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Classification of Cutaneous Vasculitis & Henoch-Schönlein Purpura

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PART I: CLASSIFICATION OF CUTANEOUS VASCULITIS

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A. Based on Vessel Size (Table — Chapel Hill / Dermatology 5e)

Cutaneous involvement occurs almost exclusively with small and medium-vessel vasculitis. Behçet disease may involve vessels of all sizes. — Dermatology 2-Volume Set 5e (Bolt/Griffiths); Fitzpatrick's Dermatology Vol. 1 & 2

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B. Histopathologic Terms

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C. By Etiology (Etiologic Classification)

1. Idiopathic (~50% of CSVV cases)
2. Drug-induced (~20%): Almost any drug; PTU, hydralazine (ANCA-associated)
3. Infection-associated: Group A β-hemolytic Streptococcus, Mycoplasma, HCV, H. pylori
4. Autoimmune-CTD associated: SLE (10–36%), Sjögren syndrome (10%), RA
5. Malignancy-associated: Solid tumors, lymphoproliferative neoplasms
6. Systemic vasculitis with cutaneous involvement: GPA, MPA, PAN, IgA vasculitis

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PART II: HENOCH-SCHÖNLEIN PURPURA (IgA VASCULITIS) — 10 MARKS FORMAT

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1. Definition & Nomenclature

1. Palpable purpura
2. Arthralgia/Arthritis
3. Abdominal pain/GI symptoms
4. Renal involvement (glomerulonephritis) — Harrison's Principles 22E (2025)

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2. Epidemiology

• Most common vasculitis in children (≥75% of cases; peak age 2–8 years)
• Also occurs in adults (average age ~50 years)
• Male predominance (M:F = 1.5:1)
• Annual incidence: ~45 per million (biopsy-proven LCV overall)
• Seasonal variation: spring peak
• — Dermatology 5e; Harrison's 22E

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3. Etiology & Pathogenesis

• Upper respiratory tract infection (most common trigger — especially Group A Streptococcal pharyngitis)
• Viral infections
• Helicobacter pylori (adult and some childhood cases)
• Drugs, foods, insect bites, immunizations

• Abnormal IgA1 glycosylation → formation of IgG-IgA1 immune complexes in antigen excess
• Circulating immune complexes deposit in postcapillary venule walls
• Complement activation → neutrophil chemotaxis → endothelial injury → leukocytoclastic vasculitis
• IgA + C3 + fibrin deposition in vessel walls of both involved and uninvolved skin (pathognomonic on DIF)
• In ANCA-associated vasculitis (for contrast), damage is pauci-immune and directly neutrophil-mediated — Andrews' Diseases of the Skin; Dermatology 5e

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4. Clinical Features

A. Cutaneous (100% of patients)

• Palpable purpura — hallmark; non-blanching, crops of lesions
• Distribution: extensor surfaces of lower extremities, buttocks; purpura above the waist is a marker of renal involvement
• Initially mottled; becomes hemorrhagic within 24 hours; fades in ~5 days; new crops appear over weeks
• May also show: urticarial lesions, vesicles, necrotic purpura, hemangioma-like lesions
• Preceded by mild fever, headache, joint pain, abdominal pain in ~40% of cases

B. Joint Involvement (~63% of patients)

• Periarticular swelling of knees and ankles (most common)
• Arthralgias → frank arthritis; non-deforming, self-limiting

C. Gastrointestinal (~65–70% of patients)

• Colicky abdominal pain (most common GI symptom)
• Nausea, vomiting, diarrhea, constipation
• GI bleeding (blood and mucus per rectum)
• Bowel intussusception (most common abdominal complication in children)
• Severe pain may mimic surgical abdomen; paralytic ileus, rebound tenderness possible
• Radiograph: "spiking" or cobblestone appearance of bowel wall

D. Renal (~10–50% in children; up to 70% in adults)

• Microscopic or gross hematuria + proteinuria with RBC casts
• Usually mild glomerulonephritis — resolves spontaneously
• Adults: more severe, insidious renal course; closer follow-up required
• 1–5% of children progress to end-stage renal disease; higher rate in adults
• Baseline renal impairment + proteinuria >1 g/day + adverse biopsy findings = high risk of chronic renal disease

E. Other

• Pulmonary hemorrhage (rare but potentially fatal)
• Myocardial involvement (rare, mainly adults) — Harrison's 22E; Andrews' Diseases of the Skin; Dermatology 5e

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5. Laboratory Findings

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6. Histopathology & Direct Immunofluorescence (DIF)

• Leukocytoclastic vasculitis — neutrophilic infiltrate around post-capillary venules
• Fibrinoid necrosis of vessel walls
• Karyorrhexis ("nuclear dust"), endothelial swelling
• Extravasation of red blood cells

• Dominant IgA deposits in vessel walls of dermal post-capillary venules (IgA > IgG, IgM)
• Also C3 and fibrin
• Distinguishes IgAV from other LCV (which show IgG/IgM); IgA deposits persist even in older lesions (unlike other immune complexes which degrade)
• DIF of uninvolved skin can also be positive — useful when skin lesions are not present (histamine trap test) — Andrews' Diseases of the Skin; Dermatology 5e

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7. Diagnosis & Diagnostic Criteria

1. Palpable purpura
2. Age ≤20 at onset
3. Bowel angina (colicky pain/bloody diarrhea)
4. Hematuria or RBC casts on urinalysis
5. IgA on biopsy (if biopsy performed)

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8. Differential Diagnosis

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9. Treatment

Note: Steroids do not prevent or shorten renal disease, do not prevent recurrences, and do not shorten overall disease duration. — Harrison's 22E; Andrews' Diseases of the Skin

