD; sarecycline 1.5mg/kg/day FDA 2018 — narrow-spectrum, less GI; minocycline) — limit to 3 months, always with BPO; combine with topical retinoid
Hormonal acne (female, jawline/lower face, cyclical): Combined OCP (ethinylestradiol/norgestimate or drospiorenone — anti-androgenic progestins preferred); spironolactone 50–200mg/day (off-label but widely used; watch K+; teratogenic — contraception); clascoterone (topical, no systemic AE)
Severe nodular/cystic or failure of above: Isotretinoin (13-cis-retinoic acid) 0.5–1.0mg/kg/day; cumulative dose 120–150mg/kg for remission; monitor: serum lipids (TG↑ up to 50%), LFT, CBC q4–6wk; absolutely teratogenic (iPLEDGE program — 2 forms contraception, monthly pregnancy test); depression monitoring (controversial causal link but monitor); dry lips/skin/eyes (universal); pseudotumor cerebri (avoid concurrent tetracycline); night blindness; premature epiphyseal closure (children <12y)

Acne Scarring

Types: Ice-pick (narrow, deep, V-shaped → TCA CROSS 100%); boxcar (broad, shallow/medium, defined walls → fractional laser/subcision/fillers); rolling (soft, wave-like → subcision for dermal tethering; microneedling; RF). Management: treat active acne FIRST; subcision (needle releases tethering bands); ablative fractional CO₂ laser (gold standard for atrophic scars, 2–6 sessions); non-ablative fractional (less downtime); punch excision for ice-pick; TCA CROSS for narrow scars; filler (HA) for rolling/boxcar; chemical peels (TCA 15–25% medium depth for field).

▼9.2 Rosacea

Pathogenesis: Neurovascular dysregulation + innate immune activation (Demodex folliculorum overgrowth → TLR2 → cathelicidin LL-37 → IL-8/VEGF → vascular proliferation + inflammation). UV triggers exacerbation.

Subtype	Features	Treatment
Erythematotelangiectatic (ETR)	Central facial flushing + persistent erythema; telangiectasias; stinging; triggers: heat/spicy/alcohol/UV/emotions	Topical brimonidine 0.33% gel (α2-agonist → vasoconstriction; rapid, temporary effect 8–12h); topical oxymetazoline 1% cream; PDL/Nd:YAG laser for telangiectasias; avoidance of triggers; broad-spectrum SPF daily
Papulopustular (PPR)	Papules + pustules on erythematous background; central face; resembles acne (no comedones); Demodex density elevated	Topical ivermectin 1% cream (anti-Demodex, anti-inflammatory — superior to metronidazole, ATTRACT trial); topical metronidazole 0.75/1%; azelaic acid 15% gel; oral doxycycline 40mg modified-release (sub-antimicrobial, anti-inflammatory Oracea) — Phase 3 trials: superior to placebo; isotretinoin low-dose for refractory
Phymatous (rhinophyma)	Skin thickening, nodularity, rhinophyma (nose most common); sebaceous gland hyperplasia; mostly men; advanced ETR/PPR	Oral isotretinoin (halts progression); surgical: CO₂ laser ablation, electrosurgery, dermabrasion (after isotretinoin)
Ocular rosacea	Blepharitis, meibomian gland dysfunction, conjunctival injection, chalazion, keratitis; may precede skin; 50% of rosacea patients	Warm compresses + lid hygiene; topical cyclosporine ophthalmic; oral doxycycline (meibomian anti-inflammatory effect); azithromycin

▼9.3 Hidradenitis Suppurativa (HS)

Pathogenesis: Follicular occlusion (NOT apocrine gland primary) → follicular rupture → inflammatory reaction → abscess + sinus tract formation. NOTCH1/2 and γ-secretase mutations in familial cases. Chronic, debilitating; female-male 3:1; axillae, inguinal, perianal, inframammary, perineal. Diagnostic hallmark: comedones (blackheads/double-ended comedones at sites).

Hurley Staging:

Stage I: Abscess formation without sinus tracts or scarring → topical clindamycin; doxycycline; punch debridement
Stage II: Recurrent abscesses; single or multiple separated sinus tracts; scarring → clindamycin + rifampicin (rifampin) 300mg BID × 10–12wk (most evidence for medical HS); dapsone; spironolactone; adalimumab if moderate-severe
Stage III: Diffuse involvement; multiple interconnected sinus tracts; extensive scarring → adalimumab; secukinumab; surgical: wide excision with secondary intention healing; laser hair removal (adjunct)

HS — FDA/EMA Approved Biologics

Adalimumab (TNF-α inhibitor): FDA/EMA approved; 160mg wk0 → 80mg wk2 → 40mg q1wk (PIONEER I&II — HiSCR 50% response ~60% vs 28% placebo); first approved biologic for HS; screen TB/HBV
Secukinumab (IL-17A): EMA approved 2023; SUNRISE 1&2 trials; 300mg q2wk → q4wk; comparable to adalimumab; candida IBD caution
Bimekizumab (IL-17A+F): BE HEARD I&II — HiSCR-75 at wk16 ~48%; FDA 2024 for HS
Clindamycin + rifampicin combination for Hurley II–III before biologic escalation

▼9.4 Key References

📚 Acne/Rosacea/HS

AAD Acne Guidelines 2016/updated 2024 (JAAD)
EDF Rosacea Guidelines 2019 (JEADV)
ATTRACT (Taieb, JAAD 2015) — Ivermectin 1% cream vs metronidazole 0.75% for rosacea: superior IGA success
PIONEER I&II (Kimball, NEJM 2016) — Adalimumab for HS: HiSCR 42%/59% vs 26%/28% placebo

10. Genodermatoses & Systemic Dermatology

▼10.1 Key Genodermatoses

Disease	Gene/Mechanism	Key Features	Board Pearls
Epidermolysis Bullosa (EB)	EB Simplex: KRT5/KRT14; Junctional EB: LAMA3/LAMB3/LAMC2 (laminin-332); Dystrophic EB: COL7A1 (type VII collagen)	Skin fragility + blistering from minor trauma; Junctional EB severe (often lethal); Dystrophic EB (recessive) → scarring, pseudosyndactyly, GI strictures, SCC (major cause of death)	Beremagene geperpavec (B-VEC, modified HSV-1 vector delivering COL7A1) FDA 2023 for rDEB; wound care is mainstay; high SCC risk in rDEB — regular surveillance
Neurofibromatosis Type 1 (NF1)	NF1 (neurofibromin, Ras-GAP — tumor suppressor); Ch17q11.2; AD; 50% new mutations	Café-au-lait macules ≥6 (≥5mm prepubertal, ≥15mm post-pubertal); axillary/inguinal freckling (Crowe sign); neurofibromas (dermal, plexiform); Lisch nodules (iris hamartomas); optic glioma; pheochromocytoma; malignant peripheral nerve sheath tumors (MPNST); learning disability	Diagnosis: ≥2 of 7 criteria (NIH 2022 revised). Selumetinib (MEK inhibitor) FDA 2020 for symptomatic plexiform neurofibromas (<18y). Screen for MPNST (rapid growth, pain). Annual ophthalmology (optic glioma)
Tuberous Sclerosis (TSC)	TSC1 (hamartin, Ch9) or TSC2 (tuberin, Ch16); mTOR pathway dysregulation; AD; 70% new mutations	Angiofibromas (nasal butterfly distribution, "adenoma sebaceum" — misnomer); ash-leaf macules (hypopigmented, Wood's lamp); Shagreen patches (connective tissue nevi); periungual/subungual fibromas (Koenen tumors); cortical tubers, SEGAs, epilepsy; renal angiomyolipomata; cardiac rhabdomyoma; lymphangioleiomyomatosis (LAM) in women	Everolimusmurolimusfirst approved treatment for facial angiofibromas, SEGAs, renal AML, LAM (mTOR inhibitor). Topical rapamycin for angiofibromas. Wood's lamp exam of newborns for ash-leaf macules (earliest diagnostic finding)
Darier Disease (DD)	ATP2A2 (SERCA2, sarco/endoplasmic reticulum Ca²+ ATPase); AD; chromosome 12q23-24	Greasy warty papules in seborrheic distribution; nail: red/white longitudinal striations + V-shaped notching at free edge (pathognomonic); palmoplantar pit-like keratoses; exacerbated by UV, heat, sweating, lithium; acral hemorrhagic variant; oral mucosa cobblestoning	Histology: acantholysis + dyskeratosis (corps ronds in spinous layer, grains in granular layer). Treatment: retinoids (acitretin/isotretinoin) — mainstay; sunscreen; avoid heat; treat superinfection (eczema herpeticum risk). Cyclical low-dose isotretinoin long-term
Gorlin Syndrome (BCNS)	PTCH1; AD; chromosome 9q22	Multiple BCCs (teens onward); odontogenic keratocysts (jaw X-ray); calcified falx cerebri; bifid ribs; palmoplantar pits; desmoplastic medulloblastoma; ovarian fibromas; macrocephaly	Avoid RT (induces BCCs in field). Vismodegib/sonidegib for multiple BCCs. Surveillance protocol essential. Genetic counseling.
Muir-Torre Syndrome	MSH2 (most common), MLH1; mismatch repair (MMR) defect; variant of Lynch syndrome	Sebaceous neoplasms (sebaceous adenoma, sebaceoma, sebaceous carcinoma — even 1 sebaceous neoplasm in young person = screen) + internal malignancy (colorectal most common, endometrial, genitourinary)	IHC for MMR proteins on sebaceous tumor → send germline testing if loss. Colonoscopy + endometrial surveillance. All sebaceous neoplasms <60y should have MMR IHC

