Vasculitis

Description

An inflammatory disorder of blood vessels

• Clinical features result from the destruction of blood vessel walls with subsequent thrombosis, ischemia, bleeding, and/or aneurysm formation.
• Vasculitis is a large, heterogeneous group of diseases classified by the predominant size, type, and location of involved blood vessels (1).
  • Small-vessel vasculitis
    • Microscopic polyangiitis (MPA)
    • Granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis)
    • Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome)
    • Antiglomerular basement membrane disease (anti-GBM)
    • Cryoglobulinemic vasculitis
    • IgA vasculitis (formerly Henoch-Schönlein purpura)
    • Hypocomplementemic urticarial vasculitis
  • Medium-vessel vasculitis
    • Polyarteritis nodosa (PAN)
    • Kawasaki disease (KD)
  • Large-vessel vasculitis
    • Takayasu arteritis (TAK)
    • Giant cell arteritis (GCA)
• Vasculitis occurs as a primary disorder or secondary to infection, a drug reaction, malignancy, or connective tissue disease.
  • Variable vessel vasculitis
    • Behçet disease
    • Cogan syndrome
  • Single-organ vasculitis
    • Cutaneous leukocytoclastic angiitis
    • Cutaneous arteritis
    • Primary CNS vasculitis
  • Vasculitis associated with systemic disease
    • Lupus vasculitis
    • Rheumatoid vasculitis
    • Sarcoid vasculitis
  • Vasculitis associated with other etiology
    • Hepatitis C–associated cryoglobulinemic vasculitis
    • Hepatitis B–associated vasculitis
    • Syphilis-associated aortitis
    • Drug-induced immune complex vasculitis
    • Drug-associated antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis
    • Cancer-associated vasculitis
• Protean features often delay definitive diagnosis.

Epidemiology

Highly variable, depending on the particular syndrome

• Hypersensitivity vasculitis is most commonly encountered in clinical practice.
• KD, IgA vasculitis, and dermatomyositis are more common in children.
• TAK is most prevalent in young Asian women. GPA, MPA, and EGPA are more common in middle-aged males.
• GCA occurs exclusively in those >50 years of age and is rare in the African American population.

Annual incidence in adults (unless otherwise specified)

• IgA vasculitis: 200 to 700/1 million in children <17 years of age
• GCA: 100 to 170/1 million in Caucasians age >50 years
• KD: depends on race/age; ~200/1 million
• PAN: 2 to 33/1 million
• GPA: 4 to 15/1 million
• MPA: 1 to 24/1 million
• EGPA: 1 to 3/1 million
• TAK: 2/1 million
• Primary CNS vasculitis: 2/1 million in adults
• Hypersensitivity vasculitis: depends on drug exposure
• Viral-/retroviral-associated vasculitis: unknown; >90% of cases of cryoglobulinemic vasculitis are associated with hepatitis C.
• Connective tissue disorder–associated vasculitis: variable

Etiology and Pathophysiology

• Three major immunopathogenic mechanisms
  • Immune-complex formation: systemic lupus erythematosus (SLE), IgA vasculitis (HSP), and cryoglobulinemic vasculitis
  • ANCAs: GPA, MPA, and EGPA
  • Pathogenic T-lymphocyte response: GCA and TAK
• Pathophysiology best understood where known drug triggers have been identified (e.g., antibiotics, sulfonamides, and hydralazine)

• Several vasculitides linked to candidate genes
• No single gene has been found to cause vasculitis.
• Angiotensin-converting enzyme insertion/deletion polymorphism is associated with susceptibility to vasculitis, especially in Behçet disease and IgA vasculitis.

Risk Factors

A combination of genetic susceptibility and environmental exposure likely triggers onset.

General Prevention

Early identification is the key to prevent irreversible organ damage in severe forms of systemic vasculitis.

