General Approach to Vasculitis

Clinical presentations of vasculitis are diverse and can be challenging to diagnose. Generally, vasculitis should be considered when a patient presents with constitutional symptoms and unexplained multiorgan involvement, FUO, pulmonary-renal syndrome, mononeuritis multiplex, skin lesions (eg. palpable purpura, ulceration), or multiple ischemic complications. Infections and malignancy are usually also on the differential.

Key History Findings

• A careful review of systems is important.
• Eye irritation, sudden vision loss, mucosal membrane ulcerations, nasal crusting, congestion, epistaxis, Raynaud’s phenomenon, motor or sensory neuropathy, and claudication can all point toward vasculitis, but patients may not mention mild symptoms until prompted.
• Exposure to certain medications or substance use: antithyroid medications, hydralazine, and levamisole (contaminant in cocaine), can precipitate ANCA vasculitis.

Exam

• New diastolic murmurs, pulse pressure differential, and absent, diminished, or tender pulses could suggest a large vessel vasculitis.
• Abnormal motor or sensory findings on neurological exam can be seen in small-medium vessel vasculitides, as can palpable purpura (blanching red-purple lesions).

Basic studies to order

• Start with basic labs. Inflammatory markers like ESR and CRP are nonspecific but are highly sensitive for active vasculitis.
• Urinalysis (blood and protein) is more sensitive than creatinine for early renal involvement.
• Check hepatitis serologies; vasculitis can be an extra-hepatic manifestation of hepatitis B or C.
• Chest x-ray to screen for pulmonary involvement.

Mimics of vasculitis

• Infection (endocarditis, TB, syphilis), malignancy, and vasculopathy.
• Vasculopathy can be due to thrombotic or embolic processes (coagulopathy, TTP/HUS, antiphospholipid syndrome, cholesterol emboli) as well as heritable disorders of connective tissue (e.g. Ehlers-Danlos, Marfans) and fibromuscular dysplasia.

Classification of Vasculitis

Vasculitis can be grouped into the vessel size that they predominantly involve, though there can be overlap. Large vessels include the aorta and its main branches. Medium vessels include large muscular abdominal arteries, CNS arteries, and coronary arteries. Small vessels include end-organ arterioles and capillaries, typically pulmonary and renal.

Large Vessel Vasculitis

Giant cell arteritis

A chronic vasculitis involving large and medium-sized arteries, specifically the thoracic aorta and its large branches, the vertebral and ophthalmic arteries, and the extracranial branches of the carotid artery.

Etiology/Risk factors

• Age: exclusively a diagnosis in patients over 50 years of age; peak incidence between ages 70-80.
• Gender: women account for 65-70% of cases.
• Ethnicity: highest risk in Caucasians of northern European descent, lowest in Asian/African descent.
• GCA/PMR overlap: 16-21% of individuals with polymyalgia rheumatic have GCA; 40-60% of patients with GCA are diagnosed with PMR before, with, or after the diagnosis of GCA. PMR often presents while steroids are being tapered after GCA treatment.

Pathogenesis

• Dendritic cells in vessel walls recruit circulating T-cells and macrophages, leading to obstructive granulomatous inflammation and downstream ischemic organ/tissue damage.

Clinical syndrome

• Classic presentation of GCA mainly involves the cranial arteries: age > 50 with new or changing headache, abrupt vision loss, scalp tenderness, jaw symptoms, unexplained fever, anemia, high ESR.
• Large vessel GCA involving the aorta and major proximal vessels (found in up to 25% of GCA patients) often presents without the classic cranial symptoms and can be overlooked.
• Onset of symptoms tends to be gradual, but may be abrupt.
• Clinical features:
  • Head pain (>2/3 patients report this, but not always temporal area. Up to half of patients may report anginal symptoms in the neck, oropharynx, or tongue).
  • Jaw claudication (34%) has highest positive likelihood ratio (+LR) of 4.2. 
  • Diplopia is the next most predictive feature, with +LR of 3.4. 
  • Fever, weight loss, fatigue also reported. Manifests as FUO in 15% of patients.
  • Amarosis fugax (painless visual loss) is present in 15-29%. Impaired vision is an early manifestation, may become irreversible, and can involve both eyes if untreated. Eye symptoms mandate emergent steroid treatment. 
  • Aortic and great vessel inflammation can cause symptoms of aortic dissection, aneurysm, and upper extremity claudication.
• Exam:
  • Tender/thickened cranial arteries with visible swelling/erythema (+LR 4.3), and may be pulseless (+LR 2.7).
  • Fundoscopic exam may reveal swollen, pale optic disc and/or blurred margins, cotton-wool patches, small hemorrhages.
  • With large vessel involvement, peripheral pulses may be diminished or absent, bruits can be auscultated over major vessels, and aortic regurgitation murmur may be appreciated.

