What is the differential diagnosis and treatment approach for cutaneous vasculitis?

Cutaneous Vasculitis: Differential Diagnosis

The differential diagnosis of cutaneous vasculitis must systematically distinguish between primary vasculitic syndromes, secondary causes (infections, drugs, connective tissue diseases, malignancy), and vasculitis-mimicking conditions (pseudovasculitis), with the diagnostic approach centered on skin biopsy extending to subcutis, direct immunofluorescence, ANCA testing, and identification of systemic involvement. 1, 2

Primary Vasculitic Syndromes

Small Vessel ANCA-Associated Vasculitides

• Granulomatosis with Polyangiitis (GPA): Presents with necrotizing granulomatous lesions and systemic vasculitis, strongly associated with C-ANCA/PR3-ANCA (84-85% positive), manifesting as palpable purpura, infiltrated erythema, nodules, or ulcers 1, 3
• Eosinophilic Granulomatosis with Polyangiitis (EGPA): Shows MPO-ANCA positivity in 30-40% of cases, with MPO-ANCA-positive patients frequently exhibiting glomerulonephritis, neuropathy, and purpura, while ANCA-negative patients more commonly manifest cardiomyopathy and lung involvement 1
• Microscopic Polyangiitis (MPA): Presents with small vessel vasculitis without granulomas, typically MPO-ANCA positive, with frequent renal and pulmonary involvement 1, 4

IgA-Mediated Vasculitis

• IgA Vasculitis (Henoch-Schönlein Purpura): Distinguished by IgA immune deposits on direct immunofluorescence, typically showing palpable purpura in dependent areas, absent in ANCA-associated vasculitides 1, 5

Cryoglobulinemic Vasculitis

• Mixed Cryoglobulinemia Syndrome: Most commonly HCV-associated, characterized by the clinical triad of purpura, weakness, and arthralgias, with low complement C4, cutaneous leukocytoclastic vasculitis, and circulating mixed cryoglobulins 1

Medium Vessel Vasculitis

• Polyarteritis Nodosa (PAN): Presents with subcutaneous nodules and livedo reticularis as the most common cutaneous manifestations, alongside systemic symptoms including fever, weight loss, and organ-specific involvement 6

Secondary Vasculitides

Infection-Associated

• Bacterial: Ecthyma gangrenosum (Pseudomonas aeruginosa, Aeromonas, Serratia, Staphylococcus aureus) begins as painless erythematous macules rapidly becoming painful and necrotic within 12-24 hours, classically in neutropenic patients 6
• Viral: Hepatitis B and C, HIV, post-herpes zoster granulomatous vasculitis 1, 7
• Parasitic: Associated with eosinophilic vasculitis patterns 7

Drug-Induced Vasculitis

• Presents as leukocytoclastic vasculitis, typically P-ANCA positive without MPO specificity, resolving with drug discontinuation 2, 5

Connective Tissue Disease-Associated

• Systemic Lupus Erythematosus: Shows lymphocytic vasculitis pattern with lichenoid interface changes 7, 8
• Rheumatoid Arthritis: Presents with rheumatoid vasculitis in severe, long-standing disease 2, 8
• Sjögren's Syndrome: Can overlap with mixed cryoglobulinemia, requires differentiation based on specific autoantibody profiles 1

Malignancy-Associated

• Paraneoplastic vasculitis showing pan-dermal small vessel and subcutaneous muscular vessel involvement, particularly with hematologic malignancies 2, 9

Eosinophilic Disorders (EGPA Differential)

• Hypereosinophilic Syndromes: Lymphocytic and myeloproliferative variants, the latter characterized by FIP1L1 fusion genes 1
• Allergic Bronchopulmonary Aspergillosis: Hypersensitivity disorder with pulmonary infiltrates and eosinophilia 1
• IgG4-Related Disease: Can present with eosinophilia and overlapping features with EGPA 1

Pseudovasculitis (Vasculitis Mimics)