▼10.2 Skin Manifestations of Systemic Disease

Skin Finding	Systemic Disease	Key Points
Acanthosis nigricans (AN)	Insulin resistance/T2DM (most common); obesity; PCOS; Cushing; acromegaly; malignancy (gastric CA if rapid onset, widespread, severe = "malignant AN")	Velvety hyperpigmented thickening of neck folds, axillae, groin; treat underlying cause; topical retinoids/lactic acid cosmetic only
Pretibial myxedema (PTM)	Graves' disease (hyperthyroidism) — NOT hypothyroidism	Non-pitting brawny edema/plaques on pretibial skin; accumulation of glycosaminoglycans; treat with potent TCS; thyroid control
Eruptive xanthomas	Severe hypertriglyceridemia (>11 mmol/L); type I/IV/V hyperlipidemia; uncontrolled DM	Crops of yellow-red papules with inflammatory halo; buttocks/elbows/trunk; resolve with TG control (fibrates/omega-3); risk of pancreatitis
Tendinous xanthomas	Familial hypercholesterolemia (FH — LDL receptor defect, Type IIa); Type III hyperlipidemia	Yellow nodules on Achilles tendon, extensor tendons of hands; xanthelasma (periocular) = LDL elevation but less specific
Pyoderma gangrenosum (PG)	IBD (UC 50%, CD 20%), RA, hematologic malignancy (AML, MDS, CML, MGUS), monoclonal gammopathy	Rapid painful ulcer; undermined violaceous border; pathergy; steroids/cyclosporine/infliximab; DO NOT debride
Calciphylaxis	CKD (ESRD on dialysis — 95%); hyperparathyroidism; warfarin; obesity; malnutrition; non-uremic (rare: hypercoagulable, malignancy)	Painful stellate ulcers/necrosis; thighs/abdomen/lower legs; calcification of small vessels; 1-yr mortality >50%; skin biopsy + plain film; treatment: sodium thiosulfate IV (reduces calcium phosphate deposition), bisphosphonates, cinacalcet (lower PTH), wound care, avoid warfarin (switch to LMWH/DOAC), consider hyperbaric oxygen
Sweet syndrome (Acute febrile neutrophilic dermatosis)	Idiopathic (30%); malignancy (AML most common); IBD; drugs (G-CSF, ATRA, TMP-SMX, hydralazine); pregnancy; infections	Fever + painful erythematous plaques (may mimic cellulitis); neutrophilic infiltrate (no vasculitis); responds dramatically to prednisolone; pathergy; neutrophilia; elevated ESR/CRP
Erythema nodosum (EN)	Most common panniculitis; Streptococcal pharyngitis (#1), TB, sarcoidosis, IBD, OCP, sulfonamides, pregnancy, Yersinia, fungi, Behçet	Tender erythematous nodules/plaques; anterior shins; bilateral; septal panniculitis (no vasculitis — histology key); self-limited 3–6 wk; treat underlying cause; NSAIDs/KI for pain; no need to biopsy classic presentation

▼10.3 Paraneoplastic Dermatoses

Dermatosis	Associated Malignancy	Key Features
Sign of Leser-Trélat	GI (gastric most common), lymphoma	Sudden explosive onset of multiple seborrheic keratoses; eruptive; often pruritic; controversial (coincidental); investigate if rapid unexplained eruption of seborrheic keratoses
Acanthosis nigricans (malignant)	Gastric adenocarcinoma (TGF-α producing)	Rapid onset, severe, widespread, involving lips/oral mucosa (tripe palms) = highly specific for malignancy
Necrolytic migratory erythema (NME)	Glucagonoma (islet cell α-tumor, pancreatic)	Migratory superficial erosive eruption in flexures (groin, axillae, perioral); healing in one area while appearing elsewhere; zinc deficiency + hyperglycemia; glucagon >1000 pg/mL; treat tumor; octreotide; zinc supplementation
Erythema gyratum repens	Lung (most common), esophageal, breast, genitourinary	Wood-grain/zebra stripe pattern; rapidly migrating concentric gyrate bands; highly specific for internal malignancy; treat underlying cancer
Paraneoplastic pemphigus (PNP)	NHL (most common), CLL, Castleman disease, thymoma	Painful stomatitis + polymorphous skin lesions + bronchiolitis obliterans; anti-envoplakin/periplakin; IIF rat bladder positive; poor prognosis
Hypertrichosis lanuginosa acquisita	Colorectal, lung, bladder	Excessive fine lanugo hair on face/trunk in adult; not androgen-dependent (lanugo not terminal hair); onset after 40y = malignancy until proved otherwise

▼10.4 Key References

📚 Genodermatoses & Systemic

Lau et al. (Selumetinib NF1 NEJM 2020) — 72% reduction in plexiform neurofibroma volume
B-VEC EB (Gurevich, NEJM 2022) — Beremagene geperpavec heals ≥50% wounds at wk3 in rDEB
NF1 NIH Diagnostic Criteria (Revised 2022)
KDIGO Calciphylaxis Guidelines 2023

11. Dermatologic Therapeutics

▼11.1 Topical Corticosteroids

Class	Potency	Examples	Site Application
Class I (Superpotent)	Highest	Clobetasol propionate 0.05%, halobetasol propionate 0.05%, betamethasone dipropionate 0.05% (augmented)	Palms/soles, scalp (short-term), lichen simplex chronicus, thick plaques; 2-week on/off cycles; max 50g/week
Class II (Potent)	Very high	Fluocinonide 0.05%, mometasone furoate 0.1% oint, betamethasone valerate 0.1% oint, desoximetasone 0.25%	Trunk, extremities (non-sensitive); NOT face
Class III–IV (Upper-mid)	High-medium	Triamcinolone 0.1% oint/cream, fluticasone 0.005% oint, betamethasone valerate 0.05% cream	Trunk/extremities; can use on thicker face areas briefly
Class V–VI (Mid-low)	Medium-low	Hydrocortisone valerate 0.2%, desonide 0.05%, fluocinolone 0.01%	Face, flexures, intertriginous; children; thin skin areas
Class VII (Least potent)	Lowest	Hydrocortisone 0.5–1%, 2.5%	Eyelids, face (delicate areas), infants; long-term maintenance

Fingertip Unit (FTU): 1 FTU = ~0.5g = cream squeezed from tip of index finger to first crease. 2 FTU covers hand + wrist (palm-sized area). For twice daily: face = 2.5 FTU; trunk (front or back) = 7 FTU each; arm = 3 FTU; leg = 6 FTU.

Adverse effects: Local: skin atrophy (striae), telangiectasias, purpura, acne/rosacea, perioral dermatitis, tinea incognito, hypopigmentation; Systemic (rare with appropriate use): HPA axis suppression (cushingoid features, adrenal insufficiency after abrupt stop), cataracts, glaucoma (periocular), growth retardation (children). Highest systemic absorption: face > genitalia > axillae > scalp > trunk > extremities > palms/soles. Enhanced by occlusion.

