Mimickers of Vasculitis: A Clinical Review for the Astute Internist

Dr Neeraj Manikath , claude.ai

Abstract

Vasculitis presents diagnostic challenges that are compounded by numerous conditions that closely mimic its clinical, laboratory, and imaging features. Misdiagnosis can lead to inappropriate immunosuppression with significant morbidity or delayed treatment of life-threatening conditions. This review examines common and uncommon vasculitis mimickers, provides practical diagnostic pearls, exposes common diagnostic fallacies, and offers evidence-based approaches to differentiation.

Introduction

Systemic vasculitides represent a heterogeneous group of disorders characterized by inflammation and necrosis of blood vessel walls. However, the clinical presentation of vasculitis—fever, elevated inflammatory markers, multi-organ involvement, and vascular imaging abnormalities—is shared by numerous non-vasculitic conditions. Studies suggest that up to 30% of suspected vasculitis cases referred to tertiary centers represent mimickers rather than true vasculitis.

The consequences of misdiagnosis are bidirectional: treating a vasculitis mimicker with high-dose corticosteroids and immunosuppression exposes patients to infectious and metabolic complications, while failing to recognize true vasculitis delays potentially life-saving therapy. This review provides a systematic approach to recognizing and differentiating vasculitis mimickers.

Classification of Vasculitis Mimickers

Vasculitis mimickers can be categorized into five major groups: infectious, embolic, thrombotic, neoplastic, and drug-related conditions.

1. Infectious Mimickers

Endocarditis

Infective endocarditis remains the quintessential vasculitis mimicker, presenting with fever, elevated inflammatory markers, embolic phenomena, glomerulonephritis, and positive ANCA in up to 30% of cases. The inflammatory vasculopathy of endocarditis can produce imaging findings indistinguishable from true vasculitis.

Pearl: In any patient with suspected vasculitis presenting with fever, obtain at least three sets of blood cultures before initiating immunosuppression, even with negative initial echocardiography. Transthoracic echocardiography has only 60-70% sensitivity for vegetations; transesophageal echocardiography should be performed when suspicion is moderate to high.

Oyster: Bartonella, Coxiella burnetii, and HACEK organisms cause culture-negative endocarditis that can present identically to ANCA-associated vasculitis with renal involvement. Serological testing for these organisms should be routine in culture-negative suspected vasculitis with cardiac involvement.

Tuberculosis and Fungal Infections

Disseminated tuberculosis and invasive fungal infections (particularly aspergillosis and mucormycosis) can involve blood vessels directly, producing angioinvasive disease that mimics vasculitis clinically and radiologically.

Hack: In endemic areas or immunocompromised patients with suspected vasculitis, always obtain tissue for acid-fast bacilli, fungal stains, and cultures. Serum 1,3-beta-D-glucan and galactomannan can assist in fungal diagnosis, though sensitivity varies.

HIV and Hepatitis Viruses

Chronic viral infections, particularly HIV, hepatitis B, and hepatitis C, can cause true vasculitis (cryoglobulinemic vasculitis with hepatitis C, polyarteritis nodosa with hepatitis B) or vasculitis-like syndromes through immune complex deposition and direct vascular injury.

Fallacy: Assuming negative viral serology rules out viral-associated vasculopathy. In acute HIV infection, serology may be negative while viral load is high. Similarly, occult hepatitis B (anti-HBc positive, HBsAg negative) can drive vasculitic syndromes.

2. Embolic Mimickers

Cholesterol Embolization Syndrome

Cholesterol emboli syndrome typically occurs following vascular procedures or anticoagulation initiation in patients with severe atherosclerosis. Clinical features include livedo reticularis, "purple toes," renal insufficiency, eosinophilia, and elevated inflammatory markers—closely mimicking small-to-medium vessel vasculitis.

Pearl: The presence of eosinophilia, hypocomplementemia, recent vascular intervention, and characteristic retinal findings (Hollenhorst plaques) should raise suspicion. Skin or renal biopsy showing cholesterol clefts confirms diagnosis, though tissue sampling may be normal due to patchy distribution.

Atrial Myxoma

Cardiac myxomas can produce constitutional symptoms, elevated inflammatory markers, embolic phenomena, and autoimmune manifestations including positive ANA and elevated immunoglobulins, creating a "pseudo-vasculitis" syndrome.

Hack: Echocardiography should be standard in any patient with suspected vasculitis presenting with constitutional symptoms and elevated inflammatory markers, particularly with embolic phenomena. Myxomas characteristically produce extremely elevated IL-6 levels.

3. Thrombotic Microangiopathies and Coagulopathies

Antiphospholipid Syndrome (APS)

APS produces thrombotic manifestations that can mimic vasculitis, including livedo reticularis, digital ischemia, renal thrombotic microangiopathy, and stroke. Catastrophic APS can present with multi-organ failure mimicking severe systemic vasculitis.

