What is the appropriate workup and treatment for a patient presenting with a diffuse pruritic bleeding rash suspected of having vasculitis, such as leukocytoclastic vasculitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis?

Vasculitis Workup for Diffuse Pruritic Bleeding Rash

For a patient with suspected cutaneous vasculitis presenting with a diffuse pruritic bleeding rash, immediately obtain a skin biopsy extending to the subcutis from the most tender, reddish or purpuric lesion, along with ANCA testing (both PR3 and MPO), urinalysis, complete blood count with differential, inflammatory markers (ESR, CRP), and renal function tests to distinguish between primary cutaneous vasculitis and systemic ANCA-associated vasculitis. 1, 2, 3

Initial Diagnostic Approach

Immediate Laboratory Testing

• ANCA testing is mandatory using high-quality antigen-specific assays for both PR3-ANCA and MPO-ANCA, as PR3-ANCA is detected in 84-85% of GPA patients and MPO-ANCA is present in 30-40% of EGPA patients 1, 3
• Urinalysis to detect hematuria with dysmorphic red blood cells, red cell casts, and proteinuria indicating glomerulonephritis 1, 2
• Complete blood count with differential to identify peripheral eosinophilia (suggesting EGPA) and assess for systemic involvement 2, 3
• Inflammatory markers (ESR, CRP) and renal function tests (creatinine, BUN) 2, 3

Critical Biopsy Technique

• Obtain a skin biopsy extending to the subcutis from the most tender, reddish or purpuric lesional skin, as serial sections are often required to identify the main vasculitic lesion 4
• Request a concomitant biopsy for direct immunofluorescence to distinguish IgA-associated vasculitis (Henoch-Schönlein purpura) from IgG-/IgM-associated vasculitis, which has prognostic significance 4
• Histopathology may reveal leukocytoclastic vasculitis, necrotizing granulomatous inflammation (GPA), or eosinophilic tissue infiltration (EGPA) 1, 5

Distinguishing Primary from Systemic Vasculitis

Red Flags for Systemic ANCA-Associated Vasculitis

The following features indicate systemic disease requiring aggressive immunosuppression rather than isolated cutaneous vasculitis 1, 6:

• Renal involvement: Rapidly declining GFR, hematuria with red cell casts, proteinuria (1-3 g/day) 1
• Pulmonary manifestations: Hemoptysis, alveolar hemorrhage, pulmonary nodules or infiltrates 1, 2
• Upper respiratory tract: Nasal crusting, epistaxis, chronic rhinosinusitis, nasal septal perforation 2, 3
• Neurological: Peripheral neuropathy, mononeuritis multiplex 1
• Ocular: Scleritis, episcleritis 2
• Constitutional symptoms: Fever, weight loss, fatigue, myalgia 5

Additional Imaging When Systemic Disease Suspected

• Chest CT (more sensitive than radiographs) for pulmonary manifestations 3
• Sinus CT when upper respiratory tract involvement suspected 3
• Brain/spinal MRI for CNS manifestations, pachymeningitis, or retro-orbital lesions 2

Treatment Algorithm Based on Disease Severity

For Isolated Cutaneous Vasculitis (No Systemic Features)

Most cases represent self-limited disease requiring conservative management 4, 7:

• Leg elevation, avoidance of prolonged standing, warming 4, 7
• NSAIDs or antihistamines for symptomatic relief 4, 7
• For mild recurrent or persistent disease: Colchicine or dapsone as first-choice agents 4, 7
• For severe cutaneous disease: Systemic corticosteroids (prednisone) or immunosuppression with azathioprine or methotrexate 4, 7

For Systemic ANCA-Associated Vasculitis (GPA/MPA/EGPA)

Severe Disease with Organ-Threatening or Life-Threatening Manifestations

Combination therapy with high-dose glucocorticoids PLUS either rituximab OR cyclophosphamide is required for remission induction 1, 3:

• Rituximab: 375 mg/m² weekly for 4 weeks 8, 9
• Alternative: Cyclophosphamide: 2 mg/kg/day (adjusted for renal function) for 3-6 months 1, 9
• Glucocorticoids: 1,000 mg IV methylprednisolone daily for 1-3 days, followed by oral prednisone 1 mg/kg/day (max 80 mg/day) with pre-specified tapering 9
• Rituximab is preferred over cyclophosphamide for relapsing disease 1, 3

Special Circumstances

• Plasma exchange should be considered for serum creatinine ≥500 μmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis 1
• Plasma exchange can also be considered for severe diffuse alveolar hemorrhage with hypoxemia 1
• Mandatory Pneumocystis jirovecii prophylaxis in all patients receiving rituximab or high-dose immunosuppression 8

Non-Severe EGPA (Without Organ/Life-Threatening Features)

Mepolizumab (IL-5 inhibitor) in combination with glucocorticoids is recommended for remission induction in relapsing-refractory EGPA without severe manifestations 1

Maintenance Therapy After Remission Induction

Continue treatment for at least 18-24 months with one of the following 1, 3:

• Rituximab: 500 mg every 6 months (MAINRITSAN scheme) or at months 4,8,12, and 16 after first infusion (RITAZAREM scheme) 1
• Azathioprine: 1.5-2 mg/kg/day for 18-24 months, then decrease to 1 mg/kg/day until 4 years after diagnosis 1
• Methotrexate or mycophenolate mofetil as alternatives 1
• Low-dose glucocorticoids (5-7.5 mg/day) should be continued for 2 years, then slowly reduced by 1 mg every 2 months 1

Critical Pitfalls to Avoid

• Do not rely solely on ANCA titers for treatment decisions; structured clinical assessment using validated tools like Birmingham Vasculitis Activity Score (BVAS) should guide management 1, 2
• Do not miss secondary causes: Exclude connective tissue diseases, severe bacterial infections (especially endocarditis), malignancy, and drug-induced vasculitis, as these require treatment of the underlying condition 4, 6
• Do not overlook the need for biopsy confirmation whenever feasible, as clinical and serological findings alone may be insufficient 1, 3
• Adults require more extensive workup than children, as secondary vasculitis and systemic necrotizing vasculitis are far more common in adults (52 of 172 adults vs. 1 of 131 children had secondary or systemic vasculitis) 6
• Monitor for treatment-related complications: Regular assessment of cardiovascular risk, testing serum immunoglobulin levels before each rituximab course, and investigation of persistent unexplained hematuria in patients with prior cyclophosphamide exposure 1