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10. Prognosis & Complications

• Excellent overall prognosis in children
• Mortality: extremely rare
• 1–5% of children → ESRD; higher rate in adults
• Relapse rate: 10–40% of patients (usually within weeks to months of initial episode)
• Poor prognostic indicators:
  • Purpura above the waist
  • Persistent proteinuria (>1 g/day)
  • Crescentic glomerulonephritis on renal biopsy
  • Adult onset
  • Presence of IgM in lesional skin (indicator of renal involvement)

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Summary Box (Quick Revision)

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Classification of Porphyrias, Heme Biosynthesis & Porphyria Cutanea Tarda

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PART I: HEME BIOSYNTHESIS

Compartments

• Mitochondria: Steps 1, 6, 7, 8 (first and last three enzymes)
• Cytosol: Steps 2–5 (middle four enzymes)

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The Eight Enzymatic Steps

Key regulatory point: ALAS1 (hepatic) is the rate-limiting step, induced by drugs, steroids, fasting, and PGC-1α. Heme exerts negative feedback on ALAS1 — when downstream enzyme is deficient, heme falls → ALAS1 upregulated → precursors accumulate. — Harrison's Principles 22E; Dermatology 5e

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PART II: CLASSIFICATION OF PORPHYRIAS

A. By Site of Principal Enzyme Expression (Traditional)

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B. By Clinical Presentation — ACUTE vs NON-ACUTE (Clinically most useful)

Acute (Neurovisceral) Porphyrias

Non-Acute Porphyrias (All Cutaneous)

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C. By Skin Manifestations — Dermatologist's Classification (Dermatology 5e)

Mnemonic for cutaneous porphyrias: PCT, EPP, VP, HCP, CEP, HEP, XLP → "PEVHCHX"

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D. By Biochemical Pattern (Fluorescence Emission)

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PART III: PORPHYRIA CUTANEA TARDA (PCT) — DETAILED DISCUSSION

1. Definition & Overview

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2. Types of PCT

For clinical symptoms to manifest, UROD activity must fall to ≤20% of normal — hence even type II carriers require additional susceptibility factors.

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3. Pathogenesis

1. UROD inhibition → uroporphyrinogen III and hepta-carboxylate porphyrinogens accumulate → auto-oxidize to photoactive uroporphyrins
2. Requires iron + oxidative stress in the liver → generation of a uroporphomethene (UROD inhibitor)
3. Uroporphyrins are water-soluble → deposit in skin dermis and papillary vessels
4. Soret band absorption (400–410 nm, UVA/visible light) → singlet oxygen + free radicals → lipid peroxidation + protein cross-linking → subepidermal blister formation
5. Festooning of dermal papillae due to PAS-positive material deposition

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4. Precipitating / Susceptibility Factors

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5. Clinical Features

A. Cutaneous (Pathognomonic)

• Skin fragility and blistering on sun-exposed areas: dorsal hands and forearms are most commonly affected; also face, ears, dorsal feet (especially shins in women), legs
• Bullae are non-inflammatory, thin-roofed, rupture easily → erosions → shallow ulcers → heal with atrophic scars + milia
• Hypertrichosis: temporal cheeks, temples (especially in women) — characteristic feature
• Hyperpigmentation: face, neck, hands — brownish discoloration
• Violaceous/pink tint of periorbital area and neck (heliotrope-like)
• Sclerodermoid/morpheiform changes: back of neck, preauricular areas, thorax, fingers, scalp → may cause scarring alopecia — directly correlates with urine uroporphyrin levels

B. Systemic

• Liver disease frequently present: hepatitis C, alcoholic liver disease, steatohepatitis
• Risk of hepatocellular carcinoma (3.5× increased risk)
• Neurological features are ABSENT (unlike AIP/VP) — key distinguishing point

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6. Investigations / Diagnosis

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7. Histopathology

• Subepidermal cell-poor blister (minimal inflammatory infiltrate)
• Festooning of dermal papillae — papillae project upward into blister floor (characteristic)
• PAS-positive material deposition around dermal vessels
• Thickened dermal vessel walls
• Direct Immunofluorescence (DIF): Immunoglobulins (IgG) + complement (C3) around blood vessels in upper dermis — "doughnut pattern"

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8. Differential Diagnosis

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9. Treatment

First-line: Phlebotomy (Venesection)

• Remove 450 mL blood every 1–2 weeks
• Target: serum ferritin → lower limit of normal
• Usually requires 5–6 sessions (more in hemochromatosis-associated PCT)
• Monitor Hb and ferritin to avoid iatrogenic iron deficiency anemia
• Plasma porphyrins normalize after target ferritin reached
• Most effective, cheapest, safest treatment

Second-line: Low-dose Antimalarials

• Chloroquine phosphate 125 mg twice weekly OR Hydroxychloroquine 200 mg twice weekly
• Mechanism: complex with porphyrins → mobilize from hepatocytes → promote urinary excretion
• Do NOT use standard doses — risk of transient severe photosensitivity flare + hepatocellular damage
• Hydroxychloroquine equally effective and safe as phlebotomy (studies confirm)
• Preferred when phlebotomy is contraindicated (anemia, cardiovascular disease)

Specific Situations

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10. Prognosis

• Complete remission achievable in nearly all patients with appropriate therapy
• Relapse possible — monitor plasma porphyrins every 6–12 months
• Risk of HCC requires periodic hepatic surveillance
• Familial (Type II) PCT patients: genetic counseling for family members
• HEP (homozygous) PCT: severe childhood-onset disease; may require bone marrow transplantation (as for CEP)

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Summary Box — PCT at a Glance

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