▼11.2 Biologics in Dermatology — Complete Reference

Drug	Target	Approved Indications	Pre-Tx Screen	Key AE
Dupilumab	IL-4Rα	AD (≥6mo), asthma, CRS with NP, EoE, PPN	TB, HBV (screen); no live vaccines	Conjunctivitis, facial erythema, ISR, headache
Tralokinumab	IL-13	AD (adults)	Standard	URI, conjunctivitis (less than dupilumab)
Lebrikizumab	IL-13	AD (adults)	Standard	Conjunctivitis, herpes
Secukinumab	IL-17A	PsO, PsA, AS, nr-axSpA	TB, HBV, HIV; IBD caution (may worsen)	Candida (oral/cutaneous ~3%), IBD flare (rare), neutropenia
Ixekizumab	IL-17A	PsO, PsA, AS, nr-axSpA	TB, HBV; IBD caution	Candida, ISR, IBD risk
Bimekizumab	IL-17A+F	PsO, PsA, AS; HS (2024)	TB, HBV; IBD caution	Oral candidiasis (highest in class ~19%), IBD
Brodalumab	IL-17RA	PsO (moderate-severe)	TB, HBV, HCV; REMS (suicidality)	Arthralgias, IBD; REMS: suicidal ideation/behavior signal
Guselkumab	IL-23 p19	PsO, PsA	TB, HBV, HIV	URI, headache; very favorable safety
Risankizumab	IL-23 p19	PsO, PsA, Crohn's disease, UC	TB, HBV, HIV	URI, fungal infection (rare); favorable profile
Adalimumab	TNF-α	PsO, PsA, HS, RA, IBD, AS, uveitis	TB (IGRA/TST), HBV, HIV, ANA; screen demyelinating disease	Infections (TB reactivation), lupus-like, injection site, paradoxical psoriasis, lymphoma (small ↑)
Omalizumab	IgE	CSU (not responding to H1-AH), asthma, CRS with NP, food allergy (peanut; Palforzia)	IgE levels; weight; no specific infectious screen	ISR, anaphylaxis (0.1% — observe 30min post-injection), headache
Rituximab	CD20 (B cells)	PV (off-label widely, FDA 2018); BP refractory; MMP; DM; vasculitis (GPA)	TB, HBV (HBsAg+/anti-HBc+ = prophylaxis mandatory), HIV, PML risk (progressive multifocal leukoencephalopathy — JC virus)	Infusion reactions (premedicate); hypogammaglobulinemia; PML (rare); hepatitis B reactivation (fatal if not prevented); late neutropenia
Mogamulizumab	CCR4 (CC chemokine receptor 4)	MF, Sézary syndrome (relapsed/refractory)	Standard; caution in planned alloSCT (can cause severe GVHD)	Skin reactions (rash), diarrhea, pyrexia, severe GVHD if prior/subsequent alloSCT

▼11.3 Systemic Immunosuppressants — Monitoring Guide

Drug	Key Monitoring	Critical Points
Methotrexate	CBC + LFT + creatinine q4–8wk; Fibroscan (cumulative dose >3.5–4g or LFT abnormal); pregnancy test; folate 5mg/wk	Teratogenic (both male and female — stop 3 months before conception); hepatotoxicity (alcohol prohibition); MTX + NSAIDs: reduce renal excretion → toxicity; pneumonitis (acute eosinophilic — dyspnea); megaloblastic anemia; give folate (not on MTX day)
Cyclosporine	BP (both arms) q2wk; creatinine q2wk (if ≥25% rise above baseline = reduce dose or stop); trough levels not routinely needed (low-dose dermatology); lipids, Mg, uric acid	Multiple drug interactions (CYP3A4); avoid concurrent nephrotoxins (NSAIDs, aminoglycosides); gingival hyperplasia + hypertrichosis (cosmetically challenging); switch to alternative if creatinine not improving after dose reduction
Azathioprine	TPMT genotype/phenotype BEFORE starting (high TPMT = safe, low/absent = high myelosuppression risk — use 50% dose or avoid); CBC q2wk × 3 months then q3 months; LFT	6-TGN (active metabolite) converted by TPMT; TPMT-deficient: dangerous myelosuppression on standard doses; allopurinol blocks xanthine oxidase (metabolizes 6-MP) → accumulation of 6-TGN → reduce AZA by 75% if co-prescribed; do NOT give with allopurinol at standard doses
Mycophenolate	CBC q2wk × 3 months then q3 months; LFT; pregnancy test (teratogenic)	GI side effects (diarrhea/nausea) dose-limiting; split dose; enteric-coated formulation (mycophenolate sodium) reduces GI AE; absolute contraindication in pregnancy; reduce dose with renal impairment
Dapsone	G6PD before starting (hemolytic anemia risk); CBC q1–2wk × first 3 months then q3 months; methemoglobin levels if symptomatic (cyanosis, dyspnea)	Methemoglobinemia: dose-dependent, blue-gray cyanosis, treat with methylene blue 1–2mg/kg IV; hemolytic anemia: universal mild, dose-dependent, severe if G6PD deficient; dapsone hypersensitivity syndrome (DRESS-like, 5–6wk latency); agranulocytosis (rare, monitor CBC); peripheral neuropathy (high dose)
Hydroxychloroquine	Baseline 10-2 visual fields + SD-OCT (ophthalmology); annual ophthalmology after 5 years (or earlier if risk factors); CBC, LFT, G6PD	Dose: ≤5mg/kg actual body weight/day; QTc prolongation (avoid concurrent QTc drugs); cardiomyopathy rare (long-term high dose); retinopathy irreversible — screen religiously; safe in pregnancy (continue during SLE pregnancy)

▼11.4 Phototherapy Protocols & Special Situations

NB-UVB Protocol: Start at 70% MED or based on skin type; increase 10–20% each treatment; 3×/week; maintenance q1–2wk once clear. Contraindications: lupus, photosensitive disorders, personal/family history of XP, concurrent photosensitizing meds (absolute), active skin cancer. Safe in pregnancy and childhood. Eyes must be protected (UV-blocking goggles). Genital protection in males.

PUVA: 8-MOP 0.6mg/kg orally 2 hours before UVA; or topical psoralen (lotion/bath) for hands/feet. Higher carcinogenicity — limit to <200 lifetime treatments; regular skin cancer surveillance; UVA-protective glasses for 24h after oral psoralen (lens uptake); contraindicated in pregnancy (psoralen teratogenic); avoid in CYP (cutaneous photosensitizing conditions — worse outcome).

Vitiligo phototherapy: NB-UVB first-line for generalized vitiligo; 2–3×/week × 6–12 months for adequate trial; face/neck respond best; hands/feet worst. Combine with topical tacrolimus or TCS for enhanced response. Excimer laser (308nm) for localized patches — faster response, targeted. NB-UVB + oral mini-pulse prednisolone (PO prednisolone 5mg alternate days) — reduces spread in progressive vitiligo.

▼11.5 Key References

📚 Therapeutics

AAD Guidelines for Topical Corticosteroid Use (2021)
British Association of Dermatologists Methotrexate Guidelines (2016)
AAD-NPF Psoriasis Biologic Guidelines (2020)
Marmor et al. AAO Hydroxychloroquine Retinopathy Guidelines (2016)
BAD Phototherapy Guidelines (2019)

12. Dermatologic Emergencies & Practice Questions

▼12.1 Dermatologic Emergencies

Life-Threatening Dermatologic Emergencies — At-a-Glance

Emergency	Hallmark	Key Action
TEN (>30% BSA)	Full-thickness epidermal detachment; positive Nikolsky; oral/ocular/genital mucositis; SCORTEN ≥3	STOP drug NOW; burns/ICU; ophthalmology daily; etanercept 50mg SC or cyclosporine; nutritional support
Pemphigus vulgaris crisis	Extensive painful oral erosions + flaccid bullae; protein-losing; secondary bacteremia	IV methylprednisolone 1–2mg/kg/day; rituximab 1g × 2 doses; IVIG adjunct; wound care; nutrition
Eczema herpeticum	Punched-out erosions on AD skin; HSV PCR+; systemically ill	IV acyclovir 5mg/kg q8h; ophthalmology if facial; wound care; treat secondary bacterial infection
Necrotizing fasciitis	LRINEC ≥6; pain out of proportion; crepitus; woody induration; rapid systemic toxicity	URGENT surgical debridement + broad-spectrum IV antibiotics (pip-tazo + clindamycin ± vanco); IVIG for STSS
Erythroderma	>90% BSA erythema; thermoregulation failure; high-output CCF; protein loss; hypoalbuminemia	Admit; warm environment; IV fluids; treat cause (psoriasis→ cyclosporine/infliximab; eczema→ TCS/dupilumab; drug→ stop drug; CTCL→ systemic; PRP→ acitretin)
Angioedema (laryngeal) / Anaphylaxis	Stridor; uvular edema; urticaria; shock	IM epinephrine 0.5mg (1:1000) STAT; IV antihistamine; IV steroids; airway management
HAE attack (laryngeal)	No urticaria; C4 low; bradykinin-mediated; epinephrine ineffective	Icatibant 30mg SC or C1-INH concentrate IV; FFP if nothing available; airway management
GPP (Generalized Pustular Psoriasis)	Widespread sterile pustules + erythroderma; fever; IL-36RN mutation	Spesolimab 900mg IV single infusion; supportive; cyclosporine/infliximab bridge; avoid systemic steroids

▼12.2 Practice Questions

Q1. A 65-year-old man presents with tense bullae on erythematous/urticarial plaques on the trunk and flexures for 2 months. He has been itching severely for 3 months before the blisters appeared. DIF of perilesional skin shows linear IgG and C3 at the BMZ. Salt-split skin IIF shows staining on the epidermal ROOF. ELISA for anti-BP180 NC16A is strongly positive. What is the first-line treatment for this elderly patient?

