What is the appropriate workup and treatment for an adult patient with suspected vasculitis, presenting with high fever, joint pain or swelling, and elevated inflammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)?

Vasculitis Workup in Adults with Fever, Joint Pain, and Elevated Inflammatory Markers

Begin with targeted laboratory testing including serum ferritin with glycosylated fraction, complete blood count with differential, liver function tests, ANCA testing by antigen-specific immunoassay, and urinalysis to distinguish between Still's disease, ANCA-associated vasculitis, and large vessel vasculitis. 1, 2

Initial Diagnostic Approach

The clinical presentation of high fever, joint pain/swelling, and elevated ESR/CRP requires systematic evaluation to differentiate between several vasculitic and inflammatory conditions:

Essential Laboratory Tests

• Serum ferritin with glycosylated fraction is critical—extremely elevated ferritin (>1000 ng/mL, often >10,000 ng/mL) with low glycosylated fraction (<20%) strongly supports Adult-Onset Still's Disease (AOSD) 1

• Complete blood count with differential to assess for neutrophilic leukocytosis and thrombocytosis characteristic of Still's disease, or cytopenias that may suggest other systemic processes 1

• ANCA testing using high-quality antigen-specific immunoassays (proteinase-3 and myeloperoxidase) as the preferred screening methodology—this is essential for diagnosing ANCA-associated small-vessel vasculitis 2

• Liver function tests should be performed as elevated transaminases are common in Still's disease 1

• Urinalysis with microscopy to detect glomerulonephritis, which would suggest ANCA-associated vasculitis or other systemic vasculitis 2

Additional Inflammatory Markers

• IL-18 and/or S100 proteins (calprotectin) strongly support AOSD diagnosis when markedly elevated 1

• ESR values >40 mm/h have high sensitivity for giant cell arteritis, while values >100 mm/h have the highest specificity 3

Critical Clinical Features to Assess

• Daily high-spiking fevers ≥39°C (102.2°F) are cardinal features of Still's disease 1, 4

• Salmon-colored evanescent rash on trunk (not folliculitis on forehead) is characteristic of Still's disease 1

• Temporal headache, jaw claudication, or visual disturbances suggest giant cell arteritis, particularly in patients over age 50 3

• Constitutional symptoms with vascular territory involvement may indicate large vessel vasculitis 5

Imaging Studies

When to Obtain Vascular Imaging

• Temporal artery ultrasound or biopsy should be performed when giant cell arteritis is suspected based on age >50 years, headache, jaw claudication, or visual symptoms—but this should not delay treatment 5

• MR angiography or CT angiography to assess for characteristic vasculitic changes in large vessels when Takayasu arteritis or other large vessel vasculitis is suspected 5, 3

• PET/CT imaging can demonstrate intense FDG uptake in vessel walls and is useful for diagnosis and monitoring of large vessel vasculitis 6, 7

Differential Diagnosis and Exclusions

A critical pitfall is delaying diagnosis while waiting for specific features like arthritis to develop—this can lead to unnecessary diagnostic delays and worse outcomes. 4

Must Exclude Alternative Diagnoses

• Malignancy, infectious diseases (including endocarditis), and other autoimmune diseases must be carefully excluded as they can present with similar fever and inflammatory markers 1, 4

• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (MAS) is a life-threatening complication that can occur at disease onset and requires active screening with ferritin, triglycerides, fibrinogen, and cytopenias 1, 4

• Thrombotic disorders (anti-phospholipid antibody syndrome) should be excluded as pseudovasculitis can mimic true vasculitis 8

Additional Serologic Testing

• Complement levels (C3, C4), immunoglobulins, cryoglobulins, and Hepatitis B/C serology help distinguish immune complex-associated vasculitis 2

• Anti-GBM antibodies if glomerulonephritis is present 2

• Anti-C1q antibodies for immune complex-associated small-vessel vasculitis 2

Tissue Diagnosis

• Temporal artery biopsy should be performed whenever giant cell arteritis is suspected, but should not delay treatment; contralateral biopsy is not routinely indicated 5

• Skin biopsy extending to subcutis from the most tender, reddish or purpuric lesional skin when cutaneous vasculitis is present—serial sections are often required 8

• Direct immunofluorescence on biopsy distinguishes IgA-associated vasculitis (Henoch-Schönlein purpura) from IgG-/IgM-associated vasculitis, which has prognostic significance 8

Treatment Initiation Based on Diagnosis

For Still's Disease (AOSD/sJIA)

Initiate treatment with IL-1 inhibitor (anakinra) or IL-6 inhibitor (tocilizumab) as early as possible when diagnosis is established, targeting resolution of fever and >50% reduction in CRP by day 7. 1

• Glucocorticoids may be needed initially but should not be used as monotherapy for prolonged periods 1

For Large Vessel Vasculitis

Early initiation of high-dose glucocorticoid therapy (typically 1 mg/kg/day prednisone, not exceeding 80 mg/day) for induction of remission is recommended. 5

• Low-dose aspirin (75-150 mg/day) should be prescribed to all patients with giant cell arteritis to protect against cardiovascular and cerebrovascular events 5

• Immunosuppressive agents (methotrexate 20-25 mg/week or azathioprine 2 mg/kg/day) should be considered as adjunctive therapy to reduce glucocorticoid requirements 5

For ANCA-Associated Vasculitis

• Rituximab 375 mg/m² once weekly for 4 weeks combined with high-dose glucocorticoids is effective for remission induction in granulomatosis with polyangiitis and microscopic polyangiitis 9

• Cyclophosphamide 2 mg/kg daily for 3-6 months is an alternative induction regimen 9

Monitoring Strategy

• Clinical monitoring aided by inflammatory markers (ESR, CRP) should inform decisions to alter therapy—there are no valid biomarkers for assessing response in large vessel vasculitis 5

• Serial vascular imaging with MRI or PET/CT may assist assessment of disease activity in large vessel vasculitis 5, 7

• Screen for MAS throughout treatment course as it can occur during treatment or even in remission 1, 4