Pearl: True vasculitis produces inflammatory vessel wall changes with leukocyte infiltration, while APS causes thrombosis without vessel wall inflammation. Biopsy showing bland thrombosis without vessel wall inflammation distinguishes APS from vasculitis. However, these conditions can coexist, particularly in SLE-associated vasculitis.

Fallacy: Relying solely on antiphospholipid antibodies for diagnosis. Antibodies can be transiently positive during acute illness or infection. Diagnosis requires positive tests on two occasions at least 12 weeks apart with clinical thrombotic or obstetric manifestations.

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

These thrombotic microangiopathies present with microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, and neurological manifestations that can mimic CNS vasculitis or systemic vasculitis with renal involvement.

Oyster: ADAMTS13 activity <10% distinguishes TTP from other microangiopathies and should be checked before plasma exchange when TTP is suspected. However, don't wait for results to initiate plasma exchange if clinical suspicion is high, as delay increases mortality.

4. Neoplastic Mimickers

Intravascular Lymphoma

Intravascular lymphoma (IVL) represents a rare extranodal lymphoma where malignant lymphocytes proliferate within small vessel lumina, producing fever, neurological symptoms, skin lesions, and elevated inflammatory markers without lymphadenopathy—a near-perfect vasculitis mimic.

Pearl: Consider IVL in patients with unexplained fever, elevated LDH, neurological symptoms, and skin lesions without lymphadenopathy. Random skin biopsies (even normal-appearing skin) have 60-70% diagnostic yield. Bone marrow biopsy increases sensitivity to approximately 75-80%.

Atrial Myxoma and Other Cardiac Tumors

As discussed above, cardiac tumors produce embolic phenomena and constitutional symptoms mimicking vasculitis.

Calciphylaxis

Calciphylaxis (calcific uremic arteriolopathy) occurs predominantly in end-stage renal disease patients, producing painful skin lesions, livedo reticularis, and tissue necrosis that can mimic cutaneous vasculitis.

Hack: Calciphylaxis occurs almost exclusively in patients with renal disease and markedly elevated calcium-phosphate product. Skin biopsy showing medial calcification of small vessels without inflammation distinguishes it from true vasculitis.

5. Drug-Induced Vasculopathy

Levamisole-Contaminated Cocaine

Levamisole, a veterinary anthelmintic used to adulterate cocaine, causes a distinctive vasculopathy with purpura (particularly of the ears and nose), positive ANCA (especially anti-MPO and atypical ANCA against human neutrophil elastase), and neutropenia.

Pearl: Consider levamisole toxicity in any patient with retiform purpura, positive ANCA, neutropenia, and cocaine use. Levamisole has a short half-life (5-6 hours), so toxicology screening may be negative. Testing for aminorex (levamisole metabolite) increases detection.

Ergot Alkaloids and Vasoconstrictive Drugs

Ergotamine, methysergide, and other vasoactive medications can cause vasospasm mimicking arterial vasculitis with claudication and distal ischemia.

Checkpoint Inhibitors

Immune checkpoint inhibitors used in oncology can trigger immune-related adverse events including true vasculitis, but more commonly cause non-vasculitic vascular toxicity.

6. Other Important Mimickers

VEXAS Syndrome

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) is a recently described autoinflammatory disease caused by somatic mutations in UBA1. It presents with fever, inflammatory markers, skin lesions, pulmonary infiltrates, and cytopenias in older men, mimicking vasculitis.

Pearl: Consider VEXAS in men >50 with treatment-refractory inflammatory symptoms, macrocytic anemia, skin lesions, and pulmonary infiltrates. Genetic testing for UBA1 mutations in bone marrow establishes diagnosis.

Scurvy

Vitamin C deficiency causes perifollicular hemorrhage and purpura that can be mistaken for cutaneous vasculitis, particularly in patients with poor nutrition, alcoholism, or eating disorders.

Fallacy: Assuming adequate nutrition in developed countries. Scurvy remains underdiagnosed, particularly in vulnerable populations. Ascorbic acid levels below 11 μmol/L confirm deficiency.

Diagnostic Approach: A Practical Framework

Step 1: Establish Clinical Pattern Recognition

Recognize patterns that should trigger consideration of mimickers:

• Fever with positive blood cultures (endocarditis)
• Recent vascular procedures (cholesterol emboli)
• Profound constitutional symptoms with embolism (myxoma)
• Thrombosis predominating over inflammation (APS)
• Predominantly thrombocytopenia with renal disease (TTP/HUS)
• Neutropenia with ANCA positivity (levamisole, drug-induced)

Step 2: Strategic Laboratory Testing

Baseline assessment:

• Complete blood count with differential
• Comprehensive metabolic panel
• Inflammatory markers (ESR, CRP)
• Urinalysis with microscopy
• Hepatitis B and C serology
• HIV testing
• Complement levels (C3, C4)
• ANCA, ANA, anti-GBM, cryoglobulins