Answer: Superpotent topical corticosteroid (clobetasol propionate 0.05% cream applied to entire body, 40g/day)

This is Bullous Pemphigoid (BP). Key features: elderly, pruritic urticarial prodrome, tense bullae (subepidermal), DIF linear IgG/C3 at BMZ, salt-split ROOF staining (epi side = BP), positive anti-BP180 NC16A ELISA. The JDFI trial (Joly, NEJM 2002) demonstrated whole-body topical clobetasol was equivalent or superior to systemic prednisone, with significantly fewer side effects (safer in elderly — less Cushingoid features, osteoporosis, infections). Systemic prednisone 0.5mg/kg/day is alternative if extensive/severe. Doxycycline + nicotinamide is a steroid-sparing option with favorable safety in elderly. Anti-BP180 ELISA titers guide treatment response and taper timing.

Q2. A 72-year-old Thai man with gout is started on allopurinol 300mg/day. Two weeks later he develops a morbilliform rash, oral erosions, and conjunctival involvement. Examination shows Nikolsky sign positive and 25% BSA epidermal detachment. He has not been tested for any genetic markers. Which HLA allele is strongly associated with this drug reaction in Thai/Han Chinese patients, and what is the appropriate immediate management?

Answer: HLA-B*58:01 — Stop allopurinol IMMEDIATELY; transfer to burns/ICU; daily ophthalmology; consider etanercept or cyclosporine

This is Allopurinol-induced TEN (SCORTEN = estimate from clinical data). HLA-B*58:01 is present in ~6–8% of Thai population and confers ~580× increased risk of allopurinol-induced SJS/TEN. Thailand has mandated pre-prescription HLA-B*58:01 screening since 2014. The most critical step is STOPPING the offending drug immediately — each day of continuation increases mortality. SCORTEN predicts mortality: calculate at Day 1 (BSA 25% = 1 point). Transfer to burns unit. Daily ophthalmology (prevent symblepharon). Etanercept 50mg SC (Wang RCT, Ann Int Med 2018) or cyclosporine 3–5mg/kg/day are the best-evidence specific therapies. Nutritional support (NG tube). Wound care with non-adherent dressings. For future gout management: use febuxostat instead of allopurinol.

Q3. A 45-year-old woman is started on carbamazepine for trigeminal neuralgia. After 5 weeks she develops fever (38.8°C), facial edema, cervical lymphadenopathy, and a morbilliform rash. Labs: WBC 14,000 with 18% eosinophils, ALT 210 U/L, creatinine 1.8 mg/dL. What is the diagnosis, and what is the most specific serologic finding supporting it?

Answer: DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) — HHV-6 IgM or rising IgG titers (HHV-6 reactivation) is the most specific serologic finding

DRESS criteria met: hospitalization required, rash, fever >38°C, lymphadenopathy, organ involvement (liver ALT ↑ + renal creatinine ↑), eosinophilia (≥1.5 = 1 point on RegiSCAR). Latency of 5 weeks is classic (2–8 weeks for DRESS vs 5–14 days for simple MPE). Carbamazepine is one of the top-5 causative drugs. HHV-6 reactivation (IgM positive or 4-fold IgG rise) occurs in ~60–70% and is thought to drive the "second wave" of immune activation. Management: stop carbamazepine IMMEDIATELY; prednisolone 1–2mg/kg/day (taper slowly over 3–6 months — rapid taper causes flare); LFT weekly; monitor thyroid at 3 months (autoimmune thyroiditis delayed). Avoid all aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital, lamotrigine) — cross-reactivity ~30–50%.

Q4. A 38-year-old Thai woman with no prior sun damage presents with a 1.5cm pigmented band under the thumbnail (melanonychia). Dermoscopy shows irregular width, irregular color (brown-black), and pigment spreading to the periungual skin (proximal nail fold). What does the periungual pigmentation indicate, and what is the next step?

Answer: Hutchinson sign — periungual pigmentation indicates melanoma until proved otherwise → nail matrix biopsy (longitudinal excision biopsy)

Hutchinson sign = pigmentation extending from the nail plate onto the periungual skin (proximal/lateral nail folds) → pathognomonic for subungual melanoma in this clinical context. This patient has acral lentiginous melanoma (ALM) risk features: Asian patient (ALM = 50–70% of melanoma in Asians/Africans), thumb involvement (thumb/hallux/index = high-risk digits), irregular dermoscopic features. Differential for melanonychia: benign melanocytic activation (most common in dark skin), nevus, lentigo. However, the Hutchinson sign shifts probability strongly to invasive melanoma. Management: nail matrix biopsy with proper technique (lateral longitudinal biopsy or punch of matrix). If melanoma confirmed: wide local excision with SLNB per melanoma staging. Note: pseudo-Hutchinson sign = visibility of nail bed pigment through transparent cuticle (nail fold) — benign; distinguished by actual pigmentation in the skin of the fold (true Hutchinson) vs below transparent cuticle (pseudo).

Q5. A 45-year-old man with plaque psoriasis (PASI 18, BSA 22%) has failed MTX 20mg/wk and phototherapy. He also has active psoriatic arthritis (dactylitis + enthesitis). His IGRA (QuantiFERON) is positive (latent TB), HBsAg negative, anti-HBc negative. What is the best treatment strategy?

Answer: Treat latent TB with INH 9 months (start now), then start an IL-17A or IL-23 inhibitor for psoriasis + PsA after completing at least 1 month of INH

This patient needs a biologic for moderate-severe psoriasis with PsA. Latent TB management: INH prophylaxis 9 months (or 3HR/4R if preferred). Can start biologic after 1 month of INH for IL-17 or IL-23 inhibitors (less TB reactivation risk than TNF-α inhibitors); for anti-TNF agents: complete 2 months before starting. Biologic selection for PsO + PsA: IL-17 inhibitors (secukinumab, ixekizumab, bimekizumab) or IL-23 inhibitors (guselkumab, risankizumab) — both treat skin AND joints effectively. IL-17i: faster skin response; particularly good for enthesitis. IL-23i: Q8–12wk dosing; no IBD risk; less candida. If dactylitis prominent: IL-17i slightly preferred. IBD exclusion: no IBD history → IL-17i safe. BRAF/KIT testing not relevant here.

Q6. A 32-year-old HIV-positive Thai man (CD4 = 45 cells/μL, not on ART) presents with 3 weeks of fever, weight loss, hepatosplenomegaly, and multiple 3–5mm umbilicated papules with central necrosis on his face and trunk resembling molluscum contagiosum. What is the most likely diagnosis and how do you confirm it rapidly?

Answer: Disseminated Talaromyces (Penicillium) marneffei — Confirm rapidly with skin biopsy (touch preparation or histology showing intracellular/extracellular yeast with central septum = "sausage cells")

Classic presentation: Thai HIV patient, CD4 <100, systemic features + umbilicated papules resembling molluscum contagiosum (but with central necrotic dell). This is the hallmark skin finding of disseminated T. marneffei. Rapid diagnosis: skin biopsy → press smear (touch prep) stained with Giemsa/Wright → see intracellular and extracellular oval yeast cells 2–8μm with distinct central septum (does NOT bud — unlike Histoplasma which buds). Culture on SDA at 25°C → blue-green colonies with characteristic diffusible red pigment (takes 2–7 days). Blood/bone marrow culture: lysis-centrifugation. Serum/urine Mp1p antigen ELISA (rapid). Treatment: IV AmB 0.7mg/kg/day × 2 weeks (induction) → itraconazole 200mg BID × 10 weeks (consolidation) → itraconazole 200mg/day (maintenance until CD4 >100 × 6 months on ART). Start ART after 2–4 weeks of antifungal. THIS IS THE MOST IMPORTANT TROPICAL FUNGAL INFECTION FOR THAI BOARD EXAM.

Q7. A 70-year-old woman with extensive bullous pemphigoid (anti-BP180 ELISA = 450 U/mL) and type 2 diabetes, hypertension, and osteoporosis has been on prednisolone 60mg/day for 3 months with only partial response. She has developed significant cushingoid features and her HbA1c has worsened to 10%. What is the most appropriate escalation?

