Vasculitides

Overview

Definition

Vasculitides are diseases of the blood vessels, with inflammation of vessel walls leading to bleeding, ischemia, and necrosis of distal tissue and organs.

Classification

The following classification is adapted from the 2012 International Chapel Hill Consensus Conference Nomenclature of Vasculitides:

• Large-vessel vasculitis (LVV): 
  • Takayasu’s arteritis (TAK) 
  • Temporal arteritis, or giant-cell arteritis (GCA)
• Medium-vessel vasculitis (MVV):
  • Polyarteritis nodosa (PAN)
  • Kawasaki disease (KD) or mucocutaneous lymph node syndrome 
  • Thromboangiitis obliterans (TAO), or Buerger disease 
• Small-vessel vasculitis (SVV):
  • Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV): 
    • Granulomatosis with polyangiitis (GPA)
    • Microscopic polyangiitis (MPA)
    • Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome
  • Immune-complex SVV:
    • Anti–glomerular basement membrane (GBM) disease, formerly known as Goodpasture syndrome
    • Cryoglobulinemic vasculitis (CV)
    • IgA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura
• Variable-vessel vasculitis (VVV):
  • Behçet’s disease (BD)
  • Cogan’s syndrome (CS)
• Single-organ vasculitis
  • Primary CNS vasculitis
  • Cutaneous leukocytoclastic angiitis (due to drug hypersensitivity)
  • Isolated aortitis

Etiology

• Primary: idiopathic
• Secondary:
  • Triggered by viral infection (e.g., hepatitis B or C) or toxin
  • Drug-induced
  • Related to connective tissue disease (e.g., systemic lupus or rheumatoid arthritis)
  • Related to malignancy

Pathophysiology

• Can either be segmental or involve the entire vessel
• PMNs responsible for acute inflammation
• Lymphocytes responsible for chronic inflammation
• Inflammation of the media of a muscular artery destroys the internal elastic lamina.
• Resolution of the inflammation can leave fibrosis and intimal hypertrophy.
• Secondary clot formation can narrow the vessel lumen and cause tissue ischemia and necrosis.
• Predominant parenchymal inflammation is a characteristic pattern that involves specific organs in different vasculitides.

Clinical Presentation

Takayasu’s arteritis

• Uncommon 
• Mostly in Asian women (< 50 years)
• Nonspecific symptoms may occur months before vascular symptoms.
  • Fever
  • Malaise
  • Night sweats
  • Arthralgias
  • Anorexia and weight loss
• Pain or tenderness of the blood vessels
• Unequal or absent pulses: 
  • Carotid
  • Radial
  • Other pulse areas

Giant-cell arteritis

• Associated with polymyalgia rheumatica
• Mean age at onset: 69 years
• Nonspecific symptoms:
  • Fever
  • Weight loss
  • Fatigue
• Specific to GCA:
  • Tenderness over the temporal arteries
  • Unilateral headache
  • Amaurosis fugax
  • Jaw claudication

Polyarteritis nodosa (PAN)

• Mean age at onset: 45–50 years
• Constitutional symptoms may occur months before vascular symptoms.
  • Fever and night sweats
  • Malaise and fatigue
  • Arthralgias and myalgias
  • Anorexia and weight loss
• Abdominal pain (due to mesenteric artery vasculitis)
• Hematuria (due to renal artery vasculitis)
• Dermatologic manifestations: 
  • Purpura
  • Nodules
  • Ulcerations
  • Livedo reticularis
• Mononeuritis multiplex (such as foot drop or wrist drop)
• 30% association with hepatitis B, also with hepatitis C
• Lungs/pulmonary arteries are not affected in PAN.

