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Large Vessel Vasculitis Online Monograph

Uncommon Vasculitides:
Vasculitis Mimics

Atul Khasnis, MD, MS

The true vasculitides — primary systemic vasculitides (PSVs) — are defined by histological evidence of inflammation of blood vessels in various tissues. Diagnosis of PSV is a challenging prospect, complicated by two central factors:

  • Absence of pathognomonic laboratory tests or radiographic findings indicative of the disease;
  • Existence of a wide variety of noninflammatory vascular disorders that may mimic primary systemic vasculitis.

As a result, excluding vasculitis "mimics" is a primary component of the differential diagnostic process. Furthermore, these vasculitis mimics have significant therapeutic implications. By complicating recognition of vasculitis mimics, their existence can delay the initiation of effective therapy, such as anticoagulation and antimicrobial therapy, for that disorder. They may also result in inappropriate use of immunosuppressive therapy through misdiagnosis of PSV.

Because there are no pathognomonic individual signs or symptoms of PSV, several causes can result in the same clinical manifestations, making the diagnosis especially challenging in the early disease stages or for disease with an atypical presentation. In addition, if the response to immunosuppression is suboptimal for systemic vasculitis, the diagnosis should be revisited and mimics considered.

The following sections present an overview of the many diseases with clinical features that mimic systemic vasculitis conditions.

Table 1. Clinical presentations of vasculitis and potential mimics.
Clinical Features Potential Mimics
Systemic: Fever, sweats Infections, systemic autoimmune diseases, malignancy, drug reaction
Vessel blockage: Ischemia (eg, limb claudication, angina), infarction (eg, skin, digit, CVA/MI) Atherosclerosis, thromboembolism, CTDs, hypercoagulable, vasospasm
Vessel weakness: Aneurysm, hemorrhage (eg, skin, renal, lung) Atherosclerosis, inherited/genetic disorders, coagulopathies, systemic infection

Abbreviations: CTD = Connective tissue disease; CVA = cerebrovascular accident; MI = myocardial infarction.


Table 2. Mimics of Large and Medium Vessel Vasculitis
Large Vessel
Atherosclerosis
Idiopathic
  • TAA with bicuspid aortic valve
  • Aortic dissection/aneurysm
Infections
  • Syphilis, TB, mycotic
Genetic – Marfan's syndrome
Cystic medial degeneration
Congenital
  • Coarctation, midaortic syndrome
Iatrogenic
  • Postoperative, post-radiation
Medium Vessel
Atherosclerosis/thromboembolism
Hypercoaguable states
  • APS, TTP, Sneddon's syndrome
Genetic
  • EDS IV, neurofibromatosis
  • Grange syndrome
Fibromuscular dysplasia (includes SAM)
Iatrogenic
  • Postoperative, postradiation therapy
Neoplasms
  • Hematologic, myxoma, sarcoma
Vasospasm
  • Phaeochromocytoma, ergotism
  • Drug-induced

Infectious Disorders

Infections (bacteria, viruses, mycobacteria, fungi, or parasites) mimic systemic vasculitides by affecting vascular vessels of all sizes. Excluding infections is a key component when evaluating a patient for PSV. The following are the most common infectious mimics.

  • Syphilis occurs most commonly in patients with aortic and aortic branch involvement resembling large vessel vasculitis, and it can be diagnosed with serologic testing.
  • Mycobacterium tuberculosis can cause granulomatous arteritis with vessel wall thickening, aneurysm formation, and stenosis affecting the aorta and its branches, thereby mimicking large vessel vasculitis.
  • Infective endocarditis can mimic the entire spectrum of vasculitides clinically, radiologically, and at histopathology by causing mycotic aneurysms that affect the aorta and its branches and pulmonary arteries, as well as small vessel inflammation either directly (eg, septic vasculitis) or through immune complexes (eg, purpura, glomerulonephritis) or embolic mechanisms.
  • Progressive multifocal leukoencephalopathy (PML), triggered by reactivation of the JC virus, causes symptoms of progressive cognitive decline, altered mental status, neurologic deficits, and subcortical white matter changes on MRI — symptoms that mimic CNS vasculitis. The diagnosis of PML must be considered in immunosuppressed patients presenting with progressive neurological deficits. A PCR for JC virus can help confirm the diagnosis; brain biopsy may be needed if clinically indicated and PCR testing is negative.