Answer: Add Rituximab 1g IV × 2 doses (2 weeks apart) — this is now the best-evidence steroid-sparing biologic for refractory BP, or consider Efgartigimod alfa (FcRn antagonist, FDA 2023 for BP)

This patient has refractory BP with steroid-related comorbidity worsening. The goals are disease control AND steroid reduction. Options: (1) Rituximab: multiple case series + retrospective data showing efficacy in BP; depletes B cells → reduces anti-BP180 IgG; anti-BP180 ELISA titers decline, correlating with response; given as 1g IV × 2 doses (2 weeks apart) as in PV protocol, or 375mg/m² × 4 weekly doses. (2) Efgartigimod alfa (FcRn antagonist): reduces total IgG including anti-BP180 autoantibodies; FDA approved October 2023 specifically for BP (BALLAD RCT: IGA DAS 0/1 at any two consecutive visits: 40% vs 22% placebo); IV infusion qwk × 4wk, then repeat per disease activity. (3) Doxycycline 200mg/day + nicotinamide (allows steroid reduction); (4) Dupilumab (significant evidence accumulating in eosinophilic/prurigo BP). Continue topical TCS during biologic transition. Monitor HBV reactivation risk with rituximab (anti-HBc testing).

Q8. A 55-year-old Thai woman presents with classic dermatomyositis features (heliotrope rash, Gottron papules, V-sign, shawl sign, proximal myopathy). Anti-TIF1γ antibody is strongly positive. She has no respiratory complaints. What is the most important next investigation and why?

Answer: Malignancy screening — Anti-TIF1γ is associated with the highest cancer risk in adult DM (up to 75% if age >45y). Perform: CT chest/abdomen/pelvis + PET-CT + nasopharyngeal endoscopy (NPC in Asians) + age-appropriate gynecologic/GI screening

Anti-TIF1γ (anti-p155/140) carries the strongest paraneoplastic association of all MSAs in adult DM. In patients >45 years old, up to 75% of anti-TIF1γ-positive DM has an underlying malignancy (breast, ovarian, colorectal, NPC — especially in Asians). This MSA pattern should trigger URGENT and comprehensive cancer screening. PET-CT is most sensitive for detecting occult malignancy. In Thai/Southeast Asian patients, add nasopharyngeal endoscopy/biopsy to screen for NPC (Epstein-Barr virus-associated, endemic in Asia). Also screen: CA-125 (ovarian), colonoscopy, mammography/breast US, gynecologic exam. Repeat cancer screen annually for 3–5 years. In contrast: Anti-MDA5 (no cancer, but severe RP-ILD risk); Anti-Mi-2 (classic DM, lowest cancer risk, best treatment response); Anti-Jo-1 (antisynthetase syndrome, ILD risk, moderate cancer risk).

Q9. A 25-year-old man with alopecia universalis (total body hair loss) is started on baricitinib 4mg/day. After 36 weeks, his SALT (Severity of Alopecia Tool) score improved from 100 to 15 (significant regrowth). He asks about risks of continuing this medication long-term. What are the most important adverse effects to counsel him about?

Answer: Class JAK inhibitor warnings — serious infections (especially herpes zoster reactivation), malignancy (lymphoma, other cancers), major adverse cardiovascular events (MACE), thrombosis (DVT/PE), and laboratory abnormalities (lipids ↑, CPK ↑, neutropenia)

Baricitinib (JAK1/JAK2 inhibitor) is FDA-approved for severe AA (≥50% scalp loss) based on BRAVE-AA1 and BRAVE-AA2 trials. The FDA requires a Boxed Warning (class effect for JAK inhibitors based on RA data — tofacitinib ORAL surveillance study): serious infections (bacteremia, fungal, TB reactivation — screen with IGRA before starting), malignancy (especially lymphoma), MACE (MI, stroke — caution in age >50 + cardiovascular risk factors), thrombosis (DVT/PE). Herpes zoster: consider prophylactic vaccination (Shingrix) before starting. Practical monitoring: CBC (neutropenia), lipids (q12wk initial), LFT, CPK; complete vaccinations before starting (live vaccines CONTRAINDICATED while on JAK-i — complete all live vaccines ≥4 weeks before). For this 25-year-old: baseline risk is lower but counsel about all above. Contraception required (teratogenic). Discontinuation = relapse of AA expected in many patients.

Q10. A 60-year-old patient on stage IIB mycosis fungoides (tumor stage) has developed multiple 3cm tumors on the scalp and trunk. Skin biopsy shows CD4+, CD3+, CD30+ (40% of infiltrate), CD26− T-cells with epidermotropism. What is the most appropriate systemic treatment?

Answer: Brentuximab vedotin (BV) — anti-CD30 antibody-drug conjugate — given the CD30+ expression (≥10%) in the tumor infiltrate (ALCANZA trial eligibility)

Brentuximab vedotin (anti-CD30, conjugated with MMAE cytotoxic) is approved by FDA/EMA for CD30-expressing CTCL (MF + primary cutaneous ALCL). The ALCANZA trial (Prince, Lancet 2017) showed ORR4 (objective response lasting ≥4 months) of 56.3% vs 12.5% physician choice (methotrexate or bexarotene) in CD30+ MF/pcALCL. CD30 expression ≥10% is the threshold for eligibility. AE: peripheral neuropathy (dose-limiting, often improves with dose reduction), neutropenia, infusion reactions. For stage IIB (tumor stage), skin-directed therapies alone are insufficient. Other options for IIB: TSEB (total skin electron beam) for multiple tumors; mogamulizumab (better for blood involvement, Stage IV); romidepsin/vorinostat (HDAC inhibitors) for refractory. Allogeneic SCT considered for fit patients with refractory/advanced disease.

13. Clinical Approach Algorithms

These diagnostic frameworks are among the highest-yield topics for dermatology board examinations and clinical practice. Master each approach as a systematic algorithm — history → morphology → distribution → investigations → diagnosis.

▼13.1 Approach to Vesiculobullous Diseases

Step-by-Step Approach to Blistering Diseases

Step 1 — History: Age; onset (sudden vs chronic); distribution (localized vs generalized); mucosal involvement (oral, ocular, genital); systemic symptoms (fever, weight loss, dyspnea); drug history (new drugs 2–8 weeks prior); family history; occupation/sun exposure; prior similar episodes; immune status.

Step 2 — Examine the blister:

Tense vs flaccid: Tense = subepidermal (BP, DH, EBA, LAD) — blister roof = full epidermis → strong; Flaccid = intraepidermal (PV, PF) — blister roof = thin stratum corneum → fragile, ruptures quickly
Nikolsky sign: Lateral pressure on perilesional skin → skin shears = intraepidermal disease (PV, PF, SSSS, TEN). Negative in BP. Asboe-Hansen sign (pressure on blister roof → lateral spread) also positive in PV.
Base of blister: Erythematous/urticarial = BP; normal skin = DH/EBA/LAD; erythrodermic = SSSS/TEN
Distribution: Flexures = BP; extensor = DH (elbows/knees/buttocks); mucosa-dominant = PV; sun-exposed = PCT/pseudoporphyria; acral/trauma sites = EB; dermatomal = VZV

Step 3 — Biopsy (critical: biopsy site selection):

For H&E: Biopsy an EARLY/FRESH blister — do NOT biopsy an old ruptured erosion (inflammatory changes mask the primary process)
For DIF: Biopsy PERILESIONAL normal-appearing skin (2–3mm from blister edge) — NOT the blister itself (proteases in blister fluid degrade immunoreactants). Exception: DH — biopsy uninvolved skin near a vesicle (papillary dermis granular IgA is diagnostic).
Send in: H&E → formalin; DIF → Michel's transport medium (or saline — use within 24h) or snap-freeze in liquid nitrogen

Key Question	Intraepidermal (Flaccid)	Subepidermal (Tense)
Blister quality	Flaccid, easily ruptured → erosions dominant	Tense, thick-roofed, persist intact
Nikolsky sign	Positive	Negative
DIF	ICS (intercellular space) staining — "chicken wire" (PV/PF)	Linear BMZ staining (BP/MMP/EBA/LAD) OR granular papillary dermis (DH)
Histology split plane	Suprabasal (PV) or subcorneal (PF, IgA pemphigus, AGEP)	Lamina lucida (BP/LAD/MMP) or sub-lamina densa (EBA) or papillary dermis tips (DH)
Key diseases	PV, PF, Hailey-Hailey, Darier, SSSS, TEN (early full-thickness)	BP, MMP, DH, LAD, EBA, PCT, porphyrias, fixed drug eruption (bullous), EB acquisita

