In a patient with livedo rash, tender skin lesions, dry‑eye symptoms, elevated C‑reactive protein and a negative antinuclear antibody, what is the next step in evaluating and managing possible vasculitis?

Evaluation and Management of Suspected Vasculitis with Negative ANA

In a patient with livedo rash, tender skin lesions, dry-eye symptoms, elevated CRP, and negative ANA, immediately test for ANCA (both MPO-ANCA and PR3-ANCA by antigen-specific immunoassay) and obtain a skin biopsy of an active lesion to confirm vasculitis. 1, 2

Immediate Diagnostic Workup

The negative ANA does not exclude vasculitis and should redirect your evaluation toward ANCA-associated vasculitis (AAV) rather than lupus-related disease. 1, 2

Essential Laboratory Tests

• Order MPO-ANCA and PR3-ANCA by antigen-specific immunoassay (ELISA), which is the preferred screening method and gold standard for AAV diagnosis 1, 2
• Perform urinalysis with microscopy specifically looking for dysmorphic red blood cells, red cell casts, and proteinuria to assess for renal involvement 3, 2
• Check serum creatinine and estimate GFR to evaluate kidney function, as rapidly declining GFR is a critical feature of AAV 3, 2
• Measure inflammatory markers including CRP and ESR, though your elevated CRP already suggests active inflammation 2, 4
• Complete blood count to assess for anemia, leukocytosis, or thrombocytopenia 1

Tissue Biopsy Strategy

• Obtain skin biopsy from an active, tender lesion to look for leukocytoclastic vasculitis or necrotizing small-vessel vasculitis 2, 5
• Palpable purpura and painful skin lesions are highly specific for active small-vessel vasculitis and warrant aggressive evaluation 5
• If kidney involvement is suspected (hematuria, proteinuria, rising creatinine), kidney biopsy has a 91.5% diagnostic yield and provides both diagnostic and prognostic information 1, 3

Critical Clinical Context

ANCA-Negative Vasculitis Considerations

About 10% of patients with true AAV are persistently ANCA-negative, and these patients are treated identically to ANCA-positive patients. 1, 2 However, when ANCA is negative, you must rigorously exclude vasculitis mimics including:

• Systemic lupus erythematosus (though your negative ANA makes this less likely, 4-13% of SLE cases are ANA-negative) 6
• Sjögren's syndrome (which could explain dry-eye symptoms and can present with vasculitis) 2
• Infections (which can mimic vasculitis clinically) 1
• Malignancies (paraneoplastic vasculitis) 1
• IgG4-related disease 2

Dry-Eye Symptoms Warrant Additional Testing

• Consider anti-Ro/SSA and anti-La/SSB antibodies to evaluate for Sjögren's syndrome, which can present with vasculitis, dry eyes, and negative ANA 2
• Sjögren's can coexist with or mimic ANCA-associated vasculitis 2

When to Initiate Treatment Without Waiting

Do not delay immunosuppressive therapy if:

• ANCA testing returns positive (MPO or PR3) AND clinical presentation is compatible with AAV 1, 3, 2
• Serum creatinine rises above 4 mg/dL (354 μmol/L), indicating rapidly progressive glomerulonephritis 2
• Patient develops pulmonary hemorrhage, severe constitutional symptoms, or other organ-threatening manifestations 3

In these scenarios, start treatment immediately with high-dose glucocorticoids (methylprednisolone 500-1000 mg IV daily for 3 days, then prednisone 1 mg/kg/day) plus rituximab or cyclophosphamide, without waiting for biopsy results. 3, 2

Referral Considerations

Transfer to a center with AAV expertise if vasculitis is confirmed or highly suspected, as these centers have:

• Rapid access to ANCA testing and histopathology 1
• Experience with rituximab and plasma exchange 1
• Intensive care and acute hemodialysis capabilities 1
• Expertise managing treatment complications and long-term relapse prevention 3

Common Pitfalls to Avoid

• Do not assume negative ANA excludes autoimmune disease - AAV is typically ANA-negative, and rare cases of ANA-negative lupus exist 1, 2, 6
• Do not confuse ANA with ANCA - these are distinct antibodies targeting different antigens 7, 8
• Do not delay ANCA testing - approximately 90% of small-vessel vasculitis cases are ANCA-positive, making this the key diagnostic test 1, 2
• Do not overlook the 10% of AAV that is ANCA-negative - tissue biopsy becomes essential in these cases 1, 2
• Do not wait for biopsy if clinical deterioration occurs - start treatment immediately in life- or organ-threatening presentations 1, 3, 2