Inherited Disorders

Disorders of connective tissue matrix such as Marfan syndrome (mutations in the fibrillin-1 gene [FBN1]) and Ehlers-Danlos syndrome (EDS) type IV (mutations in type III procollagen gene [COL3A1]) can result in thoracic aortic aneurysms as well as other arterial aneurysms. The histopathology of the arterial wall in both Marfan syndrome and EDS type IV is cystic medial necrosis, which clearly differs from the granulomatous inflammation seen with primary large vessel vasculitides.

Loeys-Dietz syndrome (LDS) (mutations in TGF-beta receptors (TGFBR 1 and 2) is characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Thoracic and abdominal aortic dissections are the leading causes of death in LDS.

Neurofibromatosis type I can cause aortic dissection and rupture in either large- or medium-sized vessels. Renal artery stenosis is the most common presentation, leading to hypertension. Other presentations include cerebrovascular lesions, pulmonary artery stenosis, and intra-abdominal vessel involvement.

Grange syndrome is characterized by a variable combination of multiple arterial stenoses and aneurysms, brachysyndactyly, bone fragility, learning disability, and cardiac defects. Arterial involvement can manifest with hypertension and angiographic "beading." Autosomal recessive inheritance is suspected although no specific genetic defect has been identified.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) results from mutations in the Notch3 gene and causes recurrent strokes that may result in multi-infarct dementia. Other presentations include migraine and psychiatric disturbances that can mimic primary CNS vasculitis. Granular osmophilic material (extracellular domain of protein coded by the Notch3 gene) found in the medial layer on electron microscopy is pathognomonic of CADASIL. Mutations of the TREX1 gene, such as retinal vasculopathy with cerebral leukodystrophy, can mimic primary CNS vasculitis.

Other Noninflammatory Vascular Disorders

Fibromuscular dysplasia (FMD) is characterized by stenoses and aneurysm formation in multiple vascular territories, usually from medium-sized vessel involvement. Renal and carotid arteries are most commonly involved, but other arteries may be involved in 10% of cases. Angiographically, FMD has been classified as multifocal ("string-of-beads" appearance), tubular, and mixed. Depending on the vessel size involved, FMD can mimic polyarteritis nodosa or Takayasu's arteritis.

Segmental arterial mediopathy most commonly affects abdominal medium-sized vessels and presents as arterial dilatation, solitary or multiple aneurysms, arterial dissections with hematomas, or arterial stenoses and occlusions that resemble polyarteritis nodosa.

Moyamoya disease is a vasculopathy of unknown etiology that most commonly affects the cerebrovascular circulation, predisposing it to stroke. The classical involvement results from bilateral internal carotid artery stenosis causing a florid collateral circulation (appearance of "a puff of smoke" on angiogram). However, the circle of Willis may also be commonly involved with "spontaneous" occlusion. Vascular smooth muscle cell hyperplasia and thrombosis are observed at histopathology, with no evidence of vascular inflammation.

Cerebral amyloid angiopathy (CAA) is a hereditary or sporadic disorder characterized by deposition of extracellular eosinophilic material (amyloid) in the cerebral vessels. Hereditary forms of CAA result from mutations in various amyloid proteins. Clinical presentations of CAA include stroke (ischemic and hemorrhagic), subarachnoid hemorrhage, transient neurologic phenomena, cognitive impairment, and dementia. Histopathology demonstrates thickening of small- and medium-sized arterial and arteriolar walls (less often veins), resulting from deposition of an amorphous, intensely eosinophilic material on light microscopy with characteristic "apple-green" birefringence on polarized microscopy after Congo red staining.

Atherosclerosis can result in aortic aneurysms (most commonly infrarenal aorta), aortic valve sclerosis, and stenoses in the aortic branches and medium-sized arteries. It can mimic vasculitis clinically (symptoms from tissue ischemia and infarction, absent or weak pulses, and bruits) and angiographically (focal, short segmental or diffuse arterial narrowing and aneurysms). Arteriolosclerosis affects small vessels causing hyalinization of the intima with proliferation and hypertrophy of the media.