Vesiculobullous DDx by Age & Setting

Age/Setting	Top Diagnoses	Key Distinguishing Feature
Neonate/infant	EB (simplex/junctional/dystrophic), Bullous impetigo (SSSS), Incontinentia pigmenti (stage 1), Neonatal varicella, Transient neonatal PV (maternal IgG transfer)	EB: present at birth/trauma; SSSS: S.aureus exfoliatin, Nikolsky+, newborn nursery outbreaks; IP: Blaschko lines, stage progression
Child	Varicella, HSV (primary gingivostomatitis), Bullous impetigo, EB, LAD ("string of pearls"), DH (gluten sensitive — less common in children)	Varicella: centripetal, all stages simultaneously; LAD: rosette pattern; IgA LAD: often drug-triggered (vancomycin)
Young adult (20–40y)	PV, HSV, Contact dermatitis (bullous), Fixed drug eruption, Drug-induced (SJS/TEN), EB acquisita, PCT	PV: oral erosions first; SJS/TEN: mucositis + systemic; PCT: sun-exposed, milia, hypertrichosis
Middle-age (40–60y)	PV, BP (can start younger), Porphyrias, HSV/VZV	PV: mucosal; BP: tense pruritic urticarial prodrome
Elderly (>65y)	BP (#1 most common AIBD in elderly), PV, DH, EBA, drug-induced BP (DPP4-i)	BP: tense bullae, elderly, anti-BP180+; check DPP4 inhibitor use (common in T2DM elderly)
Immunosuppressed	HSV disseminated, VZV disseminated, Eczema herpeticum, PNP (lymphoma), bullous drug reactions	PNP: lymphoma + stomatitis + skin + bronchiolitis obliterans; IIF rat bladder
Gluten-sensitive history/GI sx	DH → Celiac disease in virtually 100%	Granular IgA papillary dermis DIF; pruritic grouped vesicles extensor surfaces
Sun-exposed hands + skin fragility	PCT, Pseudoporphyria, Variegate porphyria, EPP (no blisters initially)	PCT: porphyrins elevated, wood lamp coral/pink urine; pseudoporphyria: porphyrins NORMAL, drug-induced

Investigation	What it Tests	Key Result Interpretation
DIF (perilesional skin)	Immunoreactant deposits in tissue	ICS IgG = pemphigus; Linear BMZ IgG/C3 = BP/MMP/EBA; Linear BMZ IgA = LAD; Granular IgA papillary dermis = DH; ICS+BMZ = PNP
IIF (monkey esophagus)	Circulating antibodies to Dsg3 (PV)	Positive ICS on monkey esophagus = PV (Dsg3-rich mucosa); normal skin = PF (Dsg1 throughout)
Salt-split skin IIF	Localize Ab to epidermis vs dermis	Roof staining = BP/MMP/LAD (lamina lucida); Floor staining = EBA (sub-lamina densa, collagen VII)
ELISA anti-BP180 NC16A	BP autoantibody	Positive = BP; correlates with disease activity; use to monitor treatment response
ELISA anti-Dsg1 / anti-Dsg3	Pemphigus autoantibodies	Dsg3+ only = mucosal PV; Dsg1+3 = mucocutaneous PV; Dsg1 only = PF; use to predict phenotype and monitor
Anti-TG2 IgA / Anti-TG3 IgA	DH / Celiac	Anti-TG2 IgA = celiac; anti-TG3 IgA = DH-specific; both positive usually in DH
IIF rat bladder	Anti-plakin antibodies (PNP)	Positive staining of transitional epithelium = pathognomonic for PNP
Urine/plasma porphyrins	Porphyrias	Elevated uroporphyrin I+III = PCT; urine pink/orange fluorescence Wood's lamp; elevated FEP = EPP
Tzanck smear	Viral cytopathic change	Multinucleated giant cells = HSV or VZV (NOT specific to either); send PCR to distinguish
Viral PCR (swab from blister base)	HSV-1, HSV-2, VZV DNA	Gold standard for diagnosis; distinguishes HSV-1 vs 2 vs VZV; guides antiviral choice

🔑 Pearl — The Most Common Mistake in Blistering Disease Biopsy: (1) Biopsying old/ruptured erosions for H&E → misses the primary histologic pattern. Always biopsy a fresh early blister. (2) Sending the blister itself for DIF → proteases degrade immunoreactants. Always biopsy 2–3mm PERILESIONAL skin for DIF. Two separate biopsies = one for H&E (formalin), one for DIF (Michel's medium) is the gold standard for any suspected AIBD.

▼13.2 Approach to Maculopapular Eruption (MPE)

Systematic Approach to Maculopapular Rash

Step 1 — Timing: Acute (<2 weeks) vs chronic/recurrent. Drug onset timing: <24h = urticaria/anaphylaxis; 1–3 days = re-exposure drug reaction; 5–14 days = first exposure MPE; 2–8 weeks = DRESS; >2 weeks = lichenoid/SCLE.

Step 2 — Distribution pattern (critical for diagnosis):

Centripetal (face/trunk → extremities): Viral exanthems (rubeola, rubella, roseola, EBV, enteroviruses)
Centrifugal (extremities/palms-soles → trunk): Rickettsial (RMSF, typhus), secondary syphilis, RMSF
Palms + soles involved: Secondary syphilis (#1 DDx — always), RMSF, hand-foot-mouth (EV71), erythema multiforme, reactive arthritis (keratoderma blennorrhagica), coxsackie
Photodistributed: Drug-induced (doxy, NSAIDs), SCLE, lupus, polymorphous light eruption, pellagra
Trunk-predominant: Drug MPE (most common), pityriasis rosea (herald patch + Christmas-tree), secondary syphilis, viral exanthems
Facial butterfly/malar: SLE, rosacea, seborrheic dermatitis, erysipelas

Step 3 — Systemic features:

Fever + rash: viral (measles, rubella, EBV, dengue, rickettsiae), bacterial (streptococcal, meningococcemia, enteric fever), drug reaction (DRESS, serum sickness, AGEP), Still's disease, adult-onset (evanescent salmon rash)
Lymphadenopathy: EBV (#1), CMV, rubella, secondary syphilis, HIV seroconversion, DRESS
Eosinophilia: DRESS, parasitic, drug reaction
Arthralgia: viral (rubella, parvovirus B19, EBV, dengue), reactive arthritis (HLA-B27), Still's, serum sickness-like, secondary syphilis

Disease	Enanthem	Exanthem Pattern	Key Features/Tests
Measles (Rubeola)	Koplik spots (white spots on buccal mucosa — pathognomonic, appear 2d before rash)	Starts face/hairline → trunk → extremities; morbilliform; becomes confluent	3 Cs: Coryza, Cough, Conjunctivitis + fever; measles IgM; notifiable; vaccination prevention
Rubella	Forchheimer spots (soft palate petechiae)	Starts face → trunk → extremities; finer, paler, shorter (3 days) than measles; posterior cervical + occipital lymphadenopathy (pathognomonic distribution)	Congenital rubella (1st trimester) = deafness/cataracts/PDA; rubella IgM serology
Roseola (HHV-6/HHV-7)	None	Rash appears AFTER fever resolves (exanthem subitum); rose-colored macules trunk; spares face; infants 6mo–2yr	High fever (39–40°C) × 3–5 days → rash as fever breaks; febrile seizures complication; HHV-6 serology/PCR
Erythema infectiosum (Parvovirus B19)	None	"Slapped cheek" (facial erythema) → lacy reticular rash arms/trunk; adult: arthropathy (symmetric, hands/wrists) without slapped cheek; recurs with heat/exercise	Aplastic crisis (sickle cell/hereditary spherocytosis/immunocompromised); hydrops fetalis (1st trimester maternal); parvovirus B19 IgM; no treatment (self-limited)
EBV (Infectious Mononucleosis)	Tonsillar exudate + soft palate petechiae (Forchheimer-like)	Morbilliform rash (~10%); ampicillin/amoxicillin → rash in >80% of EBV patients (immune complex, not true allergy)	Triad: fever + pharyngitis + lymphadenopathy; Monospot (heterophile Ab); EBV VCA IgM; splenomegaly (avoid contact sports 3–4 weeks); hepatitis common
Dengue	None; enanthem rare	Early: flushed face/chest; Day 3–6: confluent erythema with islands of sparing ("white islands in a sea of red"); late: petechiae/purpura (thrombocytopenia)	Bone-breaking fever; retroorbital pain; leukopenia; thrombocytopenia; NS1 antigen (early); dengue IgM (Day 3–5); endemic SE Asia — Thai Pearl: dengue is common cause of MPE + fever
Secondary Syphilis	Mucous patches (painless white plaques); split papules at oral commissures; condylomata lata (perianal)	Palms + soles involvement (key feature); copper-colored papulosquamous eruption; generalized; "great imitator"	VDRL/RPR (non-treponemal) + TPHA/FTA-ABS (confirmatory); ALL patients with unexplained MPE involving palms/soles → syphilis serology; treat with penicillin
Drug MPE	Absent (oral mucosa involvement → think DRESS/SJS/TEN)	Bilateral symmetric; trunk → extremities; morbilliform; pruritic; most commonly aminopenicillins, sulfonamides, anticonvulsants	Onset 5–14d first exposure; latency clue for culprit drug; check for DRESS features (eosinophilia, lymphadenopathy, organ involvement); if none → simple MPE = stop drug + antihistamines + TCS
Pityriasis Rosea	None	Herald patch (single large oval scaly plaque, trunk, 1–2wk before eruption) → generalized oval patches along skin lines → Christmas-tree pattern on back; face/extremities spared (usually)	HHV-7/HHV-6 reactivation theory; 6–8 weeks self-limited; NB-UVB speeds resolution; oral acyclovir (controversial, may shorten duration); if atypical → secondary syphilis ELISA
Still's Disease (AOSD)	None	Evanescent (comes and goes with fever) salmon-pink/faintly erythematous papules/macules; trunk/proximal extremities; appears with fever spikes (evening)	Quotidian fever (afternoon/evening spike >39°C) + arthritis + leukocytosis + ferritin >5000 (highly elevated); IL-1β/IL-18 pathogenesis; treat with anakinra/canakinumab or NSAIDs/steroids
Rickettsial (RMSF, Typhus)	None	RMSF: starts wrists/ankles → trunk (centripetal spread); petechiae/purpura; palms/soles; tick exposure; rash may appear LATE (day 3–5)	Tick bite history; thrombocytopenia; elevated LFT; treat empirically with doxycycline if suspected (do NOT wait for serology); Weil-Felix reaction (older test); IFA (gold standard)