Diagnosis

• Labs: elevated ESR, often > 100 (uncommon to see normal ESR in GCA, whereas ESR can be normal in up to 15-20% of patients with PMR); elevated CRP levels; normocytic anemia; normal WBC; reactive thrombocytosis; increased AST and alkaline phosphatase (25-35% of patients). Unlike ANCA vasculitis, there aren’t specific auto-antibodies that are diagnostic of GCA.
• Imaging: CXR is a cheap but insensitive screen for aneurysm/dilation of the ascending aorta. High resolution MRI is able to visualize temporal arteries. Compared with temporal artery biopsy (gold standard), pooled sensitivity and specificity are 93% and 81%, respectively.[SG1]  However, this imaging is not yet available at all institutions and MRI abnormalities rapidly disappear within days of starting prednisone. MRI is most useful if normal in patients in whom you have low clinical suspicion for GCA (NPV ~98% and PPV ~48%).
• Biopsy: temporal artery biopsy should be performed in all suspected cases. This is the gold standard for diagnosis. Biopsy is 85-90% sensitive. If strong clinical suspicion exists even with a negative biopsy result, biopsy should be repeated at another clinically involved site because of the segmental nature of arterial involvement. Do not delay treatment if diagnosis is strongly suspected (steroids generally do not affect biopsy yield for up to 2 weeks).   
• If temporal biopsy negative, a patient can still have GCA, particularly if isolated to the large vessels. Consider CT angiography, MR angiography, PET/CT to evaluate the aorta and great vessels or color doppler ultrasound to evaluate the cranial vessels and upper extremities.

Management

• Initial therapy: prednisone 60 mg/day. Visual symptoms of any kind are an emergency, and treatment should not be delayed for biopsy. If there is not a prompt clinical response, then increase the dose or consider inpatient IV pulse steroids for optimal immunosuppression.
• One month after clinical and laboratory parameters return to normal, begin to taper steroids (decrease by 10% q1-2 weeks).
• Daily low dose aspirin had been recommended in the past but is not currently recommended (unless otherwise indicated for ASCVD risk).
• When initiating long-term steroids at supra-physiologic doses, remember prophylaxis against bone loss and PCP, and monitor for the development of hypertension and diabetes.
• Tocalizumab was FDA approved for GCA in 2017 and is the preferred steroid-sparing agent. Methotrexate can be considered as well but data is mixed.

Takayasu arteritis

• Granulomatous inflammation of the aorta and the great vessels.
• Can be very similar to large vessel GCA but is differentiated by demographics (age 10-40, female predominance of 80-90%, predilection for Asian populations).
• Similarly presents with limb claudication, absent/weak peripheral pulses, pulse pressure discrepancy, and bruits.
• Subclavian artery is classically involved first. More rarely, there can be involvement of the coronary and mesenteric arteries.
• Diagnosis: MRA to evaluate for vessel wall inflammation and luminal occlusion, aneurysm, or stenosis.
• Treatment: steroids + glucocorticoid sparing agent (methotrexate, azathioprine, TNF-inhibitor).

Medium Vessel Vasculitis

Polyarteritis Nodosa (PAN)

• Necrotizing vasculitis affecting medium sized arteries and arterioles leading to arterial narrowing and stenosis. Inflammation can also cause aneurysm formation, rupture of which can cause life threatening hemorrhage
• Secondary PAN associated with hepatitis B is decreasing in incidence with HBV vaccination and treatment
• PAN can involve virtually any organ:
  • Mesenteric vessel -> ischemia, GI bleeding
  • Renal arteries -> HTN, renal insufficiency, renal infarct
  • Skin -> palpable purpura, ulcerations, erythematous nodules
  • Neurologic -> asymmetric polyneuropathy, mononeuritis multiplex
  • GU -> orchitis
• Diagnosis: gold standard is biopsy of the affected organ (exception: avoid kidney biopsy if you suspect involvement due to high risk of bleeding from aneurysms). CT or MR angiography could be considered and will demonstrate multiple aneurysms and constrictions (“beads on a string”).
• Initial treatment: steroids +/- cyclophosphamide (for moderate-severe disease). If secondary to acute hepatitis B, antiviral therapy +/- plasma exchange +/- steroids.

Kawasaki disease

• Classically a childhood disease, but can occur in adults (often associated with HIV)
• Presents acutely with systemic inflammation (fever, elevated inflammatory markers) and signs of mucocutaneous inflammation (conjunctivitis, mucostitis, rash, lymphadenopathy), and arthritis. Can also be associated with coronary artery aneurysms, but this is more common in children.
• Initial treatment: IVIG + aspirin (reduces risk of coronary artery aneurysms)

Small Vessel Vasculitis

Small vessel vasculitis branches into 2 main groups: ANCA associated and immune complex mediated. Classic organs affected are skin, kidneys, and lungs.