Additional testing based on clinical suspicion:

• Blood cultures (minimum three sets)
• ADAMTS13 activity (if microangiopathic hemolysis)
• Antiphospholipid antibodies
• Serum protein electrophoresis
• Cardiac imaging (echocardiography)
• Vitamin levels (C, B12) in appropriate contexts

Step 3: Histopathological Confirmation

Gold Standard: Biopsy remains the gold standard for vasculitis diagnosis. Tissue should be examined for:

• True vessel wall inflammation with leukocyte infiltration (vasculitis)
• Bland thrombosis without inflammation (APS, TTP)
• Cholesterol clefts (cholesterol emboli)
• Intravascular lymphocytes (IVL)
• Organisms (infection)
• Medial calcification (calciphylaxis)

Oyster: "Treat first, biopsy later" is appropriate only in immediately life-threatening situations (diffuse alveolar hemorrhage, rapidly progressive glomerulonephritis with renal failure). In most cases, biopsy can and should be obtained before immunosuppression.

Step 4: Imaging Wisely

Vascular imaging considerations:

• Angiography showing irregular vessel narrowing, beading, or aneurysms supports but doesn't confirm vasculitis—atherosclerosis, emboli, and vasospasm produce similar findings
• FDG-PET showing large vessel uptake occurs in large vessel vasculitis but also infection, malignancy, and atherosclerosis
• MRI/MRA for CNS involvement should include high-resolution vessel wall imaging when available, as eccentric wall enhancement suggests vasculitis while central enhancement suggests atherosclerosis

Fallacy: Over-reliance on imaging without histopathological confirmation. Imaging abnormalities require clinical and pathological correlation.

Treatment Pearls and Pitfalls

Pearl: When vasculitis versus mimicker remains uncertain after initial evaluation, avoid high-dose immunosuppression. Moderate-dose corticosteroids (0.5 mg/kg prednisone) can be used temporizing while pursuing diagnosis, as this dose treats both inflammation and provides some coverage if infection is present, while higher doses significantly increase infectious risk.

Hack: In cases where empiric immunosuppression seems necessary but infection hasn't been definitively excluded, consider combination therapy with antimicrobials. For example, in culture-negative endocarditis mimicking ANCA vasculitis, empiric antibiotics with glucocorticoids may be appropriate while awaiting tissue diagnosis.

Fallacy: Assuming ANCA or other autoantibody positivity confirms vasculitis. ANCA can be positive in endocarditis (up to 30%), cocaine-levamisole toxicity, inflammatory bowel disease, and medications (hydralazine, minocycline, propylthiouracil). Autoantibodies indicate immune activation but don't distinguish vasculitis from mimickers.

Conclusion

Vasculitis mimickers represent diverse pathophysiological processes that converge on similar clinical presentations. Diagnostic accuracy requires pattern recognition, strategic testing, and—most importantly—histopathological confirmation before committing patients to potentially toxic immunosuppression. When faced with suspected vasculitis, the astute clinician maintains diagnostic humility, systematically excludes mimickers, and remembers that tissue diagnosis remains the gold standard.

The differential diagnosis of vasculitis should be considered a spectrum rather than a binary distinction. Some conditions (viral hepatitis-associated vasculitis, drug-induced ANCA vasculitis) represent true vasculitis triggered by specific etiologies, while others (cholesterol emboli, APS) produce vascular pathology through non-inflammatory mechanisms. Understanding this spectrum allows tailored, etiology-directed therapy rather than reflexive immunosuppression.

Key References

1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.

2. Sharma A, Sharma K, Sharma SK, et al. Infections mimicking vasculitis. Int J Rheum Dis. 2017;20(6):753-762.

3. Kaichi Y, Kakeda S, Moriya J, et al. Brain MR findings in patients with systemic lupus erythematosus with and without antiphospholipid antibody syndrome. AJNR Am J Neuroradiol. 2014;35(1):100-105.

4. Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020;383(27):2628-2638.

5. Greco A, De Virgilio A, Rizzo MI, et al. Goodpasture's syndrome: a clinical update. Autoimmun Rev. 2015;14(3):246-253.

6. Stone JH. Polyarteritis nodosa. JAMA. 2002;288(13):1632-1639.

7. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2009;68(3):318-323.

8. McGrath MM, Isakova T, Rennke HG, et al. Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease. Clin J Am Soc Nephrol. 2011;6(12):2799-2805.

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Word count: ~2000 words

This review synthesizes current evidence on vasculitis mimickers with practical guidance for clinicians managing complex cases where diagnosis remains uncertain. The emphasis on tissue diagnosis, systematic evaluation, and avoiding premature immunosuppression should reduce diagnostic errors and improve patient outcomes.