In a patient with a positive skin biopsy for leukocytoclastic small‑vessel vasculitis, a negative ANA reflex, and dry‑eye symptoms, what are the next diagnostic and therapeutic steps?

Diagnostic and Therapeutic Approach to Leukocytoclastic Vasculitis with Negative ANA and Dry Eyes

Immediately order MPO-ANCA and PR3-ANCA antigen-specific immunoassays (ELISA), perform comprehensive urinalysis with microscopy for dysmorphic RBCs and red cell casts, assess renal function, and initiate high-dose glucocorticoids (50-75 mg prednisolone equivalent daily) combined with rituximab or cyclophosphamide if organ-threatening disease is present—do not delay treatment while awaiting additional test results. 1, 2

Immediate Diagnostic Workup

ANCA Testing Priority:

• A negative ANA does not exclude vasculitis; it shifts diagnostic focus toward ANCA-associated vasculitis rather than lupus-related disease 2
• Order both MPO-ANCA and PR3-ANCA using antigen-specific immunoassays (ELISA) as the gold standard diagnostic test—approximately 90% of small-vessel vasculitis cases are ANCA-positive 1, 2, 3
• The positive skin biopsy showing leukocytoclastic vasculitis strongly supports the diagnosis and warrants immediate ANCA testing 1, 4

Essential Laboratory Evaluation:

• Perform urinalysis with microscopy specifically looking for dysmorphic RBCs, red cell casts, and quantify proteinuria—these findings indicate glomerular involvement with 91.5% diagnostic yield on kidney biopsy 1, 2, 5
• Assess renal function using GFR estimating equations; serum creatinine >300 µmol/L (>3.4 mg/dL) indicates severe disease requiring plasma exchange consideration 1, 3
• Measure inflammatory markers (CRP, ESR), complete blood count, and hepatitis B/C serology 4
• Check complement levels (C3, C4) to exclude cryoglobulinemic vasculitis or hypocomplementemic urticarial vasculitis 4

Critical Clinical Assessment

Organ System Evaluation:

• Renal: Look for microscopic hematuria, proteinuria >1 g/24 hours, rising creatinine, or oliguria—these define organ-threatening disease 1, 2, 3
• Pulmonary: Assess for hemoptysis, dyspnea, or infiltrates on chest imaging suggesting alveolar hemorrhage (pulmonary-renal syndrome occurs in 10% and increases mortality) 2, 3
• Neurologic: Examine for peripheral neuropathy or mononeuritis multiplex 2, 3
• Upper respiratory: Evaluate for chronic sinusitis, nasal crusting, or epistaxis suggesting granulomatosis with polyangiitis 1, 6
• Ophthalmologic: The dry-eye symptoms warrant formal ophthalmology evaluation to distinguish between scleritis/episcleritis (organ-threatening) versus simple sicca symptoms 1

Immediate Treatment Decisions

When to Start Immunosuppression:

• Do not delay treatment if ANCA is positive (MPO or PR3) and clinical picture aligns with ANCA-associated vasculitis, even before additional biopsy results 2
• Initiate therapy immediately for organ-threatening manifestations: glomerulonephritis, pulmonary hemorrhage, rapidly progressive renal failure, meningeal involvement, cardiac involvement, or mononeuritis multiplex 1, 2

Induction Regimen for Organ-Threatening Disease:

• Glucocorticoids: 50-75 mg prednisolone equivalent daily (based on body weight), with stepwise reduction to 5 mg daily by 4-5 months 1
• Plus rituximab (preferred, especially if this represents relapsing disease) or cyclophosphamide 1
• Consider plasma exchange if serum creatinine >300 µmol/L due to active glomerulonephritis 1
• Avacopan combined with rituximab/cyclophosphamide may be considered as a glucocorticoid-sparing strategy 1

Non-Organ-Threatening Disease:

• If skin-limited without renal, pulmonary, or neurologic involvement: glucocorticoids plus rituximab; methotrexate or mycophenolate mofetil are alternatives 1, 4
• Skin-limited leukocytoclastic vasculitis may respond to rest, low-dose corticosteroids, or colchicine 4

ANCA-Negative Vasculitis Considerations

Critical Caveat:

• Approximately 10% of true ANCA-associated vasculitis patients remain persistently ANCA-negative but require the same therapeutic regimen as ANCA-positive patients 2, 3
• In ANCA-negative cases with biopsy-proven leukocytoclastic vasculitis, rigorously exclude infections (hepatitis B/C, endocarditis), malignancies, and drug-induced vasculitis before confirming primary vasculitis 2, 4
• Consider kidney biopsy (91.5% diagnostic yield) or biopsy of other affected organs for definitive diagnosis when ANCA is negative 1, 2

Alternative Diagnoses to Exclude

Mimicking Conditions:

• Sjögren's syndrome (given dry-eye symptoms)—check anti-SSA/SSB antibodies and consider minor salivary gland biopsy 2
• IgA vasculitis (Henoch-Schönlein purpura)—request IgA staining on skin biopsy specimens 4
• Cryoglobulinemic vasculitis—measure cryoglobulins and hepatitis C 4
• Drug-induced vasculitis—review all medications; discontinuation of culprit drug is usually resolutive 4
• Infection-related vasculitis or malignancy-associated vasculitis 2, 4

Referral and Monitoring

Specialist Involvement:

• Transfer to or consult with centers having vasculitis expertise for access to rapid ANCA testing, expert histopathology, rituximab protocols, plasma exchange, and intensive care/hemodialysis capabilities 1, 2
• Ophthalmology consultation for formal dry-eye evaluation and to exclude scleritis 1
• Nephrology involvement if any renal abnormalities detected 2

Common Pitfalls:

• Do not assume negative ANA excludes autoimmune disease—ANCA-associated vasculitis is typically ANA-negative 2
• Do not wait for biopsy results if the patient shows clinical deterioration or has organ-threatening disease 2
• Remember that 10% of ANCA-associated vasculitis is ANCA-negative, making tissue biopsy essential in these cases 2, 3
• Do not overlook the possibility that leukocytoclastic vasculitis may be skin-limited versus a manifestation of systemic ANCA-associated vasculitis—the distinction fundamentally alters treatment intensity 4