Commonly Associated Conditions

Hepatitis C (cryoglobulinemic vasculitis), hepatitis B (PAN), cytomegalovirus (CMV), Epstein-Barr virus (EBV), HIV (viral-/retroviral-associated vasculitis), SLE, rheumatoid arthritis (RA), Sjögren syndrome, mixed connective tissue disease (MCTD), dermatomyositis, ankylosing spondylitis, Behçet disease, relapsing polychondritis (CTD-associated vasculitis), respiratory tract methicillin-resistant Staphylococcus aureus (MRSA) in GPA, levamisole-adulterated cocaine, medications: propylthiouracil, methimazole, hydralazine, minocycline, levamisole-tainted cocaine

History

• Consider age, gender, and ethnicity.
• Comprehensive medication history
• Family history of vasculitis
• Constitutional symptoms: fever, weight loss, malaise, fatigue, diminished appetite, sweats
• CNS/PNS: mononeuritis multiplex, polyneuropathy, headaches, visual loss, tinnitus, stroke, seizure, encephalopathy
• Heart/lung: myocardial infarction, cardiomyopathy, pericarditis, cough, chest pain, hemoptysis, dyspnea
• Renal: hematuria
• GI: abdominal pain, hematochezia, perforation
• Musculoskeletal: arthralgia, myalgia
• Miscellaneous: unexplained ischemic or hemorrhagic events, chronic sinusitis, and recurrent epistaxis
• Note the organs affected and estimate the size of blood vessels involved.
• Demographics, clinical features, and the predominant vessel size/organ involvement help identify specific type of vasculitis.

Physical Exam

• Vital signs: blood pressure (hypertension) and pulse (regularity and rate)
• Skin: palpable purpura, livedo reticularis, nodules, ulcers, gangrene, nail bed capillary changes
• Neurologic: cranial nerve exam, sensorimotor exam
• Ocular exam: visual fields, scleritis, episcleritis
• Cardiopulmonary exam: rubs, murmurs, arrhythmias
• Abdominal exam: tenderness, organomegaly

Differential Diagnosis

• Fibromuscular dysplasia
• Embolic disease (atheroma, cholesterol emboli, atrial myxoma, mycotic aneurysm with embolization)
• Drug-induced vasospasm (cocaine, amphetamines, ergots)
• Thrombotic thrombocytopenic disorders (disseminated intravascular coagulation [DIC], thrombotic thrombocytopenic purpura [TTP], antiphospholipid syndrome, heparin- or warfarin-induced thrombosis), thromboangiitis obliterans
• Systemic infection (infective endocarditis, fungal infections, disseminated gonococcal infection, Lyme disease, syphilis, Rocky Mountain spotted fever [RMSF], bacteremia, ehrlichiosis, babesiosis)
• Malignancy (lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphoma, intravascular lymphoma)
• Miscellaneous (Goodpasture syndrome, sarcoidosis, amyloidosis, Whipple disease, congenital coarctation of aorta)

Diagnostic Tests & Interpretation

ALERT
Renal involvement is often clinically silent. Routine serum creatinine and urinalysis with microscopy are needed to identify underlying glomerulonephritis.

• Initial tests exclude alternate diagnoses and guide therapy.
• Routine tests
  • CBC
  • Liver enzymes
  • Serum creatinine
  • Urinalysis with microscopy
• Specific serology
  • Antinuclear antibodies (ANA)
  • Rheumatoid factor (RF)
  • Rapid plasma reagin/venereal disease reaction level (RPR/VDRL)
  • RMSF titers; Lyme titers
  • Complement levels C3, C4
  • ANCA
  • Antiproteinase 3 (anti-PR3) antibodies
  • Antimyeloperoxidase (anti-MPO) antibodies
  • Hepatitis screen for B and C
  • Cryoglobulin
  • Anti-GBM titer
  • HIV
  • Serum and urine protein electrophoresis
• Miscellaneous
  • Drug screen
  • ESR
  • C-reactive protein
  • Creatine kinase (CK)
  • Blood culture
  • ECG
• CXR, CT scan, MRI, and arteriography may be required to delineate extent of organs involved.

• Electromyography with nerve conduction can document neuropathy and target nerve for biopsy.
• Biopsy of affected site confirms diagnosis (e.g., temporal artery, sural nerve, renal biopsy).
• If biopsy is not practical, angiography may be diagnostic for large- and medium-vessel vasculitides.
• Bronchoscopy may be required to differentiate pulmonary infection from potentially life-threatening hemorrhagic vasculitis in patients with hemoptysis.

Test Interpretation
Blood vessel biopsy shows immune cell infiltration into vessel wall layers with varying degrees of necrosis and granuloma formation, depending on the type.

General Measures

• Discontinue offending drug (hypersensitivity vasculitis).
• Simple observation for mild cases of IgA vasculitis
• ANCA-associated vasculitis has two-phase treatment: initial induction followed by maintenance (steady tapering of corticosteroids with immunosuppressants or immunomodulators).

Medication

First Line
Corticosteroids are initial anti-inflammatory of choice.