Calciphylaxis is a noninflammatory vasculopathy resulting from calcification of small-sized arterial vessels with consequent tissue ischemia and infarction. It is seen most commonly, but not exclusively, in patients with advanced chronic kidney disease (eg, calcific uremic arteriopathy). Other risk factors include female gender, elevated phosphate levels, elevated alkaline phosphatase, hypoalbuminemia, obesity, liver disease, systemic glucocorticoid use, and calcium-phosphate product >70 mg2/dL2. Patients develop severe muscle pain and skin breakdown, rhabdomyolysis, and involvement of cardiac, penile, pulmonary, pancreatic, or ocular vasculature.

Drug-induced Vasculopathies

Drugs such as the antibiotic minocycline and the muscle relaxant hydralazine may be associated with positive antineutrophil cytoplasmic antibodies (ANCA) serology (without true vasculitis) and, in some cases, may be associated with true vasculitic syndromes. Sustained use of vasoconstrictor medications, such as oxymetazoline and phenylpropanolamine, can injure the nasal mucosa through ischemia and produce chronic sinusitis and nasal septal perforation, thus mimicking granulomatosis with polyangiitis (GPA). These medications, however, are not typically associated with positive ANCA testing, and they lack other systemic features.

Cocaine use is a particularly elusive mimic of GPA causing nasal mucosal irritation and necrosis, intense vasoconstriction leading to nasal septal perforation, and collapse with a saddle-nose deformity. Patients may experience facial pain, epistaxis, constitutional symptoms, and can have a c-ANCA pattern on immunofluorescence and positive antiproteinase 3 (PR3) test result. Up to 50% of patients with cocaine-induced midline destructive lesions are PR3-ANCA positive.1 Evidence for multisystem disease should be sought and favors a diagnosis of GPA. However, absence of ANCA does not preclude a diagnosis of GPA. Levamisole, a contaminant in "street" cocaine, may be responsible for some of the manifestations observed in this condition and has been reported to associated with a positive p-ANCA/anti-MPO serology.

Table 3. Nonvasculitic diseases with positive ANCA testing results.
Disease Categories Specific Diseases
Rheumatic diseases RA, SLE, Sjögren’s, etc
Other immune disorders IBD, hepatitis, PSC
Infectious diseases Endocarditis, cystic fibrosis, malaria, mycobacterial infections
Drug-induced Minocycline, PTU, hydralazine

Abbreviations: PTU: propylithiouracil; IBD: inflammatory bowel disease; PSC: primary sclerosing cholangitis; SLE: systemic lupus erythematosus.

Thrombotic and Hypercoagulable Conditions

Thrombotic thrombocytopenic purpura (TTP) is a microvascular angiopathy clinically characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, renal failure, fever, and altered mental status or other neurological deficits. Not all features are required to make this diagnosis. Histopathology of tissues demonstrates platelet-rich thrombi with little fibrin deposited in the myocardial microcirculation and variable involvement of the circulation in the kidney, pancreas, brain, and adrenal glands. The presence of schistocytes in the peripheral blood, thrombocytopenia, and platelet thrombi help differentiate TTP from PSV.

Antiphospholipid syndrome can result in multifocal thrombosis producing arterial narrowing that can mimic the clinical and angiographic appearance of vasculitis.

Vasospastic Syndromes

Reversible cerebral vasoconstriction syndromes are vasospastic disorders of the cerebral vasculature usually associated with acute, severe, recurrent headaches, with or without additional neurological signs and symptoms. It may be idiopathic or triggered by pregnancy, medications, illicit drug use, metabolic disorders, trauma, postneurosurgery, or catheter-based vascular intervention. The diagnosis is made by clinical history, normal or near normal CSF findings, and evidence of multifocal segmental arterial narrowing ("beading") on CTA/MRA or conventional dye angiography with reversal by 12 weeks.

Reversible posterior leukoencephalopathy syndrome is a vasoconstrictive disorder associated with headache, seizures, confusion, visual disturbances, and a pattern of predominantly posterior cerebral edema on imaging. Angiography demonstrates irregular vascular abnormalities of constriction and dilatation, but these are reported to be reversed at future follow-up imaging.