ANCA Associated Vasculitis (AAV)

A necrotizing vasculitis of small vessels. It does not typically have substantial deposition of immune complexes on microscopy and is therefore labeled “pauci immune”. Complement levels are typically normal. There are 3 classic variants of AAV, but there can be overlap.

Diagnostic evaluation

• C3/C4, ANA, cryoglobulins, RF, HCV, HBV, ANCAs (ANCA IF, anti-PR3, anti-MPO), CBC with diff, CMP, UA, urine protein/creatinine, ESR, CRP
• Consider blood cultures, HIV testing, Utox to rule out vasculitis mimics
• Investigation of focal manifestations (e.g. renal biopsy, BAL, etc.)

Vasculitis	Clinical Findings	Granulomas on biopsy	Peripheral eosinophilia	Classic ANCA antibody
Microscopic polyangiitis (MPA)	Pulmonary capillaritis Glomerulonephritis	No	No	MPO ANCA (~90% sensitive)
Granulomatosis with polyangiitis (GPA)	Upper airway: nosebleeds, destructive sinusitis, subglottic stenosis Pulmonary capillaritis Pulmonary nodules (often cavitary) Glomerulonephritis	Yes	No	PR3 ANCA (~90% sensitive)
Eosinophilic granulomatosis with polyangiitis (EGPA)	Upper airway: rhinosinusitis, asthma Pulmonary capillaritis Glomerulonephritis Peripheral nerve involvement	Yes	Yes (typically > 10% of total WBC)	MPO ANCA (~40% sensitive), or ANCA negative

Treatment

• For milder disease, initial treatment typically involves a combination steroids and methotrexate.
• For severe disease, initial treatment is typically either cyclophosphamide or rituximab, usually in combination with steroids. Plasma exchange previously was considered in the case of deteriorating renal function and diffuse alveolar hemorrhage, though data from the PEXIVAS trial suggests the use of plasma exchange does not reduce mortality or incidence of ESRD.

Immune Complex Mediated Vasculitis

Compared to ANCA associated vasculitis, this group of vasculitis involves significant immunoglobulin and complement deposition within the walls of small blood vessels. Systemic complement levels therefore can be depressed.

Cryoglobulinemic vasculitis

• Pathogenesis: circulating cryoglobulins are deposited in the membranes of small arterioles and capillaries. This can occur idiopathically but is often associated with hepatitis B, hepatitis C, HIV, or other autoimmune conditions.
• Most common association is hepatitis C. Note that many patients with HCV are cryoglobulin positive, but only a small subset develop vasculitis.
• Clinical features: the classic “Meltzer’s triad” of palpable purpura, generalized weakness, and arthralgia is present in 80% of patients. Other common features include neuropathy, Raynaud phenomenon, skin ulcers, and renal and liver involvement.
• Diagnosis: peripheral blood cryoglobulins (dependent on proper collection/transport, e.g. warm phlebotomy materials). Low C4 out of proportion to C3 and positive RF are often seen. Tissue biopsy is often performed to confirm presence of vasculitis.

Antiglomerular basement membrane disease (aka Goodpasture’s)

• Pathogenesis: autoantibodies directed against glomerular basement membranes and alveolar basement membranes.
• Clinical features: ~90% present with a rapidly progressive glomerulonephritis and ~50% present with diffuse alveolar hemorrhage. Compared to ANCA associated vasculitis, onset is much more acute (over several weeks).
• Diagnosis: anti-GBM antibody testing, which has >90% sensitivity and specificity. Kidney biopsy is also recommended.
  • Note: up to 50% of patients with anti-GBM disease can also have positive ANCA antibodies (typically MPO-ANCA). It is therefore important to test for both (“double positive disease”).
• Treatment: prognosis can be poor, with half of patients progressing to ESRD or death. Therefore initial treatment is aggressive with plasma exchange, cyclophosphamide, and steroids.

IgA vasculitis (Henoch-Schonlein purpura)

• Pathogenesis: deposition of IgA immune complexes.
• Typically occurs in children, but up to 10% can occur in adults.
• Clinical features: palpable purpura in gravity dependent areas (buttocks, posterior thighs), GI symptoms (classically can cause intussusception from purpuric lead point, though rarer in adults), arthralgias, and glomerulonephritis.
• Diagnosis: clinical diagnosis. IgA levels are often markedly elevated. Complement levels are usually normal as IgA does not fix complement.
• Treatment: typically resolves with supportive care, though steroids may be used for severe renal involvement.

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