Thrombotic Disorders

• Antiphospholipid Antibody Syndrome: Shows vascular occlusion without true inflammatory vessel wall destruction 2, 8
• Disseminated Intravascular Coagulation: Presents with purpura and necrosis but lacks inflammatory infiltrate 9
• Thrombotic Thrombocytopenic Purpura: Microthrombi without vasculitic inflammation 9

Other Mimics

• Cholesterol Emboli: Shows clefts in vessel lumens without inflammation 9
• Calciphylaxis: Vascular calcification with thrombosis in renal failure patients 9

Non-Vasculitic Inflammatory Conditions

• Sweet Syndrome: Neutrophilic dermatosis without true vasculitis, common in immunocompromised patients 1
• Erythema Multiforme: Target lesions with interface dermatitis, not true vasculitis 1
• Graft-versus-Host Disease: In allogeneic transplant recipients, shows interface changes rather than vasculitis 1

Critical Diagnostic Approach

Histopathologic Classification by Vessel Size

• Small Vessel (Dermal Superficial): Palpable purpura, infiltrated erythema indicating leukocytoclastic vasculitis 2, 5
• Muscular Vessel (Deep Dermal/Subcutaneous): Nodular erythema, livedo racemosa, deep ulcers, digital gangrene 2, 9
• Pan-Dermal Pattern: Coexistence of small and muscular vessel vasculitis indicates connective tissue disease, ANCA-associated vasculitis, Behçet disease, or malignancy-associated vasculitis 2, 9

Essential Biopsy Technique

• Obtain biopsy extending to subcutis from the most tender, reddish, or purpuric lesional skin (not older, necrotic lesions) 1, 2
• Serial sections often required to identify main vasculitic lesion 2, 9
• Concomitant biopsy for direct immunofluorescence distinguishes IgA-associated from IgG/IgM-associated vasculitis with prognostic significance 2, 5

Key Histopathologic Features

• Leukocytoclastic Vasculitis: Neutrophilic infiltration with nuclear debris (leukocytoclasis) in and around vessel walls 6, 5
• Fibrinoid Necrosis: Vessel wall destruction with fibrin deposition 6, 9
• Extravascular Clues: Tissue eosinophilia, granulomas, or neutrophilic infiltrates signal systemic disease risk 1, 9

Laboratory Evaluation Algorithm

• ANCA Testing: Perform in all suspected ANCA-associated vasculitis; MPO-ANCA by ELISA (not just P-ANCA by immunofluorescence) is more specific for vasculitis 1
• Cryoglobulins: Repeated testing may be necessary as levels fluctuate; temporary negativity does not exclude mixed cryoglobulinemia 1
• Complement Levels: Low C4 suggests cryoglobulinemic vasculitis 1
• Hepatitis Serology: Screen for HBV and HCV in all cases 1
• Direct Immunofluorescence: Distinguishes IgA vasculitis (Henoch-Schönlein) from other forms; immune deposits absent in ANCA-associated vasculitides 1, 5

Systemic Involvement Assessment

• Constitutional Symptoms: Fever, malaise, weight loss, arthralgias, myalgias indicate systemic disease 6, 2
• Neurologic: Mononeuritis multiplex, peripheral neuropathy (particularly in EGPA and systemic necrotizing vasculitis) 1, 6
• Renal: Hypertension, hematuria, proteinuria, elevated creatinine; assess GFR using MDRD or Cockcroft-Gault formula 1, 6
• Pulmonary: Infiltrates, nodules, cavitations on imaging 1, 3
• Cardiac: Cardiomyopathy particularly in ANCA-negative EGPA 1

Common Diagnostic Pitfalls

• Isolated P-ANCA positivity without MPO-ANCA can occur in non-vasculitic inflammatory conditions (inflammatory bowel disease); always confirm with MPO-ANCA ELISA 1
• Biopsy of older, necrotic lesions yields non-diagnostic results; target early, symptomatic, reddish lesions 2, 9
• Superficial biopsies miss muscular vessel involvement; always extend to subcutis 2, 9
• Single negative cryoglobulin test does not exclude mixed cryoglobulinemia; repeat testing required 1
• Purpura and necrosis alone do not confirm vasculitis; must demonstrate inflammatory vessel wall destruction to distinguish from pseudovasculitis 9