🔑 Pearl — Palms and Soles Rule: When a maculopapular eruption involves palms AND soles, always think: (1) Secondary syphilis (most important — "great imitator"); (2) RMSF/rickettsiae; (3) Hand-foot-mouth disease; (4) Erythema multiforme; (5) Reactive arthritis (keratoderma blennorrhagica); (6) Infective endocarditis (Janeway lesions — non-tender macules; Osler nodes — tender nodules). Syphilis serology is MANDATORY in any adult with unexplained MPE involving palms/soles.

🔑 Pearl — EBV + Amoxicillin Rash: Aminopenicillin (amoxicillin, ampicillin) given during active EBV mononucleosis causes a maculopapular rash in >80% of patients. This is NOT a true penicillin allergy — it is an immune complex-mediated phenomenon specific to EBV infection. The patient can safely receive amoxicillin again after EBV infection resolves. Document as "EBV-associated ampicillin rash" NOT "penicillin allergy" to avoid unnecessary antibiotic restrictions.

▼13.3 Approach to Leukocytoclastic Vasculitis & Palpable Purpura

Step-by-Step Approach to Palpable Purpura

Step 1 — Confirm it is truly purpura: Non-blanching on diascopy (glass slide pressure). Purpura = extravasated RBCs in skin. Differentiate: petechiae (<3mm) / purpura (3mm–2cm) / ecchymosis (>2cm). Palpable purpura = raised + non-blanching = vasculitis until proved otherwise.

Step 2 — Is it palpable (raised) or flat?

Palpable purpura = small vessel vasculitis (leukocytoclastic vasculitis, LCV) — inflammation in vessel wall → RBC extravasation + perivascular infiltrate elevates the lesion
Flat purpura/petechiae = thrombocytopenia, platelet dysfunction, coagulopathy, increased vascular fragility (senile purpura, scurvy, amyloid), vasodilation without inflammation

Step 3 — Biopsy (early lesion, <24–48h old): Choose fresh early papule/plaque. H&E: fibrinoid necrosis of vessel wall + neutrophil infiltrate + nuclear dust (leukocytoclasis = karyorrhexis of neutrophils) + RBC extravasation. DIF: Characterize immunoreactants in vessel wall → drives etiologic diagnosis.

LCV DIF Patterns → Etiologic Clue

DIF Finding	Diagnosis	Next Step
IgA dominant in vessel walls	IgA vasculitis (Henoch-Schönlein Purpura / HSP)	UA (hematuria/proteinuria), renal function, ASOT; GI symptoms; joint exam
IgM/IgG + C3 in vessel walls (immune complexes)	Immune complex–mediated LCV (infection-associated, drug, cryoglobulinemia, connective tissue disease)	Complement (C3, C4, CH50); cryoglobulins; ANA/ANCA; cultures/virology (HCV, HBV)
Scant/absent immunoreactants (pauci-immune)	ANCA-associated vasculitis (GPA, MPA, EGPA)	ANCA (p-ANCA/MPO, c-ANCA/PR3); CXR/CT (lung); renal biopsy (pauci-immune GN)
IgE + eosinophils	Allergic/drug-induced; EGPA (Churg-Strauss)	IgE levels; blood eosinophil count; drug history; ANCA (p-ANCA in EGPA ~40%)

Causes of LCV/Palpable Purpura — Systematic Approach

Category	Specific Causes	Distinguishing Features
Infection-associated (most common overall)	Streptococcal (post-pharyngitis); Staphylococcal bacteremia; Gonococcemia; Neisseria meningitidis (septicemia); Hepatitis B/C; HIV; Subacute bacterial endocarditis; Rickettsia; EBV/CMV	Fever, systemic illness; cultures; serology; blood cultures × 3 (SBE); echocardiogram
Drug-induced LCV	Propylthiouracil (ANCA+), hydralazine (ANCA+), minocycline, penicillins, cephalosporins, allopurinol, sulfonamides, NSAIDs, thiazides, phenytoin	Temporal relation (1–3 weeks after starting drug); resolves on stopping; drug ANCA: p-ANCA MPO+ (PTU, hydralazine); rechallenge confirms
IgA Vasculitis (HSP)	IgA dominant immune complex disease; GAS, viral triggers	Children > adults; lower extremity palpable purpura + arthralgia + colicky abdominal pain ± intussusception ± nephritis; DIF IgA in vessels; UA mandatory; most self-limited; prednisone for severe GI/renal
Cryoglobulinemic vasculitis	Type I (monoclonal — myeloma, Waldenström); Type II/III (mixed — HCV most common, SLE, Sjögren)	Cryocrit (blood in plain red-top tube, transport warm to lab); complement low (C4 very low in Type II — classical pathway consumption); HCV serology; purpura + arthralgias + peripheral neuropathy + renal (MPGN); treat HCV → remission in HCV-associated
ANCA-associated vasculitis	GPA (granulomatosis with polyangiitis — c-ANCA/PR3); MPA (p-ANCA/MPO); EGPA (eosinophilic granulomatosis)	Systemic: pulmonary (hemoptysis, nodules/cavities GPA; alveolar hemorrhage MPA), renal (pauci-immune crescentic GN), ENT (saddle-nose GPA, chronic sinusitis); skin: LCV, pyoderma gangrenosum-like ulcers; treat: cyclophosphamide + prednisolone induction → rituximab maintenance; avacopan (C5aR antagonist, FDA 2021 for GPA/MPA) — steroid-sparing
CTD-associated	SLE (lupus vasculitis); RA (rheumatoid vasculitis — seronegative to RF+ shift, peripheral neuropathy, pyoderma-like); Sjögren syndrome (urticarial vasculitis + hypergammaglobulinemia)	ANA, anti-dsDNA, RF, anti-Ro/La; complement levels; diagnosis of underlying CTD
Idiopathic LCV	No underlying cause found after complete workup (~50% of cutaneous LCV)	Limited/single episode: monitor; recurrent: colchicine/dapsone; renal/systemic involvement: prednisone