Kawasaki disease

• Occurs in children
• Presents with fever
• Bilateral conjunctivitis
• Mucositis (strawberry tongue)
• Desquamating rash on hands and feet
• Cervical lymphadenopathy
• Potential complication of cardiac disease, including coronary artery aneurysm

Granulomatosis with polyangiitis

• Mean age at onset: 45–50 years
• Presents with saddle nose
• Recurrent sinusitis
• Epistaxis
• Hematuria
• Unexplained hemoptysis should always raise concern for alveolar hemorrhage and AAV.
• Lab testing: proteinase 3 (PR3)–ANCA-positive
• Biopsy shows granulomas, pulmonary hemorrhage, pauci-immune glomerulonephritis (GN).

Eosinophilic granulomatosis with polyangiitis

• Elderly individuals with new-onset asthma
• Cough, allergic symptoms
• Can have pericarditis
• Skin rash/nodules
• Mononeuritis multiplex
• Labs show eosinophilia, 50% myeloperoxidase (MPO)–ANCA-positive; chest x-ray abnormal
• Lung biopsy shows eosinophilic infiltrates, necrosis, and granulomas.

Anti–glomerular basement membrane

• Constitutional symptoms for a few weeks (malaise, weight loss, fever, or arthralgias)
• 90% present with clinical features of rapid GN (hematuria, hypertension, edema, proteinuria).
• 25%–60% of individuals have concomitant alveolar hemorrhage.
• MPO–ANCA-positive

Cryoglobulinemic vasculitis

• Presentation related to serum cryoglobulins that precipitate in cold temperatures and dissolve upon rewarming and their deposition
• Palpable purpura
• Digit infarction
• Occasional mononeuritis multiplex or hemoptysis
• Associated with:
  • Hepatitis C
  • Multiple myeloma
  • Lymphoproliferative disorders
  • Connective tissue diseases
  • Infections
  • Liver disease
• Positive cryoglobulins, ↓ C3, C4, and rheumatoid factor (RF)–positive
• Immune complex GN

IgA vasculitis

• Mean age at onset: 17–26 years
• IgAV of the skin not the same as Burger IgA nephropathy
• Rash with palpable purpura; self-limited or treated with steroids

Behçet’s disease

• Recurrent painful oral aphthous ulcers
• Recurrent painful genital ulcers
• Skin lesions in 80%
  • Folliculitis
  • Acne-like rash
  • Erythema nodosum 
  • Rarely: purpuric vasculitic rash
• May also have CNS, GI, ocular, or venous thrombotic manifestations

Cogan syndrome

• Presents with ocular inflammatory lesions:
  • Interstitial keratitis
  • Uveitis
  • Episcleritis
• Inner ear disease symptoms
  • Sensorineural hearing loss 
  • Vestibular dysfunction
•  Vasculitic manifestations may include arteritis of any size vessel.

Cutaneous leukocytoclastic angiitis

• Also known as hypersensitivity vasculitis
• Presumed to be due to serum or drugs
• Single-organ, skin-isolated SVV without systemic vasculitis or GN
• Same cutaneous presentation as systemic SVVs
• Lesions with palpable and nonpalpable urticarial purpuric rash
• Biopsy with immunofluorescence testing shows leukocytoclastic vasculitis.
• Treatment involves removing the offending agent.

Diagnosis

History

• Symptoms that may characterize or exclude a suspected diagnosis
• Drug and medications that can cause vasculitis:
  • Hydralazine is the most common cause of drug-induced AAV.
  • Propylthiouracil (PTU) and methimazole are used to treat hyperthyroidism.
  • Minocycline
  • Cocaine
• Infectious disease exposure:
  • Hepatitis B is associated with PAN.
  • Hepatitis C is associated with CV.