Second Line
Cytotoxic medications, immunomodulatory, or biologic agents (e.g., cyclophosphamide (2)[B],(3)[A], methotrexate (4)[A], azathioprine (4)[A], leflunomide (4)[A], mycophenolate mofetil (2)[B], and rituximab (3)[A]) are often required in combination with corticosteroids for rapidly progressive vasculitis with significant organ involvement or inadequate response to corticosteroids. Rituximab (3)[A] is the first FDA-approved treatment for GPA and MPA. Tocilizumab (5)[A] is the first FDA-approved treatment for GCA. Mepolizumab (6)[A] is the first FDA-approved treatment for EGPA.

Issues For Referral

• Rheumatology referral for complicated cases where newer or more toxic treatments are required
• Nephrology referral for persistent hematuria or proteinuria, rising creatinine, or a positive ANCA titer
• Pulmonary referral for persistent pulmonary infiltrate unresponsive to antibiotic therapy or if gross hemoptysis

Additional Therapies

• IVIG and aspirin for KD, where corticosteroids are contraindicated
• Plasma exchange appears to improve recovery of patients with severe acute renal failure secondary to vasculitis and pulmonary hemorrhage (4)[A].

Surgery/Other Procedures

Rarely, corrective surgery is required to repair tissue damage as a result of aggressive vasculitis.

Inpatient Considerations

• Hemoptysis, acute renal failure, intestinal ischemia, any organ-threatening symptoms or signs, and/or need for biopsy
• Initial therapy is guided by the organ system involved.
  • If pulmonary hemorrhage is present, life-saving measures may include mechanical ventilation, plasmapheresis, and immunosuppression.
  • If acute renal failure is present, attend to electrolyte and fluid balance and consider plasma exchange and immunosuppression.
  • If signs of intestinal ischemia are present, make NPO and consider plasmapheresis, immunosuppression, and parenteral nutrition.
• Discharge criteria: stabilization or resolution of potential life-threatening symptoms

Follow-up Recommendations

If significant coronary artery disease is involved in KD, moderate activity restriction may be of benefit.

Patient Monitoring
Frequent clinical follow-up supported by patient self-monitoring to identify disease relapse

Diet

Alter diets for patients with renal involvement or hyperglycemia/dyslipidemia.

Prognosis

Prognosis is good for patients with vasculitis and limited organ involvement. Relapsing courses, renal, intestinal, or extensive lung involvement have a poorer prognosis.

Complications

• Persistent organ dysfunction may be the result of the disease, medications, or inflammation/scarring in the more serious forms of vasculitis.
• Early morbidity/mortality is due to active vasculitic disease; delayed morbidity/mortality may also be secondary to complications of chronic therapy with cytotoxic medications.

ICD-10

• D69.0 Allergic purpura
• D89.1 Cryoglobulinemia
• I77.6 Arteritis, unspecified
• M30.0 Polyarteritis nodosa
• M30.1 Polyarteritis with lung involvement [Churg-Strauss]
• M30.3 Mucocutaneous lymph node syndrome [Kawasaki]
• M31.0 Hypersensitivity angiitis
• M31.30 Wegener’s granulomatosis without renal involvement
• M31.31 Wegener’s granulomatosis with renal involvement
• M31.4 Aortic arch syndrome [Takayasu]
• M31.5 Giant cell arteritis with polymyalgia rheumatica
• M31.6 Other giant cell arteritis

ICD-9

• 273.2 Other paraproteinemias
• 287.0 Allergic purpura
• 446.0 Polyarteritis nodosa
• 446.1 Acute febrile mucocutaneous lymph node syndrome [MCLS]
• 446.20 Hypersensitivity angiitis, unspecified
• 446.4 Wegener’s granulomatosis
• 446.5 Giant cell arteritis
• 446.7 Takayasu’s disease
• 447.6 Arteritis, unspecified

SNOMED

• 155441006 Polyarteritis nodosa (disorder)
• 190815001 Cryoglobulinemic vasculitis
• 191306005 Henoch-Schonlein purpura (disorder)
• 195353004 Wegener’s granulomatosis (disorder)
• 31996006 Vasculitis (disorder)
• 359789008 Takayasu’s disease (disorder)
• 414341000 giant cell arteritis (disorder)
• 60555002 Hypersensitivity angiitis (disorder)
• 75053002 Acute febrile mucocutaneous lymph node syndrome (disorder)
• 82275008 Allergic granulomatosis angiitis (disorder)