LCV Workup Algorithm

Investigation	Purpose	Key Finding
Skin biopsy (H&E + DIF)	Confirm LCV; immunoreactant pattern	See DIF table above; biopsy within 24–48h of lesion onset
CBC + differential	Infection, malignancy, eosinophilia	Eosinophilia → EGPA, drug, parasitic; anemia → systemic disease; leukocytosis → infection
Urinalysis + protein:creatinine	Renal involvement (IgAV, ANCA)	Hematuria/proteinuria = nephritis → urgent nephrology referral
LFT, creatinine, BUN	Organ involvement	Hepatitis (HBV/HCV-associated, DRESS-associated); renal failure (ANCA, IgAV, cryo)
Blood cultures × 3	Bacteremia, SBE	Positive = treat infection (purpura resolves with treatment)
ANCA (p-ANCA/MPO, c-ANCA/PR3)	ANCA-associated vasculitis	c-ANCA PR3+ = GPA; p-ANCA MPO+ = MPA/EGPA; drug ANCA = PTU/hydralazine
ANA, anti-dsDNA, complement (C3/C4/CH50)	CTD, SLE, immune complex disease	Low C4 = cryoglobulinemia or SLE; low C3+C4 = severe immune complex activation
Cryoglobulins	Cryoglobulinemic vasculitis	Send in prewarmed tube, keep warm to lab; positive cryocrit → HCV serology mandatory
HCV/HBV serology	Viral-associated vasculitis	HCV → mixed cryoglobulinemia; HBV → PAN (classic medium-vessel)
ASOT, throat culture	Post-streptococcal (IgAV trigger)	Elevated ASOT = recent GAS infection; throat swab if pharyngitis
Serum protein electrophoresis (SPEP)	Paraprotein (Type I cryo, myeloma)	M-spike = monoclonal gammopathy → bone marrow biopsy
Echocardiogram	SBE if fever + positive blood cultures	Vegetation = SBE → IV antibiotics; Janeway lesions (non-tender, flat) vs Osler nodes (tender, raised)

🔑 Pearl — Differentiating Purpura in the Critically Ill:

Non-blanching petechiae + fever in children → rule out Neisseria meningitidis septicemia (purpura fulminans, DIC) → empirical penicillin/ceftriaxone IMMEDIATELY
Palpable purpura + renal involvement + ANCA+ → ANCA vasculitis → urgent cyclophosphamide + steroids
Palpable purpura + cryocrit+ + low C4 + peripheral neuropathy → mixed cryoglobulinemia → HCV testing
Flat petechiae + thrombocytopenia → ITP, TTP, DIC, meningococcemia — NOT LCV (vasculitis)
Senile purpura (flat, non-palpable, extensor forearms in elderly) = vascular fragility from photoaging/steroids — NOT vasculitis, no workup needed

▼13.4 Approach to Erythema Nodosum (EN)

Erythema Nodosum — Key Facts

Definition: Most common panniculitis (inflammation of subcutaneous fat). Septal panniculitis — inflammation in fibrous septa between fat lobules (unlike lobular panniculitis in other diseases).
Clinical: Tender erythematous nodules/plaques, bilateral, anterior shins (pretibial, most common); also ankles, thighs; non-ulcerating; no surface change; deep; tender to palpation; resolves over 3–6 weeks with color change (bruise-like — "erythema contusiformis"); does NOT ulcerate or scar
Demographics: Female > male (5:1); peak age 20–40 years; recurrence common
Histology: Septal panniculitis with neutrophils → lymphocytes; giant cells (Miescher radial granulomata in septa); NO vasculitis (key distinguishing feature from other panniculitides); NO necrosis
Biopsy: Usually NOT needed for classic presentation (bilateral pretibial tender nodules in young woman). Biopsy if atypical (unilateral, ulceration, unusual location, refractory). Must do DEEP incisional biopsy (punch biopsy misses the subcutis) — orientate vertically to include full fat lobule.

Causes of Erythema Nodosum — Systematic Mnemonic "SHIPS-BOC"

Cause	Frequency	Clues/Workup
Streptococcal pharyngitis (GAS)	#1 cause overall (28–48%)	Throat culture; ASOT (elevated); recent URTI 2–3 weeks prior; treat GAS with penicillin → EN resolves
Histoplasma / other fungi (Coccidioides, Blasto)	5–10% (endemic areas)	Travel/exposure history; chest X-ray (hilar adenopathy); serology/urine antigen (Histoplasma, Coccidioides)
Idiopathic	30–50% (no cause found after workup)	Diagnosis of exclusion; self-limited; treat symptomatically
Pregnancy (1st trimester) / hormonal (OCP)	5–10%	Beta-hCG; OCP history; usually self-limited; resolves postpartum
Sarcoidosis	10–15% (especially in Löfgren syndrome)	Löfgren syndrome = EN + bilateral hilar adenopathy (BHL) + arthritis (ankles); ACE level; CXR; HRCT; bronchoalveolar lavage; excellent prognosis in Löfgren
Behçet's disease	EN is a diagnostic criterion	Oral aphthous ulcers (recurrent, ≥3/year) + genital ulcers + uveitis + EN/pseudofolliculitis; pathergy test (positive = papule/pustule at needle site); HLA-B51; treat with colchicine (EN/arthralgias), immunosuppression for severe
Oral contraceptive pill (OCP)	See Pregnancy/hormonal	Estrogen-containing OCPs; consider alternative contraception
Crohn's disease / IBD (Ulcerative colitis)	5–10% of IBD patients	GI symptoms; colonoscopy/endoscopy; fecal calprotectin; CRP; EN correlates with IBD activity in UC; may be independent of CD activity in Crohn's
Tuberculosis (primary TB / TB enteritis)	Important in endemic areas (Thailand/SE Asia)	CXR (primary complex, hilar adenopathy); Mantoux/IGRA; TB culture/PCR; especially primary TB in endemic areas; treat TB → EN resolves
Drugs	5–10%	Sulfonamides, oral contraceptives (see above), penicillins, NSAIDs, iodides, bromides; drug history within 2–4 weeks; stop drug
Yersinia enterocolitica/pseudotuberculosis	European countries (5–10%)	GI symptoms (diarrhea, RLQ pain mimicking appendicitis); stool culture; Yersinia IgA serology; cold-enrichment culture technique
Cat scratch disease (Bartonella henselae)	Rare	Scratch/contact with cats; regional lymphadenopathy; Bartonella serology/PCR

EN Workup (Standard Minimum)

Test	Detects
Throat culture + ASOT	GAS pharyngitis (most common cause)
CXR (PA + lateral)	Bilateral hilar adenopathy (sarcoidosis / Löfgren, primary TB, fungal); pulmonary infiltrates
IGRA / Mantoux (TST)	TB infection (especially in endemic areas like Thailand)
ESR, CRP	Activity / monitor treatment response
CBC with differential	Infection, eosinophilia, lymphopenia (sarcoid), anemia (IBD)
Serum ACE	Sarcoidosis (elevated in 60% active sarcoid, low specificity)
β-hCG (women of reproductive age)	Pregnancy
Stool examination / Yersinia serology	Enteric infections (especially if GI symptoms)
ANA, anti-dsDNA	CTD (especially if arthralgia, facial rash, photosensitivity)
Liver function tests	Hepatic sarcoidosis, hepatitis

Treatment of EN

Treatment	Indication/Notes
Treat underlying cause	GAS → penicillin V 500mg BID × 10d; TB → standard ATT; OCP → stop; IBD → treat IBD; sarcoid → usually self-limited; Yersinia → ciprofloxacin/doxycycline
NSAIDs (naproxen, indomethacin, ibuprofen)	First-line for pain/inflammation; ibuprofen 400–600mg TID; naproxen 500mg BID; contraindicated in pregnancy/IBD flare
Bed rest + leg elevation	Reduces edema/tenderness; important adjunct
Potassium iodide (KI) 300–900mg/day in divided doses	Effective for recurrent/chronic EN; mechanism: anti-inflammatory via neutrophil inhibition; monitor thyroid function; avoid in pregnancy
Hydroxychloroquine 200–400mg/day	Chronic/recurrent EN, especially sarcoid-associated; colchicine 0.5–1mg BID alternative
Short-course prednisolone	Severe/disabling EN after excluding infection/TB; must rule out TB before use (can disseminate TB); 20–40mg/day × 2–3 weeks then taper

🔑 Pearl — Löfgren Syndrome: Triad = Bilateral hilar adenopathy (BHL) on CXR + Erythema nodosum + Periarticular ankle inflammation (periarthritis, not true arthritis). Most common in Scandinavian women (HLA-DRB1*03). Excellent prognosis — 90% remission without treatment. NSAIDs for EN/arthritis; steroids rarely needed. Distinguish from TB (which also has hilar nodes + EN): Löfgren has BILATERAL symmetric hilar adenopathy; TB hilar adenopathy usually unilateral. IGRA negative in Löfgren (not TB). ACE elevated in sarcoid.

🔑 Pearl — EN vs Erythema Induratum (Nodular Vasculitis): Both are panniculitides on lower legs. Key differences: EN = anterior shin, non-ulcerating, septal panniculitis; Erythema induratum (EI/Bazin) = posterior/lateral calf, ulcerates and scars, lobular panniculitis with vasculitis, associated with TB (Bazin's disease) — positive IGRA/TST in 50%, Mycobacterium tuberculosis PCR in tissue. Both can occur in SE Asia. TB therapy resolves EI in TB-associated cases.