Immunodeficiencies

Common variable immunodeficiency may mimic GPA, as it can manifest with pansinusitis, recurrent pneumonia, multisystem and pulmonary granulomatous involvement, and inflammatory polyarthritis. It can be differentiated from GPA by its qualitative and quantitative defects in cellular and humoral immune function, and by the absence of ANCA. It is diagnosed by laboratory evaluation of immune function.

HLA class I/transporter-associated protein deficiency can mimic signs and symptoms of GPA, such as granulomatous skin lesions, cutaneous vasculitis, and recurrent bacterial sinus and pulmonary infections. The diagnosis may be suspected by history of recurrent infections or may sometimes be made retrospectively based on atypical response to immunosuppression. The diagnosis can be confirmed through polymerase chain reaction and DNA sequence analysis.

Embolic Syndromes

Cholesterol embolization (atheroembolism) can occur from the arterial wall as a result of trauma from catheter manipulation, direct trauma, surgery, anticoagulation, or thrombolysis. It most commonly affects the extremities resulting in limb ischemia, purpura, ulcers, nodules, cyanosis, and frank gangrene, livedoid rash, and typically normal pulses. Renal involvement can cause acute renal failure, sometimes requiring dialysis. Ophthalmoscopy reveals retinal cholesterol emboli.

Cardiac myxomas are the most common primary benign cardiac tumors, occurring mostly in the left atrium. The tumors can produce symptoms that mimic PSV through valvular obstruction and embolization (eg, digital ischemia, cutaneous infarcts, limb claudication, pulmonary infarction, renal infarction, and cerebral infarction). Paraneoplastic manifestations of myxomas include fever, arthralgia, and weight loss, which mimic constitutional symptoms seen with systemic vasculitis. Transesophageal echocardiography or CT/MRI can be used to diagnose myxomas.

Malignancies

Intravascular lymphoma (angiotropic lymphoma) is most commonly B cell type and can result in multifocal angiographic narrowing, invoking the possibility of PSV. Tissue biopsy is the best means to secure the diagnosis.

Lymphomatoid granulomatosis is an Epstein-Barr virus-associated lymphoproliferative disease that most commonly involves the lung and can mimic GPA symptoms. Positive ANCA serology in these conditions may be misleading, biasing clinicians towards diagnosing GPA in these patients.

Summary

Many disorders can mimic the clinical, laboratory, radiologic, and/or pathologic features of PSV. Greater awareness of these vasculitis mimics will facilitate their diagnosis, which has the potential to both avoid use of unnecessary and potentially harmful immunosuppressants and provide data to manage the underlying disease. It is crucial to rule out these mimics as no one feature or result is reliably diagnostic of vasculitis.

Key Points

  • Vasculitis mimics must be excluded when attempting to make a diagnosis of PSV.
  • Some medications and drugs of abuse such as cocaine (especially if contaminated with levamisole) may cause vasculitis in addition to vasculopathy.
  • Immunosuppression should not be relentlessly escalated in patients with an atypical response; mimics should be considered in this situation.
  • Making a timely diagnosis of vasculitis mimics is as important as diagnosing a PSV itself, given the effect of early intervention on positive outcomes.
  • Mechanisms of vascular injury and repair operating in some of the vasculitis mimics are unclear at this time; it is hoped they will be revealed through systematic future research.
Leonard Calabrese, DO

Editor's Comment

Leonard Calabrese, DO

When to worry

Dr. Khasnis has given us a comprehensive review of the difficult issue of nonvasculitic mimics in the clinical diagnostic process. Yes, there are many conditions that can directly mimic many of the primary vasculitides, but when should this be a major clinical concern? Of course, accurate diagnosis is essential for effective therapy, but not all mimics are equal! I suggest that for each disease, there are crucial "must rule outs." These are mimics that are potentially either highly remedial or, more often, severely harmful if missed. Not all alternative diagnoses are Baysean.

A classic example is in the arena of PACNS. If a sarcoid vasculopathy is mistaken for PACNS of the granulomatous variety and treated with cyclophosphamide and prednisone, what will be the harm? The therapy may be highly effective. However, if a tuberculosis arteritis is mistaken for PACNS and treated similarly, disaster will ensue. Thus, practitioners need to always ask themselves, "Have I missed a 'must rule out'?"

References

  1. Wiesner O, Russell KA, Lee AS, et al. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Arthritis Rheum. 2004;50(9):2954-65.

Bibliography

 

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