Physical examination

• Identify potential sites of involvement of vasculitis and determine the extent of vascular lesions.
• Palpable purpuric rash
• Sensory or motor neuropathy
• Absent, unequal, or tender pulses

Laboratory tests

• Initial lab evaluation in suspected vasculitis includes:
  • Erythrocyte sedimentation rate (ESR)
  • CRP
  • CBC
  • Renal and hepatic function tests
  • Hepatitis B and C serologies
  • Serum cryoglobulins
  • Urinalysis 
  • Blood cultures to exclude infection
• Additional testing may include:
  • ANA
  • Complement levels: ↓ C4 in cryoglobulinemia
  • ANCA antibodies
  • Perinuclear ANCA (pANCA)
  • Cytoplasmic ANCA (cANCA)

Imaging

• Chest x-ray if pulmonary symptoms or hemoptysis
• Vascular imaging with CT and MRI/MRA for suspected large-vessel vasculitis
  • MRA of the affected area to look for stenosis or poststenotic dilatation
  • Vascular ultrasonography
• Catheter-directed arteriography if no tissue available for biopsy

Biopsy

• Biopsy of the affected artery is the gold standard.
• May see on a temporal artery biopsy in GCA:
  • Granulomatous thickening
  • Plasma cells and lymphocytes in media and adventitia
  • Fibrosis

Management

• Immunosuppressive medications
  • Corticosteroids
  • Nonbiologics: methotrexate, azathioprine, mycophenolate, leflunomide, cyclophosphamide
  • Biologics: tocilizumab, rituximab 
• Antihypertensives, if indicated
• Antivirals, if indicated, for hepatitis B or C
• Intravenous immunoglobulin (IVIG) for Kawasaki disease
• For GCA:
  • Start steroids even before biopsy, if clinically suspected.
  • If left untreated, potential complication of blindness
• Discontinue offending drug in MPA and EGPA.

Differential Diagnosis

• Systemic lupus erythematosus (SLE): chronic, autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Presentation includes malar rash, nondestructive arthritis, lupus nephritis, serositis, cytopenias, thromboembolic disease, seizures, and/or psychosis. Diagnosis is by finding antinuclear antibodies, SLE-specific antibodies, and specific clinical findings. Management is with corticosteroids, hydroxychloroquine, and immunosuppressants. 
• Human immunodeficiency virus (HIV): single-stranded RNA virus belonging to the Retroviridae family. HIV is the etiologic agent of AIDS. The virus attacks CD4+ T-lymphocyte cells, macrophages, and dendritic cells. Presentation is with constitutional symptoms, opportunistic infections and malignancies. Diagnosis is by enzyme immunoassay for HIV-1 and 2. Management is with combination antiretrovirals.
• Atherosclerosis: common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are risk factors that often can be reduced through a change in the individual’s lifestyle and behavior. The manifestations of atherosclerosis depend on the specific vessels affected and include, most notably, coronary artery disease, carotid disease, and peripheral vascular disease.
• Ehlers-Danlos syndrome: heterogeneous group of inherited connective tissue disorders that are characterized by hyperextensible skin, hypermobile joints, and fragility of the skin and connective tissue. The syndrome is due to genetic defects that affect collagen processing and synthesis. Diagnosis is mainly clinical but is confirmed via genetic testing. There is no curative treatment. 
• Fibromuscular dysplasia: nonatherosclerotic, noninflammatory, medium-sized angiopathy due to fibroplasia of the vessel wall. This fibroplasia leads to complications related to arterial stenosis, aneurysm, or dissection. Diagnosis is confirmed with imaging, and management includes lifestyle modifications, antihypertensives, and potentially revascularization. 
• Thrombotic thrombocytopenic purpura: life-threatening condition due to a deficiency of ADAMTS13. Clinical presentation can consist of thrombocytopenia, hemolytic anemia, hematuria, GI symptoms, neurologic symptoms, and renal involvement. Diagnosis is based on clinical symptoms and laboratory tests. Management includes plasma exchange and immunosuppressive therapies.
• Acute myeloid leukemia: hematologic malignancy characterized by uncontrolled proliferation of myeloid precursor cells. Clinical presentation consists of fatigue, bleeding, fever, and infection related to the anemia, thrombocytopenia, and lack of functional WBCs. Diagnosis is via peripheral blood smear and bone marrow biopsy examination showing myeloblasts. Management is mainly with chemotherapy.